Grant RM, lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Pre-exposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010. DOI: 10.1056/NEJMoa1011205
Men who have sex with men (MSM) and transgender women (persons born male who identify and present themselves as women, whether with or without gender reassignment surgery) are disproportionately affected by HIV.(1) The availability of a single, once daily oral formulation of emtricitabine and tenofovir (FTC-TDF), its favorable side effect profile, and efficacy in animal studies,(2, 3) in a study of West African women(4) and the theoretical acceptability of pre-exposure prophylaxis(5) make FTC-TDF a reasonable choice for chemoprophylaxis in this high-risk population.
To evaluate the safety and efficacy of FTC-TDF pre-exposure prophylaxis against acquisition of HIV among MSM.
Multi-site study: 11 sites located in Peru, Ecuador, South Africa, Brazil, Thailand, and the United States.
Randomized placebo-controlled trial.
Born male, age 18 years and older, HIV-negative, MSM who reported any of the following in the six months prior to enrollment 1) unprotected anal intercourse with an HIV+ partner or partner of unknown status, 2) anal intercourse with more than three men, 3) the exchange of money, drugs, gifts, or shelter for anal sex with a man, 4) sex with a man and diagnosis of a sexually transmitted infection (STI) in the past six months, 6) inconsistent condom use with an HIV-infected man. Participation required normal hematologic, renal and liver function.
Peer recruiters were used to recruit participants from a variety of venues including bars, streets, entertainment events, from surveillance sites that follow MSM over time, such as voluntary counseling and testing sites. Study procedures were conducted at medical clinics. Subjects were randomized (1:1) to once daily FTC-TDF or placebo. Participants were seen every four weeks after enrollment for drug dispensation, pill count, adherence counseling, rapid HIV antibody testing, and a medical history. Blood test for chemistry and hematology were obtained at weeks 4, 8, 12, 16, and 24 and every 12 weeks thereafter. Demographic, alcohol use, and perceived group assignment was obtained using a computer-assisted interview. Sexual risk behavior was obtained by interview every 12 weeks. A physical examination and testing for sexually transmitted diseases were conducted every 24 weeks. Participants were provided with HIV risk-reduction counseling, HIV testing, condoms, testing and treatment for symptomatic gonorrhea and Chlamydia urethritis, syphilis, and herpes simplex virus type 2 (HSV-2) at every visit. At 24 weeks, participants were screened for asymptomatic urethritis, syphilis, HSV-2, and genital warts. Participants diagnosed with any of STIs were offered appropriate treatment. Treatment for the subject's sexual partners was also provided. Participants who reported a recent unprotected exposure to a HIV-infected partner were referred for post-exposure prophylaxis. During this time, the study drug was stopped. All susceptible participants were offered vaccination against hepatitis B virus.
Rapid HIV testing was done on whole blood using two different types of tests and confirmation of reactive tests was by Western blot of the serum. Participants who seroconverted within the first 12 weeks of the study were also tested for HIV RNA using a test sensitive to 40 copies/mL. Specimens were tested for genotypic and phenotypic resistance at seroconversion.
To assess the degree of protection based upon the drug level, HIV-infected subjects were matched to two HIV-negative controls, one from each study arm. Serum was tested for the presence of FTC and TFV and peripheral-blood mononuclear cells were tested for the active intracellular metabolites of FTC and TFV using liquid chromatography and tandem mass spectrometry tests.
The data were analyzed using a modified intention-to-treat approach in which all participants were included except those found to be HIV-infected at enrollment. An as-treated analysis was done in which a time-dependent variable for drug compliance (pre-specified as less than 50% compliant based upon any of the following: the records of study drug dispensation, pill-use calculation from study drug dispensation and returns, or the subjects' self-report.
There were 4,905 persons screened of whom 2,499 enrolled between July 10, 2007 through December 17, 2009. The baseline characteristics between study arms were similar except that the FTC-TDF group was, on average, nine months older than the placebo group (mean age 27.5 years vs. 26.8 years, respectively, p=0.04). Although all subjects were born male, 29 (1%) identified as female.
There were 3,324 person-years of follow-up. Subjects who guessed their group assignment were equal between groups. Study drug was discontinued in 8 subjects and placebo was discontinued in 13 subjects for post-exposure prophylaxis. Adherence based on self-report was lower in the FTC-TDF group compared to placebo at weeks four and eight (mean 89% vs. 92%, and 93% vs. 92%,respecitively, p<0.001) but both groups reported 95% adherence thereafter. The rate of pill use based on pill count increased during the first 8 weeks and was stable after that (range 89-95%). Using pill-dispensation to estimate adherence, pill use decreased during the first year from 99% to 91%.
Sexual behaviors were similar between groups. Both groups reported a decrease in the number of partners with whom he had receptive anal intercourse and the percent of these partners who used condoms increased. The incidence of STIs was similar between groups.
Safety measures found borderline significant increases in serum creatinine in the FTC-TDF group compared to placebo group (2% vs. 1%, respectively, p=0.08) and two of these increased in grade for a total of 43 creatinine adverse events. Ten increases led to discontinuation of the drug (7 were in the FTC-TDF). Creatinine levels returned to normal following discontinuation of drug. There were no other serum creatinine-related differences between groups. Moderate nausea was reported more frequently in the FTC-TDF group compared to placebo (22 vs. 10, respectively, p=0.04). Unintentional weight loss was also more frequent in the FTC-TDF group (34 vs. 19 in the placebo group, p=0.04).
There were 110 seroconversions, 10 of these had plasma RNA detected from enrollment specimens. Of the 100 infections acquired during the trial, 36 were in the FTC-TDF arm and 64 in the placebo group resulting in a relative decrease in incidence of 44% (95% CI: 15,63). The hazard ratio using in the as-treated analysis among participants reporting 50% or greater pill use was 0.50 (95% CI: 0.12,0.82) and among participants reporting 90% or greater pill use was 0.27 (95% CI: 0.12,0.59).
Drug was not detected in plasma or cell specimens from the placebo group. Among participants in the FTC-TDF group, study drug was detected in three of the 34 (9%) participants who acquired HIV and in 22 of the 43 (51%) seronegative matched control subjects.
Of the 10 participants found to be infected at enrollment, three had FTC resistance (2 from the FTC-TDF group). Of the 36 subjects in the FTC-TDF group who acquired infection during the trial, resistance to FTC or TDF was not found.
Once daily oral use of FTC-TDF reduced the risk of HIV seroconversion by 44% with greater protection associated with greater adherence to the drug.
This study meets the criteria for a high quality RCT. Participants were appropriately randomized, participants and assessors were blinded to treatment arm, loss to follow-up was accounted for and not substantial and an intention-to-treat analysis was performed. The efficacy was also measured based upon the level of adherence to drug, another strength of the study.
There are several very important implications from this study. First is that it represents an additional effective method to reduce HIV transmission and in contrast to male circumcision and vaginal microbicides, offers protection to MSM. Although there is likely to be immediate demand for pre-exposure prophylaxis in this population, it is important to note the renal side effects and to keep in mind that many participants remain in the trial. Another important observation is that participants in both groups reduced their risk behavior, indicating effectiveness of the prevention methods in the study and potentially of the act of taking medication.
- Beyrer C, Baral SD, Walker D, Wirtz AL, Johns B, Sifakis F. The expanding epidemics of HIV type 1 among men who have sex with men in low- and middle income countries: diversity and consistency. Epidemiol Rev 2010;32:137-51.
- Denton PW, Estes JD, Sun Z, et al. Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 2008;5(1):e16.
- García-Lerma JG, Otten RA, Qari SH, et al. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med 2008;5(2):e28.
- Peterson L, Taylor D, Roddy R, et al. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin Trials 2007;2(5):e27.
- Mimiaga MJ, Case P, Johnson CV, Safren SA, Mayer KH. Preexposure antiretroviral prophylaxis attitudes in high-risk Boston area men who report having sex with men: limited knowledge and experience but potential for increased utilization after education. J Acquir Immune Defic Syndr 2009;50:77-83.