Celum et al. Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2. NEJM. 2010. 362:427-439
In HIV-1 infected populations, the seroprevalence of HSV ranges from 60-90%1
, and studies suggest that HSV may increase HIV transmission. In coinfected cells, HSV proteins bind HIV and promote transcription2–5
. HSV reactivation is associated with increased HIV levels in blood and the genital tract,6–9
and rates of sexual HIV transmission are markedly higher from persons with genital ulcers.10
Additionally, several randomized clinical trials (RCTs) demonstrate that anti-HSV therapy decreases plasma HIV levels.6,11–14
This study is an RCT designed to evaluate the effect of daily acyclovir therapy on HIV transmission.15
The investigators enrolled HIV serodiscordant heterosexual couples from seven sites in southern Africa and seven sites in eastern Africa. For each couple, the HIV-infected partner was seropositive for HSV, had CD4 cell count ≥250 cells/mm3
, no AIDS-related conditions, no current antiretroviral therapy, and no persistent genital ulcers. The HIV-negative partner was eligible whether HSV-negative or positive. The intervention group received acyclovir 400 mg twice daily, and the control group received an identical-appearing placebo. The primary outcome was HIV incidence. HIV sequencing was used to classify the transmission as ‘linked’ or ‘unlinked.’
There were 3,360 discordant couples included in the final analysis. In 68% of couples, the woman was HIV-infected. The median CD4 count was 462 cells/mm3. Sixty-eight percent of HIV-negative partners had HSV-2. There were 132 new HIV infections, corresponding to an incidence of 2.7 per 100 person-years (95% CI: 2.3 to 3.2). Eighty-four linked transmissions were included in the analysis, 41 in the acyclovir group and 43 in the placebo group (HR 0.92; 95% CI: 0.60–1.41).
The Bottom Line: Suppressive doses of acyclovir given for up to 2 years did not reduce HIV transmission, despite significantly decreased HIV viremia and symptomatic genital ulcers.
Wawer et al. Circumcision in HIV-Infected Men and Its Effect on HIV Transmission to Female Partners in Rakai, Uganda: A Randomised Controlled Trial. Lancet 2009.374:229-37
The World Health Organization (WHO) recommends male circumcision as a male HIV prevention strategy16
on the basis of several recent RCTs that reduced HIV transmission from females to their male partners17–19
This study enrolled 922 HIV-infected uncircumcised men aged 15–49 years of age who were randomized to receive either immediate circumcision or circumcision delayed for 24 months20
. One hundred sixty HIV-negative female partners were also enrolled. The primary outcome was the rate of acquisition of HIV among female partners, including all couples with at least one follow-up visit for the female partner. Seventeen of 92 (18%) women in the intervention group and 8 of 67 (12%) in the control group had incident HIV infection during the study period. Over 24 months, the cumulative probability of HIV infection was 21.7% (95% CI: 12.7–33.4) for women in the intervention group and 13.4% (95% CI: 6.7–25.8) for those in the control group. In a Cox proportional hazards regression analysis, the adjusted hazard ration (HR) was 1.49 (95% CI: 0.62–3.57; p
0.368). There were no significant differences in HIV incidence by participant characteristics or by women’s self-reported risk behaviors.
The Bottom Line: The trial was stopped early because of ineffectiveness: male circumcision of HIV-infected men did not reduce transmission of HIV to female partners of HIV-infected men in this study over a 24-month period.
Van Damme et al. Lack of Effectiveness of Cellulose Sulfate Gel for the Prevention of Vaginal HIV Transmission. NEJM. 2008. 359:463-472
More than half of all adults living with HIV/AIDS in sub-Saharan Africa are women.21
Most strides that have been made in HIV prevention (condoms, circumcision) depend largely on male cooperation. Topical microbicides offer the possibility of initiation by women. Cellulose sulfate is an entry inhibitor with in-vitro activity against HIV and demonstrated safety and tolerability. This was a randomized, double-blind, placebo-controlled trial22
of cellulose sulfate gel for prevention of HIV.
Women who were 18 or older, had a negative HIV-antibody test and reported three or more acts of vaginal intercourse/week and three or more different partners in the previous 3 months were recruited from five sites in Africa and India. The intervention group received 6% cellulose sulfate gel and controls an identical placebo (the pH of the compounds were different). The primary outcome was incident HIV infection.
Among 1,398 women, at the prespecified interim analysis point, there were 24 new HIV infections in the cellulose sulfate group and 11 among those receiving placebo (HR: 2.23, 95% CI: 1.05–5.03, p
0.02), prompting early termination of the trial. While this suggested increased risk of HIV transmission among women using cellulose sulfate, the interim analysis did not include an additional six incident cases that had not been entered in the database. Analysis including these cases yielded HR: 1.61 (95 CI: 0.86–3.01, p
0.13). An additional pre-planned analysis censoring data from participants who interrupted cellulose or placebo use (most often due to pregnancy) yielded a HR 2.02 (95% CI 0.97–4.18, p
In summary, there was a higher incidence of HIV in the cellulose sulfate group: however, this did not reach significance in the primary effectiveness analysis. It was noted by the investigators that there were non-differential pregnancy rates in the two groups. Given the contraceptive profile of cellulose sulfate, non-adherence might have been a factor in the observed results.
The Bottom Line: Cellulose sulfate is not effective in the prevention of vaginal HIV transmission.
Rerks-Ngarm et al. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. N Engl J Med. 2009. 361:2209-2220
This was a multicenter community-based, randomized double-blind, placebo-controlled trial in Thailand to evaluate the efficacy of vaccines to prevent HIV.23
The vaccine protocol consisted of a primer of a recombinant canarypox vector vaccine (ALVAC-HIV) (four injections) and two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). A total of 16,402 HIV-uninfected persons aged 18–30 years were enrolled. HIV testing was performed at baseline, 24 weeks, 26 weeks, and every 6 months for 3 years of follow-up. The primary outcomes were HIV infection and early HIV viremia.
There were 132 new HIV infections, 56 in the vaccine group and 76 in the placebo group over a total of 52,985 person-years of follow-up in the intention-to-treat analysis. This result translated to an observed efficacy of 26.4% (95% CI: -4.0–47.9, p
0.08). A modified intention-to-treat analysis excluded seven persons found to be HIV-infected at baseline. In this group, there were 125 new HIV infections, 51 in the vaccine group and 74 in the placebo group over 52,985 person-years of follow-up, corresponding to an observed vaccine efficacy of 31.2% (95% CI: 1.1–52.1, p
0.04). A per-protocol additional analysis included only those who received all scheduled vaccinations in the series, maintained eligibility in the study, and had not acquired HIV by the fourth vaccination. Among this group, there were 86 new HIV infections, 36 in the vaccine group and 50 in the placebo group in 36,720 person-years of follow-up corresponding to an observed vaccine efficacy of 26.2% (95% CI: -13.3–51.9, p
The Bottom Line: While the intention to treat analysis demonstrated only a trend towards efficacy, after excluding those with HIV at baseline, there was a significant reduction in HIV incidence in the vaccination group. Future studies must address the immune mechanisms involved as well as whether vaccine efficacy varies over time and in certain populations.