In late November, investigators released eagerly awaited data from the iPrEx trial showing that pre-exposure prophylaxis (PrEP) using tenofovir plus emtricitabine (the drugs in the Truvada combination pill) can help prevent HIV infection. A protective effect has previously been demonstrated in animal studies, but these are the first results from a human PrEP efficacy trial.
As described in the November 23, 2010, advance online issue of the New England Journal of Medicine, this Phase III trial enrolled nearly 2,500 men who have sex with men and a small number of transgender women in Brazil, Ecuador, Peru, South Africa, Thailand and the U.S. (Boston and San Francisco).
Participants were randomly assigned to take oral tenofovir/emtricitabine or placebo once daily; in addition, they received monthly HIV testing, regular risk-reduction counseling and free condoms.
During a median follow-up period of 1.2 years (maximum 2.8 years), 36 men using tenofovir/emtricitabine became infected compared with 64 men taking placebo -- a risk reduction of 44%. Among participants who achieved at least 90% adherence, the likelihood of HIV infection fell by 73%.
"The iPrEx results are extremely important and provide strong evidence that PrEP can reduce HIV acquisition among a segment of society disproportionately affected by HIV/AIDS," said National Institute of Allergy and Infectious Diseases (NIAID) director Anthony Fauci during a media conference call to announce the findings.
"This study provides the first proof that oral PrEP works in people, and the first proof of any biomedical intervention to prevent infection in gay and bisexual men," added study chair Robert Grant from the University of California at San Francisco's Gladstone Institute of Virology and Immunology.
Tenofovir/emtricitabine was generally well-tolerated, although some participants reported moderate and usually short-lived nausea. Few people overall showed signs of impaired kidney function -- a known potential side effect of tenofovir -- but elevated serum creatinine occurred more often in the PrEP group compared with placebo (2% vs. 1%).
No emergent drug-resistance mutations were detected in participants newly infected during the study. Three PrEP recipients who were actually HIV infected but not yet antibody positive at study entry developed emtricitabine resistance.
Study participants did not increase their high-risk behavior because they thought they might be protected, but rather reported more condom use and fewer sex partners. Adherence proved difficult, however; drug-level tests suggested that about half the participants did not take their pills regularly. Only three people who became infected while on PrEP had measurable drug levels.
Researchers and community advocates emphasized that PrEP is not completely protective and should not be considered a replacement for condoms or other risk-reduction measures. Furthermore, a protective effect has only been demonstrated in one population, and it is not known whether these results will extend to women or injection drug users, for example.
"PrEP could be part of a comprehensive HIV prevention package in communities like ours with epidemics still disproportionately affecting gay men," said Judith Auerbach, San Francisco AIDS Foundation's Vice President of Research and Evaluation. (See "The iPrEx Results: Lifting Hopes, Raising Questions," in this issue, for further commentary.)
Grant also noted that the iPrEx trial looked at PrEP used every day, not just before or after sex (as tested in the CAPRISA microbicide trial described in this issue). "Whether oral PrEP can be used in this fashion is completely unknown at this time," he said.
Fauci advised that gay and bisexual men who wish to start taking tenofovir/emtricitabine off-label as PrEP should be aware of potential drawbacks. "[T]here is a clear possibility of long-range toxicities of the drugs," he cautioned. Fauci said he could not give a timeframe for when the U.S. Food and Drug Administration (FDA) might approve an additional PrEP indication for tenofovir/emtricitabine, or if or when antiretroviral treatment guidelines might be changed to recommend prophylactic use. Studies of PrEP in other populations, and of episodic rather than daily use, are underway.
Liz Highleyman (firstname.lastname@example.org) is a freelance medical writer based in San Francisco.