During the 2-year follow-up of initially HIV-uninfected men, the HIV incidence rate was 1.09/100 person-years (105/9604 person-years) (). In multivariate Poisson regression, the adjIRRs of HIV acquisition were significantly increased with enrollment HSV-2 prevalent positive serostatus (adjIRR 2.78, 95% CI 1.64–5.68), baseline indeterminate HSV-2 serostatus (adjIRR 2.99, 95% CI 1.58–5.68), and markedly increased with HSV-2 seroconversion during the trial (adjIRR 5.28, 95% CI 2.79–9.98). HIV risk was also increased with washing genitals after sexual intercourse, and self-reported GUD and urethral discharge symptoms. HIV acquisition was decreased with current marriage and male circumcision.
Risk factors for HIV incident infection.
As HSV-2 infection often causes symptomatic GUD, we conducted a sensitivity analysis excluding GUD symptoms from the multivariate analysis. When GUD was excluded from the adjusted analysis, the risks of HIV acquisition among HSV-2-prevalent positive individuals was adjIRR 2.90 (95% CI 1.71–4.92) and among HSV-2 seroconverters was adjIRR 6.00 (95% CI 3.19–11.24). These estimates are higher than the adjusted risks of HIV seroconversion, which controlled for GUD (), suggesting that symptomatic ulceration may be in the causal pathway between serologic HSV-2 and HIV acquisition. To evaluate the role of confounding due to sexual risk behaviors, we also conducted sensitivity analyses that adjusted for baseline demographic characteristics, but excluded sexual risk behaviors and GUD symptoms. The risk of HIV acquisition was similar to the fully adjusted analysis for the HSV-2-prevalent positive individuals (adjIRR 3.04, 95% CI 1.84–5.03) and HSV-2 seroconverters (adjIRR 5.63, 95% CI 3.05–10.41).
As HSV-2 seroconversion was most strongly associated with HIV acquisition during the trial, the timing of HIV and HSV-2 infection was determined for 17 individuals who acquired both HIV and HSV-2 during the 2-year follow-up. One participant did not have month 6 or year 1 samples available for evaluation of the timing of co-infections. Of the 16 dual HIV, HSV-2 seroconverter men for whom timing of both infections could be assessed, four acquired HIV in follow-up intervals prior to HSV-2 (25.0%), three acquired HSV-2 prior to HIV (18.8%), and nine (56.3%) acquired HIV and HSV-2 in the same follow-up interval ().
Timing of HIV and herpes simplex virus type 2 infection in men who acquired both infections during follow-up.
To determine whether acute HSV-2 infection is associated with HIV acquisition, multivariate analysis that incorporated the temporal sequence data was performed. The four individuals who acquired HIV prior to acquiring HSV-2 were considered persistent HSV-2-negative individuals, as they acquired HIV first. If it is assumed that all nine individuals with dual infections in the same follow-up interval acquired HSV-2 prior to HIV, the HIV acquisition rate was higher among incident HSV-2 individuals than among persistent negative individuals (adjIRR 3.40, 95% CI 1.74–6.67). If it is assumed that only the three individuals with documented incident HSV-2 prior to HIV truly acquired HSV-2 before HIV (i.e., the nine men with simultaneous HIV/HSV-2 acquisition were excluded), incident HSV-2 individuals had a similar rate of HIV acquisition compared with the persistent negative individuals (adjIRR 1.06, 95% CI 0.37–3.06).