This important annual workshop always includes studies that are not presented to other meetings.

Studies in this issue of HTB include:

• Studies on pipeline ARVs: Quad, evitegravir/cobicistat, cobisistat, GSK1265744, BMS986001 dolutegravir, GSK-1265744, long acting formulations (monthly injections): rilpivirine-LA, raltegravir and patient views.
• Interactions between malaria drugs and etravirine or darunavir/r
• Antimalarial amodiaquine and nevirapine
• Atazanavir/ritonavir & voriconazole
• Atazanavir/ritonavir plus raltegravir
• Milk thistle (silymarin) and darunavir/ritonavir
• Echinacea and etravirine
• Warfarin and ARVs: impact of African American race and ritonavir

Reports on drug interactions are selected, and in some cases summarised, from a full report produced by the pharmacology group at Liverpool University (www.druginteractions.org).

The full Liverpool report is available online and in PDF format.

http://www.hiv-druginteractions.org/data/NewsItem/94_13%20PKW%20Barcelona.pdf (PDF)

It is appreciated that the organisers enable both the programme and abstract book to be available download in PDF format.

http://www.virology-education.com/

http://regist2.virology-education.com/abstractbook/2012_3.pdf

Abbreviations used in these reports:

Cmax = Maximum concentration; Cmin = minimum concentration; AUC = Area Under the Curve; GMR = Geometric Mean Ratio; IC90/50 = Inhibitory Concentration needed to reduce viral production by 90/50% in vitro.

This year the PK Workshop was notable for a number of important studies on ARVs that are already advanced in the pipeline. Please see the study abstract and Liverpool University report for more details on each study.

Quad

Quad is an investigational four-drug single pill formulation of the integrase inhibitor elvitegravir with the booster cobicistat plus tenofovir and FTC that is currently submitted to the FDA (with a decision expected by August 2012). Several studies at the workshop provided drug interaction data on components of this and other Gilead pipeline compounds.

Evitegravir/cobicistat

An oral presentation included three separate PK interactions studies. [1]

Coadministration of elvitegravir/cobicistat with rosuvastatin (10 mg single dose) had no significant effect on elvitegravir exposure, but increased rosuvastatin AUC by 38% and Cmax by 89%, although this was not considered clinically relevant.

Coadministration of elvitegravir/cobicistat and rifabutin (300 mg once daily alone or 150 mg every other day with EVG/COB) in a 13 day study reduced elvitegravir Ctrough by 67%. Although rifabutin exposure remained similar, the active metabolite increase by 4.8 to 6.3‐fold, increasing antimycobacterial activity by 21%. Coadministration is not recommended based on the reduction in elvitegravir Ctrough.

A third component of this study reported that using a reduced dose of elvitegravir/cobistat (85 mg/150 mg) with atazanavir (300 mg daily) – using the cobicistat to boost both elvitegravir and atazanavir – resulted in modest reductions in atazanavir Cmax (GMR 76.1; 90%CI 59.1, 96.9) and Ctrough (GMR 80.5; 90%CI 55.6, 117) and comparable AUC and Cmax for elvitegravir, with higher Ctrough. (GMR 192; 90%CI 163, 225) compared to elvitegravir/cobicistat 150 mg/150 mg.

Cobisistat: the PK booster in Quad

Although most research has until now used cobicistat dosed at 150 mg once-daily, a study reported that used twice-daily (150 mg BID) this resulted in approximately 4-fold higher exposure (compared to once-daily). While cobicistat had a similar impact to ritonavir when boosting darunavir, this was not seen with tipranavir. Tipranavir exposure was markedly lower when boosted by cobicistat and cobicistat exposure was 90% lower compared to cobicistat alone. [2]

Comparable bioavailabilty results were also presented for two fixed dose formulations of darunavir/cobicistat (800 mg/ 150 mg) compared with darunavir/ritonavir (800 mg/100 mg). [3]

GS7340 – tenofovir prodrug

Although selection of the 25 mg dose for single compound of the tenofovir prodrug GS7340 has been reported, a pharmacokinetic interaction reporting that cobicistat boosts GS7340 is now supporting use of 10 mg doses in coformulations. [4]

These include together with elvitegravir/cobicistat/FTC in a new version of Quad (Quad+) and with darunavir/cobicistat/FTC in a single-pill PI-based fixed dose combination. [5, 6]

Dolutegravir

Dolutegravir, an integrase inhibitor in development by ViiV, is primarily metabolised by UGT1A1, but uses CYP3A as a minor route (10-15%) but it does not have a clinical impact of inducing or inhibiting major CYP, UGT or transported pathways (except OCT2).

A helpful review of currently known interactions presented at the workshop, included significantly increased dolutegravir exposure with atazanavir (boosted and unboosted) and reduced exposure with darunavir, fosamprenavir, tipranavir, efavirenz and rifabutin (by 30%-75% and not considered clinically significant for treatment naïve patients). [7]

However, etravirine reduced dolutegravir by 88% but this might be overcome if coadministered with lopinavir/r or darunavir/r (which in turn increases dolutegravir exposure). Dolutegravir needs to be given twice daily with rifampin. Antacids need to be separated by at least two hours, due to metal cation chelation rather than a pH effect.

GSK-1265744

A follow-up integrase compound from GSK/ViiV called GSK-1265744 reported no interactions when the oral formulation was dosed with oral etravirine in 12 HIV negative adults. [8]

This study is relevant as GSK-1265744 is also being developed as a long-lasting injection formulation to compare pharmacologic properties to both oral administration, and also to the long acting formulation of the NNRTI rilpivirine, with potential use as both treatment and as PrEP. [9, 10]

BMS-986001

BMS-986001 is an NRTI with a similar structure to stavudine (d4T) but a safety profile that is unlikely to be associated which is a weak inhibitor of DNA synthesis in vitro and therefore unlikely to affect mitochondrial function and the associated side-effects of d4T.

The workshop included a Phase I/II dose finding study in treatment-experienced patients (off treatment for at lest 3 months). Following 10 days monotherapy, median reductions in viral load on day 11, were 0.97, 1.15, 1.28 and 1.15 log in the 100, 200, 300, and 600 mg groups, respectively (vs -0.07 in the placebo group) from median baseline levels across groups of 4.3 – 4.6 log (range 3.5–5.3 for the whole study). [11]

This was a new analysis by BMS from a study that was first presented two years ago. [12]

Long acting formulations (monthly injections): rilpivirine-LA, raltegravir, patient views

The development of a nanosuspension formulation of the NNRTI rilpivirine that could be given by intramuscular injection was reported several years ago. A single-dose pharmacokinetic study in HIV negative people reported prolonged exposure in plasma, genital compartments and rectal following single 300, 600, or 1200 mg doses [13], together with a study reporting a lack of negative drug interactions between rilpivirine and dolutegravir (both also presented this year at CROI) [14]

While this was presented for its potential to reducing the reliance on daily adherence in the context of PrEP, this might have important options for HIV treatment. This would require other ARVs with a similar formulation to construct a combination. The development of a similar formulation for dolutegravir is clearly of interest. [15]

A safety issue for long-acting formulations, especially in the absence of an antidote to rapidly eliminate the active compound in the event of a severe adverse reaction, might be covered by a period of oral dosing to confirm individual tolerability, especially as both integrase and NNRTI classes have been associated with hypersensitivity reactions.

A recent survey of 400 HIV positive patients attending two US clinics reported 61%, 72% and 84% interest in ART injections based on weekly, two-weekly and monthly formulation respectively, with higher interest in people with concerns about adherence, although 35% were also concerned about needle use. [16]

References

Unless stated otherwise, references are to the Programme and Abstracts of the 13th International Workshop on Clinical Pharmacology of HIV Therapy, 16-18 April 2012, Barcelona. These are published in Reviews in Antiviral Therapy & Infectious Diseases – Volume 3: 2012 and available free in PDF format online.

http://regist2.virology-education.com/abstractbook/2012_3.pdf

1. Ramanathan S et al. Pharmacokinetics and drug interaction profile of cobicistat boosted‐EVG with atazanavir, rosuvastatin or rifabutin. 13th PK Workshop, Barcelona, 2012. Oral abstract O_03.
2. Ramanathan S et al. Safety/tolerability, pharmacokinetics, and boosting of twice-daily cobicistat administered alone or in combination with darunavir or tipranavir. 13th PK Workshop, Barcelona, 2012. Poster P_08.
3. Kaduda T et al. Bioavailability of two FDC formulations of darunavir/cobicistat 800/150mg compared with darunavir/ritonavir 800/100mg co-administered as single agents. 13th PK Workshop, Barcelona, 2012. Oral abstract O_20.
4. Ramanathan S et al. Pharmacokinetics of a novel EVG/COBI/FTC/GS-7340 single tablet regimen. 13th PK Workshop, Barcelona, 2012. Abstract O_13.
5. Safety and efficacy of elvitegravir/cobicistat/emtricitabine/GS-7340 single tablet regimen versus elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single tablet regimen in HIV 1 infected, antiretroviral treatment-naive adults. http://clinicaltrials.gov/ct2/show/NCT01497899
6. Safety and efficacy of darunavir/cobicistat/emtricitabine/GS-7340 single tablet regimen versus cobicistat-boosted darunavir plus emtricitabine/tenofovir disoproxil fumarate fixed dose combination in HIV-1 infected, antiretroviral treatment naive adults. http://clinicaltrials.gov/ct2/show/NCT01565850
7. Song I et al. Metabolism and drug-drug interaction profile of dolutegravir (DTG, S/GSK1349572). 13th PK Workshop, Barcelona, 2012. Abstract O_17.
8. Ford SL et al. Etravirine has no effect on the pharmacokinetics of S/GSK1265744, a novel HIV Integrase inhibitor. 13th PK Workshop, Barcelona, 2012. Poster abstract P_15.
9. A single dose escalation study to investigate the safety, tolerability and pharmacokinetics of intramuscular and subcutaneous long acting GSK1265744 in healthy subjects. http://clinicaltrials.gov/ct2/show/NCT01215006
10. A study to investigate the safety, tolerability and pharmacokinetics of repeat dose administration of long-acting GSK1265744 and long-acting TMC278 intramuscular and subcutaneous injections in healthy adult subjects. http://clinicaltrials.gov/ct2/show/NCT01593046
11. Hwang C et a. Antiviral activity, exposure- response, and resistance analyses of monotherapy with the novel HIV NRTI BMS- 986001 in ART-experienced subjects. 13th PK Workshop, Barcelona, 2012. Oral abstract O_06.
12. Cotte et al. A phase-Ib/IIa dose-escalation study of OBP-601 (4’-ethynyl-d4T, festinavir) in treatment-experienced, HIV-1- infected patients. 50th ICAAC, 12–15 September 2010, Boston. Abstract H-933. http://tinyurl.com/6zefyte
13. Else L et al. Pharmacokinetics of long-acting rilpivirine in plasma, genital tract and rectum of HIV negative females and males administered a single 600 mg dose. 13th PK Workshop, Barcelona, 2012. Oral abstract O_12.
14. Jackson A et al. Rilpavirine-LA formulation: pharmacokinetics in plasma, genital tract in HIV negative females and rectum in males. 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle. Oral abstract 35. http://www.retroconference.org/2012b/Abstracts/44600.htm
15. Crauwels H et al. Absence of pharmacokinetic interaction between the NNRTI rilpivirine (TMC278) and the integrase inhibitor raltegravir. 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle. Poster abstract 617. http://www.retroconference.org/2012b/Abstracts/44415.htm
16. Swindells S et al. Long-acting parenteral nanoformulated antiretroviral therapy: patient interest and attitudes. 13th PK Workshop, Barcelona, 2012. Poster abstract P_01.

The steady state interactions between artemether/lumefantrine (40/480 mg for three days) and etravirine (200 mg twice daily) or darunavir/r (600/100 mg twice daily) were investigated in two groups (n=14 per group) of HIV negative subjects. Etravirine decreased the AUC of artemether, dihydroartemisinin and lumefantrine by 38%, 15% and 13%, respectively. Darunavir/r decreased the AUCs of artemether (16%) and dihydroartimisin (18%) but increased lumefantrine AUC by 2.75‐fold. Co‐administration of artemether/lumefantrine had no effect on the AUCs of etravirine, darunavir or ritonavir.

The antimalarial activity of artemether may be lowered in the presence of etravirine and therefore, the combination should be used with caution.

Pharmacokinetically, darunavir /r can be co‐administered with artemether/lumefantrine without dose adjustment however co‐administration is not recommended with other drugs that may cause QTc prolongation (such as lumefantrine).

Ref: Kakuda T et al. Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a randomised trial. 13th PK Workshop, Barcelona, 2012. Oral abstract O_05.

http://regist2.virology-education.com/abstractbook/2012_3.pdf (PDF)

The impact of nevirapine‐based ART on the disposition of amodiaquine/artesunate (600/200 mg once daily) was investigated in a parallel group study in 21 HIV positive patients (n=10 nevirapine; n= 11 ART naïve controls.

No significant differences in the pharmacokinetics of amodiaquine or desethylamodiaquine (the active metabolite) were identified between groups, however considerable interpatient variability was observed. Comparing the control to NVP group, AUCs were 242±78 vs 197±94 ng/ml.h (p=0.26) for amodiaquine and 21,311±21,012 vs 13,121±7947 ng/ml.h (p=0.26) for desethylamodiaquine, respectively. Cmin of the active metabolite did not differ between groups (137±65 vs 124±52, p=0.26).

Four individuals in the control group discontinued the study protocol due to weakness, vomiting, diarrhoea, and dizziness, while no subjects in the NVP group experienced treatment‐limiting adverse effects. Previous studies have reported similar exposure to artesunate when used with nevirapine.

Ref: Fehintola FA et al. Pharmacokinetics of amodiaquine and desethylamodiaqine in HIV‐infected patients with and without nevirapine‐containing antiretroviral therapy. 13th PK Workshop, Barcelona, 2012. Poster abstract P_05.

http://regist2.virology-education.com/abstractbook/2012_3.pdf (PDF)

Voriconazole is a broad spectrum antifungal mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Due to genetic polymorphism of CYP2C19, voriconazole AUC is on average 2‐4 fold higher in CYP2C19 poor metabolisers (PM) than in extensive metabolisers (EM). In a majority CYP2C19 EM population low dose ritonavir decreased voriconazole AUC by ~40%, likely due to induction of CYP2C19 by ritonavir.

This study assessed the two‐way drug interactions when adding voriconazole to ritonavir‐boosted atazanavir in both CYP2C19 EM and PM healthy subjects. Voriconazole was administered alone on days 1‐3, atazanavir/r (300/100mg once daily) administered alone on days 11‐20, and the drugs coadministered on days 21‐30. The voriconazole doses were 200 mg twice daily (400 mg twice daily on days 1 and 21) for EM subjects and 50 mg twice daily (100 mg twice daily on days 1 and 21) for PM subjects. A total of 20 EM and 7 PM subjects completed the study.

In EMs, coadministration decreased voriconazole AUC and Cmin by 33% and 39%, respectively; atazanavir AUC and Cmin decreased 12% and 20%, respectively. In PM subjects, coadministration increased voriconazole Cmax and AUC by 4‐6 fold; atazanavir AUC and Cmin decreased by 20% and 31%, respectively. ritonavir Cmax and AUC were generally unchanged in either population. The decrease in voriconazole AUC seen in EM subjects, (33%) is similar to the historical observation of 39% when voriconazole was given with low dose ritonavir. In PM subjects, coadministration markedly increased voriconazole exposure, likely through inhibition of CYP3A4. These results support the current recommendation that coadministration is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole.

Ref: Zhu L et al. CYP2C19 genotype‐dependent pharmacokinetic drug interaction between voriconazole and ritonavir boosted atazanavir in healthy subjects. 13th PK Workshop, Barcelona, 2012. Abstract: O_08.

http://regist2.virology-education.com/abstractbook/2012_3.pdf (PDF)

Current dosing for raltegravir is 400 mg twice daily, but atazanavir increases raltegravir exposure by 40‐72% probably through UGT1A1 inhibition. This pharmacological pilot phase II study investigated the pharmacokinetics of raltegravir 400 mg once daily in 6 HIV positive men receiving 2 NRTIs plus atazanavir/r. Three patients were taking tenfovir/FTC.

Half‐dose raltegravir exposure, when combined with atazanavir/r, seemed to be adequate in the majority of patients, with only one trough value below the IC95 (15 ng/ml). Raltegravir AUC, Cmax and Ctrough (median, IQR) were 14497 ng.h/ml (13845‐28325), 3984 ng/ml (3863‐6703) and 40 ng/mL (22‐51), respectively. Median (IQR) atazanavir AUC, Cmax, and Ctrough were 26414 ng.h/mL (23037‐33109), 2284 ng/mL (1706‐2666) and 526 ng/mL (397‐604), respectively. Median (IQR) ritonavir AUC, Cmax and Ctrough were 9147 ng.h/mL (8052‐12860), 1107 ng/mL (983‐1244), 99 ng/mL (61‐183), respectively.

The AUC of raltegravir 400 mg once daily in this study was similar to the AUC of the 800 mg once daily dosage in the QDMARK study (14895 ng.h/ml), and resulted in two‐fold higher than the reported AUC values with standard 400 mg twice‐daily dosage (6340 to6910 ng.h/ml).

However, QDMARK reported that raltegravir 400 mg once-daily with atazanavir/r resulted in poorer rates of viral suppression.

Atazanavir concentrations were comparable to historical data and Ctroughs were above the target level (150 ng/mL) in all patients.

Ref: Calcagno A et al.Pharmacokinetics of raltegravir 400 mg once‐daily in combination with atazanavir/ritonavir plus two NRTIs. 13th PK Workshop, Barcelona, 2012. Poster abstract P_05.

http://regist2.virology-education.com/abstractbook/2012_3.pdf (PDF)

Hyperlinks below to early reports for the May/June edition of HTB are published online in draft.

Introduction

This year the BHIVA spring conference was held in Birmingham and as usual it included both important national research and impressive international speakers. In addition to more than 40 oral presentations, the meeting included case studies and over 230 posters.

The selection of below only highlights some of these studies. For further details please contact the researchers directly.

The abstracts from the conference are available free online as PDF supplements to the April edition of HIV Medicine.

http://onlinelibrary.wiley.com/doi/10.1111/hiv.2012.13.issue-s1/issuetoc

As with previous years, some of these sessions will be available as webcasts and some of the slide presentations can already be viewed or downloaded from the conference website.

http://www.bhiva.org/Presentations120418.aspx

Reports in this issue include:

• One third of HIV positive people at five UK clinics have symptomatic depression: link to adherence and viral suppression – 40% cases are untreated
• Hodgkins Lymphoma: survival normalises to HIV negative rates despite more advanced disease at diagnosis
• Promising outcomes from laser ablative treatment of AIN2/3 to prevent anal cancer
• KS in the HAART era includes patients with high CD4 and suppressed viral load: importance of KS chemotherapy for some patients in addition to ART
• Oral PrEP acceptable to at least 50% of HIV negative gay men
• Recent infections common in UK; 30% gay men aged 15-25 infected within a year of diagnosis
• 3rd vs 4th generation HIV testing: almost half of UK clinics out of step with national guidelines
• Case reports of complications from ketamine use in two MSM on ritonavir-based combinations
• Intranasal and topical corticosteroids and risk of Cushing’s symptoms in HIV patients on ritonavir-based combinations
• Outcomes from London Commissioning: concerns for safety not supported
• Bite-size BHIVA: short summaries of other interesting studies

This is only a personal observation, but the level of disinterest (and even hostility) from many healthcare workers in the UK to using PrEP to prevent HIV transmission, appears to increase in proportion to the evidence that supports its potential benefit.

The practical and medical concerns relating to cost, resistance, toxicity, adherence and prescription details are all important, but when potential protection is now predicted as >99% in people who take 4-7 daily doses a week, it becomes essential that this option be available for high risk individuals, given the current statistics on continued new infections.

A study presented by the UK Health Protection Agency suggested that while PrEP may not be for everyone – a fear of those most skeptical – a significant proportion of high risk gay men see PrEP as an option they would actively choose.

The Gay Men’s Sexual Health Survey is a biennial community based cross sectional survey that in 2011 (from March to June) recruited more than 1200 gay men from social venues (bars, nightclubs and saunas) in London. The questionnaires were self-completed anonymously and 1005 participants also agreed to a saliva sample for HIV testing (anonymised soley for the survey).

In addition to sexual health and behaviour, the survey asked about prior use of PEP and PrEP and “How likely is it that you would take a pill (oral dose) on a daily basis to prevent HIV infection?”

Of the 768/842 HIV negative men who answered this part of the survey, 34% reported interest in PrEP as “very likely” and 16% as “likely”. Just as importantly, 15% were “unlikely” and 26% “very unlikely”. The important conclusion is that while some men would not want to take PrEP at least as many (twIce as many in this survey) would find a daily oral prophylactic pill acceptable.

Demographics of the 842 men who were HIV negative included mean age 34 years (SD +/- 9.2; range 18-71 years), 82% were white, 86% employed, 93% >2 years education post 16 years and 78% had an inner London postcode. While 10% had previously used PEP, only 2% had used PEP.

In multivariate analysis, the predictors for wanting to use PrEP (adjOR, 95%CI) included younger age (<35 years: aOR 1.58; 1.16-2.15), recent attendence of STI clinic (aOR 1.59; 1.03-2.46) and previous use of PEP (aOR 1.96; 1.17-3.26). Having >10 partners in the last year, unprotected anal intercourse (UAI) in the last year, or UAI with unknown status partner in the last year were statistically significant factors only in the unadjusted analysis. However, younger age (aOR 2.29; 1,68-3.13) and >10 partners (aOR 2.47; 1.76-3.48) were both strongly associated with STI attendence in the last year.

A second study on acceptability of PrEP, from a smaller survey of gay men attending Manchester Centre for Sexual Health, was presented by Thng and colleagues as a poster. [2]

Of over 3000 attendees from November 2011 to January 2012, 12% were gay men, with 95/112 men who agreed to the survey completing and returning it. The mean age was 28 years, 80% were white Caucasian, with a median of 4 sexual partners in the previous year. 84% said that they used condoms “at least 50% of the time” and staying HIV negative was important to 87%.

Willingness to use oral PrEP was reported by 64% with more than half of these replies indicating use of daily PrEP for >6 months, 90% that monitoring would be acceptable and 85% that information provided on the potential side affects also sounded acceptable. Approximately 20% of people interested in PrEP were only interested if it could be taken around or after sex, rather than daily. 66% said that taking PrEP would not change the frequency of condom use and none said that they would stop condom use altogether. Most (86%) would be unlikely to have more partners.

COMMENT

The emphasis on background risk is important. The most impressive data has come from the iPrEX study that enrolled generally young gay men who had multiple aspects of their lives that put them at high risk. This included young men, mutilple partners, high alcohol and recreational drug use, low condom use, rare discussion about HIV prior to sex, high levels of transactional sex etc. [3]

PrEP is unlikely to be affordable for most people unless this is covered by public healthcare. At current therapeutic prices, daily Truvada is likely to cost several thousand pounds a year, even with intermittent dosing (the efficacy of which has yet to be established).

The option for this intervention has the potential for a young gay man to have a higher protection than any other intervention, for what might be a short period of an otherwise long and healthy life. Last year more than 3000 gay men in the UK were diagnosed HIV positive and another HPA presentation at BHIVA highlighted than 22% of these were recent infections. When looking at the impact of age, recent infections were disproportionally higher (30%) for gay men under 25 (compared to 15% for those older than 50 years). [4]

This survey is an important first step in clearly demonstrating a high level of interest from the target group for who this intervention is likely to be appropriate and cost effective.

While this was a survey in broadly a white, educated and economically stable population, the survey was also conducted when information about the efficacy of PrEP was relatively new, and prior to the most recent efficacy data.

It also shows that it might be relatively easy to identify men at higher risk though GUM clinics and this might also broader the demographics of people at risk, given the more recent data from CROI this year supporting higher efficacy. [5]

It now becomes a public health issue, that should be promptly recognised, both for research and service provision. It is unfortunate that the PROUD study for PrEP in high risk gay men was turned down for NIHR funding, though a smaller pilot study (n=500) is still hoped to start enrolment later in 2012 using a deferred (by 6 months) vs immediate PrEP design.

References

1. Aghaizu A et al. Who would use PrEP? Predictors of use among MSM in London. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O23.
2. Thng C et al. Acceptability of HIV pre-exposure prophylaxis (PrEP) and associated risk compensation in men who have sex with men (MSM) accessing GU services. 18th BHIVA Conference, 18-20 April 2012. Poster abstract P233.
3. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 23 November 2010 (10.1056/NEJMoa1011205). Free access:  http://www.nejm.org/doi/full/10.1056/NEJMoa1011205
4. Aghaizu A et al. Recently acquired HIV infections: an overview of surveillance in the UK. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O19.
5. Anderson P et al. Intracellular tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19th CROI 2012, Seattle. Oral late breaker abstract 31LB.  http://www.retroconference.org/2012b/Abstracts/45431.htm

Two years ago the UK Health Protection Agency (HPA) expanded access to avidity testing (which inciates the likelihood that HIV infection occurred within the previous 6 months) to all newly diagnosed patients. Additionally, the agency decided to return results to patients, with the understanding that this is more sensitive on a population than individual level.

Also called the Recent Infection Testing Algorithm (RITA) and previously referred to as STARHS (Serological Testing Algorithm for Recent HIV Seroconversion), the UK AxSYM aviditiy index (AI) is a guanidine-based test where a cut off AI <0.8 is interpreted as recent infection (95%CI 5-8 months), with a 4.5% false positive rate (based on 1287 people tested >1 year after diagnosis).

An analysis of the first two years results from this programme were presented at BHIVA. More than 90 clinics and 50 laboratories have joined the scheme, sending baseline samples to the HPA laboratory in Colindale, with the percentage of newly diagnosed samples in England and Northern Ireland increasing from 26% in 2009 to 46% in 2011 (reaching 60% in 2012).

Of the 6284 results available, probable risk category was 50% gay men (n=2848) and 50% heterosexual (n=1146 men and 1706 women). Only 93 diagnoses related to IV drug use, but 491 samples were unclassified.

While 14% (95%CI 13.7-15.5%) of the overall cohort (917/6284) indicated recent infection, this vaired significantly by risk group with more than 22% (95%CI 20.7-23.8%) of recent infections in gay men, 8% (95%CI 7.1-9.1%) in heterosexual transmissions (similar for men and women) and 4% (95%CI 1.2-10.6%) in IDUs.

There was also a striking inverse correlation between older age and risk of recent infection among gay men. Recent infection accounted for approximately 30% of diagnoses in men aged 15-24 (n=118), 25% of those aged 25-34 (n=268), 18% aged 35-50 (n=209) and 13% aged > 50 years (n=37).

For heterosexual transmissions, younger age was less dramatic, but accounted for approximately 18% of women and 10% of men aged 15-24 and 8% women and 13% men in the 25-34 age group.

These results included a caution on the need for estimates of population incidence rates in order to interpret these findings. A survey of the acceptability of this service for healthcare staff has already been published in HIV Medicine, with an ongoing patient survey still ongoing. This is essentail due to the potential for results to be used together with sexual history in identifying possible source partners.

COMMENT

These results are an important new aspect of the important work carried out by the HPA.

The UK is the only country currently using avidity testing for all new diagnoses and returing results to patients.

References

Aghaizu A et al. Recently acquired HIV infections: an overview of surveillance in the UK. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O19.

The ASTRA study (Antiretrovirals, Sexual Transmission Risk and Attitudes) is a UK multicentre prospective study using self-completed questionnaires relating to HIV and depression in over 3000 HIV positive people. Importantly, the study also correlates responses to adherence and clinical outcomes.

The PHQ-9 questionnaire used in the study classifies participants according to presence/absence of depressive disorder (DD) or major depressive disorder (MDD) and a depression severity score (DSS) that divided diagnoses (from a scale of 0-27) into none, minimal, mild, moderate or severe.

Results from the first 2175 reponses (from February to November 2010) were presented by Fiona Lampe from University College London in an oral abstract session. Baseline demographics for this analysis included: 16% women; 73% MSM; 10% heterosexual men. Mean age was 44 (range 18-80). Ethnic classification was: 70% white; 15% Black African; 14% other ethnicity. Approximately 86% were on ART, 9% of whom were not suppressed (VL >50 copies/mL.

For the primary endpoints, the prevalence was 26.6% (95%C! 24.8-28.5) for DD and 19.1% (95% CI 17.4-20.7%) for MDD, with 27% participants having moderate or severe depression by DSS (>/=10/27).

Perhaps surprisingly, in multivariate analysis, there were no significant differences in DD by gender, ethnicity, country of birth or ART. Younger age was associated with higher depression rates (32% age <30 to 17% at age >60, p=0.028

Significant associations (p<0.001 for each trend) were seen with socio-economic factors including employment status (15% employed, 43% unemployed, 52% sick/disabled), education level (19% university vs 32% other), income (defined as ‘money to cover basis needs: 13% ‘yes mostly’ through to 53% ‘no’) and social support – a measure of supporting relationships (9% “high” through to 66% “low”).

Depression also correlated positively with duration of infection (20% <2 years, 24% 2-10 years, 30% 10-20 years and 35% >30 years), which is interesting given that depression was higher with younger age. Current CD4 count or ART status had no relationship to depression scores.

Higher rates of depression were closely related to lower adherence and lower rates of viral suppression. This ranged from 24% in people who had not missed ART in the past two weeks to 29% with one missed dose, 34% with two missed doses and 42% with 3 or more missed doses.

The percentage of patients with detectable viral load by depression index 14% for those with DD vs 7% for those with no DD, 13% vs 8% for MDD versus no MDD, and ranged from 7% none to 18% severe (DSS) in the non-depressed vs severely depressed groups respectively. The association between depression and viraemia remained significant after adjusting for clinic and self-reported adherence.

The study also indicated that these symptoms may be largely undiagnosed and untreated for many patients. Of the 579 people with depressive disorder (DD) by questionnaire 241 were receiving medication or other treatment and 338 were not. Conversely, of the 1596 people without depression, 200 were on (presumably effective) treatment and 1396 were not.

The total prevalence of depression (symptoms or treatment) was 35.8% (779/2175) in this study, of whom 43% (338/779) were untreated.

COMMENT

This is a large study that included six different UK centres (Royal Free, Mortimer Market, Homerton, North Manchester, Brighton and Eastbourne) with a broad patient demographic.

It is probably the largest UK study to date to comprehensively look at HIV and depressive symptoms and highlights very high rates of depression with a strong indication that this is likely to be under diagnosed and under treated.

These results, especially if confirmed in the full analysis (enrollment is now completed) support the important of indentification and management of depression as an important part of HIV care.

Reference

Lampe F et al. Depression and virological status among UK HIV outpatients: results from a multicentre study. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O10.

Further details, including the slides from this presentation are on the ASTRA study website:

http://www.astra-study.org/

High levels of treatment response to chemotherapy for Hodgkins Lymphoma (HL) in the HAART era were reported in a combined analysis from five clinics, showing similar rates of event-free and overall survival compared to HIV negative controls.

Chloe Orkin and colleagues analysed all cases of HL diagnosed at five London teaching hospitals from 1997-2010 who were treated with 4-6 cycles of AVBD (adriamycin, bleomycin, viznblastine and dacarbazine). Of these, 97/237 were HIV positive and 90/97 were on HAART during HL treatment. HIV viral load was undetectable in 52/86 HIV positive patients with data and low (<6,000 c/mL) in others but 53% (47/97) had CD4 <200 cells/mm3.

HIV patients were older (median age: 41 vs 31 years, p<0.001), more likely to be male (88% vs 59%, p<0.001). They also had higher rates of mixed cellularity (54% vs 19%, p<0.001) and had more advanced disease. This included 80% vs 33% with stage 3/4 at diagnosis (p<0.001), 81% vs 36% with B-symptoms (p<0.001), 46% vs 20% with Hb level <10.5 g/dL (p<0.001) and 76% vs 35% with albumin <4 g/dL (p<0.001) and a higher International Prognostic Score (IPS 3 in 71% vs 22%, p<0.001).

Over median follow-up of 59 months (range 8–172), similar response rates (74% vs 81%), duration of response (33 vs 44 months), 5-year event-free survival (59% vs 65%) and 5-year overall survival (79% vs 88%) were seen in the HIV positive vs HIV negative groups respectively, see Table 1. In the combined group, 40 patients relapsed at a median time of 7 months (range: 1–106).

Table 1: Responses to ABVD chemotherapy in HIV positive vs HIV negative people

COMMENT

These results are important and impressive, despite including data from the early HAART era, and especially given the more advanced disease at HL diagnosis.

Reference

Orkin C et al. HIV Status does not Impact on Outcome in Patients with Hodgkin Lymphoma Treated with ABVD Chemotherapy in the HAART Era. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O13.

The incidence of anal cancer is higher in HIV positive compared to negative populations with lower rates of clearance (87% vs 38% at 5 years) and progression rates from high-grade anal intraepithelial neoplasia (AIN 2/3) in observational studies range from approximately 8-14% over 5 years.

Thornhill and colleagues reported on retrospective results (median 69 months follow-up, range 36-180 months) from treating 91 patients (35 AIN 3; 56 AIN 2) with laser ablative treatment at Homerton Hospital in east London. [1]

Most patients were male (82/91) and MSM (80/82). Mean age was 36.9 (range 20–68). Of the 56 HIV positive patients, 66% (n=37) had a CD4 nadir of <200 cell/mm3. 45% (25/56) had been HIV positive for 15 years or more.

None of the patients in this cohort developed anal cancer suggesting that treatment may have prevented lesion progression in some patients.

The single case of anal cancer in this cohort, not included in this analysis follow-up was less than 3 years was a 49 year-old man (HIV positive for 21 years) with a CD4 nadir of 8. He had advanced 3 quadrant AIN 3 disease that presented late.

A second poster reported prospective first year results from a new ano-rectal outpatient clinic for HIV positive patients at the Royal Free Hospital. [2]

This is a monthly clinic for patients with a history of anal warts or previously diagnosed AIN. Symptomatic patients are screened by anoscopy +/- (surgical) evaluation under anaesthesia (EUA) where indicated. Patients were referred by their clinic doctor or self referred through promotion throughout the clinic.

Data was compiled from 73 patients seen over 12 months. Median (IQR) demographics included: age 45 years (IQR 41–50) years, 91% were MSM (67/73), 85% Caucasian (61/73). 95% (69/73) were on ART, 82% (60/73) with undetectable viral load. CD4 at presentation and CD4 nadir were 511 (362–741) and 152 (26–288) cells/mm3 respectively. Median time since HIV diagnosis was 15 years (10–20), with 11(6–13) years on HARRT. 75% (55/73) were smokers.

Anoscopy +/- EUA for screening was undertaken for 40% (30/73). Of these 27% (8/30) were diagnosed with AIN: AIN-1 (3), AIN-2 (2), and AIN-3 (3). 3/8 had prior diagnosis of AIN, the remainder were all newly diagnosed. 3/30 (10%) were diagnosed with ASCC and were managed by the surgeons and oncologists.

The clinic plans to expand the service to include a screening clinic specifically targeting all HIV positive, MSM who are >40 years, or have low CD4 nadir, or HIV infection > 10 years to undergo routine screening for AIN with Human Papilloma Virus (HPV) cytology, HPV typing and baseline anoscopy.

COMMENT

Greater awareness of AIN in HIV positive gay men, easier access to screening and the necessary support to diagnose complications is important.

The variable progression rates, lack of natural history data and recent availablility of effective treatments all highlight the urgent need for randomised data for the benefit of screening.

References

1. Thornhill J et al. Treatment of anal intraepithelial neoplasia and prevention of anal carcinoma. 18th BHIVA Conference, 18-20 April 2012. Poster abstract 64.
2. Grover D et al. Anal intraepithelial neoplasia: single centre experience. 18th BHIVA Conference, 18-20 April 2012. Poster abstract 68.

An overview of Kaposi’s Sarcoma (KS) in the HAART era was given by Mark Bower from the Chelsea and Westminster Hospital who focussed on the continued use for KS chemotherapy and included recent cases of KS in patients with high CD4 counts (>350 cells/mm3) and who have undetectable viral load.

While the incidence of KS has dramtically reduced since 1997 and 80% of patients diagnosed with early stage KS (T0) and with good immunity (CD4>150) commonly don’t need additional treatment to ART [2] more advanced staging (T1 – any tumour-associated oedema or ulceration, extensive oral KS or non-nodal visceral KS) and reduced immune function (CD4 <150) should be treatment with liposomal anthracycline in addition to ART (or paclitaxel for refractory KS).

The Chelsea and Westminster Hospital cohort from 1996 to 2012 now includes 521 first cases of KS. Most are men (94%) with 17% (86/521) in black Africans. Median age and CD4 counts at presentation are 38 years (range 16-71) and 168 cells/mm3 (range 0-1200) with 66% (n=342) at stage T0 and 34% (n=177). Survival rates in the T0 and T1 groups at 14 years (Kaplan-Meier) are approximately 80% and 65%, respectively. These differences were driven mainly by an early impact <3 years of visceral involvement and presence of oedema/ulceration (later impact > 6 years), rather than oral involvement.

Of note, 15% of new diagnoses (80/521) were in people on established ART (> 3 months), 6% (n=32) had an undetectable viral load and 4% (n=20) had both undetectable viral load and a CD4 count >350 cells/mm3.

The Chelsea and Westminster group has also reported KS as an IRIS-related complication (defined as rapid KS progression during the 2-4 month window after starting ART) in 7% of patients (10/150) who started ART with a KS diagnosis, but higher rates have been reported (20%) in cohorts that only use ART and not concomitant KS treatment. Recurrent KS has also been reported in virologically suppressed patients with similarly good immune responses.

As well as efficacy in addition to ART reported in a recent randomised clinical study (though not greater survival in an African setting) [4], the importance of KS chemotherapy is also supported by mimimal toxicity or prolonged negative impact on CD4 responses. This is now primarily for any patient with stage T1 disease and for the management of KS related to IRIS or in suppressed patients.

References

1. Bower M. Kaposi’s Sarcoma in the era of HAART. BHIVA invited lecture. 18th BHIVA Conference, 18-20 April 2012.
2. AIDS 2009, 23:1701–6.
3. Bower M et al. Immune Reconstitution Inflammatory Syndrome associated with Kaposi’s Sarcoma. J Clin Oncol 23:5224-5228 (2005). http://jco.ascopubs.org/content/23/22/5224.full.pdf
4. Mosam A et al. A randomized controlled trial of HAART versus HAART and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa. JAIDS 2012 (19 March) epub. http://www.ncbi.nlm.nih.gov/pubmed/22395672

In 2011, prompted by calls to the i-Base phoneline reporting wide diversity in the information given to people contacting GUM clinics for HIV testing, i-Base wanted to understand why this was often different to UK guidelines. Although 4th generation HIV tests are recommended at four weeks post exposure, many people were still being advised to wait for three months.

Results from the prospective community survey of 112 randomly selected GUM clinics that was then undertaken, were presented by Emma Rezel from the London School of Hygiene and Tropical Medicine, in an oral presentation. [1]

A mystery patient scenario was used to conduct a semi-structured questionnaire at the point of contact or a contact the caller was immediately forwarded on to.  This was to mimic the reality of advice and information made available in a natural situation to a member of the public calling a clinic with queries about HIV testing.

In response to the question “Is it a third or fourth generation test?” 40% of clinics stated it was a 4th generation test, 6% gave some indication that it was a 4th generation test, for example, mentioning that it could detect the presence of an antigen, 4% stated or gave some indication that they used a 3rd generation test, 2% stated they used both, 1% said they used a PCR test. However, 31% didn’t know, 8% gave an inaccurate or unclear response, and 8% didn’t answer.

Responses to the question “How accurate are the results and when should I come and get tested?’” were equally mixed with only 24% of clinics mentioning the accuracy of fourth generation tests at 4 weeks post exposure and 36% only referring to accuracy at 12 weeks suggesting 3rd rather than 4th generation testing procedures were being referred to.

Although nearly all clinics mentioned the need for the caller to come into the clinic, only 41% were sensitive and non-judgmental and put the service-user at ease, providing responses:

“There’s no need to be anxious. A nurse will answer all your questions if you go in for an appointment.”

“Even if he was positive, it depends on various factors, like, if he’s on treatment and if there’s blood-to-blood transmission. HIV is hard to catch so don’t worry”.

By contrast, 13% of clinics scored particularly poorly in terms of sensitivity to the anxieties of the caller provide confusing or unsympathetic responses:

“We don’t understand it all so I doubt you will either.”

“If you don’t know much about him, why did you have unprotected sex with him?”

“We only see positive tests amongst heterosexuals who have sex with someone from Africa.”

“If you’re not prepared for a positive result, don’t come in for a test.”

While these examples produced some of the few lighter moments during the conference, the implications of these findings was not lost on many attendees, especially given that an earlier BHIVA audit reported 4th generation tests being used by 95% of clinics that responded.

The study found no difference between geographical location of clinics (London vs out of London) but did find a statistically significantly better responses when callers were able to speak to a doctor, nurse or health advisor rather than an admistrator or receptionist, suggesting that some degree of retraining be developed for anyone taking direct calls from members of the public.

In response to this issue, i-Base have produced a new non-technical guide to HIV testing and the risk of sexual transmission, free to order for UK clinics. [2]

BASHH statement on the window period (March 2010)

• HIV testing using the latest (4th generation) tests are recommended in the BHIVA/BASHH/BIS UK guidelines for HIV testing (2008).
• These assays test for HIV antibodies and p24 antigen simultaneously. They will detect the great majority of individuals who have been infected with HIV at one month (4 weeks) after specific exposure.
• Patients attending for HIV testing who identify a specific risk occurring more that 4 weeks previously, should not be made to wait 3 months (12 weeks) before HIV testing.
• They should be offered a 4th generation laboratory HIV test and advised that a negative result at 4 weeks post exposure is very reassuring/highly likely to exclude HIV infection.
• An additional HIV test should be offered to all persons at 3 months (12 weeks) to definitively exclude HIV infection. Patients at lower risk may opt to wait until 3 months to avoid the need for HIV testing twice.

Reference

1. Rezel E. 4th generation (Ag/Ab) HIV testing: 47% of clinics contradict current guidelines. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O21.
2. HIV i-Base. HIV testing and risks of sexual transmission. (February 2012). http://i-base.info/home/new-i-base-guide-hiv-testing-and-risks-of-sexual-transmission

Zhou and colleagues from Brighton and Sussex Hospitals presented a poster detailing two cases of bile duct and liver complications related to recreational use of ketamine.

Both patients had regularly used ketamine for 12 months and were taking ritonavir-boosted PIs. Patients presented acutely with nausea, vomiting and epigastric pain. ALT was raised at 3.2X and 10.1X the upper limit of normal (ULN) and an ALP raised 1.7X and 2.5X ULN for cases 1 and 2 respectively.

Case one was a 38 year old Caucasian man with CD4 count of 788 cells/mm3 and undetectable viral load on stable ART (abacavir/3TC/darunavir/ritonavir) who reported daily use of 1-2 g ketamine.

Case two was a 25 year old Asian man with a CD4 count of 154 cells/mm3 and viral load of 6,500 copies/mL on ART (tenofovir/FTC/lopinavir/ritonavir), with poor adherence, who used 1 g ketamine 3 times a week and high alcohol use (>70 units/week).

Antinuclear, antimitochondrial, anti-smooth muscle and anti-liver kidney microsomal antibodies, serum copper, serum caeruloplasmin, ferritin, transferrin, A1-antitrypsin HBV, HCV and CMV serology were all negative in both cases on more than one occasion. Magnetic resonance pancreatocholangiogram (MRCP) showed marked dilatation of the common bile duct (CBD) to 18mm (6X normal) and 14mm (4.5X normal) for cases 1 and 2 respectively. No underlying ductal obstruction was seen by ERCP.

Symptoms resolved after the discontinuation of ketamine with normalisation of LFTs and reduction in CBD diameter by 28% at 4 weeks (case 1) and 29% reduction at 12 weeks (case 2).

Although these complications are known with recreational ketamine the authors stated that these are first reports in HIV positive patients and suggested a possbile faster progression (after ketamine use for 12 months vs 4 years) that may have been compounded by inhibitory impact of ritonavir on the CYP3A4 major pathway for ketamine elimination.

Reference

Zhou J et al. Dilated common bile duct and deranged liver function tests associated with ketamine use in two HIV positive MSM. 18th BHIVA Conference, 18-20 April 2012. Poster abstract 226.

Although iatrogenic Cushing’s syndrome has previously been reported as a complication from the drug-drug interaction between ritonavir and corticosteroids (we included two cases in HTB last year), two posters at BHIVA this year highlighted low awareness of this interaction, and that this can also occur with intransal and topical formulations.

Neal Marshall and colleagues from the Royal Free Hospital reported on 11 patients using ritonavir-based combinations who were also prescribed glucocorticoids: intra-articular/epidural triamcinolone (n=6), inhaled/intranasal fluticasone (n=4) and topical clobetasol (n=1). [1]

All patients had biochemical evidence of marked adrenal dysfunction and were referred to an endocrinology clinic. One or more features of Cushing’s syndrome manifested in 7/11. These symptoms can be similar to lipodystrophy (weight gain on the trunk and face but not limbs, fat accumulation in the neck and shoulders, facial swelling (“moon face”), skin and hair changes and multiple other adrenal complications.

Replacement steroids due to prolonged adrenal suppression were prescribed for 10/11 patients and 4/10 had complete, but delayed, recovery of the hypothalamic-pituitary-adrenal (HPA) axis. Other features included vertebral crush fracture after long term inhaled fluticasone (n=1), and significant deterioration of type 2 diabetes after intra-articular triamcinolone injection (n=1).

The poster stressed the importance of individualised care: switching to a non-PI based combinations when available or using alternatives to fluticasone and triamcinolone.

The second poster reported on two patients attending the Lawson Unit in Brighton who had marked adrenal insufficiency following injections of triamcinolone. Both cases were women on ritonvir-including combinations, summarised below (from the study abstract). [2]

Case 1 presented with a 4 week history of postural dizziness, lethargy, weight gain, facial swelling and had noticed difficulty getting up from a chair. She had a history of seronegative arthropathy, and had received a triamcinolone injection into both shoulders and trochanteric bursae 2 weeks before the onset of symptoms. She had cushingoid facies, with truncal obesity, abdominal striae, oral candida and proximal myopathy. A random glucose was 16.2mmol/L her random cortisol was low at 30 nmol/L and a short synacthen test showed adrenal insufficiency (baseline cortisol 14 nmol/L, 30mins 242 nmol/L, 60mins 302 nmol/L). She required steroid replacement therapy, and insulin to control her hyperglycaemia.

Case 2: A 58 year old lady attended for routine HIV monitoring blood tests and reported weight gain and increased appetite. She was HIV positive and stable on treatment with Truvada / atazanavir / ritonavir. Her CD4 count was noted to have fallen to 118 (22%) from 398 (28%), her HIV viral load remained <40copies/mL. On review it was noted she had gained 2.5kg in weight and appeared Cushingoid. She had received an intra-articular injection of triamcinolone acetate into her right knee 4/52 earlier. A random cortisol was low at 67nmol/L and a subsequent short synacthen test revealed adrenal insufficiency (Baseline 210nmol/L, 30mins 360nmol/L, 60mins 441nmol/L). 3 weeks later, her adrenal function had recovered without steroid replacement therapy.

This poster concluded: “Triamcinolone injections should be avoided in patients taking ritonavir. There are no case reports of a similar interaction between methylprednisolone and ritonavir, which may be a safer alternative to triamcinolone.”

References

1. Marshall N et al. Secondary adrenal suppression and Cushing’s syndrome caused by ritonavir boosted effects of inhaled fluticasone, injected triamcinolone and topical clobetasol: a case series. 18th BHIVA Conference, 18-20 April 2012. Poster abstract P121.
2. Conway K et al. Steroids strike again – but where is the warning? 18th BHIVA Conference, 18-20 April 2012.Poster abstract P141.

From April 2011, ARV prescribing in London clinics was changed to reflect the outcomes of therapeutic tendering by the London HIV Specialist Commissioning Group (LSCG) for drugs that have similar activity. This resulted in potential bulk discounts for some drugs if predetermined sales targets were met, while maintaining clinical criteria for prescribing based on efficacy and safety data.

In practice, this involved prescribing Kivexa rather than Truvada, when clinically appropriate for patients starting treatment and use of atazanavir/ritonavir as first-line PI, and switching to atazanavir/ritonavir when clinically appropriate, for patients using other protease inhibitors.

Whilst this important change in public prescribing was undertaken with the assurance of six monthly audits for patient outcomes, the London Commissioners have still to publish their data.

The first public data on the outcomes of one aspect of this policy – use of atazanavir switching – were presented from an audit from the Royal Free Hospital of 201 patients changing PI therapy (total 232 switches) between April 2011 and January 2012. Of these, 21 were excluded as they were switches away from atazanavir/r (62% due to side effects).

The majority (85%) of the remaining cases (153/180) switched to atazanavir/r, half (55%) due to the tender process, 28% for toxicity or intolerance, 7% viral failure/resistance and 10% for other/unknown reasons.

Only 22 people switched to darunavir/r and 5 to lopinavir/r. Reasons for not using atazanavir/r in these patients included: resistance (26%), drug interactions (22%), prior intolerance of atazanavir (11%) and using mono/dual PI therapy (19%).

Rates of short-term discontinuation (within 3 months) were similar in people who switched due to the tender (12/78; 15%) compared switching to atazanavir for other reasons (8/51; 16%), or switching to other ARVs (0/15; 0%), p=0.26. Use of tenofovir had no impact on discontinuation: 16% using tenofovir (14/90) vs 11% without tenofovir (6/54), p=0.46.

Although unrelated to the London guidelines, a separate study from the Chelsea and Westminster Hospital reported on outcomes from 192 patients who switched from lopinavir/r to either atazanavir/r (n=103) or darunavir/r (n=89) from May 2004 to May 2011 and who had at least two years of follow-up.

COMMENT

The London tender is expected to save more than £5 million over the first year with additional savings through to year two.

This snapshot appears to support the safety of the PI-switch component of the London prescription changes.

However, this does not replace the Commissioners own audit, results of which are still awaited.

References

1. Marshall N et al. Switching to atazanavir due to therapeutic tenders: short term outcomes. 18th BHIVA Conference, 18-20 April 2012. Poster abstract P195.

Although previous studies outside of the UK have reported higher levels of intimate partner violence (IPV) towards HIV positive women there is a lack of UK based data on this subject. A joint study between Homerton University Hospital and City University, London presented findings of above average IPV rates at an inner city, outpatient HIV clinic.

Results from the cross-sectional study were presented by Rageshri Dhairyawan, in an oral presentation. [1] Data was collected using a standardised questionnaire, evaluated using the HARK tool which asks whether the respondent has been humiliated, afraid, raped or kicked/hit by a partner. [2]

Of 314 women invited to participate, 198 consented and 191 women answered questions on IPV. Median age was 38 years (range 21-71 years); 70% were African, 20% black UK, 6% white and 4% other. Logistic regression models were fitted to estimate adjusted odds ratios (AOR).

Over half of the women (52%, 99/191) reported lifetime experience of IPV, 14% (27/191) within the last year and 14% during pregnancy. Women reporting HPV within the last year included: humiliation (12%), being afraid (9%), rape (3%) and hit/kicked (4%).

There was statistically significant associations between lifetime experience of IPV and self-reported mental health problems (AOR 3.44; 95% CI 1.24, 9.57) and black ethnicity not born in Africa (AOR 4.63 compared to being born in Africa, 95%CI 1.06, 20.11). Older age was associated with a reduced risk (AOR 0.92 per year increase; 95% CI 0.86, 0.97). Importantly, IPV was not found to be associated with socioeconomic or immigration status, educational background or substance misuse (all p >0.1).

In questions following the presentation it was asked whether a comparative study had been conducted in the local HIV negative population. This had not been done as a part of this study but rates of IPV in the study population were described as being higher than the local prevalence in women in primary care.

The study highlighted a need for greater awareness of IPV experienced by HIV positive women in the UK, and screening was recommended in women attending HIV clinics.

References

1. Dhairyawan R et al. Intimate partner violence in women living with HIV attending an inner city clinic in the UK. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O5.
2. Sohal et al. 2007.

From 6-10 February 2012, activists from Delhi to New York, Johannesburg to London took to the streets to appeal to the Indian government and European Commission (EC) to act to ensure that the developing world continues to have access to affordable medicines.

Currently, the EU is pushing for India to adopt measures that would choke generic production in the country, and by restricting generic exports, threaten access to medicines for millions of people worldwide. Negotiations on the proposed India-EU Free Trade Agreement (FTA) were expected to culminate at the EU-India Summit, which took place in New Delhi on 10 February 2012.

The Summit was expected to be the climax of a five-year-long negotiation process over an EU-India Free Trade Agreement (FTA). The agreement seeks to strengthen trade relations between the two economies and holds promise of huge development for many Indian industries. It also, however, is a source of concern for the global health because India is the world’s largest producer of generic medicines making it the “pharmacy of the developing world”.

India currently produces 80% of ARVs used in the developing world and 90% of paediatric HIV medicines. Despite curtailment of generic production following India’s inclusion into the World Trade Organisation in 2005, the country has successfully utilised TRIPS flexibilities to ensure that it still produces affordable medicines for for the world’s poorest countries.

The FTA, however, threatens to over rule India’s national patent laws and increase restrictions on generic pharmaceutical production from within the country.

One of the most harmful provisions within the agreement – that of data exclusivity – was the focus of activist pressure throughout 2011. The provision (known as data monopolies in the US) requires manufacturers of all generic formulations to conduct new clinical trials rather than simply demonstrating equivalence to the innovator drug, even though the FDA recognises the scientific safety and rigour of bioequivalence studies. If these trials are not conducted the generic company would be required to wait 10 years to gain access to the original trial data.

Following widespread pressure from global health advocates and activists and resistance from the Indian government the EC announced that this provision has been removed from the agreement. Despite this assurance the newer drafts of the agreement indicate that similar provisions, albeit in subtler wordings, are being pushed to be included in the final agreement.

Further harmful inclusions into the agreement include:

• Border measures – restricting the exportation of generic drugs out of the country.
• Intellectual Property enforcement measures – putting third parties such as treatment providers at risk of court cases and police action.
• The ‘Investment Chapter’ that would remove the Indian government’s right to place public health before private profits by allowing companies to directly sue the government in disputes over IP rights.

In the end, no agreement was reached on 10th February and the negotiations between the EC and India are ongoing. As pressure grows to come to an agreement in the near future there is increasing concern that provisions harmful to access to medicines may be slipped into the FTA. The consultation process is being conducted with little sign of accountability or transparency, leaving activists largely in the dark about these worrying provisions. Ongoing pressure is essential to protect India’s generic industry and ensure that the developing world retains access to the affordable medicines it needs.

For more information, and to become involved in the campaign please see: https://action.msf.org http://www.healthpovertyaction.org/campaigns/trading-with-lives/ http://www.stopaidscampaign.org.uk/

http://www.msfaccess.org/ http://donttradeourlivesaway.wordpress.com/ http://students.stopaidscampaign.org/ Pictures of the Global Week of Action are online: http://www.msfaccess.org/our-work/hiv-aids/article/1755 The Stop AIDS Campaign is an initiative of the UK Consortium on AIDS and International Development.

What can you do

Sign on to MSF initiated letter to Commissioner De Gucht, DG Trade: https://action.msf.org/en_CH

Video demonstrations

London

http://www.flickr.com/photos/stopaidscampaignactivism/sets/72157629201133095/

India

http://www.facebook.com/media/set/?set=a.329076807136539.88526.144687138908841&type=1

Nepal

http://www.facebook.com/media/set/?set=a.329076807136539.88526.144687138908841&type=1

France

http://www.actupparis.org/spip.php?article4754

South Africa

http://www.msf.org.za/event/picket-against-fta-threats-indian-generics-johannesburg

Malaysia

http://www.facebook.com/notes/stop-the-eu-india-free-trade-agreement/malaysian-groups-will-protest-tomorrow-at-eu-office-in-kuala-lumpur/381058168586572

Report shown on Sky News

http://news.sky.com/home/world-news/article/16169181

Introduction

The Conference on Retroviruses and Opportunistic Infections (CROI) conference is probably the most important annual scientific HIV meeting and it is also one of the most accessible for people who are unable to attend the meeting.

Most of the presentations are available to watch free online without registration. This includes web casts of the opening lectures, oral presentations and poster discussions.

Abstracts and PDF files for many of the full posters are also online.

http://retroconference.org

With over 1100 studies presented, we will split coverage over two issues of HTB. This issue includes reports on cure research, antiretrovirals, paediatrics, prevention studies and some hepatitis coinfection. The next issue will include PMTCT, women’s health, treatment access, TB, opportunistic infections, side effects and other complications. Some of these early reports will be posted online prior to the print edition.

This issue includes:

• Cure research takes centre stage: proof of concept for activating the latent reservoir

• Quad fixed-dose integrase combination: phase 3 studies at week 48

• Dolutegravir studies continue to show promise

• Tenofovir prodrug: 10 day monotherapy study sets dose at 25 mg for easier coformulation

• Paediatric formulations of ARVs: including an exciting new class

• Lower malaria risk in children receiving lopinavir/ritonavir-based compared to NNRTI-based ART

• High prevalence of d4T-associated lipodystrophy including lipoatrophy in children

• Lopinavir/ritonavir monotherapy in children

• Stopping treatment after early ART in infants

• PrEP: PK modeling of daily TDF/FTC (Truvada) provides close to 100% protection against HIV infection

• Risk of HIV reinfection may be similar to risk of initial HIV infection

• Case report: homozygous CCR5 delta-32 protection overcome by infection with X4 virus

• No association between atazanavir and MI or stroke in D:A:D study

• Hepatitis C coinfection studies

• Herpes Zoster vaccine safe and effective in HIV positive people

• High dose flu vaccine improves antibody responses in HIV positive people

Simon Collins, HIV i-Base

For the last two years the major HIV conferences, including CROI and the International AIDS Society (IAS) have included cure research prominently in the main programme. This is new and significant.

At CROI in 2010, Anthony Fauci, head of the US National Institute of Allergy and Infectious Diseases (NIAID) announced that the US government would be launching new funding for cure research. [1]

Many of the researchers in this field have been working on a cure years, some for decades. But the new drive for this research to receive better funding is clearly an important factor in how quickly future progress will be made.

The new funding may, in part at least, have also been driven by the responsibility that America has assumed as the largest donor for global HIV treatment programmes. Over the last ten years, ARV access in low and middle-income countries has increased from less than 0.5 million people in 2002 to over 6.5 million people in 2012. A long-term alternative to lifelong treatment is therefore likely to be an economic as well as a medical necessity. While current cure research uses specialised and expensive procedures, as with all new developments, including ARVs, high initial costs would hopefully be driven down to become more widely affordable.

The IAS has also been developing a leadership role to coordinate global funding for cure studies and to hopefully focus on a research map that will minimise duplication. [2] The IAS organised workshops prior to each of it’s last two conferences and another is planned prior to the Washington meeting in July 2012. [3] Several community workshops, including one before CROI this year have also contributed to broadening awareness of the potential for a cure. [4, 5]

In addition to an oral abstract session this year, CROI included several helpful presentations of the current research in the preconference workshops for young investigators, particularly the overview by John Mellors and the talk on animal models for latency by Vincente Planelles. [6, 7]

The Berlin cure

Whether through mediated immunity (referred to as a functional cure) or eradication (a sterilising cure), the ability to overcome lifelong treatment has always been an ultimate goal, even while the focus for recent years shifted to achieving more effective, tolerable and durable treatments.

The first report of a cure following stem cell transplantation from a donor who was naturally resistant to HIV infection (he was homozygous for the delta-32 deletion in CCR5) was at CROI in 2008 [8] and increasing press coverage since had made this a highly publicised case, and brought optimism to cure research.

The mechanism responsible for curing Timothy Brown (a.k.a. the Berlin Patient) who has been off treatment now with no evidence of HIV for over four years has not been isolated to a single component from a complex and risky set of procedures.

In addition to myeloablative chemotherapy and total body irradiation to kill both HIV infected and uninfected immune cells, he received antithymocyte globulins, cylcosporin, mycophenolate acid (MMF) and gemtuzumab (anti-CD33) that would also have killed HIV-infected and uninfected cells, followed by allogeneic stem cell transplants from a donor homozygous for delta-32 mutation, which should have reseeded an immune system resistant to CCR5 HIV infection, he developed graft vs host disease (GVHD) indicating he had accepted the donor immune system. These procedures have a 25% mortality risk and he underwent each procedure twice as the course was repeated.

An oral presentation at CROI reported on ten patients on suppressed ART who underwent autologous (self-donated) hematopoietic stem cell transplantation for AIDS related lymphoma, which is a less risky procedure than that used by Tim Brown. Unfortunately, persistent HIV viraemia was still detected in 9 of 10 patients post-transplant, with a median viral load of 1.5 copies/mL (range: <0.2 to 26) and median total HIV-1 DNA of 554 copies/million PBMCs (range: <0.4 to 2179). 2-LTR circles were detectable post-transplant in only 2 of 10 patients (range: 1 to 7 copies/million PBMC). The only patient with undetectable plasma viral load had the highest levels of HIV-1 DNA and 2-LTR circles. Additionally, plasma viraemia persisted in a patient with undetectable HIV-1 DNA in PBMC. Although the authors concluded that this showed that the CCR5 delta-32 donor was essential in the Berlin case, patients in their study also did not have total body irradiation, graft vs. host disease, and were reinfused with their own stem cells, which could have included HIV-infected T-cells. [9]

A further US study is about to open of allogeneic stem cell transplant in HIV positive people with bone marrow failure with the hope that 1 or 2 of the 15 patients may also be able to be matched to a delta-32 donor to see if the Berlin case can be repeated. [10]

This will involve overcoming the difficulty of finding and matching a delta-32 donor who is also compatible on 8 HLA types. At the community cure meeting prior to CROI, John Zaia from the City of Hope Cancer Centre near Los Angeles described an initiative to develop an inventory

of cord blood stem cell donors as an international resource, and to date, out of 13,000 donors tested, 90 have been identified as being homozygous for the CCR5 delta-32 deletion. [5]

First activation of latently infected resting T-cell reservoir in vivo

While many aspects of this research are controversial, there is broad consensus on the need for a strategy to overcome the reservoir of long- lived, latently infected, resting CD4 cells that harbour integrated HIV and that are not reached by current ART.

Most notably, an oral presentation at CROI included results from a proof of concept study that viral latency might be overcome. David Margolis from the University of North Carolina presented results in an oral late breaker presentation that the use of a single dose of the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) is able to activate latently infected resting CD4 cells. [11] In 2005, Margolis presented results from using another HDAC inhibitor, valproic acid, to stimulate the latent reservoir.

Of the 11 human histone deacetylase, HDACs 1, 2, and 3 are the primary enzymes that limit activation of HIV integrated into cells by producing a barrier that maintains latency. Vorinostat is a selective inhibitor of HDAC 1, 2, and 3 that has been shown to induce HIV expression from latently infected resting cells ex vivo. However, vorinostat, although approved as a cancer treatment also has mutogenic properties.

In this proof of concept study, the change in the latent reservoir was determined by measuring cell associated HIV RNA specifically in the resting cell population. This involves harvesting approximately four billion lymphocytes from each aviraemic patient by leukopheresis that are treated with magnetic antibody beads to leave 200-1000 resting CD4 cells that can be tested by RNA PCR.

Six study participants had baseline measures of activation, that were tested ex vivo after exposure to vorinostat and that demonstrated that a change was measurable in all patients. Each patient also undertook a single 200 mg safety dose and a separate single 400 mg dose of vorinostat for a PK study to decide the timing for the second leukopheresis used to determine efficacy.

Following a second, therapeutic 400 mg dose, all six patients responded with a highly significant mean 4.8 fold increase (range 1.5-10-fold) of RNA expression in resting CD4 cells (p<0.01). The treatment was well tolerated with no reported side effects associated with vorinostat and none greater than grade 1. Of note, and perhaps surprisingly, no increases in HIV plasma RNA were detected using a single copy/mL test.

The study concluded that is the first demonstration of activation of latent resting HIV-infected CD4 cells in vivo. However, these results are still preliminary. While the proof-of-concept is exciting, Margolis suggested that this might be seen as the equivalent of a “ddC moment in relation to HAART”.

Additionally, other molecules may be more effective compounds to activate latency and in vitro data suggesting panobinostat as more active that vorinostat were presented in a poster. [12]

Earlier in the same conference session Liang Shan reported that latently infected resting CD4 cells treated with vorinostat survived despite viral cytopathic effects, even in the presence of autologous CD8 cells from most patients on ART concluding “that stimulating HIV-1-specific CTL responses prior to reactivating latent HIV-1 may be essential for successful eradication efforts and should be considered in future clinical trials”. [13]

Treatment during early infection

Theoretically, the easiest targets for cure research might be those patients diagnosed earliest in their infection, who promptly start treatment and who maintain suppressed viraemia for many years.

Although the latent cell reservoir is established within weeks of infection and is likely to be slowly reduced after years on effective ART, in nearly all patients, viraemia rapidly returns within weeks if treatment is interrupted. Even when HIV is reduced to being present in less than 1 in 1.7 billion cells, this is sufficient for systemic infection to quickly be reestablished (within two months) if treatment is stopped. [14]

While levels this low might question the importance of a treatment to target the viral reservoir, they can so far only be achieved with very early treatment and/or many years of viral suppression. The need to reduce the viral reservoir more quickly will be a concern for everyone else who started ART during chronic infection.

Rapid viral rebound without treatment has been widely reported in numerous treatment interruption studies. However, several small cohorts have also reported viral control in a minority of patients, usually in those who initiated treatment in acute infection and maintained undetectable viral load for several years.

Last year at CROI, the ANRS Visconti study reported small numbers of patients who started treatment in early infection (after serconversion, median viral load >100,000 copies/mL), maintained viral suppression for >3 years on treatment and who have subsequently controlled viraemia off treatment for >6 years. [15] This year at CROI similar cases were reported in posters by two other groups.

Maria Salgado and colleagues reported a single case of a patient who initiated treatment during seroconversion (viral load >750,000 c/mL, western blot indeterminate) for three years and after stopping ART has since maintained viral load suppressed to <50 copies/mL off-treatment for more than nine years. Initial and current viral isolates are dual CCR5/CXCR4 tropic and fully replication-competent in vitro. Minimal viral evolution has been detected over the 11 years.

He is reported to currently have low titers of neutralising antibodies to heterologous and autologous HIV-1 isolates, and his CD8+ T cells do not have potent HIV suppressive activity suggesting a mechanism other than CTL-mediated suppression reported in elite controllers. [16]

Alain Lafeuillade from General Hospital, Toulon (who is also one of the key organisers of the International HIV Persistence Workshop that has been meeting every two years since 2003) reported that 17% (8/45) of a cohort of patients treated at seroconversion for a median of 2.2 years (range 1.8 to 4.0) have remained off treatment for more than 10 years, two of whom remain suppressed to <20 copies/mL (median 2,500 copies/mL for the other six). The 37 people who restarted treatment (due to confirmed CD4 decline to <350 cells/mm3) did this after a

median of 5.0 years (range 3.0-8.0) off-treatment. The study suggested the protective mechanism could be relate to early ART reducing the HIV reservoir but also emphasised that such responses seem to be rare. [17]

A poster from Joseph Margolick and colleagues reported small differences in viraemia between people diagnosed in early infection (within a year of infection) and randomised to immediate treatment (n=57) year) and those who did not start early treatment (n=24). However, study numbers were very low at the evaluation point (24 months after stopping treatment of 24 months after diagnosis) due to ~20% loss to follow- up and exclusion of people who restarted treatment for other reasons. [18]

Generally small differences were also reported from early treatment in the larger SPARTAC study that randomised almost 400 people (diagnosed within 6 months of infection) to deferred ART or immediate treatment for either 3 months or 12 months, and who then stopped treatment. [19]

However, in the context of eradication research, two oral presentations suggested that early treatment, while too late to prevent the establishment of the viral reservoir, might reduce the pool of latently infected cells.

Maria Buzon and colleagues estimated the size of the viral reservoir in patients treated for more than ten years who initiated ART within 3 months of infection (n=9) and compared levels integrated and total HIV DNA levels to people who started treatment during chronic infection (n=26) and to elite controllers (n=37). [20]

Integrated and total DNA levels were significantly lower in both primary treated (p=0.06 and p=0.001, respectively) and elite controllers (p=0.003 and p<0.0001, respectively) compared to those treated in chronic infection. In addition, the ratio between total and integrated HIV-DNA was significantly lower in early treated and elite controllers (both p=0.04 vs chronic) with no differences between acute and EC groups.

Although patient numbers were small, differences were also reported when comparing how soon treatment had been started with patients treated during Fiebig stage III or IV vs stage V having significantly lower levels of both total and integrated HIV DNA after two years.

An oral presentation by Alan Perelson from the Los Alamos National Laboratory used mathematical modelling to look at the impact of early treatment of 27 people treated during acute infection on the size of the latent reservoir, and the relationship of both to initial viral load and target cell ability. [21]

This study also reported that earlier ART, including earlier during primary infection, had a measurable impact related to the initial size of the reservoir, with patients who already started with very low levels of resting cell infection (who also had low levels of peak viral load) experiencing less change in the reduction of resting cell decay. The model also suggested that CD4 T cell increases in response to successful ART was not increasing the viral reservoir.

Research into a functional cure

Other groups are focusing on immunological interventions that would support a functional rather than eradicating cure.

Pablo Tebas from the University of Pennsylvania, presented additional safety and efficacy results from the use of zinc finger nuclease (ZFN) modification of CD4 cells (using SB-738) to a CCR5-deleted phenotype (in development by Sangamo BioSciences). [22]

This process involves harvesting cells by apheresis, treating them with SB-738 to produce 13-35% of cells with CCR5-detetions in vitro. The cells are then expanded, cryopreserved and 5-30 billion cells are reinfused into the donor patient.

Results were combined from three studies: one in ART responders (baseline CD4 >450 cells/mm3) who subsequently interrupted treatment (group 1, n=6) and two in immune non-responders (baseline CD4 <500 cells/mm3) who have not interrupted treatment (group 2, combined n=15). Initial results from these studies were presented at CROI and ICAAC conferences last year.

Most patients were male, white, mean age 48, with a long history of HIV infection (median 12 and 18 years in group 1 and 2 respectively). Mean CD4 count and CD4:CD8 ratio were 921 (+222) cells/mm3 and 1.4 (+0.6) in group 1 and 335 (+89) cells/mm3 and 0.7 (+0.3) in group 2.

Duration of follow-up is now a mean 325 days (range 90 – 738 days).

After infusion, CD4 cells increased by about 1500 cells/mm3 in group 1 (n=6), these then decreased during the treatment interruption but which remained significantly above baseline during follow-up. CD4 responses in group 2 involved an increase of about 500 cells/mm3 which then dropped by about 200-300 which then remained stable out to over a year in the patients who did not interrupt treatment. The expansion of CD4 cells was associated with increases in IL-2, IL-7 and IL-15.

The CD4:CD8 ratio increased significantly in both groups, normalising and remaining at approximately 1.0 throughout follow-up in the group 1 and increasing to approximately 2.5 for the six patients in group 2 decreasing during the treatment interruptions but then remaining stable.

The modified cells continued to be detected through follow-up at 2% of circulating CD4 cells at 48 weeks for most patients. Levels were higher during the treatment interruption for group 2 and then dropping to 2%. Circulation of cells to other tissue sites was confirmed by multiple rectal biopsies where levels of the CCR5-modified cells were comparable to those in blood or higher throughout follow-up.

During the treatment interruption viral load rebounded over the first 8 weeks to around 100,000 copies/mL in a similar way to other interruption studies dropping by one log during the last 4 weeks off-treatment to levels that were generally higher than pre-ART. After three months, when treatment was restarted, viral load become undetectable again in all six patients. One person, later found to be heterozygous for the delta-32 mutation, had a lower rebound (to 10,000 c/mL) and then resuppressed viral load to undetectable by week 8 and remained undetectable off treatment until restarting as per protocol at week 12.

This group used a new method to measure changes in the viral reservoir based on levels of HIV DNA sensitive to low copy numbers (although unable to distinguish between integrated DNA and 2-LTR circles. They reported no detectable change in 4/6 patients with one person have a transient 4-fold increases at week 12 and 20 during the interruption but returning to baseline levels and one person experiencing a 9-fold increase that returned to baseline 16 weeks after restarting treatment.

Side effects were mild and transient, mainly within 24 hours of the infusion (mild chills, fever, headache, fatigue) but included one report of arthritis lasting a few days and abnormal garlic-like body odour.

Next steps include using immunomodulatory drugs such as cylcophosphamide to promote engraftment and increase the percentage of modified cells and studying other patients who are heterozygous for the delta-32 deletion.

Several studies presented studies where pegylated interferon (peg-IFN) was added to ART prior to stopping HIV treatment and continuing peg-IFN. The results suggested that viral rebound was delayed by the peg-IFN via an immune-mediated rather than antiviral mechanism, but these were small studies with short-term follow up (12 and 24 weeks). [23, 24, 25]

comment

The timeline for a cure at this meeting was optimistically referred to as being at least ten years. HIV is a tricky puzzle: the virus is resilient and the range of immune responses is complex. Nevertheless, these advancements in several key and linked areas are crucial advances.

Several networks are encouraging collaborative research in order to be able to compare and evaluate different approaches. [26, 27]

Numerous compounds that are already licensed are already being looked at for their potential to overcome latency. These include prostratin, lonomycin, thapsigargin (a calcium pump inhibitor), PMA, typhostin-A (a non-selective typhosin phosphate inhibitor), CD3/CD8 antibodies for TCR signaling, PLA, toll like receptor 7 (TLR7 including GS-9620) and protein kinase-C (PKC) agonists. Several companies including Gilead and Merck are already screening for and have identified other potential HDAC inhibitors.

The important of informed community participation in partners in this research is particularly important given the ethical considerations for study volunteers. If a mechanism is discovered to cure HIV more widely, it may still only work in some patients.

With current treatment able to nearly normalise life expectancy, a cure has a high bar to overcome. Some of this research will involve asking people on stable treatment to interrupt therapy and some of the interventions will have potentially greater toxicity than their current ART. At least for the foreseeable future, the potential risks in these initial studies are likely to outweigh any personal benefits.

Treatment during primary infection early treatment may put someone at a preferential state to respond to parts of a strategy to cure HIV, and some people diagnosed this early may want to take this decision. Because the latent pool is smaller in such patients, those initiating ART during acute HIV may be the best candidates for pilot studies attempting HIV eradication.

References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle.

1. Fauci A. A Fauci. The HIV/AIDS research agenda: a view from NIAID. 17th CROI 2010, 16-19 February 2010, San Francisco. Plenary session 5. February 16, 2010.

http://retroconference.org/2010/data/files/webcast_2010.htm

2. International AIDS Society (IAS). Towards a cure: global scientific strategy. February 2011.

http://www.iasociety.org/Default.aspx?pageId=370

3. International AIDS Society (IAS). Towards a cure: global scientific strategy. Washington meeting 2012.

http://www.iasociety.org/Default.aspx?pageId=349

4. Treatment Action Group. Report: HIV cure-related clinical research workshop, October 2011.

http://www.treatmentactiongroup.org/cure/2011-workshop-report

5. ATAC Cure Research Workshop. 4 March 2012. 6. Mellors J. HIV Reservoirs and Cure Research. Workshop: Program Committee Workshop for New Investigators and Trainees (Part 2) Monday 5 March 2012 11:00 AM, Seattle.

http://retroconference.org/static/webcasts/2012/

7. Planelles V. Models for the Study of Latency. Workshop: Frontiers in Laboratory Science Workshop. Monday 5 March 2012 2:30 PM, Seattle.

http://retroconference.org/static/webcasts/2012/

8. Hutter G et al. Treatment of HIV-1 infection by allogeneic CCR5-D32/D32 stem cell transplantation: a promising approach. Poster abstract 719.

http://www.retroconference.org/2008/Abstracts/31704.htm

9. Cillo A et al. Plasma viremia and cellular HIV-1 DNA persist despite autologous hematopoietic stem cell transplantation for AIDS-related lymphoma. Oral abstract 154.

http://www.retroconference.org/2012b/Abstracts/42793.htm

10. Allogeneic Transplant in HIV Patients (BMT CTN 0903)

http://clinicaltrials.gov/ct2/show/NCT01410344

11. Margolis D et al. Administration of vorinostat disrupts HIV-1 latency in patients on ART. Oral late breaker 157LB.

http://www.retroconference.org/2012b/Abstracts/45315.htm

12. Rasmussen T et al. The histone deacetylase inhibitor (HDACi) panobinostat (LBH589) stimulates HIV-1 expression more potently than other HDACi in clinical use and disrupts HIV latency at clinically achievable concentrations. Poster abstract 370.

http://www.retroconference.org/2012b/Abstracts/43423.htm

13. Shan et al. Elimination of the latent reservoir for HIV-1 requires induction of cytolytic T lymphocyte responses. Oral abstract 153.

http://www.retroconference.org/2012b/Abstracts/43184.htm

14. Chun T-W et al. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS 2010: 24 (18): p 2803–2808 (27 November).

http://journals.lww.com/aidsonline/Fulltext/2010/11270/Rebound_of_plasma_viremia_following_cessation_of.6.aspx

15. Saez-Cirion A et al. Long-term HIV-1 Control after interruption of a treatment initiated at the time of primary infection is associated to low cell-associated HIV DNA levels: ANRS VISCONTI Study. Poster abstract 515.

http://www.retroconference.org/2011/Abstracts/41477.htm

16.Salgado M et al. 357 Title: Prolonged Control of Replication-competent Dual-tropic HIV-1 following Cessation of HAART. Poster abstract 357.

http://www.retroconference.org/2012b/Abstracts/43398.htm

17.Lafeuillade A et al. Long-term control of HIV reservoir after a 2-year ART course at acute infection. Poster abstract 358. http://www.retroconference.org/2012b/Abstracts/43198.htm http://www.retroconference.org/2012b/PDFs/358.pdf (PDF)

18. Margolick J et al. 356 Effect of randomized HAART on viral suppression off therapy in patients with acute/early HIV infection. Poster abstract 356.

http://www.retroconference.org/2012b/Abstracts/45103.htm

http://www.retroconference.org/2012b/PDFs/356.pdf (PDF)

19. Fidler S et al. The effect of short-course antiretroviral therapy in primary HIV infection: final results from an international randomised controlled trial; SPARTAC. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Oral abstract WELBX06. See:

http://i-base.info/htb-south/1528/

20. Buzon M et al. Treatment of early HIV infection reduces viral reservoir to levels found in elite controllers. Oral abstract 151.

http://www.retroconference.org/2012b/Abstracts/44634.htm

21. Perelson et al. Immediate antiviral therapy restricts resting CD4+ infection but does not accelerate the decay of latent infection. Oral abstract 152.

http://www.retroconference.org/2012b/Abstracts/43222.htm

22.Tebas et al. Induction of acquired CCR5 deficiency with zinc finger nuclease-modified autologous CD4 T cells (SB-728-T) correlates with increases in CD4 count and effects on viral load in HIV-infected subjects. Oral abstract 155. http://www.retroconference.org/2012b/Abstracts/43132.htm

23.Mexas A et al. Concurrent Measurements of Total and Integrated HIV DNA Provide Insight into the Mechanism of Reduced Reservoir Size in an Interferon-alpha followed by Structured Treatment Interruption Trial. Poster abstract 374.

http://www.retroconference.org/2012b/Abstracts/44147.htm

24. Papasavvas E et al. Immune Correlates of Sustained IFN-alpha-mediated Suppression of HIV Replication: Association with IFN-alpha-mediated Signaling and Increased NK Cell Responses. Oral abstract 93.

http://www.retroconference.org/2012b/Abstracts/43948.htm

25. Azzon L et al. Pegylated interferon-alpha 2A monotherapy induces durable suppression of HIV-1 replication and decreased HIV DNA integration following ART interruption. Poster abstract 631.

http://www.retroconference.org/2012b/Abstracts/43413.htm

26. Collaboratory of AIDS Researchers for Eradication (CARE) and the Delaney AIDS Research Enterprise (DARE).

https://www.delaneycare.org/

27. Defeat HIV – The Delaney Cell and Genome Engineering Initiative, Fred Hutchinson Cancer Research Center, University of Washington, Seattle.

http://defeathiv.org

Simon Collins, HIV i-Base

The fixed dose, single-pill, four-drug formulation of elvitegravir/cobicistat/tenofovir/FTC, developed under the name Quad, is likely to be closest to regulatory approval (and has an FDA hearing in May).

At CROI, results were presented from two randomised, double blind, placebo controlled Phase 3 studies. One study comparing Quad to efavirenz/tenofovir/FTC (Atripla) was an oral session and another comparing Quad to atazanavir/ritonavir plus tenofovir/FTC was a poster. [1, 2]

The primary endpoints in both studies were the proportion of patients with undetectable viral load (< 50 copies/mL) at week 48 by intention- to-treat analysis, with non-inferiority defined by a lower margin of -12% and that included patient stratification by baseline viral load above and below 100,000 copies/mL. Virological efficacy was around 90%, tolerability was good and discontinuations were notably low in all arms and Quad was found to be non-inferior compared to the comparator combinations in both studies.

Study 236-0102 compared Quad to Atripla enrolled 700 treatment-naive patients in the US and Puerto Rico and Paul Sax from Brigham and Women’s Hospital, Boston, presented the results. [1]

Baseline characteristics included: mean age 38 years and low median viral load (31,000 copies/mL) although one third of participants started at >100,000 c/mL. Mean CD4 count was just under 400 cells/mm3 with 12% of participants starting below 200, 32% starting at both 200 to 350 and 350-500 and 23% starting at >500 (percentages for Quad arm but similar to Atripla). The study was largely male (88%) with ethnicity 61% white, 31% African Americans and 8% other. Less than 5% of participants in each arm had either HBV or HCV coinfection.

Discontinuations before week 48 were similar in 11% vs 13% in the Quad vs Atripla arms for broadly similar reasons.

Viral load was suppressed to undetectable in 88% vs 84% patients (difference +3.6%, 95%CI -1.6 to +8.8) meeting criteria for non-inferiority, with 7% of patients in each arm having virological failure and 5% vs 9% having missing data (all Quad vs Atripla, respectively). Responses by subgroup (viral load, CD4, race, sex, age and adherence level were not significantly different but trended to favour Quad. CD4 increases favoured the Quad arm with +239 vs + 206 cells/mm3 respectively (p=0.009).

Approximately half of the patients in each arm failed with mutations associated with resistance to either integrase inhibitors (mainly E92Q) or NNRTIs (mainly K103N) in 8/14 vs 8/17 respectively.

Most side effects were reported as mild (grade 1) with statistically significant differences including more nausea in the Quad arm (21% vs 14%) and more abnormal dreams (15% vs 27%), insomnia (9% vs 14%), dizziness (7 vs 14%) and rash (6% vs 12 %) in the Atripla arm.

Discontinuations related to side effects occurred due to rash (0 vs 1.4%), renal abnormalities (1.4% vs 0), depression (0.3% vs 0.9%), abnormal dream (0 vs 0.6%) in the Quad vs Atripla arms respectively with 3% in each arm stopping due to both fatigue and paranoia.

The most frequent grade 3 or 4 laboratory abnormalities occurring in greater than five patients in each arm were broadly similar and generally low including creatinine kinase (5% vs 11%), AST (2% vs 3%), ALT (1%vs 3%), GGT (2% vs 5%), neutrophils (2% vs 3%), amylase (2% each arm) and haematuria (2% vs 1%), all in Quad vs Atripla respectively.

Serum creatinine increased by approximately 0.1-0.2 mg/dL by week 2 in the Quad arm which was maintained through to week 48 compared to no change with Atripla (p<0.001).

Increases in fasting total cholesterol, LDL and HDL cholesterol were significantly greater in the Atripla compared to the Quad arms but there was no difference between groups in the more clinically significant TC:HDL ratio or in triglycerides (+ 7 mg/dL in each arm).

The second Quad study, called 236-0103, compared Quad to atazanavir/ritonavir plus tenofovir/FTC (Truvada). It enrolled 708 treatment-naive patients and results were presented by Edwin DeJesus in a poster. [2] Baseline characteristics were broadly similar to the 236-0102 study: mean age 38 years, 90% male, and 74% white. CD4, viral load and hepatitis coinfection were also similar, with 40% of participants having viral load ≥100,000 copies/mL. Exclusion criteria for this study included eGFR < 70 mL/min.

Virological efficacy (<50 copies/mL) at week 48 was 92% vs 88% (difference +3.5%, 95%CI –1.0% to +8.0%) in favour of Quad, which met criteria for non-inferiority. In patients with baseline viral load ≥100,000 copies/mL, response rates were 85% vs 82% (NS). Virologic failure (FDA snapshot algorithm) was 5%, in both arms. Median CD4 increases were similar at + 207 vs 211 cells/mm3 and discontinuation rates for side effects were 4% vs 5% (both in Quad vs atazanavir/r arms, respectively).

Side effects occurring in ≥5% of patients, were similar in each arm, apart from elevated bilirubin levels which were significantly higher in the atazanavir/ritonavir arm. Discontinuations occurred due to diarrhoea (4% vs 5%), pyrexia (1% vs <1%), nausea (1% vs 0), nausea, vomiting and fatigue (each <1% vs 1%) and jaundice, dizziness, ocular icterus and drug eruption (each 0 vs <1%). The most frequent grade 3 or 4 laboratory abnormalities occurring in at least 2% in either arm were broadly similar including creatinine kinase (6% vs 7%), haematuria (4% vs 2%), AST (2% vs 3%), ALT (2% vs 2%), amylase (2% each arm) and increased bilirubin (1% vs 58%), all in Quad vs atazanavir/ritonavir arms respectively. Serum creatinine increased by approximately 0.08 mg/dL by week 2 in the Quad arm which was 0.12 mg/dL at week 48 compared to 0.05 with atazanavir/ritonavir (p<0.001). Median change in CLCr from baseline was –12.7 mL/min in Quad and –9.5 mL/min (p <0.001). Lipid increases were similar for TC, LDL and HDL cholesterol (all p=NS) but triglycerides increased by less in the Quad arm (+5 vs +23 mg/dL, p=0.006).

Median changes in bone mineral density were similar in each group. Spine changes reduced by about 3% at week 24 and remained stable, with reductions at week 48 of -2.45% vs -3.48% (p=0.25 for between arm comparison). Reductions at the hip were continuous slopes for both combinations of about -1.5 vs -2.0% at week 24 and -2.87 vs 3.59% at week 48 (p = 0.12).

In an answer to a question about clinical management of increases in serum creatine, in reference to increases seen in both Quad studies, Paul Sax stated that a statistical analysis of the data suggested that an increase of 0.4 mg/dL or greater was a cut-off for concerns about potential tenofovir renal tubular toxicity.

When asked whether paired cystatin C in serum would distinguish between tenofovir and cobicistat associated changes Sax said that this was a possibility, but that it might be affected by other HIV-related factors. The question of cost was also raised in the context of results that had not demonstrated superiority, perhaps related to study size.

COMMENT

Quad has already been submitted for regulatory approval to Western regulatory agencies with an FDA decision expected by August 2012.

References

1. Sax P et al. Elvitegravir/cobicistat/emtricitabine/tenofovir (Quad) has non-inferior efficacy and favorable safety compared to efavirenz/emtricitabine/tenofovir in treatment-naïve HIV-1+ subjects. 19th CROI, 5–8 March 2012, Seattle. Oral abstract 101.

http://www.retroconference.org/2012b/Abstracts/43143.htm

Webcast: State of the “ART” and Drug Resistance (Tuesday 10 am).

http://retroconference.org/static/webcasts/2012/

2. DeJesus et al. Week 48 results of an ongoing global phase 3 study comparing elvitegravir/cobicistat/emtricitabine/tenofovir (Quad) with atazanavir/ritonavir plus emtricitabine/tenofovir in treatment-naïve HIV-1+ subjects showing efficacy, safety, and pharmacokinetics. 19th CROI, 5–8 March 2012, Seattle. Poster abstract 627.

http://www.retroconference.org/2012b/Abstracts/43391.htm

Simon Collins, HIV i-Base

Results from the SPRING-1 dose-finding study of dolutegravir plus two nukes (abacavir/3TC or tenofovir/FTC) compared to the FDC efavirenz/tenofovir/FTC (Atripla) were presented in a late-breaker oral session and were broadly similar at 96 weeks to 48 week results for the 50 mg arm. [1]

Two hundred and five subjects were randomised to receive dolutegravir at 10 mg, 25 mg or 50 mg once daily compared to efavirenz. Participants were 86% male, 80% white, 26% >100,000 copies/mL viral load, and 67% used tenofovir/FTC as the nucleoside backbone.

At week 96 the proportion of subjects with viral load <50 copies/mL (TLOVR) was 79%, 78% and 88% in the 10 mg, 25 mg and 50 mg arms respectively vs 72% in the efavirenz arm. Virological failure occurred more frequently in the lower dose arms: in 13% (n=7), 8% (n=4), 4% (n=2) and 8% (n=4) of the 10 mg, 25 mg, 50 mg and efavirenz arms respectively but these were low study numbers and half these patients who counted as failure by TLOVR analysis resuppressed to below 50 copies/mL by week 96. No mutations associated with resistance to integrase inhibitors or NNRTIs were seen in these patients.

CD4 increases were not statistically different at week 96: +338 cells/mm3 for the combined dolutegravir arms vs +301 cells/mm3 for efavirenz (p = 0.155).

Only two people discontinued dolutegravir due to side effects (one in each of the 25 mg and 50 mg arms) compared to five in the efavirenz group. Side effects were lower in the dolutegravir arms although serious side effects were similar. The only grade 3/4 lab abnormalities were single cases of ALT elevation associated with acute hepatitis C. No differences in renal markers were observed between the two groups.

A second oral presentation reported from a phase 1 pharmacokinetic study in HIV negative people that an increased dolutegravir dose (50 mg twice-daily) overcomes an interaction with rifampin. [2]

Five other posters expanded the profile of this important new integrase inhibitor.

These included:

• Exciting results on a paediatric granule formulation that produced higher levels compared to the oral tablet in HIV negative volunteers used oral or dissolved irrespective of liquid. [3]
• Results from a single dose pharmcokinetic study in HIV positive adults with mild-moderate liver impairment suggested that dolutegravir could be used without dose modification in these patients. [4]
• Reporting a higher genetic barrier to resistance in vitro that may differ by HIV subtype and identification of mutations R236K and H51Y in subtype B. [5]
• Similar potency against raltegravir-associated mutations in HIV-2 as HIV-1 [6]

comment

The oral presentation of the SPRING-1 study was uncharacteristically understated: “dolutegravir has some attributes that might make it interesting for use in combination therapy” before listing once-daily dosing, no boosting, low PK variability, few expected drug interactions, potentially distinct resistance profile to raltegravir and high potency at a low milligram dose.

Further studies with this compound will be followed closely together with the back-up GSK-1265744 compound that may be used at even lower milligram doses (5-10 mg). Low milligram compounds have the potential as less expensive options to PI-based combinations in low-income countries, if patent issues are overcome.

Currently, a fixed dose formulation of dolutegravir with abacavir and 3TC has completed initial PK studies.

On 2 April, as this issue of HTB went to press, top-line results were released from the SPRING-2 phase 3 study in treatment-naive adults reporting dolutegravir to be non-inferior to raltegravir. [7]

References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle.

1. Stellbrink HJ et al. Dolutegravir in combination therapy exhibits rapid and sustained antiviral response in ARV-naïve adults: 96-week results from SPRING-1 (ING112276). Oral abstract 102LB.

http://www.retroconference.org/2012b/Abstracts/45432.htm

2. Dooley K et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin: results of a phase I study among healthy subjects. Oral late breaker abstract 148.

http://www.retroconference.org/2012b/Abstracts/43754.htm

3. Patel P et al. Pharmacokinetics of a dolutegravir paediatric granule formulation in healthy adult subjects. Poster abstract 985.

http://www.retroconference.org/2012b/Abstracts/44121.htm

4. Song I et al. Pharmacokinetics of dolutegravir in subjects with moderate hepatic impairment. Poster abstract 608.

http://www.retroconference.org/2012b/Abstracts/44103.htm

5. Oliveir M et al. Novel mutational changes involved in delayed development of dolutegravir resistance in HIV-1 B and non-B subtypes during in vitro drug selection. Poster abstract 691.

http://www.retroconference.org/2012b/Abstracts/43859.htm

6. Kobayashi M et al. Antiviral activity in vitro of the INI, dolutegravir, against raltegravir-resistant HIV-2 mutants. Poster abstract 691.

http://www.retroconference.org/2012b/Abstracts/42737.htm

7. Shionogi/ViiV press release. Shionogi – ViiV Healthcare announces initial data from Pivotal Phase III study of dolutegravir in HIV. (02 April 2012).

http://www.viivhealthcare.com/media-room/press-releases/2012-04-02.aspx?sc_lang=en

Simon Collins, HIV i-Base

Further data on the development of a tenofovir prodrug from Gilead (compound name GS-7340) were presented by Peter Ruane MD from Los Angeles. [1]

This compound is expected to have higher potency at much lower concentrations in all cell types with EC50s compared to the current formulation of tenofovir disoproxil fumerate (TDF) of 0.003 vs 0.015 uM in PBMCs and 0.014 vs 0.06 uM in macrophages. Last year at CROI a similar dose finding 10-day monotherapy study reported viral load reductions of about -1.0 log at 50 mg and 150 mg doses, compared to 0.5 log with TDF, with plasma concentrations of GS-7340 that were 88% lower and intracellular concentrations 4-fold higher compared to TDF.

This current study randomised 38 treatment-naïve or experienced (but tenofovir sensitive) patients to 10 days GS-7340 monotherapy using 8 mg, 25 mg and 40 mg with placebo and TDF arms as controls. The primary endpoint was the time-weighed average change in viral load (DAVG) at day 11.

Baseline characteristics included: age 38 years, 97% male and 50% white/38% African American. The mean viral load and CD4 counts were 31,000 copies/mL and 478 cells/mm3 respectively.

DAVG results were –0.76, –0.94, –1.13, –0.48 and –0.01 log copies/mL in the 8 mg, 25 mg, 40 mg, TDF and placebo arms respectively with median viral load reductions –1.08 (8 mg); –1.46 (25 mg); –1.73 (40 mg), –0.97 (TDF) and –0.07 (placebo). There were significant differences between both the 25 mg and 40 mg arms when compared to TDF, but not for the 8 mg dose.

Plasma tenofovir exposures across the GS-7340 groups were approximately 80 to 97% lower compared to TDF with intracellular concentrations in PBMCs 7-fold higher in the 25 mg dose and 20 fold higher with the 40 mg dose.

There were no clinically significant laboratory abnormalities or drug-related serious adverse events, no discontinuations and no evidence of resistance over the 10 days.

Phase 2 studies that are already ongoing or soon to enroll are using the 25 mg dose for development in two fixed dose formulations. One substitutes GS-7340 for TDF in Quad with elvitegravir, cobicistat and FTC (in study 292-0102) and a second in coformulation with darunavir, cobicistat and FTC to be the first once-daily single-pill PI combination (in study 299-0102).

comment

The discussion after this presentation included surprise that the dose selected for development was to be based on such a small short study and that the greater virological efficacy in the 40 mg group was not going to be explored further. Also that this decision was largely driven by the ease of coformulation with the lower milligram dose.

Another question was whether increased intracellular concentrations of GS-7340 accumulated in renal tubule cells. Although no renal concerns were seen after 10 day exposure this will be an important aspect of further studies. In vitro data in MT-2 cells, PBMCs and macrophages did not find concerns from increased levels of intracellular diphosphates. CNS penetration of GS-7340 is expected to be similar to tenofovir DF and it may also have activity against HBV.

References

1. Ruane P et al. GS-7340 25 mg and 40 mgdemonstrate superior efficacy to tenofovir 300 mg in a 10-day monotherapy study of HIV-1+patients.19th CROI, 5–8 March 2012, Seattle. Oral abstract 103. http://www.retroconference.org/2012b/Abstracts/44081.htm
2. MarkowitzMetal.GS-7340demonstratesgreaterdeclinesinHIV-1RNAthanTDFduring14daysofmonotherapyinHIV-1-infectedsubjects.18thCROI,27 February–3 March 2011, Boston. Oral abstract 152LB. http://www.retroconference.org/2011/Abstracts/42549.htm

Polly Clayden, HIV i-Base

International guidelines recommend universal and immediate treatment of HIV-infected neonates, which poses a significant challenge given the lack of suitable formulations in this age group.

Three posters at CROI showed novel “sprinkle” formulations of two integrase inhibitors and a protease inhibitor.

Dolutegravir

Dolutegravir (DTG) is a promising integrase inhibitor currently in phase 3 of development. The compound is interesting for several reasons: once daily dosing for treatment naïve patients, low milligram dose (50 mg, so potential for co-formulation and low cost), adequate plasma exposure without boosting, few expected drug interactions, an expected different resistance profile to raltegravir and a very comprehensive development plan. 96-week phase 3 data was also presented at CROI 2012 (see above).

The developers – a partnership between Shionogi & Co and ViiV Healthcare – plan to study the compound in all paediatric age groups down to young infants, a population woefully short of appropriate antiretroviral formulations. DTG is currently being studied in children 6 – 18 years in IMPAACT P1093.

Parul Patel and colleagues presented findings from an evaluation of the single dose pharmacokinetics (PK) in healthy adults of a new oral granule formulation of DTG, in development for infants and young children. [1] The granules were given with and without 30 mL of various liquids and compared to the current tablet formulation given with 240 mL of tap water.

This was a single-centre, randomised, open-label, 5-way crossover study in 20 healthy adult subjects. Subjects received a single dose of DTG 50 mg as the phase 3 tablet and in 10 g of granule given: direct to mouth with no liquid; with purified water; with mineral water containing high caution concentrations (Contrex); or with infant formula milk. All formulations were administered in fasting state.

The study treatments were separated by seven days. Safety evaluations and serial PK samples were collected over 48 hours in each dosing period. The PK parameters of DTG were estimated using noncompartmental methods; geometric least squares (GLS) mean ratios and 90% CI were generated to compare treatments. Taste was assessed using a questionnaire that examined bitterness, sweetness and colour.

The investigators reported DTG exposures of the granule formulation were all moderately higher than the tablet formulation with or without liquids (55% – 83% and 62% – 102% for AUC 0-INF and Cmax respectively, see Table 1). Exposure was highest when the granule formulation was given with formula milk.

Inter-subject variability from the granule formulation was modest with a coefficient variation for AUC of 31-43%. DTG was well tolerated and there were no withdrawals due to AEs. The subjects rated the taste as acceptable for all treatments.

These data indicate that the DTG granule formulation can be given without restriction on the type of liquid or can be given alone. The taste was not considered to be a barrier to further development although the investigators noted that children’s preference could be different to that of adults. The granule formulation is being studied further in children in IMPAACT P1093.

Raltegravir

The integrase inhibitor raltegravir (RAL) is approved as a 400 mg film-coated tablet for use in adults and for children aged 6 to 18 weighing > 10 kg, and 100 mg and 25 mg chewable tablets are approved for children > 2 to <12 years old at a maximum dose of 300 mg. [2]

The paediatric programme is ongoing in IMPAACT P1066 and an oral granule formulation is being studied in the youngest children and babies. Stephen Spector and colleagues from the study team presented intensive PK, and preliminary 24 weeks safety and efficacy data from cohort IV – 6-month- to <2-year-olds – receiving the RAL oral granule formulation. [3]

Nine HIV-infected children were enrolled in a dose-finding study. Entry criteria included HIV RNA >1000 copies/mL and either prior ART experience PMTCT failure. The children received weight-based RAL oral granule suspension at ~6 mg/kg, every 12 hours.

Intensive PK was performed between day 5 and 12 after which the site investigators optimised the children’s background regimen. A dose was selected for continued study using an AUC12 hr targeted design (geometric mean [GM] target range of 14 to 25 uM*h) with C12h target to exceed the RAL IC95 (31 nM). Virologic suppression was defined as HIV RNA <400 copies/mL or ≥1 log drop from baseline at 24 weeks.

One child’s PK data were excluded due to absorption issues. Of the remaining 8 children: 67% were male; 78% black; mean (SD) age, 13 months (6.3); log10 RNA, 5.68 copies/mL (0.95); CD4 percent, 21% (9%); CD4 count, 1338 cells (822); weight, 8.3 kg (2.6), dose, 5.94 mg/kg (0.42).

The investigators reported geometric mean values of: AUC12hr, 20 uM*h; Cmax, 10.7 uM; and C12h, 115 nM. These PK values are achieved study targets and are similar to those observed in 2 to < 12 year old children receiving chewable tablets. Of the 9 children enrolled, 3 had 16 grade >3 adverse events of which 2 were considered related to RAL.

One child had grade 1 spitting up after taking the study drug.

• Patient 1: 3 low ANC and 7 reports of elevated lipase with concurrent acute Epstein-Barr virus (EBV) infection.
• Patient 2: dyspnea non drug-related; concurrent drug related elevated bilirubin and hypoglycaemia.
• Patient 3: low ANC, non drug-related.

At week 12, 78% (95% CI 40 to 97%) of the 9 children achieved virologic suppression. The children had a median gain in CD4 percent of 5% (95% CI –3 to 7%) and CD4 cells of 687 (95% CI –297 to 1237) cells/mm3 at week 12. By 24 weeks (n=7), 85% achieved virologic suppression and CD4 gain (n=8) was 5.3% (95% CI -4.0 to 18.8%) and 446 (95% CI 13 to 696) cells/mm3.

The 6 mg/kg every 12 hours dose was chosen for continued study in this age group.

Lopinavir/ritonavir

A sprinkle formulation of lopinavir/r (LPV/r) – Lopimune – has been in development by the generic manufacturer Cipla for some time. The sprinkle formulation (40/10 mg LPV/r) consists of a finite number of mini tablets in a capsule, which is opened and sprinkled on soft food.

Jaideep A Gogtay and colleagues showed results from a randomised crossover PK study in healthy adults comparing a single dose of sprinkles from 10 capsules of LPV/r and a single dose of 5 mL Kaletra oral solution (each mL containing 80 mg lopinavir and 20 mg ritonavir).

Both formulations were administered with about 150 g porridge and 240 mL water. Blood samples were taken pre-dose and serially up to 36 hours and were analysed using a validated LCMS/MS method. PK parameters were calculated using a non-compartmental method using drug concentrations versus time profile.

Twelve subjects completed the study (ie the minimum sample size acceptable to regulatory authorities). Their PK parameters are shown in Table 2.

For LPV the Ln-transformed 90% confidence interval of the least square mean of the LPV/r sprinkles and solution for the PK parameters AUC0-t and AUC 0-IFN fall within the conventional bioequivalence range of 80 -125% while for Cmax it falls just outside. For RTV AUC0-t and Cmax fall just outside the range but AUC 0-∞ falls within it. However, the investigators noted that the differences were not large. Based on this pilot PK study, the sprinkle formulation is now being studied in HIV-infected children.

comments

These data represent great strides in paediatric drug development and, if approved, these formulations will offer important treatment options for the youngest age group. Integrase inhibitors would mean a new therapeutic class for young children that might overcome some of the shortcomings of the currently available drugs. The sprinkle formulation of LPV/r, is now being studied in CHAPAS 2 and also as part of a programme by Drugs for Neglected Diseases initiative (DNDi) to come up with an affordable regimen appropriate for children under two.

Data to guide the dosing of children less 3 years for efavirenz (EFV), the preferred first line anchor drug for older children and adults, remains elusive. A poster at this meeting showed that CYP2B6 genotype strongly influences EFV PK and safety in this age group. [5] Aggressive dosing (~40 mg/kg) produced therapeutic EFV concentrations in most (68%) children less than 3 years with GG/GT genotype, however, this leads to excessive exposure in those with TT genotype. These data suggest that optimal use of EFV in children less than 3 years requires pretreatment genotyping, and the study protocol has been amended to include this at screening. A related poster showed data from model predicting the PK of EFV in children with different CYP2B6 genotypes, with simulations that indicate that genotype- guided dose optimisation could be used in paediatric patients. [6] Although EFV could be important for use in HIV/TB coinfected infants, complex genotype screening, the risk of resistance from NNRTI exposure in PMTCT and the probability that boosted PIs will be universally recommended in RLS make it an unlikely option in this age group.

For older children, Abbott has developed a low dose tablet of LPV/r (100/25 mg). Another paediatric PK poster showed data from a small study of 8 children aged 4.5 to 9 years designed to evaluate the comparability, efficacy, and tolerability in stable patients switching to this tablet from the oral solution. [7] PK analysis showed mean LPV AUC and Cmax ratios between liquid and tablet formulations to be 1.01 and 1.02, indicating that overall, the concentrations achieved with the different formulations were essentially the same.

And recently there have been some important FDA approvals including tenofovir and raltegravir for children two years of age and above and darunavir for those three years and above, which we reported in the February edition of HTB. [8, 2, 9] Also for etravirine for children of six and above, including a new scored 25 mg tablet for paediatric use (see later in this HTB). Paediatric approval from the EMA is awaited for these drugs and unlike the US tenofovir is not approved for the 12 to 18 years age group. For details see Table 3.

For RLS it is hoped that first line treatment for children above three can be aligned with adults and dosed according to weight bands with tenofovir/3TC/EFV using suitable FDCs. A further children’s PK poster showed that tenofovir given in combination with 3TC/EFV achieved comparable plasma exposure to that achieved in adults. [10] The investigators also noted that concerns remain about bone and renal toxicities with this drug.

A final poster on paediatric PK reported from a study revealing lower than expected darunavir and etravirine concentrations when the two were given together to older children and adolescents 11 years of age and above. [11] The study highlights both the importance of studying drugs in combination – to determine the contribution of drug-drug interactions – and in different populations, in this case to determine whether the results are age-related. Whether these findings will affect clinical response requires further study.

Overall the data presented at CROI (and recent FDA approvals) shows promise for paediatric HIV treatment in the near future.

References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle.

1. Patel P et al. Pharmacokinetics of a dolutegravir paediatric granule formulation in healthy adult subjects. Poster abstract 985.

http://retroconference.org/2012b/Abstracts/44121.htm

2. FDA approve US paediatric dose for raltegravir. HTB Volume 13 Number 1/2 January/February 2012.

http://i-base.info/htb/16103

3. Spector S et al. Raltegravir oral granules formulation in children 6 months to <2 Years of age: interim results from IMPAACT P1066. Poster abstract 987.

http://retroconference.org/2012b/Abstracts/45219.htm

4. Gogtay J et al. Pharmacokinetics of a novel formulation, lopinavir/ritonavir sprinkles meant for children in healthy human subjects: A pilot study. Poster abstract 982.

http://retroconference.org/2012b/Abstracts/44330.htm

5. Bolton C et al. Strong influence of CYP2B6 genotypic polymorphisms on EFV pharmacokinetics in HIV+ children <3 years of age and implications for dosing. Poster abstract 981.

http://retroconference.org/2012b/Abstracts/43250.htm

6. Siccardi et al. Pharmacokinetics of efavirenz dose optimisation in paediatric patients using an in vitro–in vivo extrapolation Model. Poster abstract 619.

http://retroconference.org/2012b/Abstracts/44316.htm

7. Piatt J et al. Pharmacokinetics in stable paediatric patients switching from liquid LPV/r to the paediatric 100/25-mg tablets: The Tiny Tabs Study. Poster abstract 983.

http://retroconference.org/2012b/Abstracts/44693.htm

8. Tenofovir label extended to paediatric indication. HTB Volume 13 Number 1/2 January/February 2012.

http://i-base.info/htb/16106

9. FDA approve paediatric dose for darunavir. HTB Volume 13 Number 1/2 January/February 2012.

http://i-base.info/htb/16101

10. Aurpibul L et al. Tenofovir pharmacokinetics when administered according to weight-band dosing in 15-kg HIV+ children receiving tenofovir/lamivudine/efavirenz once daily. Poster Abstract 984.

http://retroconference.org/2012b/Abstracts/43602.htm

11. King J et al. Low darunavir and etravirine exposure when used in combination in HIV+ Children and Adolescents. Poster abstract 986.

http://retroconference.org/2012b/Abstracts/43429.htm

Polly Clayden, HIV i-Base

Children with HIV in sub-Saharan Africa have significant morbidity and mortality risk from malaria. Interventions including bed nets and cotrimoxazole are not sufficient to decrease the risk in this population.

HIV and malaria parasites both encode aspartic class proteases, offering the possibility that HIV protease inhibitors (PIs) might have antimalarial properties. Furthermore, in vitro studies have demonstrated some activity against Plasmodium falciparum with PIs.

In an oral presentation, Jane Achan from Uganda presented findings from a study conducted by investigators from Makerere University College of Health Sciences and Infectious Diseases Research Collaborations in Kampala and the University of California, San Francisco, to compare the efficacy of lopinavir/ritonavir (LPV/r)-based and NNRTI-based ART regimens on malaria risk reduction in HIV positive children.

The study was a randomised open label trial of 170 children with a median age of 3 years of age (range 2 months to 6 years) conducted in Tororo, Uganda between September 2009 and July 2011. The children were either, ART-naïve (approximately 70%) and eligible for treatment, or receiving NNRTI-based ART and virologically suppressed (<400 copies/mL). They were randomised to receive either NNRTI- or LPV/r-based ART and followed for 2 years. All children received bed nets and cotrimoxazole and treatment for uncomplicated malaria with artemether- lumefantrine, the standard of care in Uganda and many African countries.

Following malaria diagnosis, the children attended the clinic on days 1, 2, 3, 7, 14, 21 and 28. Lumefantrine levels were measured on day 7 as this has been shown to be an independent predictor of malaria.

The analysis was ITT and the investigators compared the incidence of malaria between the study arms using Poisson regression. Dr Achan reported a 41% reduction in malaria associated with LPV/r-based ART, see Table 1.

PYAR= person years at risk

When the investigators looked at possible explanations for this reduction, they found a 29% non-significant direct effect of LPV/r on the children’s first episode of malaria HR 0.71 (95% CI 0.45-1.12), p=0.14. An evaluation of the risk of recurrent malaria following treatment with artemether-lumefantrine, however, found LPV/r associated with a 54% reduction in risk HR 0.4 (95% CI 0.22 -0.76), p=0.004.

Median lumafantine levels on day 7 were 926 (IQR 473 – 1910) ng/mL vs 200 (IQR 108 – 510) ng/mL in the LPV/r vs NNRTI arms respectively, p<0.001, which Dr Achan explained might be associated with the boosting effect of ritonavir.

Dr Achan summarised the possible reasons for the lower risk observed in the LPV/r arm as follows:

• PK effect of LPV/r on lumafantrine leading to a prolonged post treatment prophylaxis effect following treatment with artemether-lumefantrine.
• Direct antimalarial effect of LPV/r.
• Antiparasitic synergy between LPV/r and lumafantine.

She concluded: “This study highlights the possibility of pharmacoenhancement as a tool for reducing the burden of malaria in highly endemic settings.”

comment

These data are interesting. Conversations after the session suggested that this study adds to the argument for recommending LPV/r- based ART for all infants and young children, but the issue of resistance was also raised with one drug in a combination having a prolonged half-life.

Ref: Achan J et al. Significant reduction in risk of malaria among HIV+ children receiving lopinavir/ritonavir-based ART compared to NNRTI-based ART, a randomised open- label trial. 19th CROI, 5–8 March 2012, Seattle. Oral Abstract 26.

http://www.retroconference.org/2012b/Abstracts/43194.htm

Polly Clayden, HIV i-Base

Data describing lipodystrophy in children from sub-Saharan Africa are extremely limited. However use of d4T is widespread among children receiving ART in the region: in 2008 to 2009 approximately 90% of children on ART were taking d4T.

Two posters at CROI 2012 described substantial rates of lipodystrophy in South African children aged 3-12 and less than 2 years respectively.

Steve Innes and colleagues from the Children’s Infectious Diseases Clinical Research Unit (KID-CRU), Tygerberg Children’s Hospital and Stellenbosch University Cape Town performed a cross sectional study of 100 of 300 children on ART at the Tygerberg Family HIV Clinic and 34 HIV-negative controls. [1]

In this study, two clinicians graded fat changes visually using a standardised scale and a dietician took anthropometric measurements of trunk and limb fat. DXA was performed in a sub study of 42 patients and 34 controls. The duration of ART use was recorded.

Using linear regression models the investigators compared fat distribution captured by DXA and anthropometrics among children who were HIV negative, HIV positive with lipoatrophy and HIV positive without lipoatrophy, adjusted for age and sex. The risk factors for clinical lipoatrophy were evaluated by logistic regression.

This reported prevalence of lipoatrophy was 36% (95% CI 26 – 45%). DXA and anthropometrics confirmed significant, substantial extremity fat loss in children with clinical lipoatrophy.

Mean adjusted DXA total limb fat was 2.7 kg (95% CI 2.4 – 2.9), 1.7 kg (95% CI 1.4 -2.1) and 2.3 kg (95% CI 2.1 – 2.6) in HIV negative, HIV positive with lipoatrophy and HIV positive children without lipoatrophy respectively, p = 0.001. Limb fat vs limb lean ratios were respectively, 0.63 (0.56 – 0.7), 0.36 (0.25 – 0.46) and 0.62 (0.54 – 0.7), p = 0.0001.

Mean adjusted anthropometrics found biceps skin-fold thicknesses of 5.5 mm (5.0 – 5.9), 4.2 mm (3.6 – 4.7) and 5.3 mm (4.9 – 5.7), in HIV negative, HIV positive with lipoatrophy and HIV positive children without lipoatrophy respectively, p <0.0001. Triceps skin-fold thicknesses were respectively 8.7 mm (8.1 – 9.4), 7.1 mm (6.2 – 7.9) and 8.9 mm (8.3 – 9.6), p <0.0001.

The investigators noted that diagnosis by visual grading correlated well with anthropometry and DXA, which are not commonly available in developing countries.

In multivariate analysis, controlling for age, sex and CD4 percentage, the greatest risk factor for clinical lipoatrophy was duration of d4T use, p=0.0008. Cumulative d4T use was also associated with reductions in biceps and triceps skin-fold thickness, p=0.008. Each additional year of accumulated d4T exposure gave an odds ratio of 1.9 (95% CI 1.3 – 2.9), p=0.002.

The investigators wrote: “The prevalence of lipoatrophy is higher in our cohort than non-African cohorts. Our data identify cumulative d4T exposure as the greatest risk factor for lipoatrophy, highlighting the urgent need for all children to transition to alternative medication.”

Stephanie Shiau and colleagues from the NEVEREST study team described the prevalence of lipodystrophy and associated patterns of regional fat distribution and metabolic alterations in young children who had started ART at less than 2 years of age. [1]

They performed an evaluation of 156 vertically infected children who started ART at Rahima Moosa Mother and Child Hospital, Johannesburg with lopinavir/ritonavir (LPV/r) + 3TC + d4T, and were randomised to either continue LPV/r (n = 85) or switch to nevirapine (NVP) (n = 71), while continuing 3TC + d4T. This was done on exit from the NEVEREST 2 trial after approximately 4 years on ART.

Clinicians assessed the children visually for signs of lipodystrophy, including lipoatrophy and lipohypertrophy. Anthropometrics, bio-impedance analysis, viral load, CD4, fasting total cholesterol, HDL, LDL, and triglycerides were measured. Measurements of regional fat – including trunk-extremity skin-fold ratios were estimated. Outcomes were compared across lipodystrophy groups defined as, lipodystrophy, possible lipodystropy and no lipodystrophy.

The investigators used multiple linear regression to access differences in arm, trunk and leg fat across lipodystrophy groups, adjusted for total fat, sex and age.

They found, of 156 children with a mean age 5.1 who initiated ART at a mean age of 10.7 months, 13 (8.4%) children were defined as having lipodystrophy, 18 (11.5%) as having possible lipodystophy and 125 (80.1%) as no lipodystrophy. All 13 children defined as having lipodystrophy had lipoatrophy and 6 also had signs of lipohypertrophy.

There were no differences in age, sex, age at ART initiation, duration of ART, weight-for-age z-scores, height-for-age z-scores, body mass index, or proportion of children with a viral load <50 copies/mL among the three lipodystrophy groups.

There was no difference in the proportion of children with lipodystrophy between those who remained on LPV/r and those who switched to NVP, respectively 7.1% vs 9.9%, p=0.51.

The children with lipodystrophy had significantly less body fat than children with no lipodystrophy, measured by mean (+SD) skin-fold sum, 34.1 mm (+5.7) vs 42.0 mm (+11.1), p=0.0016. Children with lipodystrophy had greater trunk-arm 0.53 mm (+0.07) vs 0.50 mm (+0.05), p=0.028 and trunk-leg skin-fold ratios 0.61 mm (+0.07) vs 0.55 mm (+0.06), p=0.004, than children without lipodystrophy.

Lipid concentrations were similar across groups, except for mean triglycerides level which was greater for children with lipodystrophy compared to those without, 101 (+45) vs 80 (+34) mg/dL, p= 0.045. The proportion of children with triglycerides >150 mg/dL was greater for children with lipodystrophy and those with possible lipoystrophy compared to those without, respectively 23.1% vs 4.8% and p=0.04 22.2% vs 4.8%, p=0.023.

“A substantial portion of young children who initiated d4T-containing ART before two years of age have lipodystrophy as classified by clinical criteria…” the investigators concluded, adding: “Lipodystrophy can be cosmetically stigmatising and adversely affect adherence to ART. Finding a substantial proportion of young children with lipodystrophy has implications for future adherence, especially during adolescence when awareness of physical appearance is greatly heightened.”

comment

These reports are concerning and the rate reported by Innes et al particularly is high compared to other (generally anecdotal) reports from other parts of Africa. This may be because children were properly evaluated, although it is not clear whether there was blinding to laboratory results when the clinical diagnosis was made but visual grading correlated well with anthropometry and DXA.

In South Africa, where FDCs are not generally used, the 1 mg/kg doses of d4T will usually be rounded up using stand alone products resulting in a dose at least equivalent 40 mg in adults (Steve Innes, personal communication), so the effects might be less or occur over a longer duration of exposure with a lower dose.

This possibility in children has been used to argue for a controversial study in adults, of lower dose (20 mg) d4T, which, the investigators hope, will mitigate the drug’s toxicity. As is usual in adult studies, Innes et al indentified “cumulative d4T exposure as the greatest risk factor for lipoatrophy” and since d4T toxicity is both dose and time dependent – as we have stated before – it seems most unlikely that this could be reduced to acceptable levels in this way and there are better solutions on the horizon. [3, 4, 5]

A Thai study suggests that some lipodystrophy in children may be reversible after substitution with another NRTI and results from CHAPAS 3 will clarify whether this occurs. [6] But for the proportion for whom it is not reversible, as Shiau et al wrote, this can be stigmatising and adversely affect adherence to ART, particularly during adolescence when awareness of physical appearance is particularly sensitive (though when is it not?). Adult guidelines have for many years stressed that lipoatrophy is better to avoid than to treat. Children should also therefore be protected from this side effect.

References

1. Innes S et al. High prevalence of objectively verified clinical lipoatrophy in pre-pubertal children is associated with stavudine—the clock is ticking: sub-Saharan Africa. 19th CROI, 5–8 March 2012, Seattle. Poster abstract 972.
http://www.retroconference.org/2012b/Abstracts/42742.htm
2. Shiau S et al. Lipodystrophy syndrome in young HIV+ children who initiate ART before 2 years of age: South Africa. 19th CROI, 5–8 March 2012, Seattle. Poster abstract 973.
http://www.retroconference.org/2012b/Abstracts/43141.htm
3. Andrieux-Meyer I et al. Why it’s time to say goodbye to stavudine … everywhere. Southern African Journal of HIV Medicine, Vol 13, No 1 (2012).
http://www.sajhivmed.org.za/index.php/sajhivmed/article/view/813
4. Venter WDF et al. Low-dose stavudine trials: a public health priority for developing countries. Southern African Journal of HIV Medicine, Vol 13, No 1 (2012).
http://www.sajhivmed.org.za/index.php/sajhivmed/article/view/812
5. Innes S et al. Why should we still care about the stavudine dose? Southern African Journal of HIV Medicine, Vol 12, No 4 (2011).
http://www.sajhivmed.org.za/index.php/sajhivmed/article/view/778
6. Aurpibul L et al. Recovery from lipodystrophy in HIV-infected children after substitution of stavudine with zidovudine in a non-nucleoside reverse transcriptase inhibitor- based antiretroviral therapy. Pediatr Infect Dis J. 2012 Apr;31(4):384-8.

Polly Clayden, HIV i-Base

Induction/maintenance strategies in children are frequently discussed but underexplored and documented.

A poster authored by Pope Kosalaraksa and colleagues from the HIV-NAT 077 study team showed week 144 results for virlogically suppressed Thai children switching to lopinavir/ritonavir (LPV/r) monotherapy.

In this study children with two consecutive viral load results <50 copies/mL at least 3 months apart while receiving double PI-containing second line regimens for at least 12 months were switched to LPV/r monotherapy. Virological failure was defined as two viral load results >500 copies/ mL or three of >50 copies/mL. Children failing LPV/r monotherapy resumed treatment with their previous double PI regimen. The primary endpoint was the proportion of children with virological suppression <50 copies/mL at 144 weeks.

There were 40 children enrolled in the study, of which 90% received saquinavir as their second PI and the remainder indinavir. 3TC was used by 28%, AZT by 10% and EFV by 5%. At the time of enrollment the children were a median age of 11.7 (IQR 10.2-13.5) years, weight of 29.4 (IQR 24.1 – 40.20) kg and CD4 percentage 27% (IQR 23.5-29.5%) cells/mm3.

None of the children had disease progression over 144 weeks of follow up, one child died in a car accident and two were lost to follow up.

At 144 weeks 31/37 (83.8%) were virologically suppressed. The proportion of children remaining on monotherapy with virological suppression was 22/24 (92%). Eleven children experienced virological failure with lopinavir monotherapy with a median viral load measurement of 1740 (IQR 598-21,450) copies/mL. No major LPV/r mutations (L10F, M46I, L76V, V82A) were reported among 10/11 children who failed and genotype testing. When they resumed their previous double PI regimen, 7/11 (63%) children had virological suppression at week 144.

In multivariate analysis viral load at switch to LPV/r monotherapy of >50 copies/mL was the only predictor of failure, OR 4.4 (95% CI, 1.3-14.8). Although all children had <50 copies/mL at screening, 10% had >50 copies/mL at baseline. Sex, CDC class, CD4 percent nadir, CD4 percent at switch and adherence by pill count were not associated.

There were no significant changes in CD4 percent, fasting cholesterol, triglyceride, and glucose from baseline. The investigators noted that frequent viral load monitoring is needed for early detection of virologic failure with this strategy.

comment

This study shows a high rate of failure in about a third of children who switched to LPV/r monotherapy. Whether there are children that could benefit from this induction/maintenance strategy (probably not treatment experienced) remains an interesting question in RLS, where starting with a LPV/r-containiing regimen in infancy is gaining momentum in settings with concerns about cost and NRTI toxicity.

Looking at darunavir/r monotherapy vs darunavir/r in a triple regimen and also once vs twice daily is currently under discussion for PENTA 17.

Ref: Kosalaraksa P et al. Lopinavir/ritonavir monotherapy in HIV+ children; week 144 results. 19th CROI. Seattle WA. March 5-8 2012. Poster abstract 962.

http://www.retroconference.org/2012b/Abstracts/43511.htm

Polly Clayden, HIV i-Base

In an oral late breaker, Mark Cotton presented the final results from the Children with HIV Early Antiretrovirals (CHER) trial.

Interim results from CHER, announced in 2007, demonstrated the need for early ART in HIV-infected infants and influenced guidelines worldwide. The standard of care is now universal treatment for infants less than one year (and in WHO guidelines in children up to two years), initiated as early as possible.

In the study, infants <12 weeks of age with CD4 percent >25% were randomised to receive deferred ART (ART-Def), immediate ART stopping after 40 weeks (ART-40W) or immediate ART stopping after 96 weeks (ART-96W). The recommendation that enrolment to ART-Def cease and all children be assessed to start ART was made by the DSMB in June 2007, as starting ART immediately reduced deaths by 75%. All children received treatment with lopinavir/ritonavir (LPV/r) + 3TC + AZT.

Treatment initiation in the deferred arm and re-initiation in the other two were in accordance with previous WHO guidance at a threshold of CD4 percent <25% in infants and <20% after infancy or with clinical disease progression. The primary endpoint was death or progression to CDC severe B or CDC C disease. All analyses were intent-to-treat using time-to-event methods.

A total of 377 infants were enrolled in CHER between 2005 and 2007. They were a median age of 7.4 weeks with a CD4 percent of 35% at baseline and 341 (91%) completed the study. Median follow up was 249 weeks (4.8 years) and the maximum was 309 weeks (5.9 years). The overall proportion of follow up time on ART in the three study arms were 81%, 70% and 69% in ART-Def, ART-40W and ART-96W respectively.

Approximately 75% in the ART-40W and 65% in the ART-96W arms re-initiated treatment by 240 weeks. The median time to starting ART in ART-Def was 20 (IQR 16-25) weeks and to restarting ART after interruption in ART-40W and ART-96W was 33 (IQR 26-45) and 70 (IQR 35- 109) weeks, respectively. Difference between the two deferred arms was 37 (95% CI -11 to 85) weeks, p=0.13. By the end of the trial only 7 children had switched to second line antiretroviral therapy.

When the investigators looked at the total primary endpoints in the study they found 39 (25%) in ART-Def, 31 (25%) in ART-40W and 25 (20%) in ART 96-W. This was mainly due to at least double the number of deaths in ART-Def compared to the other two arms: 22 (18%), 11 (9%) and 9 (7%) in ART-Def, ART-40W and ART-96W respectively. Dr Cotton noted that there were no cases of regimen limiting toxicity.

Time to primary outcome compared to ART-Def, showed 23% fewer events in ART-40W, 42% fewer in ART-96W and 35% fewer in the two arms combined. Hazard ratios (HR) relative to ART-Def were ART-40W, 0.73 (95% CI 0.46-1.17), p=0.19; ART-96W, 0.58 (95% CI 0.35-0.96), p=0.05 and ART-40W/ ART-96W 0.65 (0.43 – 0.98), p=0.04.

Progression to CDC B or C or death was also reduced by 50% and 60% respectively. HR relative to ART-Def were ART-40W, 0.5 (95% CI 0.3-0.8), p=0.005 and ART-96W and 0.4 (95% CI 0.3-0.7), p=0.0003. There were 43, 27 and 18 events in the ART-Def, ART-40W and ART-96 arms respectively. For encephalopathy there were 9, 5 and 2 events.

When the investigators compared the ART-40W and ART-96 arms – including 34 additional children included after ART-Def stopped enrollment (n=143 in each remaining arm) – there was no difference between the two in time to primary outcome, HR 0.84 (95% CI 0.51 – 1.4), p=0.49. The majority of deaths in both arms occurred early, during the initial period of ART.

At the end of the trial 30 (25%) children in ART-40W and 46 (33%) in ART-96W never started continuous ART and CD4 percent was a median of approximately 30% in both arms.

Dr Cotton concluded that treatment during early infancy protects against HIV-related high mortality and morbidity and ART interruption after infancy appeared to be safe. But further analyses of virologic suppression and resistance and immunological response to restarting and interrupting treatment are needed.

comment

Stopping treatment in infants who receive ART during acute infection appeared to be safe in CHER. Although Andy Prendegast questioned the value of the short duration off treatment before restarting (33 and 70 weeks after 48 and 96 weeks of early ART respectively), in his excellent overview exploring “controversies and consequences of early initiation” of ART in infants. [2]

Conflicting results to those from CHER were reported from The Optimising Paediatric HIV-1 Therapy 03 (OPH03) Study – a randomised trial of continued vs interrupted treatment in infants with CD4 >25%, following at least 24 months of ART and restarting if CD4 dropped to 25% – which was stopped by the DSMB due to the high proportion of children restarting by three months. [3] In this study, 42 children were randomised (21 in each arm) and 18/21 in the interrution arm (86%) restarted, the majority (14/21) before 3 months. The children in OPH03 differed from those in CHER in that they were initially treated with ART at a median of about 5 months of age with a lower pre- ART CD4 percentage. However although lower CD4 percentage at randomisation was predictive of starting treatment after <3 months (p=0.04 vs > 6 months) but neither age at ART or pre-ART CD4 were (both p=0.7).

Dr Prendegast questioned whether one or two years early treatment was enough and noted that there was no comparison to early continuous ART.

Emphasising the controversies, a speaker from the floor declared he was “shocked” that treatment interruptions were even being considered in children and suggested such an approached belonged in the “middle ages”.

References

1. Cotton M et al. Early ART followed by interruption is safe and is associated with better outcomes than deferred ART in HIV+ infants: final results from the 6-Year randomised CHER trial, South Africa. 19th CROI, 5–8 March 2012, Seattle. Oral abstract 28LB. http://www.retroconference.org/2012b/Abstracts/45459.htm
2. Prendergast A. ART for the HIV+ infant: controversies and consequences of early initiation. Symposium abstract. 113. http://www.retroconference.org/2012b/Abstracts/45282.htm
3. Wamalwa D et al. Treatment interruption in infants following 24 months of empiric ART: Kenya. Oral abstract 27. http://www.retroconference.org/2012b/Abstracts/43855.htm

Revised annually, this free guide is an introduction to treatment for people who are newly diagnosed, thinking of starting treatment or already on treatment. This non-technical resource is based on national and international treatment guidelines and is written in every day language.

The guide includes information on how treatment works, when to start, treatment choice, adherence, resistance, avoiding side effects and includes a full colour pill chart.

The guide is also already online, together with further reading, appendices and references that are not included in the print edition. Additional copies are free – please order in the usual way (online, by email or fax-back the back page of HTB). We welcome feedback on this guide and this short online survey includes space for comment:

http://www.surveymonkey.com/s/978R8F9

This issue largely features our first coverage from the annual Conference of Retroviruses and Opportunistic Infections, which this year attracted over 4000 delegates to Seattle.

Much of the conference is available as web casts on the conference website and references in HTB also link to the study abstracts. Further coverage will continue in the next issue, with pre-press articles available online.

Simon Collins, HIV i-Base

Introduction

New research at CROI suggested that protection against HIV could be close to 100% from daily TDF/FTC (Truvada) and this should change previous reservations about PrEP as an intervention. [1]

In some studies, daily Truvada dramatically reduced the incidence of HIV infection, especially in high-risk individuals, (by 42% in MSM in the iPrEX study) but produced conflicting results in other studies (notably the FEM-PrEP study in heterosexual African women).

All studies have proved complicated to interpret due to the high rates of self-reported adherence but the likely very low rates of actual adherence demonstrated in PK sub-studies finding low levels of tenofovir and FTC in both active and placebo arms. The projected efficacy of PrEP increased dramatically when PK results were taken into account (to 92% in iPrEX). [2]

This proven protection could potentially increase real-life adherence compared to that seen in historical studies. If someone knows they will be protected rather than being a participant in a placebo controlled trial, and that this protection is so effective it could eliminate the risk of HIV, this could change the pattern of low use, even in less adherent patients.

PrEP studies are further complicated by the differences in pharmacokinetic properties of individual drugs, by differences in absorption of each drug in the male and female genital tract as well as in rectal tissue, and by the intracellular concentration of the active metabolites at each sites. Differences between human and animal drug absorption may limit how closely efficacy against vaginal and rectal exposure can be interpreted from macaque studies.

At CROI new modeling data showed that the protection from PrEP may be even greater than previously thought. The report that protection approaches 100% argues for new considerations for how PrEP might be incorporated as a health intervention.

Other studies at the meeting addressed some of the concerns for why PrEP has not been universally protective in other some studies.

iPrEX: modeled prediction of 99% protection with daily adherence

Peter Anderson and colleagues presented a late breaker oral PK analysis of intracellular drug concentrations in the iPrEX study and correlated this with levels of adherence in the Strand Study. [1]

This group used regression model to estimate efficacy of PrEP based on intracellular levels of tenofovir diphosphate (TDF-DP) in viable PBMCs from 48 cases matched to 144 uninfected controls. The researchers then established TDF-DP levels achieved on observed therapy of 2, 4 and 7 day dosing in a separate PK study of 24 HIV negative volunteers (the Strand study). Finally, they used the iPrEX regression models from i-PrEX on the Strand study data to estimate PrEP efficacy based on 2, 4 and 7 day dosing.

In iPrEX, detectable tenofovir levels in either plasma or cells was seen to have steadily fallen from baseline to time of infection, to only 8% of cases (at infection) compared to approximately 40% of uninfected controls. In the month prior to infections these rates were 11% vs 50% respectively suggesting that infections occurred during periods of low drug exposure.

In the Strand study, dosing 2, 4 and 7 days a week produced median (IQR) levels (fmol/million cells) of TDF-DP of 11 (6-13), 32 (25-39) and 42 (31-47) respectively. This compared to levels of 11 fmol/M (4-11) in 8% of iPrEX cases with detectable TDF and 16 fmol/M (9-47) in the 44% of controls with detectable levels. Daily dosing could be imputed from drug levels for 18% of iPrEX controls (and that 82% controls were likely to be taking less than daily dosing).

Regression modelling produced and estimated EC90 of 16 fmol/M viable cells (95%CI 3-28) with sensitivity estimates of less than 23 fmol/M producing estimates for risk reduction of 76% (56-96%), 96% (90->99%) and 99% (96->99%) for 2, 4 and 7 day dosing (see Table 1).

comment

This study involved 615 v-PBMC and 1146 plasma samples were tested from 1212 time points (302 cases, 910 controls) but limitations include that drug levels were only proximal to time of exposure and that the impact of FTC levels were not studied.

The confidence intervals for the target IC90 of ≥15.6 fmol/M viable cells (95%CI 3.0 to 28.2) appears wide and this should be confirmed in future studies.

Partners PrEP: protection in serodifferent heterosexual couples

Jared Beaten and colleagues presented updated results from the randomised Partners PrEP Study, a randomised placebo controlled study of both TDF/FTC and TDF only in 4758 negative partners of HIV positive people who were not yet eligible for ARV therapy. [3]

The study was conducted in nine urban and rural sites in Kenya and Uganda. HIV negative partners were seen monthly for HIV testing, adherence and prevention counselling and HIV positive partners were seen every three months and approximately 20% in each arm started ARV treatment when recommended by national guidelines.

The placebo arm was discontinued in July 2010 following a recommendation by the study DSMB and those preliminary results had already been presented. Placebo arm participants were then randomised to either of the active arms and follow up continues until December 2012.

Approximate baseline characteristics for the negative partner included: just over 60% male; median (IQR) age 33 years (28, 40; with 11% less than 25 years). Although the median (IQR) duration of partnership was 7 years (3, 14) the time they had know about their partners HIV status was only 4-5 months (0.1, 2.0 years). Median CD4 count of the positive partner was almost 500 cells/mm3 (IQR 375, 660).

Study retention was greater than 95% with median follow up of 23 months (IQR 16 – 28, range 1-36). This involved more than 7800 person years of follow up (PYFU) and >99,000 study visits, with >95% dispensing of study meds.

Of the 96 new HIV diagnoses in negative partners, 14 were found to be in acute infection at baseline by retrospective PCR testing after HIV seroconversion, leaving 82 acquisition events in the primary study. Of these, 17 occurred in the TDF arm vs 13 in the TDF/FTC arm vs 52 in the placebo arm giving incidence rates/100 PYFU of 0.65, 0.50 and 1.99 respectively. This produced highly significant protection rates of 67% (95%CI 44-81%) and 75% (95%CI 55-87%) compared to placebo, in the TDF and TDF/FTC arms respectively (both p<0.0001). There were no significant differences between the two active arms (p=0.23) and both ruled out the predefined lower efficacy of -30%.

Although 60% of the negative partners were men, 45/82 infections occurred in women (n= 8 vs 9 vs 28; incidence 2.81 in women vas n=9, 4 and 24; incidence 1.49 in men; in single vs dual vs placebo arms respectively. Protection was seen for both men and women with non statistically significant differences for the differences in the results observed in men vs women (p=0.65 for single and p=0.24 for dual PrEP (see Table 2)

There were no differences between serious adverse events between arms including placebo (7% each arm) or confirmed laboratory abnormalities (each arm had <1% grade 2 or higher creatinine increase, 9% phosphorus decrease). During the first month there was significantly more mild nausea or fatigue in the active arms but these became similar to placebo rates at later time points.

Although there was one person with K65R tenofovir mutation and one person with M184V FTC mutation in the people with confirmed acute infection at baseline, no mutations were detected in infections from the main study. Four cases of NNRTI resistance was seen indication transmission of resistant virus.

About one third of participants reported additional sexual partners (41% men, 9% women)

PK results for drug levels of tenofovir in each of the active arms in the Partners in PrEP study were presented in a second oral presentation by Deborah Donnell. [4]

This study used the 29 cases (n=17 single arm, n=12 dual arm) compared to drug levels in 100 uninfected controls from each arm, using multiple samples throughout the study (at months 1, 3, 6, 12, 18, 24, 30, and 36. Drug levels were tested using LCMS with lower limit of quantification of 0.3 ng/mL. Based on other studies tenofovir would be detected for nine days after a single dose and tenofovir levels at steady state from daily dosing would be >40 ng/mL.

Tenofovir was detected in >80% of samples in uninfected controls compared to 56% of samples of cases and in only 31% (6/17) of single arm and 25% (3/12) of dual arm samples at the seroconversion visit. This produced relative risk reduction associated with detectable drug of 86% (95%CI 57%, 95%; p<0.001) and 90% (95%CI 56%, 98%; p=0.002) in the single and dual arms respectively. Only 4/9 cases of infections with detectable drug had levels > 40 ng/mL consistent with high adherence.

Patterns of adherence in controls suggested than non- or poorly adherent patients did not change their adherence of the study. By contrast, about 50% of highly adherent patients maintained this through the study but 25% either dropped to lower adherence and 25% to non-adherence.

Several other analyses were presented from the Partners in PrEP study at CROI. These included:

• A report on nearly 300 pregnancies during the study, with similar rates in each of the three arms and no safety concerns, and suggesting a specific use for PrEP in serodifferent couples wanting to have a baby. [5]
• Details of ARV update in the 817 positive partners whose CD4 count declined during the study making them eligible to start treatment, with only 420 (55%) initiating treatment. Factors included reluctance to start, loss to follow up and unavailability of treatment. [6]
• High (>90%) positive acceptance to use PrEP amongst negative partners with lower, but still high (60%) interest from positive partners in earlier treatment as prevention. [7]
• Implications from PrEP protection on the rate of false positive results from rapid tests. From over 99,000 tests, 266 were positive on dual rapid tests. Of these, 37% (99/266) were confirmed true positive by ELISA, 58% (155/266) were false positive by ELISA and 4.5% (12/266) were indeterminate. False positives were more common in the active arms 69% (110/159) vs 45% (45/107) in the placebo arm due to the lower incidence of HIV. [8]
• Modelling factors for a risk score to determine the population characteristics for most effective use of PrEP as an intervention. [9]

Why PrEP did not work in FEM-PrEP

Another late breaker oral presentation provided results from the FEM-PrEP study in which daily TDF/FTC (Truvada) used as PrEP was not effective. The FEM-PrEP study, which had enrolled just over 2000 of the planned 3900 participants was closed in April 2011 due to lack of efficacy between daily TDF/FTC compared to placebo in over 2000 African heterosexual women.

The DSMB recommended stopping the study when the study was only half way through enrollment when 28 infections had been seen in each arm. More pregnancies occurred and side effects were also higher in the active arm.

The final results from the study were presented at CROI by Lut Van Damme and colleagues. [10]

Baseline characteristics included approximately 60% younger than 25 years, 50% condom use, 13% had transactional sex with other than primary partners. However, 70% of participants thought they were at low risk for HIV, but 15% had Chlamydia and 6% had gonorrhoea at screening. Women had sex on average four times a week (mean 3.7, range 0-28).

Of 68 infections occurring during the main study, 33 infections occurred in the active arm (incidence rate, 4.7/100 person-years) and 35 in the placebo group (IR, 5.0/100 person-years), with an estimated hazard ratio (HR) for infection of 0.94 (95%CI 0.59 to 1.52, p = 0.81). Although seven infections were discounted due to lack of product at the study clinic, a sensitivity analysis censuring women at last date of product use did not change the main results (HR 0.82; 95%CI 0.49-1.36, p=0.44).

Tolerability generally good with no grade 3 events but included more nausea in the active group.

There were five cases of FTC-associated resistance (one in the placebo arm) but no cases of resistance to TDF.

As with other PrEP studies, adherence rates were very high by self-report (>95%) and pill count (~90%) but a pharmacokinetic analysis in a case-control sub study indicated that this was at best likely to be 20-30% in either arm, with detection lower in cases vs controls. Adherence levels below 50% in each arm also removed the power of this study to be able to detect a real impact of the active arm.

Of interest, an opinion piece by Anneke Grobler and colleagues in the 13 March edition of AIDS on the design challenges for future prevention studies includes a table that calculates projected effectiveness found with different levels of true efficacy of the comparator and new intervention in combination with different adherence levels. [11]

comment

Although the lack of protection in this study was assigned to low adherence, this may be more complex as adherence was also low in iPrEX. This may also involve the baseline risk of participants and perception of risk, perhaps explaining the differences seen in other heterosexual studies such as TDF-2.

There may also be implications by gender related to pharmacokinetic and intermittent adherence highlighted in macaque studies, including the poster reported below.

Intermittent TDF/FTC (Truvada) in macaques: vaginal, cervical and rectal tissue and cell PK

Jessica Radzio and colleagues from the CDA in Atlanta presented results from a pharmacokinetic study in macaques. [12]

This study was important for studying both tenofovir and FTC in tissue site and intracellular levels. Both drugs peaked – at two hours in plasma and five hours in vaginal secretions – and then declined to low levels at 24 hours. In rectal secretions, levels increased more slowly and steadily, only peaking at 24 hours but then remaining high for at least 24 hours.

This aspect of the PK profile in macaques is comparable to that seen in women. The group then looked at active intracellular levels of the active metabolites of each drug, FTC-TP and TFV-DP.

FTC drug levels were very similar in vaginal, cervical, rectal and lymphoid tissue compared to cell biopsies with vaginal:rectal ratio of 1.04 in cells and 2.10 in tissue at 24 hours. This was similar for cervical:rectal ratios. However levels of tenofovir in vaginal, cervical and lyphoid tissue, both in tissue and cells was dramatically lower, while remaining high in rectal tissue and cells, with vaginal:rectal tissue concentrations ratios dropping to 0.04 for intracellular levels and 0.02 in tissue, with similar results for cervical:rectal ratios (0.04 and 0.03 respectively).

The group then looked at whether these levels would be sufficient for vaginal exposure in six macaques following oral dosing and repeat low dose exposure weekly for up to 18 weeks (through four menstrual cycles) to SIV to approximate to human sexual exposure, with six macaque controls. TDF/FTC or placebo was given 24 hours before or two hours after exposure. All control animals became infected quickly, mainly in the first menstrual cycle but none of the active macaques receiving intermittent TDF/FTC became infected over 18 weeks suggesting that the lower PK may be protective even with intermittent PrEP to prevent vaginal transmission.

This study reported a pattern of ratio (rather than absolute concentrations) suggesting this validates the macaque model for future studies. Although this study only looked at -24 plus +2 hour dosing for vaginal exposure, the rectal macaque studies emphasised the +2 hour dose to be essential and the protection from the pre-exposure dose extended from 1 to seven days. However dosing only 2 hours before exposure correlated with significantly reduced protection, though this was still higher than if no pre-exposure dose was given.

comment

The potential for close to 100% protection against HIV infections with alternate or daily dosing should prompt pilot programmes that include access to this option in individuals who are at the highest risk for HIV.

For many people, higher risk behaviour and vulnerability to infection may be associated with a relatively short period of someone’s life. Whether this is a period of weeks, months or several years, the option to use an oral prophylaxis when other prevention methods are unlikely to be used, can prevent the complications of life-long infection and treatment.

TDF/FTC (Truvada) has already been submitted to the FDA for an indication for use as PrEP with a decision expected later this year.

References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle.

1. Anderson P et al. Intracellular tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19th CROI 2012, Seattle. Oral late breaker abstract 31LB.

http://www.retroconference.org/2012b/Abstracts/45431.htm

2. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 23 November 2010 (10.1056/NEJMoa1011205). Freeaccess:

http://www.nejm.org/doi/full/10.1056/NEJMoa1011205

3. Baeten J et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th CROI 2012, Seattle. Oral abstract 29.

http://www.retroconference.org/2012b/Abstracts/43082.htm

4. Donnell D et al. Tenofovir disoproxil fumarate drug levels indicate PrEP use is strongly correlated with HIV-1 protective effects: Kenya and Uganda. 19th CROI 2012, Seattle. Oral abstract 30.

http://www.retroconference.org/2012b/Abstracts/43156.htm

5. Mugo N et al. Pregnancy Incidence and birth outcomes among in a clinical trial of PrEP: Uganda and Kenya. 19th CROI 2012, Seattle. Poster abstract 1060.

http://www.retroconference.org/2012b/Abstracts/43083.htm

6. Mujugira A et al. Barriers to ART initiation among HIV-1+ individuals: East Africa. 19th CROI 2012, Seattle. Poster abstract 649.

http://www.retroconference.org/2012b/Abstracts/43075.htm

7. Heffron R et al. Preferences for and willingness to use ARV-based HIV-1 prevention strategies among HIV-1 serodiscordant couples: Kenya. 19th CROI 2012, Seattle. Poster abstract 1065.

http://www.retroconference.org/2012b/Abstracts/43127.htm

8. Ndase P et al. Frequency of false positive HIV rapid tests in a cohort of men and women receiving PrEP—implications for programmatic roll-out: Kenya and Uganda.19th CROI 2012, Seattle. Poster abstract 1058.

http://www.retroconference.org/2012b/Abstracts/43085.htm

9. Kahle E et al. An empiric risk-scoring tool for identifying high-risk heterosexual HIV-1 serodiscordant couples for targeted HIV-1 prevention. 19th CROI 2012, Seattle. Poster abstract 1102.

http://www.retroconference.org/2012b/Abstracts/43883.htm

10. Van Damme L et al. The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. 19th CROI 2012, Seattle. Oral late breakerabstract 32LB.

http://www.retroconference.org/2012b/Abstracts/45406.htm

11. Grobler AC, Abdool Karim SS. AIDS: 13 March 2012 – Volume 26 – Issue 5 – p 529–532.

http://journals.lww.com/aidsonline/Fulltext/2012/03130/Design_challenges_facing_clinical_trials_of_the.1.aspx

12. Radzi J et al. Intermittent oral PrEP with Truvada prevents vaginal SHIV transmission in macaques. 19th CROI 2012, Seattle. Poster abstract 1086.

http://www.retroconference.org/2012b/Abstracts/42869.htm

Simon Collins, HIV i-Base

The risk of HIV reinfection, sometimes called superinfection, has not been clearly established. Given the risk of initial sexual HIV infection from a single exposure in population studies is commonly calculated as generally low (although these estimates are dependent on the background prevalence) this is difficult to assess in small studies.

Genetic analysis is specialised and expensive and the biological evidence is strongly supported by the many viral sub-clades and recombinant forms that can only have occurred in vivo. The extensive global viral diversification provides the most practical evidence for reinfection.

Case studies have highlighted cases where reinfection with drug resistant HIV has clinical implications leading to either more rapid disease progression or treatment failure and reduced future treatment options. Although initial reports were in early or acute initial infection, cases have also included people in chronic infection, indicating that this may not be restricted by immune responses to the initial infection and in people on suppressed ART, indicating that the pressure from PrEP/PEP can also be overcome.

Three studies at CROI focused on issues of reinfection.

Andrew Redd and colleagues from the US NIH and Johns Hopkins University used high-throughput deep sequencing to retrospectively test for HIV superinfection in two regions of the viral genome (p24 and gp41) in 203 people from the Rakai Community Cohort Study (RCCS) in Uganda, who seroconverted from 1997-2002 with later samples for a total 15,000 person years of follow up (PYFU). This was compared to the primary HIV incidence rate for the HIV negative general heterosexual population in Rakai (n = 20,220; > 100,000 PY).

They identified reinfection in 7/149 people with identifiable sequences in the seroconverter cohort (1.44/100 PY (95%CI 0.37 to 2.51), all from significant changes in the gp41 region. These seven cases were initially infected with sub-type D. Four of the reinfections were with new sub- type D and three with sub-type A.

There were 1152 new infections in the general population over the same period giving an incidence rate of 1.15/100 PY (95%CI 1.08 to 1.21). This was not significantly different to from the primary HIV incidence rate (incidence rate ratio = 1.26, 95%CI 0.50 to 2.60; p = 0.26).

Differences between the risk factors for the people with reinfection (inherently at greater risk than the general population because they were clearly more susceptible to infection) were adjusted for using propensity score matching increased the background incidence rate to 3.28 /100 PYFU (95%CI 2.0-5.3) based on the baseline data but this reduced to 2.51 /100 PYFU (95%CI 1.5-4.3) using the follow up time point (when the difference between groups were more narrow).

The authors concluded: “Although other studies have examined superinfection in small groups of high-risk individuals, this is the first study to directly compare HIV superinfection rates to HIV incidence in a general heterosexual population. The finding that HIV superinfection occurs at approximately the same rate as primary HIV incidence has multiple public health ramifications, and could have significant implications for HIV vaccine research.”

In a second oral presentation, Keshet Ronen from Fred Hutchinson Cancer Research Centre and colleagues looked at the incidence of reinfection in a high-risk cohort of female sex workers in Mombasa, Kenya who were enrolled within six months of initial infection and followed for two years. This is a cohort of almost 3000 HIV negative women who have been followed prospectively with monthly visits, 311 of whom have seroconverted since 1993, with median follow-up of five years.

This group amplified and analysed ~500 bp amplicons in gag, pol, and env from plasma RNA to identify cases of multiple infection. Between 100 and 2000 sequences were obtained per genomic region per time point for a total of ~380,000 sequences.

In earlier studies this group identified 12 cases of reinfection in 56 women. In this new analysis a further 94 women have been identified, with 7 cases of reinfection in the 63 women who have so far had data analysed. They presented combined result of 19 cases of superinfection among 117 women over 621 person-years of follow up (incidence of 3.06% PYFU for reinfection vs to 3.25 for initial infection) and ongoing screening and analysis continues to reach the 150 cases needed to be powered to compare these rates, adjusting for other risks. In this study, timing of reinfection was addressed and included cases plausibly occurring five or more years after initial infection.

However, some researchers suggest the possibility that cases attributed to reinfection could come from initial dual infections, with one infection outgrowing the other after several years. In the absence of being able to confirm a reinfection event by phylogenetic comparisons to the second donor an indirect way to rule out initial dual infection would be to look for closest ancestor for each dual strain to estimate whether one infection has been present for longer than the other.

A poster from the UCSF group that have previously presented this position included two cases where reinfection (superinfection) was initially described based on limited sample sequencing but that more sensitive analyses suggested were serially expressed dual infections (SEDI). [3]

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The consensus after both studies seemed to be that initial HIV infection is not protective of subsequent infections. Researchers were divided over whether initial infection potentially increases the risk of second infection or whether longer duration of follow-up (>2 years) might uncover CTL responses.

Others suggested that cases of reinfection in these studies could easily have been underestimated by not looking early enough after initial infection and only reporting phylogenetically different infections. Further research is needed to determine risks for reinfection, currently assumed to generally be similar to those for initial infection (behaviour risk, viral load of the transmitting partner, STIs, genetics etc).

Ascribing reinfection to initial dual infection (SEDI), requires either one source partner (prompting the question of how this person became dually infected?) or exposures from multiple sources at a close time point, which becomes practically very close to dual infections as one infection must have predated the other, even if this involded a short window period.

References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle.

1. Redd A et al. Next-generation deep sequencing reveals that the rate of HIV superinfection Is the same as HIV incidence in heterosexuals in Africa. Oral abstract 58.

http://www.retroconference.org/2012b/Abstracts/43660.htm

2. Ronen K et al. Detection of frequent superinfection among Kenyan women using ultra-deep pyrosequencing. Oral abstract 59LB.

http://www.retroconference.org/2012b/Abstracts/45492.htm

3. Bentley G et al. Deep sequencing to the rescue: sorting out sequentially expressed dual infections from superinfection. Poster abstract 570.

http://www.retroconference.org/2012b/Abstracts/44792.htm

Simon Collins, HIV i-Base

A sobering and important report documented the case study of a man who was homozygous for the CCR5 delta-32 mutation that generally provides effective protection against infection from HIV.

With most circulating (and infectious) virus using the CCR5 co-receptor, individuals with this deletion in both chromosomes who are exposed to HIV provide a dead-end for the infection, with the virus unable to infection CD4 cells without the use of the coreceptor.

This case of a 39 year-old man – who was diagnosed in 1996 – was indentified by Ester Ballana and colleagues after retrospectively testing DNA from stored peripheral blood mononuclear cells (PBMCs). The man had started treatment within 6 months of diagnosis, at a CD4 count of 520 and viral load of 3,500 copies/mL. Sequence analysis of the env gene idicated homogeneous X4 virus.

Fifteen years after seroconversion, total HIV-1 proviral DNA was 60 copies/million PBMCs. CD4 count had only increased to 600-700 over this time but HLA haplotype analysis showed multiple alleles associated with slower HIC progression including HLA-B*5701 and HLA-A*2402.

Ref: Ballana E et al. HIV-1 infection in a CCR5-D32/D32, HLA-B*5701, and HLA-A*2402 subject: a case report. Poster abstract 292.

http://www.retroconference.org/2012b/Abstracts/43778.htm

Simon Collins, HIV i-Base

An update from the D:A:D cohort on the risk of cardiovascular events was presented as a poster. The D:A:D is a large cohort that includes more than 49,000 HIV positive people from Europe, Australia and the US that in recent years has become sufficiently powered to be able to look at associations between safety outcomes and individual HIV drugs.

The cohort now includes 844 cases of myocardial infarction and 523 strokes, both from over 300,000 patient years of follow up (PYFU) and this year accrued sufficient data on atazanavir (>37,000 PYFU) to present this analysis. Previous associations had been reported for cumulative exposure to indinavir and lopinavir/r but not for saquinavir or fosamprenavir.

The rate of MI was 0.28 /100 PYFY (95%CI 0.26 to 2.30) in those with no exposure to atazanavir and 0.20 (0.12 to 0.32) in those with >3 years exposure. The rate of stroke was 0.17 (0.16 to 0.19) and 0.17 (0.10 to 0.27) in the same groups respectively.

The relative rates (RR) for MI and stroke were 0.95 (95%CI: 0.87, 1.05; p=0.30) and 0.90 (95%CI: 0.81, 1.01; p=0.07) after adjustment for clinical and demographic factors including ARV use. No association was seen with cumulative exposure (<1, 1-2, 2-3, >3 years) or after further adjustment for bilirubin. Rates were similar for atazanavir used with and without ritonavir.

Reference

d’Arminio Monforte A et al. ATV-containing ART is not associated with an increased risk of cardio- or cerebro-vascular events in the D:A:D study. 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle. Poster abstract 823.

http://www.retroconference.org/2012b/Abstracts/45367.htm

Simon Collins, HIV i-Base

The conference included very encouraging results from the first studies of telaprevir (tradename Incivek, Vertex) and boceprevir (tradename Victrelis, Merck) in people with HIV/HCV coinfection.

Both studies generally showed similar response rates in HIV/HCV coinfection to those seen in HCV monoinfection. Sustained virological response (SVR) results at 12 weeks are highly predictive of SVR at week 24.

Telaprevir: SVR-12 results in HIV/HCV coinfection

SVR results at 12 weeks after treatment, from a double-blind, placebo controlled Phase 2 study telaprevir in combination with pegylated interferon (peg-IFN) + ribavirin (RBV) in 60 patients with HIV and HCV genotype-1 coinfection were presented by Douglas Dieterich. [1]

Patients were randomised to either telaprevir (750 mg every 8 hours) or placebo, plus PEG-IFN alpha-2a (Pegysys) + RBV, (800 mg/day) for 12 weeks followed by 36 weeks of peg-IFN+RBV. This was a two-part study depending on whether patients were using ART (Part B, n=47) or not (Part A, n=13). In the ART arm atazanavir/ritonavir (n=23) or efavirenz (n=24) based regimens were allowed (with an increased telaprevir dose for efavirenz patients).

Baseline characteristics included: mean age of 46 years; 88% male; 27% African American; 68% with subtype 1a and 3% had cirrhosis. HCV RNA was >800,000 IU/mL in 92% and 81% of no-ART and ART groups respectively; median CD4 counts were approximately 500-600 cells/ mm3 (range 300 – >1,100).

Undetectable HCV RNA in the combined active vs placebo groups were achieved by 68 vs 4.5%, 82% vs 32%, 63 vs 4.5% and 74% vs 55% at week 4, 12, weeks 4 and 12, and week 24 respectively, see Table1). ART use did not affect response rates. Outcomes by baseline HCV RNA were not presented.

Both safety and tolerability of telaprevir in combination with peg-IFN+RBV was comparable to that previously observed in HCV-mono-infected patients. No severe rashes were reported.

T: telaprevir; P: peg-IFN; R: ribavirin. BLQ: undetectable: lower limit of quantification: 25 IUlmL; limit of detection 10-15 IU/mL.

Interactions between telaprevir and antiretrovirals

Interaction data between telaprevir and HIV drugs was also included in the same presentation. Telaprevir concentrations were similar with efavirenz and atazanavir to reference concentrations with mean (90%CI) Cmin, Cavg and Cmax of 93 ng/mL (56, 156), 97 ng/mL (64, 146) and 101 ng/mL (72, 143) with efavirenz and 131 ng/mL (77, 222), 107 ng/mL (70, 165) and 98 ng/mL (69, 140) with atazanavir, respectively.

The mean concentration ratios to reference levels were also close to 100% for levels of efavirenz and atavanavir, indicating the higher efavirenz dose is sufficient to overcome this interaction.

Telaprevir can only be used with boosted atazanavir, efavirenz (with a higher dose of telaprevir–1125 mg tid (vs. 750 mg tid) or raltegravir. Background nucleosides are tenofovir plus FTC or 3TC

Boceprevir: SVR-12 results in HIV/HCV coinfection

SVR results at 12 weeks after treatment from a randomised double-blind, placebo controlled study of Merck’s boceprevir (BOC) with pegylated interferon (peg-IFN) + ribavirin (RBV) in 98 patients with HIV and HCV genotype-1 coinfection were presented by Mark Sulkowski. [2]

In this study, all patients were on stable antiretroviral treatment (not including NNRTIs, AZT or ddI) with suppressed viral load (<50 copies/mL). ART regimen included atazanavir/r (n=31), lopinavir/r (n=25), darunavir/r (n=17), other PI (n=7), raltegravir (n=10) and other (n=2).

Patients were randomised (2:1) ratio to receive boceprevir 800 mg every eight hours (n=64) or placebo (n=34) plus pegylated interferon-alfa-2b (Peg-Intron) and weight-based RBV (600 to 1400 mg/day). All patients also had a four-week lead-in phase with peg-IFN + RBV.

Baseline characteristics included: mean age of 45 years; 69% male; 82% white. 88% had HCV RNA >800,000 IU/mL and 65% were genotype 1a. Median CD4 counts were approximately 580 cells/mm3 (range 200 – >1,500). Only 4 patients had cirrhosis.

HCV RNA levels were undetectable in 59% vs 23% of patients at week 12 and 64% vs 29% at week 48 in the boceprevir vs control groups with SVR rates 12 weeks after the end of treatment of 61% vs 26% (see Table 2).

B: boceprevir; P: peg-IFN; R: ribavirin.

Important drug interactions between HIV PIs and bocepravir

A late breaker poster was presented by researchers at Merck reporting significant drug interactions between boceprevir and HIV protease inhibitors (atazanavir, lopinavir and darunavir) in HIV negative volunteers. [3] This highlighted not just the complexity for future HCV treatment in people already on ART, but also the importance of conducting major drug-drug interaction studies prior to coadministration in new studies.

Boceprevir significantly decreased the exposure of the PIs by up to 41-75% for AUC0-last, Cmax, and Cmin [GMR (90% CI)]. Coadministration with boceprevir also decreased the exposure of ritonavir AUCt by 34%, 22%, and 27% in the atazanavir, lopinavir and darunavir groups, respectively. Co-administration with atazanavir/r did not alter boceprevir AUCt, but co-administration with lopinavir/r and darunavir/r decreased boceprevir AUCt 45% and 32%, respectively.

comment

These results are important for people with HCV genotype 1 who are in need of urgent treatment.

The interaction data between these HCV drugs and antiretrovirals in these studies was luckily not associated with high rates of treatment failure.

For further information on HCV drug interactions please see the excellent online resource produced by the pharmacology team at Liverpool University.

http://www.hep-druginteractions.org/

UK concensus guidelines for use of these new HCV drugs were recently published online with free access, and although are not HIV- specific, they include a reference to coinfection being a population where their use should be considered. [4]

References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle. 1. Dieterich D et al. Telaprevir in combination with pegylated interferon-alfa-2a+RBV in HCV/HIV-co-infected patients: a 24-week treatment interim analysis. Oral abstract 46.

http://www.retroconference.org/2012b/Abstracts/42969.htm

2. Sulkowski M et al. Boceprevir + pegylated interferon + ribavirin for the treatment of HCV/HIV-co-infected patients: end of treatment (week-48) interim results. Oral abstract 47.

http://www.retroconference.org/2012b/Abstracts/44725.htm

3. Hulskotte E et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. Poster late breaker 771LB.

http://www.retroconference.org/2012b/Abstracts/45463.htm

4. Ramachandran P et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther, 2012, 35(6): 647-662. Free full access.http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2012.04992.x/full

Simon Collins, HIV i-Base

Encouraging results were presented from the ACTG A5247 study on the use of two doses of a live varicella zoster virus (VZV) vaccine (Zostavax, Merck) in almost 400 HIV positive people who were VZV positive or who had herpes zoster (HZ)/shingles outbreak at least one year before study entry, and who were virally suppressed on stable ART. [1]

The incidence and severity of HZ and post herpatic neuralgia (PHN) is higher in HIV positive people and early use of early acyclovir treatment is not always effective. As susceptibility to HZ increases with reduced age-related immune function, a protective vaccine response already demonstrated in HIV negative people > 60 years [2] would be particularly important for HIV positive people.

Participants from over 40 US sites were randomised 3:1 to active or placebo arms and stratified by CD4 count at screening: >350 (high) vs 200-349 (low) cells/mm3. Vaccinations were given on day 0 and at week 6, with immune responses evaluated at weeks 2, 6, 8, 12, and 24.

Primary endpoints were safety (if ≤18 patients in the active arm had primary safety endpoints) and efficacy (change in VZV gpELISA titer at 6 weeks post each vaccination).

Baseline characteristics included: 84% male; 66% white, 31% black, 22% Hispanic; median age 49 years. Median CD4 count and CD4 nadir in the high (n=203) and low (n=192) groups was 602 (nadir 276) and 283 (nadir 106) cells/mm3 respectively. Almost all participant had a previous AIDS event (>97%) with 75 having prior VZV and 33% HZ > 1 year prior to entry.

In the safety analysis, there were no significant differences between the active and placebo groups and none of the 15 primary endpoints in the active arm were vaccine related. Injection site reactions were seen more frequently in the active group (42% vs 12 %, p<0.001). VZV-like rashes were seen in 3 active and 2 placebo patients with PCR showing negative or non-vaccine-strain results.

Geometric mean fold-rise in VZV antibody titre increased by 1.75 ZV vs 1.09 placebo from baseline to week 6 (p<0.001) and this remained similar at week 12 (indicating no change from the second dose). Patients with higher CD4 count at baseline had slightly higher antibody titer over time (p=0.024).

These responses were similar to those seen in HIV negative patients > 60 years. However this study was not powered to detect difference in HZ outcome and post-study follow up is not planned.

References

1. Benson C et al. Zostavax is generally safe and immunogenic in HIV+ adults virologically suppressed on ART: results of a Phase 2, randomized, double-blind, placebo-controlled trial. 19th CROI, 5–8 March 2012, Seattle. Oral abstract 96.

http://www.retroconference.org/2012b/Abstracts/44084.htm

2. Oxman MN et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. NEJM 2005; 352:2271-8.

http://www.nejm.org/doi/full/10.1056/NEJMoa051016

Simon Collins, HIV i-Base

Noah McKittrick and colleagues presented results from a randomised, double-blinded study comparing standard (15-ug/strain) to high dose (60 ug/strain) flu vaccine in 195 HIV positive adults. This study used the trivalent, inactivated, unadjuvanted, split-virus vaccine Fluzone (Sanofi Pasteur). Antibody titers to three strains (H1N1, H3N2 and B) were measured using the hemagglutination-inhibition (HAI) assay.

Baseline characteristics included: 71% male, 68% African American and median age 45 (range 20-78) years. The median CD4 and nadir CD4 count of 452 (IQR 293 – 629) and 180 (IQR 53 – 318) cells/mm3 respectively. In this group, 89% were on HAART and 89% of these 89% had viral load <200 copies/mL.

Approximately half the patients had protective titers at baseline. By week 3, geometric mean antibody titers and the proportion of individuals with protective HAI titers were higher in participants vaccinated with the HD. Greater responses were seen in the high vs low dose groups but this was only significant for H1N1 +9% (0.9 to 17.8%, p=0.04), and B +12% (1.5 to 22.6%, p=0.03) with a non-significant difference H3N2 + 4% (-3.6 to 12.1%, p=0.39).

Both vaccines were well tolerated with no differences between groups and no serious adverse events.

The high dose group achieved protection rates of 80-90% (similar to standard dose in HIV negative studies) increased from 50-70% previously reported for standard dose use in HIV positive people.

Ref: McKittrick N et al. Improved immunogenicity with high-dose seasonal influenza vaccine in HIV+ individuals: a double-blinded, randomized trial. 19th CROI, 5–8 March 2012, Seattle. Oral abstract 97.

http://www.retroconference.org/2012b/Abstracts/44150.htm

This will provided open-label access to adults living with HIV who have documented raltegravir or elvitegravir resistance, who have limited treatment options, and who require dolutegravir to construct a viable antiretroviral regimen for therapy. [2]

As with all EAPs, this is based on the understanding that the safety and efficacy of dolutegravir has not been fully established or thoroughly evaluated by regulatory agencies, but that results from phase 2b studies usggest this may be an important life-saving option for people unable to enroll in clinical studies.

The dolutegravir EAP is now open and accepting participants in the USA and Canada.

For Europe and the International region, it’s expected that the EAP will start to open in March/April 2012 as local regulatory and ethics approvals are obtained.

Further details are available online.

http://www.dolutegravir-eap.org

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The importance of understanding the important of using dolutegravir in combination with other active drugs was highlighted by US community treatment activists. [3]

As with earlier EAP access, the benefits from using a single active drug will be limited. This may still be a life-saving option for someone at serious clinical risk of progression, but people who are able to defer use until other active drugs are available, are likely to gain the most durable response.

References

1. Dolutegravir Expanded Access Program (DEAP).

http://www.dolutegravir-eap.com

2. Dolutegravir Expanded Access Study (DEAP). ClinicalTrials.gov.

http://clinicaltrials.gov/ct2/show/NCT01536873

3. Press release. Activists caution HIV+ patients and their physicians about monotherapy in upcoming access program (9 February 2012).

http://www.acria.org/content/activists-advise-caution-about-access-program

In addition a new scored 25 mg tablet was approved for use in paediatric patients. Listed below are a summary of major changes to the product labelling.

2.2 Paediatric patients (6 years to <18 years)

The recommended dose of etravirine for paediatric patients 6 years to less than 18 years of age and weighing at least 16 kg is based on body weight not exceeding the recommended adult dose. Etravirine tablet(s) should be taken orally, following a meal. The type of food does not affect the exposure to etravirine. The safety and efficacy of etravirine have not been established in children less than 6 years of age.

Healthcare professionals should pay special attention to the accurate dose selection of etravirine, the transcription of the medication order, the dispensing information and the dosing instructions to minimise the risk of medication errors, overdosing, and underdosing.

2.3 Method of administration

Patients should be instructed to swallow the etravirine tablet(s) whole with a liquid such as water. Patients who are unable to swallow the etravirine tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following:

• Place the tablet(s) in 5 ml (1 teaspoon) of water, or at least enough liquid to cover the medication.
• Stir well until the water looks milky, if desired, add more water or alternatively orange juice or milk (patients should not place the tablets in orange juice or milk without first adding water). The use of grapefruit juice or warm (greater than 40°C) or carbonated beverages should be avoided.
• Drink it immediately.
• Rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose.

6 ADVERSE REACTIONS

The safety assessment in children and adolescents is based on the Week 24 analysis of the single-arm, Phase 2 trial TMC125-C213 in 101 particiapants. The frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adult subjects, except for rash, which was observed more frequently in pediatric subjects.

8.4 Paediatric use

Treatment with etravirine is not recommended in children less than 6 years of age.

For full details see the complete labeling posted on the FDA web site.

Source: FDA list serve. (26 March 2012).

On 22 February 2012, the eve of the Swiss pharmaceutical company’s annual shareholders meeting in Berne, Switzerland, 50 AIDS activists, students, and community group members protested at Novartis’s Institute for BioMedical Research in Cambridge, Massachusetts.

The protest was part of a global day of action drawing attention to the pharma giant’s pending lawsuit against cancer patients and the government of India, aiming to reinterpret India’s strict patent standards.

Novartis is seeking to establish a binding court precedent that will make it much easier to obtain overlapping and successive patents on minor variations to existing medicines – a precedent that will increase the number of patents on medicines and extend the length of patent monopolies, thereby limiting and delaying generic competition. In the absence of generic competition, Novartis and other “Big Pharma” companies will be able to set prices affordable to elites, but unaffordable to the broad mass of poor people in India. Because India is the “pharmacy of the developing world,” Novartis’s case threatens affordable global access to all categories of life-saving and health-enhancing medicines.

Indian generic companies manufacture 80 percent of the antiretrovirals used to treat people living with HIV/AIDS around the world. Although the manufacturing of existing AIDS and other medicines is not threatened specifically by this court case, the threat with respect to newer and future medicines is very real. With more frequent and longer patent monopolies, poor people and poor governments will be priced out of access for many, many years.

Background of the case

This court case is part of a long series of legal actions by Novartis designed to eviscerate India’s lawful efforts to restrict the widespread practice of “ever-greening” by pharmaceutical companies. In these instances, pharmaceutical companies seek new or additional 20-year patent monopolies for minor changes to existing medicines and chemical entities based on those minor changes.

In the present case, scientists had invented a basic compound imatinib, which is used to treat certain cancers. It was first patented globally in 1993, but not in India. Thereafter, researchers at Novartis tweaked the basic compound, resulting in a 30 percent improvement in the drug’s absorption into the body. This revised active pharmaceutical ingredient became the basis of a powerful anti-cancer medicine called Gleevec in the U.S. and Glivec in India. In 1998, Novartis filed a patent application on the revised drug in the India Patents Office and in many other countries.

Although the Gleevec/Glivec patent was granted in 40-plus countries that had relatively weak patent standards, the patent was denied in India for three simple reasons:

1. Prior to 2005, India (like many countries before it) did not grant patents on medicines at all. Although the 1994 World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) forced India to start granting patents on medicines in 2005, TRIPS did not require India to retroactively grant patents on medicines invented before 1995.
2. India enacted Section 3(d) of its patent law, a so-called exclusion that does not ordinarily allow patenting of variations, new uses, new combinations, and new formulations of preexisting chemical entities.
3. India incorporated a narrow exception to the no-patent-for-variations rule if, but only if, a patent applicant could demonstrate that changes to an existing substance actually showed significantly increased efficacy – which the Indian courts decided does not include changes in absorption, among other things.

Novartis continues to take action to reverse the patent’ office’s denial of its patent application, and allow section 3(d) to be reinterpreted to allow routine “ever-greening” of minor modifications to existing medicines based on a minimal showing of any positive effect.

Global protests

Demonstrators in Cambridge tried to deliver a Silver Urn (for the ashes of people who would die if Novartis’s court challenge is successful) to Novartis officials, but they were barred from the building and ordered off the premises by Cambridge police. Demonstrators in Washington, DC, delivered an “indictment” against Novartis’s CEO, and protesters in New York City “occupied” Novartis offices. Organised by Health GAP, Student Global AIDS Campaign, Occupy Boston Health Justice Group, these protesters and others were joined by a larger group of protestors at the Novartis annual general meeting in Basel. There, activists from Act Up Paris, Act Up Basel, Médicines Sans Frontières, Oxfam, the Berne Declaration and others showed videos and interacted with shareholders, many of whom were sympathetic to the campaigners’ protests against Novartis’s lawsuit.

Novartis’s reaction

In response to the protests, Novartis issued a statement to Pharmalot: “We believe that working through the judicial system is the legitimate and appropriate approach to gaining clarity on theunique aspects of India’s patent law …. We disagree with assertions … that access to medicines is threatened by our case. The basis of this argument is false and very misleading. Currently available generic drugs launched in India before 2005 – including HIV/AIDS medicines and generic versions of Glivec – will continue to be available under a grandfather clause in the Indian patent law regardless of the legal outcome of our case. All pharmaceutical products, including HIV/AIDS medications, have been patentable in India under the existing patent law since 2005, and some have been patented.”

This defense is patently evasive – the part truth that tells a lie. Yes, there is some degree of grandfathering, even for Glivec; yes, since 2005, India has patented some medicines. However, India has tried to limit patent monopolies, to address public health needs, and to ensure access to medicines within the bounds of the TRIPS Agreement. Novartis’s statement ignores that is trying to erase those legislative efforts, hiding behind the fig leaf of seeking “clarity.”

Source: Baker BK. Why global health activists are fired up about Novartis. Web blog 27 February 2012). http://sciencespeaksblog.org/2012/02/27/why-global-health-activists-are-fired-up-about-novartis/

On 14 February, the US activist organisation TAG issued a press release, summarised below, that criticised President Obama’s recent budget and policy announcements.

Treatment Action Group (TAG) is deeply disappointed by President Obama’s proposed cuts to PEPFAR (President’s Emergency Plan for AIDS Relief) and bilateral TB funds, freezing of NIH (National Institutes of Health) research as well as the insufficient attention to the worsening domestic AIDS crisis in the administration’s fiscal year 2013 budget plan. “Why does President Obama want to turn his back on the most effective, life- saving global health and development program in history?” said Mark Harrington, Executive Director of TAG,

Since 2003, PEPFAR has been the most efficient and effective U.S. global health initiative ever. [...] Now, in a stunning reversal, President Barak Obama has proposed an incomprehensible cut of over a half billion dollars — nearly 13% decrease of $543 million — in what can only be interpreted as a clear signal that the President may allow PEPFAR to expire when its current authorisation ends next year.

While Administration officials may argue that these cuts will be partly offset by program efficiencies, lower drug prices, and the proposed increase in U.S. support to the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) — which TAG supports — the reality is that U.S. support alone cannot reverse the deep effects of the broken promises of the G-20 and the other Global Fund donors. By cutting the PEPFAR budget, over half a million people will be denied life saving HIV treatment, and countless new HIV and TB/HIV infections will occur that could have been averted.

“For the first time since he entered office, President Obama also proposed a flat budget for the National Institutes of Health (NIH) – undermining our ability to translate scientific advances into cures, and jeopardising [the US] long term status as the global leader in health research. President Obama would have turned back the clock on the search for an AIDS cure, and better treatments for Hepatitis C and TB.” said TAG’s Director of Communication and Advocacy, Lei Chou.

Furthermore, the Administration’s 2013 proposal continued an unbroken string of insufficient support for U.S. Centers for Disease Control and Prevention’s (CDC) work to fight the two leading killers of people with HIV — tuberculosis and viral hepatitis. [...] The $67 million increase for ADAP (AIDS Drug Assistance Programme) will not come close to meeting the increasing demand [...] for the most marginalised amongst us.

Source: TAG press release, (16 February 2012).

http://www.treatmentactiongroup.org/press

See also:

Cohen J. Global health advocates aren’t impressed with budget plan. Science (14 February 2012).

http://news.sciencemag.org/scienceinsider/2012/02/global-health-advocates-arent.html

President’s budget request reflects strong commitment on global AIDS

http://blog.aids.gov/2012/02/presidents-budget-request-reflects-strong-commitment-on-global-aids.html

On 9 February the Advisory Committee to the US FDA rejected by a vote of 12-0 an application for a capsaicin skin patch (NGX- 4010, Qutenza) for an indication of HIV-related pain based on proven efficacy. They also voted 11-0 that data the benefits did not outweigh the risks, with the community representative abstaining. [1]

The patch was approved by the FDA in November 2009 for post herpetic neuralgia (PHN) [2] and by the European Medicines Agency (EMA) in May 2009 for treatment of peripheral neuropathic pain in non-diabetic adults, either alone or in combination with other medicinal products for pain [3].

The active ingredient in the patch comes from hot chili peppers and it has been previously approved to relieve pain from shingles. The mechanism for reducing pain comes from a prolonged desensitisation to any local pain following this acute attack on the nerve in the damage area. Lidocaine cream is required to the affected area prior to the application to reduce pain from capsaicin.

The decision was based on 12-week results from two randomised, double-blinded, controlled phase III studies, in people with moderate to severe symptomatic HIV-related PN (total n~800), one of which has been published in JAIDS. [4]

Patients were randomised to either an 8% capsaicin patch, or a low-dose (0.04%) capsaicin control patch. The patches were applied for either 30, 60, or 90 minutes in one trial and either 30 or 60 minutes in the other trial.

The primary endpoint in both was a change in average pain for 24 hours.

The studies showed no relationship between dose or duration of exposure and impact on reducing pain. This may have been related to the study design where the control patch was designed to mimic the burning sensation of the active patch and use of other pain medication by participants.

There were no new safety concerns.

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Because Qutenza has EU approval this decision by the FDA was reported to highlight the different interpretation of similar data.

A recent systematic review of randomised, controlled studies concluded that evidence of efficacy in the treatment of neuropathic pain associated with HIV-PN exists only for the Capsaicin 8% Patch, smoked cannabis, and subcutaneous recombinant human nerve growth factor (rhNGF). [5]

Up to four patches may be applied at one time, but this can only be repeated after 3 months.

References

1. FDA Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee. (9 February 2012)

http://www.fda.gov/AdvisoryCommittees/Calendar/ucm283966.htm

2. FDA. FDA approves new drug treatment for long-term pain relief after shingles attacks. (17 November 2009).

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm191003.htm

FDA briefing document (186 pages – PDF download) http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM290279.pdf

3. EMA approval documents and SPC. (May 2009).

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000909/human_med_001008.jsp&mid=WC0b01ac058001d124&murl=menus/ medicines/medicines.jsp&jsenabled=true

4. Clifford DB et al. A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. JAIDS. Volume 59 – Issue 2 – p 126–133, (1 February 2012). http://journals.lww.com/jaids/Abstract/2012/02010/A_Randomized,_Double_Blind,_Controlled_Study_of.5.aspx

5. Phillips TJ et al. Pharmacological treatment of painful HIV associated sensory neuropathy: a systematic review and meta analysis of randomised controlled trials. PLoS One. 2010;5(12):e14433. http://clinicaltrials.ploshubs.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0014433

Key additions and revisions to the guidelines include: • New section on HIV and the older patient

Effective antiretroviral therapy (ART) has led to greater longevity in HIV-infected individuals resulting in an increasing number of older individuals living with HIV infection. Compared with younger HIV-infected patients, older patients may have more comorbidities, which can complicate treatments of HIV and other diseases. This section focuses on HIV diagnosis and treatment considerations in the older HIV-infected patient.

• New table on cost of antiretroviral drugs

This new table lists the monthly average wholesale price (AWP) for U.S. Food and Drug Administration (FDA)-approved brand and generic antiretroviral (ARV) drugs, including fixed-dose combination products. (The AWP listed for an ARV may not represent the pharmacy acquisition price or the price paid by consumers for that drug.)

• Updated recommendations on initiation of antiretroviral therapy (ART) in treatment-naive individuals

The changes are primarily based on increasing evidence showing the harmful impact of ongoing HIV replication on AIDS and non-AIDS disease progression. In addition, the updated recommendations reflect emerging data showing the benefit of effective ART in preventing secondary transmission of HIV. The updated section includes more in- depth discussion on the rationale for these recommendations and on the risks and benefits of long-term ART.

ART is recommended for all HIV-infected individuals. The strength of this recommendationa varies on the basis of pretreatment CD4 cell count: CD4 count <350 cells/mm3 (AI); CD4 count 350 to 500 cells/mm3 (AII); CD4 count >500 cells/mm3 (BIII).

Regardless of CD4 count, initiation of ART is strongly recommended for individuals with the following conditions: Pregnancy (AI), AIDS- defining illness (AI), HIV-associated nephropathy (HIVAN) (AII) and HIV/hepatitis B virus (HBV) coinfection (AII).

• Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner. Therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners (AI [heterosexuals] or AIII [other transmission risk groups]).
• Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.
• Expanded discussion of use of hormonal contraceptives in HIV-infected women

This revised section includes an expanded discussion on the use of hormonal contraception in HIV-infected women. The discussion focuses on drug-drug interactions between combined oral contraceptives and ARV drugs as well as on recent data showing a possible association between hormonal contraceptive use and acquisition or transmission of HIV.

• Preliminary recommendations on coadministration of the newly approved hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs) boceprevir and telaprevir
• Recommendations on “when to start” ART in HIV-infected individuals diagnosed with tuberculosis but not receiving ART
• Discussion of the role of effective ART in preventing HIV transmission

Ref: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (March 2012)

http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/?utm_source=At-a-Glance&utm_medium=e-mail&utm_ campaign=Adult%2BGuidelines%2B1

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It is always particularly helpful that these guidelines clearly highlight all changes in the text from the previous edition. There are several notable differences compared to the UK BHIVA guidelines (March 2012 draft).

This includes the new US section on HIV and ageing, with age >50 years being an independent factor for starting treatment. Although UK guidelines included this recommendation in 2008 it has been dropped from the 2012 draft.

Also, for starting treatment at higher CD4 counts (at 500 compared to 350) with the US also having a stronger indication for starting at higher than 500, with no CD4 exclusion criteria. This last difference is not based on new evidence about the short-term risk of disease progression, AIDS events or mortality from randomised studies – this will come from the ongoing START study – but from accumulating concerns about uncontrolled viraemia and it’s impact on immune inflammation, and also on the benefit of ARV treatment to reduce further transmission.

The latest BHIVA guideline were released in draft format last month for comment and are still online while the final version is in press.

http://www.bhiva.org

Merck, the manufacturer’s of boceprevir also issued a drug warning giving the pharmacokinetic data and the recommendation that “coadministering boceprevir and ritonavir-boosted PIs is not recommended”. [2]

Source: FDA list serve

References:

1. FDA warning. Victrelis (boceprevir) and ritonavir-boosted Human Immunodeficiency Virus (HIV) protease inhibitor drugs: drug safety communication – drug interactions, (9 February 2012).

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm291144.htm

2. Merck. Dear Healthcare Professional letter. Results of pharmacokinetic study in healthy volunteers given VICTRELIS (boceprevir) and ritonavir-boosted HIV protease inhibitors may indicate clinically significant drug interactions for patients coinfected with chronic hepatitis C and HIV. (6 February 2012).

http://www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdf

A booklet by designed specifically to explain HIV and HIV treatment to children.

The booklet is produced by Medikidz and HIV is one of many health issues in a series.

A low resolution copy can be viewed online.

https://www.yousendit.com/download/M3BuYkJoZEt6RTlBSXRVag

i-Base have a limited number free copies of this booklet for HIV positive children. If you would like us to send you one please contact Rebecca McDowall at i-Base:

subscriptions@i-Base.org.uk

The following HIV related papers were published in PLoS Medicine, Volume 9(3) March 2012

CD4 Cell Count and the Risk of AIDS or Death in HIV-Infected Adults on Combination Antiretroviral Therapy with a Suppressed Viral Load: A Longitudinal Cohort Study from COHERE.

Young j et al.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001194

The European COHERE cohort shows that in successfully treated patients the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression.

No Treatment versus 24 or 60 Weeks of antiretroviral treatment during primary HIV infection: The randomized Primo-SHM Trial.

Grijsen  ML et al.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001196

This study of approximately 170 people diagnosed in primary HIV infection randomised participants to immediate treatment for either 24 or 60 weeks or to now treatment, finding that both treatment arms resulted in significantly longer time until treatment was started or restarted.

The Evolving Landscape of the Economics of HIV Treatment and Prevention.

Nosyk B et al.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001174

The cost-effectiveness of HAART roll out has been significantly underestimated because economic analyses do not account for the beneficial impact of HAART on HIV transmission.

Download HTB March/April 2012e PDF file (770 Kb)

It is very helpful that the meeting organisers have posted most of the slides for the oral presentations online, together with free access to the conference abstract book.

Abstracts and presentations are available at these links:

http://regist2.virology-education.com/abstractbook/2012_1.pdf

http://regist2.virology-education.com/2012/2ndHIV&Women/9_Jan.html

http://www.virology-education.com

Reports in this issue include:

• Similar efficacy and a few gender related differences in side effects with rilpivirine vs efavirenz at 96-weeks
• The effect of BMI on efficacy, safety and tolerability of lopinavir/r in women
• Hormonal contraception and higher risk of non-AIDS-defining events in Nashville cohort
• Poorer adherence and loss to follow up in Kenyan women who are pregnant when enrolled to ART programmes

Rilpivirine (RPV) did not show teratogenicity risk in pre-clinical studies and is therefore FDA pregnancy category B, nor does it interact with the oral contraceptives norethindrone and ethinyl estradiol. For these reasons, it could be a useful option for women of child bearing potential.

RPV was non-inferior to efavirenz (EFV) when combined with a nucleos(ti)de backbone in the pooled 96-week analysis of the phase 3 ECHO and THRIVE trials but only for baseline viral load strata <500,000 copies/mL. The primary endpoint was viral suppression to <50 copies/mL at week 48 by TLOVR analysis, with non inferiority defined by 95% CI compared to control not crossing the lower margin of -12%.

An investigation was conducted to look at safety and efficacy outcomes in women participating in these trials specifically and in comparison to men. This analysis included data from 236 (22%) women and 860 men, of these, 121 women and 429 men were randomised to RPV, and 115 women and 431 men to EFV. The women and men had similar median age of about 35 years, baseline CD4 counts of 243 and 258 cells/mm3 and viral loads of 4.9 and 5.0 log10 copies/mL respectively. Of the participants, a greater proportion of women than men (45% vs 18%) were black, and a smaller proportion (33% vs 70%) were white and Latina/o (16% vs 28%).

At 96 weeks, CD4 increases were similar in women and men in the RPV and EFV groups (approximately 225 cells/mm3).

Overall, 14% vs 6.1% of women failed virologically and/or discontinued treatment in the RPV and EFV arms respectively. The difference between the two arms was greater in the first year of treatment with 11.6% vs 3.5% failing compared to 2.5% vs 2.6% in the second year. These proportions were similar for men participating in the study: overall 14.2% vs 7%, year one 11.4% vs 4.4%, and year two 2.8% vs 2.6%, in the RPV and EFV arms respectively.

Stratification by baseline viral load showed similar rates of virological suppression for women and men with <100, 000 copies/mL receiving RPV or EFV (approximately 80%). Between >100,000 and 500,000 copies/mL, women in the RPV arm did slightly better than those receiving EFV, respectively 81% and 73% had viral loads <50 copies/mL at 96 weeks. The results for men in this viral load stratum were similar across the two arms, 72% and 73% for RPV and EFV. Above 500,000 copies/mL only 30% of women in the RPV arm had viral loads <50 copies/mL but this percentage relied on results for 3/10 women. For women receiving EFV the proportion was 57% (8/140). Of the men 67% (29/43) and 79% (46/58) in the RPV and EFV arms had viral loads <50 copies/mL at 96 weeks.

Of women who reported adherence >95%, both those receiving RPV (n=94) and EFV (n=92) had 78% rates of virological suppression <50 copies/mL. For those reporting <95% adherence suppression rates were lower, 67% and 64% for RPV (n=18) and EFV (n=14) respectively.

For men who reported >95% adherence, 96-week suppression rates with RPV (n=364) and EFV (n= 336) were 82% and 85%. Rates for those reporting <95% adherence were 52% with RPV (n=50) and 68% with EFV (n=59).

Resistance was analysed in a very small subset of women, RPV (n=15) and EFV (n=5). This revealed 20% of virologic failures with wild-type virus and 60% of with NNRTI resistance. There were more NRTI mutations in the women receiving RPV than EFV, 47% vs 0% and the most common were E138K (33%) and M184I (27%).

At week 96, rates of adverse events (AEs) leading to discontinuation of treatment were similar across treatment arms and genders. Incidence of grade 2 to 4 adverse events was significantly lower with RPV than EFV in women, 15.7% vs 34.8% and men, 17.5% vs 32.7%, both p<0.001.

Nausea occurred more frequently in women than men receiving both RPV and EFV, 19% vs 11.2%, 18.3% vs 9.7%, both p<0.05. But the incidence of treatment-related psychiatric adverse events was significantly lower in women than men receiving RPV, 9.1% vs 18.2%, p<0.05). Both these rates were lower than those in women and men receiving efavirenz, 16.5% vs 29.5%, p<0.05).

There were lower rates of abnormal dreams and nightmares in women than men receiving RPV 4.1% versus 11.4%, p<0.05. Women also experienced less of these events than men with EFV, 8.7% vs 17.4%, p<0.05. Rates of diarrhoea were similar in women and men receiving RPV, 13.2% versus 16.3%, but lower in women than men receiving efavirenz, 9.6% vs 18.6%, p< 0.05.

Women and men receiving RPV reported lower incidence of neurologic AEs compared to those receiving EFV, 15.7% vs 34.8%, p<0.05, and 17.5% vs 32.7%, p<0.001, for men and women respectively. There was also lower incidence of dizziness, 12.4% vs 27.8%, p<0.05 and 8.8% vs 28.8%, p<0.0001; and rash, 5.8% vs 16.5%, p<0.05 and 6.8% vs 12.5%, p<0.05.

Women and men receiving RPV had less grade 3 or 4 laboratory abnormalities 7.4% vs 11.5% and 10% vs 18.7% but this only reached statistical significance in men, p<0.05.

There were less grade 1 to 3 elevations in LDL cholesterol with RPV than EFV in women 19.9% vs 49.6%, p< 0.05, and men 19.6% vs 43.1%, p<0.001.

For all groups, there were significant increases from baseline in limb fat at week 96 with no statistical differences between treatment groups. Women receiving RPV appeared to have greater increase than the EFV group, median 1592g vs 641g. For men the two groups had similar median increases 828g vs 835g.

There was a trend towards greater BMD changes in women for both arms, but this was in a small sample size (n=30).

Reference:

Short W et al. Sustained efficacy and safety observed for RPV vs EFV plus FTC/TF and with a few gender differences in pooled 96-week ECHO and THRIVE analysis. 2nd International Workshop on HIV and Women. 9-10 January 2012, Bethesda, MD. Oral abstract O_14A.

The last issue of 2011 highlighted serious concerns for global health, and the Treatment Access news in this issue continues this theme, with an indication that funding uncertainties will continue throughout the year.

This includes further changes at the Global Fund and responses to the suspension of Round 11 grantsan outcome-that became likely when donor pledges last year failed to match even the minimum working budget.

Fortunately these sobering events are balanced by more positive news.

The  FDA recently approved new indications and formulations of three important antiretrovirals. Tenofovir is now available as an oral powder and lower dose pills for an indication in children of two years and older. Raltegravir is available in a 100 mg scored chewable tablet and a 25 mg chewable tablet for children older than 2 and weighing greater than 20 kg. Finally, an oral suspension of darunavir was approved with two bands of dosing recommendations (age 3 to 6 years; and, older than 6 years) that, as with adult dosing include separate recommendation for naïve and experienced patients.

Our conference coverage in this issue comes from a meeting on HIV and women’s health, and from a biannual workshop on HIV persistence and cure research.

The report from Richard Jefferys both summarises the latest state-of-the-art in this field and comments on the complexity of interpreting these early data.  The excitement is that the slow momentum from numerous research groups carries our ultimate hope to for a future that may offer alternatives to our current life-long reliance on ARVs.

Finally, and closer to home, BHIVA have published both new monitoring guidelines and the draft for the 2012 UK treatment guidelines. As this is the first update since 2008, with only a few weeks to comment it is important that the writing committee receive feedback promptly if this to be considered for the final document.

Body mass index (BMI) can lead to alterations in pharmacokinetics and pharmacodynamics. Data describing the relationship between BMI and clinical outcomes of ART in women are limited.

Investigators from Abbott conducted a meta-analysis in women taking lopinavir/ritonavir (LPV/r)-based regimens in order to look at the effect of BMI on efficacy, safety, and tolerability. Ashwaq Hermes presented findings from this study.

All prospective randomised controlled trials (RCTs) in the company database in adults receiving LPV/r in regimens with two NRTIs, having BMI data, and baseline to week 48 efficacy, safety, and tolerability data were included.

Women were stratified by baseline BMI (kg/m2) into <18.5, ≥18.5-< 25, ≥25-<30 and ≥30 groups. As the number of women with BMI <18.5 was low (n=28), the investigators selected categories of <25 (normal), ≥25-<30 (overweight) and ≥30 (obese) for the analyses.

The meta-analysis included 485 women from seven RCTs, 258 with normal BMI, 130 were overweight women, and 97 categorised as obese. There were statistically significant differences (p<0.05) among the normal, overweight, and obese groups in baseline demographic characteristics: percentage of white women, 53.9%, 36.9% and 25.8% respectively; percentage of Latina women, 17.4%, 33.8%, and 20.6%, respectively and rate of hepatitis C co-infection, 17.2%, 10.8%, 6.2%, respectively.

There were also statistically significant differences in the three groups in baseline disease characteristics: mean viral load, 4.6, 4.4, and 4.3 log10 copies/mL, respectively, and mean CD4 counts 214, 244, and 278 cells/mm3, respectively.

Efficacy was similar across the groups at week 48. Similar proportions of women had viral load <50 copies/mL, 65.1%, 57.7% and 57.7%, respectively (ITT analysis). Mean increases in CD4 counts were also similar across the normal, overweight, and obese groups, 197, 158, and 172 cells/mm3, respectively.

Incidence of grade 3 and above adverse events (AEs) was also similar across the groups, 29.5%, 29.2%, and 41.2%, respectively, p=0.087. Differences were seen in the incidence of moderate/severe abdominal pain, 0.8%, 0%, 7.2%, respectively and diarrhea 9.3%, 10.8%, and 22.7%, respectively in the normal, overweight and obese groups, both p<0.05. These AEs were significantly higher, p<0.05, in the obese women compared with the other two groups. There was no significant difference in the incidence of nausea and vomiting among the three groups.

The investigators noted that increasing BMI is associated with a greater prevalence of diarrhea and abdominal pain, but not nausea or vomiting, in the general population. Also dietary differences among the BMI groups could be confounding, and this information was not collected or controlled for in the meta-analysis. Furthermore people with high BMI have elevated incidence of non-alcoholic fatty liver disease, which is associated with liver fibrosis and changes in drug metabolism.

They concluded that direct comparisons of dose safety and efficacy by BMI groups are needed to increase the understanding of obesity related changes and the impact on treatment.

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As reported in other studies, increased weight did not lead to higher rates of virological failure, suggesting that pharmockinetics for lopinavir do not have a direct association with higher weight, even though the PK data were not available or analysed.

However, although the results were not significantly different, it is unclear whether a formal test of equivalence was performed. There is >7% difference between the normal group and the other two groups and response rates appear lower in heavier groups. It would be interesting to see the confidence intervals for the differences which would have to be to conclude equivalence. The CD4 count increases also seem to be lower.

It would also have been interesting to see whether lopinavir/ritonavir has an impact on BMI in relation to baseline BMI.

Reference:

Hermes A et al. A meta-analysis of the effect of BMI on efficacy, safety, and tolerability of lopinavir/ritonavir in HIV-infected women in randomised clinical trials. 2nd International Workshop on HIV and Women. 9-10 January 2012, Bethesda, MD. Oral abstract O_15.

Studies evaluating the effect of hormonal contraceptives (HC) on HIV disease progression have shown conflicting results. Previous findings have been from resource limited settings (RLS) and have not looked at the effect of HC on non-AIDS defining events (non-ADE).

Mainly observational data from Africa and Asia has shown both higher and lower rates of HIV disease progression in women receiving HC. Observational data in HIV negative women has shown an association between HC and metabolic complications.

Vlada Melekhin presented findings from a retrospective cohort study of HIV-positive women attending the Comprehensive Care Center (Nashville, TN) between 1998-2008. The study investigated the association between HC (oral and injectable methods used >28 days) and AIDS-defining events (ADE), non-ADE (ie cardiovascular, renal, liver, and metabolic diseases and non-AIDS associated malignancies) and death.

Eligible women were <55 years old with no history of pulmonary or deep venous thromboembolism, breast cancer, hysterectomy, or bilateral tubal ligation and not pregnant at first clinic visit. Women with no HC were evaluated from their first clinic visit and those using HC at HC start.

Logistic regression analysis included age, race, baseline CD4 count, viral load, and haemoglobin, CD4 nadir, history of ADE, non-ADE, HCV, antiretroviral (ART and non-ART) use, smoking status, IV and non-IV drug use, year of study start, and year of HC start.

Of 467 HC-eligible women, 112 (24%) were on HC at any time during the follow up. At baseline women on HC were younger, median 28.6 vs 35.6 years. They had higher CD4 count 523 vs 364 cells/mm3 and nadir, 340 vs 280 cells/mm3, and lower median viral load, 3.1 vs 4.1 log10 copies/mL. They were less likely to be coinfected with HCV, 5% vs 15% or inject drugs, 16% vs 27%, both p<0.03.

There was no statistical difference in ART use between the HC and no HC groups, 30.4% vs 26.8%, respectively, nor in prior ADE or non-ADE.

Of the 112 women using HC, 51 used oral and the remaining 61 used injectable for a median duration of 7.6 and 13 months respectively, p=0.26.

HC users had longer follow-up compared to non HC users, median 2.8 vs 1.5 years for ADE, 2.8 vs 1.6 years for non-ADE and 3.8 vs 2.1 years for death.

The investigators reported a lower proportion of deaths in the HC group, 6% vs. 15%, p=0.01. But these women had more new cardiovascular non-ADEs, 12% vs. 5%, p=0.02.

In the adjusted analyses, HC use was associated with a statistically significantly higher risk of non-ADE HR 2.0, (95% CI 1.28, 3.1), p=0.02 and non-ADE/death HR 1.89, (95% CI 1.25, 2.87), p=0.03). Risks of ADE and ADE/death were also higher among HC users but did not reach statistical significance: HR 1.51 (95% CI 0.59, 3.85), p=0.39 and 1.49 (95% CI 0.72, 3.11), p=0.29, respectively. Women using injectable HC were at a higher risk of non-ADE and non-ADE/death, HR 2.0 and 1.9 respectively, both p=0.03 and those using oral HC only non-ADE, HR 1.9, p=0.02.

The investigators plan further analyses from this cohort including looking at the effect of ART and suggested as the number of women with HIV who are of child-bearing age increases, it is important to better understand any negative effect of HC on their health.

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Investigations into the use of hormonal contraceptive methods and its effect on disease progression in HIV positive women have led to conflicting results,

One randomised controlled trial conducted in Zambia showed risk of CD4 decline or death with hormonal contraception, compared to use of the copper IUD. [2] But the study was designed to look at the incidence of pregnancy and pelvic inflammatory disease in the IUD users and there was considerable discontinuation and switching between methods. Data from several observational studies do not confirm this effect.

The association with non-AIDS events found by Melekin are interesting but should be interpreted cautiously given that two large trials have reached very different conclusions. Observational data is vulnerable to unmeasured confounding and (as they are in the general population) lifestyles are very different between those that use hormonal contraception and those that do not. These differences could (feasibly) explain differences in incidence of some of these serious events. For example, even smoking and alcohol use may be different in the groups. Whille the researchers may have used propensity scores, these do nothing to tackle unmeasured confounding (and are arguably little better than standard multivariable logistic regression models).

The WHO recently held a stakeholders meeting to review the evidence on hormonal contraception and HIV, not only to consider the effect on disease progression but also female to male HIV transmission and HIV acquisition by negative women. The organisation and partners are producing three systematic reviews and there will be a statement from the consultation.

Currently the WHO medical eligibility criteria for contraceptive use defines hormonal contraceptives as category 1 – ie no restriction on the use of the methods for women with HIV (including AIDS).

References:

1. Melekin V et al. Hormonal contraceptive use is associated with a higher risk of non-AIDS-defining events in HIV-1-infected women. 2nd International Workshop on HIV and Women. 9-10 January 2012, Bethesda, MD. Oral abstract O_13.
2. Stringer EM et al. A randomised trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol 2007 August; 197 (2):144-148. Free full text:
   http://www.ajog.org/article/S0002-9378(07)00399-7/fulltext

There are concerns that women diagnosed with HIV during pregnancy may have greater difficulty with adherence to ART than those who are already aware of their status. This may lead to increased rates of vertical transmission and the development of drug resistance.

April Bell showed findings from a retrospective analysis of data collected from January 2006 to July 2011 by the United States Agency for International Development-Academic Model Providing Access to Healthcare (USAID-AMPATH) programme in Western Kenya.

The study compared adherence rates and pregnancy outcomes between women enrolled in the programme during pregnancy and those who became pregnant after they were already enrolled. Women from both groups were ART-naïve when their pregnancy was identified. Those meeting the eligibility criteria for treatment in Kenya at the time – CD4 <200 cells/mm3 – started ART immediately and those with CD4 >200 cells/mm3 started at 28 weeks gestation.

The women enrolled during pregnancy were younger, with a median age of 27 (IQR 23.2-31.7) years (n=8926), compared to 30.8 (IQR 26.6 – 35.1) years in the group already enrolled (n=5108). At enrollment a higher proportion were married, 69.6% compared to 52% and had a higher median CD4 count 371.5 (IQR 222 – 543) cells /mm3 compared to 282 (IQR 133-461) cells/mm3 for women who became pregnant when they were already enrolled in the programme. All comparisons, p<0.0001.

The women who were pregnant at enrollment were less adherent, 89.7% compared to 93.2% with perfect adherence, and were more likely to be lost to follow up before delivery, 29.6% compared to 3.4%, both p<0.0001.

Among the women who remained in the programme post-partum, there was no difference in the rate of mother-to-child transmission, 7% compared to 8.8%, p=0.0053, or early infant death, 3.2% compared to 4.2%, p=0.032, in those enrolled during pregnancy or became pregnant after enrollment respectively.

Although this study was limited by incomplete data, the investigators were able to conclude that women who are pregnant at enrollment into an HIV care programme are at higher risk for loss to follow up and poor adherence than those already enrolled in care at the time of pregnancy.

They suggested, “Interventions targeting women newly diagnosed with HIV infection during pregnancy are necessary to improve retention and adherence to therapy”.

Reference:

Bell A et al. Adherence and retention rates: a comparison of women enrolled in an ART programme during pregnancy and those who become pregnant after enrollment. 2nd International Workshop on HIV and women. 9—10 January 2012, Bethesda, MD. Oral abstract O_17.

Introduction

This meeting had a limited numbers of attendees and brought together an impressive group of leading researchers.

The abstract book and late breaker abstracts are available in PDF format from the conference website and links:

http://www.hiv-workshop.com/workshop-2011.htm

http://www.hiv-reservoir.net/index.php/the-news/189-abstract-book-2011-hiv-persistence-workshop.html

The site also contains daily rapid summaries of the workshop that will be followed in the next few weeks by more detailed reports.

As has been extensively documented, Brown’s apparent cure resulted from a debilitating odyssey of treatments required for the grim diagnosis of acute myelogenous leukemia, enhanced with a mix of insight and good fortune on the part of his doctor Gero Hutter, who was able to provide a stem cell transplant from a donor lacking the major HIV co-receptor CCR5.

The sea change wrought by this fortuitous ‘proof of concept’ was much in evidence at the 2011 persistence workshop this past December; the tentative forays into basic science that were once emblematic of the field are now mixed together with more ambitious plans for advancing ideas into the clinic. Perhaps most strikingly, two large pharmaceutical companies—Gilead and Janssen/Tibotec—described their use of industrial scale screening to search for compounds that are active against latent HIV; this represents an unprecedented expansion of efforts once confined to under-resourced academic labs.

A number of online resources are available with information on presentations at the 2011 persistence workshop: Lafeuillade runs a website called the Reference Portal on HIV Reservoirs & Eradication Strategies which includes an expanding number of reports, video interviews and commentary. [1]

David Margolis from the University of North Carolina has written a comprehensive report for Jules Levin’s National AIDS Treatment Advocacy Project (NATAP) website. [2] Jon Cohen also covered one the most notable presentations in the journal Science. [3]

This report and commentary represents my subjective take on events.

To try and briefly summarise the top-line stories that emerged from the 2011 meeting:

• A triumvirate of researchers – Courtney Fletcher, Mario Stevenson and Tim Schacker – presented data suggesting that sporadic, very limited rounds of HIV replication may occur in some individuals on ART due to poor penetration of certain drugs into the lymphoid tissues. However, preliminary data were only available from a small number of participants (~4-5) so the implications are still uncertain. According to the clinicaltrials.gov entry for the study, it is now expanding from the original enrollment target of 12 to 40 so additional information should soon be forthcoming. [4] Alain Lafeuillade has posted an interview with Mario Stevenson about the findings, and these presentations were the subject of Jon Cohen’s story in Science. [5]
• An Italian research group led by Andrea Savarino described a retrospective analysis involving 18 rhesus macaques infected with SIVmac251 that participated in various studies combining ART with drugs targeting the viral reservoir. The analysis found an association between the number of ‘anti-reservoir’ drugs animals received and the likelihood of controlling SIV to undetectable levels after ART was interrupted; however only three macaques controlled SIV to this degree so the findings should be considered very preliminary. The workshop organisers issued a press release about the data suggesting that for the first time they show that anti-reservoir drugs may be able to contribute to what is now frequently referred to as a ‘functional cure’ (control of viral load in the absence of ART). In an interview with Alain Lafeuillade, Savarino is careful to note that the findings require confirmation in human studies because they could relate to unknown factors specific to the three macaques that controlled SIV in the experiment. [6] This caveat is underscored by the fact that there are relatively few studies involving ART treatment of SIVmac251 in macaques to provide context, and in those that have been published there appear to be some examples of animals that spontaneously controlled viral load after ART interruption (both in control groups and in recipients of a DNA-based therapeutic SIV vaccine).
• David Margolis from the University of North Carolina presented the first data on the use of a histone deacetylase (HDAC) inhibitor named SAHA (aka vorinostat) in individuals with HIV. HDAC inhibitors are at the forefront of efforts to pharmaceutically urge HIV out of latency, so news from Margolis’s trial has been eagerly awaited. While very preliminary, and derived from just four participants, the results so far suggest that the approach is able to increase HIV expression by latently infected cells. It took Margolis many years to get the trial started due to concerns about the safety of HDAC inhibitors (which are used as cancer treatments and can cause serious toxicities) but no serious side effects have occurred to date. As Margolis stressed, much more work is needed before any conclusions can be drawn about the promise of the approach.
• The burgeoning involvement of the pharmaceutical industry in cure-related research – represented by presentations from Romas G from Gilead and Roger Sutmuller from Janssen/Tibotec – was important news because it promises to transform the drug discovery effort by increasing the number of compounds that are being screened by many orders of magnitude.

The workshop agenda was divided into discrete topic areas spread over three days. The first session addressed the subject of animal models, and was led off by Jeff Lifson from the National Cancer Institute (NCI) at Frederick who has nearly two decades of experience studying SIV infection in rhesus macaques. Lifson outlined some of the considerations in developing an appropriate model for cure-related studies, which include mimicking the degree of viral suppression achieved with ART in humans and developing tools to comprehensively assess the impact of additional interventions on SIV reservoirs.

The models currently in use include:

• Macaques infected with hybrid SIV/HIV viruses encoding HIV reverse transcriptase (SHIV-RT), treated with efavirenz, emtricitabine and tenofovir
• Macaques infected with SIVmac251 or SIVmac239 treated with multi-drug regimens (e.g. tenofovir, emtricitabine, raltegravir and ritonavir-boosted darunavir +/- maraviroc)
• Pigtailed macaques infected with SIV/17E-Fr and SIV/Delta B670 treated with tenofovir, integrase inhibitor, saquinavir, atazanavir (this model is primarily being used to assess issues relating to viral activity in the brain)

Lifson described a study conducted by his laboratory in which macaques were infected with the highly virulent challenge virus SIVmac239 and, after sixteen weeks, treated with a multi-drug antiretroviral regimen comprising an integrase inhibitor, tenofovir, emtricitabine, and ritonavir-boosted darunavir. Suppression of viral load to less than 30 copies/mL was eventually achieved, but Lifson noted that it took longer than is seen with HIV in humans. Like the vast majority of macaque studies, the experiment involved Indian rhesus macaques, and Lifson suggested that viral load suppression might be easier to achieve in Chinese rhesus macaques (this subspecies has been shown to control SIV somewhat better in the absence of ART). Lifson acknowledged that refinement of the SIV/macaque model for cure-related research is ongoing, and he cautioned against the premature adoption of any one approach as a standard. As an example of the pitfalls of premature standardisation, he cited the HIV vaccine field’s mistake in adopting a SHIV89.6p challenge model that turned out to have essentially no relevance to human HIV infection.

One potentially important new technology that Lifson highlighted is called digital PCR, which is vastly superior to traditional PCR for measuring small quantities of nucleic acid in samples. PCR amplifies nucleic acid sequences from a single sample by inducing rounds of copying of the original sequence, then back-calculating how many were originally present using a formula that takes into account the number of rounds of copying; however these calculations can be imprecise for a number of reasons. Digital PCR divides a sample into many discrete ‘microfluidic’ wells and then uses PCR to look for the nucleic acid sequence of interest in each well, providing a readout as to whether the sequence is absent (0) or present (1). The total amount of nucleic acid sequence that was present is then calculated based on the number of negative and positive wells, using an approach called a Poisson distribution. Digital PCR assays have only recently been commercialised and a number of laboratories are now busy using them to measure SIV and HIV in research studies.

The presentations following Lifson illustrated the diversity of animal models in use, and the uncertainties associated with them. Andrea Savarino from the Istituto Superiore di Sanità in Rome provided an update on experiments conducted by his group involving macaques infected with SIVmac251. In a paper published in AIDS last year, Savarino and colleagues reported that the gold-based rheumatoid arthritis drug auranofin reduced the reservoir of SIV-infected cells in animals treated with combination ART. [7]

At the workshop, Savarino presented results of a retrospective analysis of 18 macaques (including those included in the experiments reported in the paper) that have received various combinations of antiretrovirals and ‘anti-reservoir’ drugs including auranofin and buthionine sulfoximine (BSO). The breakdown of the antiretroviral regimens employed was as follows:

• ART: tenofovir, emtricabine, raltegravir
• Intensified ART (iART): tenofovir, emtricabine, raltegravir, ritonavir-boosted darunavir
• Mega-ART: tenofovir, emtricabine, raltegravir, ritonavir-boosted darunavir, maraviroc

Three of the 18 macaques have controlled SIVmac251 to undetectable (<40 copies/mL) levels after interruption of all treatment for several months, and Savarino reported that there was a significant correlation between the number of ‘anti-reservoir’ drugs received and this salutary outcome (for the purposes of this analysis, the CCR5 inhibitor maraviroc was counted as an anti-reservoir drug due to evidence that it reduced the amount of SIV DNA when added to intensified ART and preliminary results from a human study suggesting it may impact reservoirs). Some macaques also received the HDAC inhibitor SAHA, but an impact on the SIV reservoir could not be demonstrated.

The complicated sequence of treatments and outcomes in the three macaques that have controlled viral load off ART can be roughly summarised as follows:

• Macaque P252: ART, ART+auranofin, iART+auranofin, iART+SAHA, iART+auranofin, treatment interruption, viral load control to limit of detection, viral load rebound, Mega-ART, treatment interruption, viral load control, viral load rebound, viral load control, viral load rebound, Mega-ART, viral load control, viral load rebound, Mega-ART+BSO, viral load control (100+ days)
• Macaque P157: ART, iART, Mega-ART+auranofin+BSO, treatment interruption, viral load rebound, viral load control (~60 days), viral load blip, viral load control (~50+ days)
• Macaque P177: ART, iART, Mega-ART, Mega-ART+auranofin, treatment interruption, viral load rebound, Mega-ART, treatment interruption, viral load rebound, viral load control, viral load rebound, viral load control (~50+ days)

The data appear encouraging but there are some potential caveats:

• The model of SIVmac251 infection treated with combination ART (the drugs used in the study included tenofovir, emtricabine, raltegravir, ritonavir-boosted darunavir and maraviroc) is not well characterised, at least in terms of the published literature
• There were very few control animals, and the results are not from a single study but rather from multiple experiments, sometimes involving the same macaques being rolled over from prior experiments
• As can be seen from the sequence of events in the three controlling macaques, the treatments were complex and there was variability between animals in terms of exactly when different interventions were administered

As Savarino stresses in his video interview with Alain Lafeuillade, human trials are now required to ascertain if the macaque results can be translated to HIV.

Paul Luciw presented results of an experiment in which macaques infected with SHIV-RT had prostratin and valproic acid added to long-term ART (efavirenz, emtricitabine and tenofovir) prior to an interruption. Luciw showed evidence of reduced viral RNA and DNA in tissues but when treatment was interrupted there was no significant difference in viral load rebound compared to macaques treated with ART alone. Daria Hazuda from Merck has included several of Luciw’s slides in her recent presentations on cure research so the main findings can be viewed online, however note that prostratin is only referenced as a ‘protein kinase C activator’ and valproic acid as an ‘HDAC inhibitor’. [8]

Luciw also mentioned that he repeated the experiment adding raltegravir to the ART regimen and in that case there was no additional viral RNA and DNA reduction in tissues resulting from the anti-reservoir drugs, but he was running out of time and was unable to give any details; this finding is perhaps a reminder of how much uncertainty still surrounds macaque models for cure research.

Jerome Zack is trying to make drug-delivery nanoparticles out of weird cellular particles called ‘vaults’ made of three proteins and a bit of RNA. [9] Zack presented some preliminary evidence that they can be engineered to deliver potential latency activators prostratin and bryostatin, Zack is also working with Paul Wender at Stanford to develop better analogues of these drugs to use. The goal is to come up with some lead vault-delivered anti-latency compounds to test in the BLT humanised mouse model.

Shifting topics to the virological aspects of HIV persistence, Sarah Palmer from the Karolinska Institute reported results of an intensive evaluation of viral genetics pre-ART and on long-term ART (up to >12 yearrs) in 12 people (seven treated at acute infection, five during chronic infection) to look for evidence of viral evolution that would be indicative of ongoing replication. No evidence suggestive of HIV replication was found in various CD4 subsets and other cell types in blood, lymph tissue, bone marrow and gut. Palmer noted that no hematopoetic progenitor cells (HPCs) containing HIV DNA could be found; occasional positive signals from HPC samples turned out to be due to low-level contamination with CD4 cells. This finding was recently echoed in a paper from Bob Siliciano’s group at Johns Hopkins. [10]

Palmer drew attention to one case where a large amount of HIV DNA containing a huge deletion encompassing all of the protease gene was discovered. Since HIV can’t replicate without protease, this demonstrates that the division of CD4 T cells carrying integrated, non-functional proviral HIV DNA can contribute to what may appear to be an HIV reservoir by some measures (but really isn’t because the virus is defective). Mario Stevenson coined the term ‘junkyard DNA’ for these non-functional proviruses, and it was quickly adopted at the workshop.

Tae-Wook Chun from the National Institute of Allergy and Infectious Diseases (NIAID) offered some data suggesting HDAC inhibitors may not be all they’re cracked up to be in terms of reversing HIV latency, in the hands of his lab they didn’t induce a significant amount of viral RNA from latently infected cells compared to prostratin (which is a potent activator generally considered too toxic for human use). Chun also said that the latently infected cells induced to produce viral RNA don’t seem to die (“we haven’t seen any evidence of cell death’), suggesting that induction using HDACs might have little effect in the absence of an immune response capable of killing the infected cell.

Day two

Day two of the persistence workshop featured the presentations from industry, with Romas Geleziunas from Gilead and Roger Sutmuller from Janssen/Tibotec talking back-to-back about the ongoing work at their companies.

Gilead is looking at both virus activators and immune modulators, with Romas Geleziunas seemingly already having taken on board what Tae-Wook Chun had suggested the previous day: reactivating latent infection may not be enough to kill a cell, hence immune mechanisms may need to be induced to deliver the coup de grace. Geleziunas described Gilead’s high throughput primary cell screening assay, which is a modified version of an assay developed by Vincente Planelles and Alberto Bosque. [11]

So far they’ve identified three HDAC inhibitors from the Gilead drug library, imaginatively named 001, 002 and 003. 001 is 10-fold more potent than SAHA but inhibits all classes of HDACs (which I think is a bit of a worry from a toxicity perspective) while 002 is of interest because while less potent it doesn’t score positive on the AMES test (the standard test for assessing mutagenic potential). 001 and 003 were both AMES positive. Rats tolerated 3 weeks of 002 in a preliminary safety study. Romas noted that HDAC inhibitors only activate a fraction of the virus expression seen with pan-activating CD4 T cell stimulation using CD3 and CD28 antibodies, raising the question of whether the HDAC inhibitors are only activating a proportion of the latently infected CD4 cells, or rather causing less virus expression per cell. This question remains to be resolved.

High throughput screening of a Gilead library and a commercially available drug library produced a 1% hit rate, identifying 89 compounds that could be grouped into 15 clusters based on their structures. One was a calcium pump inhibitor named thapsigargin, possibly after a character from Lord of the Rings. It was a ‘robust activator’ of latency in cells from 6 out of 6 donors. Romas didn’t say anything more about it and Wikipedia offers an explanation as to why: “It is a tumor promoter in mammalian cells”. Another was a “broad spectrum nonspecific tyrosine kinase inhibitor” called tyrphostin A which worked on cells from 3/6 donors. Since they hadn’t expected to find kinase inhibitors, they then tried screening a library of those and got a 20% hit rate. Evidence of activity at low concentrations and dose responses were seen. Next steps are to confirm activity with more selective kinase inhibitors and explore the signaling pathways that are causing these compounds to work.

Switching to the topic of bolstering immunity, Romas said Gilead is looking at a TLR7 agonist it has in development for hepatitis B. It’s been tested in chimps and woodchucks, where it has shown antiviral activity and dose-dependent induction of alpha interferon production and T cell and B cell activation. In woodchucks, it led to induction of antibodies against the hepatitis B surface protein. A small phase I human study has been safely conducted, also showing evidence of some T cell and B cell activation. Next step is to study the impact on HIV-infected cells and potentially test it in animal models in combination with HDAC inhibitors.

Meanwhile the overarching goals of Gilead’s program continue to be:

• More high throughput screening
• Uncover novel mechanisms (e.g. as may happen as a result of the identification of kinase inhibitors)
• Discover new chemical entities (NCEs).

Roger Sutmuller from Janssen/Tibotec then described his company’s efforts which have not been discussed publically before. He outlined the basic goal of discovering safe and effective compounds to reactivate latent HIV i.e. those that cause little or no cell activation and ideally have the potential to be combined. Unlike Gilead, Tibotec starts with a Jurkat cell line assay to identify compounds, after which they have a preplanned set of steps involving evaluation of:

• Toxicity/immune stimulation
• Virus reactivation in primary T cell assays
• Virus reactivation in latently infected cells from HIV+ individuals ex vivo
• Medicinal chemistry selection of lead compounds
• Testing in a humanised mouse model developed by Roberto Speck
• Testing of the pathways involved in drug activity eg using microarrays, HIV mutants with various signaling elements disabled, short-interfering RNAs etc.

Using the Jurkat cell line assay, 35,000 compounds have been screened to date, and the next step is to screen 480,000 compounds from a Johnson & Johnson ‘diversity library.’ Of those screened to date, 800 HDAC inhibitors have popped out (a 20% hit rate), 25 protein kinase C agonists (a family prostratin belongs to) and 600 unknowns that can be grouped into 11 different ‘chemotypes.’

Sutmuller went on to describe their in-house primary T cell assay, which involves fresh cells expanded in the lab and infected with an HIV encoding green fluorescent protein (GFP). Cells are rested to create latency and then drug activity is measured based on the extent to which the cells light up green. They’re using this assay to screen medium sized libraries; it can handle about 2,000 compounds per week. He showed some data from one compound ‘229,’ which induced virus at about half the level of pan-stimulator PMA, and worked even better in combination with SAHA. The next step is to study these and other compounds in Roberto Speck’s humanised mouse model, which involves 3TC and TDF given in food pellets and a long-acting version of TMC 278 that is delivered by weekly injection. They have seen good viral suppression and can recover latently infected CD4 cells using this system.

Among the other highlights from day two, Una O’Doherty from the University of Pennsylvania showed that CD8 T cells from elite controllers can kill what appear to be latently infected CD4 cells because they express the HIV Gag protein, just with much slower kinetics than seen with activated CD4 cells (and without causing spreading infection). O’Doherty suggested that perhaps this means latently infected CD4 cells aren’t as invisible to the immune system as has been thought, which provoked some controversy because—as she happily acknowledged—it is not yet known whether the same holds true for latently infected CD4 cells from individuals on ART.

In an effort to hone in on which elements of the Berlin patient’s treatment were necessary to achieving the apparent cure of HIV infection, the ever-curmudgeonly John Mellors (University of Pittsburgh) presented an analysis of ten people who had undergone myeloablative chemotherapy and autologous stem cell transplants for lymphoma. None of these individuals were cured of HIV infection, leading Mellors to conclude that in the case of Timothy Brown, the CCR5-negative transplant was important, possibly along with the graft-versus-host disease Brown experienced. In the Q&A afterwards, workshop attendee Mike McCune from UCSF suggested that total body irradiation (TBI) might also have played a role.

Santiago Moreno (Hospital Ramon Y Cajal, Madrid, Spain) presented some preliminary evidence that the CCR5 inhibitor maraviroc may activate a protein complex named NF-kappaB when the drug binds to the CCR5 receptor. Because NF-kappaB activation can stimulate latent HIV, Moreno suggested that maraviroc might have anti-reservoir activity, as was previously suggested by a small uncontrolled pilot study conducted by Moreno’s laboratory and reported at a symposium prior to the 2010 International AIDS Conference in Vienna. However, results from a randomised trial of ART intensification with maraviroc were debuted at the persistence workshop by Maria Puertas, and this study was unable to document any additional declines in HIV reservoirs associated with receipt of the drug (HIV DNA levels fell by ~8-fold in both arms).

In a session on acute HIV infection, Marty Markowitz from Aaron Diamond AIDS Research Center presented 96-week results from a 3-drug vs. 5-drug treatment study, showing essentially no significant differences in a variety of reservoir and immunological measures in blood and gut. There was a slight reduction in cell-associated HIV RNA levels at week 96 in the 5-drug group but Markowitz felt this was unlikely to be meaningful. Jintanat Ananworanich (HIV Netherlands Australia Thailand Research Collaboration) described a study involving treatment of people with very, very early HIV infection, in which 60 people have so far been enrolled, with an average time from screening to enrollment of just 3 days. This would not seem like much time for someone to process the news that they have become HIV infected and make a decision to enter a trial involving a multiple treatments and sampling from the peripheral blood, CNS and GI tract, but Ananworanich said “acceptance rates are quite high.” Individuals were in what in the following Fiebig stages of seroconversion:

• 34% stage I: within 5 days of infection
• 9% stage II: within 10 days of infection
• 48% stage III: within 13 days of infection
• 9% stage IV: within 19 days of infection

24-week results on a subset of participants indicated significantly smaller reservoirs in blood and gut of stage I vs. III or IV, with total and integrated HIV DNA being undetectable in a proportion of the earliest-treated individuals.

The very last presentations of day two involved the tag team of Timothy Schacker (University of Minnesota), Courtney Fletcher (University of Nebraska) and Mario Stevenson (University of Miami) outlining very preliminary results from their small study of viral replication in anatomical and cellular reservoirs. A total of 12 individuals are enrolled, ART naive at baseline but then treated (mostly with TDF, FTC and ritonavir boosted atazanavir) and analysed regularly up to six months. Not all individuals have data available yet, and the number of individuals from whom data were reported varied between the different presenters. Courtney Fletcher looked at drug levels in nine people, finding that some drugs (particularly atazanavir, FTC and efavirenz) may not reach adequate levels in lymph nodes and gut. Mario Stevenson then showed that in some study participants, 2-LTR circles increased in lymph tissue after starting ART, in one case along with a rise in proviral DNA. In one other individual, levels of both 2-LTR circles and proviral DNA went down. Stevenson stated: “this does not necessarily denote ongoing replication” but proposed an alternative model in which a population of long-lived cells can generate virions that infect one more cell and that’s it – just one cycle of replication, in other words. He stated this would not lead to viral evolution but could replenish the latent reservoir. In the Q&A, John Coffin from the NCI got up to the microphone and noted that since latency is a rare event in infected cells, and since Stevenson was saying these were single-cycle rounds of infection, the number of times latency would be created is not known, and may well not be often enough replenish the reservoir.

Timothy Shacker closed out the talks with a description of his efforts to correlate Fletcher’s and Stevenson’s results with measurements of viral RNA on the follicular dendritic cell (FDC) network in lymph tissue (using in situ hybridisation). Schacker created 3D graphs for several participants that included 2-LTR circle levels, DNA levels, levels of viral RNA on FDCs and, lastly, drug levels. There appeared to be correlations between the various measures, but how many people had evidence of ongoing HIV replication cycles was unclear. Schacker noted that there was a significant inverse correlation between levels of FTC diphosphate in lymph tissue and viral RNA on FDCs. Additional results from the expanded version of this study are needed in order to understand if this is a broadly applicable phenomenon, and whether poor tissue penetration of antiretrovirals represents an under-appreciated obstacle to curing HIV infection.

Day three: Margolis reaches a milestone, the crowd thins for functional cures

The major news on day three of the workshop was the presentation by David Margolis (University of North Carolina) of very preliminary results from the phase I/II study of the HDAC inhibitor vorinostat (SAHA). The trial has a complicated schema, largely due to the safety concerns of the FDA regarding the drug, which scores positive on the AMES mutagenic test (a red flag for regulators even though the significance is not fully understood).

The first step of the protocol involved screening potential participants to assess whether vorinostat could reactivate latent HIV from their CD4 T cells ex vivo. Thirteen individuals had ~4 billion lymphocytes extracted by leukopheresis, then sorted into discrete pools of 1 million purified resting CD4 cells each (ending up with 24-36 pools per participant). These pools were exposed to either vorinostat or no drug, and a mean level of HIV RNA per million cells (and a standard deviation) was calculated for each person (the assay used can measure down to 10 copies per million cells). Margolis noted that the statistical approach used to calculate the mean RNA levels is robust but complicated, and a paper explaining it is currently in press at an unnamed statistics journal.

Four of the thirteen people screened showed a statistically significant upregulation of HIV RNA expression in this analysis and were therefore recruited into the next step of the trial. A 200mg dose of vorinostat was given first for safety, followed by a 400mg dose to study pharmacokinetics and for analyses of histone acetylation and acetylation of the p21 gene (in other words, analyses of the effects of the drug on cellular genetic machinery and not HIV). The pharmacokinetic data mirrored that reported in cancer studies and cellular acetylation (both total and p21 gene) was maximal by 8 hours then trended down by 24 hours.

A final 400 mg dose of vorinostat was then administered with leukopheresis performed 4-6 hours afterward based on the pharmacokinetic data indicating this would be around the time of maximum activity. No grade 1 or greater toxicities were seen, and HIV RNA expression increased compared to baseline in all four individuals by a mean of 4.4-fold (range: 3-6.6 fold). HIV RNA in peripheral blood was also assessed using a single copy assay but no change was detected, perhaps not surprisingly given that this was a single dose study.

Margolis was obviously very encouraged by the data and stated that they had successfully “demonstrated induction of full length HIV RNA expression within a window of time after a single vorinostat exposure.” He concluded that obstacles to HIV RNA expression can overcome “at least in some cells.” But he stressed that many questions remain, including:

• Is there an equal effect to multiple doses or does it become attenuated?
• How much exposure is needed?
• Should drug be administered continuously or pulsed?
• Will toxicities emerge?
• What number of cells is needed to measure relatively rare reactivation events?
• Does RNA expression lead to virion production or clearance of cell?
• Are additional inducers needed?
• Are additional interventions needed to clear the latently cells that have been induced to express HIV RNA?

The final session of the meeting was on functional cures. Dishearteningly, the crowd of attendees thinned noticeably but the first presenter, Paula Cannon, was undeterred. “This is the first time people are going to be talking about functional cures,” she opened sunnily. “I know you’re all very obsessed with the reservoirs but we don’t really care about the reservoir – if there’s a little bit of virus left in the body, so what?” Having stuck fear into the hearts of any remaining reservoir obsessives, she then outlined what she meant, highlighting three key goals for those in pursuit of a functional cure:

• Reducing the pool of HIV target cells and thereby reducing the harmful immune activation and inflammation that is central to pathogenesis.
• Creating HIV-resistant HIV-specific CD4 T cells.
• Taking advantage of HIV as a selection agent to drive the expansion of resistant cells.

Cannon went on to review the Sangamo zinc finger nuclease (ZFN) approach to deleting CCR5, the work conducted by her laboratory to adapt it to modify hematopoietic stem cells (HSCs), and the efficacy demonstrated in a published experiment in which humanised mice were engrafted with the CCR5-deleted stem cells and challenged with HIV. Work is now underway to advance the approach into HIV positive people who need stem cell transplants as treatment for lymphoma, in collaboration with John Zaia and David DeGusto from City of Hope who have previous experience of studying gene-modified HSCs in this setting. Cannon explained that preparation for the trial has involved switching from relatively easy-to-use HSCs obtained from fetal cord blood to rather more uncooperative adult stem cells. These cells are called mobilised peripheral blood stem precursor cells (mPSCs) and sampling involves giving G-CSF for four days then conducting apheresis to extract white blood cells, followed by ex vivo purification of CD34+ cells. This procedure has now been performed on 13 donors, obtaining 42 billion white blood cells of which around 0.5% were CD34+ cells; Cannon estimates that around 1% of the CD34+ cells are ‘true’ stem cells. These mPSCs are now being used in mouse studies to address a number of issues prior to human testing.

One such experiment assessed whether pre-existing immunity to adenovirus might be problematic, because an adenovirus vector is used to deliver the zinc finger nuclease into the mPSCs. Mice were given a high titer of anti-adenovirus antibodies prior to delivery of the mPSCs and, encouragingly, no difference was seen in the extent of engraftment compared to controls given phosphate buffered saline (PBS).

Next steps include large scale tumorigenicity studies in ‘NOD scid gamma’ (NSG) mice and evaluation of modified mPSC under ‘maximising’ conditions to test the upper limit of on and off target effects (there is some evidence that ZFNs can disrupt genes other than the CCR5 target, particularly a similar region of the CCR2 gene). Mice given the maximised mPSCs will be kept for many months and extensively analysed for safety.

Following Paula Cannon, Carl June gave an update on the use of the same technology to modify CD4 T cells that are extracted from individuals with HIV using apheresis, expanded and modified in the laboratory, and reinfused into the same individual. Previous presentations of data from these phase I trials has generated considerable excitement, because the proportion of modified CD4 T cells persisting in the blood and gut of participants far exceeds the extremely modest levels obtained with prior gene therapies delivered using the same approach. Significant CD4 T cell count increases have also been documented out to nine months of follow up. Unusually, CD4:CD8 ratios have also significantly improved from an average of 0.5 at baseline to 1.5 at last analysis; this type of improvement is rarely observed as a result of ART, and may have implications in terms of improving long-term health because inverted CD4:CD8 ratios are a well-documented risk factor for illness in the HIV-uninfected elderly.

Most intriguing, however, is a trial involving a 12-week analytical treatment interruption (ATI). Data is now available from six individuals who have undergone the ATI and while all experienced a viral load rebound, levels began falling prior to the reinitiation of ART, which June noted was not the case in a prior gene therapy study involving an ATI (an evaluation of a candidate named VRX496).

One notable individual controlled viral load to below the level of detection (<50 copies/mL) before ART was restarted. This person turned out to be heterozygous for the delta32 CCR5 deletion, which means that the ZFNs could work more efficiently because only one CCR5 gene in each cell had to be disrupted in order for CCR5 expression to be completely abrogated (instead of two as is normally the case). Importantly, June found a significant correlation between the proportion of modified CD4 T cells and viral load control during the ATI. This suggests that an antiretroviral effect is achievable with the approach, and that the potency of the effect may be boosted if the proportion of modified cells can be increased.

In the Q&A period, June was asked if he had assessed whether gene-modified HIV-specific CD4 T cells may have contributed the viral load results; he replied that HIV-specific CD4 T cell responses have not yet been analyzed in the ATI trial.

The last two talks in the final workshop session addressed the development of methods that attempt to specifically target latent HIV and excise it from the DNA of infected cells (or damage the provirus in order to render it non-functional). On paper, at least, these approaches sound very appealing but it was clear that significant hurdles remain. Jan van Lunzen (University Medical Centre Hamburg-Eppendorf) discussed the modification of an enzyme called Cre recombinase to target HIV DNA. The modified version, dubbed Tre recombinase, has successfully excised proviral DNA from cells in vitro and work is now underway to study how it might be delivered. Next steps involve studies in humanised mice using a lentiviral vector to deliver the Tre recombinase to CD34+ stem cells; the vector is designed to be ’self-inactivating’ in cells that do not contain HIV DNA. As an aside, Jan van Lunzen also mentioned a patient of his who started ART during early infection, was treated for five years, then stopped six years ago, had a small viral load blip and has been undetectable ever since. HIV RNA cannot be found in blood, gut or CNS. According to van Lunzen, the individual has a “very strong HIV-specific CD4 response,” and he highlighted the case as being similar to Christine Rouzioux’s report of five individuals treated very early who have controlled viral load to undetectable levels off ART for an average of around five years. [12] These case reports may bode well for prospects for a functional cure, van Lunzen suggested.

Keith Jerome from the Fred Hutchinson Cancer Research Center recounted the efforts of his group to employ different enzymes, endonucleases, to target latent HIV. The idea in this case is to induce mutations in the HIV provirus in order to render it non-functional. Some success has been achieved in vitro but considerable challenges remain in terms of improving the efficiency of targeting and developing delivery methods that might be able to get the endonucleases to where they are needed. Jerome’s work is now being supported by a Martin Delaney Collaboratory grant from NIH.

The last word at the 2011 persistence workshop was given to Nobel laureate Françoise Barré-Sinoussi, who outlined the International AIDS Society’s development of a Global Scientific Strategy ‘Towards an HIV Cure’ and encouraged audience members to attend an IAS symposium on the subject that will take place in Washington DC immediately ahead of the 2012 International AIDS Conference. Barré-Sinoussi also stressed the importance of the work and the need to continue the momentum which has placed curing HIV infection back at the top of the research agenda.

The 6th International Workshop on HIV Persistence, Reservoirs & Eradication Strategies is scheduled for 2013 in Miami.

References

1. Reference Portal on HIV Reservoirs and Eradication Strategies website.
   http://www.hiv-reservoir.net/
2. Margolis D. HIV Persistence during Therapy 5th International Workshop. natap.org, 2011.
   http://www.natap.org/2011/HIV/122111_01.htm
3. Cohen J. Tissue says blood Is misleading, confusing HIV cure efforts. Science 23 December 2011: Vol. 334 no. 6063 p. 1614.
   http://www.sciencemag.org/content/334/6063/1614.summary
4. Clinical Trial. Tissue drug levels of HIV medications.
   http://clinicaltrials.gov/ct2/show/NCT01490346
5. Mario Stevenson Interview. (9 December 2011).
   http://www.youtube.com/watch?v=_fhb95p__9g
6. Andrea Savarino Interview on HIV Cure. (10 December 2011).
   http://www.youtube.com/watch?v=xIqdDU_OEFU
7. Lewis MG et al. Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS. 25(11):1347-1356, July 17, 2011.
   http://journals.lww.com/aidsonline/toc/2011/07170
8. Hazuda D. Powerpoint can be downloaded at the bottom of this page, Luciw’s data is on slides 21-25):
   http://www.iasociety.org/Default.aspx?pageid=416#session5
9. TEDxUCLA – Leonard Rome – online video. (29 August 2011).
   http://tedxtalks.ted.com/video/TEDxUCLA-Leonard-Rome-Vaults-mo
10. HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy. J Infect Dis. (2012). First published online: 24 January 2012.
    http://jid.oxfordjournals.org/content/early/2012/01/24/infdis.jir884.abstract
11. Bosque A et al. Studies of HIV-1 latency in an ex vivo model that uses primary central memory T cells. 2011 Jan;53(1):54-61. Epub 2010 Oct 21.
    http://www.ncbi.nlm.nih.gov/pubmed/20970502
12. Hocqueloux C et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. 19 June 2010 – Volume 24 – Issue 10 – p 1598-1601.
    http://journals.lww.com/aidsonline/Fulltext/2010/06190/Long_term_immunovirologic_control_following.27.aspx

The lead in dose of 200 mg once daily (using the original formulation) is still required, with the same caution not to increase to the 400 mg daily dose if the patient shows rash at the end of these 14 days.

The daily price of nevirapine PR has been price matched to the price of the 200 mg formulation.

Reference:

Boehringer press release: Viramune (nevirapine) prolonged-release once-daily formulation receives approval in the EU. (Septemebr 2011).

http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/21_september_2011nevirapine.html

The recommended oral dose of 200 mg etravirine is one tablet taken twice daily following a meal. The previous formulation required 2 x 100 mg twice-daily.

These tablets are dispersible in a glass of water. This option may be important given the new pill is slightly larger than the 100 mg formulation (22 mm vs 19 mm long).

The monthly list price for the 200 mg formulation is matched to the current daily price for the 100 mg formulation at £301.27.

Source: Janssen PR: Janssen launches 200mg etravirine (Intelence) for anti-retroviral treatment-experienced adults with HIV-1. (17 January 2012).

An oral powder (40 mg per 1 gram of oral powder) formulation and 150 mg, 200 mg and 250 mg tablets were also approved to support dosing in paediatric patients.

The major changes to the product labeling include information on dosing plus efficacy and safety concerns based on clinical studies.

These include:

Dosing

• Recommended dose in paediatric patients 2 years of age and older is 8 mg of tenofovir DF per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets. Tables 1 and 2 of the product labeling contain dosing recommendations for tenofovir oral powder and tablets based on body weight. Weight should be monitored periodically and the tenofovir dose adjusted accordingly.
• Tenofovir oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder, which contains 40 mg of tenofovir DF. Tenofovir oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g. applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer tenofovir oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer tenofovir oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling.
• Tenofovir is also available as tablets in 150, 200, 250 and 300 mg strengths for paediatric patients who weigh >/=17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.
• There are no data to recommend use of tenofovir tablets 150, 200 or 250 mg or tenofovir oral powder in patients with renal impairment.

Safety and Efficacy

The safety and efficacy data of tenofovir in paediatric patients is supported by data from two randomised trials (Studies 352 and 321). This involved only 184 treatment-experienced children (aged 2 to <18 years), only half of who received tenofovir and half received d4T or AZT. Tenofovir was later provided to these children.

Bone Mineral Density (BMD)

Bone effects were similar to those observed in adult subjects. Under normal circumstances BMD increases rapidly in paediatric patients. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the tenofovir and the d4T or AZT treatment groups. Total body BMD gain was less in the tenofovir compared to the d4T or AZT treatment group. One tenofovir-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z-scores were -0.012 for lumbar spine and -0.338 for total body in the 64 subjects who were treated with tenofovir for 96 weeks. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the tenofovir compared to the placebo treatment group. Six tenofovir treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were -0.341 for lumbar spine and -0.458 for total body in the 28 subjects who were treated with tenofovir for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected. Markers of bone turnover in tenofovir-treated paediatric subjects suggest increased bone turnover, consistent with the effects observed in adults.

Eighty-nine paediatric subjects received tenofovir in Study 352 (48 who were initially randomised to tenofovir and 41 who were initially randomised to continue stavudine or zidovudine and then received tenofovir in the extension phase) for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these four subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score.

For full details please refer to the new label:

http://www.accessdata.fda.gov/scripts/cder/drugsatfda

In addition a 100 mg scored chewable tablet and 25 mg chewable tablet was approved for use in paediatric patients.

Safety, efficacy and formulation data were from the IMPAACT P1066 Phase I/II study in 126 treatment experienced children (age 2 to 18 years) who received either the 400 mg film-coated tablet formulation (6 to 18 years of age) or the chewable tablet formulation (2 to less than 12 years of age). Raltegravir was administered with an optimised background regimen.

The Dosage and Administration section includes the following dosing recommendations and dosing recommendations for pediatrics. Main changes to the product label are also included below.

General Dosing Recommendation

• Raltegravir Film-Coated Tablets and Chewable Tablets can be administered with or without food
• Maximum dose of chewable tablets is 300 mg twice daily.
• Raltegravir Chewable Tablets may be chewed or swallowed whole.
• Raltegravir Film-Coated Tablets must be swallowed whole.
• Because the formulations are not bioequivalent, the chewable tablets should NOT be substituted for the 400 mg film-coated tablet.
• During coadministration of raltegravir 400 mg film-coated tablets with rifampin, the recommended dosage of raltegravir is 800 mg twice daily in adults. There are no data to guide co-administration of raltegravir with rifampin in patients below 18 years of age. All interaction studies were performed in adults

Paediatric Dosing

Dosing is recommended based on age and weight:

• 12 years of age and older:
  • One 400 mg film-coated tablet orally, twice daily
• 6 to less than 12 years of age:
  • If at least 25 kg in weight:
    • One 400 mg film-coated tablet orally, twice daily OR
    • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 – please refer to prescribing information for details.
  • If less than 25 kg in weight:
    • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 – Please refer to prescribing information for details.
• 2 to less than 6 years of age:
  • If at least 10 kg in weight:
    • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 – Please refer to prescribing information for details.

Warnings and Precautions

Raltegravir chewable tablets contain phenylalanine, a component of aspartame. Each 25 mg raltegravir chewable tablet contains approximately 0.05 mg phenylalanine. Each 100 mg raltegravir chewable tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

Adverse Reactions

In the IMPAACT P1066, frequency, type and severity of drug related adverse reactions through week 24 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

The following information was added to Section 12.3 Pharmacokinetics:

• Under Absorption: Based on a formulation comparison study in healthy adult volunteers, the chewable tablet has higher oral bioavailability than the film-coated tablet
• Under Effect of Food on Oral Absorption: Administration of chewable tablet with high fat meal led to an average 6% decrease in AUC, 62% decrease in Cmax and 188% increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food
• Special Populations: The doses recommended for HIV-infected children and adolescents 2 to 18 years of age resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily. A Table was added to the package insert to display the raltegravir steady state pharmacokinetic parameters in paediatric patients.

Clinical Studies

The median age of the 96 study participants in IMPAACT P106 receiving the recommended raltegravir dose was 13 (range 2 to 18) years, 51% female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0 – 2361) and median CD4% was 23.3% (range: 0 – 44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).

Ninety-three (97%) subjects completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 72% achieved HIV RNA <400 copies/mL or =1 log10 HIV RNA drop from baseline. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).

Source: FDA HIV/AIDS Update (21 December 2011).

For full details please refer to the updated prescribing information:

http://dailymed.nlm.nih.gov/dailymed/about.cfm

Additionally, the product labeling was updated to provide dosing recommendations for paediatric patients ages 3 to less than 6 years of age and for adult and paediatric patients greater than 6 years of age who can not swallow darunavir tablets.

Treatment-naïve adults and treatment experienced adults with no darunavir resistance associated substitutions can take darunavir 8 ml once daily with 1.25 ml of ritonavir once daily with food. The 8 mL dose should be taken as two 4 mL administrations with the included oral dosing syringe.

For treatment-experienced adults with at least one darunavir resistance associated substitution the dose for oral suspension is 6 mL twice daily with 1.25 mL ritonavir twice daily with food.

For paediatric patients, dosing with oral suspension or tablets is based on weight. Please refer to full prescribing information for details. Do not use darunavir/ritonavir in paediatric patients below 3 years of age.

Section 6 Adverse Reactions (ADRs) was updated as follows:

• ADRs to darunavir/ritonavir (all grades, >/= 3%), excluding lab abnormalities, were diarrhea (19%), vomiting (14%), rash (10%).
• There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study.

Section 14: Clinical Studies was updated to reflect the results from the paediatric trial as follows:

Study TMC114-C228

Treatment-experienced paediatric subjects between the ages of 3 and less than 6 years and weighing greater than or equal to 10 kg to less than 20 kg received darunavir oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs. Twenty-one subjects received at least one dose of darunavir/ritonavir.

The 21 subjects had a median age of 4.4 years (range 3 to less than 6 years), and were 48% male, 57% Black, 29%, Caucasian and 14% other. The mean baseline plasma HIV-1 was 4.34 log10 copies/mL, the median baseline CD4+ cell count was 927 x 106 cells/l (range: 209 to 2,429 x 106 cells/l) and the median baseline CD4+ percentage was 27.7% (range: 15.6% to 51.1%). Overall, 24% of subjects had a baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL. All subjects had used greater than or equal to 2 nucleoside reverse transcriptase inhibitors (NRTIs), 62% of subjects had used greater than or equal to 1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and 76% had previously used at least one HIV protease inhibitor (PI).

Twenty subjects (95%) completed the 24 week period. One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir.

The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was -57% and 81%, respectively. The mean change in CD4+ percentage from baseline was 4%. The mean change in CD4+ cell count from baseline was 109 x 106 cells/L.

Dose recommendations from the two studies were based on the following:

• Similar darunavir plasma exposures in children compared to adults, and
• Similar virologic response rates and safety profile in children compared to adults

Source: FDA HIV/AIDS Update (16 December 2011).

For full details please refer to the updated prescribing information:

http://dailymed.nlm.nih.gov/dailymed/about.cfm

If Sustiva is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of Sustiva to 800 mg once daily is recommended.

The recommendation to increase the dose of efavirenz to 800 mg in patients weighing 50 kg or more when efavirenz is co-administered with rifampin is based on empirical data from two drug-drug interaction trials (one trial in healthy volunteers and one trial in HIV-1 infected patients) and semi-mechanistic population pharmacokinetic modeling. The population pharmacokinetic model was constructed using data collected in the drug-drug interaction trials and single-and multiple dose pharmacokinetic data of efavirenz from other healthy volunteer trials.

The data from the drug-drug interaction trials showed that rifampin decreased the exposure of efavirenz 600 mg once daily. Further, the systemic exposure of efavirenz, when efavirenz 800 mg was coadministered with rifampin, was similar to the systemic exposure of efavirenz when efavirenz 600 mg once daily was given alone. The results from the population pharmacokinetic analysis were consistent with the empirical data.

Source: FDA HIV/AIDS Update (06 January 2012).

For full details please refer to the updated prescribing information:

http://dailymed.nlm.nih.gov/dailymed/about.cfm

FDC: Fixed Dose Combination

‘Tentative Approval’ means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but because of existing patents and/or exclusivity rights, it cannot yet be marketed in the United States. Tentative approval does, however make the product eligible for consideration for purchase under the PEPFAR program for use outside the United States.

Fixed Dose Combinations are reviewed for PEPFAR under the FDA guidance titled ‘Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously approved Antiretrovirals for the Treatment of HIV’. This document was developed to clarify what regulatory requirements apply to such applications, what issues might be of concern, and how these issues should be addressed. The guidance is intended to encourage sponsors to submit applications for combination and co-packaged products, and to facilitate submission of such applications to FDA.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079742.pdf

Effective patent dates are listed in the agency’s publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book:

http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm

An updated list of generic tentative approvals (now at 140) is available on the FDA website:

http://www.fda.gov/oia/pepfar.htm

Source: FDA list serve:

http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm

Some of the first indications that the economic debt crisis in Europe will contribute to 2012 being a disastrous year for global health came in articles from the corporate financial institution Bloomberg Businessweek (not known for it’s focus on HIV news) and the mainstream scientific journal Nature.

This year will not be business as usual for anyone, and those most dependent on international aid are most vulnerable.

The impact of the suspension of Round 11 of Global Fund grants, reported in both this and the previous issue of HTB is causing global concern. The Bloomberg article includes MSF data on 28,000 people in the Democratic Republic of the Congo who will not now be able to start treatment. This seems likely to be an underestimate. Similar reports and concerns – often with a greater human impact – are likely to apply to every country with limited access to HIV treatment.

For example, in a report on the implications of the funding crisis for Malawi, which currently has no funding past 2013, an estimated 200,000 people currently in need of treatment will not be able to access antiretrovirals.

Both reports focus on the impact that unfulfilled pledges from 2008 from leading European countries has had on the Global Fund. According to the Fund’s website, outstanding pledges include $168 million from Italy (from 2009) and $116 million from Spain (from 2010). Five countries – Italy, Spain, Greece, Iceland and Portugal – also made no pledges last year. Holland has cut the proportion of GDP allocated to development assistance from 0.8 to 0.7%. While the US increased funding by 1.6% to $7.6 billion and the UK and Germany (the second and third largest donors after the US) increased pledges by 14%, global donor commitments that had increased to $8.7 billion in 2008, flat-lined in 2009 and dropped by 10% in 2010. The budget available for treatment in the PEPFAR fell by 17% and was accompanied by a shift from adult care exclusively to a mother and child programme. In countries where funding programmes has made treatment is available – and over six million people now access ARVs – it remains largely based on archaic use of d4T (stavudine) despite alternatives such at tenofovir being cost effective. The funding uncertainty will clearly also undermine key WHO recommendations to switch away from use of d4T and earlier treatment using a CD4 threshold of 350 rather than 200 cells/mm3.

Access to treatment has always provided the incentive for people to come forward to test. Whether this was for AZT in 1987 or HAART in 1997 in Western countries or in any of the global access programmes rolled out since 2000. Without the hope of any intervention to improve a person’s individual health it has always been difficult to argue that learning you are HIV positive is going to improve your quality of life. Even with treatment, diagnosis is currently late for the majority of people, when defined as a CD4 count lower than the threshold recommended for starting treatment. But without it, HIV will be driven back underground, testing programmes will falter, and the progress from the last ten years will slowly be lost.

It is spectacularly short sighted for this to be occurring at exactly the time when effective treatment is not only cheaper than every before but also proven to be the most effective method of preventing further transmission.

References:

Bennett S. Financial crisis may kill in Congo as global health aid stalls. Bloomberg Buisnessweek. 17 January 2012

http://www.businessweek.com/news/2012-01-18/financial-crisis-may-kill-in-congo-as-global-health-aid-stalls.html

MSF press statement: DRC: Majority of people living with HIV denied treatment. (25 January 2012).

http://www.doctorswithoutborders.org/press/release.cfm?id=5742&cat=press-release

Farquhar D et al. Breaking promises to the poor: the donor retreat puts Malawi’s AIDS programme in peril (unpub).

Wadman M. Cutbacks threaten HIV gains. Nature; 480; 159-160. (08 December 2011).

http://www.nature.com/news/cutbacks-threaten-hiv-gains-1.9581

The Medicine Patent Pool, founded and financed by UNITAID, seeks to increase access to HIV medicines by negotiating with pharmaceutical companies for voluntary licenses for ARVs that are still covered by patents. The work of the Pool has received support from the World Health Organization, UNAIDS, the Global Fund to Fight HIV, TB, and Malaria, and the G8.

Licensing agreements have already been developed with Gilead Sciences and the US National Institutes of Health, with ongoing negotiations with Boehringer-Ingelheim, Bristol-Myers Squibb, F. Hoffman LaRoche, Sequoia Pharmaceuticals, and ViiV Healthcare (GSK/Pfizer).

Generic companies contribute a royalty to make lower cost versions of new HIV treatments for use in developing countries.

Source: Patent Pool press release. Johnson & Johnson says ‘no’ to joining the Medicines Patent Pool. (19 December 2011).

http://www.medicinespatentpool.org/NEWS-ROOM/News-from-the-Pool/JandJ-Says-No

This included support for four years for the Medicines Patent Pool to negotiate voluntary licenses from brand companies to generic manufacturers to facilitate affordable access to HIV/AIDS medicines in developing countries.

“Precisely because funding for AIDS is threatened by the economic crisis, we need to leverage all the tools at our disposal to ensure staunch commitment to increase treatment coverage,” said Philippe Douste-Blazy, Chairman of the UNITAID Executive Board. “Innovative mechanisms that can increase treatment availability and decrease prices, such as the Pool, are critical components of UNITAID’s strategy to address the funding gap… The Pool has achieved promising results in its first year and we urge all pharmaceutical companies to enter into licensing agreements to breach the gap of 15 million people who need treatment.”

The UNITAID Board committed US$62 million to continue supporting the scale-up of HIV/AIDS treatment for children in partnership with the Clinton Health Access Initiative. US$50 million was committed to the Global Fund to increase access to artemisinin-based combination therapy in the eight African countries that bear the largest malaria burden.

Source: UNITAID press release: UNITAID continues funding the Patent Pool and paediatric HIV medicines: Additional US$50 Million Allotted to Malaria. (14 December 2012).

http://www.unitaid.eu/en/component/content/article/3-press/380-additional-us-50-million-allotted-to-malaria

On 24 January 2012, Michel Kazatchkine announced that he will “step down” as Executive Director of the Global Fund by mid-March. He said that his planned resignation resulted from a decision by the Global Fund Board two months ago to appoint a General Manager who will supervise many Global Fund activities and who will report direct to the Board. GFO understands that this decision by the Board to transfer many of Dr Kazatchkine’s responsibilities to someone else arose from the Board’s concern that the Fund’s managerial leadership was not sufficiently effective.

“For the last ten years, the Global Fund has been my passion and my most important undertaking,” Prof. Kazatchkine said in a statement to staff. Simon Bland, Global Fund Board Chair, responded by saying, “Few individuals have played a more central role in the creation and evolution of the Global Fund than Michel.”

The Global Fund also announced today that the General Manager will be Gabriel Jaramillo, a prominent banker from Latin America who was one of the members of the High Level Panel that extensively evaluated the work of the Global Fund during 2011. Mr Jaramillo spent three days last week meeting senior staff at the Global Fund.

The Global Fund said that Mr Jaramillo will take up a 12-month appointment on 1 February. The Fund did not specify whether Mr Jaramillo will serve as Acting Executive Director once Dr Kazatchkine leaves, but it implied that he will when it said, in a Q&A document sent to Board delegation members, that Mr Jaramillo will “take over all of the management responsibilities of the Global Fund Secretariat.” A spokesman told GFO that the Global Fund will launch a search for a new Executive Director “in due time.”

Mr. Jaramillo, a native of Colombia and a citizen of Brazil, is a former Chairman and Chief Executive Officer of Sovereign Bank. Since he retired a year ago, he has served as a Special Advisor to the Office of the Special Envoy for Malaria of the Secretary General of the United Nations. Mr Bland said in a press release that Mr Jaramillo “is an outstanding choice, and exactly what we need at this time: an excellent manager and a proven financial leader who can direct change and improve performance in a large institution during a time of transition.”

Source: Global Fund Observer (GFO) Issue 174: 24 January 2012.

http://www.aidspan.org.gfo

http://www.theglobalfund.org/en/mediacenter/pressreleases/2012-01-24_The_Global_Fund_Executive_Director_to_step_down_in_March/

Organised by civil society activists at the World AIDS Campaign they state that the cancellation by the Global Fund of all new programming until 2014 will cost lives and cripple international efforts to deliver on health-related goals, and that it breaks promises made to some of the world’s most vulnerable people.

The Call to Action demands that the Global Fund hold an emergency donor conference and issue a new call for proposals before the International AIDS Conference in July 2012. The Call says, “This is 200 days from 1 January. 200 days to save the Global Fund.”

Further information:

http://www.worldaidscampaign.org/2011/12/global-fund-call-to-action/

Source: Global Fund Observer (GFO) Issue 169: 5 December 2011.

http://www.aidspan.org.gfo

At its meeting in December 2010, the Global Fund Board approved the launching of Round 11. At its meeting in May 2011, the Board discussed but did not change this decision.

Therefore, in August 2011, Round 11 was launched, and many CCMs devoted enormous amounts of work to preparing their proposals. Then last month, in November 2011, the Board cancelled Round 11.

Why was Round 11 launched and then cancelled? And what does the decision to cancel Round 11 tell us about the Global Fund’s financial condition?

In a nutshell, the answer is…

Unlike what some news reports have suggested, the Global Fund has billions of dollars in the bank, with billions more expected to arrive during the next two years. The problem is that most of that money is needed for the current and renewal phases of existing grants. In addition, the Fund has introduced a more cautious methodology for estimating how much funding it will receive in future. Primarily because of these two factors, the Global Fund now estimates that until 2014, it will have almost no money for new grants. Hence, the need to cancel Round 11. It is not accurate to say that Round 11 was cancelled because of decisions by donors since May to cancel, reduce or delay their pledges, because that is not happening.

In somewhat more detail, the answer is….

As Simon Bland, Global Fund Chair, said, recently, the Global Fund disbursed $8 billion during the three-year period 2008-2010, and the Fund forecasts that it will have enough money to be able to disburse $10 billion during 2011-2013. This is a 25% increase from one period to the next.

Unfortunately, however, the $10 billion that the Global Fund expects to be able to disburse in 2011-2013 is about $1 billion less than the Fund had forecast in May 2011. Almost all of the $10 billion will be needed to fund existing grants and the renewals of existing grants. Grants are normally approved for a two-year Phase 1 followed by a three-year Phase 2. The Global Fund’s policies require that priority be given to Phase 2 renewals of existing grants, over the funding of new grants.

In May 2011, when the Global Fund was forecasting that it would be able to disburse about $11 billion in 2011-2013, the Fund estimated that $1.55 billion of that would be available for Round 11 grants. By the time of the Board meeting in November, that estimate went down to minus $0.6 billion. That meant that not only was there no money for Round 11, but also the Global Fund was short of money to pay for grant renewals and probably also for some unsigned Round 10 grants.

The decisions that were made during the Board meeting – decisions that achieved savings by reducing the amount of money required for future grant renewals – increased the estimate of available money from minus $0.6 billion to plus $0.6 billion. However, this amount was not deemed to be enough to permit the launching of Round 11 before 2014. Rather, the money has to be used primarily for funding those Round 10 grants for which grant agreements have not yet been signed, and for funding transitional arrangements (i.e., essential services) for grants that will end soon.

Thus, new grants now cannot be approved until 2014, though the Fund may decide to invite applicants to start preparing proposals during 2013.

In the last few years, the Global Fund has had some serious problems with certain donors, particularly the following:

• Italy has not yet pledged any money for 2011-2013, and has not delivered any of the $347 million it pledged for 2009-2010.
• Spain has not yet pledged any money for 2011-2013, and has not delivered $116 million of the $250 million it pledged for 2010.
• Ireland has not yet pledged any money for 2011-2013, and has not delivered $35 million of the $46 million it pledged for 2010.
• Netherlands has not paid $37 million of the $119 million it pledged for 2010.

However, those problems were all known when the Board agreed in May 2011 to launch Round 11. They are not new. The main factors that last month caused the Global Fund to reduce its revenue projections from the May 2011 levels, and therefore to cancel Round 11, were as follows:

• Many donors make their pledges in Euros and other non-dollar currencies. Between May and November, those currencies, on average, weakened against the dollar, so the anticipated dollar value of those pledges decreased by about $100 million.
• Some of the $4.0 billion that the U.S. announced last year for 2011-2013 will not be received until 2014, because U.S. legislation specifies that not all of each year’s money can be handed over until the U.S. government can certify to Congress that a number of conditions have been met.
• There has been a reduction in estimated interest earnings from the Fund’s money in the bank.
• Most significant by far: The Global Fund has developed a new and more cautious forecasting methodology regarding future income from donors. (The Global Fund refers to this as producing “risk-adjusted” forecasts.) The new methodology was introduced because the negative economic situation and the challenging political environment create uncertainties that are difficult to reflect in a multi-year forecast. In its new risk-adjusted forecasts, the Global Fund no longer automatically assumes that all countries will give the exact amount they pledged or that the funds will arrive equally distributed across the years to which the pledge applied. For example, the amount announced by the U.S. for the fiscal years 2011-2013 ($4.0 billion) is subject to Congressional approval each year. The Global Fund hopes – but cannot be certain – that the U.S. Congress will approve the full amount each year.

It is important to point out that only one country has formally cancelled or reduced the pledge that it originally made for 2011-2013. This is Denmark, which reduced its pledge by approximately $10 million; this represents well under one percent of what would have been needed for Round 11.

At the Accra Board meeting, the Executive Director said that the problems which then led the Board to cancel Round 11 represented a “perfect storm” of factors. Some participants privately blamed the Secretariat for not taking the possibility of those factors into consideration when it launched Round 11. Others blamed the Board for accepting the Secretariat’s May projections.

Source: Global Fund Observer (GFO) Issue 170: 9 December 2011.

http://www.aidspan.org.gfo

The following reactions from key organisations to the Global Fund’s decision to do away with Round 11 were highlighted in a GFO article.

Health GAP

“The funding window that was cancelled today would have enabled scale-up of lifesaving treatment and prevention services for HIV, tuberculosis and malaria to millions of poor people in developing countries.

“What is particularly scandalous about this cancellation is that donors didn’t have to do it. The amounts of money we’re talking about are barely a rounding error in donor budgets.”

MSF

“There’s a shocking incongruence between both the new HIV science and political promises on one hand, and the funding reality that is now hitting the ground on the other. Donors are really pulling the rug out from under people living with HIV/AIDS at precisely the time when we need to move full steam ahead and get life-saving treatment to more people.”

ITPC

“The lack of political and financial commitment to the AIDS response is deeply worrisome. The millions of people living with and fighting against these deadly diseases will pay an enormous price. Rather than building on the new evidence that AIDS treatment saves lives and prevents new infections, and scaling up treatment programs to try to end this epidemic, donor governments are now implicitly supporting a policy of triage, determining who lives and who dies.”

“The shortfall in funding for the Global Fund is an insignificant amount in comparison to the bank bailouts made by the U.S. and European governments, or even the bonuses set aside for Goldman Sachs executives this year.”

International HIV/AIDS Alliance

“The news that the Global Fund Board had decided to cancel Round 11 has devastated civil society organisations across the Alliance global partnership. We should not be shy in saying this decision and the financial situation of the Global Fund at this moment is a disaster for Africa.”

“International solidarity, perhaps the most precious resource needed to reach the Millennium Development Goals, is in dangerously short supply. A few days ago at the Fund’s meeting, tensions were high among representatives of implementer countries: They were fighting to be granted the dubious recognition of being the poorest among the poor in order to guarantee their access to the few resources still left. During these discussions, we tend to forget that people have a right to live regardless of where they were born.”

Coalition of AIDS activist organisations in Southern Africa

“It is a disaster for Zimbabwe as a country. More than 86,000 people will be left without treatment and about 5,000 children will be affected. The situation in Swaziland, where approximately 26 percent of the population of 1.2 million live with HIV, is dire, with stockpiles of ARVs already dwindling”.

The Guardian

The Global Fund has been “staring at a financial black hole ever since its big replenishment meeting in New York a year ago failed to deliver the sums it hoped for. It wanted $20bn. It got $11.7bn. That was in spite of exhortations to donors to pledge money from the U.N. Secretary General, Ban Ki-moon, who warned that the stakes were high and that lives would be lost if pressure on the big killer diseases was not maintained.”

New Statesman

“it reveals just how precarious daily life has become for the global 99 per cent: those whose very health, as much as their job security, is pegged to the rise and fall of the money markets. The politics of austerity we are going through has not even begun to be properly costed. This is the real lesson of the Global Fund’s demise and it will require much more than simply getting wealthy donors back on board to address it.”

Source: Adapted from Global Fund Observer (GFO) Issue 169: 5 Dec. 2011.

http://www.aidspan.org.gfo

In writing to the Bill and Melinda Gates Foundation, the group were advocating against the proposed financial support for continued research into the use of the nucleoside analogue d4T (stavudine), even at the proposed lower 20 mg dose. [2]

Stavudine has long been discontinued in Western countries due to an unacceptably high risk of serious side effects in comparison to alternative drugs in the same class.

The letter argues strongly against this research and was concerned that previous meetings with representatives from the Foundation had not been formally answered. It argues for a focus on increasing access to safer cost-saving alternatives to d4T, not on seeking a comeback for a drug virtually abandoned in rich countries.

The objections, summarised from the letter, include:

d4T’s significantly worse side effects are well documented

In 2004, d4T was removed from the list of preferred first-line antiretroviral drugs recommended by the US Department of Health and Human Services (DHHS). [3]

Starting in 2006, the WHO recommended that countries start moving away from d4T, and in 2009 recommended that the drug be phased out in first-line antiretroviral treatment (ART) programmes. [4]

In 2011, the European Medicines Agency (EMA) revised the indication for d4T, noting, “…that the use of the medicine should be severely restricted in both adults and children… Prescribers are reminded of the severe side effects seen with Zerit [d4T] and should only use the medicine when other appropriate treatments are not available. Patients being treated with Zerit should be assessed frequently and switched to appropriate alternatives as soon as possible.” [5]

Evidence of d4T’s toxicity in an operational setting has been reported from studies in Lesotho [6] and South Africa. [7]

There is no prospect that d4T 20 mg is a better option than tenofovir and retains significant toxicity even at lower doses. Results from over 10,000 patients randomised to receive 40 (30) mg or 20 (15) mg in early access (1992-94), reported rates of 15% vs 21% in the lower vs higher dose arms. [8]

The cost of these side effects will significantly reduce price savings

MSF report higher inpatient care and essential drug costs were higher for people on d4T than those on tenofovir. In Lesotho, the tenofovir-containing regimen generated higher life years and QALYs than AZT or d4T-based treatment. [9] As the costs of tenofovir and especially efavirenz drop, the cost benefit to patients and to health systems will become clearer. Since the study was completed, the global best price of efavirenz – which partly drives tenofovir costs – has almost halved ($97 ppy in 2009 to $52 today).

d4T’s long-term toxicity will not be studied

The proposed 20 mg d4T dose might be acceptable in a short-term 48- or even 96-week virologic endpoint study (although Bristol-Myers Squibb studied and rejected 20 mg BID). But, because mitrochondrial toxicity is both dose and time dependent, many of d4T’s most serious side effects (such as peripheral neuropathy and lipoatrophy) would not necessarily emerge until after such a study was completed. This study does not include monitoring of surrogate markers for mitochondrial toxicity, so it cannot shed light on the incidence of this serious adverse event.

This trial will not therefore be able to answer the primary policy question which drives it – whether long-term 20 mg d4T BID is as good as tenofovir QD in first-line ART regimens for use in public health programmes in resource-limited settings.

Implications for HBV coinfection

A tenofovir-based regimen is recommended for HIV/hepatitis B (HBV) coinfection, because d4T has no activity against HBV and resistance to lamivudine is inevitable. While HIV/HBV co-infection is an exclusion criterion for this trial, it may encourage persistent use of a suboptimal regimen for HIV/HBV co-infected people. Giving a d4T/lamivudine-based regimen to HIV/HBV co-infected people will create lamivudine resistant HBV in this population (90% at four years). [10, 11]

Potential savings may be out-dated when the study ends

The rationale for this trial is to lower treatment costs but the price of alternatives, notably tenofovir, has come down dramatically in the last several years, and is expected to decrease further as demand increases. According to MSF’s annual ARV pricing report, tenofovir is now cheaper than AZT, with the price of single-drug tenofovir having decreased by 52% from 2008 to 2011, and the price of the triple fixed-dose combination of tenofovir, lamivudine and efavirenz having decreased by 53% to US$173 per person per year over that same time period. [12]

The proposed study will not have 96-week results before 2014, and will need perhaps five-year field effectiveness trial to determine longer-term tolerability.

The anticipated cost savings associated with d4T could easily be overtaken by expected further price reductions for tenofovir. Currently a one-pill-once-a-day regimen containing efavirenz and tenofovir costs roughly half of what d4T-based combinations cost when they was first introduced a decade ago.

Potentially greater savings could be achieved if the tenofovir prodrugs in development with both Gilead and Chimerix are approved. A recent announcement by Gilead of an agreement with Tibotec to develop an FDC of darunavir, emtricitabine, GS 7340 and cobicistat with “less than one tenth of the amount of the 300 mg of tenofovir disoproxil fumarate contained in Viread and Truvada” suggests that this is feasible. [13] Low milligram dosing (and therefore low potential cost) is also used for the integrase inhibitor dolutegravir (50 mg once daily).

The letter was signed by activists from Médecins Sans Frontières , HIV i-Base , Treatment Action Group (USA), Treatment Action Campaign (South Africa), Health GAP (USA) and the European AIDS Treatment Group.

The letter can be read in full on the TAG website:

http://www.treatmentactiongroup.org/hiv/2011/lowdose-stavudine-trial

comment

In the short time since the letter was distributed two further publications has supported caution into further use of d4T. Vichet Phan and colleagues published data on rates of severe d4T-associated toxicity in a cohort of patients in Cambodia, with 7% of people having neuropathy within the first years and a cumulative incidence of lipoatrophy of 56% by 3 years and 72% by 6 years. [14]

Further concerns from people directly affected by continued use of d4T, the Malawi Network of People Living with HIV/AIDS (MANET+) held a press briefing concerned by the slow pace for phasing out current use of this drug in Malawi. Despite the funding crisis the Malawi government has a priority for this to be completed by June 2012. [15]

It is unclear why the Gates Foundation considers this study to be a priority and it seems an aberration in an otherwise carefully considered strategy for supporting research into the optimisation of ART for resource limited settings . This includes the ENCORE 1 study of low dose efavirenz, the reformulation of tenofovir to increase its bioavailability (working with CHAI) and the development of innovative potentially long acting formulations.

As Bad Science’s Ben Goldacre wrote: “Why is the Gates Foundation supporting this trial of a rubbish AIDS drug?”. [16]

References

1. Andrieux-Meyer I et al. Letter Opposing a Proposed Low-dose Stavudine Trial (14 December 2011).
   http://www.treatmentactiongroup.org/hiv/2011/lowdose-stavudine-trial
2. A randomised, double-blind study to demonstrate non-inferiority of stavudine (20 mg BID) compared with tenofovir (300 mg QD) co-administered with lamivudine and efavirenz in antiretroviral-naive patients over 96 weeks. If funded and approved, the trial is anticipated to start early 2012.
3. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 29 October 2004.
   http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL10292004002.pdf
4. WHO Rapid Advice: Antiretroviral therapy for HIV infection in adults and adolescents. November 2009, page 10.
   http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf
5. EMA 17 February 2011. EMA/127094/2011. EMEA/H/C/000110/R/79. Questions and answers on the review of Zerit (stavudine): Outcome of a renewal procedure.
   http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/human/000110/WC500102227.pdf
6. Adjusted hazard ratio: 5.43, 95% confidence interval: 3.31 to 8.91. Bygrave H et al. 2011. Implementing a tenofovir-based firstline regimen in rural Lesotho: clinical outcomes and toxicities after two years. J Acquir Immune Defic Syndr. 2011 Mar 1;56(3):e75-8.
   http://www.ncbi.nlm.nih.gov/pubmed/21164354
7. Menezes et al. A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects. BMC Infectious Diseases 2011, 11:244 doi:10.1186/1471-2334-11-244
8. Anderson R et al. Design and implementation of the stavudine parallel track programme. Comparison of safety and efficacy of two doses of stavudine in a simple trial in the US parallel track programme. J Inf Dis. 1995; 171:118-22.
9. Jouquet et al. Cost and cost-effectiveness of switching from d4T or AZT to a TDF-based first-line regimen in a resource limited setting in rural Lesotho. JAIDS Publish Ahead of Print. DOI: 10.1097/QAI.
10. Communication Dr Mark Sonderup, Division of Hepatology, University of Cape Town.
11. Benhamou Y et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virusinfected patients. Hepatology. 1999;30:1302-1306.
12. Untangling the Web of Antiretroviral Price Reductions, 14th Edition. July 2011. Médecins Sans Frontières Campaign for Access to Essential Medicines
13. Gilead press release. Gilead Sciences finalises agreement with Tibotec Pharmaceuticals to develop and commercialise a single-tablet regimen of Prezista(R) with Emtriva(R), GS 7340 and Cobicistat. (15 November 2011).
14. Phan V et al. Incidence of Treatment-Limiting Toxicity with Stavudine-Based Antiretroviral Therapy in Cambodia: A Retrospective Cohort Study. PLoS ONE 7(1): e30647. doi:10.1371/journal.pone.0030647
    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0030647
15. Nkhoma P. Manet+ wants ARV d4T phased out. The Daily Times (Malawi). (30 January 2012)
    http://www.bnltimes.com/index.php/daily-times/headlines/national/4079-manet-wants-arv-d4t-phased-ou
16. Goldacre B. Why is the Gates Foundation supporting this trial of a rubbish AIDS drug?
    http://bengoldacre.posterous.com/why-is-the-gates-foundation-supporting-this-t

The decision to start ART in children is made with guidance based on age and CD4 percentage or count. Guideline recommendations are based on observed short-term risk of morbidity and mortality. ART can be delayed in children with CD4 values above the recommended thresholds for initiation to avoid toxicities, resistance and some of the practical considerations associated with giving ART to children.

Investigators from ICH and the PENTA group suggest that current guidance assumes such a delay in treatment initiation is without detrimental long-term consequences. In a paper published ahead of print in JID, 28 December they write that evidence suggests differences between children and adults in the level of T-cell repopulation due to children’s greater thymic activity. A number of paediatric studies show poorer recovery of CD4 count on ART is associated with older age and lower CD4 count at initiation. Using longitudinal data from the PENTA 5 study and non-linear mixed-effects models, the group investigated the relationships between age, CD4 count at start of treatment, and CD4 repopulation. As well as confirming the associations previously described, their findings illustrate the importance of the naïve subpopulation for this recovery and they explore the consequences for ART naïve children of different age groups and with different CD4 counts.

The PENTA 5 trial assessed different ARV regimens in perinatally infected, treatment-naïve children. Among the 127 children starting treatment, the median age at initiation was 5.3 (IQR 2.4 to 8.6) years; CD4 count was 620 (IQR 343 to 912) cells/mm3; z-score (indicating the rank of a recorded CD4 count within the expected distribution for HIV-negative children of the same age, born to HIV-positive mothers expressed in terms of the standard, normal distribution) was -2.3 (IQR -4.1 to -1.3) and follow-up was 5.7 (IQR 5.1 to 6.5) years.

In a multivariate model the investigators estimated the children’s pre-treatment z-score to be -0.41+ 0.07 (point estimate ±SE) lower for each year older at initiation and their long term z-score -0.5+ 0.03 lower for each year older at initiation, both p<0.001. In addition to these effects, there was a strong positive association (p<0.001) between pre-treatment and long-term z-score – that is, children with z-scores below (or above) average for their age before treatment still had below (or above)-average scores in the long term.

Naïve and memory CD4 counts were recorded in a substudy of 26 children. This analysis revealed T-cell reconstitution in these children appeared to arise mainly from the naïve compartment with a comparatively small increase memory cell count, although on a faster timescale. However this potential for recovery via the naïve pool is apparently progressively reduced with age and/or duration of infection. The model illustrated suggests that the threshold currently recommended for initiating treatment in younger children results in a higher count in the long term than that for older children. Therefore guidelines for older children may not be optimal for maintaining CD4 counts in adulthood.

Reference:

Lewis J et al. Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution. JID. Published ahead of print 28 December 2011.

Two ongoing concerns for HIV positive people on ART are (1) whether long-term side effects shorten life-expectancy? and (2) is premature ageing related to either ART or HIV?

While both short and medium term outcomes have so far been very good, data for these questions requires following large numbers of patients over many years. Since it is impossible to have randomised control groups, the interpretation of cohort results also needs to consider numerous confounding variables.

The second question is a particular focus for current research. But a new analysis from the EuroSIDA cohort comes close to answering the first. In an article published in the 21 January 2012 edition of AIDS, there was no evidence in this huge cohort that the risk of death, all-cause or AIDS, increased with length of time on ART. [1]

EuroSIDA is one of the largest prospective observational ART cohorts. It includes nearly 17,000 patients from Europe, Israel and Argentina. This cohort’s researchers previously have published important papers showing the benefits of ART on life expectancy. The authors explain that this is the first study “to look into the association of non-AIDS deaths with duration of time spent on combination antiretroviral therapy (cART) and with a long-term perspective of exposure to treatment. The results are reassuring that so far prolonged use of cART does not appear to be leading to increased risk of death due to some previously identified cumulative effect or a drug effect whereby there is a long induction period before disease appears.”

Just over 12,000 patients were followed from baseline, defined as the time of starting ART or enrolment into EuroSIDA after 1996. Three quarters of the cohort is male. About 40% acquired HIV homosexually, 22% from IDU and 30% heterosexually. Interestingly, nearly 60% of the cohort are current or previous smokers and smoking status was unknown in more than 20%. At baseline about 21% were confirmed hepatitis C positive and about 53% were confirmed negative. About 10% had confirmed hypertension and just over 2% confirmed diabetes.

The researchers calculated incidence rates of death, AIDS-related and non-AIDS-related, per 1000 person-years of follow-up stratified by time of exposure to cART (< 2 years, 2 to 3.99 years; 4 to 5.99 years; 6 to 7.99 years and > 8 years).

During 70,613 person years of follow-up, a total of 1,297 patients died. AIDS caused 413 and non-AIDS diseases caused 884 deaths. Incidence rates per 1,000 years of follow-up were 18.3 overall (95% CI: 17.4-19.4), 5.85 for AIDS deaths (95% CI: 5.28-6.41) and 12.5 for non-AIDS deaths (95% CI: 11.7-13.3).

For the non-AIDS related deaths, 121 were due to infections, 182 due to liver-disease, 125 due to cancer, 122 due to cardiovascular disease, 90 due to violence (including suicide) and 91 due to other causes.

The main analysis compared mortality over the predefined periods on ART. The researchers used 2 to 3.99 years on ART as reference. In a multivariate analysis controlling for sex, ethnic origin, region of Europe, hepatitis B and C status, diabetes, hypertension, smoking, viral load, CD4 cell count, prior AIDS and age, they found the following incidence rate ratios of all-cause, AIDS-related and non-AIDS related deaths (see Table 1).

Longer time on ART was associated with a reduction in the risk of liver-related death, violent, and unknown deaths. But longer time on ART was also associated with an increase in mortality attributed to non-AIDS-related cancers. The researchers suggest this “may reflect ageing of the HIV population, as the effect was no longer present after adjustment for time updated age …”

comment

This article is reassuring for people who are recently diagnosed, who have access to modern ARVs and a medical history that is uncomplicated by coinfections or prior drug resistance. It is important that there is no signal of additional risk from treatment that is otherwise stable and effective.

The risk of premature ageing is the focus for research into immune activation and inflammation. It is also dependent on HIV negative controls to understand the impact of residual inflammation in people suppressed on HAART. In an editorial in Current Opinion Infect Diseases, Martin Fisher and Vanessa Cooper suggest caution over links between HIV or ART and ageing. They conclude, “Although undoubtedly there are higher rates of comorbidities in the HIV-positive population [...] Further research is needed to explore the mechanisms by which HIV/HAART may contribute to age-related diseases, the contribution of other important and potentially modifiable risk factors including smoking, alcohol and drug use, and the role of comorbid disease.” [2]

References:

1. Kowalska JD et al. for EuroSIDA. Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy. AIDS 26:315-323. (28 January 2012). Free full text online.
   http://journals.lww.com/aidsonline/Fulltext/2012/01280/Long_term_exposure_to_combination_antiretroviral.7.aspx
2. Fisher M and Cooper V. 2012. HIV and ageing: premature ageing or premature conclusions? Curr Opin Infect Dis 25:1-3. Free full text online.
   http://journals.lww.com/co-infectiousdiseases/Fulltext/2012/02000/HIV_and_ageing___premature_ageing_or_premature.2.aspx

Two experimental drugs for the treatment of MDR TB have completed phase II clinical trials. While neither is ready yet to be registered with a regulatory authority, bedaquiline (formerly TMC207, manufactured by Tibotec) is already better tested than most second-line TB drugs and has a good side-effect profile. The results of a Phase II trial of delamanid (formerly OPC-67683, manufactured by Otsuka Pharmaceuticals) are expected to be published soon.

Bedaquiline

HTB previously reported the development of bedaquiline and Phase II trial results [1,2]. Tibotec reported further results at a Critical Path to TB Drug Regimens meeting in Arlington in November. In this trial of 160 MDR TB patients, that compared an optimised background regimen plus either placebo or bedquiline, there was faster culture conversion in the bedaquiline arm by 24 weeks (p=0.003). This was the primary endpoint. In secondary analyses, median time to culture conversion was 12 weeks vs 18 weeks. And at 24 weeks 79% of bedaquiline patients vs 58% of placebo ones had converted to sputum-negative (p=0.008). Side effects were distributed evenly over the two groups. There were no serious study drug-related side effects nor were there clinically significant differences in laboratory results. QT prolongation was seen on the bedaquiline arm, but there were no adverse events associated with this nor were there any prolongations greater than 500 milliseconds. [3]

In an ongoing open-label study (C209) that is assessing safety, efficacy and tolerability over two years of bedaquiline in smear-positive MDR TB patients, there was an 80% response rate at 24 weeks. Resistance to more drugs was associated with poorer response rates (56% for XDR, 77% for pre-XDR and 87% for MDR; p=0.0006). Patients with no cavitations also responded better (p=0.0157), as did patients on three or more potentially active drugs (p=0.0376). The most frequent side effects were nausea (11%), arthralgia (12%) and hyperuricaemia (14%). About 2% of the patients stopped bedaquiline due to an adverse event.

Tibotec has planned a Phase III superiority study (C210) with 600 subjects. The primary endpoint is intended to be relapse free cure at 15 months and a final analysis will also be done at 21 months.

The company is also considering a paediatric trial of 60 children to examine PK and safety.

The company has a compassionate use/expanded access programme. In countries that have a mechanism to authorise pre-approval access of unregistered medicines, patients with pre-XDR or XDR TB at what the company describes as validated centres can obtain bedaquiline. In countries where this is not feasible, such as China, Russia and Lithuania, an expanded access trial is planned. But at the time of the Critical Path meeting when this was presented, fewer than 30 patients had accessed the drug via compassionate use or expanded access.

Delamanid

In a phase II trial (Trial 204), about 480 patients with MDR TB were divided into three arms, stratified by disease severity. All patients received optimised background regimens. The first group received placebo, the second delamanid 200mg/day and the third delamanid 400mg/day for eight weeks. Patients were followed for an additional four weeks for safety and to confirm sputum conversion. The trial took place at 15 sites in 9 countries. Those patients who successfully completed Trial 204 were eligible to enroll in a 26 week open label protocol. Those who participated in Trial 204 and received placebo therefore had 26 weeks exposure to delamanid and those who received delamanid in trial 204 had a total of 34 weeks exposure to delamanid. [4]

Otsuka is currently recruiting for a Phase 3 trial to test the safety and efficacy of delamanid 200mg daily. [5]

comment

These two drugs are the furthest along in the pipeline to treat drug-resistant TB. It is essential that they soon be tested together, so that if or when they are approved clinicians do not have to grapple with whether or not to add a single drug to failing regimens.

TB drug development is painfully slow. Consider that rilpivirine (TMC278), an antiretroviral of minor importance, was presumably discovered after bedaquiline (given that TMC278 signifies a chronologically later drug than TMC207). Yet the rilpivirine phase III trial started in 2008 and the FDA approved the drug last year. In contrast, bedaquiline is not expected to be registered in the very near future. This is not to single out Tibotec: indeed their TB development is the most advance. But this example shows the comparative lack of resources invested in getting TB drugs to market. Regulatory hurdles specific to TB worsen the situation. For example, some regulators want to see two-year relapse rates before granting approval.

Pre-regulatory approval expanded access should be a priority. Tibotec has committed to this but because of regulatory hurdles, lack of knowledge about the programme and perhaps lack of urgency from the company, we remain far from significant expanded access. It is unclear what commitment Otsuka has to expanded access.

Activists and patients must increase the pressure on Otsuka, Tibotec, health ministries and service providers to make these drugs available more widely for pre-approval access. More pressure must be put on the entire industry to develop more drugs, though as recent TAG/i-Base pipeline reports show, this is starting to improve.

References:

1. Geffen N. 2009. TMC207 reduces time to sputum conversion in phase II trial on patients with drug-resistant TB. HTB 10(7) July/August 2009.
   http://i-base.info/htb/4403
2. Clayden P. 2011. Faster conversion rates with TMC-207 versus placebo plus OBT for the treatment of MDR-TB. HTB 12(1-2) January/February 2011.
   http://i-base.info/htb/14441
3. Presentation by Tibotec to Global TB Community Advisory Board at CPTR 2011.
4. Otsuka. A Placebo-controlled, phase 2 Trial to Evaluate OPC 67683 in patients with pulmonary sputum culture-positive, multidrug-resistant tuberculosis (TB).
   http://www.clinicaltrials.gov/ct2/show/NCT00685360 5.
5. Otsuka. Safety and efficacy trial of delamanid for 6 months in patients with multidrug resistant tuberculosis.
   http://www.clinicaltrials.gov/ct2/show/NCT01424670

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV respectively in Africa.

However, there is the potential for drug interactions with this combination as artemether and lumefantrine are substrates of CYP3A4 and nevirapine is both a substrate and inducer of CYP3A4.

This parallel-design pharmacokinetic study, obtained concentration-time profiles for lumefantrine, artemether, dihydroartemisinin and nevirapine in two groups of HIV-infected patients: ART-naïve and those stable on nevirapine-based therapy. Both groups (n=18 per group) received the recommended artemether-lumefantrine dose (80/480 mg). The primary outcome was day-7 lumefantrine concentrations, as these are associated with therapeutic response in malaria.

Nevirapine decreased artemether (p<0.0001) and dihydroartemisinin (p=0.01) AUC, but unexpectedly increased lumefantrine exposure. Median (range) day 7 lumefantrine concentrations were 622 ng/mL (185-2040) and 336 ng/mL (29-934) in the nevirapine and ART-naïve groups, respectively (p=0.0002). In the ART-naïve group, 6/18 subjects had day 7 lumefantrine concentrations below target (280 ng/ml) compared with 1/18 in the nevirapine group (Odds Ratio=8.5, 95%CI 0.9 to 80.02, p=0.061). Adverse events were similar between groups, with no difference in electrocardiographic QTcF and PR intervals.

The mechanism of inhibition of lumefantrine remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.

Source: hiv-druginteractions.org (16 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=564

Reference:

Kredo T et al. The interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1 infected patients. Antimicrob Agents Chemother, 2011, 55(12): 5616-5323.

http://www.ncbi.nlm.nih.gov/pubmed/21947399

The use of traditional/complementary/alternate medicines in HIV/AIDS patients who reside in Southern Africa is quite common. This review looks at the mechanisms of pharmacokinetic interactions and summarises the published clinical studies and case reports of antiretroviral-herbal interactions. In vitro screening studies of several African traditional medicinal plants and extracts are described and details given in a very useful table.

The review highlights the lack of clinical studies – despite a high incidence of HIV/AIDS in the African region, only one clinical study (efavirenz and Hypoxis hemerocallidea) has been conducted. More studies on African traditional medicines are warranted in order for more meaningful data to be generated and the true potential for such interactions to be determined.

Source: hiv-druginteractions.org (24 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=567

Reference:

Müller AC, Kanfer I. Potential pharmacokinetic interactions between antiretrovirals and medicinal plants used as complementary and African traditional medicines. Biopharm Drug Dispos, 2011, 32(8): 458-470.

http://www.ncbi.nlm.nih.gov/pubmed/22024968

This study aimed to i) evaluate the safety and toxicity of rapamycin (sirolimus) in HIV-infected individuals with KS receiving antiretroviral therapy, ii) investigate rapamycin interactions with both PI-containing and NNRTI-containing regimens, and iii) assess clinical and biological endpoints.

Seven participants, 4 on ritonavir-boosted PIs (2 lopinavir, 2 atazanavir) and 3 on NNRTI-based regimens (2 efavirenz, 1 nevirapine), had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. Maintenance rapamycin doses in the PI subjects were 0.1 mg and 0.2 mg twice weekly with lopinavir and 0.2 mg twice weekly and 0.3 mg three times weekly for atazanavir; doses in the NNRTI subjects were 2.3 mg and 6.7 mg daily for efavirenz and 2.8 mg daily for nevirapine. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses.

Rapamycin appears safe in HIV-positive individuals with KS and can, in some cases, induce tumour regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations, but may be exploited to achieve therapeutic benefit.

Source: hiv-druginteractions.org (29 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=566

Reference:

Krown SE et al. Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium Study. J Acquir Immune Defic Syndr, 2011, epub ahead of print.

http://www.ncbi.nlm.nih.gov/pubmed/22067664

• Read this guide online
• Order a free printed copy
• Download PDF

HIV Testing and Risks of Sexual Transmission was produced in response to the growing number of testing and transmission questions that i-Base receives.

This resource brings together research into the impact of treatment on transmission and explains aspects of transmission that are often missed from resources that focus almost exclusively on condoms to explain risk.

This guide, written in non technical language, will hopefully be as useful for training as for general information.

The guide is also already online, together with further reading, appendices and references that are not included in the print edition.

Additional copies are free – please order in the usual way (online, by email or fax-back the back page of HTB).

We welcome feedback on this guide and this short online survey includes space for comment:

http://i-base.info/guides/testing/feedback

The scope of this document includes guidance on the initiation of ART in those previously naïve to therapy, support of patients on treatment, management of patients experiencing virological failure and recommendations in specific patient populations where other factors need to be taken into consideration.

The Treatment Guidelines Writing Group is grateful for all comments, which will be reviewed before publication.

Comments can be made online at the same URL for the draft document:

http://www.bhiva.org/treatmentguidelinesconsultation.aspx

comment

These guidelines have been produced based using a new methodology and grading system compared to earlier documents, and are clearly the result of considerable additional work.

The evidence base is published in a separate 270 page appendix.

Of note, some of the recommendations in the current draft include differences between the BHIVA writing committee and current prescribing by the London consortium.

Readers have until 5 March to comment.

Two case reports of unintended pregnancies suggest that etonogestrel implants should be used with caution in patients on efavirenz.

The first case had been receiving efavirenz, zidovudine and lamivudine since November 2002 and had an etonogestrel implant inserted in January 2004. Pregnancy was detected in April 2006 and conception dated to December 2005. The second case had an etonogestrel implant inserted in July 2005 and started efavirenz, tenofovir and emtricitabine in April 2007: in October 2007 she became pregnant following a condom rupture. In both cases, implants were removed at pregnancy diagnosis and were found to have been properly inserted.

The most probable mechanism explaining the contraceptive failure is low etonogestrel concentrations due to induction of cytochrome P450 by efavirenz. As it is not currently possible to predict the decrease of etonogestrel implant efficacy when an enzyme inducing drug is coadministered, an alternative method of contraception should be recommended.

Source: hiv-druginteractions.org (06 December 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=568

Reference:

Leticee N et al. Contraceptive failure of etonogestrel implant in patients treated with antiretrovirals including efavirenz. Contraception, 2011, epub ahead of print

http://www.ncbi.nlm.nih.gov/pubmed/22036046

The comprehensive 40-page document includes a detailed review of the most important routine monitoring. It is an essential reference for understanding the current recommended minimum standard of care.

These guidelines include suggestions for audited targets and cover each stage of the treatment pathway from initial diagnosis, through to naïve and experienced management, and includes the case of transferred care.

It is also important for highlighting simple and inexpensive aspects of care that are important but if overlooked have the potential to greatly impact on patient quality of life. These include full patient history, psychological assessment (including depression, anxiety and social support), sexual history (including sexual health), support for evaluating adherence, baseline evaluations (including physical examination, waist circumference, blood pressure and BMI). Mental health has a separate consideration.

Recommendations for CD4 and viral load monitoring are similar to earlier guidelines. In naïve patients, as long as CD4 count remains 100 cells higher than the threshold for starting treatment (currently this would be 450), CD4 monitoring should be every 4-6 months, and 3-4 monthly if it falls below this. CD4 count should still be monitored four weeks after starting therapy (with viral load). In people who maintain an undetectable viral load for more than one year and whose CD4 count is greater than 200, CD4 monitoring can be reduced to six-monthly.

Viral load should still be a factor when deciding to initiate HAART, needing at least two results for patients in chronic infection to establish a reliable set point, six monthly thereafter and repeated within one month prior to treatment. Short term efficacy needs to be confirmed by a drop of at least I log, four weeks after starting treatment, and further tests at 3 and 6 months. Undetectable (<40 or <50 copies/mL) should be achieved by 4-6 months. Subsequent monitoring should be 3-4 monthly, and six-monthly viral load can be considered in a strictly adherent patients on stable treatment. Viral rebound to >50 copies/mL needs to be conformed with a new sample.

The cut-off for switching treatment is only briefly mentioned but blips are described as transient increases to between 50 and 1000 copies/mL (subsequent test being < 50 copies/mL) and multiple blips a signal to review drug potency, adherence, tolerability, resistance and potential modifications to the combination.

Resistance testing is still strongly recommended for all newly diagnosed patients and again prior to starting treatment if reinfection is possible, or in patients without results from first diagnosis, at week four of treatment if viral suppression is less than 1 log copies/mL, in all patients with confirmed viraemia (while on the failing combination) recognising that specialised labs are able to work with samples where viral load is ‘just over’ 50 copies/mL.

The guidelines also address laboratory monitoring for renal, hepatic, cardiovascular, bone and biomarkers, other infections including sexual health and for specific patient groups (women, older patients, injecting drug users and late presenters.

References and links:

British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011

BHIVA site link:

http://www.bhiva.org/Monitoring.aspx

HIV Medicine, January 2012 Volume 13, Issue 1 Pages 1-88.

http://onlinelibrary.wiley.com/doi/10.1111/hiv.2011.13.issue-1/issuetoc

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of HIV-infected pregnant women.

The scope includes guidance on the use of ART therapy both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration such as co infection with other agents.

Comments can be made online at the same URL for the draft document:

http://www.bhiva.org/PregnancyGuidelinesConsultation.aspx

• Increasing the uptake of HIV testing among black African communities living in England
• Increasing the uptake of HIV testing among men who have sex with men

The free access support tools from NICE includes:

• Online educational module developed in conjunction with BMJ Learning to help healthcare professionals in primary care and non-HIV specialist settings improve their knowledge of key clinical areas in relation to HIV testing
• Audit support for general practice, secondary care and specialist services to assist with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. This consists of audit criteria and data collection tool(s) and can be edited or adapted for local use
• Self assessment tools for services or local partnerships to establish how close their current practice is to that recommended in the guidance and to help with prioritising implementation activity
• Costing report which provides an overview of both the potential costs and savings from putting the NICE guidance into practice
• Costing template helps individual NHS organisations and local health economies to quickly assess any impact that the NICE guidance may have on local budgets
• Slide set for primary and secondary care featuring key recommendations for clinical practice: developed to support professionals in general practice and secondary care who are not specialists in HIV testing or treatment
• Clinical indicator diseases table (reproduced with kind permission from the British HIV Association) to accompany the above slide set
• Slide set for commissioning of specialist sexual health services developed for those involved in the commissioning or strategic planning of sexual health services, it provides an overview of all recommendations from both pieces of guidance.

The NICE tools and guidance are online via the following guidance pages:

• http://guidance.nice.org.uk/PH33
• http://guidance.nice.org.uk/PH34

The London SCG Commissioning intentions have been published and are available at this link below.

http://www.londonspecialisedcommissioning.nhs.uk/?assetId=705&assetGroupId=704

London Adult HIV Needs Assessment

The London SCG has published the Executive Summary of the Adult HIV Needs Assessment, This shows that HIV is one of the fastest growing chronic conditions in London.

http://www.londonspecialisedcommissioning.nhs.uk/?assetId=707&assetGroupId=704

Ensuring access to HIV care and treatment in London

With over 30,000 HIV positive patients receiving care in London, developing a plan to secure continued access to the best available treatment is critical.

http://www.londonspecialisedcommissioning.nhs.uk/?assetId=709&assetGroupId=704

Simon Collins, HIV i-Base

This is the second edition of a book by the US activist Nelson Vergel. It is a users guide to testosterone by an HIV positive man who has researched the subject over many years for his own care.

The non-technical sections include helpful tips about what not to do as well as the best approaches. This looks at how to assess potential testosterone deficiency, including what to measure (free vs total), when and how, and the impact of age on target ranges including fluctuation in levels throughout the day. The information is in the context of supplementary approaches being dependent on working with your doctor, not only to ensure that an appropriate dose and formulation are used (oral supplementation being the least useful), but that routine monitoring guides the safety of this approach.

Replacement therapy is discussed, usually recognising this as a lifelong treatment, as testosterone supplementation reduces the need and ability for the body to continue it own production. The risks from interrupting treatment and a period of testosterone depletion until the body adjusts include depression, weight loss, lack of motivation and reduced sex drive – often the symptoms that suggested treatment in the first place.

The guide also discusses side effects from testosterone and how to manage these, including the experimental use of Human Chorionic Gonadotropin (HCG) to maintain normal testicular function and reverse shrinkage. It discusses alternative treatment for low sex drive and erectile dysfunction including a review of data (or lack of it) for non-approved products. It also includes the importance of lifestyle modifications including diet and exercise, the importance of adherence and on finding a doctor that will monitor and prescribe treatment.

This is a users guide, written by an activist who has used many of the available approaches for over 16 years and he shares his experiences of different approaches. But the author professionally trained as a chemical engineer, and this informs his discussion on the chemistry behind a daunting range of formulations (including injections, topical creams, patches, implants, underarm products and sublingual and buccal preparations).

Although titled ‘a man’s guide’ the book includes information on testosterone use in women, including links for further reading, though for future editions this might be helpful if this was collated and compiled in a separate chapter.

Nelson is also co-author of Built to Survive, a similar guide to using anabolic steroids, nutrition and exercise to develop and maintain muscle mass for HIV positive men.

Nelson Vergel – Testosterone: a man’s guide: practical tips for boosting physical, mental and sexual vitality; 2nd edition, 2011.

IBSN: 978-0-9837739-1-7. £12.00, paperback; £6.41 Kindle.

The abstract book and the late breakers are available in PDF format. This site includes daily summaries of the workshop that will be followed in the next few weeks by more detailed reports.

http://www.hiv-reservoir.net/index.php/the-news/189-abstract-book-2011-hiv-persistence-workshop.html

The article reviews the available evidence to demonstrate how a comprehensive response can reduce HIV infection rates in people who use drugs, by implementing coherent public health and law enforcement strategies. It is argued that cost-effective interventions such as needle and syringe exchange programs, increased access to treatment and the decriminalisation of people who use drugs, to name but a few, would benefit individuals, families and communities.

The documents can be downloaded from:
http://www.soros.org/initiatives/drugpolicy/articles_publications/publications/time-to-act-20100907

http://jac.oxfordjournals.org/content/early/2012/01/31/jac.dkr599.full

Are there reasons to be optimistic that a cure for HIV infection may be achieved? From our point of view the answer is ‘yes’, but this will not be achieved in the short term.

Registration details, including for community and community press are included on the relevant websites.

19th Conference on Retroviruses and OIs (CROI)

5–8 March 2012, Seattle

http://retroconference.org

10th European HIV & Hepatitis Drug Resistance

28–30 March 2012, Barcelona, Spain

http://www.virology-education.com

13th Intl Workshop on Clinical Pharmacology of HIV Therapy

16–18 April 2012, Barcelona

http://www.virology-education.com

47th European Liver Conference (EASL)

16–18 April 2012, Barcelona

http://www.easl.eu

18th Annual BHIVA Conference

17–20 April 2012, Birmingham

http://www.bhiva.org

20th International HIV Drug Resistance Workshop

9–13 June 2012, venue tbc

http://www.informedhorizons.com/resistance2012/

14th International Workshop on Co-morbidities and Adverse Drug Reactions (Lipodystrophy Workshop)

19–21 July 2012, Washington

http://www.intmedpress.com/comorbidities/

7th International Workshop on HIV Transmission

19–20 July 2012, Washington

http://www.virology-education.com

4th International Workshop on HIV Paediatrics

20–21 July 2012, Washington

http://www.virology-education.com

Towards a Cure: IAS pre-conference symposium

20–21 July 2012, Washington

http://www.iasociety.org/Default.aspx?pageId=606

19th IAS World AIDS Conference

22–25 July 2012, Washington

http://www.aids2012.org

11th International Congress on Drug Therapy in HIV

11–15 November 2012, Glasgow

http://www.hiv11.com

Download HTB January/February 2012e PDF file (600 Kb)

Unfortunately abstracts are not yet available online, and although webcasts, podcasts and PowerPoint slides are available these require a login name and password (obtainable by email from the EACS secretariat).

The same login details can also be used to access training resources from a pre-meeting training for doctors and other resources. iPhone and iPad versions are accessible using the free Talks On The Go App.

http://www.europeanaidsclinicalsociety.org/

The following reports are included in this issue.

• European guidelines (EACS) – 2011 update
• Raltegravir achieves superiority over efavirenz after four years
• Higher plasma levels of tenofovir and darunavir but not efavirenz in older patients
• Ritonavir levels reduced with high fat meal (900 kcal)
• Transplacental transfer of raltegravir and delayed plasma clearance in preterm neonates

The launch of 2011 guidelines from the European AIDS Clinician Society (EACS), extensively revised and updated, was probably one of the scientific highlights of the conference.

The three guidelines, previously printed separately, have now been collated together in a slightly larger format. This makes the print edition now more comprehensive and also easier to use and reference.

Based on essential bulleted lists, treatment algorithms, and reference tables the guidelines are an excellent format for rapidly reviewing the current best standard of care in four key areas of HIV management:

1. Assessment and monitoring at initial and subsequent visits
2. ARV treatment in adults
3. Prevention and management of non-infectious co-morbidities
4. Clinical management and treatment of hepatitis B and C in HIV-positive patients

Although additional resources have been produced to compliment the guidelines in many important areas of HIV management, these had no yet been posted online when we went to press.

The guidelines (version 6.1) can be downloaded free as a PDF file and print copies can be order on the EACS website:
http://www.europeanaidsclinicalsociety.org/

Print versions can be ordered from EACS:
info@eacsparis.org

Four year results from a five year, double-blind, randomised, non-inferiority study comparing raltegravir to efavirenz (each with tenofovir plus FTC) in treatment-naïve patients were presented by Jurgen Rockstroh.

The study design, matched baseline characteristics and safety and efficacy results from earlier analyses have already been presented at earlier meetings. The new subgroup analyses (including baseline CD4 <200 copies/mm3, viral load >100,000 copies/mL, hepatitis and demographic responses) focused on virological efficacy with discontinuations related to viral failure included but discontinuations for other reasons excluded and using an observed failure approach.

From approximately 280 patients in each arm at baseline, 223 (79%) and 197 (70%) completed the 192 week analysis, in the raltegravir and efavirenz arms respectively. Discontinuations were all less frequent in the raltegravir arm: virological failure (n=5 vs 8); side effects (n=13 vs 26); and loss to follow-up (n=8 vs 17)

At 192 weeks, the primary analysis of viral suppression to <50 copies/mL (non-completer=failure) saw raltegravir achieve statistical superiority compared to efavirenz [76% vs 67% (difference = +9.0; 95%CI 1.6, 16.4, p < 0.001: with the lower limit for non-inferiority set at –12% and superiority being achieved when both confidence intervals became greater than 1.0].

CD4 increases were + 60 cells/mm3 higher in the raltegravir arm (95%CI 24, 95).

Overall clinical events (96% vs 98%, p = 0.16), discontinuations due to drug-related events (5% vs 8%, p = 0.173) and serious adverse events (18% in each arm, p = 0.91) were similar between the two study groups, raltegravir was associated with significantly fewer drug-related events (50% vs 80%, p < 0.001).

There were no statistically significant differences in response between groups by gender, age, race/ethnicity, viral load >100,000 c/mL, CD4 > 200 cells/mm3, hepatitis coinfection or HIV sub-type. Raltegravir showed a significantly stronger virological response in the <100,000 c/mL group (93% vs 81%; difference +12; 95% CI 3, 22). Interpretation of a difference in favour of raltegravir when baseline CD4 was 50-<200 cells/mm3 is complicated by a trend to favour efairenz when CD4 counts were <50 cells/mm3.

comment

These results support durability and safety of raltegravir. they also show that after week 192 raltegravir achieves superiority compared to efavirenz with the difference largely driven by efavirenz-related side effects.

The CD4 difference may also be important for patients with sub-optimal CD4 responses on other HAART combinations.

Reference:

Rockstroh JK et al. Long-term efficacy of raltegravir or efavirenz combined with TDF/FTC in treatment-naïve HIV-1-infected patients: week-192 subgroup analyses from STARTMRK. 13th EACS, 12–15 October 2011, Belgrade. Abstract PS 1/1.

Several studies looked at the association between older age and antiretroviral pharmacokinetics (PK).

Tenofovir

Muge Cevik from the Chelsea and Westminster Hospital London reported results from a PK study suggesting that tenofovir clearance is significantly reduced with increasing age and resulting in higher drug levels (AUC and Ctrough). [1]

This included steady-state plasma levels from 52 men and 2 women (12 of whom were on PI/r-based combinations). Median age was 54 years (range 40–81 years) with only two people younger than 50. Samples were drawn randomly and population pharmacokinetics applied to predict values.

Tenofovir median clearance (CL/F), AUC (24hr) and Ctrough (C24) were 110.0 L/r (27.4–248.3). 2.2 mg.hr/L (1.0–9.0), and 0.06 mg/L (0.01–0.3) respectively.

Increasing age was significantly associated with slower clearance (p=0.0012), higher AUC (p=0.0012) and higher Ctrough (p=0.0017). People older than 60 had significantly lower clearances (p=0.0447) and higher AUC (p=0.0457) than those younger than 60.

No PK differences were seen between PI and NNRTI based combinations (p=0.08).

Efavirenz and darunavir/ritonavir

A similar analysis was presented by Ahmed and colleagues from the same group at Chelsea and Westminster on the PK of efavirenz or darunavir/ritonavir used by older patients (median age was 54 years (range 27-77) and 56 years (28-76), respectively). [2]

In 70 men and 7 women taking efavirenz, no differences were seen in any PK parameter when comparisons were made between people older and younger than 50 (all p-values >0.05 for between age comparisons).

In 33 men and one woman taking darunavir/ritonavir (23 using once-daily) oral clearance was significantly lower in people over 50 years old (10.3 vs 13.0 L/h; p=0.027) with higher AUC (80.9 vs 61.6 mg.h/L; p=0.021) and Ctrough levels (1.9 vs 1.2 mg/L; p=0.008) than those younger than 50.

Once-daily vs twice-daily could not be assessed because of unequal age distribution between the two dosing regimens.

References:

1. Cevik M et al. Tenofovir (TFV) pharmacokinetics (PK) in HIV infected individuals over 40 years of age. 13th EACS, 12–15 October 2011, Belgrade. Abstract PS 6/1.
2. Ahmed A et al. Efavirenz and Darunavir Plasma Concentrations in HIV-infected Patients Aged 50 Years or over. 13th EACS, 12–15 October 2011, Belgrade. Abstract PE6.2/1.

Researchers at Makerere University, Kampala and the pharmocology group at Liverpool University reported a significant interaction between high fat meals and ritonavir as a booster in lopinavir/r (Kaletra).

Three meal conditions were studied in an open-label, three part, cross over study in 12 HIV positive people (6 men, 6 women) using lopinavir/r (2 x 400/100 mg tablets) as second-line therapy. Median (IQR) age and weight of patients was 48 (44 – 49) years and 62 (59-68) kgs.

Intensive PK sampling after a moderate (20 g fat) and high (36 g) fat meal (on Day 1 and 8 respectively) were compared to fasted state on Day 15.

Compared to the fasting, administration with a high fat meal resulted in 29% lower ritonavir AUC (geometric mean ratio 0.71; 90%CI 0.61-0.84) and 29% lower Cmax (GM 0.71; 90%CI 0.60-0.84) while C12 increased non-significantly by 12% (GM 1.12 (90%CI 0.94-1.33).

Reference:

Lamorde M et al. – Steady-state exposure of ritonavir is reduced by a high fat meal in Ugandan patients receiving lopinavir plus ritonavir co-formulated tablets. 13th EACS, 12–15 October 2011, Belgrade. Abstract PE6.6/1 (BPD1/1).

Preterm birth is common in infants born to HIV positive mothers and is associated with an increased risk of mother to child transmission. Oral drug absorption in infants is unpredictable due to the immaturity of the gastro intestinal tract at this age. Preloading the foetus with maternal nevirapine (NVP) is common in these cases.

Raltegravir (RAL) is pregnancy category C and data to guide its use in pregnancy are limited. However, it has been used to achieve a rapid reduction in viral load before delivery, for preloading the foetus where poor oral absorption is anticipated and in cases where there is resistance or intolerance to other antiretrovirals.

RAL is absorbed rapidly (with a T max of about three hours) it takes two days to reach steady state concentrations and has an elimination terminal half-life of 9 hours. It uses the UGT 1A1 metabolic pathway. About half of the oral dose is excreted unchanged in the stool and 30% in the urine (about a third of which is as unchanged RAL and the remainder as the metabolite). There is considerable inter patient variability in its metabolism.

In an oral presentation, Aseel Hegazi from St Georges University Hospital, London showed three maternal infant case studies in which pregnant mothers of preterm neonates received RAL as part of their prevention of mother to child transmission (PMTCT) regimens. [1] The investigators looked at transplacental transfer of the drug and plasma clearance in the infants.

The same group has previously described the use of RAL in PMTCT regimens in mothers of three term infants. In these cases they found good transplacental transfer with higher concentrations in the infants than the mothers approximately three hours after delivery. [2] They also reported persistence of neonatal concentrations at three days (although below the therapeutic range). They suggested that poor neonatal and foetal maturity of the UGT-dependent pathways could account for this. And that it is possible that increased activity of UGT1A1, associated with progesterone, observed in pregnant women contributed to the disparity.

In the three cases of RAL use in preterm delivery, paired blood samples were taken as close as possible to delivery and then post partum. Maternal and neonatal RAL plasma concentrations were measured using liquid chromatography and mass spectrometry. Table 1 summarises these cases.

Dr Hegazi concluded that therapeutic RAL plasma concentrations (> 15ng/mL) might be persistent for up to five days in preterm neonates. She noted that this is longer than that observed in term infants and is probably linked to immature UGT1A1 mediated gluronidation. She suggested that maternal RAL preloading might be a good alternative to NVP where oral absorption is unreliable (particularly with preterm infants) and maternal options are limited

comment

These case studies are interesting and this use of RAL could prove important. RAL used this way is likely to be mentioned in the next BHIVA guidelines (although data is very sparse so evidence will be weak).

IMPAACT 1097 is a washout (passive) PK and safety study designed to investigate this phenomenon in neontates. It is the first clinical trial of an investigational drug to look at neonatal PK. It is recruiting mothers already receiving RAL in pregnancy and the infants will be sampled at intervals up to 30 to 36 hours after dosing.

After a review of PK and safety data from this and IMPAACT1060 – which is investigating this drug in children in de-escalated age bands with those below two years, receiving a granule formulation, now being studied – the company is planning a study of infants born to HIV positive mothers from immediately after birth until their status has been confirmed.

References:

1. Hegazi A et al. Raltegravir in the prevention of mother to child transmission of HIV: effective transplacental transfer and delayed plasma clearance observed in preterm neonates. 13th EACS, 12–15 October 2011, Belgrade. Oral abstract PS 6/7.
2. Mckeown D A et al. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women AIDS. 24 September 2010. Volume 24. Issue 15. p 2416–2418.

• Statin blocks negative impact of PIs on bone formation in vitro
• HIV linked to frailty in middle-aged IDUs, especially with poor HIV control

Ritonavir-boosted or unboosted atazanavir or lopinavir promoted stem cell changes that could lead to decreased bone formation, according to results of cell studies by Jacqueline Capeau and colleagues at Saint-Antoine Hospital in Paris. Exposing the cells to pravastatin blocked these protease inhibitor (PI)-induced changes. [1]

Bone density declines with HIV infection, and that decline can accelerate with antiretroviral therapy. Treatment with certain PIs or tenofovir heightened the risk of osteopenia and osteoporosis in longitudinal studies. SMART trial participants randomised to take antiretrovirals continuously had more bone loss than those randomised to CD4-based treatment interruptions. [2]

Indinavir and nelfinavir – two PIs rarely used today – resulted in poorly functioning osteoblasts, the cells responsible for new bone formation. Capeau and coworkers planned a series of cell studies to see if two currently prescribed antiretrovirals, lopinavir and atazanavir with or without ritonavir, affect cell properties that could promote bone loss in people with HIV.

The researchers used menenchymal bone marrow stem cells from young, healthy donors. They passaged these stem cells every 5 days to simulate ageing. For up to 40 days, they exposed the cells to doses of lopinavir, atazanavir, and ritonavir equivalent to maximum concentrations of those PIs typically attained in people taking them at prescribed doses.

Stem-cell numbers dropped sharply after 10 to 15 days of lopinavir (with or without ritonavir) and after 20 to 25 days of atazanavir (with or without ritonavir). The PIs had no effect on cell survival, a finding suggesting that decreased proliferative capacity accounted for these declines in stem cell number.

Assessing stem-cell senescence by measuring senescence-associated beta-galactosidase activity, the researchers found that both atazanavir and lopinavir significantly induced premature senescence. Increased reactive oxygen species (ROS) production in these cells suggested that oxidative stress may be responsible for cell ageing. Atazanavir and lopinavir also raised levels of superoxide dismutase, an antioxidant enzyme, in these cells. Both PIs increased expression of the cell-cycle inhibitors P16 and P21. Finally, the two PIs induced accumulation of prelamin A, a cell-ageing marker associated with cell senescence.

Mesenchymal stem cells normally differentiate into an even balance of osteoblasts and adipocytes (fat cells). With ageing, differentiation to adipocytes begins to outweigh differentiation to osteoblasts. Age-related bone loss is marked by increased bone marrow fat, which leads to decreased bone formation.

Stem cells pretreated with lopinavir or atazanavir lost their ability to differentiate into osteoblasts, a result Capeau suggested could mean these PIs irreversibly affect the menenchymal stem cell pool in bone marrow. Lopinavir-exposed stem cells also failed to differentiate into adipocytes, while atazanavir-exposed cells promoted increased differentiation into adipocytes. The investigators proposed that atazanavir could lower the number of osteoblasts in treated people by upsetting the balance between adipocytes and osteoblasts in bone marrow.

When Capeau and colleagues exposed stem cells to pravastatin and the study PIs, they found that this statin prevented PI-induced senescence, reduced oxidative stress, and restored the differentiation of stem cells to an even balance of osteoblasts and adipocytes.

The researchers concluded that their cell-study data “show that some PIs can alter osteoblast formation by a direct effect on osteoblast differentiation and also by inducing premature senescence of the bone marrow progenitors.”

References

1. Hernandez-Vallejo S et al. Some HIV protease inhibitors induce premature senescence and alter osteoblastic cell fate determination of human bone marrow mesenchymal stem cells. 2nd International Workshop on HIV and Aging. October 27-28, 2011. Baltimore, Maryland. Abstract: O_14.
2. Grund B et al for the INSIGHT SMART Body Composition Substudy Group. Continuous antiretroviral therapy decreases bone mineral density. AIDS. 2009;23:1519-1529.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748675/?tool=pubmed.

Comparing HIV-positive and negative injection drug users (IDUs) in a large Baltimore cohort, researchers determined that HIV infection independently raised the risk of objectively defined frailty and prefrailty. Frailty and prefrailty risks were highest in people with a CD4 count below 350 and a detectable viral load. [1]

Frailty boosts chances of hospital admission, disability, and death in older people without HIV.

In the Multicenter AIDS Cohort Study of HIV-positive and negative gay men. HIV infection raised the odds of earlier frailty [2], and frailty before combination antiretroviral therapy begins independently predicted AIDS or death [3]. But the impact of HIV on frailty risk and clinical outcomes is still in an early phase of study.

In this analysis Johns Hopkins University researchers focused on 1206 current or former IDUs with or without HIV infection seen from 2005 through 2009 in a prospective observational cohort. All cohort members were at least 18 years old and made twice-yearly visits for follow-up. The Hopkins team defined frailty (by the Fried system) as meeting 3 or more of 5 criteria: weakness determined by grip strength, slowed walking speed, weight loss, low physical activity, and exhaustion. They defined prefrailty as one or two of these criteria.

Of the 1206 IDUs assessed, 345 (29%) had HIV infection. Median age stood at 48 years, and one third in both the HIV-positive and negative groups were women. Higher proportions in the HIV group were African American (95.7% versus 87.6%), had less than a high school education (65.2% versus 57.0%), and were hepatitis C positive (93.3% versus 81.0%) (P < 0.05 for all comparisons). Lower proportions of HIV-positive cohort members were recent injectors (36.2% versus 47.4%), actively used alcohol (48.3% versus 56.8%), abused prescription drugs (6.4% versus 12.9%), or had a spouse or common-law partner (4.7% versus 8.8%) (P < 0.05 for all).

HIV-positive people had a median CD4 count of 290, a median CD4 nadir of 138, and a median viral load of 3.1 log (about 1250 copies). Half (51%) were taking combination antiretrovirals, and 21.7% had an AIDS diagnosis.

Overall frailty prevalence stood at 8.3%, with rates of 10.7% in the HIV group and 7.3% in the HIV-negative group; 59% of cohort members met prefrailty criteria. Through 4652 person-visits, both frailty and prefrailty proved more common in older IDUs, women, those with less than a high school education, people without a spouse or partner, those who abused prescription drugs, and those with depressive symptoms. African-American cohort members had a lower risk of prefrailty. Adjusting for all these factors, the researchers determined that HIV infection raised the prefrailty risk 28% (adjusted odds ratio [AOR] 1.28, 95% confidence interval [CI] 1.06 to 1.53), while raising the frailty risk 75% (AOR 1.75, 95% CI 1.27 to 2.39).

Compared with HIV-negative IDUs, HIV-positive cohort members had a higher risk of prefrailty or frailty with worse HIV disease status, as noted by the AORs (and 95% CIs) in Table 1.

The Hopkins teams evaluated frailty as a predictor of new hospital admissions in all 1206 cohort members from July 2005 through December 2009. During that time there were 374 hospital admissions, and the admission rate was significantly greater in frail than in nonfrail people (P = 0.006).

Compared with nonfrail cohort members, prefrail people did not have an independently higher risk of hospital admission, but frail people had a 60% higher risk (adjusted hazard ratio [AHR] 1.59, 95% CI 1.10 to 2.30). Female gender made hospital admission 66% more likely, homelessness raised the odds by 42%, active alcohol use by 32%, hepatitis C by 90%, and prescription drug use by 56%. Compared with HIV-negative people, HIV-positive people with a CD4 count under 350 and a detectable viral load had a doubled risk of hospital admission (AHR 2.12, 95% CI 1.61 to 2.79).

The Johns Hopkins investigators concluded that HIV infection boosts the risk of prefrailty and frailty in current and former IDUs. They proposed that “early identification of frail and prefrail IDUs may provide opportunities for arresting progression to adverse clinical states.”

References:

1. Piggott D et al. Frailty and incident hospitalization in a cohort of HIV-infected and uninfected injection drug users (IDUs). 2nd International Workshop on HIV and Aging. October 27-28, 2011. Baltimore, Maryland. Abstract O_06.
2. Desquilbet L et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286.
3. Desquilbet L et al. A frailty-related phenotype before HAART initiation as an independent risk factor for AIDS or death after HAART among HIV-infected men. J Gerontol A Biol Sci Med Sci. 2011;66:1030-1038.

Unfortunately the conference restricts public access to this research. Although abstracts available online (for a short time) the database to access abstracts is not very user friendly and the long URLs often change, making referencing problematic.

Also, few, if any studies are supported by webcasts or the option to view slides or full PDF posters.

The following studies are largely thanks to natap.org.

• Monitoring kidney function change with cobicistat
• Intracellular raltegravir concentrations better with twice-daily than once-daily dosing