March 7, 2012
This update summarizes just a few of the news items emerging from the ongoing Conference on Retroviruses and Opportunistic Infections in Seattle, Washington—specifically new data from the FEM-PrEP, iPrEx and Partners PrEP trials (all sessions summarized below can be viewed online). As a reminder, AVAC will be hosting a webinar on PrEP at CROI on Tuesday, March 13 at 10am ET. Click here to register. (Please note that the US goes on daylight savings time on March 11 so please double check the webinar time in your area at www.timeanddate.com.)
Getting a clearer picture of what we know (and don’t) about PrEP in women
The following data were presented Tuesday, March 6th at an oral abstract session on HIV Prevention: PrEP, Microbicides, and Circumcision. Tuesday also featured a special symposium: Next Steps in Using ARV for Prevention. All presentations can be viewed at http://retroconference.org/static/webcasts/2012/.
Lut Van Damme, of FHI 360, presented data on adherence among participants in the FEM-PrEP trial, which evaluated daily oral TDF/FTC (brand name Truvada) among African women at high-risk of acquiring HIV. In April 2011, the trial’s independent data and safety monitoring board (DSMB) conducted a routine review of interim data and recommended that the trial halt due to “futility”. There were roughly equivalent numbers of infections among women in the active arm who received TDF/FTC plus a standard prevention package compared to women who received the placebo plus a standard prevention package.
One of the most common questions after a DSMB recommends stopping a trial for futility is: “So, does this mean the product itself doesn’t work?”. The new FEM-PrEP data—which will eventually be a full, peer-reviewed publication—move us closer to understanding what might have happened.
In the case of a user-dependent method, like oral PrEP, it’s important to figure out whether there was no benefit because the women took the product and it didn’t protect them, or whether there was no benefit because women didn’t take the product on a consistent basis as they were counseled to at study visits.
The data presented by Dr. Van Damme at CROI suggest that, in FEM-PrEP, the lack of observed efficacy is related to low levels of adherence. All participants were tested for HIV and gave blood samples at monthly study visits. The FEM-PrEP team looked at the samples taken from women in the active arm of the study who were counseled to use daily oral TDF/FTC and became HIV-positive during the trial. They looked specifically at the sample from the last visit at which a woman tested HIV-negative, and the sample from the visit at which a woman tested HIV-positive. They also looked at the samples from women who remained HIV-negative over the course of the trial, identifying women who’d been in the study for the same duration and at the same sites as the women who became HIV-positive. (This approach of comparing subsets of participants with similar characteristics for additional analysis is known as a “case-control” approach—it was also used in the iPrEx and Partners PrEP trials, as described below.)
At the last visit prior to testing HIV-positive, 25.9 percent of women who became HIV infected had detectable tenofovir in their blood. This is an indicator of whether they were taking the drug. At the first visit where these women tested HIV-positive, 21.2 percent of this group had detectable tenofovir. Approximately fifteen percent of these women had detectable drug at both visits. For women in the matched comparison group (those in the TDF/FTC study arm and remained HIV-negative), the corresponding numbers were: 35.1, 38 and 25.7 percent.
The take-home message, say FEM-PrEP investigators, is that adherence in FEM-PrEP was too low for the trial to evaluate the efficacy of daily oral TDF/FTC as a prevention strategy in this population.
Evidence that oral PrEP using TDF or TDF/FTC can reduce HIV risk in HIV-negative women who are able to adhere to a daily regimen came from the Partners PrEP trial, which enrolled heterosexual HIV serodiscordant couples in which one partner, either the man or the woman, was HIV-negative and the other HIV-positive. In this trial, the HIV-negative partner received either daily oral TDF or daily oral TDF/FTC. Early results reported in Rome last July showed high levels of effectiveness for both drugs in both men and women. These findings were reviewed at CROI, with no major changes to the estimated effectiveness of either drug.
At CROI Deborah Donnell from the Partners PrEP team presented analyses of plasma tenofovir levels in trial participants who became HIV-positive and a group of 1,000 participants who did not. (They used the case-control methodology described above.) Two key findings were: 1) Individuals who remained HIV-negative had detectable blood levels of tenofovir at 82 percent of their study visits. 2) Having detectable tenofovir in your blood at any given study visit was highly predictive of being HIV-negative at that visit. Having tenofovir detected was associated with approximately 90 percent reduced risk of HIV.
The Partners PrEP data clearly show that oral TDF and TDF/FTC both reduce HIV infection risk in women and men. These individuals were in serodiscordant relationships and, for the majority, their primary route of exposure was via unprotected sex with their spouse or stable partner. These characteristics are important—see the next paragraph—but even so, the Partners PrEP data provide a solid basis for biological effectiveness of oral tenofovir-based PrEP in women and men. Put more simply: in the trials (Partners PrEP and the CDC-sponsored TDF2 trial) where women and men took daily tenofovir-based PrEP, they had a reduced risk of HIV.
It is critical to note that women in FEM-PrEP were younger than women in Partners PrEP (59 percent were less than 25 years old) and, at enrollment, roughly 13 percent reported engaging in some form of transactional sex. We know from FEM-PrEP that oral TDF/FTC as explained and delivered in the study wasn’t a strategy that these women used—either because of feasibility, acceptability or some other factor. Data analyses are ongoing, and we might still learn some more about these issues as more data become available. The FEM-PrEP data underscore the fact that, for an intervention to work, people—women or men—have to be willing and able to use it. Any steps towards PrEP implementation will have to involve rigorous evaluation of different program strategies designed to provide women and men with support for self-evaluation of HIV risk, adherence support and regular HIV testing that the trials to date tell us are essential.
Towards a threshold of adherence and protection for PrEP
Another look at the relationship between drug exposure (having detectable drug in the blood or tissue) and efficacy came from an analysis using iPrEx samples (a trial of daily TDF/FTC as PrEP in MSM, which showed a 42 percent reduction in risk for those in the active arm). Peter Anderson of the University of Colorado presented a case-control analysis of drug levels in iPrEx participants who received TDF/FTC and either became infected or remained HIV-negative. (For an explanation of this approach, see the FEM-PrEP section above.) Anderson and his colleagues conducted an analysis of both the iPrEx case-control study and another study, called STRAND, which established blood levels of the active form of the drug (tenofovir diphosphate or TFV-DP) in people who took two, four or seven directly observed doses of TDF per week. Because the doses were directly observed, STRAND gave clear data on what blood levels of TFV-DP look like after different dosing frequencies. Anderson and colleagues compared the levels seen in STRAND participants with the levels in iPrEx participants. They calculated that the blood-drug level was associated with a dosing frequency of four doses per week was associated with a 95 percent reduction in HIV risk.
More work needs to be done to confirm and expand on these findings, but they are important in that they give the first estimate of the level of adherence needed for protection, and they suggest a blood-drug level that could inform current and future studies evaluating intermittent regimens and strategies to promote consistent PrEP use. We caution, however, that this data should not be used by individuals or others to construct private "intermittent" or less than daily dosing in use of PrEP. More work remains to be done.
Resistance data in Partners and FEM-PrEP
The Partners PrEP and FEM-PrEP teams also reported on rates of drug resistance in their trials. In Partners PrEP, there were 17 HIV infections among participants assigned to receive oral TDF and 13 among those who received daily oral TDF/FTC. The Partners PrEP team reported on resistance data for 27 out of these 30 individuals. None of them had detectable drug resistance. There were 14 individuals who were HIV-seronegative and in the acute phase of infection at the time of randomization. Of these, five were assigned to the TDF arm and three to the TDF/FTC arm. One individual in each group had drug resistance. In FEM-PrEP, there were no cases of TDF drug resistance among women who acquired HIV during the trial. There were five cases of resistance to FTC, one of which was in the placebo group. Two of the four cases of FTC resistance identified among women in the active arm of the trial were identified as cases of transmitted drug-resistant virus, and were not attributed to women taking active drug at the time that they became infected. Clearly, frequent HIV testing must be a critical component of implementing PrEP interventions.
More to come
The data described above suggest that oral tenofovir-based PrEP can reduce HIV risk in HIV-negative men and women, that high levels of adherence are essential for protection, and that more information is needed about how to deliver oral tenofovir-based PrEP to men and women at risk who may want to use it as an HIV prevention tool, so that they are able to take it safely and consistently. The resistance data underscore the need for programs that effectively identify HIV infection before someone starts taking PrEP and as soon as possible if they become infected while taking PrEP.
At a CROI Symposium on Tuesday, Jared Baeten from the Partners PrEP team provided an overview of the field in a presentation entitled What Can the Twisted Tale of PrEP Results Teach Us?, a webcast of which is available to download here. It provides a useful summary of what we do and don’t know, and what possible next steps are.
These data are just some of the presentations on PrEP at CROI. On March 13 at 10am ET, AVAC will be hosting a global advocates’ webinar to review these and other data presented at that conference, with an opportunity for questions and answers with many of the researchers who presented. Click here to register.
Data not summarized above include acceptability of a new formulation of tenofovir gel for rectal use. These will be discussed on a March 15 AVAC/IRMA webinar. Register here.
As always, questions or comments are most welcome at firstname.lastname@example.org.