- Category: Pre-exposure Prophylaxis (PrEP)
- Published on Monday, 22 November 2010 21:13
- Written by Liz Highleyman
Pre-exposure prophylaxis (PrEP) using a daily combination of tenofovir and emtricitabine (the drugs in the Truvada coformulation) reduced the risk of acquiring HIV by 44%, according to a large international study of men who have sex with men. As described in the November 23, 2010 advance online edition of the New England Journal of Medicine, the iPrEx study found that men who achieved good adherence had more than a 70% reduction in new infections. The drug combo was well-tolerated over nearly 3 years of follow-up, with mostly mild, transient side effects.
With recent figures estimating that more that more than 56,000 new HIV infections occur each year in the U.S. -- and some 2.7 million worldwide -- the need for better methods of preventing transmission remains urgent. Over the past decade, studies of HIV vaccines, microbicides, and other approaches have largely produced disappointing results...but the tide has recently started to turn.
Pre-exposure prophylaxis, or PrEP, refers to HIV negative people taking antiretroviral drugs in an effort to prevent infection. A number of studies have shown that PrEP using tenofovir (Viread) plus emtricitabine (Emtriva) reduces the risk of new infections in non-human primates.
The iPrEx study, conducted by an international team of investigators led by Robert Grant the Gladstone Institute of Virology and Immunology in San Francisco and Javier Lama from Investigaciones Medicas en Salud in Lima, Peru, was among the first to evaluate the effectiveness of PrEP in humans; earlier studies have shown that the approach appears safe and feasible. iPrEx was funded by the U.S. National Institutes of Health and the Bill and Melinda Gates Foundation, and study drugs were provided by Gilead Sciences (Gilead had no role in designing the study or collecting or analyzing data).
The study enrolled 2470 men who have sex with men (MSM) and 29 transgender women who have sex with men at 11 sites in Brazil, Ecuador, Peru, South Africa, Thailand, and the U.S. (Boston and San Francisco) between July 2007 and December 2009. All participants tested HIV negative at study entry. They were sexually active and considered to be at high-risk for infection; the average number of sexual partners during the past 3 months was 18, and about 60% reported receptive anal intercourse.
Participants were randomly assigned to receive either oral tenofovir/emtricitabine (using the 300mg/200mg Truvada coformulation) or placebo, both once-daily. Follow-up continued for a median of 1.2 years, reaching a maximum of 2.8 years.
In addition to their daily medication, participants also received monthly HIV testing, risk-reduction counseling, free condoms, and diagnosis and treatment of other sexually transmitted diseases. During these visits they also submitted pill counts to monitor adherence and participated in adherence counseling. They were encouraged to maintain safer sex practices and were told that tenofovir/emtricitabine was not yet proven to prevent HIV infection and that they might receive the placebo.
A total of 100 new HIV infections occurred during 3324 person-years of follow-up (an additional 10 people were later determined to have been HIV-infected at enrollment):
- 36 new infections among 1251 participants in the tenofovir/emtricitabine group;
- 64 infections among 1248 placebo recipients.
- This difference represented a 43.8% reduction in HIV incidence (P = 0.005).
The benefit of tenofovir/emtricitabine was greater among participants who achieved better adherence:
- >50% adherence (taking pills at least half the time): 50.2% fewer new infections (P = 0.006);
- >90% adherence: 72.8% fewer infections (P = 0.001).
- Within the tenofovir/emtricitabine arm, people with detectable drug levels had about a 13-fold or 92% lower risk of HIV acquisition than those with undetectable levels.
- Further analysis of participants who became infected in the tenofovir/emtricitabine arm found that only 3 people (9%) had detectable plasma drug levels, and all of these individuals had below average cellular drug levels.
- There was no significant difference in degree of protection based on region, race/ethnicity, age, circumcision status, education level, or alcohol use.
- Participants reduced their risk behavior during the study, including using condoms more often and having fewer sex partners.
- No new drug-resistance mutations were detected in participants who were newly infected during the study; however, 3 people who were actually HIV positive at the start of the study developed emtricitabine resistance.
Tenofovir/emtricitabine was generally well-tolerated:
- People in the tenofovir/emtricitabine group were significantly more likely than those in the placebo group to report moderate nausea during the first 4 weeks of treatment (22 vs 10 events, respectively), but this typically resolved over time.
- Both groups had similar rates of serious adverse events.
- 2% of participants in the tenofovir/emtricitabine group and 1% in the placebo group experienced elevated serum creatinine, a marker of impaired kidney function.
- Most cases of creatinine elevation were transient, but 7 patients taking tenofovir/emtricitabine and 3 taking placebo discontinued therapy for this reason.
Based on these findings, the investigators concluded, "Oral [tenofovir/emtricitabine] provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect."
"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 Director Anthony Fauci during a media conference call on Monday.
Robert Grant, the iPrEx Protocol Chair, noted that 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."
Interestingly, data from the CAPRISA 004 trial, presented at this summer's International AIDS Conference (AIDS 2010) in Vienna, showed that a vaginal gel microbicide containing 1% tenofovir used before and after sex lowered women's risk of HIV acquisition by 39%, offering about the same degree of protection as daily oral tenofovir/emtricitabine.
Fauci and Grant both emphasized that the latest results come from a single study in a specific population. While the number of participants was large enough to show a real protective effect -- rather than just differences due to chance -- it is not yet known whether tenofovir/emtricitabine PrEP will work for women, heterosexual men, or injection drug users. Studies looking at other populations, and at intermittent tenofovir/emtricitabine taken on a less frequent schedule or before and after having sex, are now or soon will be underway.
The study findings suggest that one commonly expressed concern surrounding biomedical prevention -- that people who believe they are protected will relax safer sex practices, known as "behavioral disinhibition" or "risk compensation" -- was not a problem, given that participants actually used condoms more often during the study.
Taking pills everyday, however, proved to be a challenge -- as it is with all diseases. Participants' reported adherence (around 90% or better) was higher than that indicated by drug level measurements. The researchers suggested that inexpensive methods for measuring long-term drug exposure, for example hair analysis, might be useful. In addition, Grant suggested that adherence might be better in a real-world setting where people know they are taking the active drug and know that it works to reduce the risk of HIV infection.
The emergence of resistance among 3 participants who were mistakenly identified as uninfected at study entry -- meaning they were, in effect, treating HIV with NRTI-only dual therapy -- underscores the importance of ensuring HIV is not already present when starting PrEP, even if an individual has not yet produced enough antibodies to show up on a standard screening test. Grant noted that a majority of participants who became infected showed non-specific symptoms of acute viral infection, and suggested that symptomatic individuals should not start PrEP.
Another area of concern relates to cost-effectiveness and access to PrEP drugs, especially in resource-limited settings where even HIV positive people who require treatment are not always able to get the drugs they need. But Grant suggested that, "by preventing new infections, the burden on treatment programs will eventually decrease." It remains to be seen whether private insurance or public benefits programs will see fit to cover the cost or PrEP.
Asked about at-risk individuals who might wish to start using tenofovir/emtricitabine PrEP on an off-label basis right away, Fauci said, "I won't recommend one way or the other to them, but they should make sure they understand the caveats. This has been shown in MSM, so it's one demographic group, there is a clear possibility of long-range toxicities of the drugs, that it should not be used in a vacuum, but should be used with other comprehensive prevention modalities."
He also said it was impossible to give a time frame for when antiretroviral guidelines might be changed or the Food and Drug Administration (FDA) might approve an additional PrEP indication for tenofovir/emtricitabine.
Early community response to the study findings was generally positive.
"Today marks a major step forward in our quest to combat HIV among MSM and other populations," said amfAR CEO Kevin Robert Frost. "These results suggest that PrEP could be a very important prevention tool for gay men and MSM when used in combination with other prevention interventions including condoms."
"This discovery alters the HIV prevention landscape forever," concurred Jim Pickett of the AIDS Foundation of Chicago and International Rectal Microbicide Advocates. "While this level of efficacy is relatively strong, PrEP is not quite ready for prime time and work remains before this strategy is rolled out. However, we are thrilled to have a new prevention option beyond male and female condoms visible on the horizon."
"These important results add to the evidence that antiretrovirals can block sexual transmission of HIV," said Treatment Action Group (TAG) Executive Director Mark Harrington. "[H]owever, they also raise questions about the acceptability of daily PrEP, because the data suggest that consistent daily use of the regimen was problematic for many of the study participants."
San Francisco-based advocacy organization Project Inform issued a statement saying the new data "represents the most promising development in HIV/AIDS since the introduction of triple combination drug therapy in 1996."
Nevertheless, Project Inform "strongly urges gay and bisexual men and trans females not to attempt PrEP on their own at this time," the statement continued. "We stress that iPrEx data are based on taking [tenofovir/emtricitabine] daily along with participation in behavioral counseling, condom use, medication adherence counselling, and clinical monitoring. There are no data whatsoever to suggest that using PrEP episodically or around the time of sex is at all effective."
Investigator affiliations: Gladstone Institute of Virology and Immunology, San Francisco, CA; University of California, San Francisco, CA; HIV Research Section, San Francisco Department of Public Health, San Francisco, CA; Investigaciones Medicas en Salud, Lima, Peru; Asociación Civil Impacta Salud y Educación, Lima, Peru; Asociación Civil Selva Amazónica, Iquitos, Peru; University of Colorado, Denver, CO; Fundación Ecuatoriana Equidad, Guayaquil, Ecuador; Instituto de Pesquisa Clinica Evandro Chagas-Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Projeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil; Brown University, Providence, RI; Fenway Institute, Fenway Health, Boston, MA; Division of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, Brazil; Instituto de Investigação em Imunologia, São Paulo, Brazil; Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; Desmond Tutu HIV Centre and Department of Medicine, University of Cape Town, South Africa; Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Gilead Sciences, Foster City, CA; DF/Net Research, Seattle, WA; Applied Health Research, Brighton, MI; Center for Health, Intervention, and Prevention, University of Connecticut, Storrs, CT.
RM Grant, JR Lama, PL Anderson, and others. Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. New England Journal of Medicine (Abstract). November 23, 2010.
iPrEx website. www.globaliprex.net.
amfAR. amfAR Welcomes iPrEx Study Results, Calls for Additional Research and Demonstration Projects. Press release. November 23, 2010.
International Rectal Microbicide Advocates. AIDS Drug Shown to Prevent HIV in Multinational Trial of HIV-Negative Gay Men. Press release. November 23, 2010.
Treatment Action Group. Pre-Exposure Prophylaxis Proves Effective in Preventing HIV Infection. Press release. November 23, 2010.
Statement by Project Inform on iPrEx findings. November 23, 2010. Available at www.projectinform.org.