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Recent Herpes Simplex Virus Type 2 Infection and the Risk of Human Immunodeficiency Virus Type 1 Acquisition in India

  1. Steven J Reynolds1,
  2. Arun R Risbud3,
  3. Mary E Shepherd2,
  4. Jonathan M Zenilman1,
  5. Ronald S Brookmeyer2,
  6. Ramesh S Paranjape3,
  7. Anand D Divekar3,
  8. Raman R Gangakhedkar3,
  9. Manisha V Ghate3,
  10. Robert C Bollinger1 and
  11. Sanjay M Mehendale3
  1. 1Division of Infectious Diseases, School of Medicine, and
  2. 2Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland;
  3. 3National AIDS Research Institute, Pune, India
  1. Reprints or correspondence: Dr. Steven J. Reynolds, Div. of Infectious Diseases, Johns Hopkins University, Ross 1150, 720 Rutland Ave., Baltimore, MD 21205 (sreynol1{at}jhmi.edu)
 
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Abstract

To estimate the impact of prevalent and incident herpes simplex virus type 2 (HSV-2) infection on the acquisition of human immunodeficiency virus type 1 (HIV-1), stored serum samples from a cohort of 2732 HIV-1-seronegative patients attending 3 sexually transmitted infection clinics and 1 reproductive tract infection clinic in Pune, India, were screened for HSV-2-specific antibodies. Incident HSV-2 infection was defined serologically as “recent” if a negative result of testing for HSV-2 could be documented within the previous 6 months or “remote” if >6 months had elapsed since the last negative test result. The prevalence of HSV-2 at enrollment was 43%. The HSV-2 incidence was 11.4 cases/100 person-years, and the HIV-1 incidence was 5.8 cases/100 person-years. The adjusted hazard ratios of HIV-1 acquisition from exposure to HSV-2 infection were 1.67 for prevalent HSV-2, 1.92 for remote incident HSV-2, and 3.81 for recent incident HSV-2. Recent incident HSV-2 infection was associated with the highest risk of HIV-1 in this study, which suggests that prevention of HSV-2 infection may reduce the risk of HIV-1 acquisition

Sexual transmission of human immunodeficiency virus (HIV) is facilitated by the presence of genital ulcer disease [1–6]. Herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease in both developed and developing countries [7–12]. A clear relationship has been established between genital herpes and HIV acquisition, but almost all studies have evaluated prevalent genital herpes infection [13–17]. Recent studies conducted in Zimbabwe and Tanzania suggest that an association exists between incident HSV-2 infection and HIV-1 acquisition [18, 19]. HSV-2 and its potential interaction with HIV have emerged as a major public health problem for countries facing the global HIV-1 pandemic [20]

Our group found the presence of a clinically apparent genital ulcer at the time of screening in 79% of patients with sexually transmitted infections (STIs) who had acute HIV-1 infection in India [3]. This, coupled with the fact that HSV DNA was isolated from 26% of genital ulcer specimens in our clinic patients, led us to believe that genital herpes was a major factor in the current HIV-1 epidemic in India [8]. The high rates of both HSV-2 and HIV-1 in our study population and a schedule of frequent follow-up visits afforded a unique opportunity to study the association of these 2 viral STIs with greater attention to the relative timing of these infections and, ultimately, to provide insight into any causal association that may exist between incident HSV-2 infection and HIV-1 acquisition

Recent serologic data illustrate that the majority of incident cases of HSV-2 infection are clinically asymptomatic [21–23]. The commercial availability of type-specific serologic assays for HSV, coupled with our clinical data on genital ulcer disease, provided the additional opportunity to explore what role, if any, asymptomatic HSV-2 infection plays in HIV-1 acquisition

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Patients, Materials, and Methods

Study participants HIV-1-seronegative patients attending 3 referral STI clinics and a reproductive tract infection clinic were enrolled in a prospective study of HIV-1 infection in Pune, India, from May 1993 through April 2000. The study population represents a mixture of male patients with STIs, female partners of male patients with STIs, female commercial sex workers, and women with reproductive tract infections

Study design The original study design has been described elsewhere [2]. In brief, all patients received pre- and posttest counseling for HIV and other STIs. At screening, participants were interviewed using a structured questionnaire about demographic characteristics, STI history, medical history, sexual behavior, HIV/AIDS knowledge, and clinical symptoms. At the time of the physical examination and interview, investigators and participants were unaware of participants' HIV antibody status. The presence of a genital ulcer was assessed at each visit by physical examination. Blood was obtained for serologic testing for HIV at enrollment and follow-up visits. Unused serum was stored at −20°C for future testing. All participants were informed of the confidentiality of their test results. The present analysis was a retrospective cohort study using stored serum

Serologic testing for HIV Serum samples were screened with a commercially available EIA kit for identification of HIV-1 and HIV-2 antibodies (Recombigen HIV-1/HIV-2; Cambridge Biotech). Positive results of EIA were confirmed with a rapid test for HIV-1 and HIV-2 (Recombigen HIV-1/HIV-2 Rapid Test Device; Cambridge Biotech). When the results of these tests were discrepant, a third EIA or Western blot assay (Cambridge Biotech) was used. Western blot assays were interpreted according to the Centers for Disease Control and Prevention criteria [24]

Serologic testing for HSV-2 Serologic testing for HSV-2 was performed on all baseline specimens, using a type-specific, HSV-2 gpG2 IgG EIA (Focus Technologies). Incident HSV-2 infection was defined as infection in a patient who was seronegative for HSV-2 at the enrollment visit and seropositive at a follow-up visit. HSV-2 serostatus was not known to the participants at the time of the study

Statistical analysis The time of incident HSV-2 and HIV-1 infection was estimated, by interpolation, to be the midpoint between the last negative and the first subsequent positive test result. Risk factors for prevalent HSV-2 infection were assessed using χ2 and Fisher's exact tests. Adjusted odds ratios (ORs) were estimated from a logistic regression model, with fit assessed using the Hosmer-Lemeshow goodness-of-fit test [25]. Crude HSV-2 and HIV-1 incidence rates were calculated as number of seroconversions divided by the summed person-years of follow-up. A Poisson distributed variable was used to calculated 95% confidence intervals (CIs) [26]. Unadjusted rate ratios were computed as the ratio of the incidence rate in the category of interest divided by the rate in the referent category, with 95% CIs based on exact Poisson methods

Cox proportional hazards regression models with both time-independent and time-dependent covariates were used for multivariate analyses of incident infection. Participants who seroconverted were matched to the risk set by follow-up time: data collected at the visit at which seroconversion was demonstrated were compared with data collected from the risk set at the visit matching closest in terms of follow-up time. Variables for the multivariate analyses were chosen on the basis of previously identified risk factors for HIV-1 infection in this cohort, and the results of forward stepwise regression [2]. Participants with positive results of serologic testing for HSV-2 at enrollment were considered to have prevalent HSV-2 infection. Because the main hypothesis was that recent exposure to incident HSV-2 infection was independently associated with HIV-1 acquisition, incident HSV-2 cases were classified as either remote or recent. Remote incident infections were defined as those acquired after study entry but with >6 months since the last negative HSV-2 test, and recent incident infections as those where a negative HSV-2 test was documented within the past 6 months. Follow-up time for all participants who seroconverted to HSV-2 positive was classified according to these time-dependent criteria and used in the calculation of HIV-1 incidence rates, with the initial 6 months after HSV-2 seroconversion classified as recent exposure and any additional follow-up time classified as remote. Thus, a participant could potentially transition from the recent to the remote exposure category and contribute person-years to both. All statistical analyses were performed using SAS software (version 8.0; SAS Institute)

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Results

Characteristics of the study participants Of 2732 persons enrolled, 2260 were male, 9 were hijra (eunuchs), and 463 were female; 1175 participants (43%) had HSV-2 antibodies. The demographic characteristics of study participants are described in table 1. The median duration of follow-up was 10.7 months, and the median number of follow-up visits was 3. Of the enrolled participants who attended their first follow-up visit, 62.4% returned for the second visit. Participants with more lifetime sex partners (10–99 partners) tended to have a longer duration of follow-up (median, 13.1 months) but were less likely to report for the regular quarterly follow-up visit. Participants with high school-level education tended to have a longer duration of follow-up (median, 12.9 months) and were more likely to report for the regular quarterly follow-up visit. HSV-2 prevalence did not differ significantly by duration of follow-up, but it was significantly associated with an average interval between visits of >6 months (prevalence was 47.1% for an average interval of >6 months and 41.3% for an average interval of ⩽6 months; P=.005)

Figure 1
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Figure 1

Herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) serostatus, at enrollment and at completion of follow-up, in a cohort of patients at 3 sexually transmitted infection clinics and 1 reproductive tract infection clinic in Pune, India, May 1993 through April 2000

Figure 2
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Figure 2

Risk of human immunodeficiency virus type 1 (HIV-1) acquisition, by herpes simplex virus type 2 (HSV-2) infection status, in a cohort of patients at 3 sexually transmitted infection clinics and 1 reproductive tract infection clinic in Pune, India, May 1993 through April 2000. HIV-1 incidence per 100 person-years is given above each column

Table 1
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Table 1

Characteristics of individuals participating in a study of human immunodeficiency virus type 1 incidence in Pune, India, and associations with herpes simplex virus type 2 (HSV-2) prevalence

Characteristics of study participants with prevalent HSV-2 infection Of HSV-2-seropositive individuals, 44% reported no history of genital ulcer disease. Multiple associations between genital ulcer disease and prevalent HSV-2 infection were identified in the unadjusted analysis (table 1) and were included in the multivariate model. The prevalence of HSV-2 infection at baseline was higher among female patients with STIs than among male patients with STIs (50.9% vs. 38.1%; adjusted OR, 2.50; 95% CI, 1.70–3.68). Commercial sex work was the strongest independent risk factor identified (adjusted OR, 11.06; 95% CI, 5.91–20.7). Other independent risk factors associated with prevalent HSV-2 infection included age >30 years, marital status, greater lifetime number of sex partners, history or clinical presentation of genital ulcer, and earlier calendar period of screening (1993–1996) (table 1)

Incidence and predictors of HSV-2 infection During the study, 217 participants seroconverted to HSV-2 positive, resulting in a crude HSV-2 incidence rate of 11.4 cases/100 person-years (95% CI, 9.9–13.0 cases/100 person-years). Risk factors for HSV-2 acquisition identified in the unadjusted analysis included earlier calendar period of follow-up (1993–1996), younger age, female sex work, lower education level, living away from family, lack of condom use, genital lesion at the current or a previous visit, and coincident HIV-1 infection (table 2). Independent predictors of incident HSV-2 infection included the presence of a genital lesion at a previous clinic visit only (adjusted hazard ratio [HR], 3.81; 95% CI, 2.77–5.23), the presence of a genital lesion at the current clinic visit (adjusted HR, 2.73; 95% CI, 1.56–4.79), and the presence of a genital lesion at both the current clinic visit and a previous visit (adjusted HR, 5.77; 95% CI, 3.91–8.52). When the group of male patients with STIs was used as a reference in the multivariate model, hijras and female sex workers had significantly higher HSV-2 incidence rates (adjusted HR, 5.87; 95% CI, 1.44–23.9; and adjusted HR, 3.90; 95% CI, 1.99–7.62, respectively)

Table 2
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Table 2

Risk factors for incident herpes simplex virus type 2 (HSV-2) infection among patients at 3 sexually transmitted infection (STI) clinics and 1 reproductive tract infection clinic in Pune, India, May 1993 through April 2000

HSV-2 infection and the risk of HIV-1 acquisition The unadjusted rate ratio of HIV-1 acquisition among participants exposed to prevalent HSV-2 infection was 2.07 (95% CI, 1.53–2.83; table 3). Of the 224 participants with incident HIV-1 infection, 28 were found to have both incident HSV-2 infection and incident HIV-1 infection during the follow-up period (figure 1). For the majority of these 28 participants (n=22), serologic evidence of these 2 infections was detected simultaneously. The unadjusted rate ratio of HIV-1 acquisition among participants exposed to remote incident HSV-2 infection was found to be 2.08 (95% CI, 1.20–3.48); among participants exposed to recent incident HSV-2 infection, the rate ratio was 6.26 (95% CI, 2.59–13.07). The adjusted HR of HIV-1 acquisition increased with relative timing of HSV-2 infection, from 1.67 (95% CI, 1.22–2.30) among those exposed to prevalent HSV-2 infection to 1.92 (95% CI, 1.15–3.21) among those exposed to remote incident HSV-2. Exposure to recent incident HSV-2 infection conferred a 3.81-fold (95% CI, 1.81–8.03) increased hazard of HIV-1 acquisition (figure 2)

Table 3
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Table 3

Risk factors for incident human immunodeficiency virus type 1 (HIV-1) infection among patients at 3 sexually transmitted infection (STI) clinics and 1 reproductive tract infection clinic in Pune, India, May 1993 through April 2000

Interaction between HSV-2 serostatus and genital ulcer disease The interaction between clinically apparent or self-reported genital ulcer disease and HSV-2 serostatus was investigated in a proportional hazards model of HIV-1 acquisition. Of the 217 individuals with serologic evidence of incident HSV-2 infection, 51 (23.5%) had a genital lesion documented at the same visit at which seroconversion was demonstrated. A statistically significant interaction was found between prevalent HSV-2 infection and clinically apparent or self-reported genital ulcer (symptomatic infection) and the risk of HIV-1 infection. The presence of asymptomatic prevalent HSV-2 infection (no clinically apparent or self-reported genital ulcer) conferred an adjusted HR for HIV-1 infection of 2.14 (compared with no genital ulceration and negative results of serologic testing for HSV-2; 95% CI, 1.32–3.46). Symptomatic prevalent HSV-2 infection conferred an adjusted HR of 5.06 (95% CI, 3.19–8.03). No statistically significant interaction of clinically apparent or self-reported genital ulcer and incident HSV-2 infection with the risk of HIV-1 infection was found

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Discussion

The findings of this study demonstrate that individuals who experience incident HSV-2 infections are at the greatest risk for HIV-1 acquisition, compared with individuals who are not infected with HSV-2 or who have prevalent HSV-2 infection. Individuals with serologic evidence of recent incident HSV-2 infection in our study had the highest HIV-1 incidence (adjusted HR, 3.55) when the analysis was controlled for other sexual risk behaviors, which illustrates that incident infection with this common sexually transmitted virus is independently associated with HIV-1 acquisition (figure 2)

The majority of new infections with HSV-2 have no clinical manifestations [22]. Most HSV-2 transmission events between sex partners who are serodiscordant for HSV-2 are not associated with exposure to a sex partner who has experienced a clinically recognized recurrence [27, 28]. Despite the paucity of clinical symptoms associated with HSV-2 infections, frequent shedding of HSV-2 virus has been shown in HSV-2-seropositive individuals [29, 30]. The biological plausibility of an association between HSV-2 and HIV-1 has been explained through the possible generation of a portal of entry by mucosal disruption in the context of active genital ulcer disease. The findings of this study support this hypothesis in the context of prevalent HSV-2 infections, in which we found a significant interaction of clinically apparent or self-reported genital ulcer and serologic evidence of HSV-2 with the risk of HIV-1 acquisition. Individuals in this study who had prevalent HSV-2 infection but no clinically apparent or self-reported genital ulcer were also found to be at increased risk of HIV-1 acquisition, which highlights the importance of asymptomatic infection with HSV-2. The majority of incident HSV-2 infections in this study were asymptomatic, and the presence of a clinically apparent or self-reported genital ulcer did not significantly modify the risk of HIV-1 acquisition. Individuals in this study were not educated about recognition of herpes symptoms, and our findings may, therefore, reflect a lack of awareness of typical symptoms, in addition to some ulcerations that were not clinically amenable to inspection

Recent in vitro studies offer some insight into the association of HSV-2 with HIV-1 at the cellular level. HSV-2 infection may increase the risk of HIV-1 acquisition through the influx of CD4+ lymphocytes that has been observed in the context of recurrent HSV-2 infection and through the ability of HSV-2 to up-regulate HIV-1 replication [31–33]. The elevated risk of HIV-1 acquisition observed in our study among individuals with exposure to recent incident HSV-2 infections may reflect a more vigorous immune response in individuals who are immunologically naive to HSV-2. Further studies examining the local immune response to incident HSV-2 infection may help explain the elevated risk of HIV-1 acquisition that is associated with exposure to incident HSV-2

The elevated risk of HIV-1 acquisition among participants with incident HSV-2 infection observed in the present study could result from the exposure of study participants to sex partners who were coinfected with both HSV-2 and HIV-1, leading to the acquisition of both infections simultaneously. Infection with HSV-2 at the mucosal surface could result in higher local HIV-1 shedding, coupled with the increased risk of transmission in the presence of genital ulceration [34–36]

Studies in Zimbabwe and Tanzania also found an association between incident HSV-2 infection and HIV-1 acquisition [18, 19]. Given the overlap in the window periods between exposure and seroconversion of these 2 infections and the possibility that incident HSV-2 infection may pose an independent risk for HIV-1 acquisition, it is not surprising that these infections are most often detected at the same clinic visit, as was observed in these studies. The overlap in seroconversion windows has limited any examination of temporality between incident HSV-2 infection and HIV-1 acquisition. By modeling the follow-up time of HSV-2 exposure as “recent” or “remote,” we were able to illustrate a strong relationship between the relative timing of HSV-2 infection and HIV-1 acquisition

Residual confounding by sexual risk behavior remains a major limitation in any study of the association between HSV-2 and HIV-1. Sexual risk behavior is dynamic in nature, as a result of the different types of exposures that individuals enrolled in a cohort study may experience over the duration of the study. All changing risk behaviors in this study were treated as time-dependent exposures at each visit, to account for the changing exposure profiles over time and minimize residual confounding

There are a number of potential limitations in our observation of an association between HSV-2 infection and HIV-1 acquisition. Differential follow-up rates between high-risk individuals (those with commercial sex worker contacts and greater lifetime numbers of sex partners) and low-risk individuals could result in bias. Participants in this study who had a greater lifetime number of sex partners had a longer median follow-up time but were less likely to report for the quarterly follow-up visit. The use of qualitative methods to assess sexual risk behavior relies on the assumption that participants will accurately report on topics that are not openly discussed in India. The counselors conducting the interviews in this study had extensive training in counseling methods, in an attempt to minimize error in the measurement of sexual risk behaviors. There may be a component of misclassification bias in the remote and recent incident HSV-2 categories; some participants who seroconverted to HSV-2 positive and who did not have a documented negative HSV-2 test in the last 6 months may have been classified as having remote, rather than recent, infection. Participants who seroconverted to HIV-1 positive were more likely to have delayed follow-up visits (>7 months), which could result in bias and lead to the finding of a lower risk of HIV-1 infection in association with remote incident HSV-2 exposure than was truly present in our study

The HSV-2 EIA used in our study has been shown to be 100% sensitive and 96% specific, compared with a Western blot assay [37]. Some of the exposure due to HSV-2 might, therefore, represent false-positive laboratory tests. However, technicians who were blinded to the HIV-1 status of the participant performed all testing, and, therefore, any misclassification in HSV-2 status would be nondifferential and would result in an underestimation of the true association between HSV-2 infection and HIV-1 acquisition

Two large population-based studies in Mwanza, Tanzania, and Rakai, Uganda, have yielded mixed results on the impact of STI treatment on HIV-1 transmission [38–40]. One hypothesis raised by the authors of the Mwanza and Rakai studies to explain the discrepancy in the outcomes of these 2 trials is that the high rate of untreated HSV infections in Rakai, compared with that in Mwanza, may partially account for the lack of impact of STI control on HIV-1 infection rates [40]. Future studies designed to evaluate the impact of suppressive antiviral therapy on individuals with prevalent HSV-2 infection may help clarify this controversy

The study of HSV-2 and HIV-1 infection in India adds an important component to the investigation of the interaction between these 2 viral infections. We found that a strong association exists between recently acquired HSV-2 and the risk of HIV-1 acquisition. If an effective vaccine against HSV-2 were available, a targeted approach to primary prevention of HSV-2 in young attendees of STI clinics could have a major impact on the risk of HIV-1 infection for these patients. Suppression of prevalent HSV-2 using antiviral agents may also have an impact on the risk of HIV-1 acquisition in contexts in which the prevalence of HSV-2 infection is high

The HIV-1 epidemic in India is now 16 years old and has spread rapidly across the country; as a result, India has the potential to have more HIV-1-infected individuals than any country in the world [41]. Little was known, before the present study, about the impact of genital herpes on the HIV-1 epidemic in India. High HSV-2 prevalence and incidence rates were found among patients of STI and reproductive tract infection clinics. The elevated risk of HIV-1 acquisition associated with exposure to recent HSV-2 infection found in our study, coupled with the growing body of evidence that prevalent HSV-2 plays a major role in HIV transmission, provides a strong argument for the prioritization of HSV-2 vaccine development and other HSV-2 prevention strategies as key components of the current global HIV prevention research agenda

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Acknowledgments

We thank Sangeeta Kulkarni, Mycal Pereira, Michel Lubaki, and Sheila Keating, for their excellent laboratory support, and Hanumant Shedge, for his excellent data management

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Footnotes

  • Presented in part: 14th International AIDS Conference, Barcelona, Spain, 7–12 July 2002 (abstract MoOrC1012)

    Informed consent was obtained from all patients participating in the study. The human experimentation guidelines of the US Department of Health and Human Services and of participating institutions were followed in conducting this research

    Financial support: Indian Council of Medical Research (ICMR); National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH; grants AI 41369 and AI 01633); Family Health International (FHI), NIAID, NIH (contract AI 35173); Fogarty International Center, NIH (fellowship 5 D43 Tw00010-AITRP); R. Samuel McLaughlin Foundation (grant to S.J.R.)

    The views expressed do not necessarily reflect the view of the ICMR, the NIH, or the FHI

  • Received September 10, 2002.
  • Accepted December 3, 2002.
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  1. J Infect Dis. (2003) 187 (10): 1513-1521. doi: 10.1086/368357
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