It's a bad day for the AIDS virus. Results from two studies in sub-Saharan Africa, simultaneously announced today, show for the first time that daily doses of anti-HIV pills taken by uninfected men and women can prevent heterosexual transmission of the virus. Widely hailed as a "breakthrough" in HIV prevention by public health officials, the studies—one of which dropped its placebo arm today because of the convincing effects of the intervention—add powerful new tools to derail transmission of the virus in the population that accounts for most of the 34 million infections in the world.
"The evidence we're providing today is extraordinarily strong," says Jared Baeten, an epidemiologist at the University of Washington, Seattle, who co-led the larger of the two studies. "We're thrilled." Epidemiologist Lynn Paxton, who coordinated the second study for the U.S. Centers for Disease Control and Prevention (CDC), says the word " 'exciting' is a low-key term for this."
The thrill and excitement were shared around the world as select HIV/AIDS researchers over the past 2 days received confidential briefings about the results from the two pre-exposure prophylaxis (PrEP) studies. "I'm as happy as a guy could be," says Robert Grant, a virologist at the University of California, San Francisco (UCSF), and head of a large study that reported in November a PrEP success in men who have sex with men (MSM). "We have many new opportunities to stop HIV transmission." Salim Karim, an epidemiologist at the University of KwaZulu-Natal in Durban, South Africa, who co-ran a vaginal microbicide study that showed in July 2010 the first positive results with PrEP, said these "amazing results" are "set to revolutionize HIV prevention."
CDC and University of Washington coordinated the release of their results today because on 10 July, Baeten and his co-workers, who run a study called Partners PrEP, received a surprise. To prevent bias, researchers are blinded from trial results until it ends, but an independent board occasionally peeks at the data to monitor safety and effects. The board recommended that the study abandon its placebo arm and now offer treatment to all uninfected participants.
Partners PrEP began in July 2008 and enrolled 4758 "discordant" couples in Kenya and Uganda that at the start had only one HIV-infected partner. The uninfected partners randomly received a placebo or a pill that contained a licensed anti-HIV drug: either tenofovir or a combination of tenofovir and emtricitabine known as Truvada. The infected partners, by their own country's standards, had not suffered enough immune damage to qualify for free treatment with antiretroviral (ARV) drugs; in May, a separate study of discordant couples found that treating the infected partner in a discordant couple decreased the risk of transmission by 96%. Partners PrEP provided every couple free condoms, counseling, and treatment for other sexually transmitted infections.
As of 31 May, 78 people had become infected with HIV. Of these, 47 were in the placebo group, 18 took tenofovir alone, and 13 received Truvada. So tenofovir reduced infections by 62%, Truvada by 73%. The results had high statistical significance, and Baeten said both drugs worked "comparably" in uninfected men and women, although he would not specify the number of infections by gender in different arms of the study. No serious side effects occurred.
The robust efficacy raises intriguing questions about earlier PrEP studies. The Truvada trial in MSM, completed in November 2010, had a more modest efficacy of 44%. The vaginal tenofovir gel, reported 1 year ago, protected only 39% of women. A study of Truvada in sub-Saharan African women at high risk of HIV infection, FEM-PrEP, in April ended early because no difference existed between participants receiving the pills or placebos. "Adherence is the most likely explanation for the differences," says Timothy Mastro of FHI 360, the group in Durham, North Carolina, that ran the FEM-PrEP study.
An "adherent" participant takes all medication as instructed by researchers. But often, people in the earlier clinical trials did not take their pills or insert the vaginal gels. The antiretroviral drugs, of course, can only work if they are in the blood or tissues when HIV attempts to establish an infection, so nonadherent participants who are in treatment arms of these studies make it exceedingly difficult to tease out whether infections occurred because of the drug failure or their own behavior. In the MSM trial, a sub-study of people's blood who received Truvada showed that if they had detectable levels of the drug, it reduced their risk of infection by 92%—more than double what was found in the study as a whole.
Partners PrEP plans to do studies of drug levels in blood but calculated that adherence was 97% by monitoring how many pills participants had at the end of each month. More than 95% of the participants also stayed in the study. "Our participants were extraordinarily committed to the study," Baeten says. "Being in a known, discordant partnership really motivates people to reduce their HIV risk." None of the other PrEP studies recruited discordant couples.
CDC's new PrEP data come from a trial dubbed TDF2. The 6-year study found that Truvada reduced the risk of heterosexual sex transmitting HIV by 63%. TDF2 recruited 1219 men and women in Botswana who were not coupled to each other. The dropout rate was about 20%, which complicated the analysis of the results. "In Botswana, we have an incredibly mobile population, and the study went on for a long time," CDC's Paxton says. This primary analysis included people who formally left the trial for extended periods and had no known access to Truvada, which accounted for 10 of 33 infections documented. Eliminating these 10 people, who were evenly divided between placebo and treated groups, showed that efficacy increased to nearly 78%. (CDC planned to reveal the findings next week at an international AIDS conference in Rome but went public earlier to coordinate with Partners PrEP.)
The heartening new PrEP data raise several complex issues. Researchers leading a large, ongoing study in women called VOICE that compares PrEP with pills to a vaginal microbicide plan to revaluate the ethics of continuing to use a placebo control group given the new evidence of oral Truvada's powerful impact. Sharon Hillier, a reproductive infectious disease specialist at the University of Pittsburgh in Pennsylvania, who heads VOICE, stresses that the field still needs a clearer idea of why FEM-PrEP did not work. "We need to understand much better what's going on before we say we know what's going on," Hillier says. "It drives me crazy—people have such certitude about this. It's super interesting, and we're really excited about the new results, but we need a lot more information and to talk with our stakeholders about how we weigh this body of data."
Aside from altering the design of clinical trials, the new data raise difficult financial questions. Truvada now is licensed only as an HIV treatment. If regulators change the drug's label to indicate that it works as a preventive, this could prove critical to whether insurers and governments will pay for Truvada PrEP, which at a discounted rate still costs more than $100 a year when used daily. But the world cannot now afford to treat all the already-infected people who need antiretrovirals, raising the dilemma of where scarce funds should go, to prevention or treatment. Further complicating matters, treatment makes infected people less infectious and is a form of prevention itself; next week, the World Health Organization is expected to recommend that all infected people in discordant couples receive ARVs—a huge challenge for many resource-limited countries.
UCSF's Grant stresses that people need many options to prevent transmission of HIV and that all of these advances that research has provided during the past year must be put into action. "We need more resources devoted to the war on HIV," Grant says. "The amount of money needed is small compared to other security and safety issues. This is now a fight that we can win, and we should do what it takes."