Dear Advocate,
This update is the first in a series of three summaries highlighting biomedical HIV prevention research data presented at the International AIDS Conference, which took place last week (July 18-23) in Vienna, Austria. This first update focuses on antiretroviral (ARV)-based prevention findings; the next two summaries, one on AIDS vaccine research and one on male circumcision for HIV prevention, will be released the week of August 2.
The AIDS 2010 conference website contains a wealth of materials including posters, slide sets with audio and abstracts. While AVAC's post-Vienna update series focuses on biomedical prevention research, the conference was marked by its emphasis on human rights as the foundation for an effective AIDS response. No biomedical strategy, however effective, will have a lasting impact without concurrent action on stigma, criminalization, legal rights and evidence-based, human-rights focused approaches.
ARV-based prevention was one of the major headlines of this meeting, with the history-making release of data from the CAPRISA 004 trial of the 1% tenofovir gel microbicide. AVAC's publication, A Cascade of Hope and Questions: Anticipating the results of ARV-based prevention trials, released prior to the announcement of these results, provides background on this trial. The week of August 9, we will publish an updated version incorporating these and other new data released in Vienna. In addition, our next issue of our quarterly newsletter, Px Wire, will focus on some of the crosscutting themes that emerged around treatment as prevention focused on using ARVs in HIV-positive people to reduce their risk of transmission--another topic that was central to this memorable conference.
CAPRISA 004
Standing ovation
As AVAC reported from Vienna, the conference reached a pinnacle of hope and excitement on its second full day, with the presentation of data from the first ARV-based microbicide effectiveness trial, known as CAPRISA 004. The trial, conducted by South African researchers with support from USAID and the South African government, enrolled 889 South African women. It found that 1% tenofovir gel use lowered HIV risk by approximately 39 percent. The data were presented in a special session and were greeted with a standing ovation from a crowd that filled the room to capacity, and spilled over into two additional viewing rooms. The excitement stemmed both from the unprecedented evidence that a microbicide could reduce women's risk of both HIV and HSV-2 infection, and from the strength of the data, which showed consistent evidence of protection regardless of which type of statistical analysis was used. View the webcast here, and links to other resources, including the publication of the data in Science here.
Steps in the search for a correlate
At the special session where the results were released, Angela Kashuba of University of North Carolina, Chapel Hill, presented data on levels of tenofovir in samples obtained from some of the CAPRISA 004 participants. The samples, which included blood, cervicovaginal fluid and genital tract biopsies, came from women who acquired HIV and those who remained HIV-negative during the study. Higher concentrations of tenofovir in cervicovaginal fluid were associated with lower rates of HIV seroconversion. Put another way, women using 1% tenofovir gel who remained HIV-negative during the study had higher concentrations of tenofovir in their cervicovaginal fluid and vaginal tissue than women using 1% tenofovir gel who became HIV infected. Kashuba noted that tenofovir levels in cervicovaginal fluid could be a promising marker for measuring adherence to gel use. Overall, there were very low levels of tenofovir (less than 1 nanogram per milliliter) detected in the blood in both HIV-positive and -negative participants. This is encouraging in terms of concerns about tenofovir-resistant virus emerging among women who become HIV infected while using 1% tenofovir gel.
Up close and personal
A more personal view of the CAPRISA 004 findings came at the research team's press conference on Tuesday afternoon. The team screened a brief video called Gabi's Gift, which highlighted one of the trial participants on her journey through the study. In the final moments of the press conference, Hilary Beard, a journalist working with the Black AIDS Institute, asked what the gel tasted, smelled, felt and looked like. By way of response, CAPRISA 004 co-principal investigator Quarraisha Abdool Karim handed Beard a filled applicator of the gel. As Beard dispensed a small amount of gel into her own palm, members of the media began to stream towards her, extending their hands for a sample. Some smelled it, others tasted it, and others rubbed it between their hands--a memorable reminder that, ultimately, use of a microbicide will depend as much, if not more, on the sensory, sensual and highly personal experience of individual women and men as it will on the science.
Safety Data on Oral PrEP
US PrEP safety study
In a late-breaker session on the last day of the conference, Lisa Grohskopf from the US Centers for Disease Control and Prevention (CDC) presented preliminary findings from a safety and behavioral study of daily oral tenofovir among gay men and other men who have sex with men in the US. This trial was not designed to evaluate the effectiveness of PrEP. (For slides and audio of this presentation visit http://pag.aids2010.org/session.aspx?s=643.)
The trial enrolled 400 HIV-negative men and randomly assigned them to one of four arms. Participants in two arms of the study received either tenofovir or placebo (a tablet without active medication) immediately upon enrollment, while participants in the remaining two arms received either tenofovir or placebo after nine months of enrollment. This design allowed researchers to compare risk behaviors among those taking a daily pill and those not taking pills. Neither the research team nor the participants knew who was receiving placebo or tenofovir. Additional data analyses are still underway, however the preliminary data show no significant differences in rates of HIV risk behavior among men who were taking the pill at the beginning of the study, compared to those who started at month nine after enrollment. The presentation emphasized that all of the men in the study received ongoing risk-reduction counseling that incorporated messages about PrEP being an unproven, experimental strategy. This intensive prevention intervention also likely influenced participants' behaviors.
The trial also gathered information on safety. There are extensive data on tenofovir as part of combination therapy for HIV-positive people, and, while the drug is generally safe and well tolerated, there have been reports of uncommon, but more serious health problems related to kidney function and reductions in bone mineral density. Trials of PrEP in HIV-negative people are monitoring for these and other side effects. The CDC safety trial reported no serious adverse events on the basis of its preliminary analysis.
Safety and feasibility of intermittent PrEP
Two posters presented preliminary data from two small safety, adherence and feasibility trials of intermittent PrEP using tenofovir/emtricitabine (TDF/FTC or Truvada). The trials, known as IAVI E001 and E002, were conducted by the International AIDS Vaccine Initiative (IAVI) and its partners in Kenya and Uganda.
Safety and adherence to intermittent emtricitabine/tenofovir (FTC/TDF) for HIV pre-exposure prophylaxis in Kenya and Uganda (e-poster available at http://pag.aids2010.org/PDF/2521.pdf) provided preliminary data on pill-taking behavior and adverse events. It reported on the Kenyan trial, which enrolled five female commercial sex workers and 67 men who have sex with men, and the Ugandan trial, which enrolled 36 serodiscordant couples, for a total of 72 trial participants. The trial participants were randomized to one of four arms: daily TDF/FTC or placebo, or intermittent TDF/FTC or placebo (with doses on Mondays and Fridays, and post-coital doses within two hours after sex, not to exceed one dose per day). The trial remains blinded, meaning that neither participants nor trial staff knows who received TDF/FTC or placebo in either the daily or intermittent arm, and there were no significant differences among rates of adverse events across any of the trial arms.
The trial used several strategies to track adherence. Participants were asked about their patterns of pill use (self report); pill use was calculated using MEMS (Medication Event Monitoring Systems), an electronic pill bottle cap that captures each time the pill bottle has been opened; participants in the intermittent dosing arms received daily text messages asking whether they had had sex and taken a pill within two hours afterwards. The overall unadjusted adherence rates were significantly higher among discordant couples in both the daily and intermittent arms, compared to female sex workers and men who have sex with men in these same arms. This finding might be related to factors such as housing instability, stigma, criminalization and other factors affecting marginalized groups. Should PrEP show effectiveness, it will be critical to explore optimal strategies for supporting PrEP use in these groups.
Self-reports (including reports at study visits and SMS responses) of adherence were much higher than rates suggested by MEMS data. For example, MEMS data for the participants in Kenya suggested an average of 26% adherence to the post-coital dose, while self-report and SMS responses gave an adherence rate of roughly 100 percent. The research team concluded that post-coital dosing appeared difficult in these trial settings, and that additional qualitative studies are needed to understand barriers to adherence to such strategies.
It is important to remember that the strategy tested in these two trials is just one of several potential intermittent dosing regimens that might be considered if PrEP effectiveness trials show benefit. All of the ongoing effectiveness trials are exploring daily dosing. (Click here for more information about PrEP.)
Using an interactive short message service (SMS) data collection system in an HIV pre-exposure prophylaxis (PrEP) trial in Kenya and Uganda (e-poster available at http://pag.aids2010.org/PDF/11109.pdf) presented in-depth detail on one of the strategies developed to measure adherence and sexual behavior in the IAVI intermittent PrEP trials. Trial participants were given a mobile phone and SIM card if they did not own one and instructions on sending text messages, also known as SMS messages. During the four-month study period, participants received daily messages with queries about sexual activity and condom use. Replies were restricted to "yes" or "no" answers, using numerical codes. The median daily response rate (excluding days with major service outages) was 33 percent for Kenyan volunteers and 80 percent for Ugandan volunteers. In the discussion, the research team noted that major service outages and a request to change SIM cards part way through the Kenyan trial may have led to lower response rates. Qualitative research is ongoing to explore acceptability of this method of data collection for future studies.
ARV-Based Prevention Sessions at the Conference
There were numerous sessions that explored these and other related issues. Here is a selection of some particularly relevant sessions that include webcasts and slideshow downloads that may be of interest.
Please look for AVAC's round-up of AIDS 2010 presentations on AIDS vaccines and medical male circumcision for HIV prevention next week, and an update of A Cascade of Hope and Questions: Understanding the results of ARV-based prevention trials the week after that. If you attended Vienna or followed it on line and saw a presentation or talk that stood out, or if there's a topic you want to explore in more detail, let us know at avac@avac.org.
Best,
AVAC
