Researching the use of ARVs for Treatment *and* Prevention in Key Populations

“Key populations* have high burdens of HIV with low access to services — and in way too many countries, they are the last people in line. So when we think about changing the guidelines with increasing access to care, that, it seems to me, is the fundamental issue that we need to address. No one should be excluded from antiretroviral treatment (ART) access because of substance use, because of sexual orientation, gender identity or sex work,” said Professor Chris Beyrer, Director of Johns Hopkins Center for Public Health & Human Rights (as well as its Fogarty AIDS International Training and Research Program) — and President-elect of the International AIDS Society (IAS). “Those are very fundamental principles I think we would all agree with, but they are, remarkably, commonly abrogated in much of the world.”

Professor Beyrer was speaking at a global consultation, co-sponsored by IAS and the World Health Organisation (WHO) on 29 June 2013 — held one day before the start of to the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, which took place in Kuala Lumpur, Malaysia from the 30^th of June to the 3^rd of July.

One of the big events at the IAS conference was the release of WHO’s new 2013 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treatment and Prevention. These guidelines take a number of bold steps that, if implemented widely, would dramatically increase access to antiretroviral therapy to millions of additional people across the globe. These include, among other things, recommendations to start treatment earlier: when a person living with HIV has a CD4 cell count of 500 or below (rather than 350), and even, in the case of children under the age of five and in people with concurrent Hepatitis B (HBV), or tuberculosis (TB), a recommendation to offer universal ART regardless of the CD4 cell count — in order to reduce the high risk of mortality and morbidity in these populations.

Additionally, the guidelines recommend offering universal ART regardless of CD4 cell count to HIV-positive pregnant women and to people living in people living with HIV who have a partner who is HIV-negative, largely to capitalise on the benefits that ART offers for prevention of HIV transmission — as demonstrated by HPTN 052 and other studies.[1]

“Many people will be very happy with our guidelines,” WHO’s Dr Meg Doherty said at the IAS conference pre-meeting. However, “many will find that there are missing elements to our guidelines.”

Among the elements that could be deemed missing? Namely, that despite the importance of key populations (defined as: men who have sex with men, transgendered persons, people who inject drugs, and sex workers) in the HIV epidemic, the guidelines explicitly state that WHO cannot at this time recommend that individuals from the key populations receive a universal offer of ART irrespective of CD4 cell count (unless they happen to also have TB, HBV or are pregnant). This is because the guidelines review committee did not feel that there was enough consistent high quality evidence from randomised and observational cohorts to make a recommendation regarding the role of ART for treatment and prevention in these groups — at least not yet.

Ergo, the need for this global consultation, titled: “Maximizing the Treatment and Prevention Benefits of Antiretrovirals for Key Populations: What Additional Evidence is Required?”

The meeting brought together many of the leading experts in HIV/AIDS and implementation research, public health and programme specialists, policymakers, as well as civil society groups and people living with HIV to share information on current research efforts and to discuss the challenges and opportunities for implementation research to provide what Dr Doherty called, “the missing evidence WHO would need to further expand treatment access and treatment availability for key populations.”

“This meeting is to help us set the tone for the next two to three years of what sort of research needs to be done; what sort of evidence needs to be developed; and to help inform the WHO and other global policy makers of the next steps,” she said.

The scientific landscape on key populations

Professor Beyrer presented some data illustrating the high and often profoundly disproportionate burden of HIV among key populations.

• There is an enormous burden of HIV in people who inject drugs across Eastern Europe and Central Asia, where more than twenty per cent are HIV-positive.[2] Not coincidentally, this is “the global region where HIV is still expanding and largely because of lack of access to services for these folks,” said Prof Beyrer

• Women who sell sex are 13.49 (95% CI 10.04-18.12) times more likely to be living with HIV than other women of the same age in the same populations — even in the regions with the highest HIV burdens for women in sub-Saharan Africa

• In the 15 countries where data are available, the burden of HIV is even more disproportionate among male to female transgendered persons. In a pooled analysis, the increased risk for HIV infection among transgendered women compared to other people of reproductive age was 48.8 (95% CI 31.2-76.3)

• Similarly, among MSM, in a comparative analysis across all global regions where there’s data the most affected region is actually sub-Saharan Africa with a hugely disproportionate burden in MSM, while the most markedly affected are the Caribbean, which is where there are the most repressive and restrictive anti-gay and homophobic laws.[3]

Additionally, globally, despite the era of antiretroviral access, the incidence data show continued expansion among MSM— especially in the last two years.

“So treatment as prevention – as now it is being delivered, despite tremendous impacts we are seeing in lots of generalized epidemics, is not delivering on it’s promises for men who have sex with men,” said Prof Beyrers.

“Of course, this doesn’t have to be the way it is,” Prof Beyrers continued as he showed data from France showing that the country has achieved an extremely low HIV incidence rate among people who inject drugs the implementation of a combination package of interventions (i.e. treatment on demand, needle syringe exchange and good ARV access for drug users). “So this is really a problem which we can solve.”[4]

But the trajectory of HIV incidence in MSM in France is going in the other direction.

“So when we think about key populations, one size is not going to fit all, there are different challenges for these different populations and we have to be subtle about that in our deliberations,” said Prof Beyrers.

Even so, recent data from KwaZulu-Natal show tremendous declines in new infections in areas where the antiretroviral treatment prevalence among the general population of people living with HIV is above 40 per cent (Tanser F et al. Science). Additionally, “there is good evidence that ARVs can play real roles in controlling epidemics in HIV with injecting drug users, and some evidence for the other key populations, that combination prevention and treatment are clearly going to be needed for all of these populations.

Looking more closely at the role for treatment in MSM HIV epidemics, however, the picture is somewhat more clouded.

In HPTN 052, there were thirty-seven serodiscordant male-male couples—none had a linked transmission though two had unlinked transmissions (from sex outside of the relationship). The biological plausibility for ART as prevention in MSM HIV discordant couples is high however. Nevertheless, network/population level impacts of treatment for prevention are unclear. In five ecologic reports, findings were mixed for MSM predominant epidemics — the most positive data came out of San Francisco.

There are several other factors compounding the issue in MSM: first, it is unclear what proportion of HIV transmission occurs in couples — estimates range from one third to two thirds. There is a also much higher risk of HIV transmission per act/per partner associated with anal sex. A higher proportion of infections in MSM networks appear to be due to recent infections which may not be detected and treated by universal treatment and prevention programmes. Also, in the US and lower middle income countries, the highest HIV incidence among MSM is in the youngest age strata — who are least likely to be in care and to access ART. In fact, across the globe, still in 2013, most men do not initiate treatment until their CD4 cell count is below 300. And on top of all that, perhaps because HIV treatment means that HIV is no longer a death sentence, there has been an increase in risk taking behaviour, evidenced by increases in other STI in the USA, UK, France, Australia.

Clearly, more research is needed to, at the very least, to help inform MSM about what the best choices may be for their own health and the health of their partner regarding antiretroviral drugs for treatment and prevention.

Further posts to come

Subsequent presentations at the consultation addressed the community and ethical perspectives of universal ART for treatment and prevention in key populations; reviewed the implementation questions for maximizing the treatment and prevention benefits of ART in two countries, Brazil and Vietnam.

Representatives from the US National Institutes of Health, PEPFAR, AmFAR, the Elton John Foundation presented scientific updates on work they are doing among key populations and described funding opportunities and on-going research collaborations.

Finally, there were detailed presentations looking at proposed interventions to improve engagement of key populations as part of the ART cascade, a review of what is known about the transmission dynamics in key populations (including acute infection, on-going research), as well as programmatic monitoring and evaluation of ART impact (incidence assays, community viral load, mortality, morbidity, and other key metrics).

A more complete report on these presentations and the rich discussion that followed will be published on the treatmentsciencewriters.com site shortly — all of which helped inform the development of a list of research questions.

Identifying and rank-ordering research questions:

At the start of the meeting, Dr Doherty had explained that during a guideline review process, WHO looks for evidence — published in the medical literature — that comes from either randomized controlled trials (which receive the most weight) and /or observational data. However, “we think at this point in time, there may or may not be the opportunity to do randomized controlled trials in key populations.”

Consequently, WHO’s HIV Department is trying to be more proactive by developing research agendas in order to generate the sort of evidence they need in their review.

So the consultation participants were told they would be asked to help identify and prioritise a list of research questions which will eventually be used to develop a 5-year research agenda that could generate high quality evidence on the treatment and prevention benefits of ART use by individuals from key populations with CD4 counts higher than 500 which could then better inform future guidelines revisions.

Each question was then to be graded, based on defined criteria adapted from the Child Health and Nutrition Research Initiative (CHNRI).[5] The CHNRI method had previously been adapted by WHO to define priority research questions for TB-HIV in HIV-prevalent and resource-limited settings. In this case the criteria of effectiveness of an intervention, its deliverability, answerability, possible effect on equity, and for its maximum potential for disease burden reduction.

Unfortunately, due to time restraints, participants were unable to score the questions identified over the course of the meeting. That process is now taking place online, with a deadline of 12 August, 2013.

Again, we will be posting other pieces on presentations from this meeting here, as well as updates on those questions and the grading process, so please stay tuned to treatmentsciencewriters.com site.