Studies have shown that about 80% of the sexual transmission of HIV-1 subtype B and C is characterised by a genetic bottleneck, that is currently explained by low efficiency of virus penetration through mucosal layers and potential selective pressure at the sites of transmission in either the donor or the recipient.

Dukhovlinova and colleagues took a step further and looked whether and to what extent this phenomenon is present with the intravenous HIV-1 transmission. The researchers performed a single genome amplification (SGA) to analyse HIV-1 quasispecies in intravenous drug users (IDU) from St Petersburg, Russia and quantified the multiplicity of infection. The results of 17 IDUs from different cohorts in the city were analysed. Those were samples from people with acute, early and chronic infections. SGA followed by direct sequencing was used to determine the complexity of full-length env gene. A minimum of 20 single env amplicons for each patient was used to identify and to characterise the transmitted virus.

The recently infected IDU (n=13) had multiple viral variants in only 31% (4 of 13) of the subjects. Four chronically infected subjects had complex viral populations. All but one analysed HIV-1 strains belonged to the Eastern Europe lineage of subtype A. The viral strains in one sample represented the mixture of HIV-1 CRF06_cpx strains with its subsequent recombinant CRF-06_cpx/subtype A. No evidence of superinfection was discovered. All but 1 of the transmitted viruses was estimated to be CCR5-tropic based on the sequence of the V3 loop.

The researchers concluded that the ‘results suggest that infection in this cohort is most often initiated with the minimum infectious dose, i.e. a single virion, even in those subjects where parenteral transmission was the predominant risk’.

Ref: Dukhovlinova E et al. A significant transmission bottleneck among newly and recently HIV-1-infected IDU in St Petersburg, Russia. Poster abstract 477.

http://www.retroconference.org/2010/Abstracts/38528.htm

In this study the researchers examined the impact of IDU status and a series of clinical indicators on immunologic response. The treatment outcomes of treatment naïve adults (≥18 years old) initiating HAART after the year 2000 were assessed.

The clinical indicators used were:

1) Having <3 versus >3 CD4 count measurements in the first year of follow-up;

2) Having <3 versus >3 viral load measurements in the first year of follow-up;

3) Having a genotypic resistance testing done at baseline requested by the enrolling doctor in samples with viral load >250 copies/mL;

4) Having started therapy with <200 cells/mm3 CD4 cell count;

5) Having started on non-recommended HAART;

6) Having achieved viral suppression at 6 months since therapy initiation.

The model was adjusted for sex, age, CD4 cell count, viral load at baseline, and adherence to therapy during the first 6 months. Immunologic response was defined as the percent change in the 12-month CD4 cell count from the CD4 at baseline. Because the response was categorised as percent change >100%, percent change >0% and <100% and percent change <0%, a partial proportional odds model was used.

402 out of1633 (25%) of the people participating in the study reported IDU status. IDU were more likely to be female, younger, have adherence <95% during the first 6 months, <3 CD4 cell count and <3 viral load measurements during the first year on HAART, having started HAART with a CD4 cell count of 160 cells/mm3, and against all odds, being able to achieve suppression at 6 months since the initiation of HAART (P <0.01). The multivariate model (Table 2) estimated that IDU versus non-IDU immunologic responses did not differ significantly when stratified by the clinical indicators. Of note, as seen in the table, IDU and non-IDU had similar overall responses to HAART when stratified by adherence rates. This clearly indicates that a change in the general discourse on the benefits of HAART in the IDU population is necessary.

Table 2: Comparison of immunological and virological responses to ART between IDUs and non-IDUs based on level of adherence

Ref: Lima V et al. Similar Immunologic Responses to Modern HAART among IDU and Non-IDU in a Populational Setting. Poster abstract 516.

http://www.retroconference.org/2010/Abstracts/38235.htm

This model evaluates Highly Active Antiretroviral Therapy (HAART) as an intervention to reduce HIV incidence and prevalence in IDU communities. The model used is a network model based on a Mover-Stayer framework and on a previous cellular automaton model to evaluate HAART as prevention.

In the model, IDU are distinguished based on syringe-sharing behavior and HIV status, and exert social influence on peers, encouraging, or discouraging syringe sharing. HAART is applied at coverage levels of 0% to 100%, assuming complete adherence and no drug resistance, tracked HIV incidence, and prevalence to equilibrium. Community composition, needle sharing frequency (60/month), and initial HIV prevalence (31%) were derived from data on IDU enrolled in the Vancouver Injection Drug User Study (VIDUS). Published transmission rates for HIV disease stages were used. HAART, initiated after 5 years (Scenario 1), was combined with reduced risk behavior (Scenario 2), the latter repeated with HAART initiated after 1 year (Scenario 3).

Without intervention (Table 3), HIV spreads rapidly and reaches very high prevalence (90%) in the model. With increasing HAART coverage, HIV incidence and prevalence decrease for all scenarios, eventually reaching 0%. Without change in risk behavior (Scenario 1), HIV prevalence decreased gradually to 60% HAART coverage, dropping rapidly thereafter. Behavioral interventions (Scenarios 2 & 3) amplified HAART effects. At 40% to 50% HAART, both incidence and prevalence were reduced by about half. Above 80% coverage, the epidemic was effectively eliminated. Early HAART initiation showed little impact.

Table 3: Effect of HAART coverage on HIV incidence and prevalence in a network model of injecting drug users

Ref: Bastani P et al. Highly active antiretroviral therapy eliminates HIV epidemics in a network model of an Injecting Drug User community. Poster abstract 997.

http://www.retroconference.org/2010/Abstracts/38240.htm

• Increasing uptake of HAART in HIV-positive ongoing drug users

This study looked into the effect of HAART in a group of HIV infected patients infected through injecting drug use (IDUs) compared to patients infected via other routes. In the Danish HIV cohort study, patients who initiated HAART from 1 January 1997 to 31 December 2007 were identified. CD4+ cell counts and viral load were followed. For CD4+ cell counts, medians for the two groups were compared and for viral load the percentage of full viral suppression defined as <500 copies/mL.

The study included 3615 patients, representing 22,804 person years of observation. A total of 346 people (9.6%) were categorised as IDUs.

IDUs were diagnosed with a higher median CD4 cell count (IQR) [300 (170-480) vs 248 (109-418), p< 0.0001] but initiated HAART on average 125 (19-560) days after they were first eligible to treatment according to national guidelines, compared to non-IDUs who started after a median of 31 (5-158) days.

IDUs were more likely to receive a first regiment based on PIs compared to NNRTI based regiments for non-IDUs, and IDUs received more Trizivir. Importantly, more than half of IDUs had fully suppressed viraemia within the first 3 months of HAART.

Ref: Larsen M V et al. Efficacy of highly active antiretroviral treatment in HIV-1 positive injecting drug users – results from the Danish HIV cohort study. PE20.3/1

This study analysed the trends of antiretroviral therapy (ART) uptake among HIV-positive current drug users seeking substance abuse treatment in the HAART era at three hospitals in Barcelona, Spain, between 1997 and 2007. The results were divided into 3 periods (p) p1: 1997-1999; p2: 2000-2003; p3: 2004-2007), reflecting the evolution of HAART regimens over time.

In this analysis, 705 HIV-positive people were eligible (74.6% men); 299 were admitted in p1, 249 in p2 and 157 in p3. Mean age was 34 years, 94.7% had previous injection drug use (IDU) and 67.7% were current IDUs at admission. CD4 cell count was 399 cells/mm3 [IQR 203-632]. Lifetime prevalence of ART use was 59.4% (416/705), increasing from 48.1% in p1, to 64.6% in p2 and 72.6% in p3 (p<0.05). The prevalence of ART uptake at admission was 40.7%, increasing from 31.4% (p1) to 41.0% (p2) and 58.0% (p3) (p<0.05).

In multivariate logistic regression analysis, age, calendar period, and non-IDU were predictors of being in ART at admission. Among those taking ART, 21.6% were on suboptimal combinations, mostly during the first period. Overall, 44.6% of patients were on PI + NRTI-based regimens, 21.9% on NRTI + NNRTI-based regimens and 9.4% on triple NRTI-based regimens.

The researchers concluded that HAART uptake is steadily increasing in ongoing HIV-positive drug users. The continued “However, a remarkable percentage still remains ART-naïve despite immunosuppression. Interventions focused on the integration of both substance abuse and HIV/Aids treatment are necessary to increase survival in this population’.

Ref: Vallecillo G. et al. Increasing uptake of HAART in HIV + ongoing drug abusers. PE20.3/2

It is commendable that this conference is already organised as a regular event and focuses on a region that was not so high on the list of other major international HIV/AIDS events. It is also good that local researchers can show their concepts of science development and scientific agenda. Unfortunately, the quality of the majority of abstracts was not high and hardly any research breakthroughs were presented. The section on HIV treatment in IDUs illustrates this, though the same can be said for many mainstream HIV medical meetings.

While recognising that IDU is heavily political, especially in the Russian Federation, not allocating enough of time and attention to this topic is a particularly near-sighted, given that the main characteristic of the HIV population in the region is still IDU.

The following article is a general overview of three abstracts that I found of the more interest. Nevertheless, the community should insist on more research and better in terms of methodology research among the IDUs in the region.

Dolzhanskaya and colleagues analysed medical notes to study the attitude of doctors to providing narcological help and HAART assessed the situation with providing help with overdose in different countries from the region. It is well documented that educational programmes have small to insignificant effect in avoiding overdose, while naloxone, a medicinal product that helps people in overdose to recover from it, has the potential to have a major impact.

They found that many medical forms were not filled as required and that there was considerable amounts of missing data, especially on patients’ social background and their risk behavior. This may be due to either doctors not valuing this information to patients withholding information through concerns related to disclosure.

People who were registered with AIDS Centres and who are IDUs were hardly ever referred to, or visited, the Narcological Units. The lack of medical documentation for visits to TB Units or STI clinics also indicates that there is no clear idea about these patient needs, as well as perhaps little or no cooperation among the different institutions that are involved in provision of treatment, care and support for PLWHA.

A group of researchers from Armenia looked into the use of HAART and survival of HIV-positive IDUs in Armenia. [2]

Even though this topic has been researched on many occasions and in quite diverse settings and the results have been consistently good, it is commendable that now we have findings from the Caucasus too.

The study included 71 HIV-positive men using injecting drugs who were on first- or second-line ARV therapy (according to the National Guidelines of Armenia) and who were followed from February 2005 till May 2009. CD4 count, viral load and hepatitis B and C markers were recorded. Adherence was evaluated through a special computer programme that was created by the National AIDS Centre of Armenia.

During the study period, all people started therapy but 18 (25.3%) interrupted the treatment either because of complications (including side effects) or as a personal decision and 10 people consequently died. In this group, 62 (87%) of the participants had AIDS, 45 (63%) had hepatitis C and two (3%) had hepatitis B. One person had both hepatitis B and C. TB was registered in 46.5% patients.

All 10 people who died were staged as AIDS. Their average CD4 count was 93 cells/mm3. Nine had chronic hepatitis C and six had TB coinfection. It was postulated that two deaths were a result of drug overdose. Four people stopped ARVs as a result of complications (hepatotoxicity and anaemia), one gave up treatment as a personal decision, two died as a result of TB complications and one as a result of complictions from hepatitis C.

From the 33 (62%) people continuing therapy, 8 had adherence <95% and 25 >95%. Three people on therapy failed to reduce their viral load to undetectable, probably due to low adherence. In people continuing therapy, the average CD4 count increased to 245 cells/mm3.

Shonning and colleagues presented an abstract on the results of a study conducted by the Eurasion Harm Reduction Network in 2008. Shockingly, in 2006 from 3 555 568 registered IDUs, 9354 died of overdose. The researchers assessed the situation with providing help with overdose in different countries from the region. It is well documented that educational programmes have small to insignificant effect in avoiding overdose, while naloxone, a medicinal product that helps people in overdose to recover from it, has the potential to have a major impact.

The pilot programmes for distributing naloxone in Tajikistan and Russia showed that this is a viable option. The researchers suggest that if the existing harm reduction programmes are allowed to enhance access and start delivering naloxone to IDUs, their partners, relatives, etc, many unnecessary deaths from overdose will be avoided. Easy access to naloxone will also help with avoiding the psychological barriers to search help-fear of contacting the medical establishment and/or police or in cases logistics problems like late arrival of the ambulance.

References

Unless otherwise indicated, all references are to the book of abstracts of the conference.

1. Должанская Н и др. Анализ медицинской документации и изучение отношения врачей к оказанию наркологической помощи пациентам с ВИЧ-инфекцией и готовности к проведению совр. методов лечения (ВААРТ). Стр. 81

2. Мкртчян А и др. ВААРТ и выживаемость ВИЧ-инфицированных потребителей инъекционных наркотиков в Армении. Стр. 83

3. Шоннинг Ш. и др. Передозировка: основная причина предотвратимой смертности среди ЛЖВ.

The study had a very innovative and interesting design. It was a community-based, prospective, randomised controlled trial of 6 months of DAART compared with self-administered therapy.

The primary endpoint was the proportion of participants with a virological suppression after 6 months post intervention, defined as achieving either a ≥1.0 log reduction from baseline or HIV-1 RNA <400 copies/mL. Secondary endpoints included change in CD4 count.

The DAART group (n=88) was more likely to have a virological success (70.5% vs 54.7%, p=0.02), mean reduction in HIV-1 RNA level (-1.16 vs -0.29 log copies/mL; p=0.03) and a change in CD4 count (+58 vs –24 cells/mm3; p=0.002).

After further 6 months, however, when all subjects received HAART as self-administered therapy, the DAART (n=82) and self-administered therapy (n=52) arms did not differ on virological success (DAART 58% vs self-administered therapy 56%, p=0.64), mean reduction in viral load (–0.79 vs –0.31 log copies/mL, p=0.53), nor mean change in CD4 lymphocyte count (+60 vs –15 cells/mm3, p=0.12). Statistically, in the multivariate analysis, only high levels of social support significantly predicted virological success.

Researchers suggest that “a longer DAART duration or incorporation of self-efficacy or social support components, which may provide durability to this otherwise effective intervention” may be necessary to improve the clinical outcomes among HIV-positive IDUs.

References:
Smith-Rohrberg Maru D et al. Waning of Virological Benefits following Directly Administered ART among Drug Users: Results from a Randomised, Controlled Trial. 16th CROI, 2009, Montreal. Abstract 579.
http://www.retroconference.org/2009/Abstracts/35670.htm

An analysis from a large international cohort study from the Antiretroviral Therapy Cohort Collaboration (ART-CC) has calculated that antiretroviral treatment currently extends life expectancy for HIV-positive people to an average of 65 years. The study model used patients from high-income countries who start treatment when either 20 or 35 years old.

Using data from 43,000 patients from 14 cohorts from Canada, Europe and the US, the researchers estimated the life expectancy since 1996 on the basis of reported deaths within the cohorts. They compared rates in treatment-naïve patients starting treatment in the 1996–99 period to patients starting treatment from 2003–05.

Compared to the earlier treatment group, life expectancy for patients starting treatment in 2003-05 increased by 13 years.

Although life expectancy increased similarly in all groups there were significant absolute differences between different groups of patients,

Women had higher life expectancies than men (overall mortality rates/1000 patient years [95%CI]: 9.1 [8.2-10.1] vs 12.9 [12.3-13.6].

Patients with presumed transmission via injecting drug use had lower life expectancies than did those from other transmission groups (32·6 [1·1] years vs 44·7 [0·3], based on starting treatment aged 10).

Life expectancy was lower in patients with lower baseline CD4 cell counts than in those with higher baseline counts (32·4 [1·1] years for CD4 cell counts below 100 cells/mm3 vs 50·4 [0·4] years for counts of 200 cells/mm3 or more).

COMMENT

One of the most common responses to an HIV-diagnosis, and one of the key unanswered questions even for long-term survivors relate to life expectancy. It is therefore important to draw on the most recent studies to inform these discussions.

Antiretroviral therapy since 1996 has dramatically reduced mortality and extended life in all countries where there is access treatment, and as experience with treatment and availability of new and better drugs improves, projected life expectancy has similarly increased.

Every few years a new study produce more optimistic figures – 12 years, 25 years and now 35 years in the latest studies. [1, 2] It likely that future studies will close the gap between HIV-positive and HIV-negative populations.

But it we are not there yet. The paper from ATCC still shows 10-20 year differences due to HIV status. Patients starting at lowest CD4 levels have 10–20 years lower life expectancy and injecting drug use also impacts by 10 years.

ARV treatment, if used carefully, does not appear to have a built-in shelf life. Once virus is suppressed to below 50 copies/mL, ongoing viral evolution is stopped, rather than slowed, and resistance is related to poor adherence, or more rarely, re-infection with a resistant strain.

Experience with HAART over ten years suggests that initial concerns about compartmental sites, especially in relation to drug penetration and compartmental resistance has not led to systemic virological failure on a significant or measurable level. There are little data to predict whether this will become an important concern with longer use of treatment.

However, real concerns related to HIV-positive patients and aging include the greater risks for neurological complications, brain disorders (including Alzheimer’s and Parkinson’s), reduced bone mineral density, bone disease and fractures, virally-mediated cancers, diabetes, and heart disease.

The extent to which an extended period of uncontrolled viraemia prior to starting treatment may explain some of these increased risks is one of the questions addressed by several research groups, including the START study, due to enrol later this year. [3]

References

1. The Antiretroviral Therapy Cohort Collaboration Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. The Lancet, Volume 372:293-299., 26 July 2008.

http://www.thelancet.com/journals/lancet/article/PIIS0140673608611137/abstract

2. Lohse N et al. Survival of Persons with and without HIV Infection in Denmark, 1995–2005. Annals 2007 146: I-39.

http://www.annals.org/cgi/content/abstract/146/2/87

3. Overview of MRC Studies. HIV Treatment Bulletin May/June 2008.

http://www.i-base.info/htb/777

Jens Lundgren from the INSIGHT research group presented an analysis of nucleoside toxicity and cardiovascular disease from the SMART treatment interruption study. [1]

This issue was one of the most discussed clinical topics of the meeting as GSK also presented an analysis from their trial database. [3]

In February 2008, the D:A:D study showed an increased risk of cardiovascular risk from current or recent use of abacavir – a finding that was unexpected and challenging for people skeptical of a cohort study identifying a new effect with an as yet unexplained mechanism. [4]

Cautious reactions to the D:A:D results looked for validation from other studies which were not allayed by GSK’s more limited dataset, originally published as a letter to the Lancet. [5]

The SMART researchers analysed patients in the continuous treatment arm of SMART, by use of NRTIs relating to the previous D:A:D findings: using abacavir (but not ddI) n=1019, using ddI (but not abacavir) n=643, and other NRTI combinations with netheir abacavir nor ddI (n=2882). Baseline characteristics of these three groups were similar, including common cardiovascular risks (~4% prior CVD, 40% current smokers, 35% ischemic abnormalities and 7% diabetic). Lipid lowering drugs and blood pressure medications were each used by just under 20% of patients. 15% patients had >5 cardiovascular risk factors.

In multivariate analyses adjusting for CVD risk factors, all four categories of cardiovascular disease defined by the group showed increased hazard ratios (HR) for abacavir compared to other NRTIs (see Table 1).

Table 1: Adjusted HR of cardiovascular event with abacavir use vs. other NRTIs in SMART

Importantly, the results were similar when patients receiving tenofovir were used as reference group and when the approximate 10% of patients with events in both D:A:D and SMART databases were excluded from the analysis.

The SMART study also showed a strong association between elevated levels of some inflammation biomarkers with levels of viral load rebound and risk of serious event. In this analysis, patients using abacavir had D-dimer and IL-6 that were 27% and 16% higher at study baseline than patients in the reference group using other NRTIs (both p=0.07).

These levels could have been higher for reasons unrelated to abacavir use and will need to be examined in a study looking prospectively at changes in these biomarkers in patients starting abacavir. Interestingly, the HEAT study from GSK reported reductions in hs-CRP and IL-6 in both the abacavir/3TC and tenofovir/FTC over 48 and 96 weeks with no differences seen between the two arms. [2]

Similar to D:A:D, the clinical significance from abacavir use was greatest in patients with the highest underlying cardiovascular risk factors. Those patients with five or greater cardiovascular risks or ischemic abnormalities on ECG showed three-fold increased risk from using abacavir compared to other NRTIs (both HR 3.1).

Earlier in the conference, GSK, reported that their retrospective meta analysis from 54 phase 2 and 3 abacavir registrational studies did not find an association between cardiovascular events and either abacavir or non-abacavir use. [3]

While this was important from a regulatory perspective – any safety signal requires a company to look at their own dataset – the limitations of both this database and the presented analysis were unlikely to resolve the concerns highlighted by D:A:D and SMART.

Of the 54 trials, only 13 were randomised for abacavir use, 33 included abacavir in background regimens and 8 did not include abacavir. Just over 14,000 adults and 500 children were included. Events were identified by a search for cardiovascular-related events and rates in naïve and experienced patients were calculated per 1000 person years.

No differences were seen in the relative rates by abacavir use for any cardiovascular event (RR=0.59; 0.35-1.01; p-value=0.055) or any MI (RR=0.863; 0.40-1.86; p=0.706).

Myocardial infarctions (MI) were only identified in 16 patients using abacavir (10 using non-PI and 6 on PI-containing regimens. Of the 11 MIs in the non-abacavir group, all used PI-based regimens except for one patient using an NNRTI-based combination.

Several limitations were raised concerning this data. Firstly, that there were too few events to have statistical power to detect an association either way. Many cardiovascular risks were not recorded at baseline, including smoking status, hypertension, HDL and LDL. Patient numbers were much lower (~7000 and 4500 PYFU in the abacavir and non-abacavir groups), and importantly median follow-up time was less than one year.

By comparison, D:A:D included 33,000 patients who needed to be followed for seven years (160,000 PYFU) until there was sufficient power to make associations to a single-drug effect.

Secondly, patients in clinical trials are and were generally younger, healthier, with lower cardiovascular risks. Interestingly, GSK did not present an analysis relating to the comparator regimens used in these studies, which were PI-based, and therefore already carried a higher risk of CVD.

comment

The significance of these results from the SMART study, which are already published as a fast track paper in the 12 September edition of AIDS [6], is that they support the earlier D:A:D findings in two ways. They report a similar association between current or recent abacavir use and cardiovascular disease; and they found that the clinical impact was most significant in patients with highest underlying CVD risk.

BHIVA guidelines have, for several years, included the recommendation to routinely assess CVD risk using Framingham calculators on first diagnosis, prior to starting treatment and annually thereafter. Taken together, the D:A:D and SMART results suggest that for patients at the highest CVD risk (>20% 10-year Framingham), abacavir only be used when alternative options are not available.

References
1. Lundgren J, Neuhaus J, Babiker et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the SMART study. Late breaker abstract THAB0305.
http://www.aids2008.org/Pag/Abstracts.aspx?SID=291&AID=16113
2. Smith K, et al. Similarity in efficacy and safety of abacavir/lamivudine (ABC/3TC) compared to tenofovir/emtricitabine (TDF/FTC) in combination with QD lopinavir/ritonavir (LPV/r) over 96 weeks in the HEAT Study. 17th IAC Mexico City, 2008. Poster LBPE1138.
http://www.aids2008.org/Pag/Abstracts.aspx?AID=15873
3. Cutrell A et al. Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical trials. Oral abstract WEAB0106.
http://www.aids2008.org/Pag/PSession.aspx?s=264
4. D:A:D Study Group, Sabin CA et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008 Apr 26;371:1417-26.
5. Cutrell A et al. Abacavir and the potential risk of myocardial infarction. The Lancet. 2008 Apr 26;371:1413. 6. Lundgren et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008, 22:F17-24.