Sexually Transmitted Diseases:
Prevalence of Herpes Simplex Virus Type 2 Infection, Human Immunodeficiency Virus/Herpes Simplex Virus Type 2 Coinfection, and Associated Risk Factors in a National, Population-Based Survey in Kenya
Mugo, Nelly MD*†; Dadabhai, Sufia S. MHS‡; Bunnell, Rebecca ScD§; Williamson, John PhD¶; Bennett, Eddas MPH∥; Baya, Isaack MS**; Akinyi, Nelly MS§††; Mohamed, Ibrahim MD‡‡; Kaiser, Reinhard MD§
From the *Department of Gynaecology, Kenyatta National Hospital, Nairobi, Kenya; †Department of Global Health, University of Washington, Seattle, WA; ‡Global Health Sciences, University of California San Francisco, Nairobi, Kenya; §Division of Global HIV/AIDS, U.S. Centers for Disease Control and Prevention, Nairobi, Kenya; ¶Center for Global Health, U.S. Centers for Disease Control and Prevention, Kisumu, Kenya; ∥Division of Global HIV/AIDS, U.S. Centers for Disease Control and Prevention, Atlanta, GA; **National HIV Reference Laboratory, Kenya National Public Health Laboratory Services, Nairobi, Kenya; ††Kenya Medical Research Institute, Nairobi, Kenya; and ‡‡Kenya National AIDS and STI Control Programme, Nairobi, Kenya
We thank Dr. George Rutherford for his careful comments on an earlier version of the manuscript and Dr. Anna Wald for her insights.
Presented at Conference of the International AIDS Society, July 2009, Cape Town, South Africa, Abstract MOPEB016.
The findings and conclusions in this paper are those of the author(s) and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention.
Supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Centers for Disease Control and Prevention and the U.S. Agency for International Development; and by the Joint United Nations Programme on HIV/AIDS.
The authors declare that we fulfill the criteria for authorship and that no author has any financial or non-financial association to an institution that might have an interest in the submitted work.
Correspondence: Sufia S. Dadabhai, MHS, 1201 W. Mount Royal Avenue, 529, Baltimore, MD 21217. E-mail: email@example.com.
Received for publication April 3, 2011, and accepted July 18, 2011.
Background: Herpes simplex virus type 2 (HSV-2) is a known biologic cofactor for human immunodeficiency virus (HIV) transmission and acquisition. The Kenya AIDS Indicator Survey 2007 provided Kenya's first nationally representative estimate of HSV-2 prevalence and risk factors.
Methods: KAIS was a household serosurvey among women and men aged 15 to 64 years. The survey included a behavioral interview and serum testing for HSV-2, HIV, and syphilis infections. Results were weighted for sampling design and nonresponse.
Results: Of 19,840 eligible individuals, 90% completed an interview and 80% consented to testing. In all, 35% were infected with HSV-2, of which 42% were women and 26% were men. Between 15 and 24 years of age, HSV-2 prevalence increased from 7% to 34% in women and 3% to 14% in men. Among couples, 30% were HSV-2 concordant-positive, 21% were discordant, and 49% were concordant-negative. In all, 81% of HIV-infected persons were coinfected with HSV-2. HIV prevalence was 16% among those with HSV-2 and 2% among those without HSV-2. Women with circumcised partners had an HSV-2 prevalence of 39% compared to 77% of women with uncircumcised partners.
Conclusions: One-third of Kenyans were HSV-2 infected. HIV-1 infection, age, female sex, and lack of male circumcision were population-level predictors for HSV-2 infection. Targeted prevention interventions are needed, including an effective vaccine.
Herpes simplex virus type 2 (HSV-2) is endemic in low-, middle-, and high-income countries.1 An estimated 16% (536 million) of adults and adolescents are infected worldwide. HSV-2 infection persists for life and can cause painful recurrences, shame, embarrassment, disruption of relationships, and in some cases, severe complications such as encephalitis. Viral shedding occurs as often in symptomatic individuals as in asymptomatic individuals.2,3 Though HSV-2 is not generally a life-threatening infection, it has been reported to cause fulminant hepatitis in pregnant women and severe persistent infection in immunocompromised and occasionally immunocompetent adults.4–6 Moreover, perinatal transmission can lead to life-threatening disseminated infections in neonates with an infant mortality rate >80% among those infected.5,7
HSV-2 has also been implicated in the human immunodeficiency virus (HIV) pandemic. A large body of scientific data provides evidence for a synergistic relationship between HIV and HSV-2 transmission,8–14 and populations with high HSV-2 prevalence have equally high HIV-1 seroprevalence.15,16
Population-based prevalence estimates for HSV-2 are rare, particularly in sub-Saharan Africa, the region with the largest HIV disease burden. In Senegal, 16% of women attending antenatal clinics and 23% of sex workers were found infected with HSV-2 in 2003.17 A cross-sectional study of adults in 4 African cities revealed an estimated prevalence of 50% in women and over 25% in men in Yaoundé, Cameroon, Kisumu, Kenya, and Ndola, Zambia; with a lower prevalence in Cotonou, Benin, at 30% in women and 12% in men.15 Studies of higher-risk populations such as sex workers, sexually transmitted infection (STI) clinic patients and migrant workers have consistently indicated that half of the members in these subpopulations are infected with HSV-2.18 General population prevalence estimates have not been previously available for Kenya, a country with a maturing and largely diverse HIV epidemic. Through the Kenya AIDS Indicator Survey 2007, the Kenyan Ministry of Health conducted HSV-2 serological testing among a nationally representative sample. We present here the prevalence of HSV-2 and HIV/HSV-2 coinfection along with significant correlates of infection and coinfection.
MATERIALS AND METHODS
Study Population and Study Design
KAIS was a nationally representative, cross-sectional, household serosurvey of adults aged 15 to 64 years conducted between August and December 2007. The study used a 2-stage, stratified sampling design to produce national estimates and separate estimates for urban and rural areas and for each of the 8 provinces. Eligible persons were asked for separate informed consent for participation in interviews and blood draws. The KAIS protocol was approved by Kenya Medical Research Institute and the U.S. Centers for Disease Control and Prevention institutional review boards. Further details of KAIS methods are published elsewhere.19
KAIS included an interview and venous blood draw, but not a physical examination for STI symptoms. We used a structured, interviewer-administered questionnaire to obtain information from consenting participants. Questions included socio-demographics such as age, wealth, and marital status; sexual behaviors such as condom use, self-reported history of STI symptoms and genital ulcers (men only), number of sexual partners, circumcision (men only), and pregnancy status (women only). Wealth was a composite index of the living standard of a household, calculated using data on a household's ownership of selected assets, materials used for housing construction, water access, and sanitation facilities. The wealth index placed households on a continuous scale of relative wealth using principal components analysis. Individuals were categorized according to the score of their household and the sample was divided into quintiles, each with an equal number of individuals, ranging from the poorest to wealthiest. We defined “single” as persons who reported having never married or cohabited. Condom use was defined as condom use at last sex.
Laboratory tests were performed by the Kenya National Public Health Laboratories. Quality assurance (QA) testing was conducted by the laboratory at the Kenya Medical Research Institute/U.S. Centers for Disease Control and Prevention in Nairobi, Kenya. For HSV-2 testing, we used Kalon enzyme immunoassay (EIA) based on IgG-2 according to the manufacturer's recommendations (Kalon Biological Limited, Guildford, United Kingdom). This test has been compared with other commercially available kits in 3 large studies of sera from Kenya. Relative sensitivity and specificity varied from 92% to 94% and 79% to 95%, respectively. The 3 studies concluded the Kalon EIA performed best against the reference test (Western Blot).20–22 All specimens reactive with the first EIA run were retested with a repeat Kalon read by a second laboratory technician. For quality control, all reactive specimens, 5% of randomly selected nonreactive specimens and specimens in gray zones were retested at the QA laboratory using the same Kalon EIA testing algorithm. Specimens with discordant results between the laboratories were reported as indeterminate. Specimens were screened for HIV-1 using Vironostika HIV-1/2 test (Bio-Mérieux Diagnostics, Marcy-l'Etoile, France) and confirmed with Murex HIV.1.2.O EIA (Abbott Laboratories, Abbott Park, IL) in a serial testing algorithm. All HIV seropositive and 5% of seronegative specimens were retested at the QA laboratory using the same algorithm.
Univariate, bivariate, and multivariable data analyses were performed using survey procedures in SAS 9.2 (SAS Institute, Cary, NC). Hypothesis tests were considered statistically significant for P < 0.05. Logistic regression was used to model HSV-2 prevalence adjusting for differences in socio-demographics and sexual behavior between those infected and not infected with HSV-2. Separate models were fit for women and men. Survey variables that were independently associated with HSV-2 infection in bivariate analysis or potential confounders were included in the preliminary logistic regression model. Backward elimination was used to fit the model; if a predictor was found to be significant in either the model for women or men, it was included in both models for comparability. Education level and self-perceived HIV risk for both women and men; condom users among men were the only variables associated with HSV-2 infection dropped from the multivariable model due to nonsignificance. Pairwise interactions were evaluated, although none were found to be significant and are not reported here. History of symptoms of genital ulcer disease (GUD) and male circumcision was only included in the model for men; these questions were not asked to women.
We also conducted descriptive analysis on HSV-2 and HIV test results from couples. Couples were defined as the head of household and his or her married or cohabitating partner. In case of a polygamous partnership, the husband and only one partner were included. A couple was considered discordant if only one partner was HSV-2 and/or HIV infected. A couple was concordantly infected or concordantly uninfected if both partners were either infected or uninfected, respectively, with HSV-2 and/or HIV. Population estimates, including 95% confidence intervals, and the logistic regression model were adjusted for sampling design and nonresponse.
A total of 19,840 individuals were eligible for the survey, of which 17,940 (90.0%) consented to be interviewed. Of these, 15,853 (88.4%) consented to biologic testing and 15,707 (87.5%) individuals had both HSV-2 and HIV test results. Concordance between results from the primary testing laboratory and the QA laboratory was 97% for both reactive and nonreactive samples. Among the 15,707 participants, HSV-2 seroprevalence was 35.1%, 16.4% of whom were also infected with HIV-1. Conversely, among the 1100 HIV-infected participants, 884 (80.7%) were infected with HSV-2.
Women had significantly higher HSV-2 prevalence than men (42% vs. 26%, P < 0.001). Those with HIV or syphilis infection also had higher HSV-2 prevalence than those not infected with HIV or syphilis (Table 1). For both women and men, HSV-2 prevalence increased with age (P < 0.001); prevalence among women was higher than men in all age groups. Among persons aged 15 to 24 years, HSV-2 prevalence increased rapidly and linearly for women (P < 0.001) but not for men (P = 0.15) (Fig. 1). There was a significant difference between women and men at all ages, similar to but more extreme than the pattern observed for HIV infection (Fig. 1). HSV-2 prevalence reached 34% and 14% in 24-year-old women and men, respectively (Fig. 1, P < 0.001). Prevalence of HSV-2 also varied significantly by geography. Women (57.3%) and men (37.7%) in Nyanza Province had a higher prevalence than adults in other provinces.
HSV-2 prevalence was significantly higher if women and men had more than one lifetime partner (Table 1) and increased linearly with the number of lifetime partners (Fig. 2, P < 0.001). Similar to age, prevalence among women was higher than men in all lifetime partner categories (Fig. 2). Among women with sexual activity in the year before the survey, a significantly higher proportion of those reporting recent STI symptoms were infected with HSV-2 (61%) than among women who reported no recent STI symptoms (47%, P < 0.001). Similarly, among men with recent sexual activity, significantly more men reporting recent GUD symptoms (56%) tested positive for HSV-2 compared with men without GUD symptoms (26.1%, P < 0.001). Circumcised men had significantly lower rates of HSV-2 than uncircumcised men (24% vs. 39%, P < 0.001); women with circumcised partners had a significantly lower prevalence of HSV-2 infection (39% vs. 77%, P < 0.001). History of condom use was protective for men (19% vs. 34%) but not for women (Table 1). However, on subset multivariable analysis of sexually active men, condom use at last sex was no longer significant (odds ratio: 0.8, 95% confidence interval: 0.5–1.1, P = 0.1). Both women and men who perceived themselves at risk for HIV had an increased likelihood of having HSV-2 infection compared with men and women who did not self-perceive to be at risk for HIV infection.
In multivariable analysis (Table 2), uncircumcised men had 2 times the odds for HSV-2 infection. Married or cohabiting individuals were twice as likely as single persons to be infected; syphilis was associated with 3.5-fold odds of HSV-2 in women and 2.4-fold odds in men. HIV-1 infection was strongly associated with HSV-2 infection, with HIV-infected women and men having 7.5- and 4.4-fold odds of HSV-2 compared with those without HIV, respectively.
Of the 3256 identified couples in KAIS, 2708 couples had both HSV-2 and HIV results available. In 777 (30%) couples, both partners were infected with HSV-2, and in 576 (21%) only one partner was infected. Of the couples concordantly infected with HSV-2, 10% were discordantly infected with HIV. Similarly of the couples discordantly infected with HSV-2, 9% were discordantly infected with HIV. Among couples in whom neither partner was HSV-2 infected, only 0.4% were concordant and 2.6% were discordant for HIV-1 infection (Table 3).
In a nationally representative sample, 35% of Kenyan adults were infected with HSV-2. Older age, female sex, marriage or cohabitation, residence in Nyanza Province, syphilis infection, HIV infection, recent GUD or STI symptoms, and lack of male circumcision were associated with HSV-2 infection. Interestingly, we were able to demonstrate lower prevalence of HSV-2 in women whose primary partner was circumcised, suggesting a secondary benefit of male circumcision, which has not yet been demonstrated for HIV-1 infection.23 For men, the protective effect of circumcision has been demonstrated for both HIV-1 and HSV-2 incidence.24 In Nyanza, the relatively low proportion of circumcised men (48% compared with 85% nationally19) and the substantial burden of HIV infection (15% compared with 7% nationally19) may help explain the higher prevalence of HSV-2 in this province.
The interaction between HSV-2 and HIV is clear and compelling. Only 19% of HIV-infected persons did not have HSV-2 infection. Although 3 randomized controlled trials were unable to demonstrate a protective effect of herpes suppression on HIV transmission,25–27 suppression has been shown to decrease HIV shedding.28–30 In 81% of couples discordant for HIV, one or both partners were infected with HSV-2, placing the HIV-uninfected partner at increased risk of HIV acquisition compared to couples without HSV-2 infection.
Women experienced higher HSV-2 prevalence across all ages and sexual risk patterns compared to men. Young women in particular had a rapid increase in HSV-2 prevalence between ages 16 and 24 years, similar to but more extreme than the HIV-1 prevalence pattern in this age group (Fig. 1). This pattern is similar to findings from population surveys conducted in Mexico and the United States.31,32
KAIS had both limitations and strengths. First, cross-sectional surveys do not allow for determination of the sequence of behaviors and infections which complicates interpretation of associations. Second, all sexual behavior was self-reported. Participants may have underreported sexual activity and sexual risk factors, which, coupled with the small but existing possibility of false positive assay results, may explain why participants who reported no sexual partners tested positive for HSV-2. Finally, physical examinations were not performed, so there may have been under- or overreporting of circumcision. Nonetheless, the direction of the misclassification is unlikely to be unidirectional. Strengths of the study include its large, nationally representative sample and its ability to match socio-demographic, behavioral, and laboratory results.
Study findings should be used to increase awareness of the high population prevalence of genital herpes infection in Kenya. These results can also help identify vulnerable groups (i.e., youth, women, uncircumcised men and their partners, and persons with multiple partners) and opportunities to monitor and alter population risk for both HSV-2 and HIV. In addition, findings reinforce the need to advance our understanding of HSV-2 as a biologic cofactor in HIV acquisition and transmission.33 It is also important to develop programs for prevention, diagnosis, and management of this STI in keeping with World Health Organization guidelines recommending the use of acyclovir as first-line syndromic GUD treatment in countries with high HSV-2 prevalence (≥30%).34 HSV-2 suppression with twice daily acyclovir assessed in clinical trials did not prevent HIV acquisition25,27 or transmission.26 An antiretroviral vaginal gel has recently shown promising results in reducing HSV-2 acquisition.35 In addition, an HSV-2 vaccine research should continue as a priority in spite of the fact that recent data from an HSV-2 vaccine study did not find efficacy.36
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