Is treatment as prevention ready to roll out, or do we need to know more?

Major randomised studies of the impact of antiretroviral treatment expansion on new infections are getting underway, and should provide important evidence to guide further implementation, researchers reported at the International Association of Physicians in AIDS Care summit, Controlling the HIV epidemic with antiretrovirals, in London this week.

However, some delegates attending the meeting, which comprised physicians, community advocates, donors and programme managers, argued that expansion of antiretroviral treatment in order to achieve an impact on new infections should not be held back by the need to conduct further research.

Prof. Julio Montaner of the University of British Columbia, Canada, a long-time advocate of the use of antiretrovirals for prevention purposes, argued passionately that the available evidence obliged donors, programme managers and physicians to move swiftly to make treatment more widely available.

“People have been talking about [another] 1996 moment. Please remember what 1996 was like. We had early results from two clinical trials, we didn’t have clinical endpoints, viral load hadn’t been validated, [but] we put it all together and flew by the seat of our pants. Morbidity and mortality declined by 90% within a year. My concern is, we have the evidence today – what are we going to do to expand treatment to everyone who is eligible?”

However, when questioned about perceptions of treatment as prevention in their own countries, 51% of delegates said that medical providers were unsure and wanted to see more data before implementing it, and 43% of delegates at the meeting questioned through an electronic polling system said that they thought more research was needed before implementation.

Prof. Montaner told the meeting: “100% coverage of everyone who is eligible is non-negotiable”, but debate over who should be eligible persists despite evidence of the impact of antiretroviral drugs on transmission from the HPTN 052 study.

“HPTN 052 showed impact at an individual level, but we don’t know the population effectiveness of treatment as prevention,” said Dr Sarah Fidler, of Imperial College, London, an investigator on a planned study of treatment as prevention. The HPTN 052 study showed that when treatment was commenced at a CD4 count above 550 by the HIV-positive partner in a serodiscordant relationship, transmission to partners was reduced by 96%.

Dr Fidler noted that ecological studies in specific locations, such as San Francisco and the Canadian province of British Columbia have shown a correlation between expanded treatment coverage and a decline in new HIV diagnoses at a population level. Research in KwaZulu-Natal province, South Africa, also shows an association between the expansion of antiretroviral coverage and a decline in the hazard of HIV acquisition between 2004 and 2011.

However, each of these pieces of evidence is drawn from a setting where treatment was being provided under prevailing guidelines, without aggressive efforts to enrol everyone eligible onto treatment. The majority of infections are passed from undiagnosed individuals, unaware of their HIV status, and it is likely that the majority of infections occur before individuals are eligible for antiretroviral treatment under current guidelines. Proposals for wider treatment, at CD4 cell counts above 350, coupled with efforts to achieve near-universal knowledge of HIV status through community HIV testing campaigns, have never been evaluated in a real-world setting.

For example, said Dr Fidler, we don’t know the likely uptake, or the impact on already stretched HIV services (although it is worth noting that pilot campaigns run by the Kenyan Ministry of Health, in which linkage to antiretroviral treatment was one part of a larger package of interventions offered as a result of HIV counselling and testing, achieved uptake above 80% in Nyanza province when evaluated in 2008-09). Long-term retention and adherence are also a concern to some, although others point to evidence showing that where community support services are robust, retention and adherence are correspondingly stronger.

There is also uncertainty regarding the long-term benefits and risks for the individual of earlier treatment: is the risk of toxicity or drug resistance as a result of a number of years of extra treatment sufficiently offset by a long-term health benefit in people who are otherwise healthy apart from HIV infection? A long-term randomised study, START, is currently evaluating the question of whether starting treatment at a CD4 count above 500 results in superior outcomes when compared to starting treatment at a CD4 count of 350, but is not expected to report results for five years.

Wider use of treatment as prevention also poses a range of uncertainties regarding social factors such as changes in HIV stigma as a result of wider HIV testing and wider treatment coverage, coercion onto treatment and disinhibition of sexual behaviour.

Several major studies to address these questions are planned. Dr Fidler outlined her team’s study, PopART, or HPTN 071, which is being supported by the Gates Foundation, OGAC, NIH and NIAID, to look at the population impact of community-wide 'test and treat' campaigns in Zambia and South Africa. The study will recruit 52,500 people in 21 communities. The study will evaluate the impact of three strategies on HIV incidence over a two-year period:

• Universal voluntary HIV testing and immediate ART for everyone diagnosed with HIV.

• Universal voluntary HIV testing and treatment for everyone with CD4 counts below 350.

• Standard-of-care provision of HIV testing and antiretroviral therapy according to prevailing national guidelines.

Communities, or clusters, each with a population of 30 to 60,000 will be randomised to one of these treatment strategies.

Sarah Fidler said that the trial’s designers were still debating whether a standard of care arm would be necessary, given the speed at which the standard of care is evolving in many settings. For example, the inclusion of a standard-of-care arm would provide useful information on the impact of universal HIV testing in comparison to existing practices, but if testing campaigns become more extensive, it may not be necessary.

In addition to a standard package of prevention interventions that will include syndromic treatment of sexually transmitted infections, condom distribution, and counselling, the trial will also offer circumcision to all men who test negative, and 'community HIV providers' will deliver counselling, testing, linkage to care and support on treatment.

PopART will also evaluate sexual risk behaviours, HIV-related stigma, community viral load (the average viral load of everyone with HIV in the community), drug resistance, CD4 cell count, mortality, TB prevalence and the uptake and cost-effectiveness of the interventions.

Prof. Victor de Gruttola of Harvard University School of Public Health described another cluster-randomised study planned for Botswana that will randomise communities either to standard-of-care or universal testing, with an offer of treatment for all people with a viral load above 10,000 copies/ml. This threshold is associated with a significantly enhanced risk of HIV transmission, so treating all those with viral loads above this level might be expected to have a greater impact on incidence. In circumstances where resources for expanding treatment beyond currently eligible groups might be limited, this strategy – if proven effective – could help to target limited resources. Given that viral load is also a driver of CD4 decline, this strategy would also discriminate in favour of people at higher risk of CD4 decline, and represents a cut-off point currently being evaluated for point-of-care viral load tests and viral load testing on dried blood spots.

The study will also offer a combination prevention package that aims to pursue the highest possible coverage for male circumcision and prevention of mother-to-child transmission interventions. The study will follow participants for four years to assess the impact on HIV incidence, and will also attempt to investigate the sexual networks in which HIV is being transmitted in order to learn more about which interventions are not working, and where.

Asked whether studies that test combination prevention in addition to antiretroviral therapy are necessary, Prof. de Gruttola said: “We’re better off throwing everything we have at the epidemic, and then learning whether we can scale back. I would hope that approach would save time.”

Several other cluster-randomised studies are planned, or have already begun enrolling:

• The Iringa study, developed by Johns Hopkins University and sponsored by USAID, will compare the standard of care with an intensive HIV counselling and testing campaign and treatment for everyone with CD4 counts below 350. This trial will seek to maximise uptake of other prevention interventions such as male circumcision and STI treatment in both arms.
• The TasP trial, sponsored by the French HIV research agency ANRS, is already conducting a feasibility study in KwaZulu-Natal for a much larger trial that will compare the impact on HIV incidence of immediate ART for everyone with HIV, to treatment at a CD4 count of 350. Once again, an intensive combination prevention package will be delivered to communities in both arms.
• In the United States, the HPTN 065 study is evaluating TLC+ – testing, linkage to care, plus treatment – in a number of communities in the US. The study will evaluate the success of each element by offering it at a selection of the participating sites in Washington DC and the New York borough of the Bronx. The overall impact will be evaluated through epidemiological surveillance data, and compared with similar data from four non-participating cities.

Once fully enrolled, these studies will take between two and four years to begin to produce evidence. The more immediate challenge, said Prof. Montaner, is to convince political leaders that universal access to treatment by 2015 – a United Nations commitment – remains a moral obligation. He praised recent US government commitments to end AIDS and paediatric HIV, but he concluded: “We need President Obama and those political leaders who got it to move those political leaders who don’t get it towards universal access. We are not talking about decades [for spending on treatment to show an effect], we are talking about one political lifetime.”