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Risk compensation

Changes in the WHO Guidelines for treatment of HIV

5 Nov, 15 | by Leslie Goode, Blogmaster

The WHO has released early its revised guidelines on the treatment of those infected with HIV (WHO early release guideline; WHO press release).  There are two important changes.  First, ART is recommended to all HIV infected individuals regardless of their CD4+ count.  Second, PrEP is recommended for people at ‘substantial’ risk of HIV infection as part of a comprehensive package of services.

The first of these revisions comes in the train of repeated rises over recent years in the recommended treatment threshold: first (2010), to350 CD4 per mm3; then (2013), from 350 to 500.  The latest revision is doubtless based on the results of randomized controlled trials (RCT) such as the START (Strategic Timing of Anti-Retroviral Therapy) trial (A Case for Immediate ART Initiation (STI/blog)).  The second builds on a WHO 2014 guideline which already recommended PrEP for MSM populations.  Here again recent RCTs demonstrating the effectiveness of PrEP, such as PROUD and IPERGAY (PrEP highly effective for HIV in MSM (STIs/blog)) will have played their part.

The removal of the threshold has resource implications that will pose a serious challenge in resource poor settings.  Writing in 2010 Hamilton and Crowley (STIs) estimated that setting the threshold for ART initiation at 250 CD4+ would by 2012 increase the need for treatment by a median of 15%, whereas setting at 350 CD4+ would increase it by 42% and 500 CD4+ by 84%. Contributors like Hallett & Garnett (STIs) (Zimbabwe) and Zwahlen (STIs) have sought to develop projections for individual countries.

Also, it has been argued that late diagnosis (even by current standards), and poor retention in care are significant factors in suboptimal health outcomes (Mubezi & Shuha (STIs)Hussey (STIs).  What the revised guidelines will deliver in real terms no doubt depends on the context of implementation.  Yet, even in the relatively more affluent settings (US), some recent research has argued for the reallocation of resources from linkage to retention in HIV care, in order to optimize utilization of scarce resources (Retention in Care (STI/blogs)Sherer (STIs). This could prove hard to square with the prioritization of ever lower thresholds for linkage to care – even if the recommended policy is in the interests of improving individual outcomes.

PrEP highly effective against HIV in MSM and has limited impact on risk compensation

22 Oct, 15 | by Leslie Goode, Blogmaster

The year 2015 is likely to turn out a decisive one for the story of PrEP (pre-exposure prophylaxis for HIV).  After a slow and faltering beginning, with trials in sub-Saharan Africa dogged by problems of poor adherence (Haberer & Bangsburg/STI/blog; VOICE D/STI/blog; Hendrix & Bumpus/STI/blog), this intervention appears at last to have proved its worth – at least in high-risk populations such as MSM in Europe and America.  This is to be seen in a succession of results from recent or still ongoing trials.

Following the report of encouraging headline figures at last February’s Conference on Retroviruses and Opportunistic Infections (CROI), the UK PROUD study (Pre-exposure Option for reducing HIV in the UK immediate or Deferred) has published its results (McCormack & Gill; PROUD/STI/blog).  As stated in my earlier blog, this study, based in 13 UK clinics, aimed, in its design, to replicate real-life conditions in being an ‘open-label’, as opposed to a blind placebo controlled, randomized study.  September also saw the publication of a brief report of a San Francisco based study (Volk & Hare) investigating HIV and STI incidence amongst a comparable number of patients (650) referred for PrEP over 2 and a half year period in a clinical practice under the health insurance provider Kaiser Permanente.  Finally, the PROUD study refers to the still ongoing IPERGAY study run by French and Canadian researchers (IPERGAY; Molina & Delfraissy).  The latter differs from the PROUD study, first in respect to the PrEP regime followed, which is ‘on demand’ (i.e. before and after sex) rather than daily; second, in having a blind placebo controlled, rather than an ‘open-label’, design.

The three studies investigate relatively high-risk, largely MSM, populations – to judge by the high rates (c. 34%-50% within a year of follow-up) of STIs and especially (18%-32%) of rectal STIs.   Rates of HIV transmission, however, were, in all cases, similarly low.  As indicated in my blog (PROUD/STI/blog), the PROUD study headlined an HIV incidence of 1-2 per 100 person years (py) in the immediate initiation, as against 9 per 100 py in the ‘deferred initiation’ arm.  The IPERGAY study saw rates of 0.94 as against 6.75.  The San Francisco study was without a control arm, but saw zero cases of HIV among PrEP users over the two and a half year study period.  All this would suggest that amongst self-selecting high-risk MSM, PrEP interventions can be successful in preventing HIV transmission.  It would, however, be reassuring to know more about the impact of PrEP on risk compensation – always the supposed ‘Achilles heel’ of MSM PrEP (Cassell & Halperin) – especially as rates of STI incidence following PrEP initiation were very high in all studies.  Here the published version of the PROUD study has the advantage of being able to compare incidence of other STIs between the intervention and the control arm of the study.  No significant difference between the two arms was observed.  This was particularly encouraging as the PROUD study was designed to replicate the conditions of a real-life intervention in that those in the intervention arm knew they were taking PrEP, and could have adjusted their behaviour on the basis of this knowledge.

A final issue that PROUD and IPERGAY may begin to help health professionals to address is that of cost effectiveness.  The PROUD researchers calculate that ‘thirteen men in a similar population would need access to 1 year of PrEP to avert 1 HIV infection’.  This would make PrEP targeted at this group cost-effective at current prices if the cost of tenofovir and emtricitibine were halved.  It could also be achieved if the proposed intervention were to adopt the ‘on demand’ regimen trialled by IPERGAY:  namely, two tablets 2-24 hrs before sex, one taken 24hr, and a further tablet 48 hrs. after.  IPERGAY, it will be remembered, demonstrated the same 86% reduction in HIV incidence that was observed by PROUD.

Reported 86% effectiveness for MSM PrEP by PROUD study makes this intervention a viable option for UK health services

25 Mar, 15 | by Leslie Goode, Blogmaster

The Conference on Retroviruses and Opportunistic Infections has recently taken place.  At that event the UK PROUD (PRe-exposure Option for reducing HIV in the UK: immediate or Deferred) study of pre-exposure prophylaxis (PrEP) for MSM reported its results, prior to publication in the coming months.  The headline figure is an astonishing 86% for the reduction of risk of infection in the intervention group.  Hitherto, results of PrEP trials, largely conducted in Africa, have often been disappointing.  This is probably on account of poor adherence (VOICE D( STI/blog); Haberer & Bangsberg (STI/blog); Hendrix & Bumpus (STI/blog)).  The good result achieved here is no doubt attributable to good adherence.  It demonstrates, as these earlier trials have not, the true effectiveness of PrEP.

The UK trial included 545 participants at 13 practices. 276 were randomized to receive PrEP immediately, while the remaining 269 received it after a year.  Earlier PrEP trials have been blind and placebo-controlled.  But this design had the advantage of demonstrating the effectiveness of PrEP in real life. The participants were aware if they were taking the active drug and could have changed their sexual behaviour accordingly.  Given one of the major concerns around PrEP is that of risk compensation – i.e. taking advantage of the protection of PrEP to engage in more risky behaviour than they would otherwise (Marcus & Grant (STI/blog); Baeten & Celum (STI/blog)) – this was a valuable aspect of the trial.

In the period to October 2014, there were 22 HIV infections – 3 in the immediate, and 19 in the deferred group.  This gives us the headline figure of 86%.  At this point, ethical considerations dictated that the study design be changed so all participants received PrEP from then on.  Initially, this study was intended to be a pilot, and to be followed by a larger scale trial.  The decisiveness of the interim findings, however, led to cancellation of that further study.  (For an interesting commentary on the need for researchers to keep pace with changing ethical parameters, see Cohen & Sugarman (STI/blog)).  Cost-effectiveness analyses are apparently underway.  No details are given in the report.  But evidently the high effectiveness observed in the study will allow investigators to present a far more positive case for PrEP than has been warranted by earlier trials (see Borquez & Hallett (STI); Gomez & Hallett (STI/blog); Cremin & Garnett (STI)).  They are also working with stakeholders on how PrEP services could be commissioned across NHS and local authorities.

Does risk compensation behaviour neutralize the benefits of voluntary medical male circumcision?

18 Aug, 14 | by Leslie Goode, Blogmaster

The effectiveness and feasibility of voluntary medical male circumcision (VMMC) as a preventative intervention against HIV has been demonstrated in a variety of non-circumcising African communities.  The WHO has designated 14 countries in southern and eastern Africa as priority areas for VMMC scale-up.  Attempts to model the progress of the epidemic have long sought to factor in the potential contribution of VMMC (STIs/Hallett & Abu-Raddad).  However, the possibility of risk-compensation remains an ongoing concern (i.e. that the known preventative effects of VMMC will lead to increased sexual risk-taking).  Current evidence has been largely limited to behavioural evaluations and extended follow-up in populations where RCTs of VMMC were being conducted (e.g. Rakai, Uganda; Orange Farm, South Africa; Kisumu, Kenya).  The evidence has been reassuring, by and large.  Yet it is also inconclusive – for two reasons: first, on account of the rigorous risk reduction counselling invariably provided by these trials, which is far in excess of what would be offered in operational settings; second, due to the lack of certainty as to the preventative effectiveness of VMMC that prevailed at the time when these RCTs were being conducted.  These are precisely the issues that bedevil studies seeking to evaluate risk compensation in the context of pre-exposure prophylaxis (PrEP): see STIs/blog/Marcus & Grant; STIs/blogs/Mugwanya & Baeten.

A recent prospective, longitudinal study conducted in Nyanza Province, Kenya (Westercamp & Bailey) claims to mark an important step forward towards understanding the relation between VMMC and sexual risk-taking in everyday operational settings.  Participants in the study were not exposed to unrealistic levels of risk reduction counselling, and the preventative efficacy of VMMC had already been well established prior to commencement of the study.  Participants were followed up, at six monthly intervals over a two year period, having assigned themselves either to a circumcision (1,5888) or a control (1,599) group, using (as far as possible) audio computer-assisted self-interview questionnaires to investigate sexual behaviour.

The result?  No risk-compensation, apparently.  In fact, the findings show an increase of 30%/6% in condom use at last sex (for the circumcised/control group), and a broadly comparable decline for both groups across a range of indicators, including transactional sex in the last six months (26-12%), most recent sex with a casual partner (20-12%), and having multiple partners in the last six months (26-16%).  The only adverse finding was an increase in sexual activity for both groups among the younger participants – but this seems to be largely explained by transition to married status.

The decline might be due to some limited exposure to HIV education through participation, or reflect “cognitive dissonance” – i.e. the re-evaluation of behaviours in the light of the personal investment involved in getting circumcised.  But there is evidence it might be part and parcel of a decrease in sexual risk-taking in the community at large due to the implementation of the VMMC programme over the period of the study 2008-2011.  A curious finding was the greatly reduced perception of high HIV risk among the “cross-over group” of those 20% of the control group who subsequently chose to be circumcised, as against the perceptions of those who initially assigned themselves to the circumcision group.  This, according to the authors, suggests that men motivated to early adoption of VMMC may represent a higher risk group.  When this finding is taken together with recent evidence of high (90%) acceptance of VTC services among men undergoing circumcision, the case stacks up for ensuring the provision of high-quality counselling as a priority throughout the commencement and rapid initial sale up of VMMC services.

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