Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis

Abstract

Background: HIV and herpes simplex virus type 2 (HSV-2) infections cause a substantial global disease burden and are epidemiologically correlated. Two previous systematic reviews of the association between HSV-2 and HIV found evidence that HSV-2 infection increases the risk of HIV acquisition, but these reviews are now more than a decade old.

Methods: For this systematic review and meta-analysis, we searched PubMed, MEDLINE, and Embase (from Jan 1, 2003, to May 25, 2017) to identify studies investigating the risk of HIV acquisition after exposure to HSV-2 infection, either at baseline (prevalent HSV-2 infection) or during follow-up (incident HSV-2 infection). Studies were included if they were a cohort study, controlled trial, or case-control study (including case-control studies nested within a cohort study or clinical trial); if they assessed the effect of pre-existing HSV-2 infection on HIV acquisition; and if they determined the HSV-2 infection status of study participants with a type-specific assay. We calculated pooled random-effect estimates of the association between prevalent or incident HSV-2 infection and HIV seroconversion. We also extended previous investigations through detailed meta-regression and subgroup analyses. In particular, we investigated the effect of sex and risk group (general population vs higher-risk populations) on the relative risk (RR) of HIV acquisition after prevalent or incident HSV-2 infection. Higher-risk populations included female sex workers and their clients, men who have sex with men, serodiscordant couples, and attendees of sexually transmitted infection clinics.

Findings: We identified 57 longitudinal studies exploring the association between HSV-2 and HIV. HIV acquisition was almost tripled in the presence of prevalent HSV-2 infection among general populations (adjusted RR 2·7, 95% CI 2·2-3·4; number of estimates [N_e]=22) and was roughly doubled among higher-risk populations (1·7, 1·4-2·1; N_e=25). Incident HSV-2 infection in general populations was associated with the highest risk of acquisition of HIV (4·7, 2·2-10·1; N_e=6). Adjustment for confounders at the study level was often incomplete but did not significantly affect the results. We found moderate heterogeneity across study estimates, which was explained by risk group, world region, and HSV-2 exposure type (prevalent vs incident).

Interpretation: We found evidence that HSV-2 infection increases the risk of HIV acquisition. This finding has important implications for management of individuals diagnosed with HSV-2 infection, particularly for those who are newly infected. Interventions targeting HSV-2, such as new HSV vaccines, have the potential for additional benefit against HIV, which could be particularly powerful in regions with a high incidence of co-infection.

Funding: World Health Organization.

Figure 1

Study selection *The search was done in parallel by two reviewers (KJL and JARE). The results for one reviewer are shown; the results were very similar between the two reviewers. Each reviewer found eight publications to be relevant that the other reviewer did not. HSV-2=herpes simplex virus type 2.

Figure 2

Pooled adjusted RR estimates of the association between HIV incidence and exposure to HSV-2 infection Estimates for effect of both prevalent and incident HSV-2 infection on HIV acquisition (timing 1; ie, HSV-2 seroconversion was observed in a previous time interval and so definitely occurred before HIV seroconversion) are shown. Estimates are shown for women and men combined when they could not be obtained separately by sex. Multiple estimates for the same study corresponding to different study countries or areas are shown when these could not be combined or when it was not appropriate to do so (ie, countries spanning two sub-regions); however, all estimates are independent (ie, for non-overlapping study populations) within each HSV-2 exposure subcategory. N_e=number of estimates. RR=relative risk. HSV-2=herpes simplex virus type 2. *Data from these studies were obtained from reference 11.

Figure 3

Sub-pooled adjusted RR estimates of the association between HIV incidence and exposure to HSV-2 infection Estimates for effect of both prevalent and incident HSV-2 infection on HIV acquisition (timing 1; ie, HSV-2 seroconversion was observed in a previous time interval and so definitely occurred before HIV seroconversion) are shown. Estimates were added for sub-pooling if they were available by subcategories, although only independent study estimates were included within a subcategory. RR=relative risk. HSV-2=herpes simplex virus type 2. N_e=number of estimates. FSWs=female sex workers. MSM=men who have sex with men.