For HIV-negative men who have sex with men, taking preemptive antiretrovirals seems to reduce the risk of getting infected by about 44 percent, according to a new international study. Among those who reported having unprotected receptive anal sex, the prophylactic drug treatment was about 58 percent effective in preventing infection, and among all study subjects who took the recommended daily dose at least 90 percent of the time, the treatment had about a 73 percent efficacy in preventing transmission.



"These results represent a major advance in HIV prevention research," Kevin Fenton, director of the U.S. Centers for Disease Control and Prevention (CDC) National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, said in a prepared statement.



The Phase III clinical trial followed 2,499 HIV-negative men and transgender women (who had once been men) who have sex with men. The individuals, aged 18 to 67, lived in cities in one of six countries (Brazil, Ecuador, Peru, South Africa, Thailand and the U.S.) and were randomized to either the antiretroviral group, which took once-daily doses of Truvada (emtricitabine and tenofovir disoproxil fumarate, or FTC-TDF) or the placebo-pill group.



After a median 1.2 years of follow-up, 100 new cases of HIV were found: 64 in the placebo group and 36 in the antiretroviral group. The results were published November 23 in The New England Journal of Medicine.



"Given the heavy burden of HIV among gay and bisexual men, a new tool with potential additive benefit is exciting and welcome news," Fenton said. But, he cautioned, this strategy "cannot be seen as the first line of defense against HIV." Although the prophylactic doses seemed to decrease the rate of infection substantially, in this study, the infection rate did not drop to zero. And rates of infection were low overall—about 5.2 percent of the placebo group and 2.9 percent of the experimental group contracted HIV during the study period.



Both groups also received a suite of prevention help, including counseling, condoms, testing and other services. And during the course of the study, the number of reported recent anal sex partners decreased whereas reported condom use increased. Some researchers suggest that the simple act of taking a daily prophylactic pill can serve as a reminder that one is at risk (and should take other precautions as well). With this and other placebo-controlled HIV prevention studies, however, there is concern that if participants are told they might be receiving an intervention to reduce their risk, they will be more likely to engage in risky behaviors.



Given the estimated 56,300 new cases of HIV in the U.S. each year, "the need for new HIV prevention methods is critical," Robert Grant, of the Gladstone Institute of Virology and Immunology at the University of California, San Francisco, and lead author of the study, said in a prepared statement. And men who have sex with men make up a particularly large share (about 53 percent) of the new cases, according to the CDC.



Despite the antiretrovirals' "significant" protective effect in reducing infection rates, it was "not as high as originally hypothesized during the design of the study," the researchers wrote. Although most people reported taking the pill daily as prescribed at least half of the time, drug levels measured in blood samples did not always show high levels of the medication.



The use of a chemoprophylaxis to prevent HIV infection is not new. Doses of antiretrovirals help reduce transmission of the infection from mothers to infants during birth and breast-feeding, and they have been recommended for years as a treatment for people working with HIV-infected fluids who think they might have been exposed to the virus. Also, a tenofovir-containing vaginal gel showed about 39 percent reduction in transmission among women in a study published earlier this year.



The side effects of the drugs are relatively mild and can include nausea, especially in the first month of use. This might help to explain why, at week four of the trial, slightly more—about 3 percent—of the individuals in the placebo group reported taking the pill every day than in the antiretroviral group. But these numbers evened out (to a mean reported adherence of about 95 percent) by the second month.



No cases of tenofovir-resistant HIV were detected during the study (and only three cases of emtricitabine resistance were found).



The CDC, National Institutes of Health and others will review the findings and issue guidelines for possible pre-exposure prophylactic antiretroviral use in the coming months. Advisory groups will "determine whether and how these findings should be incorporated into ongoing HIV prevention programs," Howard Koh, assistant secretary for health at the U.S. Department of Health and Human Services, said in a prepared statement.



In the meantime, the CDC has issued a preliminary list of cautions to at-risk individuals and their doctors.



"It is important to note that the new findings pertain only to the effectiveness of [pre-exposure prophylaxis] among men who have sex with men and cannot at this point be extrapolated to other populations," Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said in a prepared statement. And interventions are rarely as effective outside the clinical trial setting, where adherence—especially to something as regular as a lifelong daily dose prescribed to a healthy population that includes a large number of people—is quite challenging. "No single HIV prevention strategy is going to be effective for everyone," Fauci said.