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Preventative effect of ART

HIV prevention through HAART: a victim of its own success?

28 Feb, 17 | by Leslie Goode, Blogmaster

A recent study (Kalichman & Allen (K&A)) involving a series of four cross-sectional surveys (1996-2016) at a Gay Pride event in US Atlanta Georgia adds to the mounting body of evidence that substantial changes have occurred in community-held beliefs about the safety of certain sexual behaviours in the era of HIV treatment as prevention.

It might seem surprising, in view of the known effectiveness of ART as a preventative tool, that its deployment has generally failed to deliver the preventative benefits that might have been anticipated.  It is essential to achieve progress right along the ‘treatment cascade’, including, not only access to testing, but integration into treatment and viral suppression, for those benefits to be realized.  The fact remains that levels of infection amongst MSM, even in countries that have scaled up testing and treatment, have remained stable or are actually rising.

The obvious hypotheses, tested by K&A in this study, are that, 1., the perception of safety on the part of MSM has led to an increase in condomless anal sex, and that, 2., the growing incidence of STIs resulting from these sexual practices has itself had a direct impact in reducing the protective effects of ART.  (Of course, this is not to deny that sizeable proportion of the MSM community in the US – as in Australia (Mao & de Wit) – be successfully engaged in deliberate HIV risk-reduction strategies.)  The four surveys adopted identical measures and procedures, and involved ascertaining proportion of condom use during anal intercourse and number partners over the previous six months as well as assessment of beliefs regarding the preventive effectivess of ART (nine items of the questionnaire).

Results were as follows.  For HIV negative men: condomless anal sex (CAS) increased from 43% (1997) to 61% (2015); reporting two or more condomless sex partners from 9% to 33%.  For HIV positive men:  CAS from 25% to 67%; reporting two or more condomless sex partners from 9% to 57%.  As regards beliefs that ART was protective, comparisons across survey times indicate a main effect for year of survey, F(3, 1829) = 6.3,p<0.01, with an effect across survey year for men who engaged in CAS, F(1,1829) = 9.3,p<0.01.  Most evident from figures is a precipitous drop in perception of risk amongst both groups between the third and fourth survey (2006 and 2016).

K&A’s hypotheses (one or both) would seem to be corroborated from another quarter by the observed association with the introduction of HAART of an increased infection rate of gonorrhoea and syphilis (Stolte & Coutinho (STIs)) and of viral STIs (de Laar & Richel (STIs)).  Indeed rates of MSM syphilis increase coinciding with HAART introduction have been so dramatic in some places (e.g. Buenos Aires (Bissio & Cassetti (STIs)) as to lead to a hypothesis that HAART agents may actually be impairing immunity to the virus (Rekart & Cameron (STIs); Tuddenham & Ghanem (STIs)).  Whatever the validity of the latter hypothesis, evidence of STI epidemics is consistent with evidence of attitudinal and behavioural changes, such as those proposed by K&A.

First study of population-level preventative impact of Medical Male Circumcision and ART on HIV incidence in a country of sub-Saharan Africa

14 Sep, 16 | by Leslie Goode, Blogmaster

Clinical studies have demonstrated the potential effectiveness of ART (HPTN 052) and Voluntary Medical Male Circumcision (VMMC) (Gray & Kigozi/STIs) as preventative measures against HIV.  This led WHO/UNAIDS to launch a Joint Strategic Action Framework (JSAF) setting a target in 14 priority sub-Saharan countries of 80% VMMC by 2016.

What, then, are the potential gains of ART and VMMC interventions in these countries?  Comparative ecological studies have shown the population-level impact of male circumcision as a cultural practice (MacLaren & Vallely/STIs). Various mathematical modelling studies have sought to quantify that potential effect of interventions both in the realm of VMMC (Jenness & Cassels/STIs) and ART (Shafer & White/STIs)  (though other studies have highlighted the challenges that scale-up of these interventions is likely to present (Kaufman & Ross/STIs)).

Now, for the first time, a study has sought to quantify the real-life population-level impact of these interventions.  Kong & Gray (K&G) base their study on data from the 1999-2013 Rakai Community Cohort Study (Uganda)).  Among the 45 Rakai communities (44,688 participants surveyed over 24.6 years), VMMC coverage had, by 2013, increased from 19% to 39%, and ART had risen, in males, from 0% to 21%, and, in females, from 0% to 26% – and HIV incidence had fallen, concurrently, from 1.25 per 100 person-years to 0.84 per 100 person-years in males, and from 1.25 to 0.99 in females.  As regards VMMR, each 10% increase in the rate was associated amongst males with a decline in incidence that could be quantified, on multivariate analysis, at 0.87 – though, in females, the reduction was statistically insignificant.  As for ART, the decline attributable was not statistically significant in either case, but, when ART coverage was modelled as a categorical variable, and coverage of over 20% was compared with coverage of under 20%, a decline in HIV incidence was observed in the former group of the order of 0.86 among males, and 0.77 among females.

These results are not surprising.  VMMC is, in the first instance, protective of men – though, of course, in the longer term women too will benefit from any population-level effect. (There is, in fact, a worrying possibility, investigated by Maughan-Brown & Thornton/STIs, that men could incorrectly assume that their VMMC will be directly protective of their partners, and modify their behaviour accordingly.)  As for ART, here too the (as yet) limited impact in Rakai is what we might have expected.  Tanser & Newell, in a South Africa-based study only observed significant association when ART coverage was over 30%.  However, population level decline in incidence – especially that associated with VMMC – is encouraging.  The results of this study allow us to predict that increasing VMMC coverage more than 40% could reduce male incidence by approximately 39% at population level.   A major limitation of the study, of course, is its assumption that sexual networks, and hence HIV transmissions, are internal to the community. However, a recent study by Chemaitelly & Abu-Raddad/STIs would seem to indicate that, in a context like sub-Saharan Africa the contribution of networks going beyond the wider community is likely to be limited.

Viral suppression through ART prevents HIV transmission between long-term sero-different MSM and heterosexual partners regardless of condom use

8 Sep, 16 | by Leslie Goode, Blogmaster

The HPTN 052 study demonstrated the preventative benefit of ART, showing a dramatic 96% reduction in HIV transmission in HIV+ participants randomized to early ART initiation compared with the group that deferred treatment.  This is very encouraging.  But from the perspective of a gay person considering the risk of engaging in condomless sex with a long-term HIV+ partner, these results do not provide an adequate basis on which to make a decision.  For a start, HPTN 052, like other such studies, focuses largely on heterosexual couples engaging in vaginal sex – which is recognized to carry only a fraction (c. 0.1) of the risk of HIV transmission of anal sex.  Besides, the study reports high levels (93%) of condom use.  Much remains obscure, therefore, as to the level of protection that a gay person could reasonably expect from ART against HIV transmission through condomless anal sex with a long-term partner.

This question is squarely addressed, however, in a recently reported prospective observational study – PARTNER (Partners of People on ART – A New Evaluation of the Risks) – involving 888 sero-different MSM (330) and heterosexual (548) couples reporting condomless sex who contributed a total of 1,238 eligible couple-years.  This study did not limit itself to establishing cases of transmission, but conducted phylogenetic analysis in those cases in order to determine whether or not the transmission had resulted from sex with the long-term partner.  Of the 11 transmissions that took place in the course of the 1,238 couple-years (10 amongst heterosexual, one amongst the MSM, couples), none were found to be phylogenetically linked.  The paper also examined the association between the HIV transmission which did take place (i.e. not from primary partner) and the sexual behaviours reported by HIV- partners.  Not surprisingly, this was found to be elevated in heterosexual couples where anal sex was reported, and in MSM where anal sex was receptive and receptive with ejaculation (1.68 and 2.70 per 100 couple-years, respectively).

With the couple-years accrued hitherto, appreciable levels of risk over the long-term, especially with anal sex, cannot yet be excluded: a rate of 2.2 per 100 couple-years remains the upper limit (20% over ten years) – though, of course, the risks could prove to be considerably lower than this.   With a view to arriving at a more precise estimation, the MSM side of the PARTNERS study remains ongoing.  So far, however, the news seems to be good.

Aside from its implications for personal decision-making about condom use, the question of the preventative effectiveness of ART could presumably also have relevance for health policy decisions affecting resource allocation that involve determining the relative priority to be accorded to interventions promoting engagement and retention in treatment as against other interventions (e.g. PrEP) (Punyacharoensin & White/STIs/blogNHS kicks PrEP into the long grass/STIs/blogs). The greater the effectiveness of viral suppression through ART as an HIV prevention tool, the better the case for prioritizing interventions to achieve higher targets for engagement and retention in treatment.

Inadequacy of ‘treatment as prevention’ strategy for combating HIV in young US MSM

23 Feb, 16 | by Leslie Goode, Blogmaster

The secret of containing the HIV epidemic is the successful engagement of key populations, we are told. In the case of the US that evidently includes young MSM (YMSM), amongst others.  The scale of the task that confronts public health interventions aimed at prevention in this group is brought out in a recent study by Wilson & Hightow-Weidmann  (W&H) who investigate the behavioural and social correlates of not achieving virological suppression.

If we take the HIV-infected population of the US as a whole, the relative impact on HIV onward transmission of the segment of the population that is infected, but not virologically suppressed (VL+), is critical to the control of the epidemic.  This is on account of the large proportion of total transmissions attributable to it.  One recent modeling study discussed in this blog (Skarbinski & Mermin {STI/blogs) (S&M)) has estimated the proportion of onward transmission attributable to VL+ at 61.3%, as against to 30.2% attributable to the undiagnosed.  (This model also takes account of the greater HIV infectivity of the non-virologically suppressed, through the impact of this is debated (Increased HIV infectivity (STIs/blog)).

So one can imagine the impact on onward transmission of failure to achieve virological suppression among YMSM, given that the proportion of HIV diagnosed who are VL+ is estimated by W&H at c.70%.  Further to this, W&H consider a factor that contributes an additional importance to the low level of viral suppression.  The headline statistic of their study is that the VL+ are considerably more likely to engage in risky sexual behavior than the rest.  Data obtained from the 20 US adolescent clinics that feature in the study show rates of condomless anal intercourse (CAI) for VL+ at 54.7%, as against 44.4% for VL-, and rates of serodiscordant CAI at 34.9%, as against 25%.  Other correlates of being VL+ are drug abuse, daily alcohol use and unemployment, suggesting a pattern or relative social marginalization that would tend to make this group harder to engage.

In their conclusions, W&H highlight the inadequacies of treatment as prevention as the sole risk reduction method.  A more underlying issue would seem to be retention in care and engagement with services, for socially marginalized populations.

Sherer (STIs) analyses the structural factors which make this particularly a problem for the US.  Access to sexual health services has been improved by the Affordable Care Act.  However, there remains considerable debate about how this will affect publically funded STD clinics which seem to have been financially squeezed in recent years.  Also about what role, if any, these clinics will continue to play in the US health system and what the implications of this will be for the accessibility of sexual health services for the socially marginalized (Mettenbrink & Cornelis (STIs); Stephens & Berstein (STIs); Hoover & Gift; Bocour & Shepard).

Increased HIV infectivity in the acute phase of infection may be a less important factor in HIV transmission than we thought

12 Jun, 15 | by Leslie Goode, Blogmaster

Assessing, as far as we can, the preventative impact of ART on HIV transmission dynamics is evidently very important – both to inform judgments about ART initiation (Wayal & Hart (STI); Cohen (STI)), and also, at the policy level, to be able to evaluate the possible preventative gains of ART scale-up (Shafer & White (STI); Boily & Mishra (STI)).   One important piece of the jigsaw is the impact of ART on sexual behaviour.  This has been discussed by a number of recent studies (Wayal & Hart (STI); Hogben & Ford (STI); Shafer & White (STI)).  Another piece of the jigsaw is the impact of ART on HIV infectivity.  Of particular concern here are the relatively high levels of infectivity that occur in the period immediately after infection.  In view of this, investigators have stressed the importance of the earliest possible initiation of therapy, if the full preventative benefits of ART are to be enjoyed (Cohen (STI)).

The recent study, Bellan & Meyers (B&M), addresses itself to this second, important but potentially less easily investigable piece of the jigsaw. They observe that investigators have tended to proceed on the basis of the known relationship between viral load and infectivity. Empirical evidence of relative infectivity of acute versus chronic phases of the infection is practically unobtainable, for various reasons.  For a start, newly-infected individuals are rarely diagnosed in the acute phase and, if infected by stable partners may provide no evidence on onward tradition; if susceptible non-infected partners are at risk, then, clearly, ethical guidelines dictate that further transmission be stopped – not investigated.  According to B&M, most subsequent studies have relied for direct epidemiological measurement of acute phase infectivity and duration on a retrospective cohort in Rakai, Uganda (Wawer & Quinn; Hollingsworth & Fraser). B&M reassess previous analyses of this evidence.  They find significant bias – especially in two areas.  The first has to do with the neglect of the contribution to total risk of couples who were censored from the cohort owing to couple dissolution, loss to follow-up or study termination.  The second concerns the extent to which some of the estimated difference in risk between the acute and chronic phases may reflect heterogeneity in the risk behaviour of those couples entering the study sero-discordant, as against those entering it sero-concordant negative.

The findings of B&M are intriguing. They argue that combined effect of these sources of bias in earlier analysis of the Rakai evidence has been enormously to inflate estimates of relative acute phase – relative to chronic phase – HIV infectivity. B&M estimate the relative hazard of transmission during acute phase at 5.3, the acute phase duration at 1.7 months, and the “extra-hazard months” contributed by the acute phase (a measure adopted by the authors in order to ensure comparability of study results) at 8.4. Previous estimates give levels of increased infectivity due to acute phase which are equivalent to between 31 and 141 hazard months. If the results of B&M are confirmed in subsequent studies, the preventative gains of ART scale-up could be greater than hitherto supposed.

Can financial incentives help address the problem of HIV lost-to-follow-up in the US?

21 Apr, 15 | by Leslie Goode, Blogmaster

An article by Skarbinski & Mermin, discussed in my recent blog, Skarbinski & Mermin (STI/blogs), throws into sharp light the problem of the 45.2% of the HIV/AIDS infected population who are diagnosed but lost to follow-up.  According to their estimate this group are responsible for 61.3% of transmissions.  Various local attempts have been made to address this problem through more “wrap-around” approaches to health care (Bocour & Less (STI/blog)), or through computer assisted self-interviewing (Dombrowski & Golden (STI).  Another approach is the use of financial incentives.  Relatively small-scale and local experiments in various forms of conditional cash transfer have been described by a number of studies recently featured in STIs.  These have aimed, for example, to reduce STIs and pregnancy among Latino youth in San Francisco (Minnis & Padian (STI)), to encourage HIV-infected men to bring their wives for testing in Pakistan (Khan & Khan (STI), to incentivize villagers to remain HIV-free in Lesotho (Bjoerkman-Nyqvist & Svensson (STI)), or to promote syphilis testing amongst indigenous groups in Edmonton, Canada (Gratrix & Talbot (STI)).

Yet what role could financial incentives play in the broader context of mainstream HIV management in the US?  Could they help to address the problem of retention in HIV care across the range of HIV care settings?

A recent US study, HPTN 065 (TLC-Plus) reported at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) addresses this very question.  It involved two-year RCT in a total of 37 testing sites in Bronx and Washington DC., randomized to an intervention and a control arm.  The intervention offered incentives for both linkage-to-care, and viral suppression.  For linkage-to-care, the incentive consisted in the issue to HIV diagnosed of a $25 coupon redeemable when the participant returned to have blood taken for laboratory tests, and a $100 coupon redeemable when he/she returned for test results and to discuss a long-term care plan.  For viral suppression, it took the form of the issue of a $70 gift card to patients taking medication at the end of every three months if they had an undetectable viral load.  Over the duration of the trial, 1,061 coupons were given for linkage-to-care, and 40,000 gift cards were dispensed to 9,153 patients for viral suppression.

Disappointingly, no overall increase was observed in intervention compared to control settings, either in linkage-to-care or in the proportion of patients achieving viral suppression.  However, the intervention brought significant improvements in viral suppression and continuity of care (completion of four out of five possible visits for tests in last 15 months) within certain specific care settings.  In particular, these were: care settings where <65% of the patients were achieving viral suppression at the start of the study (improvements of 10% overall, 13% as measured in the last three months of the study); small-scale care settings (improvements of 13% as measured in the last three months, and of 19% overall in continuity of care).  The investigators conclude that there may be a role for financial incentives in specific health care settings.

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.

Responding appropriately to differentials in HIV care outcomes – are local answers needed?

12 May, 14 | by Leslie Goode, Blogmaster

The recent discovery of the preventative potential of anti-retroviral therapy (ART) (STIs/blog/modelling ART impact)  throws into sharp relief the challenge represented for the US by the very inadequate proportion of its 1.2 million HIV+ citizens (<30%) who are virally suppressed.  Nunn & Mayer  use new geographical mapping tools to bring home forcibly the epidemiological dimension of the problem by visualizing the association which HIV+ incidence/mortality show with social status and ethnicity as reflected in residence.  The picture that emerges is of an enormous concentration of the problem in certain very circumscribed neighbourhoods.  To give just one example of what is best conveyed in the diagrams (figures 1 & 2), age-adjusted death rates rise from <11.2 per 1000 people living with AIDS (PLWHA) to 19.4-32.5 per 1000 PLWHA as one passes from a predominantly white neighbourhood with large gay population and high rates of HIV/AIDS (≥2142 per 100,000 population) to the predominantly Afro-Caribbean neighbourhood of Harlem.

For Nunn & Mayer (N&M), these visualizations raise the question whether either (1.) the allocation of resources to metropolitan areas, or (2.) the nature of the strategies employed by public health interventions, reflects the very geographically focussed nature of the problem of HIV/AIDS incidence and mortality.  Their response to the epidemiological dimension of the problem revealed by their mapping tools is to urge the importance of implementation research as a vital component of HIV initiatives.

N&M’s emphasis on viraemia suppression, rather than just HIV incidence, accords well with their insistence of the epidemiological importance of the local dimension.  Retention in care is a factor that is presumably amenable to initiatives at local level – whereas HIV incidence may owe much to transmission through sexual contacts external to the community (STI/blog/Grabowski & Gray).

Their message is in line with increasing public health interest over recent years in “program impact evaluation methods that take account of the complex interactions among interventions and between intervention packages and the context into which they are introduced” (STIs/Aral & Blanchard).  There is surely a strong argument in favour of designing interventions to take place within an evaluative framework allowing a reflection on the kind of program mix likely to be most effective in a given context.  On the other hand, N&M may be in danger of undervaluing the potential of interventions of a non-localized character that act on the socio-economic determinants of the HIV problem, and especially non-retention in care – for example, the wider provision of medical insurance (STI/blogs/ObamaCare).  It would be interesting to see how far a geographical mapping of the incidence of other health problems in New York or Philadelpia coincided with N&M’s mapping of HIV/AIDS mortality.  How far is the effect of “micro-epidemics”, conjured up by epidemiological language, just a reflection of socio-economic determinants that produce identical results wherever they happen to be present?



Are African HIV epidemics sustained by exogenous introduction of infection?

24 Apr, 14 | by Leslie Goode, Blogmaster

What is the relative importance of exogenous and endogenous transmission in sustaining HIV epidemics?  In a study of HIV sub-type distribution in the Middle East, Mumtaz & Abu Raddad (STIs) stress the role of multiple exogenous introductions, as evidenced in the wide diversity of genetic sub-types present in most countries.  At a more local level, the answer to our question will, of course, depend on how “exogenous” and “endogenous” are defined – and may have little meaning where we are concerned with the  HIV transmission networks in gay communities that are the object of a number of studies featured in STIs (Potterat & Muth (STIs); Drumright & Frost (STIs)).  Yet, the situation is surely very different when it comes to the kind of geographical communities that are constituted by the studies designed to evaluate the local epidemiological effect of ART deployment – such as HPTN 071 study in Zambian and South Africa.  Here, the location of the communities targeted by the trial establishes a clear boundary, and gives meaning and importance to our question.  How far are the preventative effects of ART coverage within the community likely to be neutralized by introductions that are exogenous to it?

Grabowski & Ray, in recent analysis of data deriving from the Rakai Community Cohort Study, Round 13 (2008-9), has sought to give some insight into the spatial dynamics of HIV transmission, through investigating a cohort of 14,594 individuals in 46/50 communities in the Rakai region of Uganda.  Its goal: to determine the relative epidemiological importance, in this particular context, of transmissions within the household, across the boundary of the household but within the community, and across boundary of the community.  A difficulty foreseen by the study is that transmissions from outside tend to be less easily traced.  The researchers have therefore adopted a multi-faceted approach:  an analysis of the spatial clustering (1) and a phylogenetic analysis (2) are complemented by an analysis of individual partnerships on the basis of data supplied at interview (3).  The phylogenetic analysis investigated the relationship of phylogenetic clustering (in terms of genetic closeness in the gag and env genes) to geographical location.

The findings of the study suggest the relative importance of repeated introductions of HIV across the community, and indeed, regional boundary, as against the importance of onward transmission through intra-community networks (other than those within the household).  The spatial clustering analysis shows very strong household clustering (RR of HIV+ person, as opposed to non-HIV+ person, being in the same household as another HIV+ person 3.2, and RR 10.8 for incident cases), but practically no clustering outside the household.  The phylogenetic analysis identified 95 clusters, of which 53 (55.8%) spanned households; of these 53, 38 (71.7%) crossed community boundaries; of the 38, 18 (47.4%) spanned geographic regions.  The individual transmission analysis shows 39.5% of new cases from extra-household partners; of these, 62.1% were from partners outside the community; of these (where location of partner was known) 50% outside Rakai district, and geographically dispersed throughout Uganda.

Taken together, the three analyses seem to offer a consistent picture. The surprise is the importance of more exogenous, as against more endogenous, transmissions, with intra-community transmission (excepting within the household) not playing the role that might have been expected.  Of course, these findings may not be generalizable to other sub-Saharan, still less non-African, settings.  But they do raise pertinent questions  to any attempts to evaluate the preventative possibilities of localized ART interventions.


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