Introduction HIV and herpes simplex virus type 2 (HSV-2) infections cause a large burden of disease globally and are correlated epidemiologically through shared risk factors. There is also evidence for direct, biological interactions, with HSV-2 infection increasing HIV susceptibility (and vice versa). We update and expand on two previous systematic reviews of the association between HSV-2 infection and HIV acquisition published over a decade ago.

Methods We conducted a systematic review and random-effects meta-analysis of 56 longitudinal studies of the association between HSV-2 infection and HIV acquisition. We calculated pooled effect sizes using DerSimonian-Laird inverse-variance methods for the association between existing (prevalent) HSV-2 infection and HIV seroconversion and the first-ever pooled effect sizes for new (incident) HSV-2 infection on HIV. We extended previous evaluations through detailed meta-regression and sub-group analyses.

Results The risk of acquiring HIV infection was approximately doubled in the presence of prevalent HSV-2 infection, and higher among general populations (aRR=2.7; 95% CI 2.2–3.4, n=24) than higher-risk populations such as commercial sex workers and men who have sex with men (aRR=1.7; 95% CI 1.4–2.1, n=25). Incident HSV-2 infection was associated with the highest risk of acquiring HIV: up to aRR=4.7 (95%CI 2.2–10.1, n=6). Adjustment for confounders was often incomplete, but this did not meaningfully influence results in subgroup analysis. Substantial heterogeneity across study estimates was explained by risk group, timing of HSV-2 infection, and world region.

Conclusion There is good evidence for a direct effect of HSV-2 infection on HIV acquisition risk. This has important implications for managing individuals diagnosed with genital herpes, given the greater risk of acquiring HIV, especially for those newly infected. Interventions targeted against HSV-2, such as new HSV vaccines, have the potential for an additional benefit against HIV, which could be substantial particularly in regions where co-infections are abundant.