In a randomized, controlled study of an HIV prevention intervention conducted among high-risk men who have sex with men, HIV infection rates were elevated among those who acquired herpes simplex virus type 2 (HSV-2) during follow-up, particularly within six months of the herpes diagnosis.1 The risk of herpes, in turn, was elevated among black men and among men who engaged in certain risky behaviors; it was not reduced among those who participated in the intervention.

The study, which was carried out in six U.S. cities from 1999 to 2003, recruited HIV-negative men who were at least 16 years old, had had anal sex with a man in the year before enrollment and were not in a mutually monogamous relationship of two or more years’ duration with an HIV-negative partner. Participants who were assigned to the intervention received individualized counseling in 10 hour-long sessions over 4–6 months, followed by quarterly maintenance sessions; those assigned to the control group received standardized pretest and posttest counseling and semiannual HIV tests. At six-month intervals, participants completed audio computer-assisted self-interviews about their sexual risk behavior since the previous interview, and provided blood samples for HIV and herpes testing. HSV-2 infections acquired during follow-up were categorized as recent incident at the visit at which they were detected, remote incident at visits within the next 24 months and prevalent at all subsequent visits. The analyses were based on the 3,909 participants for whom valid HSV-2 tests were available (91% of the cohort). These men were about evenly divided between the intervention and control groups; in both, the median follow-up time was 36 months.

Twenty percent of men in the analytic sample had HSV-2 infection when they entered the study, 75% were seronegative throughout the study and 4% acquired the virus during follow-up; the incidence of HSV-2 did not differ between the intervention and control groups. After conducting univariate regression analyses to identify potential predictors of herpes infection, the researchers performed multivariate hazard analyses to assess independent associations. These calculations confirmed that the likelihood of acquiring HSV-2 was similar for those assigned to the intervention and controls. Black men were significantly more likely than whites to become infected during follow-up (hazard ratio, 1.9), and those who reported having had unprotected receptive anal intercourse five or more times since the previous interview were more likely to do so than were those who said they had not engaged in this behavior (2.6). The likelihood of HSV-2 acquisition also was raised among men who, in the last six months, had had an HIV-positive male partner (1.6) or had had six or more partners (1.5).

Overall, the rate of HIV acquisition during follow-up was 1.9 per 100 person-years. Rates were significantly higher, however, among participants with herpes infection—6.9 per 100 person-years among those with recent incident infection, 6.8 per 100 among those with remote incident HSV-2 and 2.7 per 100 among those with prevalent infection. In analyses controlling for study arm, study site, age, race and a variety of risky behaviors, men with recent incident HSV-2 infection and those with prevalent infection were significantly more likely than those who remained free of HSV-2 to acquire HIV (hazard ratios, 3.6 and 1.5, respectively). Remote incident herpes infection was associated with an increase in the likelihood of HIV acquisition in the univariate analysis, but not in the multivariate analysis.

Twenty participants acquired both HSV-2 and HIV during follow-up; seven had the HSV-2 diagnosed before the HIV, and 13 had both infections detected at the same visit. No herpes infections were detected after an HIV diagnosis, because participation in the study ended if a man tested positive for HIV. The researchers note that distinguishing between a causal association and simultaneous acquisition of the two infections “is very difficult and would require very frequent HSV-2 and HIV testing.”

Given that the behavioral intervention was not associated with a reduced risk of HSV-2 acquisition, the researchers stress the need for studies to evaluate other prevention approaches, including education, counseling and potential vaccines. Furthermore, they conclude that HSV-2 infection is an important risk factor for HIV acquisition in this population and therefore “appears to be an important target for HIV prevention interventions.”—D. Hollander


1. Brown EL et al., High risk of human immunodeficiency virus in men who have sex with men with herpes simplex virus type 2 in the EXPLORE study, American Journal of Epidemiology, 2006, 164(8):733–741.