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pre-exposure prophylaxis

The PrEP ‘care continuum/cascade’: how would it look?

8 Mar, 17 | by Leslie Goode, Blogmaster

We take for granted the value of the care continuum (or ‘cascade’), now increasingly seen as the key measure of health system response to HIV (Cassell (STIs editorial)).   The application of this model to HIV has provided a benchmark for evaluation in contexts as diverse as Moscow (Wirtz & Beyrer (STIs)), South Africa (Schwartz & Baral (STIs)) or the Netherlands (van Veen & van der Sande (STIs)).   But could the same model also offer a means of evaluation in the case of other complex sexual health interventions such as PrEP (Pre-Exposure Prophylaxis)?

An on-line soon-to-be-published paper by Nunn & Chan (N&C), building on an earlier attempt by Kelley & Rosenberg (K&R), does precisely this.  An important difference from the earlier paper seems to be the more concrete definition of a larger number of steps (nine as against five) – especially in the central area of ‘uptake’ and engagement in care.  Here K&R define three stages: ‘need for awareness of PrEP and willingness to use it’, ‘need for good access to healthcare’, and ‘need for a prescription for PrEP.  N&C replace these with a more concrete conceptualization of the process in five stages involving: an occasion where PrEP access is facilitated (4); an appointment arising from that occasion where the assessment is performed (5); the prescription of PrEP, where indicated (6); the actual initiation of PrEP (i.e. when the client starts taking the pills) (7).  Also important is N&C’s substitution of two final steps – adherence (8)) then retention (9) for K&R’s single final step of ‘adherence’.  N&C point out that, whereas, with ART, ‘adherence’ is once-and-for-all and secures the ultimate goal of viral suppression, in the case of PrEP, we can envisage multiple trajectories depending on whether PrEP continues to be indicated (e.g. the client may no longer be exposed to risk).  Finally, K&R’s first step – ‘identifying at risk MSM’ – gives way to three: identifying at risk individuals (1), enhancing HIV awareness (2), enhancing PrEP awareness (3).

Is this nine-stage definition of a PrEP cascade overly “complex” (EECAAC2018)?

Answering such a question requires us to reflect on the function that the ‘cascade model’ is called upon to perform.  If the model divides up the total course of an intervention into a series of staged tasks, this is presumably because the health benefit depends on the completion of the whole intervention, yet the accomplishment of each step is necessary to the achievement of subsequent ones.  The idea of the cascade can provide a fair way of evaluating the progress of an intervention before its potential health benefits have been delivered – and can also identify the precise points at which the intervention is failing (i.e. where clients become ‘disengaged’).

It follows that each step should correspond to a potential outcome that is not inferable from previous or later outcomes but is worthy of independent evaluation.  If everyone who accesses PrEP (4) also attends an appointment at which suitability of PrEP is discussed (5), or everyone who adheres to PrEP (8) is also retained in PrEP (9), then steps (4) and (5), or steps (8) and (9), can be merged.  This is not stated in so many words by the authors of the model.  However, I would assume that it must lie at the basis of their thinking.

UK National Health Service (NHS) kicks PrEP into the long grass

18 Jul, 16 | by Leslie Goode, Blogmaster

A recent BMJ editorial condemns the NHS position that it will not consider PrEP for direct NHS funding.  The decision was first communicated in an NHS statement issued in March, then confirmed by a review on 31st May, following reconsideration in response to objections raised by interested groups.  This brought to an end an eighteen-month process of discussion between Department of Health, doctors and patients groups, Public Health England and other stakeholders.  The NHS decision is currently under judicial review – which no doubt explains the timing of the BMJ editorial.

Advocates of PrEP argue that the NHS has powers under the Health and Social Care Act (2012) directly to commission services ‘prioritized for investment’, and that PrEP should qualify for consideration on this basis.  But the conclusion of the NHS is that PrEP does not qualify to be so considered because the Local Authorities Regulations (2013) clearly stipulate that commissioning for sexual health prevention is legally the responsibility of local government.

Technically, then, the argument turns on whether the NHS can commission for PrEP directly, given that PrEP is a form of sexual health prevention. Needless to say, in the eyes of the advocates of PrEP, this is a mere technicality invoked by the NHS in order to shirk its responsibilities.  The NHS statements also include the proposal to work with local government authorities on exploring how they should go about commissioning PrEP services most effectively, and to dedicate £2m to the establishment of local pilots.  The problem here is that local authorities, having lately had £200m shaved off their funding for sexual health services, are presumably not in a hurry to pick up the tab.

So what about the case for PrEP? As regards effectiveness for high-risk MSM populations, PrEP has emerged with flying colours from recent trials, including the UK PROUD  study (PrEP Highly Effective/STIs/blog; PROUD/STIs/blog) and trials with similar populations undertaken in France (IPERGAY) and California (Volk & Hare).  Cost effectiveness, however, is another matter – and here PrEP has failed to make the grade.  Recent studies have shown that in the UK PrEP is not even borderline cost-effective without substantial reductions in the cost of the drugs (Cambiano & Phillips/STIs; PrEP Highly Effective/STIs/blog; PrEP cost effectiveness study). And, of course, even cost-effectiveness is not the same as affordability.  When it is borne in mind how much in the way of demonstrably very cost effective services have recently been rendered unaffordable by government cuts (Unprotected Nation/Report), the case for PrEP in the present climate does not look strong.

Is the UK meeting its national guidelines for HIV testing of MSM?

9 May, 16 | by Leslie Goode, Blogmaster

The potential role of frequent HIV testing in curbing the HIV epidemic among the MSM population has long been recognized. The introduction of the strategy of ‘opt-out’ testing in the UK (2007), as in other countries at around the same time, brought a steep rise in testing, followed by stabilization (McDaid & Hart (STIs); Saxton & Hughes (STIs) (for New Zealand); Heijman & Prins (STIs)  (Netherlands)), and may now ‘have reached its limit in maximizing routine uptake’ (McDaid & Flowers).  Nonetheless, amongst UK MSM at least, HIV incidence is not declining.  UK guidelines currently recommend annual HIV testing for MSM, and three-monthly testing for those ‘at higher risk’.  But how far are these goals being met?  An audit conducted in UK GUM clinics (Desai & Suillivan/STIs) was reassuring;  but a recent (2013) cross-sectional survey of gay bars in Glasgow reports levels of HIV testing over the previous six months of only 37%, and a relatively high proportion of ‘high-risk’ takers figuring among those who had never tested (OR: 0.51)( McDaid & Flowers (STIs)).

Last month saw the publication of study (McDaid & Flowers (M&F)) based on data from three cross-sectional surveys – Glasgow/Edinburgh gay commercial venues; an internet-based Scotland-wide survey; London gay social venues – and including 2409 MSM in total.  Frequency of testing was reckoned over a two-year period, and classified as ‘one or less’, ‘two or three times’, or ‘four or more times’.  On this basis, the study estimates the proportion testing annually at only 54.9%  – and the proportion of those reporting higher risk unprotected anal intercourse (UAI) (=37.8% of the total) who tested four or more times at only 26.7%.  So neither in respect to MSM in general, nor in respect to those ‘at high risk’ are the UK national guidelines being met.  Moreover, involvement in higher risk UAI – unlike number of sexual partners and AI partners – turns out not to be significantly correlated with the highest rates of testing; while more of those reporting higher risk activities claimed to have tested as a result of a perceived risk event, rather than as part of a regular check-up.  The authors conjecture the episodes of higher risk UAI may have been less frequent events (albeit reported by a third of participants) after which the participants, being risk-aware, took appropriate preventative action.  This seems a plausible interpretation.

Studies of HIV testing in other countries published in STI Journal seem to show a broadly comparable situation, with testing levels for MSM and high-risk MSM consistently falling short of respective national guidelines.  Thus Saxton & Hughes (STIs) in location based surveys in Auckland report levels of MSM annual testing rising slowly to 50% in 2011; while Guy & Hellard (STIs) surveying testing in Australian GP clinics give figures for annual testing by MSM, and high-risk MSM, of 35% and 15% respectively as of 2010.  As for the US, Katz & Stekler (STIs) report levels of annual testing of 77%, but, as the location of this survey was GP clinics, an appropriate UK comparator would be the study reported by Desai & Suillivan/STIs, which reports levels of 92%.

In their recommendations M&F stress the importance of reducing the known barriers to HIV testing, and also draw our attention to the key role that testing will have in facilitating the effectiveness of future PrEP interventions, given the need for participants in PrEP to have an accurate knowledge of their HIV status.

 

 

Another failed sub-Saharan #PrEP study: unpicking the disappointing performance of the dapivirine ring

30 Mar, 16 | by Leslie Goode, Blogmaster

The potential value of PrEP as an intervention in Western MSM populations has recently been conclusively demonstrated (PROUD – 86% (PROUD study/STIs/blog)), despite results from a whole series of trials in sub-Saharan African populations that seemed to cast doubt on its likely efficacy (CAPRISA 004 – 39%; iPrEX – 44%; CDC TDF2 – 62%; Partners-PrEP – 75%; FEM-PrEP – 0%; VOICE– 0%). The difference in outcome achieved in these two contexts would seem to have been the result of very different levels of compliance on the part of the study participants (VOICE D/STIs/blog). Evidently, the biologic efficacy of PrEP holds out hope for reducing transmission among MSM populations. But the jury remains out over the potential value of PrEP in combating the 50% of infections represented by the sub-Saharan hetero-sexual epidemic. An approach that has seemed promising in view of the evident problems of compliance posed by a daily or pre-coital regime of oral tenofovir is to deliver the ARV drug in the same way that contraception or HRT is sometimes delivered, via a ring that is inserted monthly into the vagina. Last month saw the final publication of the results of one of the two major studies that have been trialing this technology: MTN-020 – ASPIRE (Baeten & Hillier (B&H)).

The results of B&H – as indeed those of the other major sub-Saharan dapivirine ring study (IPM/Ring Study) – are disappointing and hard to interpret. Disappointing, because HIV incidence in the intervention arm was only 27% lower than in the control arm (though, when data from two (out of 15) study sites were excluded on the grounds of reduced retention and adherence, that figure rose to 37%). Hard to interpret, because – in response to problems of compliance that emerged in the earlier studies mentioned above – the study built in measures for the objective assessment of adherence including quarterly plasma sampling for dapivirine, and, after the first year of the trial, testing for residual dapivirine in used rings; and results from the latter suggested levels of compliance between 70% and 85%, depending on age group (with age positively associated with compliance).

One might be tempted to conclude that the dapivirine ring showed relatively poor efficacy. On the other hand, a post hoc age-stratified analysis of the data indicated levels of protection of 56% among those aged over 21 years, and zero protection for those aged 21 years or under. These figures are most easily interpreted as suggesting that non-compliance was at least an important factor – and, indeed, B&H themselves admit that their thresholds for non-compliance were set too low. If we disregard the objective assessments of compliance, then the post hoc analyses of levels of protection by age group would seem to suggest that the younger participants (aged 21 and under), almost unanimously removed their rings after each clinic visit, only to re-insert them, shortly before the next. The fact that an unknown proportion of the older participants might have been doing the same thing makes it impossible to reach any adequate conclusion as to the biologic efficacy of the dapivirine ring in this population.

Why the non-compliance – especially of younger participants? When VOICE D sought to investigate the non-compliance in earlier trials of oral tenofovir by confronting study participants with the objective evidence, the reason most frequently given was fear of the side effects of the drug, fuelled by peer participants and relatives and by the negative attitudes of community members. This might explain the positive association between compliance and age, if we assume a greater responsiveness on the part of younger participants to peer pressure. If this is the case, then the solution to these problems may be the development of more accurate measures of objective adherence.

 

Modeling the potential effectiveness of PrEP as against other preventative interventions in addressing MSM HIV

1 Mar, 16 | by Leslie Goode, Blogmaster

 

Despite the known preventative benefits of ART, the incidence of HIV among UK MSM population has remained relatively constant over the last 10 years and looks set to remain so. The UN 90:90:90 target will soon be achieved for this population, yet the goal of eliminating the infection seems no nearer.  Not surprisingly there is an appetite among health professionals for alternative measures – like PrEP.

A recent study (Punyacharoensin & White) claims to be the first to model, on the basis of detailed behavioural and surveillance data, the  impact of seven potential interventions – including PrEP – on HIV incidence in this population.  There is a considerable diversity in the nature of these interventions.  One of them consists in the roll-out of the recent WHO policy of ‘diagnose and treat’: others in the achievement of specific targets, such as yearly HIV testing for a given percentage of MSM: others again in the fulfilment of what seem little more than aspirations, given the absence of any indication of how they might be achieved – such as halving one-time partners or unprotected anal intercourse. The potential impact of each intervention is assessed independently, and then in various combinations with other interventions.

It is evident from the way that the various combinations of interventions are grouped into two sequences that the primary issue for these authors is the potential of PrEP (which happens to be the only genuinely new tool in the box).  The first sequence combines PrEP at varying levels of coverage and effectiveness with the achievement of one-year testing for different proportions of the population, ‘test and treat’, and various levels of risk compensation.  The second sequence goes through much the same process but with PrEP now replaced by a putative 0.5 drop in repeat partnerships.  The main study outcome appears to be the demonstration that introducing PrEP at certain levels of coverage and effectiveness could, in certain combinations, have an impact on incidence (-43.6%) that would be of the same order (-41%) as the achievement (by unspecified means) of a putative 0.5 drop in repeat partnerships.

The biggest problem for the modelers, of course, is the difficulty of predicting the effectiveness of PrEP in a real-life setting.  When empirical evidence of this finally emerges, then the value of this intervention as against traditional interventions will presumably be determined by its relative cost-effectiveness.  In other words, the question to confront health policy makers will be how much of what they would otherwise have spent on traditional interventions should be diverted into PrEP.

In the meantime, if there is key message to emerge from this study, it is that PrEP is worth a try.

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.

Failed PrEP trial (VOICE) participants give reasons for their poor adherence

13 Nov, 14 | by Leslie Goode, Blogmaster

Despite indications of the acceptability of Pre-Exposure Prophylaxis (PrEP) among certain populations (MSM in London (STI/Aghaizu & Nardone) 2013, and Australia (STI/Holt & De Wit) 2012), the extremely varied results that have emanated from large studies seeking to determine its efficacy and effectiveness as a preventative intervention remain a concern.  To name the most important examples, levels of risk-reduction were estimated as follows: CAPRISA 004 – 39%; iPrEX – 44%; CDC TDF2 – 62%; Partners-PrEP – 75%; FEM-PrEP – 0%; VOICE– 0%.  The reasons for this variation have been the topic of a number of contributions to this blog (especially: STI/blogs/Hendrix & Bumpus; STI/blogs/Haberer & Bangsberg), with consensus tending towards the poor adherence of study participants.

Last week in Cape Town results were briefly reported from a sub-study (VOICE D) of one of the less successful of these trials (VOICE). Microbicide Trials Network’s (MTN) VOICE study, discontinued in 2011, trialled daily tenofovir, in the form of vaginal gel or tablet, in 5,029 (mostly young) women from a representative range of sub-Saharan countries – S. Africa, Zimbabwe and Uganda. On the basis of self-reporting measures in the original VOICE trial, levels of adherence to the tenofovir regime had been estimated at 90%.  However, blood samples taken from participants found evidence of the drug in less of a third of the participants in the tablet arm, and less of a quarter of the participants in the gel arm, of the study.

After the closure of the VOICE study itself, the sub-study, VOICE D, engaged 127 former VOICE participants in in-depth interviews at which they were challenged with evidence of their poor adherence – with a view to stimulating frank discussion. When confronted with the evidence of blood tests, poor adherers initially expressed surprise and disbelief. Yet, according to the report, the aim of engaging frank discussion would seem to have been met.  The reason most frequently given was fear of the side effects of the drug, fuelled by peer participants and relatives and by the negative attitudes of community members.

Current trials of PrEP have re-evaluated and strengthened efforts to enhance adherence in the light of previous failures.  These include: the Follow-on African Consortium for Tenofovir Studies’ FACTS 001 (tenofovir gel before and after sex), the MTN’s ASPIRE and the International Microbial Partnership’s Ring Study (both the latter of vaginal ring releasing the ARV drug dapivirine) (MTN Trials). It is interesting that the Partners-PrEP study incorporated intensive “adherence interventions” for participants whose adherence levels fell below 80% (STI/blogs/Haberer & Bangsberg).

However, the VOICE D results may have implications for the usefulness of PrEP interventions more generally. At the very least, they discredit any idea that PrEP is able to offer a panacea. The value of PrEP, relative to other preventative interventions, is a contentious issue.  STI/Mukandavire & Vickerman (2013), for example, conclude that a scale-up of condom use is in most circumstances likely to be more effective than PrEP, but that PrEP could have a specific application in the case of female sex workers. STI/Verguet & Walsh (2012) see a future for PrEP in sub-Saharan countries with high HIV prevalence and without circumcision practice, such as S. Africa.  STI/Ying & Barnabas (2013) see targeted PrEP as a cost-effective addition to ARV.

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iPrEx finds no evidence that PrEP use is associated with risk compensation

14 Feb, 14 | by Leslie Goode, Blogmaster

A great concern in respect to the deployment of Pre-Exposure Prophylaxis (PrEP) as an HIV prevention tool is risk compensation – i.e. the possibility that the protection afforded by PrEP would itself encourage sexual risk-taking (STI blogs/Sugarman & Mayer).  Recent studies of PrEP efficacy would seem an unpromising context in which to assess the likely impact of such a factor, given that a dependable level of HIV protection – such as might encourage risk-taking behaviour – is precisely what these studies are seeking to demonstrate.  This difficulty has not deterred the researchers, however.  The most recent attempt to evaluate risk compensation in such a context (Marcus & Grant) (M&G) is a spin-off from the recent iPrEx study of the efficacy of PrEP using metricitabine/tenofovir disoproxil fumarate (FTC/TDF) in 2,500 MSM and transgender women (recruited at 11 sites in Peru, Ecuador, South Africa, Brazil, Thailand and the US) (Grant and Glidden (2010)).  Marcus and Grant’s study follows closely on another spin-off risk-compensation study arising from the Partners PrEP study covered in an earlier STI blog (STI blog/Mugwanya & Baeten).

Not only were participants in the Marcus & Grant study uncertain of the degree of protection that PrEP would afford (the eventual outcome was a 44% reduced risk of HIV acquisition, and 92% reduction for participants with detectable drug levels); they were also, of course, unaware of whether they had been assigned to the intervention or placebo arm of the study.  Marcus & Grant therefore use perceived treatment assignment and belief in PrEP efficacy as surrogates for the assurance of HIV protection which future PrEP users might be tempted to see as offsetting any increase in their risk-taking behaviour.  Sexual practices were assessed at baseline and quarterly thereafter; perceived treatment assignment and belief in PrEP efficacy were assessed at 12 weeks.  Practice of receptive anal intercourse without condom (ncRAI) was taken as the indicator of sexual risk-taking behaviour.

Findings of the study were as follows.  Mean number of RAI partners decreased (10-6) in the first twelve weeks from baseline, then remained more or less constant, while condom use with RAI partners rose in the same period (c.50-c.75%), and then plateau-ed.   The researchers found no indication of any association between risk-taking and participation in the trial – we may wonder though whether anyone would have expected there to be one.    However, a clear association emerged between ncRAI/no ncRAI at base line and perceived assignment to PrEP/placebo (53%/47% for PrEP, and 61%/39% for placebo).  Marcus and Grant are inclined to interpret this association as a reflection of the impact of risky behaviour on attitudes to treatment (“the belief could have served as a psychological mechanism to reduce concerns about sexual behaviour”), rather than that of treatment optimism on sexual behaviour.  However, the key finding for our authors was the absence of any difference in risk behaviour (ncRAI) between the treatment optimists and the treatment pessimists – and between those who claimed to have greater confidence in PrEP efficacy and those who claimed to have less.  This suggests the absence of a risk compensation effect.

A number of study limitations are discussed in the paper (not least of which that of reporting bias), but not the limitation that is patently the most serious: namely the questionable adequacy of perceived treatment assignment as a surrogate for the assurance of a certain level of PrEP efficacy.

On this point Mugwanya and Baeten (W&B) offer an interesting comparison (STI blog/Mugwanya & Baeten).  Participants in the intervention arm of the Partners PrEP study were informed of the study outcome (indicating a 96% reduction in HIV transmission between infected and uninfected partners), and follow-up, including monitoring of STI incidence, was continued for a further year, allowing comparison between sexual behaviour of participants before and after knowledge of PrEP efficacy.  M&B seem to corroborate the Markus & Grant’s finding of no risk compensation – and on the basis of far more solid evidence.  However, M&B’s finding relates to the behaviour of heterosexual couples, and is prima facie unlikely to be generalizable to the behaviour of MSM and transgender women.

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