In high risk HIV-seronegative males, do antiretroviral therapies reduce the rate of HIV seroconversion?
In high risk HIV-seronegative males, prophylactic treatment with emtricitabine-tenofovir (FTC-TDF) reduce the risk of HIV seroconversion by 44%.
Primary prevention of HIV has been demonstrated among pregnant women with oral AZT in PACTG 076 (1999) and among heterosexual women with intravaginal TDF in CAPRISA 004 (2010). This is one of the largest primary prevention trial among men.
The Iniciativa Profilaxis Pre Exposicioni ("Preexposure Prophylaxis Initiative", or iPrEx) trial randomized 2,499 HIV-seronegative men and 29 transgender women who have sex with men to either FTC-TDF combination (emtricitabine/tenofovir is sold under the brand name Truvada) or placebo. This regimen was chosen because of its once-daily dosing, excellent safety profile, and absence of interactions with anti-TB or anti-malarial therapy, hormonal therapy, or feminizing therapy. All participants also received HIV testing, condoms, and counseling regarding STIs. After a median followup of 1.2 years, FTC-TDF was associated with a 44% relative risk reduction in the incidence of HIV-seroconversion (3.0% vs. 5.8%; P=0.001; NNT=35). The intervention was more effective in those receiving unprotected anal sex and those with higher adherence to the therapy.
Practical limitations of this trial include prohibitive cost of the intervention, unclear effects on risk-taking behaviors, and the potential for viral resistance.
Subsequently, the 2013 Bangkok Tenofovir Study found a similar reduction in HIV-seroconversion in HIV-seronegative injection drug users in Thailand treated with daily TDF alone. Oral and vaginal FTC-TDF or TDF formulations were ineffective for primary prophylaxis among African women in the 2015 VOICE study, though adherence was low.
Efficacy of intermittent PrEP was demonstrated in the 2015 ANRS IPERGAY trial.
CDC/HHS HIV Preexposure Prophylaxis (2014, adapted)
- FTC-TDF 200-300 mg PO qday for preexposure prophylaxis as one prevention option in:
- Sexually active adult MSM at substantial risk for acquiring HIV infection (IA)
- Adult heterosexually active men and women at substantial risk for acquiring HIV infection (IA)
- Adult IVDU at substantial risk of HIV acquisition (IA)
- Multicenter, double-blind, parallel group, randomized, placebo-controlled trial
- N=2,499 high-risk HIV-seronegative men and transgender women who have sex with men
- FTC-TDF (n=1,251)
- Placebo (n=1,248)
- Setting: 11 centers in 6 countries
- Enrollment: 2007-2009
- Follow-up: 1.2 years (median)
- Analysis: Intention-to-treat
- Primary end point: HIV seroconversion
- Male sex
- Age ≥18 years
- High risk for HIV infection in prior six months:
- Anal sex with ≥4 partners
- Diagnosis of STI
- Transactional sex activity
- Condomless anal sex with partner with positive or unknown HIV status
- Karnofsky performance status ≥80
- Laboratory tests defined in the supplementary appendix
- Serious and active illnesses (eg, medication-controlled DM, TB, or cancer)
- Substance use likely to impair compliance
- Use of nephrotoxic agents
- Non-traumatic bone fractures
- Possible or definite treatment with antiretrovirals or an HIV vaccine in a clinical trial
- Age: 27.5 vs. 26.8 years (P=0.04)
- Transgender female: 1%
- Education level:
- Less than secondary: 21%
- Completed secondary: 35%
- Postsecondary: 42%
- Race/ethnicity: Hispanic 72%, mixed or other 69%, white 18%, black 9%, asian 5%
- Location: Peru 56%, Brazil 15%, Ecuador 12%, United States 9%, Thailand 5%, South Africa 4%
- Risk factors
- ≥5 alcoholic drinks per day: 54%
- No. of partners in past 12 wks: 18
- Unprotected receptive anal sex in past 12 wks: 59%
- Unprotected anal sex with partner with positive or unknown HIV status in past 6 mos: 80%
- Transactional sex in past 6 mos: 41%
- HIV-seropositive partner in past 6 mos: 2%
- STIs at screening: Syphilis 13%, HSV-2: 36%
- HBV status:
- Susceptible: 65%
- Natural infection immunity: 19%
- Previous vaccination immunity: 13%
- Current infection: 1%
- Indeterminate: 2%
- Randomization with stratification by site to either FTC-TDF or placebo
- Office visits every 4 weeks with safe-sex counseling and laboratory screening
Comparisons are FTC-TDF vs. placebo.
- HIV seroconversion
- 3.0% vs. 5.8% (HR 0.53; 95% CI 0.36-0.78; P=0.001; NNT=35)
- Unprotected receptive anal sex (P=0.01)
- Yes: 3.1% vs. 7.4% (HR 0.42; 95% CI 0.26-0.80; P not specified; NNT=23)
- No: 2.5% vs. 1.6% (HR 1.59; 95% CI 0.66-3.84; P not specified)
- Pill use (p-value for intereaction is 0.02)
- <90% pill use: percentages not given (HR 0.79; 95% CI 0.48-1.31; P not specified)
- ≥90% pill use: percentages not given (HR 0.27; 95% CI 0.12-0.59; P not specified)
Interactions non-significant for as treated analysis, age above or below 25 years, education level, ethnic group, region, alcohol use, circumcision, or HSV-2 positivity.
There were no differences in any adverse reaction or serious adverse events. FTC-TDF was associated with a higher rate of nausea and unintentional weight loss.
- Results cannot be extracted to other high risk groups like IVDU
- Unclear if the use of chemoprophylaxis will lead to riskier behaviors, which may be domstrated by increasing rates in RPR positivity during the trial
- Poor compliance likely worsened the results; it is unclear that outside of the rigidity of a clinical trial if adherence would worsen and the protective effect still exist
- The safety of long-term use in seronegative individuals is unknown
- May lead to increased rates of viral resistance, especially since multiple medications were not used
- Unclear about the significance of renal impairment
- The cost to prevent one infection in one year is $500,000, twenty times the cost of treating one person with HIV for the same timeframe
- It unclear if long-term prophylaxis will be of benefit, a more appropriate treatment path may be peri-intercourse prophylaxis
- Bill and Melinda Gates Foundation
- Division of Acquired Immunodeficiency Syndrome at NIH
- FTC-TDF and placebo donated by Gilead Sciences who also provided travel funds
- J. David Gladstone Institutes
- Authors with multiple conflicts of interest
- Shaffer N, et al. "Effect of zidovudine on perinatal HIV-1 transmission and maternal viral load." The Lancet(1999)354;9173:157-158.
- Karim, Quarraisha Abdool, et al. "Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women." Science.(2010)329;5996:1168-1174.
- Choopanya K, et al. "Antiretroviral prophylaxis for HIV infection in injecting drug users in Bankok, Thailand (the Bangkok Tenofovir Study): A randomised, double-blind, placebo-controlled phase 3 trial." The Lancet. 2013;381:2083-2090.
- Marrazzo JM, et al. "Tenofovir-based preexposure prophylaxis for HIV infection among African women." The New England Journal of Medicine. 2015;372(60):509-518.
- Supplementary Appendix
- Concurrent editorial
- NEJM Letters to the Editor