Antiretrovirals (ARVs) used to treat HIV infection have proved to be powerful tools for HIV prevention. Scientific evidence shows that early treatment of ARVs in HIV-positive people dramatically reduces their risk of transmitting the virus to their partners.1 Promisingly, recent studies show that ARVs can also be used as prevention in HIV-negative people. However, there is much to learn about this new method of prevention intervention and even successful study results raise many questions that need timely attention from stakeholders if the promise of research is to be turned into practice.
In November 2010, the first ever pre-exposure prophylaxis (PrEP) effectiveness data were published in the New England Journal of Medicine. These data came from a multi-national study known as iPrEx. It showed that a PrEP regimen of once-daily TDF/FTC (marketed as Truvada), a drug approved for use in combination therapy to treat HIV, reduced the risk of HIV infection by approximately 44% in HIV-negative gay men, other men who have sex with men (MSM), and transgender women.2 Participants in the TDF/FTC arm of the study who better adhered to the study regimen (as measured by levels of drug detectable in the blood of these participants) showed even higher rates of protection against infection. All trial participants also received a comprehensive HIV prevention package, including testing for other sexually transmitted infections (STIs), risk reduction counseling, and condoms.
The results of the iPrEx trial built on momentum from the CAPRISA 004 trial, which proved the efficacy of a 1% tenofovir gel, called a microbicide. This study, conducted in heterosexual women in South Africa, showed that the gel reduced risk of HIV by approximately 39%. The field of ARV-based prevention saw two proof-of-concept results in less than six months. And while each of these data sets was limited to its study population and respective regimen, the field was buzzing in anticipation of the results of other ARV-based prevention trials.
Data from additional PrEP effectiveness trials were not expected until late 2012 or early 2013.3 Thus, the field of HIV prevention was caught off-guard when in April of this year a study, known as the FEM-PrEP trial, closed ahead of its anticipated end date.
The FEM-PrEP trial was designed to study the safety and effectiveness of once-daily oral TDF/FTC for HIV prevention in heterosexual women at sites in Kenya, South Africa, and Tanzania. It was implemented by FHI, a global health and development organization, in partnership with local research centers and funded by the U.S. Agency for International Development (USAID), with early funding from the Bill & Melinda Gates Foundation.
After a scheduled meeting of its independent data monitoring committee (IDMC), it was revealed that over three quarters of the anticipated HIV infections had occurred in the study, and there was no difference in the number of infections between the group receiving TDF/FTC and the group receiving a placebo pill. The trial team concluded that continuing the trial to its scheduled end in an attempt to demonstrate effectiveness was futile in these circumstances.
Detailed analyses are underway to help understand this outcome. However, this does not change the effect seen in the iPrEx trial, which showed that daily oral TDF/FTC was effective in reducing HIV risk in MSM.
It is still unclear whether or not oral TDF/FTC works to prevent HIV in women. Daily oral TDF/FTC was not effective at reducing risk of HIV infection in women participating in the FEM-PrEP trial, but researchers are uncertain whether this result was due to a) low adherence to the study product by the women in the trial, b) whether TDF/FTC does not prevent HIV in the trial populations where it was conducted, c) whether TDF/FTC given in this regimen simply does not prevent HIV in women, or d) another unknown factor.
For PrEP to be effective in preventing HIV infection during sexual exposure, the right amount of drug has to be in the right place (i.e., the vagina or the rectum) at the right time (before or perhaps shortly after sexual contact). Currently, it is unknown what regimen will provide the drug levels needed for protection in either the vagina or the rectum. Researchers have not yet identified a threshold drug level for providing protection, although one may be identified over the course of future trials and related research. However, one possible explanation for the FEM-PrEP results is that the TDF/FTC levels in the vagina that resulted from daily oral pill use were inadequate to prevent HIV infection. In the CAPRISA 004 microbicide trial, 1% tenofovir gel did reduce women's risk of HIV infection. This gives evidence that if enough ARV is present in the vagina at the time of exposure, ARV-based tools can work for women. Exactly which tools are effective -- oral versus topical medication, vaginal ring, or long-acting injectable dosing -- remains to be seen. Additional research is needed to help answer these questions.
In addition to the ongoing research to help determine the effectiveness of oral PrEP and ARV-based microbicides in women, there are a range of follow-up activities that have been spurred by the positive results of iPrEx showing that daily TDF/FTC can reduce risk in HIV-negative MSM.
The iPrEx open-label extension (OLE) study is a continuation of the iPrEx study designed to provide additional information about the safety of PrEP and the behavior of study participants when PrEP is taken over a longer time period. Importantly, the study may also shed light on whether or not participants behave differently during sexual contact knowing the intervention is partially effective. The study began in June 2011 and will follow participants for 72 weeks. It is open to all iPrEx trial participants, and HIV-negative participants will be offered daily TDF/FTC. There will be no placebo arm in this study.
Advocates are also pushing for demonstration projects for PrEP in MSM in the U.S. and elsewhere. These projects would look to test a pilot program in a small area or population to look at how PrEP would be used in a "real world" setting, outside of a clinical trial setting. They can provide answers to many outstanding questions (e.g., What if PrEP were offered at local health clinics? What would that program look like? How would people access it? What is realistic for testing frequency?), as well as provide essential data for PrEP use and implementation in a range of settings and populations. The U.S. National Institutes of Health is looking into the possibility of funding demonstration projects in a handful of U.S. cities.
At the same time, the U.S. Centers for Disease Control and Prevention (CDC) is working on Public Health Service (PHS) guidelines for PrEP. In January, the CDC published interim guidance on PrEP for health care providers who may want to provide PrEP to high-risk MSM.4 A draft of the PHS guidelines is expected to be ready for public comment in late 2011.
It was also made public earlier this year that Gilead, the pharmaceutical company that produces Truvada (TDF/FTC), is planning to file an application with the U.S. Food and Drug Administration (FDA) for a prevention indication.5 If approved, this could help with financing and monitoring of TDF/FTC as PrEP. Currently, Truvada is only available via a prescription for off-label use.
ARV medications that are powerful life-saving treatment for millions of HIV-positive men, women, and children are now showing great promise for HIV prevention. Development of and access to these new prevention tools should be prioritized among federal governments, public health agencies, and other stakeholders to bolster current prevention options and curb the global HIV epidemic.
Deirdre Grant is senior program manager, AVAC.