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The Role of Herpes Simplex Virus Type 2 and Other Genital Infections in the Acquisition of HIV-1 among High-Risk Women in Northern Tanzania

  1. Saidi H. Kapiga1,6,
  2. Noel E. Sam6,7,
  3. Heejung Bang4,
  4. Quanhong Ni4,
  5. Trong T. H. Ao1,
  6. Ireen Kiwelu6,7,
  7. Sarah Chiduo6,7,
  8. Uzodinma Ndibe6,
  9. George Seage III2,
  10. Paul Coplan5,
  11. John Shao6,
  12. Zeda F. Rosenberg5 and
  13. Max Essex3
  1. 1 Departments of Population and International Health, Harvard School of Public Health, Boston, Massachusetts
  2. 2 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
  3. 3 Departments of Immunology and Infections Diseases, Harvard School of Public Health, Boston, Massachusetts
  4. 4 Division of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, New York, New York
  5. 5 International Partnership for Microbicides, Silver Spring, Maryland
  6. 6 Kilimanjaro Reproductive Health Program, Kilimanjaro Christian Medical Centre, Moshi, Tanzania
  7. 7 Department of Clinical Laboratories, Kilimanjaro Christian Medical Centre, Moshi, Tanzania
  1. Reprints or correspondence: Saidi H. Kapiga, Harvard School of Public Health, Dept. of Population and International Health, 665 Huntington Ave., Bldg. 1-1105 Boston, MA 02115 (skapiga{at}hsph.harvard.edu).
 
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Abstract

Background. We examined the role of herpes simplex virus type 2 (HSV-2) and other genital infections on human immunodeficiency virus type 1 (HIV-1) incidence in a cohort study conducted between 2002 and 2005 among female bar/hotel workers in Moshi, Tanzania.

Methods. At baseline and every 3 months thereafter, participants were interviewed, and blood and genital samples were collected. Predictors of HIV-1 incidence were evaluated using a Cox proportional hazards regression model.

Results. Of 845 women who were HIV-1 seronegative at baseline, 689 (81.5%) were monitored in the study for a total of 698.6 person-years at risk (PYARs). The overall HIV-1 incidence was 4.6/100 PYARs (95% confidence interval [CI], 3.0–6.2/100 PYARs), and condom use was very low. After adjustment for other risk factors, the risk of HIV-1 was increased among women with HSV-2 at baseline (hazard ratio [HR], 4.3 [95% CI, 1.5–12.4]) and in those who acquired HSV-2 during the study period (HR, 5.5 [95% CI, 1.2–25.4]). Other independent predictors of HIV-1 were baseline chlamydial infection (HR, 5.2), bacterial vaginosis (HR, 2.1), and the occurrence of genital ulcers (HR, 2.7).

Conclusion. HSV-2 and other genital infections were the most important risk factors for HIV-1. Control of these infections could help to reduce HIV-1 incidence in this population.

The HIV-1 epidemic is a major public health challenge in sub-Saharan Africa, where >25 million people are infected [1]. Although most countries in this region are experiencing high rates of HIV-1 infection, rates vary among a variety of populations. One of the groups disproportionately affected by the epidemic is women working in bars and hotels in urban centers and periurban communities. In most countries, the risk of HIV-1 and other sexually transmitted diseases (STDs) is higher among such women than among other women in the general population [2–6]. Women working in these settings are part of multilevel, complex sexual networks involving multiple partners and the exchange of sex for gifts or money [5, 6]. Thus, female bar and hotel workers may be part of core groups contributing to the continued expansion of the HIV-1 epidemic in Africa.

Between June and October 2000, we conducted a cross-sectional study to determine the behavioral and biological risk factors for HIV-1/STDs among bar and hotel workers in Moshi, Tanzania [5]. Although that study provided valuable information about factors associated with prevalent HIV-1 infection in this population, it was limited by its cross-sectional design; thus, both the rate and predictors of acquisition of new HIV-1 infections remained unknown. Accurate estimates of HIV-1 incidence are essential for planning intervention programs and in the design of clinical trials of promising interventions. In addition, the role of herpes simplex virus type 2 (HSV-2) infections in HIV-1 acquisition has not been established in this population. HSV-2 infection is known to be a cofactor for HIV-1 [7, 8]. To obtain this information and describe the evolution of the HIV-1 epidemic among female bar and hotel workers in Moshi, we conducted a prospective cohort study and examined the role of HSV-2, other genital infections, and behavioral factors on the incidence of HIV-1 in this population.

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Subjects and Methods

Study design and data collection. The study procedures have been detailed elsewhere [9]. In brief, women ≥14 years old, working in registered bars/hotels in Moshi, and willing to provide written consent were eligible to participate in the study. Information about the number and location of registered bars/hotels in all 15 administrative wards of Moshi was collected. We initiated data-collection activities in the ward with the largest number of bars/hotels and progressed to the ward with the next largest number of bars/hotels until a predetermined sample size was reached. In each ward, outreach workers visited the bars/hotels and met with female workers to provide brief information about the study and to invite them to the study clinic to obtain more-detailed information. Between December 2002 and November 2003, 1050 women working in these settings were enrolled from bars/hotels located in 7 of 15 wards. This sample size was determined to provide 80% power to detect a minimum HIV-1 incidence of 3.4/100 person-years at risk (PYARs).

At baseline, participants were interviewed by female nurses to obtain information about potential risk factors for HIV-1/STDs. After the interviews, pretest counseling was provided before blood for HIV-1, syphilis, and HSV-2 testing was obtained. A physical examination, including a speculum examination with the collection of specimens for laboratory diagnosis of STDs and other genital infections, was performed by a female physician. Participants returned to the clinic for follow-up visits once every 3 months for 1 year. At each visit, a structured follow-up questionnaire was administered to obtain information regarding the preceding 3 months (or since the last visit if the subject did not return to the clinic within 3 months). After the follow-up interviews, pretest counseling and a medical examination, including a blood draw for HIV-1/STD testing, were performed using the same the procedures as those at baseline.

Syndromic treatment was given at no cost to participants with signs or symptoms of STDs and other genital infections, in accordance with Tanzania Ministry of Health guidelines. Participants returned to the clinic within 7 days for results and posttest counseling. At each visit, women received individual HIV-1 risk-reduction counseling, including the recommendation to use condoms during each sexual exposure. Condoms were provided at no cost, as was additional treatment when indicated by the laboratory results. Women were encouraged to bring their male partners for counseling and STD testing. For participants who seroconverted, counseling included provision of information on behaviors that place them and their partners at increased risk of STDs and HIV-1. This research was conducted as a collaborative effort of the Kilimanjaro Christian Medical Centre and the Harvard School of Public Health, and ethical approval was obtained from both institutions.

Laboratory methods. HIV-1 testing was performed at baseline and every 3 months thereafter using 2 ELISAs. Murex 1.2.0 (Murex Biotech) and Enzygnost HIV-1/HIV-2 (Behring) tests were used for screening, and Vironostika HIV Uni-Form II plus ELISA (Organon) was used for confirmation. Indeterminate results were resolved by Western blotting (Genetic Systems; Bio-Rad Laboratories). HSV-2 was detected using the type-specific HSV-2 ELISA in accordance with the manufacturer's instructions (Focus Technologies). As part of the quality assurance system, all samples testing positive for HIV-1 and HSV-2 during the study and 10% of the negative samples were retested to confirm the results. Active/recent syphilis was diagnosed if serum was reactive on the rapid plasma reagin card test (Becton Dickinson) with a titer ≥1:8 and on the Treponema pallidum hemagglutination assay (Murex Biotech).

A wet mount of a vaginal swab was examined microscopically for the presence of motile Trichomonas vaginalis and yeast cells. Candidiasis was diagnosed by the isolation of gram-negative yeastlike cells on Saboraud's dextrose agar (Remel). Chlamydia trachomatis antigen was detected using ELISA (Murex Biotech). Positive samples were confirmed by a blocking assay. This method has a sensitivity of 65%–92% and a specificity of 96%–100%, compared with culture methods [10]. Disturbances of vaginal flora and bacterial vaginosis (BV) were diagnosed on the basis of 4 clinical criteria, as proposed by Amsel et al. [11].

Statistical analysis. Data were entered twice into a computer database and were later checked for consistency and accuracy. To be included in the present analysis, participants had to be HIV-1 negative at enrollment. The acquisition of HIV-1 infection was defined by seroconversion at any of the follow-up visits. Incidence rates were calculated by dividing the number of new infections by the total PYARs of follow-up, with 95% confidence intervals (CIs) computed using a Poisson model for the count data [12]. For participants who seroconverted for HIV-1 infection, PYARs were calculated as the time from enrollment to the midpoint between the last HIV-1—negative test result and the first positive result. For participants remaining HIV-1 negative, PYARs of observation were the time up to the last observed date of follow-up. We also computed HIV-1 incidence rates for various subgroups defined by demographic characteristics, baseline and follow-up sexual behavior, the presence of STDs, and other risk factors.

Correlates of HIV-1 incidence were evaluated using the Cox proportional hazards regression model [13]. Unadjusted hazard ratios (HRs) and associated 95% CIs were estimated for baseline and follow-up covariates. A multivariate model was also fitted to determine independent predictors of HIV-1 incidence. All variables significant in bivariate analysis at P < .20 were entered into a full model; those remaining significant at P < .05 were retained in the parsimonious model. Later, we assessed potential confounding of variables not retained in the parsimonious model by entering 1 variable at a time. Variables that changed any of the coefficients of the predictors in the model by >10% were considered to be potential confounders and were thus retained in the final model regardless of their statistical significance. The proportional hazards assumption was assessed by the Kolmogorov-type supreme test, and model diagnostics were also performed via martingale and deviance residuals [14]. Finally, the population-attributable risk percentage of HIV-1 infection for predictors in our final model was estimated by using the adjusted HRs [15].

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Results

Of 1050 women enrolled, 1044 (99.4%) provided blood samples for HIV-1 antibody screening at baseline. A total of 199 (19.1%) of 1044 women were already HIV-1 positive at this visit. Of the 845 initially HIV-1—seronegative women at risk of subsequent HIV-1 seroconversion, 156 (18.5%) did not return for any of their follow-up visits. Thus, the final sample for this analysis was 689 (81.5%). Compared with women who did not return for follow-up, those who returned were relatively older, had worked longer in the bar/hotel, and were more likely to be HSV-2 seropositive at baseline (table 1). Women who returned for follow-up were also more likely to have initiated sexual activity at a relatively older age and were less likely to have a male partner who had other sex partners. All other baseline characteristics did not differ between the 2 groups.

Table 1.
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Table 1.

Baseline characteristics of women followed and those lost to follow-up in a prospective study of female bar and hotel workers, Moshi, Tanzania, 2002–2005.

Women were monitored in the study for a total of 698.6 PYARs. The median duration of follow-up was 1.04 years (range, 0.21–2.25 years), and the median time between follow-up visits was 3.2 months. During the follow-up period, there were 32 HIV-1 seroconversions, yielding an overall HIV-1 incidence rate of 4.6/100 PYARs (95% CI, 3.0–6.2/100 PYARs). The incidence rate was 4.6/100 PYARs at 3 months of follow-up, 6.1/100 PYARs at 6 months, 6.9/100 PYARs at 9 months, and 4.2/100 PYARs at 12 months.

Table 2 presents the associations between HIV-1 and sociodemographic and behavioral factors. Compared with women with no formal education, the risk of HIV-1 seroconversion was significantly reduced among women with 7–8 years (HR, 0.3 [95% CI, 0.1–1.0]) and ≥ 9 years (HR, 0.2 [95% CI, 0.0–0.8]) of formal education. The increase in risk of HIV-1 among women with 1 previous pregnancy, compared with those who had never been pregnant, was of borderline statistical significance (HR, 2.6 [95% CI, 1.0–6.8]). HIV-1 was not associated with age, marital status, or other sociodemographic variables, including religion, ethnicity, alcohol use, duration of working in the bar/hotel, and level of education of the spouse/cohabiting male partner (data not shown). Greater involvement with alcohol, as measured by frequency of use and number of drinks per occasion, was not associated with HIV-1 (data not shown).

Table 2.
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Table 2.

Associations between sociodemographic and behavioral factors and HIV-1 seroconversion among female bar and hotel workers in Moshi, Tanzania, 2002–2005.

We examined the associations between HIV-1 acquisition and a number of potential behavioral risk factors. The risk of HIV-1 increased as the number of sex partners at baseline increased, with the highest risk among women with ≥4 partners during the preceding 5 years (HR, 4.5 [95% CI, 1.6–12.4]) and among those with ≥3 partners during the preceding year (HR, 6.3 [95% CI, 1.1–37.9]). The incidence of HIV-1 was also positively associated with the number of partners during the follow-up period. However, none of these behavioral measures were significant in the multivariate analyses. Women who reported meeting their last partner at their workplace were at increased risk of HIV-1 (HR, 2.0 [95% CI, 1.0–4.3]). The proportion of women who ever used condoms increased slightly, from 47.4% at baseline to 53.7% during the follow-up, and consistent condom use also increased, from 21.4% to 28.9% (both P < .0001). Those who ever used condoms during the follow-up period had an increased risk of HIV-1 (HR, 2.1 [95% CI, 1.0–4.6]).

Other STDs and genital infections were common in this population (table 3). The prevalence of BV was constant during the study period (28% at baseline vs. 28.2% during the follow-up period), and most women (68%) with abnormal vaginal flora at baseline had abnormal vaginal flora during the follow-up period. The rates of candidiasis (19.8% vs. 26.6%; P = .0002) and active syphilis (1.0% vs. 3.3%; P = .0002) increased during the study period, whereas those of trichomoniasis (7.5% vs. 4.2%; P = .017) and chlamydial infection (5.1% vs. 3.0%; P = .001) decreased. A higher risk of HIV-1 was seen among women with BV and chlamydial infection at baseline and among those with genital ulcer disease (GUD) during the follow-up period. Approximately 85% of women with GUD were HSV-2 positive at baseline or during the follow-up period.

Table 3.
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Table 3.

Associations between sexually transmitted diseases (STDs) and other genital infections and HIV-1 seroconversion among female bar and hotel workers in Moshi, Tanzania, 2002–2005.

The risk of HIV-1 was also increased among women with prevalent HSV-2 infection (HR, 4.9 [95% CI, 1.7–14.1]) and was further increased among those with recent (incident) HSV-2 infection (HR, 5.3 [95% CI, 1.2–23.6]). Of the 3 HIV-1 seroconversions observed among women with incident HSV-2 infections, 1 was recorded during the same follow-up interval, and the other 2 were recorded after HSV-2 infection had been detected during prior follow-up intervals. The incidence of GUD was 1.7% among HSV-2–negative women, 6.8% among women with prevalent HSV-2 infection, and 10.3% among women with incident HSV-2 infection.

After adjustment for other risk factors in multivariate analyses (table 4), the risk of HIV-1 acquisition remained increased in women with HSV-2 at baseline and in those with incident HSV-2 infection during the follow-up period. Other independent predictors of HIV-1 incidence were baseline chlamydial infection and BV and the occurrence of GUD during the follow-up period. None of the baseline and follow-up measurements of sexual behaviors remained significant in the final models. Having a male partner with another partner, although not significant, was retained in the final model because it confounded other predictors. The estimated attributable risk percentages of HIV-1 acquisition for BV and HSV-2 in this population were 22.7% and 62.8%, respectively.

Table 4.
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Table 4.

Results of multivariate analysis of risk factors for HIV-1 seroconversion among female bar and hotel workers in Moshi, Tanzania, 2002–2005.

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Discussion

In this cohort study, conducted among female bar and hotel workers in Moshi, Tanzania, from 2002 to 2005, the HIV-1 incidence was 4.6/100 PYARs. These findings are consistent with the results of a study conducted among female bar/hotel workers in Mbeya, Tanzania, during 2000–2003 [16] and of similar studies conducted in other African countries [17, 18]. The high HIV-1 incidence observed in our study confirms that female bar/hotel workers are at increased risk of HIV-1 and underscores the need for effective interventions in this population.

Other STDs and genital infections were important risk factors for HIV-1 in this population. Prevalent and incident HSV-2 infections were the strongest risk factors for HIV-1 acquisition. Women with prevalent HSV-2 infections had a 4-fold increased risk of HIV-1 acquisition, whereas the risk associated with incident infections was even higher. We estimate that ∼63% of the HIV-1 incidence was attributable to prevalent HSV-2 infections. The role of prevalent HSV-2 infection as a cofactor for HIV-1 transmission has been well established [8, 19]. Genital herpes is a major cause of GUD and mucosal disruption, both of which provide a portal of entry for HIV-1 [20] and increased activation of HIV-1—susceptible cells in the genital tract [19]. In the present study, most women with GUD were HSV-2 seropositive. The risk of HIV-1 acquisition remained elevated among women with GUD after adjustment for HSV-2 and other risk factors, which suggests that GUD may be a risk factor for HIV-1 independent of HSV-2 or that it could be a marker of recurrent lesions in HSV-2—seropositive individuals.

Most women infected with HSV-2 did not report symptoms related to this infection, despite being given information to recognize genital herpes during the study. Thus, other biological mechanisms, apart from mucosal disruptions, may account for the increased risk of HIV-1 among asymptomatic HSV-2—seropositive individuals. Subclinical reactivation of HSV-2 is known to be associated with the influx of activated CD4+ cells that could be infected with HIV-1 [21]. In addition, HSV-2 transregulatory proteins have been shown to promote HIV-1 expression and transactivation [22].

Women with incident HSV-2 infections had a relatively higher risk of HIV-1 than women with HSV-2 at baseline, although the number of HIV-1 seroconversions associated with incident HSV-2 infections was small and not statistically significant. To our knowledge, only 2 other studies have reported similar findings in women [23, 24]. Another study involving both men and women from India reported an increased risk of HIV-1 in subjects with more-recent HSV-2 infections [25]; however, this was no longer significant when stratified by sex [8]. Studies in men have reported mixed results, with some studies showing an increased risk of HIV-1 associated with incident HSV-2 infections [26–28] and others not observing this association [29, 30].

Taken together, these results suggest that incident HSV-2 infection may have a stronger effect on HIV-1 acquisition than prevalent infection. Individuals newly infected with HSV-2 are known to experience more frequent clinical and subclinical recurrences [31] and, possibly, more-vigorous immune responses [25]. In addition, primary HSV-2 infections are associated with larger total ulcerated mucosal surface area and a longer duration of ulceration. These factors may account for the observation of the effect of recent HSV-2 on HIV-1 acquisition. In the present and other studies, some participants acquired both HSV-2 and HIV-1 infections during the same follow-up period. Thus, the observed associations between recent HSV-2 infection and HIV-1 incidence could be due to the simultaneous acquisition of both infections from partners coinfected with these viruses.

The present results, together with those of our previous report from Tanzania [5], demonstrate that abnormal vaginal flora and BV are common conditions among female bar/hotel workers. Women with BV at baseline had a 2-fold higher risk of HIV-1 than women with normal vaginal flora. Our study confirms the findings of previous reports, including prospective studies from a general population in South Africa [32], pregnant women in Malawi [33], and sex workers in Kenya [34]. Women with BV-related symptoms received treatment, but the overall prevalence of this condition during the follow-up remained unchanged, mainly because of the high rate of recurrence. In addition, most women with abnormal vaginal flora and BV at enrollment did not achieve and maintain normal vaginal flora during the study period, which suggests that persistent abnormal vaginal flora and BV may be more important as a risk factor for HIV-1 acquisition.

Several factors could account for the increased risk of HIV-1 among women with BV. Hydrogen peroxide (H2O2) produced by lactobacilli is a natural microbicide in the vaginal ecosystem and is toxic to a number of organisms, including HIV-1 [35]. Hence, a reduced concentration of H2O2-producing lactobacilli could facilitate HIV-1 transmission. The loss of H2O2-producing lactobacilli leads to increased vaginal pH, which is associated with increased CD4+ cell activation and HIV-1 target cells in the vagina [36]. Furthermore, BV increases a number of cytokines, including endocervical interleukin-10, which is associated with increased susceptibility of macrophages to HIV-1 [37], and other proinflammatory cytokines, which increase viral expression within infected cells [38].

The prevalence and incidence of most other curable STDs were high in this population. Women with these infections had a relatively increased rate of HIV-1, although only chlamydial infection remained a significant predictor after adjustment for other risk factors. The lack of association between other curable STDs and HIV-1 acquisition may be due to insufficient power and potential confounding. A sizable proportion of women reported high-risk sexual behaviors, with 38% of women at enrollment reporting having received gifts or money in exchange for sex. Furthermore, 63% reported multiple sex partners during the follow-up period, and consistent condom use was very low. With high rates of curable and chronic STDs, these high-risk behaviors provide the necessary conditions for an explosive HIV-1 epidemic in this cohort. Therefore, development of effective behavioral interventions remains a major public health priority in this population. Provision of ongoing counseling and condoms was not entirely successful in reducing high-risk behaviors, with only a modest increase in condom use observed during the study period. This indicates an urgent need for innovative behavioral interventions, such as programs targeting a wide range of male partners and the development of female-controlled methods of HIV-1 prevention.

The prospective cohort design and large sample size, along with a relatively high retention rate of ∼82%, support the validity of the findings of the study. In addition, regular screening of study subjects allowed for accurate determination of the timing of the exposure in relation to outcome. These study strengths should be considered in the context of a number of important limitations. Losses to follow-up of women enrolled in the study, although relatively small, might have introduced bias and compromised generalizability. We compared the baseline characteristics of women in the study and those lost to follow-up and found that these groups were comparable with regard to most potential predictors. This suggests that the loss to follow-up was unrelated to baseline risk factors and the risk of seroconversion and that bias may not be a major problem. We cannot rule out the possibility of residual or unmeasured confounding having contributed to the observed associations. Interviews were conducted in private rooms by highly experienced female counselors, in an attempt to minimize errors in the measurement of sexual behaviors.

In conclusion, our results underscore the importance of other STDs and genital infections, particularly with HSV-2, in the evolution of the HIV-1 epidemic in this population. The results provide strong justification for a comprehensive approach in the control of curable and long-term chronic STDs and other genital infections as a possible strategy for HIV-1 prevention. Because incident HSV-2 infections appear to be associated with an increased risk of HIV-1, primary prevention of HSV-2 infection, including the development of an effective vaccine, could have a major impact on reducing further expansion of the HIV-1 epidemic. In addition, improved treatment of recurrent HSV-2 infections and long-term suppression by using antiviral drugs could be beneficial. Control of BV is warranted in view of our findings, to reduce both the risk of HIV-1 and the effects of BV on other well-known reproductive health complications.

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Acknowledgments

We thank the study participants, for their patience and the time they gave to respond to interview questions and take part in other study procedures; the research and administrative staff of the Kilimanjaro Reproductive Health Program, for their efforts in data collection; the Kilimanjaro Christian Medical Centre, the Harvard School of Public Health, and the Moshi Municipal Council, for providing institutional support; and Mary Solomon, Coleta Mbuya, Esther Mchome, Elisante Masenga, Grace Mhango, Basidi Bamba, Christopher Mtamakaya, George Suleman Mgomella, Lulu Oguda, Annalene Nel, and Isaac Malonza, for their dedication and support.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Financial support: Rockefeller Foundation (grant 2002 HE 036); International Partnership for Microbicides.

  • Received June 5, 2006.
  • Accepted November 10, 2006.
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  1. J Infect Dis. (2007) 195 (9): 1260-1269. doi: 10.1086/513566
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