Brown JM, Wald A, Hubbard A, Rungruengthanakit K, Chipato T, Rugpao S, Mmiro F, et al. Incident and prevalent herpes simplex virus type 2 infection increases risk of HIV acquisition among women in Uganda and Zimbabwe. AIDS 2007 Jul 31;21(12):1515-23.
To estimate the effects of prevalent and incident herpes simplex virus type 2 (HSV-2) infection on HIV acquisition in women.
A large, multi-center prospective cohort study.
Three sites in Kampala, Uganda and four sites in Harare and Chitungwiza, Zimbabwe.
Study participants were recruited and followed between November 1999 and January 2004. Participants were enrolled from a non-probability quota sampling of consecutive women seeking reproductive and general healthcare services. Women eligible for enrollment were 1) sexually active; 2) aged 18-35 years; 3) HIV-uninfected at screening; 4) not pregnant; 5) using combined oral contraceptives (low-dose, monophasic pills containing 30 µg ethinylestradiol and 150 µg levonorgestrel),150 mg depot-medroxyprogesterone acetate (DMPA), or no hormonal contraceptives (condoms, withdrawal, traditional methods, sterilization, no method) for at least three months. Each site enrolled roughly equal number of women using the three different contraceptive methods.
At enrollment, women completed a standardized interview to assess sociodemographic characteristics, lifetime history of sexual partners and sexually transmitted infections (STI), lifetime reproductive history, sexual behavior over the past three months, and characteristics of their current sexual partner. The study provided contraceptive counseling, HIV/STI risk-reduction counseling, and condom-use counseling, and provided condom and hormonal contraception. Clinicians performed physical (including pelvic) exams on study participants. Blood was collected to test for HSV-2 and HIV by antibody assay with polymerase chain reaction or Western blot confirmation for HIV, as well as for syphilis. Urine was collected for pregnancy testing. Cervicovaginal specimens were also collected to test for Chlamydia trachomatis, Neisserria gonorrhoeae, Trichomonas vaginalis, Candida albicans, and bacterial vaginosis. Treatment for vaginal and sexually transmitted infections was provided for participants, and those who tested positive for HIV were offered ongoing counseling and referred for medical care and emotional support. Study participants were evaluated at quarterly study visits for 15-24 months, depending on date of enrollment. Follow-up procedures were similar to those at enrollment.
The primary outcomes were HIV incidence, HSV-2 incidence, and the relationship between prevalent and incident HSV-2 infection and HIV incidence.
A total of 8,346 women were screened and 4,531 women were enrolled; 2,235 in Uganda and 2,296 in Zimbabwe. The mean follow-up time was 21.9 months; median time between visits was 81 days. The 24-month retention rate was 92%: 96% in Uganda and 88% in Zimbabwe. The median age of study participants was 25 years; median education was 10 years; median lifetime pregnancies was two; most participants (83%) lived with their primary sexual partners. Few participants (4%) reported having more than one sex partner in the three months prior to enrollment, and less than half (42%) of participants reported any condom use in the month prior to enrollment.
Approximately half of the study participants tested HSV-2 seropositive at enrollment: 51.5% in Uganda and 53.2% in Zimbabwe.
Overall, 324 HSV-2 seroconversions were detected, for an incidence rate of 9.6/100 person-years in Uganda and 8.8/100 person-years in Zimbabwe. In comparison with HSV-2 seronegative women, those with prevalent HSV-2 infection at enrollment in Uganda were older, less educated, married, and had a history of genital ulcers. In Zimbabwe, these women had similar characteristics, except they were not married and had more lifetime sexual partners. During follow-up, Ugandan women with prevalent HSV-2 infection were more likely to use hormonal contraception, have unprotected sex, have an uncircumcised partner, engage in commercial sex, report having a genital ulcer, test positive for N. gonorrhoeae and have pelvic inflammatory disease, and were less likely to be pregnant. In Zimbabwe, women with prevalent HSV-2 where more likely to have a new partner, an older sexual partner, or a partner with a genital ulcer; to engage in commercial sex, to report having a genital ulcer, and to test positive for T. vaginalis, C. trachomatis, N. gonorrhoeae, and bacterial vaginosis. Ugandan women who acquired HSV-2 infection during follow-up were less educated, more likely to be in a polygamous marriage, more likely to have more sexual partners or an older sex partner prior to infection, and were more likely to also be pregnant, and to test positive for N. gonorrhoeae and candidiasis when they seroconverted to HSV-2. Zimbabwean women who acquired HSV-2 during follow-up tended to be unmarried and more likely to have engaged in commercial sex, more likely to test positive for T. vaginalis, C. trachomatis, N. gonorrhoeae, and bacterial vaginosis, and more likely to have a genital ulcer by clinical examination.
A total of 211 HIV seroconversions were detected, which equates to a HIV incidence rate of 1.6/100 person-years in Uganda and 4.1/100 person-years in Zimbabwe. In Uganda, HIV incidence rates among women without HSV-2, with prevalent HSV-2 infection, and with incident HSV-2 infection were 0.7, 2.0, and 2.9/100 person-years, respectively. In Zimbabwe, HIV incidence rates among women without HSV-2, with prevalent HSV-2 infection, and with incident HSV-2 infection were 1.2, 5.8, and 9.7/100 person-years, respectively. Overall, approximately 84% of all HIV seroconversions occurred among women with prior HSV-2 infection. Ugandan women who acquired HIV were younger and more likely to be HSV-2 positive. They were also more likely to report having had a new sexual partner, more likely to also test positive for N. gonorrhoeae and bacterial vaginosis, and more likely to have a genital ulcer by clinical examination at the time of HIV diagnosis. Zimbabwean women who acquired HIV were less likely to be in a monogamous marriage, more likely to be HSV-2 infected, more likely to report being engaged in commercial sex, and more likely to also test positive for T. vaginalis, C. trachomatis, N. gonorrhoeae, bacterial vaginosis, and candidiasis at the time of HIV diagnosis.
The hazard ratio (HR) for HIV among women with prior HSV-2 infection, compared with women without HSV-2 infection, was 3.2 (95%CI, 1.7-6.3) in Uganda and 4.6 (95% CI, 2.8-7.6) in Zimbabwe after adjusting for confounding. The population attributable risk percent (PAR%) for HIV associated with prevalent and incident HSV-2 infection was 42% in Uganda and 65% in Zimbabwe. HR values for HIV among Ugandan women with prevalent HSV-2 infection and incident HSV-2 infection, compared with women without HSV-2, were 2.8 (95% CI, 1.5-5.3) and 4.6 (95% CI, 1.6-13.1), respectively, after adjusting for confounding. In Zimbabwe, these HRs were found to be 4.4 (95% CI, 2.7 -7.2) and 8.6 (95% CI, 4.3-17.1), respectively.
The authors conclude that both prevalent and incident HSV-2 infections are significant risk factors for HIV acquisition among women from the general population. They estimate that 42-65% of new HIV infections could be averted if all women remained HSV-2 negative. They further conclude that the control of both prevalent and incident HSV-2 infections could play an important role in preventing HIV transmission.
Based on the Newcastle-Ottawa rating system for observational cohorts, this study is of good quality. This study was limited by the lack of male partners' serostatus for HSV-2 and HIV, which could have been an important unmeasured confounding factor. That is, new acquisition of HSV-2 could be a marker for having a new partner infected with both viruses, as HIV-infected persons reactivate HSV-2 more frequently than HIV-uninfected persons and may be more likely to be infectious for HSV-2.
This is the first longitudinal study to provide evidence that both prevalent and incident HSV-2 infections significantly increase the risk for HIV acquisition among women from the general population. A number of previous studies have demonstrated the association of genital ulcers, and HSV-2 in particular, with HIV.(1,2) Prospective studies among men have shown an increased risk of acquiring HIV in both heterosexual and homosexual HSV-2 positive men, whereas prospective studies among women have had mixed results.(2) The authors posed two explanations for these previous results: 1) the transmission probability of HIV from men to women is higher than from women to men; hence, the baseline probability of women being exposed to HIV-positive partners is higher and lower relative risks would be observed; and 2) previous studies among women had relatively small sample sizes and incomplete control over confounding.
The PAR% in this study is consistent with the hypothesis that HSV-2 is responsible for a large proportion of new HIV infections in Africa. Existing interventions, such as condom promotion, suppressive treatment of HSV-2, and serological testing along with counseling, may help control the spread of HSV-2 and therefore have the potential to make a considerable impact on HIV transmission. Authors suggest that additional methods for controlling HSV-2, such as therapeutic and prophylactic vaccines, male circumcision and a topical microbicide, should be explored.
- Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis 2002 Jan 1;185(1):45-52.
- 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 Jan 2;20(1):73-83. Review.