AHF PrEP Ad Controversy: What Do the Numbers Mean?
A new campaign from the AIDS Healthcare Foundation has kicked off another round of controversy about HIV pre-exposure prophylaxis (PrEP) and how to interpret data from prevention studies.
The AHF ad features a chart showing overall efficacy in eight major studies of PrEP using Truvada (tenofovir plus emtricitabine) or tenofovir alone in pill or gel formulations. Figures range from a high of 75% in the Partners PrEP trial of heterosexual couples in Africa to less than 10% in the Fem-PrEP study of African women.
“Overall efficacy was low in all studies due to low adherence,” the ad states. “[AHF] has taken the position that the scientific data do not support the large-scale use of Truvada as a community-wide public health intervention.” In fact, AHF president Michael Weinstein suggested, “the government-sanctioned widespread scale-up of PrEP appears to be a public health disaster in the making.”
In contrast, proponents say PrEP is highly effective—in the 90% to 100% range—when used consistently. Once-daily Truvada was tested in clinical trials and this is the regimen approved by the FDA in July 2012 and recently recommended by the CDC. But study data show that Truvada can still provide a high level of protection even if people miss some doses.
The battle of the numbers arises from the different ways researchers can report medical study results.
In randomized controlled clinical trials, the gold standard is “intent-to-treat” results, or how well a drug works among everyone assigned to take it. This includes people who may not have used it regularly or who stopped early due to side effects or for other reasons. This is usually the primary type of data reported in medical journals and at scientific conferences.
Another method, known as “as-treated” or “per-protocol” results, considers only the subset of study participants who actually took the drug as directed—that is, those with good adherence.
In general, as-treated results will make a treatment look more effective than intent-to-treat results. A drug may have strong antiviral potency, for example, but if many people find it too inconvenient or too toxic to use regularly, its actual effectiveness in practice may be low.
iPrEx by the numbers
The PrEP debate mainly revolves around the various reported figures from the iPrEx study, which enrolled about 2,500 HIV-negative gay and bisexual men and a small number of transgender women at 11 sites in six countries. Participants were randomly assigned to take either Truvada or an inactive placebo once daily. The study was double-blind, meaning neither the participants nor the researchers knew who was taking what. Everyone also received regular HIV testing and prevention services including risk-reduction counseling and free condoms.
As SFAF medical director Robert Grant and colleagues reported in the December 30, 2010, New England Journal of Medicine, after an average follow-up period of about one year, the risk of HIV infection was 44% lower overall in the Truvada group compared with the placebo group in an intent-to-treat analysis of the main iPrEx study—the figure shown in the AHF ad. For participants that self-reported taking Truvada as directed most of the time, the risk of infection dropped by 73%. Among people with blood drug level measurements indicating good adherence, risk reduction was 92%. A mathematical model later estimated that risk reduction would reach 90% if participants took Truvada at least four days per week, and could hit 99% with daily use—the figure often cited by PrEP advocates.
After the main study ended, all participants (even those assigned to take placebo during the main study) had the option of receiving Truvada in the iPrEx open-label extension (OLE). About 1,600 participants took part in iPrEx OLE with three-quarters choosing to take Truvada and the rest serving as an untreated control group. Unlike the original randomized part of the trial, OLE participants knew they were getting the active drug and were informed about findings showing that it reduced HIV risk.
As Grant reported at the recent International AIDS Conference in Melbourne, the overall risk reduction in the OLE was 49% in the Truvada group compared with the untreated group.
“Under more or less ideal conditions, the best they could get to was 50 percent [risk reduction],” said Weinstein. “That’s not a big success—that’s a big danger.”
Yet among people who had blood drug levels indicating that they took Truvada at least four times per week, there were no new infections—100% efficacy. However, only one-third managed to reach this level of adherence. People who took Truvada two or three times per week still had a risk reduction of 84%, while those who took fewer than two doses saw no significant protective effect.
What Does It Mean?
With so many numbers being tossed around, many people are understandably unsure about which ones to focus on. Yet the issue is not really which risk reduction estimates are “true,” but rather what these percentages mean in real life.
Taken together, studies of gay men, heterosexual couples, and people who inject drugs have shown that Truvada (or even tenofovir alone) is highly effective with consistent daily use.
“We know that people who did take the drug had very high levels of protection,” said Jim Pickett, director of Prevention Advocacy and Gay Men’s Health at the AIDS Foundation of Chicago. “This drug works extraordinarily well to prevent HIV if you use it.”
However, randomized studies and open-label demonstration projects have found that many participants don’t maintain good adherence. A U.S. PrEP demonstration project found that while 92% of San Francisco participants had blood drug levels indicating that they took Truvada at least four times per week, this fell to 57% in Miami. At the other extreme, adherence levels in two PrEP studies of women in Africa—VOICE and Fem-PrEP—were so low that they could not demonstrate a protective effect.
While Weinstein argues that condoms are the best way to prevent HIV infection, PrEP advocates stress that most gay men do not use condoms all the time — as demonstrated at an SFAF Real Talk discussion where an audience poll showed that 100% had ever had sex without a condom.
As with PrEP, the level of protection in condom studies also varies widely. While effectiveness in preventing pregnancy approaches 100% with perfect use, a study by Dawn Smith from the CDC and colleagues found that gay men who reported using condoms all the time were about 70% less likely to become infected than those who said they use them sometimes or not at all.
“Does that mean we tell guys [condoms] are only 70% effective? No, partly because some guys probably didn’t use them religiously or correctly,” explained David Evans, director of research advocacy at Project Inform. “So what we say is that they are highly effective if used correctly and used every time. That’s what most of us are saying about PrEP.”
Importantly, iPrEx and other studies have found that using PrEP does not make people less likely to use condoms, but in fact is associated with a reduction in sexual risk behavior. And compared with condoms, PrEP is more forgiving of less-than-optimal adherence.
“Having used a condom yesterday provides no protection if you don’t use a condom today,” said Grant. But the iPrEx OLE results “demonstrate that PrEP remains highly effective, even in real-world circumstances in which adherence may not be perfect.”
“It’s important to note that PrEP is not simply a pill, it’s a program,” Pickett told BETA. “It’s a program that includes quarterly testing for HIV, regular STD screens (and STD treatment as necessary), medical monitoring, adherence support, and sexual health counseling.”
Liz Highleyman (liz (at) hivandhepatitis.com) is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.