Bob Roehr: The changing complexity of HIV vaccine trials

BangkokSuccesses in treating and preventing HIV infections are making it more difficult, more expensive, and perhaps more uncertain to plan and conduct HIV vaccine trials in the countries most affected by the epidemic. That is because those trials are driven by the endpoint of new infections, which are being reduced.

The worldwide incidence of new HIV infections peaked in 1996 and has declined since then by about 20% to about 0.8% a year. But the prevalence of infection has increased because more people have access to treatment and are living longer, thanks largely to programs like PEPFAR, run by the US government, and the Global Fund to Fight AIDS, tuberculosis, and malaria.

More people have access to treatment than ever before and revised WHO/UNAIDS guidelines recommend starting treatment earlier, at a 350 CD4 count, though many countries have not fully implemented that guideline. It means that there are fewer people walking around with higher viral loads that correlate with increased risk of transmission and new infections.

Thailand was so successful with its early HIV prevention campaigns, which were focused around increased use of condoms, that it has become impossible to conduct vaccine trials within the general population. Much of that activity has shifted to sub-Saharan Africa, and what remains in Thailand is in high risk populations such as men who have sex with men (MSM), female sex workers, and injection drug users.

And now there is a broader array of prevention interventions with demonstrated effectiveness that have become or may soon become more widely available. Voluntary circumcision is finally being rolled out on an expanded basis. The most recent studies have shown that it can have a 70% effectiveness rate when the impact of herd immunity is taken into account.

A successful microbicide trial has led to the hope that such a product might become available within a few years. And PrEP (pre-exposure prophylaxis), using antiretroviral drugs to prevent infection, has demonstrated its efficacy and is being rolled out in pilot programmes in high risk populations such as serodiscordant couples and MSM.

The net effect of these changes, or at least their potential which must be planned for in conducting vaccine clinical trials, is to reduce the incidence of new infections and lead to larger, longer clinical trials.

“If you halve the incidence, you have to double the sample size” of the study, said James Kublin, with the HIV vaccines treatment network. Extending the length of the trial can also help to compensate for lower incidence of infection, but the dropout rate tends to increase with time and that raises its own set of issues.

The US National Institutes of Health has been the largest single source of funding for HIV vaccine research, $632 million or 72% of all spending, according to the latest annual report from AVAC, an international charity that advocates for HIV prevention research. But its budget over the last several years has barely kept pace with inflation. Given the current fiscal crisis that the US and much of the world are facing, that situation is unlikely to improve and may well deteriorate.

Carl Dieffenbach, NIH’s principle administrator for HIV research, was grateful that there have been so many advances in the prevention field in recent years, even if they do require further study and funding to figure out how best to use those tools.

He said the impact of interventions such as circumcision, microbicides, and PrEP will depend in large part upon what host countries decide to do as their national policies. “But there are a series of contingency plans that are very robust, that indicate we can do these trials, assuming a level NIH budget.”

The NIH and its partners are moving forward with clinical trials in Thailand and Africa that build upon the surprising success of the Thai RV144 study, which was announced in 2009.