Polly Clayden, HIV i-Base

We conclude our reports from this important conference with the following paediatric studies.

Reports from the conference.

• Early infant diagnosis

• Difficulties with implementation

• Infant outcomes

• Improved neurodevelopmental outcomes

• Treating children exposed to single dose nevirapine for PMTCT

• Using a nevirapine-containing fixed dose combination in the CHAPAS trial

• Once a day lamivudine and abacavir, and abacavir hypersensitivity in the ARROW trial

A wealth of paediatric data was presented at IAS 2009 held in Cape Town in July. Also preceding the conference was the 1st International Workshop on HIV Pediatrics, which looks as if it will become an annual fixture on the conference calendar and gave an additional opportunity to present and discuss the state of the art in the field.

Overall, far too much was presented to review here. Abstracts, some slides and, for IAS2009, webcasts can be viewed on the respective conference websites.

Several themes occurred over and over again at both meetings.

National capacity for early infant diagnosis, which not only enables early initiation of treatment but also gives a clearer picture of how well prevention of mother-to-child transmission (PMTCT) programmes are performing, with the goal of vastly reducing cases of paediatric HIV, is not yet nearly sufficient in most places.

Where infants are diagnosed in time, early initiation of treatment is not without its difficulties. It can, however, be extremely beneficial in young children.

Treatment of children who are HIV-infected despite exposure to single-dose nevirapine through PMTCT is another challenge, as is what to do in the longer term with exposed children initiated on a protease inhibitor-containing HAART to overcome the risks of NNRTI resistance.

Strategies to simplify regimens, including paediatric fixed-dose combinations and once-a-day dosing, are essential for successful management of children with HIV, as are strategies to enable co-treatment of tuberculosis in this population.

The research summarised below addresses these issues.

The conference website includes all abstracts and many PDF or powerpoint slides of posters and oral presentations, together with a limited amount of webcasts.

http://www.ias2009.org

Reports from the conference

For the first time, web casts of several sessions are available via the conference website together with searchable online abstracts and PDF files of many or the posters or presentations

http://www.ias2009.org

The abstract database from the meeting is online at the same site.

In this issue we include the following articles:

• Overview of ARV studies at IAS
  • First results of new integrase compound: GSK1349572
  • Raltegravir in treatment naive-patients
  • Nevirapine vs atazanavir/ritonavir in treatment-naive patients: the ARTEN study
  • Darunavir/r monotherapy studies
  • Maraviroc results similar to efavirenz when analysed using more sensitive tropism test
• Lipid and metabolic changes with ARV combinations
• Maximal suppression achieved with three drugs: no additional virological impact of raltegravir intensification
• Tenofovir and renal safety
• Time from seroconversion to treatment in Europe and Africa
• Pharmacokinetics of atazanavir/ritonavir during pregnancy
• Presentation with late stage HIV in women diagnosed during pregnancy
• Low transmission rates and favourable pregnancy outcomes reported in the DREAM study
• Pregnancy rates and outcomes among women in the DART trial
• Pregnancy outcomes in HAART exposed infants in Johannesburg
• Efavirenz conceptions in Soweto
• Impact of regimen and duration of therapy on risk of mother-to-child HIV transmission in Johannesburg
• A cost-effectiveness analysis of the OCTANE trial
• The PEARL study
• Results from HSV-2 acyclovir studies
• Overview of TB-related studies at IAS

Three posters at the meeting provided insight into a new compound in development from Shionogi and GSK.

Lalezari and colleagues presented first virological efficacy data from a 10-day Phase IIa dose-finding study (2, 10 and 50mg monotherapy or placebo, all once-daily) of GSK1349572 (GSK572) in 35 treatment-naive patients. [1]

Patients in the 50mg arm showed a mean viral load drop of almost 2.5 logs and 7/10 patients in this arm had viral load reductions to <50 copies/mL.

The 10 mg and 2mg doses reached mean viral load declines of approximately -2.0 and -1.5 logs respectively. No serious side effects were observed and reported events were generally similar to the placebo group.

Two pharmacology studies showed the advantages of limited interpatient variability and an indication that the 50mg dose left a significant safety buffer before activity dropped, and that higher doses were unlikely to increase activity. Median half-life was 15 hours. Steady state geometric mean (CV%) AUC (0-24) and Cmax ranged from 16.7 (15) ug.h/mL and 1.5 (24) ug/mL at 10 mg once daily to 76.8 (19) ug.h/mL and 6.2 (15) ug/mL at 50mg once daily. The geometric mean steady-state C24 at 50mg was 1.5 ug/mL which is ~23-fold higher than the in vitro protein-adjusted IC90. [2, 3]

In vitro results with a broad panel of resistant isolates, suggested minimal cross-resistance to elvitegravir and raltegravir. with high level resistance only developing after serial passaging for 56 and 84 days respectively. [4]

A second resistance poster looking at GSK572 susceptibility to a range of common integrase mutation patterns seen in raltegravir and elvitegravir studies (based on limited in vivo data), suggested that cross-resistance with other integrase inhibitors might be sufficiently likely for GSK572 not to be able to rescue people with previous integrase resistance. For example, although G140S/Q148H resulted in a median fold-change in susceptibility of less than 4-fold (n=7), G140S/Q148R lead to a range of around 8-19-fold changes (n=2). By comparison both these dual mutations confer high-level phenotypic resistance to raltegravir (>87-fold). [5]

Of note, in addition to greater virological impact during a short monotherapy than other currently used drugs, this compound is being developed as a once-daily drug, does not require boosting and PK is unaffected by food.

References
1. Lalezari J et al. Potent antiviral activity of S/GSK1349572: a next generation integrase inhibitor (INI), in INI-naïve HIV-1-infected patients: ING111521 protocol. 5th IAS 2009, Cape Town. Abstract TUAB105.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2120
2. Song I et al. Pharmacokinetic (PK) and pharmacodynamic (PD) relationship of S/GSK1349572, a next generation integrase inhibitor (INI), in HIV-1 infected patients. 5th IAS 2009, Cape Town. Abstract WEPEB250.
http://www.ias2009.org/pag/Abstracts.aspx?AID=534
3. Min S et al. Pharmacokinetics (PK) and safety in healthy subjects of S/GSK1349572, a next generation, once-daily HIV integrase inhibitor (INI). 5th IAS 2009, Cape Town. Abstract WEPEA099.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2108
4. Sato A et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor. 5th IAS 2009, Cape Town. Abstract WEPEA097.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1181
5. Underwood M et al. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor-resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. 5th IAS 2009, Cape Town. Abstract WEPEA098.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2051

In July 2009, raltegravir was approved in the US as first-line therapy, and also received a positive opinion from the CHMP for a similar indication in Europe, based on 48-week results from the STARTMRK trial. [5, 6]

In summary, raltegravir showed similar virological efficacy compared to efavirenz (86% vs 82% <50 copies/mL at week 48), when used with tenofovir+FTC. [7]

At the IAS conference, longer-term safety data was available from 144-week follow-up from the initial dose-finding study (Protocol 004), where, after the first year, all patients (n=160) were switched to, or continued receiving, raltegravir at the 400mg twice-daily dose. [8]

Viral efficacy remained similar between the two arms (78% vs 76% <50 copies/mL). Drug-related side effects were similar or less frequent in the raltegravir arm, as were grade 3/4 laboratory abnormalities (except pancreatic amylase (>2xULN: 2.5% vs 0) and creatinine kinase (10 xULN: 8.8% vs 2.6%). Lipid changes in combined raltegravir groups were not sgnificant for total cholesterol, LDL-cholesterol or triglycerides and HDL-cholesterol increased by a mean of +6.6 mg/dL (compared to +11.7 in the efavirenz arm). This meant that there was no significant difference in the total:HDL ratio between the two groups (-0.5 vs -0.4, p=0.451).

COMMENT

Although in a limited number of patients, this extended safety and efficacy data are encouraging.

To date, this more favourable lipid profile has not led to differences in body composition. A study presented at ICAAC as HTB went to press that we will report in full in the next issue showed similar DEXA results when compared to efavirenz at 48 weeks. [9]

Given that fat accumulation is one of the principal concerns for patients, and the mechanism is still unexplained, preliminary data should be made available for bone and body fat changes with all new drugs at the same time as other efficacy and safety data.

Ten years after lipodystrophy was identified as a major side effect, it is not acceptable to have wait for years after approval for these results.

However, another study at ICAAC reported encouraging data in respect to raltegravir activity in the CSF. [10]

Currently, access to raltegravir is imited for patients in the UK who could benefit from it’s tolerability profile, due to the high cost.

References
5. Isentress (raltegravir) indication extended for the treatment of HIV-1 infection in treatment-naïve patients. FDA announcement (08 July 2009).
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm171317.htm
6. CHMP poat-authorisation summary of postive opinion fro Isentress. (23 July 2009).
http://www.emea.europa.eu/pdfs/human/opinion/Isentress_47115109en.pdf
7. Lennox JL et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009. Early online publication, 3 August 2009. doi:10.1016/S0140-6736(09)60918-1.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60918-1/abstract
8. Gotuzzo E et al. Sustained antiretroviral efficacy of raltegravir as part of combination ART in treatment-naive HIV-1 infected patients: 144-week data. 5th IAS 2009, Cape Town. Abstract MOPEB030.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1895
9. DeJesus E et al. Metabolic profiles and body composition changes in treatment-naïve HIV-infected patients treated with raltegravir 400 mg bid-based vs. efavirenz 600 mg qhs-based combination therapy: 48-week data. 49th ICAAC, 12-15 September 2009, San Francisco. Abstract H-1571.
http://www.natap.org/2009/ICCAC/ICCAC_17.htm
10. Letendre S et al. Raltegravir concentrations in CSF exceed the median inhibitory concentration. 49th ICAAC, 12-15 September 2009, San Francisco. Abstract A1-1311.

A late breaker poster from Soriano and colleagues presented 48-week results from the ARTEN study. This international non-inferiority trial randomised 569 treatment-naïve patients to nevirapine 400mg once-daily (n=188), nevirapine 200mg twice-daily (n=188) or atazanavir/r (300/100mg) once-daily (n=193), all in addition to background tenofovir+FTC. [11]

The lower margin for non-inferiority was -12% and patients were recruited based on with CD4 counts below the upper recommended upper limit (250 and 400 cells/mm³ for women and men respectively).

The primary end-point was suppression to < 50 copies/mL at weeks 48 by Intent-to-treat (ITT) analysis, with a secondary sensitivity analysis looking at time to virological failure (TLOVR).

Baseline demographics and HIV-related characteristics were similar between groups. Mean CD4 and viral load were 183 cells/mm³ and 5.1 log copies/mL, respectively. Although <10% patients had a CD4 count <50 cells/mm³, 64%had viral load >100,000 copies/mL.

In the main analyses, nerirapine was non-inferior to atazanavir/r. For the primary endpoint, by ITT analysis the combined nevirapine groups were non-inferior to atazanavir/r (66.8% vs 65.3%; <50 copies/mL: difference 1.9% [95% CI -5.9% to 9.8%]). Using the TLOVR algorithm, the results were 70% and 74% of NVP and ATZ/r patients, respectively [difference 2.9% (95% CI -10.4% to 4.5%)].

CD4 responses were also similar (+170 vs +185 cells/mm³ in the NVP and ATZ/r groups, respectively).

Although side effects were similar, there were significantly higher discontinuations in the nevirapine arms: 22% in QD, 28% BID and 9% with ATZ/r.

Grade 3/4 events occurred in 12%/5% of NVP and 16%/3% of ATZ/r patients. Rash was reported in 16% of NVP and 12% of ATZ/r patients, but more NVP patients were discontinued due to rash compared with ATZ/r (5% vs 0%). Most nevirapine-associated rashes developed during the lead-in phase, with no Grade 4, SJS or TEN and no deaths due to liver or skin toxicity.

Nevirapine had a better impact on HDL-cholesterol and triglycerides (both p<0.0001) but not for for total cholesterol (p=0.41) or LDL-cholesterol (p<0.011). Overall though, the change in the TC:HDL ratio favoured nevirapine (-0.24 vs +0.13, p=0.0001).

Grade 3/4 increases in liver enzymes occurred in <5% patients but were higher in nevirapine patients, (see Table 1). Although exclusion criteria excluded active HBV or HCV infection, numbers of coinfected patients or response were not reported by this hepatitis status. Only one patient discontinued atazanavir/r due to increased bilirubin.

Table 1: Grade 3/4 liver enzyme elevations at week 48 (%pts)

* only 1 patient discontinued ATZ/r

COMMENT

It is reassuring that the high virological failure rate observed in smaller studies when nevirapine was used with tenofovir+FTC [12, 13] and which is highlighted in US guidelines [14], was not seen in ARTEN.

The data also support a reduced risk of nevirapine-associated severe reactions when prescribed to patients within the recommended CD4 thresholds. Although no cases were reported of fulminant liver failure, this remains the main reason for reduced use of nevirapine in Western countries.

The results are important, as nevirapine-based regimens remain widely used as first-line therapy, usually with d4T/3TC.

References
11. Soriano V et al. Prospective comparison of nevirapine and atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment-naïve HIV-1 infected patients: ARTEN study week 48 results. 5th IAS 2009, Cape Town. Late breaker poster abstract LBPEB07.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3709
12. Rey D et al. Early virolgic non-response to once daily combination of lamivudine, tenofovir, and nevirapine in ART-naive HIV-infected patients: preliminary results of the DAUFIN Study. 14th CROI, 2007, Los Angeles. Abstract 503.
http://www.retroconference.org/2007/Abstracts/29768.htm
13. Lapadula G et al. Risk of early virological failure of once-daily tenofovir-emtricitabine plus twice-daily nevirapine in antiretroviral therapy–naive HIV-infected patients. Clin Infect Dis 2008 Apr 1; 46:1127.
http://www.journals.uchicago.edu/doi/full/10.1086/591802#rid_rf2
14. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008; 1-139. Table 6, page 38.
http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

Several studies presented results from using darunavir/r monotherapy.

José Arribas and colleagues from the Tibotec sponsored MONET study. This study randomised 256 patients, who had been suppressed on their current HAART (< 50 copies/mL) for at least six months, to switch to darunavir/r 800/100 mg once-daily, either as monotherapy (n=127) or with 2 nukes (n=129). [15]

The primary endpoint was virological suppression at week 48 by TLOVR analysis (time to loss of virologic response) and the study had 80% power to show non-inferiority for the monotherapy arm (lower limit -12%).

Participants generally had responded well to their initial treatments (median CD4 ~570 cells/mm³ with only 12-14% with CD4 counts below 350 cells/mm³. Mean (+SD) prior ARV use was 6.4 (4.0) and 7.4 (4.2) years in the triple and mono arms respectively, with 48% and 35% still on their first NRTI combination. About a quarter of each group were PI-naive at baseline. A lower percentage of patients in the triple therapy arm were coinfected with HCV (11% vs 19%).

At week 48, both the per protocol and ITT analyses by TLOVR <50 copies/mL showed non-inferiority for the monotherapy arm, with 87.8% vs 86.2% (-1.6%; lower limit 95%CI: -10.1%) and 85.3% vs 84.3% (-1%; lower limit 95%CI: -9.9%), in the triple vs mono arms respectively.

CD4 remained stable at baseline levels and tolerability was good and generally similar between the two groups.

As with monotherapy studies using lopinavir/r, patients using darunavir/r monotherapy experienced more blips (n=1 vs 7) but were similarly resuppressed when nukes were added, and PI mutations were rare (in only one patient). Two patients in each arm had viral load rebounding consistently to >400 copies/mL. Nine patients per arm discontinued randomised treatment for either adverse events or other reasons. No new or unexpected safety signals were detected.

A similar study design was used for the French MONOI study, presented by Cristine Katlama as a late-breaker. [14]

In this study, 242 patients on HAART who were suppressed to < 400 copies/mL for at least 18 months were, after an 8-week induction phase of darunavir/r (600/100 mg bid), randomised to either continuing the triple-drug regimen (2NRTI+DRV/r) or switching to DRV/r monotherapy. Virologic failure was defined as two consecutive viral load results above 400 copies/mL, or modification/discontinuation of study treatment by week 48. The trial had 80% power to show non-inferiority for the DRV/r arm (lower limit = -10%).

Virological responses at week 48 in the Per Protocol and ITT analysis were 99.0% vs 94.2% (difference -4.9% [- 9.0 to - 0.7%]; and 92.0% vs 87.5% (difference -4.5% [-11.2 to 2.1%], for the triple and monotherapy arms respectively.

Therefore, in this study, non-inferiority was only proven for darunavir/r monotherapy in the per protocol and not the ITT analysis (although the lower margin was -10% compared to the commonly used -12%).

COMMENT

Even with promising results using either lopinaivr/r or darunavir/r monotherapy, there is limited data on some aspects of this strategy, including the importance of penetration into the CNS and other compartments. For patients in the UK, many of these questions will be answered by the currently-enrolling MRC-sponsored PIVOT study. [17]

This MRC study randomises people stable on first-line HAART to continue on their current treatment or switch to ritonavir-boosted PI monotherapy. Choice of PI is not specified and follow-up continues for five years.

References
15. Arribas J et al. The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA < 50 copies/mL at baseline. Oral abstract late breaker TUAB106-LB.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3626
16. Katlama C et al. Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label non-inferiority trial, MONOI-ANRS 136. Oral abstract late breaker WELBB102.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3689
17. PIVOT: Protease Inhibitor monotherapy Versus Ongoing Triple-therapy in the long-term management of HIV infection. MRC website.
http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=56

Several studies provided results that might increase the confidence in using the CCR5 inhibitor maraviroc. Although approved over two years ago, the potential use was has been limited because Phase III studies, using background AZT/3TC, did not shown non-inferiority compared to efavirenz, and it was not approved in Europe as a first-line option.

However, the efficacy of CCR5 inhibitors are dependent on accurately screening and enroling patients who are CCR5-tropic, which in turn is dependent of the accuracy of the available tropism test.

A post-hoc analysis of the 48-week results from the MERIT study (called MERIT-ES), using the recently developed more sensitive Trofile ES tropism test, provided an indication of current results that could be expected based on this change in standard of care diagnostics. [18]

The initial analysis from MERIT also showed poorer responses in patients from the Southern compared to Northern hemispheres and in patients with higher baseline viral load (> vs <100.000 copies/mL.

Virologic results, summarised in Table 1, showed that using Trofile ES, maraviroc produced comparable results to the efavirenz group at any baseline viral load, and for patients in the Northern hemisphere. A difference remains for Southern hemisphere patients that has yet to be explained.

Table 1: MERIT ES: 48-week response rates <50 copies/mL

Significantly more patients changed treatment due to side effects in the efavirenz arm (13.6% [49/361] vs 4.2% [15/360]), with changes occurring earlier (78.0% vs 60.0% by week 16) and at higher viral load (69.0% vs 60.0% ≥ 50 copies/mL) before discontinuation.

The sustainability of these results out to week 96, together with a modelled analysis for the impact on the non-inferiority criteria (defined lower limit -12%) were presented by Saag and colleagues, and are summarised in Table 2 (though neither MERIT nor MERIT ES studies were powered to assess results at this time point). [19]

Table 2: MERIT ES: non-inferiority analysis at week 96: difference* (lower bound of 1 sided 97.5% CI)

* Adjusted for randomisation strata; For descriptive purposes only; TLOVR = time to loss of virologic response.

References
18. Nelson M et al. Virologic suppression on maraviroc in treatment-naïve patients with R5 HIV-1 is similar to efavirenz at high baseline viral load, and maraviroc discontinuations for adverse events are less likely to show drug resistance: 48-week results from the MERIT Study. Poster abstract MOPEB040.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2657
19. Saag M et al. The MERIT study of maraviroc in antiretroviral-naive patients with R5 HIV-1: 96-week results. Oral abstract TUAB103
http://www.ias2009.org/pag/Abstracts.aspx?AID=2556

Lipid results can be complicated to interpret, especially between studies, given the lack of consistency in the method of reporting. Changes in lipid parameters, both from baseline and between-arm comparisons can often be statistically significant, for differences that are modest in absolute (and therefore clinical) terms.

While total cholesterol:HDL ratio is most useful in terms of having an impact on Framingham-based calculation of cardiovascular risk, other studies report results by the percentage of patients reaching guideline target for starting lipid-lowering drugs (LLDs). This is further complicated, particularly in treatment-naive studies by a return-to-health effect that reverses earlier HIV-related metabolic changes.

Comparative and detailed results on body composition supported DEXA/CT scaning – probably the most important results for patient currently experiencing lipohypertrophy on existing regimens – are still scarce, even in Phase III studies for the most recently approved drugs.

The MERIT study reported more favourable lipid parameters in patients using maraviroc compared to efavirenz (each with FTC/TDF) evaluated by the percentage of each group that exceeded NCEP guidelines for lipid lowering therapy. At week 96, in the maraviroc vs efavirenz groups respectively, approximately 11% vs 39% for total cholesterol; 6% vs 27% for LDL-cholesterol (>3.4mmol/L), both p<0.0001; and 16% vs 19% triglycerides (NS). [1]

Although the main finding of the ALTAIR study was the under-performance of a 4-nuke arm, the lipid profile of efavirenz produced greater increases in HDL-cholesterol (but also conversely glucose) compared to atazanavir/r. [2]

Metabolic changes were measured by DEXA and CT imaging. This was a three-arm open-label study that compared atazanavir/r to efavirenz and to AZT/abacavir all using FTC/tenofovir, in just over 300 treatment-naive patients. The four-nuke combination was significantly less effective virologically, but also (compared to atazanavir/r) for HDL-cholesterol, LDL-cholesterol, total cholesterol and glucose changes. The inclusion of AZT resulted in significant peripheral fat loss in arm, leg and total body fat and a reduction in the VAT:SAT ratio. Broadly similar responses were seen in the efavirenz and atazanavir/r groups (+0.6% and +1.7%) in limb and total body fat, though efavirenz produced a significantly greater increase in HDL (+0.18 vs +0.09, p = 0.006) and glucose (+0.34 vs -0.03, p<0.001).

The impact of 100mg ritonavir on lipid levels when boosting atazanavir (with background 3TC/abacavir) was shown in the ARIES study. This study randomised 419 patients, who were initially suppressed for 36 weeks on atazanavir/r (300/100mg daily), to either continue on the boosted regimen or switch to unboosted atazanavir (400mg daily). [3]

At 48 weeks after the switch, median total cholesterol, LDL-cholesterol and triglycerides declined in the unboosted group while continuing to increase (slightly) in the boosted arm. HDL-cholesterol remained unchanged in each arm (both slightly higher compared to study baseline: median +10mg/dL). Use of lipid-lowering drugs was similar (16% vs 13% in the boosted vs unboosted groups).

The lipid profile of nevirapine was slightly better when compared to boosted atazanavir, in the ARTEN study, again each with FTC/tenofovir. [4]

Lipid changes at week 48 showed a -0.24% reduction in the TC:HDL ratio in the nevirapine group compared to an increase of +13% in the atazanavir/r group. This was driven by proportionally greater increases in HDL-cholesterol, as total cholesterol, LDL-cholesterol, HDL-cholesterol all increased in both groups. Although statistically significant (p<0.0001) both changes were modest terms in absolute terms. Triglycerides increased by 28mg/dL in the atazanavir/r group but remained similar to baseline levels in the nevirapine group. Previously, in the CASTLE study, ritonavir-boosted atazanavir showed a small improvement in TC:HDL ratio.

The impact of the integrase inhibitor raltegravir on glycemic changes in HIV-negative volunteers, resulted in a more favourable profile compared to lopinavir/r. [5]

Changes in insulin sensitivity and glucose disposal, measured by euglycemic clamps, were recorded in in a 2-phase cross-over study, separated by a 2-week wash-out period, in HIV-negative individuals exposed to either lopinavir/r or raltegravir (each for two weeks). Supporting results from earlier studies, the lopinavir/r group experienced a mean reduction of insulin sensitivity of -16% compared to no changes seen during raltegravir exposure (p=0.018). Total cholesterol, LDL-cholesterol and triglycerides all increased significant during lopinavir/r exposure (by about 14%, 15% and 37%, respectively) compared to during raltegravir exposure, when no significant changes were seen. Mean levels of adiponectin, an insulin-sensitising adipokine, also increased in the lopinavir/r groups (by 15%, p=0.03 compared to raltegravir) indicating that peripheral fat cells were working harder to become insulin sensitive during lopinavir/r exposure.

Finally, lipid changes for darunavir/r (800mg/100mg once-daily) in the ARTEMIS study were compared to lopinavir/r (in both once- and twice-daily regimens). At 96 weeks, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides all increased from baseline in both arms, although the increases in both total cholesterol and triglycerides were significantly greater for lopinavir/r (TC: +28 vs +35; TG +18 vs 65 mg/dL), with all grade 2-4 lipid changes higher in the lopinavir/r vs darunavir/r groups (~15% vs 8%).

Use of lipid-lowering drugs were similar (darunavir/r: 8% [statins: 7%; fibrates 1%]; lopinavir/r: 11% [statins: 5.5%; fibrates: 3.5%].

Although patients in the darunavir/r arm had greater increases in weight (+2.5kg [IQR -0.2, +6.1kg] versus 1.3kg [-1.0, +5.0kg]; p=0.006) and in median BMI (0.9kg/m2 vs 0.4kg/m2; p< 0.006) these differences not considered clinically relevant. Symptomatic lipodystrophy changes (fat loss or gain, investigator judged) were reported in <1% of patients in each group.

References
Unless stated otherwise, all references are to the Programme and Abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 19-23 July 2009, Cape Town.

1. Heera J et al. The MERIT study of maraviroc in antiretroviral-naive patients with R5 HIV-1: 96-week results. Oral abstract TUAB103.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2556
Session:
http://www.ias2009.org/pag/PSession.aspx?s=2421
2. Cooper D et al. Safety and efficacy of three different combination antiretroviral regimens as initial therapy for HIV infection: week 48 data from a randomised, open-label study. Late-breaker poster abstract LBPEB09.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3799
3. Squires K et al. Similar efficacy and tolerability of atazanavir (ATV) compared to ATV/ritonavir (RTV, r), each in combination with abacavir/lamivudine (ABC/3TC), after initial supression with ABC/3TC + ATV/r in HIV-1 infected patients: 84 week results of the ARIES trial. Late breaker abstract WELBB103.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3754
4. Soriano V et al. Prospective comparison of nevirapine and atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment-naïve HIV-1 infected patients: ARTEN study week 48 results Late breaker poster abstract LBPEB.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3709
5. Randell P et al. The impact of raltegravir and lopinavir/ritonavir on lipids, adiponectin and peripheral glucose disposal in HIV negative subjects. Poster abstract TUPEB171.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2667
6. Baradli E et al. Effects of once-daily darunavir/ritonavir versus lopinavir/ritonavir on lipid parameters and anthropometrics in treatment-naïve HIV-1-infected ARTEMIS patients at week 96. Poster abstract MOPEB034.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1902

A late-breaker presentation by Rajesh Gandhi and colleagues from ACTG 5244 provided addtional data that are important for understanding the impact of HAART on the pathogenesis of HIV. [1]

Several small intensification studies have already shown similar results (including Maldarelli et al at last years Resistance Workshop). [2]

This new study benefited from larger patient numbers and intensification with an integrase inhibitor.

The study randomised 53 patients to either add raltegravir or placebo to their combination for 12 weeks. At week 12, patients crossed over to the alternative arm for a further 12 weeks. The primary endpoint was averaged plasma viral load between weeks 10 and 12. Patients needed to be on HAART for at least one year, with viral suppression <50 copies/mL (but have viral load >0.02 copies/mL at baseline using a more sensitive test).

Median baseline CD4 count and viral load were 589 cells/mm³ and 1.7 copies/mL (a similar low level has been reported in other studies). The median viral load at week 10/12 did not differ between the raltegravir (n=25) and placebo (n=24) groups (1.1 vs. 1.7 c/mL, p=0.80), nor did the median change in viral load from baseline to week 10/12 (-0.3 and -0.1 c/mL, p=0.52). There was also no significant change from weeks 10/12 to weeks 22/24 during the cross-over study.

Interestingly, there was a trend towards greater CD4 cell count increases from baseline to week 12 in the raltegravir group (+42 vs. -44 cells/mm³, p=0.08), which reversed after the cross-over.

COMMENT

This study supports the hypothesis that effective HAART (that maintains viral suppression to <50 copies/mL) stops onging viral evolution, and that residual HIV originates from recent activation of latently infected cells.

This demonstrates a ceiling of antiretrovial activity that many patients achieve with current three-drug combinations – though treatment-experienced patients may benefit from using additional drugs to overcome drug resistance.

References
1. Gandhi R et al. Raltegravir (RAL) intensification does not reduce low-level residual viremia in HIV-1-infected patients on antiretroviral therapy (ART): results from ACTG A5244. 5th IAS, 2009, Cape Town. Late breaker oral abstract WELBB104.

http://www.ias2009.org/pag/Abstracts.aspx?AID=3645

2. See: Lack of virological impact of treatment intensification in suppressed patients supports latent viral reservoir as source of residual viraemia. Reports from XVII Intl HIV Drug Resistance Workshop (IHDRW) 2008, Sitges. HTB, July/August 2008.

http://i-base.info/htb/596

A couple of posters presented interesting data relating to renal safety associated with tenofovir.

Firstly, and encouragingly, a sub-study from the international DART study suggested that while tenofovir may have a slightly greater renal toxicity compared to either abacavir or nevirapine, this still occurred in a small minority of patients. [1]

DART randomised over 3,300 treatment-naive patients in Uganda and Zimbabwe to routine CD4 and labaoratory monitoring or to clinical monitoring (with only grade 4 laboratory results reported in real time). Virological results were reported in the last issue of HTB. [2]

Patients used one of three treatment arms: tenofovir (n=2469, 74%), nevirapine (n=547, 16%) or abacavir (n=300, 9%), each used in combination with AZT/3TC), allowing safety and efficacy to be compared by drug class.

Elevated creatine (>360umol/L(4.1mg/dL) was an exclusion criteria. GFR was estimated by Cockcroft-Gault, and was adjusted for body surface area.

For this renal sub-study, glomerular filtration rate (GFR) severity was defined as mild, moderate and severe if 60-<90, 30-60 and <30 ml/min/1.73m2 respectively. Chronic kidney disease (CKD) was defined as GFR <60 on two tests for > 3 months or a 25% reduction in patients with eGFR <60 at baseline. An analysis also looked at 25% reduction rates in all patients.

Baseline demographics included 65% women; median age 37 years; CD4 86 cells/mm³; and weight 57 kg. Median eGFR was 89: with 48% >90; 45% 60-90; 7% 60 – 30 and 0.2% <30.

By week 216, patients in all three groups had small mean increases in GFR (lowest in the tenofovir group, and a slightly higher incidence of GFR decreases to <30 and <60, and in the percentages of patients with more than a 25% reduction, see Table 1. Renal disease contributed to death in 0.4% (n=13) patients on tenofovir-based therapy.

The incidence of severe reductions (GFR<30) was higher in the clinically monitored group [3.4% (2.7-4.5%) vs 2.3% (1.7-3.1%), p=0.05]. However, the study emphasised that rates were low in all arms.

The main DART study, showed an almost 90% 5-year survival rate without routine laboratory monitoring, and contrasted with <10% survival rates pre-HAART. In this context, the researcher are right to concluded that the study showed supportive safety data for wider use of tenofovir in reseource-limited settings. This is particularly important given the toxicities associated with d4T and AZT.

Table 1: Changes in renal function in DART study

The second study resented results on the reversibilty of kidney damage associated with tenofovir in 26 adult male patients who either switched from tenofovir (n=24) or dose-reduced (n=2) due to renal impairment.

Median eGFR (using MDRD) was 72 (IQR 60, 88) before starting tenofovir, and fell to 49 (IQR 37, 54) mL/min/1.73m2 prior to the change in regimen. After a median of 15 months, his increased to 56 (IQR 45, 70) mL/min/1.73m2. Howverer, although the changes were only slight and developed slowly, with only 10 (38%) patients reached their pre-treatment level.

Although in small patient numbers, this is one of the first studies to show a potential reversal of reduced kidney function after switching from tenofovir, though the improvements were very modest in clinical terms.

References:
1. Reid A et al. Glomerular dysfunction and associated risk factors through four years following initiation of ART in adults with HIV infections in Africa in the DART trial. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town. Poster abstract TUPEB184.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2546
http://www.ias2009.org/pag/PDF/2546.pdf
2. Carr A et al. Reversibility of tenofovir-related renal toxicity. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town. Poster abstract TUPEB177.
http://www.ias2009.org/pag/Abstracts.aspx?AID=524

People who are newly diagnosed with HIV, commonly expect to delay HAART for 5-8 years. However, the UK Register of Seroconverters has previously reported that at least a quarter of patients may need to start treatment within two years of infection. In a review of this cohort published in AIDS in January 2008, the median time from seroconversion to HAART initiation was 5.0 years but the IQR was 2.1 to > 10 years. The 25th percentile of time to starting HAART was 2.0, 2.0, 2.0 and 1.4 years in 1998-1999, 2000-2001, 2002-2003 and 2004-2006, respectively. [1]

This was also a conservative analysis as it excluded patients who started treatment within six months of infection due to complications during seroconversion. This analysis related to the period when UK guidelines recommended starting treatment before the CD4 count dropped below 200 cells/mm³.

At the IAS meeting, two studies from the CASCADE cohort of European seroconverters (which includes the UK data) provided further information on time to progression.

A European analysis, presented by Sara Lodi from the UK’s MRC, looked at time to CD4 counts dropping to below 500 cells/mm³, in order to inform policy should guidelines broaden to this higher threshold. [2]

Of over 11,700 adults (age >15 years) who seroconverted after 1992, over half (57%) reached CD4 <500 cells/mm³ during a median of 20 months (95%CI: 19.6, 20.5), with 29% censored at initiation of antiretroviral therapy. The proportion of patients with CD4 counts above 500 at 6, 12, 24 and 36 months after seroconversion was approximately 92%, 72%, 43% and 30%, respectively.

From these results, the authors concluded that 50% of patients would require treatment within 20 months of seroconversion, if future guidelines change the CD4 initiation threshold to 500 cells/mm³.

Increasing age at seroconversion was associated with faster progression (HR, 95%CI: 1.06,1.03-1.09 per 10-year increment). For example, 50% of the patients aged 15-20 still had counts >500 cells/mm³ after two years compared to only 35% of patients who were older than 40 at diagnosis. Unadjusted median times for those aged < 20, 20-29, 30-39, and 40+ years were 25.5, 21.9, 19.8 and 17.6 months, respectively.

No association was found with gender, transmission group and acute infection. Although numbers of patients with sub-type A, C and D were very low, there was an indication that progression may have been faster compared with sub-type B.

A second study from the CASCADE group, presented by Andrea de Luca, reinforced the finding that older age is associated with a shorter time to starting treatment, but also that older age was associated with better virological response (suppression to <50 copies/mL viral load). [3]

Of over 7100 patients who seroconverted after 1993 that were included in the analysis, just under half (48%) initiated antiretroviral treatment. Median time to starting treatment was 3.32, 3.15, 2.64 and 2.08 years for patients aged 15-29, 30-39, 40-49 and 50+ years respectively.

Later calendar period and seroconversion illness, but not age, were found to be independent predictors of CD4 count at ARV initiation. Increasing age was associated with better viral response (HR (95%CI)= 1.17 (1.06, 1.29); 1.30 (1.15, 1.47); and 1.25 (1.07, 1.47) for 30-39, 40-49 and 50+, respectively, compared to 15-29 year olds at seroconversion).

Data on progression rates in an African cohort were presented from the French ANRS 1220 Primo-CI cohort 1997-2008, in patients from Abidjan, Côte d’Ivoire. [4]

This study had a similar design, though it was a much smaller cohort (of 254 adults enrolled, 112 had baseline CD4 >500 cells/mm³). Baseline characteristics of these 112 patients followed included 65% men, median age was 28 years (IQR 25-34), median time from estimated seroconversion was 7 months and median CD4 cell count was 677 cells/mm³ (IQR 591-800). Median duration of follow-up was 7.1 years (IQR 4.2-9.3; 790 person-years).

The probability of reaching CD4 <500 cells/mm³ (the guideline for starting PCP prophylaxis) was 0.58, 0.70, and 0.78, at 2, 4 and 5 years, respectively. The probability of reaching CD4 <350 cells/mm³ was 0.22, 0.47, and 0.49, at 2, 4 and 5 years, respectively. Baseline CD4 count and haemoglobin were associated with a CD4 decrease below 500.

The study concluded that, in this cohort, half of patients reached CD4 <350 within five years of infection. They also reported higher morbidity and mortality at CD4 counts between 350 and 500 (compared to higher CD4 counts). Mortality was 0.9 per 100 patient years and incidence of WHO stage III/IV events was 0.5.

COMMENT

Highlighting the significant interpatient variability in the time to starting treatment would give newly diagnosed patients a more realistic understanding of the chance that the optimal time to start may well be within two years. The probability is likely to be over 25% for any setting where the recommended CD4 threshold is now 350 rather than 200.

The association with older age at infection support the BHIVA guidelines recommendation to consider earlier treatment in older patients.

References:
1. Ewing F et al. Survival following HIV infection of a cohort followed up from seroconversion in the UK. AIDS, 2 January 2008, Volume 22, Issue 1; p 89-95. doi: 10.1097/QAD.0b013e3282f3915e. Free text access.
http://journals.lww.com/aidsonline/toc/2008/01020
2. Lodi S et al. Time to reaching CD4≤500 for individuals followed-up since HIV seroconversion. 5th IAS, 2009, Cape Town. Poster abstract MOPEB050.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3043
3. de Luca A et al. Timing of cART initiation and subsequent virologic response by age for individuals followed up since HIV seroconversion. 5th IAS, 2009, Cape Town. Poster abstract CDB075.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3169
4. Minga A et al. Evolution to the need of care in HIV-1 seroconverters adults with CD4+ cell count above > 500/mm?. The ANRS 1220 Primo-CI cohort1997-2008, Abidjan, Côte d’Ivoire. Poster abstract CDD026.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1949

Previous reports have shown plasma concentrations of some PIs are reduced in pregnant women.

A late breaker poster authored by Francesca Conradie and coworkers from the A1424182 study showed PK data from women receiving atazanavir/ritonavir (ATV/r) once daily during pregnancy.

This was a multicentre, open label, single arm phase I study with sites in South Africa, Puerto Rico and the USA. Women were enrolled who were between 12 and 32 weeks gestation with CD4 >200 cells/mm³.

This study determined multiple clinical and PK parameters during the second and third trimesters, and post-partum.

ATV was dosed ATV/r 300/100 mg (n=20) or ATV/r 400/100 mg (n=21) in combination with AZT/3TC 300/150 mg twice-daily during the third trimester. Second trimester and post partum dosing was ATV/r 300/100mg.

Third trimester exposures were compared to historical ATV 300/100mg exposures in non-pregnant adults. Foetal:maternal ratio was determined using cord blood samples. Infants were followed up for 6 months.

The investigators reported all mothers had fully suppressed viral load (<50 copies/mL) before or at delivery. At the time of analysis all infants (n=40) were HIV DNA negative. There were no infant deaths.

Maternal drug-related serious adverse events (SAEs) were: hyperbilirubinemia (n=1) and anaemia (n=4). Grades 3-4 hyperbilirubinemia occurred in 6/20 and 13/21 mothers in the 300/100mg and 400/100mg groups, respectively.

Three infants had drug-related SAEs. Infant bilirubins were within normal limits to day 14; 7 had Grade 3 hyperbilirubinemia after day 14 (maximum 8.5 mg/dL at day 15). One infant received 3 days phototherapy from day 3. This infant had other risk factors (low birth weight and prematurity).

For the 300/100mg group, they reported that Cmax and AUC during the third trimester were 27% and 21% lower and C24 was similar to historical data in non-pregnant HIV-positive patients taking ATV/r 300/100 mg once-daily.

For the 400/100mg group they found AUC and Cmax similar to, and C24 39% higher than, historical levels; post partum exposures were also higher than historical. The investigators noted that elevated levels have been observed with other PIs in the post partum period. Levels of ATV appeared to normalise by 16 weeks post partum.

The ATV foetal:maternal ratio was 0.19 and 0.12 for 300/100 and 400/100, respectively. This ratio indicates that ATV, like other PIs, has poor transplacental transfer.

The investigators concluded that this phase I study suggests that no dose modification of ATV 300/100mg once daily is necessary in the third trimester of pregnancy. Clinical outcomes indicate that this dose suppressed HIV viral load effectively in the participating women, and prevented vertical transmission of HIV to their infants, when used in combination with AZT/3TC twice daily. Treatment with ATV/r in the mothers appeared to be well tolerated.

Ref:
Conradie F et al. The safety, efficacy, and steady state pharmacokinetics of atazanavir/ritonavir (ATV/r) once daily given in combination with twice daily AZT/3TC during pregnancy: results of study AI424182. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract LBPEB06.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3732

HIV-positive women are frequently unaware of their status prior to antenatal testing.

Late diagnosis of HIV results in some advanced management considerations. The extent to which this occurs in pregnancy in Europe has not previously been quantified, nor have the implications for maternal and child health.

Claire Townsend from the European Collaborative Study presented data from an analysis performed to quantify this occurrence within the cohort, describe management strategies and the impact of late diagnosis on MTCT, prematurity and low birth weight.

The investigators defined late diagnosis as women diagnosed antenataly with CD4 count <200 cells/mm³. The analyses used logistic regression and linear mixed effects models.

Date of first positive HIV test was available for 3605 women, of which 1256 had CD4 data available.

Overall 654 (53%) were white, 499 (41%) black and 73 (6%) were of other ethnicities. Of these 15% (185/1256) had late stage diagnoses. This proportion has increased over time with 12% between 1985-89 and 19% between 2005-2008, p=0.24.

The median baseline CD4 count was 140 cells/mm³ (IQR 90-147) among the late diagnosis women vs 460 cells/mm³ (IQR 333-650) among non-late diagnosis women. Of the late diagnosis group, 11% (n=20) had an AIDS-defining illness in pregnancy.

In logistic regression analysis limited to 613 women enrolled after 1996, the investigators found adjusted late diagnosis rates were positively associated with black African ethnicity vs white ethnicity (OR 2.02; 95%CI 1.17-3.48, p=0.01) and older maternal age (OR 2.17; 95% CI 1.10-4.25, p=0.02) for women aged 30-34 years vs <25 years.

More women with late diagnosis received antenatal HAART than other women 85% (94/110) vs 67% (388/580), p< 0.001. The median duration of HAART was 16.9 (IQR 11.6-20.7) weeks vs 13 (IQR 11.6-20.7) for women with late stage and non-late stage diagnosis respectively.

Adjusting for time of measurement and type and duration of regimen, late stage diagnosis was associated with a significantly higher viral load throughout pregnancy, +0.29 log copies/mL vs non late-stage diagnosis women, p<0.001. The estimated mean viral loads at time of delivery were 2.94 log copies/mL and 2.65 log copies/mL for late diagnosis and non-late diagnosis women respectively.

More infants born to women with late diagnosis were premature, 24.0% (44/183) vs 13.7% (145/1062), p< 0.001 and of low birth weight, 27.5% (46/167) vs 16.1% (165/1022), p< 0.001 than other infants.

In the period 2000-08, MTCT rates were similar, 3.0% (95%CI 0.37-10.5) and 1.5% (95%CI 0.5-3.51), p=0.4 in the late diagnosis and non-late diagnosis groups respectively.

This analysis found that an increasing minority of HIV-positive women in Europe, newly diagnosed through antenatal testing, already has advanced disease. Although these women are more likely to initiate HAART, and to do so earlier, they still have worse pregnancy outcomes than women with better functioning immune systems.

“Barriers preventing timely access of women to HIV testing are important to address, both for the health of the mother and her infant”. Dr Thorne concluded.

Ref:
Thorne CN et al. Presentation with late stage HIV disease at diagnosis of HIV infection in pregnancy. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract TUAC103.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1155

Drug Resource Enhancement and Malnutrition (DREAM) is a large HAART programme with sites in sub-Saharan Africa attended by about 75,000 people. A major part of DREAM is nutritional supplementation and prevention of mother-to-child transmission of HIV.

Women in DREAM receive HAART in pregnancy irrespective of their CD4 counts. Those indicated for treatment with CD4 <350 cells/mm³ receive NVP-based HAART from 14 weeks gestation which is continued indefinitely. Women with CD4 >350 cells/mm³ receive HAART from 25 weeks gestation, which is stopped after weaning at 6 months post partum. Women who stop treatment continue to receive AZT/3TC for 21 days to cover the nevirapine PK tail. PCR DNA determines infant infection.

In two oral presentations, Leonardo Palombi presented data from Mozambique and Malawi describing transmission rates and infant outcomes. Both analyses were retrospective record reviews.

Rates of transmission and infant mortality

This analysis looked at:

1. HIV free survival at 1 and 6 months

2. Transmission rates by maternal CD4

3. Infant health at 6 months

Between July 2005 and December 2008, there were 3148 live births from 3273 pregnancies. At one month, 93 infants were lost to follow up, 7 had died, and 2,994 had test results. Of these 22/2994 (0.7%) were HIV-infected.

Transmission was 0.9% (26/2,707) in mothers who received at least one dose of HAART before delivery (median viral load 3.55 log) and 5.1% (2/39) in women who did not initiate HAART until delivery (VL 4.51 log), p<0.001. Infant HIV free survival at one month was 97.6%.

At 6 months, a further 143 infants were lost to follow up and 41 had died. Six-month testing found 15/2120 infected infants (5 awaiting confirmation). The cumulative 6-month transmission rate was 1.4-1.9%, the mortality rate was 2.1% and loss to follow up was 7.5%.

The investigators found that duration of antenatal HAART and the combined endpoint of infant infection or death were associated across baseline maternal CD4 counts: 1.3% (16/1231) vs 3.8% (6/157) infants were infected or died who had mothers with CD4 <350 cells/mm³ who received >=30 days and <=30 days HAART respectively, OR 0.33 (95% CI 0.12-0.86). And 0.7% vs 2% infants were infected or died who had mothers with CD4 >350 cells/mm³ who received >=30 days and <=30 days HAART respectively, OR 0.33 (95% CI 0.10-1.09).

In multivariate analysis at one month, adjusted for maternal baseline viral load, CD4, haemoglobin and BMI, there was an association between antenatal HAART-exposure and transmission or death: 2.4% with 1-30 days, 1.1 % with 31-90 days and 0.9% with >90 days, (OR 0.57; 95% CI 0.36-0.88).

At six months, 3.1% vs 8.8% infants were infected or died who had mothers with CD4 <350 cells/mm³ who received >30 days and <30 days HAART respectively, OR 0.33 (95% CI 0.16-0.7). And 1.8% vs 2.1% infants were infected or died who had mothers with CD4 >350 cells/mm³ who received >30 days and <30 days HAART respectively, OR 0.81 (95% CI 0.24-2.83). ). That is, at higher maternal CD4 counts the impact of HAART > 30 days vs <30 days was not significant.

In multivariate analysis at 6 months, duration of HAART and maternal viral load were associated with transmission or infant death.

At six months, HIV free survival was 90.9% in infants whose mothers had received <30 days pre-delivery HAART, and 96.6% for those whose mothers received >30 days pre-delivery HAART.

Dr Palombi noted that the effect of HAART observed in DREAM was found across all maternal CD4 counts and that mothers with >350 cells/mm³ comprised 37% of transmissions where they occurred

Overall transmission rate at 6 months was 2% in this cohort.

Outcomes

In the second analysis, the investigators looked at maternal health/mortality, and infant outcomes ie prematurity, spontaneous abortion and stillbirth (defined as foetal death at < or >32 weeks gestation respectively).

Overall they reported 42 maternal deaths giving a maternal mortality rate (MMR) of 1.2%. The majority of women in DREAM received longer duration of HAART but 68 women received none and 365 women <30 days HAART. Although infrequent, maternal mortality was significantly associated with HAART (7.4% if no HAART vs 0.7 >90 days antenatal HAART) and CD4 count (3.2% vs 0.7% if >200; p< 0.001).

Foetal death included 3.1% stillbirth and 2.1% spontaneous abortion. The prematurity rate was 19.1%.

Duration of antenatal HAART was associated with infant outcomes. The rate of abortion and stillbirth was 5.2% among infants whose mothers received >90 days HAART compared to 26.5% among those whose mothers received no HAART and 7.1% <30 days HAART, p<0.001.

Maternal CD4 was also associated with abortion and stillbirth, with a rate of 16.7% among mother with CD4 <200 cells/mm³.

In this cohort, prematurity was associated with shorter duration or no HAART. The investigators reported a 70.8% reduction (Mantel-Haenszel test) overall, OR=0.16 (95% CI, 0.12-0.21) and within each CD4 strata.

In multivariate analysis, BMI (OR 0.27; 95% CI,0.15-0.50) and viral load at delivery (OR 1.44; CL95% 1.22-1.70) were associated with prematurity (see Table 1). Low birth weight was 11.5% and not associated with HAART duration or CD4 count.

Table 1: Prematurity rates in DREAM

(Table reproduced from abstract)

The investigators found low incidence of SAEs: 8.6% women had grade 3/4 anaemia; 6.9% d4T-associated peripheral neuropathy; 2.2% grade 3/4 liver toxicity; and 2.4% grade 3/4 rash. However, Stevens-Johnson Syndrome was reported in 1.2% patients.

They also found no resistance in a small sub-study of women (n=26) who had discontinued HAART after weaning.

They wrote: “HAART was strongly associated with improved pregnancy outcomes including reduction in prematurity, regardless of CD4 strata. HAART is beneficial for PMTCT and protects against unfavorable pregnancy outcomes”.

COMMENT

The data from DREAM seem impressive and it was suggested that they demonstrate that the low rates of transmission now associated with HAART during pregnancy in resource-rich settings can be reproduced in a large roll-out programme in a resource-poor environment.

However, several things make these data very difficult to interpret including significant loss to follow-up and that the number of infants evaluated at different time points is different.

The data on premature delivery and HAART are curious. The authors conclude that short-duration of HAART is associated with prematurity, and at <30 days with as much as 71.4%, these rates are extremely elevated. But perhaps this finding is not surprising since duration is timed from initiation to delivery, and will inevitably be shorter in those who deliver preterm. Data reported by Karin van der Merwe from Johannesburg (reported on in this issue) looking at HAART vs no HAART and longer vs shorter HAART, found higher rates of preterm delivery with HAART and with longer HAART, completely contradicting the DREAM data.

The extensive use of nevirapine-based HAART in this study, with relatively little toxicity reported, despite use at CD4 counts >250 cells/mm³ is also noteworthy and adds to the extensive literature of uncertainty regarding nevirapine, pregnancy and CD4 cell counts.

So these data raise a lot of questions. It was unfortunate that neither the slides nor the webcast from these sessions were available online to check some of the information presented.

References
1. Marazzi MC et al. Extended use of highly active antiretroviral therapy (HAART) during pregnancy in Southern Africa is highly protective in HIV-1 prevention of mother-to-child-transmission (PMTCT) also in women with higher CD4 cell counts. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Oral abstract TUAC101.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2013
2. Marazzi MC et al. Favorable pregnancy outcomes with reduction of abortion, stillbirth, and prematurity rates in a large cohort of HIV+ women in Southern Africa receiving highly active antiretroviral therapy (HAART) for prevention of mother-child-transmission (PMTCT) 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Oral Abstract TUAC102.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1874

Pregnancy rates and outcomes and outcomes among women participating in DART were shown in a poster authored by Paula Munderi and coworkers on behalf of the DART trial team. [1]

The investigators had previously shown findings from an evaluation of pregnancy at a median of 2.8-years of follow-up, which we reported previously in HTB. [2]

This further analysis was at a median of 4.6 years follow-up from January 2003 to June 2008, and included information on maternal/infant outcomes and infant feeding. Longer-term infant follow-up and documentation of infant outcomes are ongoing in a separate sub-study.

Of the 2156 women enrolled in DART, 1876 (87%) were of childbearing age (<45 years). No women were pregnant at enrollment and pregnancy tests were performed six-monthly. Women in DART were given contraceptive advice, including free condoms, counselled if they wished to conceive, and encouraged to disclose any pregnancy.

If they became pregnant on the trial they continued HAART in their study randomisation, received extra diagnostics as required for pregnancy within the trial, and were referred for routine antenatal care.

Data on infant follow up to 2 weeks of age were analysed for congenital abnormalities, early infant survival, and HIV status if tested.

The investigators reported that 378 pregnancies occurred in 299 women. The majority had one pregnancy (n=235) but 50, 13 and 1 women/woman had 2, 3 and 4 pregnancies respectively.

Multiple pregnancies occurred in 16% women <45 years and 33% women <30 years and this rate was similar across sites.

The overall pregnancy rate in women <45 years was 4.83/100 woman years (95% CI 4.36-5.34). Incidence pregnancy rates peaked at 2-3 years across all age groups and then declined. It was highest in the 18-29 years age group.

The median CD4 count was greater among women who were ever pregnant vs never pregnant 106 (IQR 32-142) vs 87 (IQR 31-141) cells/mm³ respectively, p=0.01.

The majority of mothers (60%) received TDF+AZT+3TC regimens. Of the remaining, 17% received NVP+AZT+3TC; 7% d4T-containing HAART; 6% second-line with LPV/r; 5% ABC+AZT+3TC; 3% were off HAART and 2% received other first line HAART.

Four mothers died, 2 during pregnancy (I due to malaria, 1 due to septic abortion) and 2 peripartum (1 post partum haemorrhage and 1 puerperal psychosis).

There were 206 live births and 26 stillbirths. Any congenital abnormalities were reported in 7 (3%) infants. These were club-foot (3; 2 tenofovir, 1 nevirapine); hydrocephalus (1 tenofovir, died); cardiac anomaly (1 nevirapine); undescended testes (1 nevirapine) and skin tag on neck (1 tenofovir).

Prematurity <37 weeks occurred in 9% live births (16% live and still births). Low birth weight <2.5kg occurred in 17% of live births (13% >=37 weeks). The mean weight in infants >37 weeks was 3.0kg (SD +0.54).

At two weeks post partum, the investigators reported 9 neonatal deaths, of which 6 occurred within 24 hours; 5 infants were HIV-DNA PCR negative and 4 were not tested. Causes of death were: foetal distress (2), prematurity (1), intestinal obstruction (1), haemorrhagic disease (1) and 4 were from unknown causes.

Only a small number of children (n=15, 7%) were tested by the DART assessment visit at 2 weeks and none were HIV-infected.

The infant follow up sub-study has enrolled 174/206 infants. Of these 152 are known to be still alive. Of the 137/174 (74%) infants with results available, none are HIV-infected.

At two weeks only a minority of women (30%), across all study sites, chose to breastfeed.

The investigators concluded that in this group of women, pregnancy rates increased after the first year and declined from the fourth year on HAART. Rates were higher among younger women with less severe HIV disease.

Rates of foetal loss were high and are consistent over time. They suggest that this may reflect improved reporting within a clinical trial but note that increased foetal loss has been reported in other studies.

The low rates of congenital abnormalities are encouraging and similar to those shown elsewhere: 3.0/100 95%CI 2.4-3.7) among HIV-positive women with first trimester HAART exposure in the Antiretroviral Pregnancy Register (APR) and 2.7/100 live births in the CDC birth defects register.

COMMENT

At first sight the preterm delivery rate is encouragingly low, much lower than in most other studies (eg 19% in DREAM see above, 17% in Europe, 18% in North America). Contributing factors may include conception on therapy, negating the effect of HIV infection on preterm delivery, and the regimen prescribed. Conversely the stillbirth rate is high and highly associated with preterm delivery. More data on the gestational age are needed to interpret these findings.

The low rates of congenital abnormalities are also encouraging and this large dataset from women receiving TDF in pregnancy is very useful. These data have been submitted to the Antiretroviral Pregnancy Registry. [3]

References
1. Munderi P et al. Pregnancy rates and outcomes among women on triple-drug antiretroviral therapy (HAART) in the DART trial. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract WEPEB261.
2. http://i-base.info/htb/2667/
3. http://www.apregistry.com

There are conflicting reports concerning the association between preterm birth or low birth weight and HAART.

Karin van der Merwe and coresearchers investigated the impact of HAART exposure on birth weight and gestational age among infants of South African women with advanced HIV disease attending antenatal antiretroviral clinics in Johannesburg. [1]

This review included 1630 women attending clinics between April 2004 and July 2008. All women had CD4 <250 cells/mm³.

Gestation and birth weight of infants were compared: maternal HAART exposed vs unexposed; early (<28 weeks gestation) vs late (>=28 weeks) and PI-based vs NVP-based vs EFV-based. Multivariate logistic regression was used and included maternal CD4 and infant HIV status (PCR).

The investigators found the median CD4 counts for mothers of infants exposed and unexposed to HAART were 154 (IQR 101-229 and 191(IQR 136-220) cells/mm³ respectively, p<0.001. The two groups were similar for other risks of adverse infant outcomes: smoking, alcohol, hypertension, diabetes, anaemia, syphillis serology and history of previous miscarriage.

Prematurity rates were 6% (8/143) in HAART-unexposed infants vs 14%(129/949) in HAART-exposed infants (p=0.01). The HAART-exposed infants had mothers with a higher rate of previous preterm infants than the unexposed group, 11% vs 6%, p=0.055.

See Tables 1 and 2 for infant outcomes by duration of exposure and HAART regimen.

Table 1: Infant outcomes in women exposed and unexposed to HAART and by duration of exposure

The investigators concluded that, in this analysis, any HAART exposure was associated with preterm birth between 34-37 weeks gestation. This was strongest when HAART was initiated before 28 weeks gestation. However, they did not find an increased risk of extremely preterm birth (<34 weeks gestation).

Table 2. Infant outcomes in women exposed to HAART by regimen

Overall, they found neither low birth weight nor very low birth weight to be associated with HAART exposure. In this cohort, infants unexposed to HAARTwere more likely to have low birth weight.

PI exposure was not a risk factor for preterm or low birth weight. But, of the three regimens, early EFV exposure was associated with low birth weight. The investigators suggested that higher levels of TB among this group of women could be confounding, as EFV is frequently used in South Africa in pregnancy in the presence of HIV/TB coinfection. TB is a risk factor for preterm birth and low birth weight.

They added that these findings could help guide PMTCT policies in South Africa.

COMMENT

As the investigators suggest, the observation that there was an association between early efavirenz exposure and low birth weight may be subject to confounding due to TB.

They included two useful tables (see Tables 3 and 4) showing published studies that looked at HAART exposure and preterm delivery or low birth weight. Data from Africa is slowly emerging.

Table 3: Major studies showing a link between preterm birth or low birth weight and HAART exposure

Table 4: Major studies showing no link between preterm birth or low birth weight and HAART exposure

References
1. van der Merwe K et al. The impact of in-utero antiretroviral therapy (HAART) exposure on infant outcomes in Johannesburg, South Africa. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract WEPEB262.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2256
2. Lorenzi P et al. Antiretroviral therapies in pregnancy: maternal, foetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS 1998, 12:241-247.
3. Thorne C et al. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe. AIDS 2004, 18:2337-2339.
4. Cotter A et al.Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis 2006. 193:1195-1201.
5. Townsend CL et al. Antiretroviral therapy and premature delivery in diagnosed HIV-infected women in the United Kingdom and Ireland. AIDS 2007, 21: 1019-1026.
6. Tuomala RE et al. Antiretroviral therapy in pregnancy and the risk of adverse outcome. N Eng J Med 2002, 346: 1863-1870.
7. Tuomala RE et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir immune Defic Syndr 2005, 38: 449-473.
8. Szyid EG et al. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. AIDS 2006, 20: 2345-2353.
9. Schulte J et al. Declines in low birth weight and preterm birth among infants who were born to HIV-infected women during an era of increased use of maternal antiretroviral drugs. Pediatric spectrum of HIV disease, 1989-2004. Pediatrics 2007, 119: 900-906.

A poster from the Perinatal Research Unit in Soweto, South Africa, showed findings on the rate of miscarriages and still births from a retrospective review of women receiving efavirenz (EFV) in pregnancy. [1]

Although EFV is FDA category D, increasingly women are conceiving while already receiving this antiretroviral.

In this review, the investigators looked at records of 886 women receiving HAART between August 2004 and March 2008. Among this group, 117 pregnancies were recorded and 83 women (70.9%) had conceptions that were EFV-exposed for a mean duration of 97.05 days (range 12-343 days). Of these, 3/83 (2.6%) miscarried, 1/83 (1.2%) was a stillbirth, and 28/83 (33.7%) were electively terminated.

The remainder of HAART exposed conceptions, 34/117 (29.1%), were EFV-unexposed; of these 5/34 (14.7%) miscarried, 1/34 (2.9%) were stillbirths, and 2/34 (5.9%) were electively terminated.

The investigators found that compared to live births, elective termination of pregnancy (TOP) rates were significantly higher among EFV-exposed than non-EFV exposed, p=0.00418.

They also note that South African public sector surveillance reports a miscarriage rate of 6.3% (2001), a stillbirth rate of 2.4% (2006-07), and an elective termination of pregnancy rate of 13.6% (2001).

They suggest that this high rate of TOP in women receiving EFV-containing HAART may reflect provider teratogenicity counselling. Additionally, they suggest that it reflects provider choice to initiate EFV-containing regimens for women not expressing the desire to have children. They note that they did not find an increase in miscarriage or stillbirths in women receiving EFV compared with the general population.

COMMENT

The investigators explained that this evaluation was performed in response to findings from Brazil showing a higher rate of miscarriage among EFV-exposed pregnancies. [2]

In our comments concerning the Brazilian data [3] we wrote:

“These data should be treated with extreme caution. The miscarriage rate reported from this notes review is extremely low (1.38%). It is generally thought that approximately 30% of conceptions are miscarried. The potential for biased reporting is very high and this is more likely to be seen with efavirenz than other antiretroviral drugs. Although the congenital anomaly rate is reported to be more than twice the background for Rio de Janeiro (2.2% v 0.8%) the later figure is only about one third of the normally cited of congenital malformations and 2.2% is a more realistic figure.”

This South African review did not find a higher rate of miscarriage or stillbirth among women receiving EFV at conception.

However, the high rate of termination of pregnancy among women taking efavirenz is striking and the investigators suggest that this may reflect provider teratogenicity counselling. FDA category D states that there is evidence that the drug is associated with teratogenicity in humans. This is a relative contraindication and this FDA classification also states that the benefits may outweigh the potential risk (category X states that the drug should not be prescribed in pregnancy because of the risk). Despite this categorisation, the Antreroviral Pregnancy Registry, which now has sufficient numbers of first trimester efavirenz exposures to detect at least a two-fold increase in risk of overall birth defects, report no such increase to date, 14/477, 2.9% (95% CI, 1.6-4.9%). [4]

The data from DART above show that even in a clinical trial with pregnancy counselling 4.8% of women conceived per annum. In this cohort from Soweto 13% of the women on HAART conceived with the majority (71%) taking an efavirenz-based regimen.

So, as the investigators suggest, consideration needs to be given both to provider antiretroviral choice and to provider counseling with women of child-bearing age who may or do become pregnant.

References
1. Laher F et al. Efavirenz conceptions in Soweto, South Africa. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract TUPEC047.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1121
2. Joao E et al. Increased incidence of spontaneous abortion during first trimester exposure to efavirenz. 4th IAS conference, Sydney, 2007. Poster abstract TUPEB113.
3. http://i-base.info/htb/2216
4. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2009.
http://www.APRegistry.com

There are limited data describing the effects of HAART on mother-to-child transmission among HIV-positive women in Africa with CD4 counts <250 cells/mm³.

A poster authored by Risa Hoffman and coworkers showed an analysis of the impact of HAART regimen and duration of treatment on risk of transmission in women attending antenatal clinics in Johannesburg. [1]

This group had looked at transmission among women initiating HAART in pregnancy in an earlier analysis from this cohort. They found that for each additional week of HAART, the odds of transmission were reduced by 27%. We reported this study previously in HTB. [2]

In this more recent analysis they included both women who became pregnant while receiving HAART and those initiating HAART during pregnancy. The authors used chi square tests and logistic regression to evaluate the effects of regimen and duration on transmission. An infected infant was defined as having a positive DNA PCR at 6 weeks.

A group of 1115 women were followed from April 2004 until July 2008. At baseline the women were a mean age of 31 years and their mean CD4 count was 159 cells/mm³. Most women (97.3%) received a nucleoside backbone of d4T/3TC. Similar proportions received LPV/r (448; 40.2%) and EFV (469; 42.1%); and a smaller group of women received EFV (198; 17.8%).

Data for initiation of therapy were available for 874 women. Of these, 16.0% became pregnant while already receiving HAART. For those already on HAART the mean duration was 93.4 weeks. For those initiating HAART in pregnancy the mean duration was 10.7 weeks of therapy.

The investigators reported an overall transmission rate for women with known date of initiation of 4.7% (43/874). They found no significant differences between HAART regimens. This finding remained with or without adjustment for prior single-dose NVP.

Women who became pregnant on HAART had significantly lower transmission rates than women who initiated HAART during pregnancy, 0.7% vs 5.7%, p=0.01.

Women initiating HAART during pregnancy (n=553) had higher transmission rates with shorter duration of therapy: 9.3%, <4 weeks; 5.5%, 4-16 weeks and 3.5%, 17-32 weeks. There were no transmissions among women receiving >32 weeks of HAART. Each additional week of HAART reduced the odds of transmission by 8%, OR 0.92, p=0.02, CI 0.87-0.99.

“To improve rates of MTCT, strategies are needed to facilitate earlier identification of HIV-infected pregnant women”, they wrote.

COMMENT

Data continues to accumulate to support early identification of HIV-positive women in pregnancy and timely initiation of treatment.

References
1. Hoffman R et al. Impact of antiretroviral therapy regimen and duration of therapy on risk of mother-to-child HIV transmission in Johannesburg, South Africa. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract WEPEB260.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1127
2. http://i-base.info/htb/1863

The Optimum Combination Therapy After Nevirapine Exposure (OCTANE)/ACTG5208 trial found superior outcomes among women exposed to single dose nevirapine (NVP) receiving lopinavir/ritonavir (LPV/r)-based HAART compared to those receiving NVP-based regimens. [1, 2]

In OCTANE, women with CD4 <200 cells/mm³ exposed to NVP as PMTCT prophylaxis a median of 17 months prior to HAART initiation were randomised to receive either LPV/r- or NVP-based HAART. Over a median of 73 weeks follow up, women in the LPV/r arm had significantly lower risks of virological failure or death compared to those in the NVP arm. We covered these findings in previous issues of HTB.

However, the difference in cost between the two drugs is quite considerable: LPV/r is12 times more expensive than NVP.

Andrea Ciaranello presented an analysis that examined the cost-effectiveness of first line LPV/r based HAART, compared to first line NVP-based HAART, for women with prior single dose NVP exposure in South Africa. [3]

This analysis utilised the Cost-effectiveness of Preventing AIDS Complications (or CEPAC) computer simulation model. The model included incidence, prophylaxis, and treatment of opportunistic infections in South Africa, CD4 count, viral load and HAART efficacy. The investigators used data for the modeling from OCTANE and from published South African cohorts, including natural history data from the Cape Town AIDS Cohort.

They projected two year and lifetime outcomes associated with first line HAART strategies for women with prior single dose NVP exposure. These projections included risk of opportunistic infections, deaths, and per-person HIV-related costs.

Dr Ciaranello explained that cost-effectiveness analysis a method of comparing alternative health care strategies. This method uses an incremental cost-effectiveness ratio (ICER). To calculate the ICER, the number of additional health care resources needed for one strategy compared to another is determined. This is divided by the additional health benefits gained by this strategy compared to the other.

Currency per year of life saved (YLS) is the most common unit for an ICER. A lower ratio, when less money is needed to produce a health benefit, shows a more cost-effective intervention.

To determine whether an intervention is cost effective, WHO compare ICER to per-capita GDP. ICER <1xGDP/YLS is considered to be “very cost effective” and ICER <3x GDP/YLS is “cost effective”. South African GDP (2006) is $5400.

Three strategies were evaluated in this analysis:

1. No HAART (comparitor)

2. First line NVP/TDF/FTC (Second-line LPV/r/ddI/AZT)

3. First line LPV/r/TDF/FTC (Second-line NVP/ddI/AZT).

Following second line failure, women were assumed to receive a maintenance regimen of LPV/r and 3TC, which was common practice at OCTANE sites.

Baseline data for the women were used from the OCTANE cohort and included median: 31 years of age; CD4139 cells/mm³; viral load, 5.15 log copies/mL and 17 months since exposure to single dose NVP.

The efficacy of each regimen was modeled on that observed in the OCTANE trial. Efficacy was defined as achieving viral load suppression <400 copies/mL at 24 weeks after initiation of HAART.

With a median time from single dose NVP exposure of 17 months, efficacy of the first line NVP regimen was 84.6%, and the efficacy of the first-line LPV/r regimen was 96.7%.

The investigators noted that these data are slightly different from those previously presented, as a composite endpoint of virologic failure or death was shown.

There are very few data on the efficacy of NNRTI-based second-line regimens. For the model data were extrapolated from two studies to give an estimate of 43% virologic suppression at 24 weeks for second-line NVP. Data for second-line PI-based HAART are more common and, using multiple sources, an estimate of 72% suppression was used.

The investigators assumed that routine viral load tests were not available and that HAART was switched for severe opportunistic infection, 50% CD4 decline or toxicity.

They used HIV-related healthcare costs derived from the South African Health Systems Trust. These included the cost of a day in hospital of $221, the cost of an outpatient clinic visit of $11 and the cost of a CD4 test of $9.

For drug costs, they used prices from the Clinton Foundation HIV/AIDS Initiative. Annual drug costs were $38 for NVP and $444 for LPV/r. For the nucleosides, the figures were $142 for TDF/FTC and $238 for ddI/AZT.

Projecting outcomes for the entire cohort at two years revealed that with no HAART, 41.7% of women would survive at a per-person cost of $2650. Using a NVP-based first-line regimen survival was 96.1% at a per-person cost of $2450, and providing LPV/r-based HAART first-line, survival was 97.1% at a per-person cost of $2780. Compared to first-line NVP, LPV/r gave a 26% risk reduction in mortality at an additional per-person cost of $330.

Projecting long-term outcomes showed live expectancy of 1.8 years at a per-person cost of $3540 if the cohort were untreated. With NVP-based first line survival increased by 13.6 years to 15.4 years at a per-person cost of $14,040 for an ICER of $770/YLS. Using LPV/r-based first-line gained a further 1.1 years survival (16.5 years) at a per-person cost of $16,180 for an ICER of $1970/YLS. So using LPV/r first-line would be ”very cost effective” compared to NVP according to WHO criteria for South Africa.

Additionally, the investigators then conducted a sensitivity analysis. They evaluated many model inputs parameters and assumptions. Dr Ciaranello presented estimates for parameters of particular importance.

Importantly, they evaluated the efficacy of second-line NVP, for which there are few data (in the range of 16-45%). The investigators looked at 0-100% efficacy and found that LPV/r remains “very cost effective” by WHO criteria unless the efficacy of second-line NVP is less than 15%.

They also looked at the influence of NNRTI resistance at the time of initiation of HAART. Among the OCTANE cohort, 86% of women had no detectable NNRTI resistance using standard genotype assay at the time of starting treatment. For this group of women the efficacy of first line NVP was greater than for the cohort overall, 89% vs 85% (97% for LPV/r first line). For women with no resistance the ICER of first line LPV/r compared to NVP was $10,990/YLS, and no longer a “very cost-effective” intervention in South Africa.

OCTANE also included stratification by time from NVP exposure to initiation of HAART. Looking at cost effectiveness according to these strata, the investigators found LPV/r was “very cost effective” with 6-24 months between NVP exposure and treatment, at an ICER of $2000/YLS. However, >24 months the ICER reached the WHO threshold for South Africa at $5400. They noted that LPV/r first-line became less cost effective as time from NVP exposure increased.

Dr Ciaranello acknowledged that the limitations to these estimates include some input data from cohorts of both men and women; costs and cost effectiveness thresholds that are specific to South Africa and results are sensitive to data that are not yet available from the OCTANE trial.

She stressed that reducing the impact of NNRTI resistance related to single dose NVP is particularly important in order for women to benefit from available classes of antiretrovirals in the treatment of their own HIV.

She also emphasised the importance of HIV and CD4 testing of pregnant women in order to initiate HAART in eligible women before delivery, both improving maternal health and reducing mother-to-child transmission.

However she added: “Despite these efforts, many of the single dose NVP-exposed women living in resource-limited settings are likely to need to initiate HAART soon. The choice of optimal first-line HAART for these women will require important data about long-term outcomes, particularly outcomes of second-line HAART. Such outcomes can only be observed after the conclusion of most clinical trials. OCTANE, cohort studies, and HAART programme monitoring and evaluation efforts will be crucial sources of these data”.

COMMENT

This cost-effectiveness analysis is useful to demonstrate that for NVP-exposed women, particularly those with an interval since exposure of <24 months, using LPV/r-based HAART first-line is very cost-effective.

However, it would be better to avoid risk of resistance in the first place by early identification and treatment for women indicated for their own health (with CD4 <350 cells/mm³), and more complex PMTCT regimens for healthier women (short course PI based HAART, AZT plus single dose NVP plus tail coverage).

As the investigators suggest, the future options for NVP-exposed women for second-line treatment are unclear in resource-limited settings.

References
1. http://i-base.info/htb/261
2. http://i-base.info/htb/1449
3. Ciaranello A et al. Lopinavir/ritonavir (LPV/r)- compared to nevirapine (NVP)-based ART following receipt of single-dose nevirapine (sdNVP) for prevention of mother-to-child HIV transmission in South Africa: a cost-effectiveness analysis of the OCTANE (ACTG A5208) trial. 5th IAS Conference, Cape Town.19-22 July 2009. Poster abstract TUAD103.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1862

David Coetzee from the University of Cape Town presented data from the PEARL study. This study was a four-country evaluation of the effectiveness of PMTCT programmes in Africa. [1]

PEARL evaluated 43 sites in Zambia, Cote D’Ivoire, South Africa and Cameroon. The primary outcome was coverage ie the proportion of mother-child pairs with HIV antibody-positive cord blood with confirmed receipt of maternal (detectable NVP in cord blood) and infant (documented) NVP. The study also evaluated AZT and 3TC where appropriate.

All PMTCT sites used a minimum intervention of single dose NVP. Some also used short course AZT plus single dose NVP and/or HAART.

Cord blood was collected anonymously from every delivery between April 2007 and October 2008 and tested for HIV (there was an excellent collection rate of about 98% of consecutive deliveries). If the result was positive, the presence of NVP (AZT and 3TC if applicable) was determined by high performance liquid chromatography.

The investigators also used documented information collected anonymously from patients’ notes including infant ingestion of NVP.

The investigators collected 28,060 cord blood samples of which 3250 were HIV-positive.

Evaluating both sets of information together they described the “coverage cascade” (see Table 1), where coverage is defined as maternal and infant ingestion of nevirapine.

Table 1: Coverage cascade

They reported wide variation in coverage across different sites (17%-69%).

Reasons for failed coverage included: no offer of HIV test; HIV test declined; testing declined; test result not given; NVP not dispensed; mother did not adhere and infant not dosed.

The risk of failed coverage increased with younger age: <20 years adjusted OR 1.58 (1.23-2.02) vs >30 years. The association also increased with fewer antenatal visits: 0-1 visits AOR 2.92 (2.22-3.84) vs >6 visits.

Risk of poor maternal adherence was significantly higher in the 26-30 years age group, adjusted OR 1.42 (1.04-1.93) vs >30 years; with greater gravidity, OR 1.62 (1.12-2.34), 4 vs 1; fewer antenatal clinic visits OR 2.98 (2.07-4.48), 0-1 vs >6 visits; vaginal delivery OR 1.51(1.11-2.05) vaginal vs caesarean; and AZT plus NVP prophylaxis, OR 1.42(1.04-1.93) vs NVP alone (HAART was not significantly associated with poorer maternal adherence). All rates are adjusted.

The study included an analysis of PMTCT in the Western Cape, where guidelines have recommended HAART for women with CD4 <200 cells/mm³ and short course AZT plus single dose NVP with CD4 >200 cells/mm³ since 2007.

In this province 12% women received HAART (the investigators used detectable 3TC as a surrogate for HAART) and 47% AZT plus NVP, so overall 59% received standard of care. However, 6% received only NVP, so 65% received “at least NVP”; 8% received AZT alone and 27% of pregnant women received nothing at all. The investigators noted that CD4 data was not collected in this study (so they would not be able to estimate how many women should have received HAART).

The investigators concluded that failures in the “cascade” of interventions occur at every step of the way, giving only 50% coverage overall across sites.

Even in settings with two-drug prophylaxis and HAART over a quarter of women are not covered by PMTCT prophylaxis (so also not receiving HAART for their own HIV if indicated).

“Interventions must systematically target better performance at each step to maximise their benefits”, they wrote.

COMMENT

These data provided an important reality check and show that despite interventions that benefit maternal health and/or prevent transmission to their infants, inadequate roll out and coverage is the norm.

The PEARL Study’s primary outcome variable is uptake of PMTCT interventions. As such, PEARL measures programme coverage, but does not assess programme effectiveness at preventing or treating HIV infection. During the conference, reports on national roll out of PMTCT protocols were notable for the absence of infrastructure to detect infant HIV infection, and therefore the effectiveness of PMTCT interventions in practice. Early detection of paediatric HIV is belatedly but rapidly becoming a priority in many countries. We will report on research presented on infant diagnostics in the next issue of HTB South.

WHO PMTCT consultations have also used PMTCT cascades and Lynne Mofenson showed estimations from these in her plenary at the paediatric meeting preceding the IAS conference. [2] In a “typical” scenario they estimate that of 1000 mothers, 90% (900) will attend ANC; of these 70% (630) will be counselled and tested for HIV and 50% of this group (315) receive ARVs. If 685 women receive no ARVs, that will mean 25% (172) of their infants will be infected.

In this estimation, overall transmission rates, if all women with CD4 <200 cells/mm³ receive HAART and the remainder receive either single dose NVP, short course AZT plus single dose NVP or HAART, would be 19.7%, 18.1% and 17.6% respectively.

With improved uptake, if 96% (960) mothers attended ANC, 99% (950) were counselled and tested and 98% (931) received ARVs, that would mean 69 mothers receive no ARVs and 17 infants would be infected. In this estimation the overall transmission rates would be 9.1%, 4.5% and 3.1% for single dose NVP, AZT plus single dose NVP and HAART respectively.

Coceka Mnyani and coworkers showed data from January to December 2008 from the Soweto programme on which the improved figures were based. [3] In March 2008 short course AZT was introduced in addition to single dose NVP for women with CD4 >200 cells/mm³. During this period, 30180 women attended ANC of which 99% (29968) accepted HIV testing and 29% (8774) tested HIV-positive. Of these 5704 mothers and 6641 infants received AZT plus single dose NVP and 96% (8137/8514) elected to formula feed. A total of 324/5572 infants were HIV-infected giving a transmission rate of 5.8%. The transmission rate was 7.2% during the period when single dose NVP was used alone and 4.4% using AZT plus NVP, OR 1.67 (95%CI, 1.24-2.3), p=0.0004.

As Lynne Mofenson explained, “Programme efficacy is as much related to the PMTCT cascade as the specific regimen.”

References

1. Coetzee D et al. Evaluation of PMTCT coverage in four African countries: the PEARL study. 5th IAS Conference, Cape Town.19-22 July 2009. Oral abstract WELBD101.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3792
2. Mofensen L et al. Update and controversies on prevention of mother-to-child transmission. 1st International Workshop on prevention of mother-to-child transmission. 1st International workshop on HIV paediatrics Cape Town, 17-18 July, 2009. Session 5.
http://www.hivpresentation.com/index.cfm?vID=5BB28A44-423A-F6F7-C70DC6EC268CFF57
3. Mnyani CN et al. Reducing PMTCT in practice: results from a successful model of a PMTCT program in a high prevalence HIV urban African setting. 5th IAS Conference, Cape Town.19-22 July 2009. Poster abstract TUPEC048.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1542

Acyclovir studies at IAS 2009

Connie Celum, the principal investigator on the HPTN 039 trial, together with Jai Lingappa, the medical director, and other members of the Partners in Prevention HSV-HIV Transmission Team presented findings at IAS2009 on a counterpart trial to HPTN 039. This study, in HIV serodiscordant couples, looked at whether suppressing HSV-2 in people dually infected with HSV-2 and HIV infections could reduce HIV transmissions to their HIV-negative partners. [1]

HPTN 039 was a double-blind placebo controlled trial of standard doses of acyclovir for HSV-2 suppression (400 mg twice daily) to prevent HIV acquisition among over 3200 African women and MSM in Peru and the United States who were HIV-negative and HSV-2 positive. HTPN 039 found that acyclovir suppression did not reduce HIV incidence compared to placebo. Results were reported at CROI2008 and subsequently in the Lancet. [2]

Celum presented the main results of this new double-blind placebo controlled trial, conducted at 14 sites in sub-Saharan Africa, including South Africa, Kenya, Zambia, Botswana, Tanzania, Rwanda and Uganda.

Of 6544 heterosexual HIV discordant couples screened, 3408 were enrolled. The inclusion criteria for the coinfected partner included a CD4 cell count >250/mm³. The other partner could be either HSV-2 positive or negative, but had to be HIV-negative. HIV-positive participants could not be eligible for ART at trial entry according to their country guidelines.

The HIV-positive partners were randomised to receive either 400mg acyclovir twice-daily or placebo twice-daily. Couples were followed for a maximum of 24 months. Participants were provided with ART if they became eligible for it according to country guidelines.

The primary endpoint was HIV infection in the HIV-negative partners. The secondary endpoints included plasma and genital HIV viral load in the HIV-positive partners, and HIV disease progression. The trial was set up so that if 88 ‘linked’ HIV transmissions (i.e. the virus transmitted from the enrolled partner to the seroconverting partner was determined by molecular sequencing to be linked) were observed, the trial would have high statistical power (90%) to see a 50% reduction in HIV transmissions in the acyclovir arm.

Baseline characteristics of the group included:

• 67% of HIV-positive partners were female;
• 65% of volunteers were <35 years old;
• average partnership duration was five years;
• 90% were cohabiting;
• a median of five sex acts were reported in the month prior to baseline measurements:
• 29% reported unprotected sex;
• 22% of the HIV-positive partners reported genital ulcer disease (GUD) in the prior three months;
• 4% of HIV-positive and 7% of HIV-negative partners reported outside partners respectively;
• median CD4 count was 460 cells/mm³ and median plasma HIV viral load was 4.2 log.

Monthly follow-up visits included medication provision, pill count and adherence support and individual and couple HIV risk reduction counselling. Every three months, HIV-positive partners were examined for GUD and plasma viral load and HIV-negative partners were tested for HIV and given risk reduction counselling. CD4 cell counts were taken every six months.

Retention was high. At 24 months, 92% of HIV-positive and 84% of HIV-negative participants were still in follow-up. Adherence measured by pill count was also high: 88% of all bottles were dispensed and 97% of dispensed bottle doses were taken.

No significant differences in incidence

There were 136 seroconversions at a rate of 2.8/100py (95% CI: 2.3-3.3), one after an incorrect drug kit was dispensed. Of the remaining 135, 68 occurred on the acyclovir arm and 67 on the placebo arm (HR: 0.92; 95%CI 0.60-1.41; p=0.70).

In a modified intention to treat analysis, 43 transmissions were linked by viral sequencing technology to partners on the acyclovir arm and 47 were linked to partners on the placebo arm. However, two in the acyclovir arm and four in the placebo arm were excluded from analysis because the study drug was withheld during pregnancy. Here too, there were no significant differences between the two arms. The sequencing methodology for this study was explained in a late breaker poster from Mary Campbell. [3]

Benefits of acyclovir

There were fewer GUD events in the acyclovir arm (217 vs 550; RR: 0.39; 95% CI: 0.32-0.48; p<0.001). HSV-2-positive GUD as determined by DNA PCR was also lower in the acyclovir arm (92 vs 336; RR: 0.27; 95%CI 0.2-0.36; p<0.001).

The acyclovir arm also had a 0.25 log reduction in plasma viral load (95%CI: 0.22-0.29).

A novel component of this study was evaluation of herpes suppression on HIV disease progression, an important secondary endpoint of the Partners in Prevention trial. In a separate analysis presented by Jairam Lingappa, 3,381 of the HIV-positive participants were followed up until a composite endpoint of first of CD4 cell count <200 cells/mm³, ART initiation, or death from non-trauma causes. [4]

In the acyclovir arm, 284 participants reached this endpoint versus 325 in the placebo arm (HR 0.83; 95%CI: 0.71-0.90; p=0.03). Similar reductions were found for each component of the composite endpoint analysed separately. However, Lingappa’s team further calculated that for every 43 people treated with the trial dose of acyclovir for a year, only one person would be prevented from attaining the composite endpoint. (We have previously reported findings demonstrating acyclovir and its pro-drug, valacyclovir’s effect on HIV plasma RNA levels, in the October 2006 and July/August 2008 issues of HIV Treatment Bulletin, but this is the first report documenting impact of herpes suppression on HIV disease progression.)

Among participants with CD4 counts >350 cells/mm³ at enrollment, acyclovir delayed the time to CD4 < 350 cells/mm³ (HR 0.81; 95%CI 0.71-0.93; p=0.002). Here, 20 people would need to be treated to prevent one person from progressing to a CD4 count < 350 cells/mm³.

Acyclovir effect on genital viral load

A late breaker poster by Jared Baeten et al presented the results of a substudy that examined genital HIV RNA concentrations as a surrogate marker for HIV infectivity. [5]

Endocervical and semen samples were collected from 2,521 (1,805 women and 716 men) of 3,408 HIV-positive participants. For 1,797 of these, plasma was concurrently taken. For the remainder a plasma viral load within six months was available. Since the genital samples were taken only once during the study, the genital viral load was analysed as a time-independent variable.

HIV was detected in 60% of endocervical swab samples and 57% of semen samples. The median endocervical HIV concentration was 3.2 log (IQR 2.08-3.87) overall. Genital HIV-1 concentrations were significantly lower among those randomised to acyclovir (median 2.98 vs 3.29 for endocervical swabs; p<0.001 and 2.38 vs 2.76 for semen; p=0.008). The key finding of the study was that genital HIV concentrations were higher among HIV transmitting couples, where transmission was genetically linked to the partner (3.44 vs 2.49 log copies/mL for semen, p<0.001 and 3.91 vs 3.18 log copies/swab for endocervical swabs, p<0.001). Each log increase in genital HIV-1 RNA concentration was associated with 1.85-fold increased odds of HIV transmission for semen (p<0.001) and 2.03-fold increased odds of transmission for endocervical swabs (p<0.001). The study found no significant difference in genital HIV concentration for participants whose partners acquired HIV from outside sexual partners versus those who did not transmit HIV.

However, despite a 73% reduction in GUD and 0.25 log decline in plasma HIV levels and an approximately 0.3 log decline in genital HIV levels, acyclovir conferred no reduction in HIV transmission. The authors interpret the overall results of the trial to indicate that the plasma and genital tract HIV viral load reduction from herpes suppression with standard doses of acyclovir is too small to confer a protective effect against HIV transmission.

Future acyclovir trials

Nevertheless, given the promising effect of acyclovir on HIV viral load, Steve Reynolds described an ongoing double-blind placebo controlled trial in Rakai, Uganda. [6]

The purpose of the trial is to evaluate the effect of suppressive HSV-2 therapy among HIV-1/HSV-2 co-infected individuals on progression to AIDS, defined as CD4 count < 250 cells/mm³ or WHO stage IV disease. Volunteers with CD4 counts between 300 and 400 cells/mm³, not on ART, without WHO III/IV symptoms and no history of opportunistic infections, other than mucocutaneous Kaposi Sarcoma, candida or treated TB were eligible for inclusion. Enrollment was completed in November 2008. The trial assumes that 40% of individuals in the placebo arm will progress to CD4 counts <250 cells/mm³ or AIDS over 24 months and is powered to detect at least a 20% reduction in HIV disease progression in the intervention arm.

COMMENT

These studies show that a standard dose of acyclovir for HSV-2 suppression does not reduce HIV transmission. These are disappointing findings for an HIV prevention strategy that is already available.

A mechanism for the lack of protection has been suggested by Laurence Corey and colleagues in a recent paper in Nature Medicine. [7]

By analysing regular skin biopsies taken during acute lesions and over 20 weeks follow-up, they indentified a ‘massive localised infiltration’ of CD4 and CD8 cells, thereby increasing the targets for HIV infection. Eight weeks after lesions healed, these levels were still 8-fold higher (655 and 618 cells/mm² of skin, respectively, compared to 68 and 55 cells/mm² in unaffected skin samples).

This paper is reported in detail in the Basic Science section of this issue of HTB. [8]

It has been conventional wisdom that wider availability of acyclovir for patients with genital herpes outbreaks would reduce HIV transmissions. We now know this is incorrect, at least with the doses of acyclovir (400 mg twice daily) used in these trials. However, efforts to make acyclovir widely accessible should continue because herpes is a debilitating, unpleasant disease which acyclovir effectively treats and because HSV-2 in widely prevalent in both HIV-negative and HIV-positive people. One of the barriers to its accessibility remains its high price in many developing countries.

Despite the negative findings, this trial and its substudies have set a high standard for the testing of future HIV prevention interventions. Furthermore, modeling studies using the data from this trial provide a potential threshold of HIV plasma viral load reduction in HIV-infected persons that will be needed to impact HIV transmission.

We now need to know whether a therapeutic dose of acyclovir could delay the time until initiation of HIV treatment, and whether this would be cost effective. The trial in Rakai described by Steve Reynolds using 400 mg twice-daily dose will provide complimentary information to the Partners in Prevention trial.

Studies with higher doses of valacyclovir will evaluate whether greater reduction in plasma HIV levels is feasible compared to acyclovir 400 mg twice daily. However, this research could be overtaken by new developments in ART management, if guidelines recommend earlier treatment.

References

Unless othewise stated, all references are to the Programme and Abstracts of 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town.

1. Celum C et al. Twice-daily acyclovir to reduce HIV-1 transmission from HIV-1 / HSV-2 co-infected persons within HIV-1 serodiscordant couples: a randomized, double-blind, placebo-controlled trial. 5th IAS 2009, Cape Town. Oral abstract WELBC101.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3699
2. Celum C et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet, 21 June 2008. 371(9630):2109-19.
http://www.ncbi.nlm.nih.gov/sites/entrez/18572080
3. Campbell M et al. Determination of transmission linkage in the Partners in Prevention Study. 5th IAS 2009, Cape Town. Poster abstract LBPEC07.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3756
4. Lingappa JR et al. Daily acyclovir delays HIV-1 disease progression among HIV-1/HSV-2 dually-infected persons: a randomised trial. 5th IAS 2009, Cape Town. Oral abstract WELBC102.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3714
5. Baeten J et al. Genital HIV-1 RNA concentrations and heterosexual HIV-1 transmission risk. 5th IAS 2009, Cape Town. Poster abstract LBPEA07.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3770
6. Reynolds SJ. HSV-2 Suppression Trial, Rakai, Uganda. Partners in Prevention presentation reported with permission.
7. Zhu J et al. Persistence of HIV-1 receptor–positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nature Medicine. Published online: 2 August 2009 | doi:10.1038/nm.2006.
http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.2006.html
8. Jefferys R. Immune surveillance below the radar: study offers explanation for acyclovir’s failure to reduce HIV risk. HTB September/November 2009. Vol 10, No 4. (Vol 2, No 3 of HTB South).

Some useful TB research has been published since the last issue of HTB. With approximately 120 TB-related abstracts at IAS2009, we summarise some of the most important.

Epidemiology

The most interesting TB research presented at the IAS conference dealt with the epidemiology of TB/HIV co-infection.

A presentation by Keren Middelkoop and colleagues analysed the association between the introduction of HAART in a community and active TB rates. [1]

They collected TB notification data, prior to HAART (1998 to 2004) and after HAART was introduced (2004 to 2008), in Masiphumelele township in Cape Town. HIV prevalence was estimated to be 23% in the township. Pre-ART adult TB notifications increased by an average of 212 cases per 100,000 people per year (p =0.005 for trend). Post-HAART, adult cases decreased by 116 per 100,000 people per year (p=0.16, NS for trend).

TB rates in HIV-negative people did not change substantially over the period and averaged 697 cases per 100,000 per year. TB rates in HIV-positive people increased by an average of 826 cases per 100,000 per year over the same period (p value for trend 0.08), but after the introduction of HAART, declined by 600 cases per 100,000 per year (p=0.16, NS for trend). For HIV-positive people not on HAART, the average decline in the post-HAART era was 421 cases per 100,000. For people on HAART, it declined by 1,394 cases per 100,000 and this trend was significant (p=0.05). The authors concluded that wide-scale HAART implementation and the community’s well-functioning TB programme were associated with modest TB declines.

Masiphumelelo’s population is only 20 to 30,000 which might explain a lack of power to detect statistically significant trends. But another study in Masiphumelelo also conducted by Middelkoop and colleagues makes the argument for the effect of ART on a declining TB rate more compelling. [2]

In 2008 they repeated a randomly sampled cross-sectional survey that was first performed in 2005. About 30% of HIV-positive adults were estimated to be on HAART in 2008. Two sputum samples were obtained from each participant. Participants also filled in questionnaires on TB history. Those who were not being treated for TB and had two TB-positive sputum or culture tests were considered to have undiagnosed TB. The survey measured a significant decline in the TB rate in HIV-positive people since 2005 (all testing was anonymous), including a significant decline in undiagnosed TB in this group. No such decline was seen in HIV-negative people. The study also found that after adjusting for age, sex and HIV status, the overall 2008 TB prevalence was significantly lower than the overall 2005 prevalence (p=0.02). See Table 1.

Shortly after the conference, members of this research group published an article in AIDS that examined the association between current CD4 count and risk of TB. [3]

They analysed TB incidence in 1480 patients receiving ART for up to 4.5 years. Updated CD4 cell counts were measured 4-monthly. During 2785 person-years of observation, 203 cases of TB were diagnosed, giving an overall incidence of 7.3 cases/100 person-years. TB incidence by CD4 count strata is described in Table 2 (p<0.001).

Table 1: Results of surveys in 2005 and 2008 in Cape Town township

Table 2: TB incidence by CD4 count strata (from Lawn et al.)

The authors found that updated CD4 cell counts were the only patient characteristic independently associated with long-term TB risk. They concluded that updated CD4 cell counts were the dominant predictor of TB risk during ART in this low-resource setting. They also found that among those with baseline CD4 cell counts less than 200 cells/mm³, the excess adjusted risk of TB during the first four months of ART was consistent with unmasking of disease missed at baseline screening. They noted that TB incidence at CD4 cell counts of 200-500 cells/mm³ remained high and concluded that TB prevention would be improved by ART policies that minimised the time patients spend with CD4 cell counts below 500 cells/mm³.

These studies provide evidence that widespread ART implementation can reverse the growth in active TB rates in Southern Africa.

A study by Van Rie and colleagues analysed risk factors for TB in patients who had been on HAART for greater than six months in a prospective cohort from the Themba Lethu clinic in Johannesburg. [4]

This study provided quantitative data on TB incidence and its relationship to patients failing treatment. Of 5934 adults, 217 (4%) developed TB after six months. Median time to TB was 418 days (IQR: 276-672, incidence of 2.3 cases per 100py). The incidence was four times lower than in the first six months of ART. Significant risk factors associated with active TB were BMI <18.5 compared to BMI ≥25 (HR: 6.52, 95%CI: 3.60-11.80) history of TB treatment (HR: 1.50, 95%CI: 1.09-2.50), current viral load >10,000 copies/mL (HR: 2.44, 95%CI: 1.57-3.79) and CD4 count ≤ 50 cells/mm³ (HR=0.84, 0.45, and 0.34, for CD4 51-100, 101-200, and 201-350 respectively).

In a study from Khayelitsha, Pepper and colleagues examined patients in their cohort who had clinical deterioration. [5]

They enrolled 298 people with who had initiated TB treatment from June to August 2008 and then followed them for six months. In this group, 209 (71%) were HIV-positive, with a median CD4 count of 129 cells/mm³ (IQR: 62-277). At TB diagnosis, 35 (17%) HIV-positive patients were receiving HAART. This rose to 112 (54%) on HAART six months later.

Within 6 months, 117 patients (39%) experienced 208 episodes of clinical deterioration. Of these, patients, 71% were HIV-positive. There was an escalating risk of clinical deterioration in HIV-positive patients as CD4 counts decreased (CD4>350: RR:1.4; 95%CI=0.7-2.9; CD4 200-350: RR:2.0, 95%CI: 1.1-3.6; CD4< 200: RR=3.0, 95%CI=1.9-4.8).

AIDS-defining illnesses (n=30), TB-IRIS (n=22) and MDR-TB (n=10) were important causes for clinical deterioration. The number of deaths was 17, of whom 15 were HIV-positive with a CD4 count <200 cells/mm³ at TB diagnosis. The authors also noted that health-care use was significantly higher in HIV-positive patients with low CD4 counts. They pointed out that starting HAART initiation at higher CD4 counts is likely to reduce this clinical burden.

De Bruyn and colleagues presented data from Soweto that showed an association between ART and neutrophil count. [6]

They explain that neutrophil granules contain antimicrobial peptides that kill M.tuberculosis. In HIV-negative people exposed to TB, neutrophil count is inversely associated with risk of latent TB infection and positively associated with ability to contain mycobacterial growth in vitro. However, neutrophil functional defects occur in HIV-positive patients. The authors therefore examined the association of incident TB with neutrophil count.

They followed a prospective cohort of almost 2700 HIV-positive adults for over 5500 person-years. Median age was 32. Women comprised 79% of the cohort. Median CD4 count was 282 cells/mm³. The median neutrophil count was 2.46 copies/nL. TB incidence was 5.2/100py (95%CI: 4.6-5.8). ART was associated with a reduced risk of TB (HR: 0.26; p<0.001), as was increasing CD4 count. Increasing neutrophil count was also associated with increased risk of TB (HR: 1.18; p=0.02). For patients on ART, there was a trend showing that risk of TB was reduced by 75% per nL increase in neutrophil count (HR: 0.25, p=0.08).

The authors conclude that the association between neutrophil count and risk of tuberculosis in HIV-positive adults varies according to whether HAART is administered. Their results suggest that HAART critically influences the relationship between neutrophils and the risk of TB.

COMMENT

The potential role of earlier ART in reducing the epidemiological impact on TB is encouraging.

This supports the recommendation to start HAART at CD4 counts over 350 cells/mm³ in patients coinfected with TB.

Drug resistance

Research on drug-resistant TB continued to be a concern.

A study by Max O’Donnell and colleagues who have produced excellent data on the drug-resistant TB epidemic, found that health care workers in Kwazulu-Natal had a much higher incidence of TB than the general population. [7]

Based on data from King George V Hospital, MDR-TB incidence was 58.9 per 100,000 people for the province’s health workers and 10.7/100,000 for the province’s general population (OR: 5.53; 95%CI; 4.70-6.50). XDR-TB incidence was 4.0/100,000 among health workers and 1.0/100,000 in the general population (OR: 3.89 95%CI: 2.02-7.11). There were 235 cases of health workers with drug-resistant TB and 3,391 cases for non health-workers at the hospital. About half of drug-resistant patients were HIV-positive and this did not differ between health workers and the general population. The high incidence amongst health workers is clearly related to occupational exposure. The researchers therefore conclude that screening and controlling occupational exposure among health workers is critical to limit nosocomial spread of drug-resistant TB.

In another Khayelitsha study, Helen Cox and colleagues reported on the prevalence of drug-resistant TB. [8]

This team conducted a representative cross-sectional survey of clients attending two clinics suspected of having pulmonary TB between May and November 2008. Of 1,850 TB suspects surveyed, 536 (30%) were culture-positive. HIV status was known for 427 (80%) cases with 261 HIV-positive (61%). Rifampicin resistance was found in 4% of new cases and 10% of previously treated cases (p=0.003), and in 8.0% of HIV-positive and 4.8% of HIV-negative cases (p=0.18). They estimated rifampicin resistance in Khayelitsha to be 50 to 72/100,000 people per year. They concluded that there is extremely high prevalence of drug-resistant TB in the township. Moreover, that it is high amongst HIV-negative people too.

PACTG 1041 was a double-blind placebo controlled trial to test isoniazid preventative therapy (IPT) in perinatally HIV-exposed infants. The primary endpoint was TB disease, infection or death. The DSMB stopped the trial because of futility. Partial results were reported at ICAAC 2008 (covered in HTB Nov/Dec 2008) and CROI 2009. At IAS2009 a poster by Anneke Hesseling and colleagues reported the results of an analysis of the 22 culture-confirmed cases of TB in the trial. [9]

Of these, 18 were sent for drug-susceptibility testing. Five were drug-resistant (one to INH, four MDR-TB). The authors conclude that the high rate of drug-resistant TB in the trial is consistent with the growth of the adult drug-resistant TB epidemic and has potential consequences for the programmatic implementation of IPT.

COMMENT

The growing evidence of a rising drug-resistant TB epidemic that might undermine the benefits of IPT, particularly in infants, is concerning. So too are the high rates of drug-resistance in HIV-negative people beyond nosocomial infection in Khayelitsha. The South African government is still not demonstrating adequate commitment to co-ordinating and prioritising infection control measures and contact tracing. For example, it would be useful to have a project to revamp clinic waiting rooms (along similar lines to the waiting room at the Ubuntu clinic in Khayelitsha, which has heaters and a roof, but no walls allowing a continuous flow of air). A public information campaign to keep windows open in public places (e.g. buses and taxis) is also important.

Izoniazid preventative therapy (IPT)

One concern about community-wide IPT is that it will result in higher isoniazid resistance. A study by Halsema and colleagues provides promising data that will help allay, albeit not completely, this fear. [10]

The Thibela TB study is a large cluster-randomised trial to study IPT strategies in South African gold mines. Individual mine shafts are randomised to receive either standard TB control (IPT to miners with silicosis or HIV infection) or the intervention (IPT to everyone in the mine, from miners to executives).

In this case-controlled study, drug susceptibility data from TB cases among people who received IPT in the Thibela TB intervention clusters were compared to two groups: (1) TB cases in the control clusters and (2) a subset of patients from a laboratory substudy confined to the first TB episodes in the control clusters. The comparison cases were restricted to the same calendar period as the intervention cases. The Thibela TB intervention began in July 2006 and the study included all TB cases in the intervention clusters up to mid-February 2009.

The intervention group included all participants receiving IPT who attended at least one follow-up visit and were subsequently treated for TB, unless they did not have positive TB cultures. Of the 126 individuals who met the inclusion criteria in the intervention arm all but one were male. The median age was 43 years. Of 103 patients with known HIV status, 89 (86.4%) were HIV-positive. Median CD4 cell count was 196 cells/mm³ (n=51). The median time from starting IPT to TB treatment was 316 days (IQR: 174-491). For 75% people (n=94) this was their first TB episode and 25.4% (n=32) were retreated. TB was pulmonary for 87 (69.0%), extra-pulmonary for 22 (17.5%) and disseminated for 17 (13.5%).

Amongst the intervention cases, 96 outcomes had been documented at the time of the analysis: 39 (41%) were cured, a further 23 (24%) completed treatment, 8 (8.3%) died, there was one treatment interruption, one treatment failure, 11 (11.5%) transferred out or were lost-to-follow-up and for 13 (13.5%) cases the outcomes were unknown.

The authors concluded that TB disease after IPT may be largely due to re-infection in this high HIV prevalence group.

Data on drug susceptibility was presented for 58 people in the intervention group, 182 in the control clusters and 32 in the laboratory substudy. Table 3 presents the results of their analysis.

Table 3: Drug-resistance in three groups from Thibela TB study

There were no significant differences between the groups in any of these outcomes. However, the authors noted the very wide confidence intervals (depicted graphically on their poster). In their discussion, they explained that if IPT is more effective at treating isoniazid susceptible latent TB, then an increased proportion, but not absolute numbers, of isoniazid resistant TB cases would be expected among those who have taken IPT. They concluded however, that the proportion of TB episodes in the intervention groups did not differ from the controls, and that these data do not support concerns about IPT induced resistance.

TB treatment

The standard model for the management of TB patients that is promoted by the WHO involves directly observed treatment (DOT). In this model, patients come daily to their health facilities to take their pills under the supervision of a health worker.

Atkins et al. described an alternative model piloted from April 2007 to March 2008 in five health facilities in Cape Town. [11]

In this intervention, adult TB patients received adherence counselling. They also selected a treatment buddy. Lay health workers supported patients’ self-supervised treatment.

Using information stored in a routine electronic TB register, TB data from these five clinics was compared against another five clinics that use DOT. Across the five intervention clinics 75% of new patients were treated using the new model. In these clinics, treatment success was 72.4% (95%CI: 67.4-77.4) and in the control clinics it was 75.9% (95%CI: 70.8 to 80.9), a non-significant difference.

In the previous issue of HTB South, we reported on the results of the CAPRISA trial that compared immediate versus deferred HAART in patients coinfected with TB. It showed significant reduced mortality in the immediate arm. We commented on the importance of integrating TB and HIV services to make this intervention easier to implement. Further evidence of the benefits of integrating TB and HIV treatment comes from a Malawian study.

Malawian TB case notifications have risen dramatically over the last two decades. Chan and colleagues described what happened when the Zomba Central Hospital ART Clinic, which opened in 2004, began integrating TB services. [12]

Zomba district has a population of 670,000 (80% rural). HIV prevalence amongst 15 to 49 year-olds is estimated to be 16.5%. Routine national TB programme data shows that 69% of TB patients are HIV-positive.

Integration of services began in September 2007 through monthly HIV/TB integration days. By April 2008, services were fully integrated with a daily TB/HIV Integration clinic where all patients registered for TB were also tested for HIV and referred for HIV care in the same physical area. Ministry of Health TB patient records and HAART records from September 2007 to December 2008 were reviewed to assess uptake of HAART. Following integration, HAART uptake increased dramatically from 4% to 33% in HIV monoinfected patients and from 25% to 50% in patients with HIV/TB coinfection. See Table 4.

The CARINEMO-ANRS 12146 Trial is a randomised, open-label non-inferiority study comparing 48 weeks virological suppression and safety of nevirapine (400mg daily without leading dose) vs efavirenz (600mg daily) co-administered with rifampicin. The other ARVs in the study regimen were d4T and 3TC. HAART was started four to six weeks after TB treatment. Bhatt and colleagues presented preliminary safety data, covering the period November 2007 to December 2008. [13]

By the end of this period, 236 patients with CD4 counts <250 cells/mm³ and who were co-infected with active TB had been randomised. Of these, 11 (4.7%) discontinued the study (6 due to death, 3 withdrew consent, 1 lost-to-follow-up and 1 other).

Follow-up included weekly clinical assessments for the first eight weeks of HAART and monthly assessments thereafter. Patients also had aminotransferase (ALT) measurements every two weeks during the first eight weeks followed by monthly measurements. 204/236 patients (86.4%) presented at least one adverse event. There were 26 serious adverse events, of which six resulted in death. None of the deaths were drug-related.

Skin-related adverse events were reported in 47 patients (19.9%), but none were severe. Also, 11 (4.7%) patients had an ALT increase (> grade 3). Five patients (2.1%) interrupted treatment due to hepatitis. However, there were no cases of severe rash. The researchers concluded that this plus the relatively low number of cases of severe hepatitis and treatment interruptions due to adverse events were reassuring but needed to be confirmed. Final results are expected at the end of 2010. A study by Kamateeka and colleagues of children taking rifampicin and nevirapine is also reviewed in this issue of HTB.

A study from a Uganda found that efavirenz is associated with a greater decline in TB incidence than nevirapine. Hermans and colleagues reported data from their large cohort of ART patients (n=7,648). [14]

Between May 2002 and January 2009 they identified TB events in patients who had been on HAART for two years or less.

At baseline, median CD4 was 111 cells/mm³ (IQR: 38-179) in the cohort and 85 cells/mm³ (IQR: 30-149) in patients with TB coinfection. For the whole cohort, 30% were in WHO stage I or II, 40% in stage III and 30% in stage IV (the TB patients had similar proportions).

In the first two years of HAART (almost 13,600 PYFU), there were 360 (4.7%) new TB events (2.65 per 100PY; 95%CI: 2.39 ¬ 2.94). Incidence rates declined with time on HAART. For 0-3, 3-6, 6-12 and 12-24 months they were 9.91 (95%CI: 8.51-11.55), 5.14 (95%CI: 4.11-6.44), 2.16 (95%CI: 1.66-2.82) and 0.82 (95%CI: 0.64-1.05), respectively.

Table 4: Numbers of patients (%) in HAART uptake following integration of TB and HIV clinics at Zomba Central Hospital , Malawi

In a multivariate analysis, baseline CD4 count <50 cells/mm³ (HR 1.58; 95%CI: 1.10-2.27; p=0.01) and male sex (HR 1.43; 95%CI: 1.15-1.77; p=0.001) were significantly associated with increased risk for TB.

A key finding of the study is that 100 patients out of 2842 receiving AZT/3TC/efavirenz versus 227 out of 3974 using d4T/3TC/nevirapine developed TB (832 used other regimens). Compared to the d4T/3TC/nevirapine regimen, the HR for the AZT/3TC/efavirenz was 0.7 (95%CI: 0.53-0.89; p=0.003).

This difference could not be explained by differences in baseline CD4, calendar year starting HAART or immune restoration status after 14 months of HAART. In a multivariate analysis, the HR was 0.67 (95%CI: 0.53-0.86; p=0.002). The researchers further point out that this association occurred despite clinician bias towards prescribing efavirenz to patients with any TB symptoms to avoid subsequent switching due to interactions between nevirapine and rifampicin. This has not been previously described.

Is therapeutic drug monitoring needed in people with MDR-TB taking ofloxacin? This was a question that arose in a small proof of technology study reported by Mugabo and colleagues at Brooklyn Chest Hospital in Cape Town. [15]

Previously, PK values for ofloxacin have been obtained primarily using high performance liquid chromatography (HPLC) from cohorts in rich country. This study tested liquid chromatography coupled with mass spectrometry and found it to be simple, specific, accurate, sensitive and reproducible.

The inclusion criteria for their study included adult patients (18-65 yrs old) on ofloxacin therapy for at least two weeks who had TB that was resistant to isoniazid and rifampicin but sensitive to second line anti-TB drugs (i.e. strict definition of MDR-TB). Pregnant or breastfeeding women, patients intolerant of ofloxacin or patients on any drugs, other than ARVs, known to interact with ofloxacin PK were excluded.

They researchers found that the PK values of their eight patients with MDR-TB on ofloxacin differed from previous studies, with reduced AUC and Cmax, and prolonged T1/2 and Tmax.

Five patients were HIV-positive (one was female and four male). The woman and two men were on HAART (d4T, 3TC and efavirenz). All eight patients received kanamycin, ethambutol, ethionamide and pyrazinamide. None were on capreomycin, aminosalicylic acid and terizidone.

Obviously this is a very small study, but the results are concerning because they suggest MDR-TB patients are receiving sub-optimal doses of ofloxacin. The authors therefore recommend ofloxacin plasma monitoring in order to maintain therapeutic plasma levels. Larger studies of patients with MDR-TB taking ofloxacin are also needed to ensure that optimal dosages and timing are determined, taking into account the effects of HIV, liver and kidney dysfunction.

Bhaijee and colleagues reported on a drug-induced life-threatening condition related to the commonly prescribed anticoagulant warfarin. [16]

The incidence of warfarin induced skin necrosis is low (estimated 0.01-0.1%), and by 2000, only 300 cases had been reported. Most of these were in patients receiving treatment for venous thromboembolism. This study was a retrospective review of six cases that occurred in GF Jooste Hospital in Cape Town from April 2005 to July 2008. This is a high concentration at one facility for such a rare condition. All patients were HIV-positive women (aged 27 to 42) with venous thrombosis and with active TB coinfecton. Four died, likely from systemic sepsis when resistant bacteria infected their wounds and one of the survivors underwent bilateral mastectomies and extensive skin grafting at a specialist centre. Median time from skin necrosis to death was 43 days (range 23-45).

No common pattern was detected: three were on HAART, two had TB-IRIS, two had previous TB. While five had low nadir CD4 counts (range 10-56), one of these (on HAART) has a CD4 count of 396 cells/mm³ at the time of the necrosis. The site of skin necrosis included breasts, buttocks, and thighs.

The authors made four recommendations: (a) active prevention and appropriate management of venous thromboses, (b) parallel heparin therapy for at least the first four days of warfarinisation in patients with venous thrombosis (which they suggest may limit the occurrence of skin necrosis), (c) effective infection control measures, and (d) expedited referral to specialist centres for surgical review for patients who develop this warfarin induced skin necrosis.

Wilkinson and colleagues prospectively analysed their cohort to find immunological differences in drug-sensitive and drug-resistant patients with TB IRIS. [17]

They compared 12 rifampicin-resistant cases (nine had MDR-TB) to 27 case controls. They found no significant differences in the median duration of IRIS, days of HAART to development of IRIS, baseline CD4 count or days of TB treatment prior to HAART between drug-resistant and drug-sensitive groups. They also found no difference between the IFN-gamma spot forming cells/ million PBMCs in response to several M. Tuberculosis antigens (ESAT-6, Acr1, Acr2, 38kDa, PPD and heat killed H37Rv). C reactive protein was elevated in both groups, but without significant difference from each other. The authors concluded that both drug-sensitive and drug-resistant TB-IRIS, are clinically and immunologically indistinguishable, and that the occurrence of TB-IRIS is an opportunity to screen for previously undetected drug resistance.

COMMENT

While news on TB treatment is hardly breathtaking, some of the studies described above are important and merit further comment.

The model of care described by Atkins, based on the HAART model, demonstrated that there are workable, more affordable and more convenient alternatives to DOT that give patients greater autonomy. It deserves further study, and ideally a randomised trial.

The increased uptake of HAART following TB/HIV integration at Zomba Central Hospital offers further evidence of the importance of integration. Although the data from this study can be used for advocacy, one caution should be noted: increased uptake could also have been linked to the general improvements in the facility over time.

The Hermans data is important. One limitation of the study is that a complex and potentially error-prone method was used to merge two separate databases containing patient data to determine the number of TB events. Nevertheless, this data offers evidence that efavirenz and AZT reduced the risk of TB compared to d4T and nevirapine. Their findings are worth testing in clinical trials and perhaps the CARINEMO-ANRS 12146 trial will provide more insight, at least regarding nevirapine versus efavirenz. Furthermore, if d4T-including regimens offer less protection against TB, it is another reason to limit their use in southern African countries.

Diagnostics data at IAS were more disappointing. Data on several methods were presented, including, but not limited to, acid-fast stain, urine lipoarabinomannan and the quantiFERON-TB Gold In-Tube assay. In the last of these, one study found an association between indeterminate results and increased risk of disease progression, but these patients also had lower median current and nadir CD4 counts, which are both, probably, better predictors. [18]

However, no studies at IAS showed algorithms with a combination of high speed, sensitivity and specificity.

The problem is global. One Cambodian study analysed sensitivity and specificity of smear and culture of urine, stool and lymph node aspirate as well as blood culture. It found they added little additional value. The authors aptly concluded, “In HIV settings, there is an urgent need for simple methods for mycobacterial cultures to detect earlier smear-negative tuberculosis.” [19]

References

Unless othewise stated, all references are to the Programme and Abstracts of 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town.

1. Middelkoop K et al. Can antiretoviral therapy contain a previously escalating TB epidemic in a high HIV prevalence community? 5th IAS 2009, Cape Town. Poster abstract CDB041.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2932
2. Middelkoop K et al. Widespread ART is associated with decline in TB prevalence. 5th IAS 2009, Cape Town. Oral abstract WELBB105.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3844
3. Lawn et al. Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. AIDS. 2009 Aug 24;23(13):1717-25.
http://www.ncbi.nlm.nih.gov/pubmed/19461502
4. Van Rie et al. Risk factors for incident tuberculosis six months or more after ART initiation – experience from Johannesburg, South Africa. 5th IAS 2009, Cape Town. Poster abstract TUPEB135.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1933
5. Pepper DJ et al. Clinical deterioration during TB chemotherapy in HIV-1 infected patients. 5th IAS 2009, Cape Town. Poster abstract LBPED07.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3674
6. De Bruyn et al. Neutrophil count and risk of tuberculosis in HIV-infected adults. 5th IAS 2009, Cape Town. Poster abstract CDB038.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1539
7. O’Donnell et al. High incidence of multidrug resistant and extensively drug resistant tuberculosis among South African health care workers. 5th IAS 2009, Cape Town. Poster abstract TUPEB149.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3139
8. Cox H et al. Prevalence of drug resistant tuberculosis and association with HIV in Khayelitsha, South Africa. 5th IAS 2009, Cape Town. Poster abstract MOPEB019.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2902
9. Hesseling A et al. High prevalence of drug resistance amongst HIV-exposed and infected children with culture confirmed tuberculosis enrolled on a tuberculosis prevention trial. 5th IAS 2009, Cape Town. Poster abstract MOPEB019.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1610
10. Van Halsema CL et al. Good tuberculosis treatment outcomes and no evidence of increased drug resistance in individuals previously exposed to isoniazid preventive therapy in a population with high HIV prevalence. 5th IAS 2009, Cape Town. Poster abstract MOPEB021.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1966
11. Atkins S et al. An evaluation of a new tuberculosis treatment support programme: Implications for integrating TB and HIV/AIDS treatment programmes. 5th IAS 2009, Cape Town. Poster abstract WEPED231.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2944
12. Improved uptake of antiretroviral therapy (ART) following integration of TB and HIV services in a district in southern Malawi. 5th IAS 2009, Cape Town. Poster abstract CDD062.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2166
13. Bhatt NB et al. Preliminary safety results of co-administration of nevirapine (NVP) or efavirenz (EFV), and rifampicin (RMP) in HIV-tuberculosis (TB) co-infected patients in Maputo (Mozambique): CARINEMO-ANRS 12146 Trial. 5th IAS 2009, Cape Town. Poster abstract MOPEB032.
http://www.ias2009.org/pag/Abstracts.aspx?AID=589
14. Hermans SM et al. The use of efavirenz is associated with a decreased incidence of tuberculosis after antiretroviral therapy initiation in an urban HIV clinic in sub-Saharan Africa. 5th IAS 2009, Cape Town. Poster abstract TUPEB136.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2109
15. Mugabo P et al. Determination of plasma concentrations using LC/MS and pharmacokinetics of ofloxacin in patients with multi-drug resistant tuberculosis and in patients co-infected with multi-drug resistant tuberculosis and HIV/AIDS. 5th IAS 2009, Cape Town. Abstract CDB101.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1916
16. Bhaijee F et al. Warfarin induced skin necrosis in HIV-1 tuberculosis patients with venous thrombosis: a case series. 5th IAS 2009, Cape Town. Poster abstract CDB115.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1358
17. Wilkinson KA. Immunological analysis of the overlap between Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) and antitubercular drug resistance. 5th IAS 2009, Cape Town. Poster abstract TUPEB130.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1448
18. Aichelburg MC et al. Indeterminate results of the QuantiFERON-TB Gold In-Tube assay indicate an increased risk for disease progression in HIV-1-infected individuals. 5th IAS 2009, Cape Town. Poster abstract TUPEB131.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1546
19. Pe R et al. Diagnostic evaluation of smear microscopy of different samples as screening tool for tuberculosis in HIV patients at Sihanouk Hospital Center of Hope, Phnom Penh, Cambodia. 5th IAS 2009, Cape Town. Poster abstract CDA102.
http://www.ias2009.org/pag/Abstracts.aspx?AID=1714

The conference website includes all abstracts and many PDF or powerpoint slides of posters and oral presentations, together with a limited amount of webcasts.

http://www.ias2009.org

As we went to press with this issue of HTB just as this important conference was concluding, we only include a brief overview of some of the most important studies. Further coverage will be included in the next issue.

In this issue we include the following articles:

• Five-year survival rates of 87% without routine CD4 or laboratory monitoring in DART study demonstrate an important model for ARV access programmes
• Biomarkers associated with mortality: long-term follow up from SMART
• Update on Interleukin-2 clinical trials
• Influenza vaccine effective in HIV+ adults
• Reducing HIV transmission during breastfeeding
• Treating children previously exposed to single dose nevirapine

For the first time, web casts of several sessions are available via the conference website together with searchable online abstracts and PDF files of many or the posters or presentations:

http://www.ias2009.org

The abstract database from the meeting is online at the same site.

The most important study results presented at the 5th IAS conference were from the DART (Development of AntiRetrovial Treatment in Africa) trial. [1]

Sponsored by the UK’s Medical Research Council and University College London, DART randomised over 3300 treatment-naive patients in Uganda and Zimbabwe to be managed by either routine three-monthly CD4 count and laboratory monitoring (LCM group), or by clinically driven monitoring (CDM). Laboratory monitoring was also performed for this group, but results were only given to the treating doctor when a grade-4 toxicity was identified. Viral load was not monitored in either arm.

Criteria for switching patients to second-line therapy included a CD4 count less than 100 cells/mm3 in the LCM group or by symptoms/progression in the CDM group.

Patients were also randomised to one of three treatments, all with background AZT+3TC: abacavir (9%, n=300), nevirapine (7%, n=247) or tenofovir (74%, n=2469). d4T was not included as a first-line regimen, even though some patients switched to d4T during the study (for example to avoid anaemia). They were then followed for five years (median 4.9 years, IQR 4.5 – 5.3).

The Data and Safety Monitoring Board (DSMB) closed an earlier component of DART looking into treatment interruptions in March 2006.

The rationale behind DART was to determine whether ARVs could be used effectively without routine monitoring, in order to broaden access to treatment in settings where CD4 and laboratory monitoring are either no available or where they are difficult to access.

Enrollment criteria included being treatment-naive with a CD4 count <200 cells/mm3. Baseline median CD4 count and mean viral load were 86 cells/mm3 (IQR 31-139, range 0-199; one-third of patients had a CD4 count <50 cells/mm3) and 5.4 log (SD +0.7) copies/mL. WHO stage 2/3/4 was diagnosed in 20%, 56% and 23% patients respectively.

At the conference DART had a separate satellite symposium within the main conference programme and this is one of the sessions that has been web cast. The top line results were both impressive and challenged common assumptions. Both arms showed a remarkable and similar 5-year survival rate – 90% vs. 87% in the lab and clinical arms respectively – separated only by a small percentage difference that only occurred after the first two years on study. This compared to an historical 5-year survival rate prior to HAART of only 8%. Clinic attendence was >98% with high reported adherence and only 7% patients lost to follow-up over five years.

The event rates for a new WHO Stage 4 event or death were 6.94 versus 5.24 per 100 person-years in the CDM vs. LCM arm [n=459 (28%) vs. 356 (22%) HR 1.31 [1.14-1.51], log-rank p=0.0001]. Death rates/100PY were 2.94 in CDM versus 2.18 in LCM (p=0.004). Differences between strategies occurred from the third year on ART whereas lower rates of switching to second-line ART occurred in CDM from the second year. There were no differences between strategies in time to first serious adverse event, grade-4 toxicity or ART-modifying toxicity (see Table 1).

Table 1: 5-year event results from DART study

Around 60% of patients in each arm remained on their first line therapy after five years, with 20% modifying one or more drugs for tolerability and 20% of patients in each arm switching to second-line.

The higher mortality in the clinical monitoring arm was explained by patients being switched to second-line treatment at lower CD4 counts than the laboratory monitored group.

In an analysis of the two strategies, 3-monthly routine monitoring was determined to not be cost effective (based on the cost of treatment used in DART and relative to the WHO target for Incremental Cost Effectiveness Ratio (ICER) of 3 x GDP per capita). [2]

Lab unit costs were CD4 ($8.80), haematology ($5.30) and biochemistry ($29.50), with biochemistry carrying the highest cost with the least efficacy benefit. This was used to support the DART main conclusion that treatment shold not be witheld while waiting for monitoring and that resources for treatment access programmes should prioritise treatment over monitoring.

Several other presentations at the IAS conference presented a wealth of other aspects of the study including:

• Impact of different WHO 3/4 events on ART on subsequent survival (Abstract MOPEB003)
• Impact of cotrimoxazole in patients on ART: showing a 50% reduction in mortality during the first 72 weeks independent of CD4 count (Abstract MOPEB020)
• 5 year follow-up of participants initiating ART with Combivir plus nevirapine or abacavir (randomised): showing >90% survival and >80% alive and event-free, with clear virological and CD4 advantages for the nevirapine arm (Abstract MOPEB057)
• Assigning clinical endpoints in clinical trials in resource limited settings (Abstract TUPEB098)
• Impact of ART on incidence of malaria in Uganda (Abstract TUPDB104)
• 5 year follow-up of creatinine and estimated GFR in patients receiving and not receiving TDF first-line: showing overall low incidence of renal impairment on all regimens (2.9% GFR ever <30, 5.9% confirmed <60) with no differences between the LCM and CDM arms (Abstract TUPEB184)
• Pregnancy outcomes in women in DART: showing 378 pregnancies (57% live births, 6% still births and 36% termination/miscarriage), similar rate of congenital abnormalities (~3%) as the ARV pregnancy register, and no HIV-infected babies to date (Abstract WEPEB261)

These and other presentations are now posted on the MRC website. [3]

See the next issue of HTB for detailed coverage of some of these studies.

COMMENT

These results strongly support expanding access to treatment to wider populations independent of access to routine laboratory monitoring and that delaying treatment access while waiting for laboratory infrastructure to be developed is resulting in extensive mortality and morbidity.

While the cost effectiveness analysis was limited to the strategy determined at the study outset, a sensitivity analysis looking at absolute real world costs based on using generic drugs (rather than subsided Western brands) and using an annual CD4 count from year two would be likely to bring this within the WHO target, and may reverse the slightly higher mortality linked to late CD4 switching seen in the clinical monitoring arm.

For example, in DART the annual drug costs for the three first line treatment arms were $432 (tenofovir), $444 (nevirapine) and $698 (abacavir) and $954 for second-line (lopinvir/r + ddI).

The modelling for the DART analysis concluded that CD4 tests would have to drop to $3.80 or less to be cost-effective, but this was based on providing 4 tests per year. Simply adding an annual test after two years would raise the minimum target cost per CD4 test to $15.20, which is well over the current costs. This implies that an annual CD4 test is actually cost effective and would detect those patients with CD4 counts <100 cells/mm3 who are at highest risk of serious events.

It is important to note that DART did not recommend excluding laboratory monitoring: the strategy was for treating without routine three-monthly monitoring, and the difference is critical to the study interpretation.

These results should also not be used to reduce the research and investment into the development of low cost diagnostics.

References:

1. Mugyenyi P et al. Impact of routine laboratory monitoring over 5 years after antiretroviral therapy (ART) initiation on clinical disease progression of HIV-infected African adults: the DART Trial final results. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town. Oral abstract TUSS102.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3807
2. Gilks C et al. Cost effectiveness analysis of routine laboratory or clinically driven strategies – DART trial. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town. Oral abstract TUSS103.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3830
3. DART study home page, MRC.
http://www.ctu.mrc.ac.uk/dart

A poster at IAS2009 by Nick Paton and the INSIGHT SMART Study Group presented long-term follow-up data from the SMART study on biomarkers associated with mortality. [1] This analysis extended an earlier nested case-controlled study of the association between biomarkers and mortality.

The earlier study identified all 85 patients who had died up to 11 January 2006, ie the date that enrollment into SMART was stopped. Each death was matched to two controls by country, age, gender and randomisation date. The study evaluated four inflammatory markers, hsCRP (C-reactive protein measured using the highly sensitive test), interleukin-6 (IL-6), Serum amyloid A and serum amyloid P. It also examined three coagulation markers, D-dimer, PA1-1 and Prothombin fragment 1+2 (F1.2). Three markers, hs-CRP, IL-6 and D-dimer, were found to have a statistically significant association with mortality on both adjusted and unadjusted odd ratios.

Table 1: Case-controlled odd ratios by baseline biomarker levels

The extended analysis reported at IAS2009 included all deaths up to 11 July 2007 in order to determine whether the association between these biomarkers and mortality persists. There were 167 deaths in the SMART cohort up to that point, 85 before the protocol modification (to offer all patients continuous treatment) and 82 post-modification. For this analysis, the deaths were however divided into early (<=2 years after randomisation, n = 95) or late (>2 years, n = 71). Two cases were matched to each death as in the baseline study. The baseline values of two of the three biomarkers (IL-6 and D-dimer) continued to be statistically significant predictors of late deaths and there was a trend for CRP to be a predictor of late deaths (see Table 2).

Table 2: Baseline biomarker levels and risk of death

* 4th/1st quartile

Greater predictors of risk than other factors

Table 3 shows some of the other risk factors for deaths that have been found in SMART (note that where p-values show non-significance, the factor can still be significant when the early and late groups are counted together).

Table 3: Risk factors associated with mortality in SMART

The authors noted that IL-6, hs-CRP and D-dimer are associated with greater risk of mortality than smoking and diabetes and about an equivalent risk of prior cardiovascular disease. They conclude that interventions to decrease inflammatory and coagulation pathway activation may be of long-term benefit for people with HIV.

COMMENT

The association between mortality and hs-CRP, IL-6 and D-dimer is significant, even after long-term follow-up and the termination of the structured treatment interruption arm. This highlights the importance of further research on whether anti-inflammatory medicines will have an additional role in HIV management of high-risk patients.

It would be interesting to know the association between these biomarkers and mortality is in the uninfected population. If they are similarly prognostic, then the question is how much of the associations seen in SMART are HIV-specific.

The role of early HAART in mitigating the association with mortality also needs to be determined.

References

1. Paton N. Association between activation of inflammatory and coagulation pathways and mortality during long-term follow up in SMART. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 19-22 July 2009, Cape Town. Oral abstract MOPEA034.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3388

In March/April 2009 we reported on the results of the SILCAAT and ESPRIT interleukin-2 (IL-2) trials. These trials found no clinical benefit from using IL-2 with ART. At IAS2009, Abdel Babiker presented a pooled data analysis of the two studies. [1]

In addition, Jorge Tavel presented the findings of the STALWART IL-2 trial, which was unblinded early following the negative results of the SILCAAT and ESPRIT trials. [2]

In the combined ESPRIT and SILCAAT analysis, 2,920 patients were randomised to ART plus IL-2 and 2,886 took ART without IL-2. There were 39,902 person-years, 550 primary events and 381 deaths. The pooled analysis showed no statistically significant differences in opportunistic disease or death between ART + IL-2 compared to ART alone (HR=0.93; 95%CI: 0.78-1.09; p=0.33). For opportunistic diseases alone, HR=0.88 (95%CI: 0.68-1.13; p=0.32). For all cause mortality alone, HR=0.96 (95%CI: 0.78-1.17; p=0.68). There were however significantly more adverse events in the IL-2 arms (HR=1.19; 95%CI: 1.06-1.33;p=0.002).

Babiker explained that this suggests that cells induced by IL-2 have no role in host defense or that the negative effects of IL-2 neutralised any improvements in host defense conferred by IL-2.

The STALWART trial had three arms, IL-2 alone (IL-2; n=89), IL-2 with short-course ART at the time of IL-2 cycles (IL-2+; n=87) and a control group that using neither IL-2 nor ART (n=91). The cycled ART regimen involved 14 days of ART preceding the first IL-2 cycle (which lasted five days) followed by two days of ART. This was the same in subsequent IL-2 cycles, except the pre-IL-2 ART regimen was shortened to three days.

As with ESPRIT and SILCAAT, there was a significant rise in CD4 counts for people on both IL-2 arms (+114 on IL-2; +110 on IL-2+; -21.8 in the control; p<0.001 for both arms compared to control). A greater number of patients assigned to the control subsequently started ART.

Both IL-2 groups were associated with a significantly greater number of grade 3 or 4 adverse events. Five patients in each of the IL-2 groups experienced an opportunistic disease or died versus one patient in the control. People in the IL-2 groups started continuous ART less frequently probably because of their IL-2 elevated CD4 counts.

COMMENT

These results confirm the lack of clinical benefit from IL-2 in the setting of HAART, and no apparent functional advantage from IL-2-induced increases in CD4 count.

CD4 counts in patients who have used IL-2 may therefore be artificially high, and HAART should perhaps be started in these patients at higher CD4 counts than recommended in treatment guidelines.

References

1. Babiker A. An analysis of pooled data from the ESPRIT and SILCAAT studies: findings by latest CD4+ count. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 19-22 July 2009, Cape Town. Oral abstract TUAB101.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3120
2. Tavel J. Immunologic and virologic effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy (ART): The INSIGHT STALWART Study. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 19-22 July 2009, Cape Town. Oral abstract TUAB102.
http://www.ias2009.org/pag/Abstracts.aspx?AID=2965

A poster at IAS 2009 by Madhi and colleagues reported the results of a double-blind, randomised, placebo-controlled trial to examine the efficacy of influenza vaccines in HIV-positive adults. Specifically, the study tested the seasonal trivalent subunit vaccine, which protects against three H1N1 and H3N2 influenza strains, two of which were isolated in 2006 and one in 2007. [1]

This was the first community-based randomised controlled trial of the trivalent subunit influenza vaccination in HIV-positive adults. A previous randomised controlled trial in the US on HIV-positive out-patients at a military health facility found that 10/47 patients who received placebo acquired laboratory confirmed influenza versus 0/55 patients who received this type of vaccine (p<0.001). [2]

A Cochrane Review of the vaccine in healthy adults has found this type of vaccine to be 30% effective (95%CI 17%-41%) against influenza-like illness, and 80% (95% CI 56% to 91%) effective against influenza when the vaccine matched the circulating strain and circulation was high, but decreased to 50% (95%CI 27%-65%) when it did not match the circulating strains. [3]

Participants were vaccinated prior to the 2008 influenza season in South Africa. Oropharyngeal swabs were taken from patients with influenza-like symptoms or respiratory illness. Culture and PCR tests were used to identify influenza strains. Only events 14 days post-vaccination were compared.

The number of HIV-positive people enrolled was 506. Of these, 101 were ART-naive (52 received vaccine, 49 received placebo) and 405 were on ART (203 received vaccine, 202 received placebo). Median age was 36. Female to male ratio was 5 to 1 in the vaccine arm and 6 to 1 in the placebo one. Median CD4 was 372 (IQR: 254-489) and 363 (IQR: 252-517) in the two arms respectively. Nine women were pregnant in the vaccine arm and four in the placebo one.

Over 90% of patients on HAART were virally suppressed in both arms. The median time on HAART at the time of randomisation was 23 months.

The percentage of people who developed influenza on the placebo arm was 5.3% using a passive surveillance method. [4] The rate of influenza illness was 0.06 per 100 person weeks in the vaccine arm and 0.25 per 100 person weeks in the placebo one. The vaccine efficacy was 75.4% (95%CI 14-93). The protective effect against the seasonal H1N1 strain was 73.5% (95%CI 4-93). There was one case of influenza B and no cases of H3N2 or untyped A.

The authors concluded that their findings support the use of the trivalent subunit influenza vaccine in HIV-positive adults.

COMMENT

This study supports vaccinating HIV-positive adults against seasonal influenza, as is routinely recommended in the UK. Because the vaccine is developed seasonally, its efficacy will change from year to year. The seasonal vaccine does not provide protection against the current H1N1 strain of swine flu.

At present there is no data on the effect influenza vaccines would have on reducing mortality in HIV-positive people as the contribution of HIV to influenza mortality is not well understood. Nevertheless, it is plausible that the reduced influenza cases conferred by the vaccine will reduce mortality as well.

References

1. Madhi S et al. Efficacy of influenza vaccine in HIV-infected (HIV+) adults: a double-blind, placebo randomised controlled trial in South Africa. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 19-22 July 2009, Cape Town. Late breaker poster LBPEB04.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3805
2. Tasker SA et al. Efficacy of influenza vaccination in HIV-infected persons: a randomised, double-blind, placebo-controlled trial. Ann Intern Med. 21 September 1999, 131, 430-433.
http://www.annals.org/cgi/content/abstract/131/6/430
3. Demicheli V. Vaccines for preventing influenza in healthy adults. Cochrane Review. 2006.
http://www.cochrane.org/reviews/en/ab001269.html
4. Personal communication with S Madhi.

Introduction

Three late breaker posters showed data from randomised trials evaluating different maternal and infant ARV regimens, among women not indicated to receive HAART by current guidelines, in order to reduce the risk of mother to child transmission, particularly during breastfeeding. [1, 2, 3]

Mma Bana

In an oral presentation, Roger Shapiro from Harvard University, Boston, presented findings from the Mma Bana Study. Mma Bana is a randomised controlled trial, conducted in Botswana, comparing antiretroviral regimens in pregnant and breastfeeding HIV-positive women. [1]

This study enrolled 730 women from four clinical sites. Women were stratified by CD4 count. Those who did not meet the eligibility criteria for HAART, with CD4 >200 cells/mm3 were randomised to receive: abacavir (ABC), zidovudine (AZT) and lamivudine (3TC) co-formulated as Trizivir (Arm A), or lopinavir/ritonavir (LPV/r), AZT and 3TC as Kaletra and Combivir (Arm B). Women with CD4 counts <200 cells/mm3 were enrolled into an observational arm and received nevirapine (NVP) plus AZT and 3TC in accordance with Botswana National Guidelines.

Women with higher CD4 counts (n=560) were randomised between 26-34 weeks of gestation to Arm A or Arm B and they continued treatment until weaning their infants within 6 months. Women in the observational arm (n=170) initiated treatment at 18-34 months and continued indefinitely. This group also weaned their infants before 6 months.

All women received supplementary AZT during delivery. Infants received a single dose of NVP and one month AZT post partum. Follow up will continue for two years post partum.

The primary endpoints of the study were viral load <400 copies/mL at delivery and throughout breastfeeding and overall rate of mother to child transmission (MTCT).

Dr Shapiro reported low loss to follow up with 95% of mothers and 97% of mothers followed to 6 months or death. The majority of participants met both virologic and transmission endpoints: 99% women had viral load <400 copies/mL at delivery and 99.7% during breastfeeding; and 99.6% infants had birth PCR results (3 died before test) and 95% at 6 months or within one day of testing.

Baseline characteristics of the women were similar in the two randomised arms, their median ages were 26 and 25 years, CD4 393 and 403 cells /mm3 and viral load 13,300 and 9,100 copies/mL in Arm A (n=285) and Arm B (n=275) respectively. Both randomised arms had a median baseline gestational age of 27 weeks. Women in the observational arm (n=170) were older, median 29 years, with lower CD4 counts, 147 cells/mm3 and higher viral loads, 51,700 copies/mL. Women received a median of 11 weeks in the randomised arms and 13 weeks in the observational arm of HAART prior to delivery.

Adherence to breastfeeding and HAART was good, 97% of women initiated breastfeeding and 93% breastfed exclusively until weaning. The majority of women, 71%, breastfed for >=5months and only 1% breastfed beyond 6 months. HAART adherence was similar across all three arms, 6% of women missed >= 3 days treatment.

At delivery (n=709), 96%, 93% and 94% of women in Arms A, B and the observational arm respectively had viral load <400 copies/mL (A vs. B, 95% CI for difference, -2%, 10%). During breastfeeding (n=669), 92%, 93% and 95% had viral load <400 copies/mL (A vs. B, 95% CI for difference, -8%, 6%). Risk factors for detectable viral load were higher viral load at baseline, p<0.001 and later gestational age at enrolment, p<0.001.

At 6 months the overall transmission rate in this study was 1% (95% CI, 0.5%, 2.0%). Of these, 5 occurred in utero, there were no intrapartum transmissions and two were during breastfeeding (see Table 1: MTCT at 6 months in Mma Bana).

Table 1: MTCT at 6 months in Mma Bana

There was no statistically significant difference between Arms A vs. Arm B, p=0.53. Dr Shapiro noted that these results excluded one unconfirmed HIV-infected infant that died in Arm A. When this infant was included in the analysis the difference did not reach statistical significance, p=0.42.

Maternal risk factors for transmission at delivery were fewer weeks of HAART, higher baseline viral load and poorer adherence. Higher baseline viral load and poorer adherence were also risk factors for transmission during breastfeeding.

Stillbirth occurred more frequently in the observational arm: 11 (7%) vs. 8 (3%) and 5 (2%) in Arms A and B, randomised vs. observational, p=0.07. Prematurity was more frequent in Arm B vs. Arm A, 61 (23%) and 42 (15%) respectively, A vs. B, p=0.04, and in 16 (10%) in the observational arm. Low birth weight did not differ by HAART regimen, 37 (13%), 45 (11%) and 23 (15%) in Arms A, B and observational respectively. Nor was there a difference in congenital abnormality, which occurred in 5 infants in each arm (2%, 2% and 3% respectively).

There were few maternal deaths, 1 (<1%) in Arm A and 3 (2%) in the observational arm. Grade 3 or 4 maternal adverse events occurred in 42 (15%), 32 (12%) and 48 (28%) women in Arm A , Arm B and the observational arm respectively. These were treatment-limiting in 7 (2%), 6 (2%), and 18 (11%) women in Arms A, B and observational.

Dr Shapiro concluded that using maternal HAART, among 709 live births, the overall mother to child transmission rate was only 1% with only 2 (0.3%) of infections occurring during the 6-month period of breastfeeding. “The lowest MTCT rate ever recorded in a breastfeeding population”, he said.

BAN

In second oral late breaker, Charles Chasela from the University of Northern California Project, Lilongwe, Malawi showed preliminary, 28 week, results from the Breastfeeding Antiretroviral and Nutrition (BAN) study. [2]

Formula feeding is not recommended in Malawi due to its high cost and greater association with infant mortality frequently observed in resource- limited settings.

BAN is a randomised controlled trial of mother infant pairs. Its aim is to evaluate two antiretroviral interventions over 24 weeks of exclusive breastfeeding followed by a four-week period of weaning, among women with CD4 counts >250 cells/mm3 with infants uninfected at birth and >2000 grams.

In this study all mothers and infants received single dose NVP plus one week AZT/3TC “tail” coverage. All women received nutritional supplementation, which the investigators described as, “enhanced standard of care”. Mother and infants were randomised to receive maternal HAART or NVP infant prophylaxis or nutritional supplementation alone (control). After cessation of breastfeeding, infants receive plumpy nut weaning food until 48 weeks. The primary endpoint was infant HIV status at 28 weeks.

A total of 2367 mother infant pairs were randomised within one week of birth; 851 received maternal HAART, 848 received infant NVP and 668 were in the control arm. There were no significant differences in the participants across the arms. The women’s median ages were 26, 25 and 26 years in the HAART, NVP and control arms respectively, p=0.7. Their median CD4 counts were 428, 440 and 442 cells/mm3, p=0.16.

Dr Chasela noted that during the trial the maternal HAART changed from a NVP-based regimen to nelfinavir in February 2005 and to LPV/r in January 2006. Nucleosides were AZT and 3TC.

There were no significant differences in maternal grade 3/4 toxicities except for low neutrophil count in women receiving HAART, 6.7% vs. 2.9 and 2% in the HAART, NVP and control arms, p<0.0001. This is known to be associated with AZT.

Among the infants, 16/848 experienced possible NVP hypersensitivity which all resolved when the NVP was discontinued. Additionally symptoms were observed in one infant whose mother was receiving NVP.

The investigators found both the infant NVP and maternal HAART regimens significantly reduced 28 week HIV transmission to the infants compared with the enhanced control arm.

The 28-week transmission in the infant NVP arm was 1.8% vs. 6.4% in the control arm, p< 0.0001. In the maternal HAART arm the transmission rate was 3.0% vs. 6.4% in the control arm, p=0.0032.

The estimated HIV-transmission or infant death rate was 7.6% in the control arm vs. 4.7% in the maternal HAART arm, p=0.031. This estimation was 2.9% vs. 7.6% in the NVP and control arms, p>0.0001.

Dr Chasela concluded that this study shows both maternal and infant ARV prophylaxis during 28 weeks of breastfeeding are safe and effective in reducing postnatal mother-to-child transmission of HIV.

He added, “Although this study was not powered to directly compare the maternal and infant interventions, there was some suggestion that the transmission of HIV was lower in the Infant NVP arm.”

Final 28-week visit for this study will be August of this year and 48-week visit will be January 2010.

Kesho Bora

And a late breaker poster authored by Isabelle de Vincenzi and the Kesho Bora Study Group reported preliminary data from a comparison of maternal HAART to short course prophylaxis regimens in women also not currently eligible for treatment.

In this study – conducted in five sites in Burkina Faso, Kenya and South Africa – pregnant women with CD4 counts 200-500 cells/mm3 were randomised between 28 and 36 weeks gestation to receive either maternal HAART (AZT+3TC+LPV/r to approximately 6.5 months after delivery or breastfeeding cessation if earlier) or short- course AZT plus single-dose NVP in labour. All infants received single-dose NVP post partum. During the course of the study one-week maternal “tail” coverage was added to the short course regimen and one week AZT for all infants.

Participating women received infant feeding counselling recommending either replacement feeding with free formula or exclusive breastfeeding, weaning from 5.5 months over a two-week period.

Women in both study arms were a median age of 27.4 and had a median CD4 count of 335 cells/mm3 at enrollment.
There were 805 live births, 402 in the HAART and 403 in the short course arms.

The investigators reported 76.4% and 78.2% of infants were ever breastfed in the HAART and short course arms respectively. Of these 47.5% and 45.6% were breastfed exclusively and the median duration was 21.4 weeks.

Kaplan-Meir estimates of the culmulative infant infection rates in the HAART arm were: 1.8% (95% CI, 0.8-3.7) at birth, 3.3% (95% CI, 1.9-5.6) at 6 weeks, 4.9 (95% CI, 3.1-7.5) at 6 months and 5.5 (95% CI, 3.6-8.4) at 12 months.

In the short course arm these rates were: 2.2% (95% CI, 1.2-4.3) at birth, 4.8% (95% CI, 3.1-7.4) at 6 weeks, 8.5 (95% CI, 6.1-11.8) at 6 months and 9.5 (95% CI, 6.9-13.0) at 12 months. This gave a 42% reduction in transmission risk at 12 months, p=0.039.

Provisional estimate of cumulative death rate at 12 months showed 6.3% (95% CI, 4.3-9.3) in the HAART arm vs. 10.0% (95% CI, 7.3-13.6) in the short course arm. This was a risk reduction of 37% but this was not significant, p=0.086.

And provisional estimate of HIV infection or death at 12 months showed 10.4% (95% CI, 7.7-13.9) in the HAART arm vs. 16.3% (95% CI, 12.9-20.5). Giving a 36% risk reduction, p=0.022.

Subgroup analysis of infants who ever breastfed revealed a cumulative infection rate of 5.0% vs. 8.8% at 6 months and 5.9% vs. 10.2% at 12 months, in the HAART vs. short course arms. This was not significant, p=0.064.

Cumulative infection rate for infants whose mothers had a baseline CD4 200-350 cells/mm3 was 5.5% vs. 10.5% at 6 month and 6.1% vs. 11.1% at 12 months in the HAART and short course arms, p=0.044.

Among infants whose mothers had a baseline CD4 350-500 cells/mm3 the rates were 4.1% vs. 5.9% at 6 months and 4.9% vs. 7.4% at 12 months, which were not significant, p=0.33.

The investigators concluded that maternal HAART given to women with CD4 counts 200-500 cells/mm3 during pregnancy and through breastfeeding reduces risk of HIV transmission and improves HIV- free survival compared to standard short course regimen. They noted that the largest effects were between 6 weeks and 6 months and among infants with mothers with baseline CD4 200-350 cells/mm3.

Importantly they found some postnatal HIV transmissions occurred despite maternal HAART and suggest that mothers may not have been able to wean at 6 months, underlining the importance of continuing HAART until complete breastfeeding cessation, or that this may be explained by inadequate adherence.

Final 12 months results from this study will be available in December 2009 and 18 months results in June 20010. These will include data on maternal health.

COMMENT

Together these data contribute to what we know and will influence policy and clinical practice. However, they do not yet resolve the question of how best to prevent mother to child transmission among women not yet indicated for treatment for their own health during pregnancy and breastfeeding.

It is difficult to compare transmission rates between these studies, as there are differences to consider between duration of antepartum treatment, maternal baseline CD4, exclusive vs. mixed breastfeeding, and levels of adherence, etc.

Mma Bana reported 93% exclusive breastfeeding, over 90% adherence and nearly three months antepartum treatment, all of which combine to give lower transmission rates than the other studies. This does not tell us though whether HAART is better than short course plus infant prophylaxis for women with high CD4 count. In Kesho Bora, for the subgroup of women with CD4 350-500 cells/mm3, there was no difference with HAART vs. short course and no postnatal prophylaxis.

Kesho Bora looked at two issues: transmission rates at birth, and postnatal transmission rates. Transmission at birth reflects receipt of HAART vs. short course during pregnancy and here transmission rates were almost identical. Postnatal transmission rates after birth reflect a comparison of HAART vs. nothing during breastfeeding. HAART was better than nothing. HAART is better than short course with nothing during breastfeeding. We already know infant prophylaxis is better than nothing, so that question is no longer relevant. The important question for breastfeeding is: maternal HAART vs. infant prophylaxis. The BAN study showed both work and, in this study, if anything, infant prophylaxis had the lower postnatal transmission rate.

But for maternal HAART to be most effective, starting at birth (as in BAN) is not an ideal intervention, it takes weeks, even months, for someone to be fully suppressed with HAART so starting too late in pregnancy (or at delivery) will put the baby at risk while the virus is detectable (though the threshold viral load for quantifying risk is not clear). In Mma Bana, the investigators found starting HAART >30 weeks gestation led to only 85% suppression by delivery whereas starting <30 weeks was associated with 97% suppression at delivery. This may be associated with early breastfeeding risk as well as in utero/intrapartum risk (previous studies correlate breast milk viral load with transmission risk and plasma and breastmilk viral load are also correlated).

In Kesho Bora there was less exclusive breastfeeding and possible poorer aherence and the rate of viral suppression was not presented (but should be soon). Their median time on HAART before delivery was shorter than Mma Bana so it is likely that more women were unsuppressed at delivery and in early breastfeeding. Concerns about mixed feeding in later breastfeeding are probably less important than those of suppression and adherence. If there is little or no virus in breast milk then that would most likely prevent additional risk from gut issues related to mixed feeding, but the relative contribution of different transmission risks have not yet been studied.

It was interesting to see data for a triple nucleoside regimen in Mma Bana for women with higher CD4 counts, but it is likely that lopinavir/r-based regimens will remain the standard of care for women in this situation particularly as it more available and cheaper in Africa and has more safety data. Importantly both regimens performed very well in this study.

None of these studies looked at breastfeeding beyond 6 months post partum, which could contribute to better infant survival but also to more potential risk for failure over longer duration and greater cost.

So we still need data to answer questions concerning the efficacy and optimal duration of maternal HAART vs. infant prophylaxis for preventing post-natal mother to child transmission. And we need more information about the safety of stopping (or continuing) maternal HAART if used just to prevent mother to child transmission in healthier women. PROMISE, a multi-country study beginning soon will look at these questions in 8,000 women who do not need treatment for their own health (<350 cell/mm3).

Our next issue of HTB will include our full report on maternal/infant health and mother to child transmission from IAS 2009.

Thanks to several researchers, particularly Roger Shapiro and Lynne Mofenson, for discussion of these studies.

References

1. Shapiro R et al. A randomized trial comparing highly active antiretroviral therapy regimens for virologic efficacy and the prevention of mother-to-child HIV transmission among breastfeeding women in Botswana (The Mma Bana Study). 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Abstract WELBB101.
http://www.ias2009.org/pag/Abstracts.aspx?SID=2435&AID=3821

2. Chasela C et al. Both maternal HAART and daily infant nevirapine (NVP) are effective in reducing HIV-1 transmission during breastfeeding in a randomized trial in Malawi: 28-week results of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Abstract WELBC103.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3751

3. de Vincenzi I et al. Triple-antiretroviral (ARV) prophylaxis during pregnancy and breastfeeding compared to short-ARV prophylaxis to prevent mother-to-child transmission of HIV-1 (MTCT): the Kesho Bora randomized controlled clinical trial in five sites in Burkina Faso, Kenya and South Africa. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Abstract LBPECO1.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3631

Two studies presented at the 1st International Workshop on HIV Pediatrics, 17-18 July 2009, Cape Town, South Africa and 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009 looked at strategies for treatment of HIV-infected children with prior exposure to nevirapine (NVP) to prevent mother to child transmission.

IMPAACT  P1060

In an oral presentation at the paediatric workshop, Avy Violari from the University of Witwatersrand, Johannesburg, South Africa, presented preliminary findings from the IMPAACT P1060 trial. [1] These data were also shown at the 5th IAS Conference as a late breaker poster. [2]

IMPAACT 1060 was a randomised trial conducted at 10 sites in 7 African countries. In this trial, two groups of HIV-infected children age 6 months to 3 years and eligible for treatment according to WHO criteria: Cohort 1, exposed (n=288) and Cohort 2, unexposed (n=288) to single dose NVP, were randomised to receive either lopinavir/r or NVP plus zidovudine (AZT) and lamivudine (3TC), with 144 children in each treatment group.

Children were stratified by age <12months vs. >=12 months with equal number to be enrolled in each age group.

The primary endpoint was virologic failure (defined as <1 log decrease in viral load between weeks 12 -24 or >400 copies/mL at week 24), treatment discontinuation or death by week 24.

The investigators used Kaplan-Meier curves to estimate failure rates at week 24. Differences between treatment arms were weighted by the inverse of the variance in each age group.

A similar study of mothers exposed and unexposed to single dose NVP had also been conducted (A5208). In this trial – which we reported in previous issues of HTB – the arm in which exposed mothers received NVP-containing HAART was stopped early by the Data Safety Monitoring Board (DSMB) due to superior performance of the LPV/r- containing HAART arm. [3, 4]

Dr Violari reported that following a scheduled DSMB review of IMPAACT 1060 on 20 April 2009, enrolment to Cohort 1 had also closed prematurely due to a trend towards consistency with the A5208 results. Children in Cohort 1 were evaluated and discussions with their parents or guardians were held to decide whether to switch children receiving NVP to LPV/r. Cohort 2 is to continue enrolment and study as planned.

At the time of the DSMB review, Cohort I had enrolled 153/288 children with a median follow up of 48 weeks. The median baseline age of the children was 0.7 years (75% <12 months), median CD4 percentage 19%, and median viral load >750,000 copies/mL. Results at week 24 by primary endpoints are detailed in Table 1.

Table 1: Cohort 1, week 24 primary endpoints (from Kaplan- Meier curve)

Difference in week 24 failure rate (NVP-LPV/r): all 18% (95% CI 2%-33%), p=0.015.

Of 115 children tested, 16 (14%) had baseline NVP resistance, mostly Y181C (n=14). The investigators found the difference in viral failure between arms was greater among the 16 children with baseline resistance (57%) compared to the 99 without resistance (17%).

The investigators suggested these data emphasise the need for better prevention of mother to child transmission strategies including post partum “tail” coverage and maternal HAART. And that prioritisation of resources for mother-infant pairs should be encouraged.

NEVEREST

Several guidelines already recommend using LPV/r-based treatment for single dose NVP-exposed infants.

Louise Kuhn from Colombia University, New York, USA and Ashraf Coovadia from the University of the Witswatersrand, Johannesburg, South Africa, presented findings from the NEVEREST study. NEVEREST is an investigation to see if NVP-exposed children, initially suppressed on LPV/r-based HAART can safely switch to a NVP based regimen.

In this study children 6 weeks to 2 years of age and eligible for treatment (n=323), were initiated on LPV/r plus 3TC and d4T. After achieving a viral load <400 copies/mL and maintaining it for >= 3months, children were randomised (n=195) to either remain on LPV/r (control, n=99) or switch to NVP (switch, n=96), and then followed to 52 weeks post randomisation.

Baseline (pre-treatment) characteristics of the randomised children were mostly similar: median age, 11 months vs. 9 months; median CD4 percentage 19.0% vs. 18.4%; and 57% vs. 54% had a viral load >750,000 copies/mL in the control and switch groups respectively. There was a larger group of younger children age 1-12 months in the switch group, 57.6% vs. 68.8%, but this difference was not significant.

At randomisation the median age of the children were 20 months vs. 19 months; median CD4 percentage 28.9% vs. 28.5% and 61% vs. 66% had a viral load <50 copies/mL in the control and switch groups respectively. The median time on LPV/r based therapy was 9 months in both groups.

Two children in each group died; 3 children in the control and 5 in the switch group were lost to follow up and 3 children in the control and 5 in the switch group started TB treatment.

The investigators reported 80% vs. 86% of children were adherent to the study medication at 36 weeks post randomisation in the control and switch groups respectively.

When the investigators looked at viral load <50 copies/mL to 52 weeks they found 42.4% children in the control group and 56.2% in the switch group sustained viral suppression, p=0.01. But allowing for one elevated result (blip) the two groups were similar, 72.8% vs. 73.4% in the control and switch groups respectively.

They suggested that poorer adherence in the control group, due to the unpleasantness in taste of LPV/r syrup, may have led to more blipping and, in turn, unsustained viral suppression to 50 copies/mL during follow up.
In contrast, when they looked at sustained suppression to <1000 copies/mL, 98% vs. 80% of children in the control and switch groups achieved this, p=0.001.

An analysis of patterns of viral suppression after the children were randomised revealed that of the children >50 copies/mL, 56% in the control group had viral load between 50-1000 copies/mL and the remaining 2% more than 1000 copies/mL. In the switch group more children had viral load more than 1000 copies/mL 20%; but fewer, 24%, were between 50-1000 copies/mL.

In the switch group, viral suppression <50 copies/mL at randomisation was predictive of sustained viral suppression <1000 copies/mL through 52 weeks: 86.1% of children with viral load <50 copies/mL at randomisation sustained viral suppression <1000 copies/mL through 52 weeks vs. 63.5% with viral load 50-400 copies/mL at randomisation, p<0.001. Likewise, the presence of NNRTI mutations prior to treatment predicted sustained viral suppression after switch: 88% children with no mutations sustained viral load <1000 copies/mL through 52 weeks vs. 55.3% with mutations, p=0.007.

The median CD4 percentage at 24 weeks in the control group was 30.0% vs. 33.2% in the switch group, p<0.0001. In the control group 16.3% of children had a CD4 percentage decline of 10% vs. 3.2% in the switch group, p=0.004. Weight for age declined >1 z-score in 13.1% of children in the control group vs. 4.2% in the switch group, p=0.03.

The investigators wrote that this study provides proof of concept that re-use of NVP is possible under some circumstances for HIV-infected children exposed to NVP prophylaxis and should be further investigated. They note that the clinical significance of low-level viraemia in the control group needs further study. Switching may provide a promising option for children originally initiated on PI-based HAART to preserve second-line options. At this stage, switching requires close virological monitoring after the switch in order to be done safely.

COMMENT

The 1060 results are unsurprising and entirely consistent with the earlier maternal data. Baseline nevirapine resistance and younger age appear to be associated with the performance of the nevirapine arm.

NEVEREST was interesting and this strategy deserves further investigation. Another NEVEREST trial of efavirenz vs. lopinavir/r is planned in nevirapine-exposed children >3 years old.

Both studies underscore the limited treatment options that are available for children, particularly in resource limited settings.

References

1. Violari A et al. Nevirapine vs. lopinavir-ritonavir- based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV infected infants: preliminary results from the IMPAACT P1060 trial. HIV Pediatrics, 17-18 July 2009, Cape Town. Abstract O_08.
2. Palumbo et al. Nevirapine (NVP) vs. lopinavir-ritonavir (LPV/r)- based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV-infected infants: preliminary results from the IMPAACT P1060 trial. 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009, Cape Town. Abstract LBPEB12.
3. http://i-base.info/htb/261
4. http://i-base.info/htb/1449
5. Coovadia A et al. Randomized clinical trial of switching to NVP-based therapy for infected children exposed to nevirapine prophylaxis. HIV Pediatrics, 17-18 July 2009, Cape Town. Abstract O_09.
6. Coovadia A et al. Randomized clinical trial of switching to nevirapine-based therapy for infected children exposed to nevirapine prophylaxis. 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009, Cape Town. Abstract MOAB103.