Bollen LJM, Whitehead SJ, Mock PA, et al. Maternal herpes simplex virus type 2 coinfection increases the risk of perinatal HIV transmission: possibility to further decrease transmission? AIDS 2008;22:1169-76.
Herpes simplex virus type 2 (HSV-2) has been associated with increased risk of HIV acquisition.(1,2) A case-control study found higher rates of HIV perinatal transmission among HSV-2 seropositive women.(3) The role of HSV-2 shedding in the risk of perinatal HIV transmission has not been previously evaluated.
To measure the effect of HSV-2 seropositivity and HSV-2 genital shedding on the risk of perinatal HIV transmission.
Two hospitals in Bangkok, Thailand
Secondary analysis of a randomized clinical trial of perinatal HIV prevention conducted from May, 1996 through December, 1997.(4)
HIV-positive pregnant women who participated in the study and had stored plasma and cervicovaginal lavage (CVL) specimens
Perinatal HIV transmission
The clinical trial consisted of randomizing 397 HIV-infected pregnant women to receive zidovudine placebo before and during labor. Blood was collected at 36 weeks, plasma at 38 weeks, and at delivery, and CVL samples at 38 weeks of gestation. Infant whole blood was collected at birth and 2 months and tested for HIV using a modification of the DNA Roche Amplicor HIV-1 PCR. In utero transmission was defined as the infant being PCR-positive at birth, and intrapartum transmission was defined as the infant being PCR-negative at birth and PCR-positive at 2 months. The women did not breastfeed their infants. Women who delivered by caesarean section before onset of labor or had ruptured membranes, who transmitted HIV in utero, and who were without infant PCR at birth were excluded from the intrapartum analysis. Plasma and CVL specimens were tested for HIV.
The stored samples were tested for HSV using an enzyme-linked immunosorbent assay (ELISA) for plasma and DNA for CVL. Women whose CVL specimen was positive for HSV-2 DNA were considered to have genital HSV-2 shedding, and those with ELISA-positive specimens were considered to be HSV-2 seropositive. Women who were HSV-2 seronegative at 38 weeks were retested at 6 months or at 1 month if a 6-month sample was not available.
Risk factors for HIV transmission were measured using the X2 test, t-test, and Wilcoxon rank sum test. Adjusted odds ratios (ORs) with 95% confidence limits (CLs) for HSV-2 transmission were calculated using logistic regression. HSV-2 seropositivity and HSV-2 genital shedding both were evaluated as risk factors for HIV transmission, and known predictors of transmission, including HIV viral load, were included in the multivariable analysis.
This analysis included 307 women from the zidovudine study. The HIV transmission rate was 15.3% and the intrapartum transmission rate was 10.5%.
Of these 307 women, 228 (74.3%) were HSV-2 seropositive at 38 weeks and 23 (10.1%) had genital HSV-2 shedding at 38 weeks. Among the 79 women who were HSV-2 seronegative at 38 weeks, 76 had a 6-month plasma sample available and 3 had a 1-month sample available. Post-partum, 7 women were HSV-2 positive; 1 had HSV-2 detected from her CVL specimen, resulting in a total of 24 women with genital HSV-2 shedding.
HIV transmission among HSV-2 seropositive women was greater than that among HSV-2 seronegative women (18.0% vs. 7.65%, P=0.03) and HSV-2 seropositivity was an independent predictor of HIV transmission (adjusted OR 2.6; 95% CL: 1.0, 6.7). HSV-2 transmission was greater among women with genital HSV-2 shedding than among women not shedding HSV-2 (33.3% vs. 13.8%, P=0.02); however, genital shedding was not an independent predictor of HIV transmission.
Among women who received placebo, HIV transmission was 33.3% among women shedding HSV-2, 19.8% among HSV-2 seropositive women, and 12.5% among HSV-2 seronegative women. Among women treated with zidovudine, HIV transmission was 33.3% among women shedding HSV-2, 12.5% among HSV-2 seropositive women, and 2.6 among HISV-2 seronegative women.
Intrapartum transmission was 12.4% among HSV-2 seropositive women and 5.5% for HSV-2 seronegative women (P=0.1). HIV transmission was greater among women with genital shedding than among those without (27.3% vs. 9.0%, P=0.01). Genital shedding was independently predictive of intrapartum HIV transmission when compared with HSV-2 seronegative women (OR 6.1, 95% CL: 1.5, 24.6). Compared with women who were neither shedding virus nor seropositive, women with genital shedding had a significantly greater risk of transmitting HIV (OR 2.9, 95% CL: 1.0, 8.5).
HIV viral load was higher among women with genital shedding at 38 weeks (4.2 vs. 4.1 log10 copies/ml, P=0.05). A higher proportion of women with genital HSV-2 shedding had detectable HIV in CVL specimens when compared with women not shedding HSV-2 (62.5% vs. 34.3%, P=0.006).
HSV-2 seropositivity increases the risk of perinatal HIV transmission, and HSV-2 genital shedding increases the risk of intrapartum HIV transmission.
Although the data for this study were obtained from a clinical trial, the data presented in this analysis are observational. The cases (HSV-2 seropositive and presence of HSV-2 in CVL specimens) and controls were similar, although information regarding the representativeness of the sample is not stated. Ascertainment of exposure and outcome was excellent and follow-up time was adequate. Overall this was a high quality study.
This study provides strong evidence that there is increased risk of mother-to-child HIV transmission in the presence of coinfection with HSV-2. A previous study found that the presence of genital ulcers conferred an increased risk of HIV transmission.(5) This study also demonstrated that genital shedding of HSV-2 was associated with greater HIV viral load and it offers a biologically plausible mechanism for the increased HIV transmission. Both HIV and HSV-2 are highly prevalent in sub-Saharan Africa. Although the current evidence does not support HSV-2 suppression in sexually active adults to reduce HIV transmission,(6) its role in the prevention of mother-to-child transmission has not been fully evaluated. Further studies of this potential preventive measure are warranted.
- Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004;35:435-45.
- Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006;20:73-83.
- Cowan FM, Humphrey JH, Ntozini R, Mutasa K, Morrow R, Iliff P. Maternal herpes simplex virus type 2 infection, syphilis and risk of intra-partum transmission of HIV-1: results of a case control study. AIDS 2008;22:193-201.
- Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomized controlled trial. Lancet 1999;353:773-80.
- Grosskurth H, Gray R, Hayes R, Mabey D, Wawer M. Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials. Lancet 2000;355:1981-7.
- Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in Tanzania. New Engl J Med 2008;358:1-12.