Population-based seroprevalence of HSV-2 and syphilis in Andhra Pradesh state of India

Reports from sexually transmitted disease clinics and single health care institutions in India suggest an increase in genital ulcerative sexually transmitted infections and decline in non-ulcerative sexually transmitted infections [1, 2]. Amongst sexually transmitted ulcerative infections, Treponema pallidum, the bacterium causing syphilis and herpes simplex virus type-2 (HSV-2) have the highest prevalence [1] followed by chancroid and donovanosis which are in decline [3]. HSV-2 seroprevalence rates in the general adult population in India have been reported to range from 7.9 to 18.9% [4–6], translating into 100-200 million individuals who have acquired HSV-2 infection. While HSV-2 can be a cause of significant morbidity through genital ulcer disease, central nervous system disease, and liver involvement, one of the major reasons for interest in HSV-2 is because of its strong association with HIV infection. Despite two recent large randomized trials that demonstrated a lack of an effect of pharmacologic herpes suppression in preventing incident cases of HIV infection [7, 8], the continued significant and strong epidemiological evidence linking HIV to HSV-2 continues to support research into novel strategies to mitigate new HIV infection in those who are HSV-2 infected. Moreover, in a study in the state of Karnataka in India, there was significant heterogeneity of HSV-2 infection with higher rates in rural areas and amongst women [6].

The little information available on rates of syphilis in India suggest an incidence rate of 5.4 per 100 person years in a sexually transmitted disease clinic in India from 1993-2000 and prevalence rates as high as 21.9% amongst a convenience sample of long-distance truck-drivers in 2000 [4, 5]. Syphilis has also been implicated in increasing susceptibility to HIV infection [9], and HIV prevention interventions based on syphilis and other STI control have, except for in one isolated instance [10], also led to disappointing results [11, 12]. Additionally, spikes in syphilis infection has become a concern in men who have sex with men (MSM) communities in other settings [13]. However this has yet to be reported from India, where MSM have one of the highest rates of HIV prevalence amongst groups at high risk of sexual transmission of HIV [14].

Thus HSV-2 and syphilis infection could have a great impact on the Indian population. A better understanding of population level data on the prevalence of HSV-2 and syphilis, and the risk factors for these two important causes of genito-ulcerative diseases could improve public health STI prevention efforts in the country and their integration with HIV prevention efforts.

We report seroprevalence rates and potential risk factors for HSV-2 and syphilis from a population-based study in Guntur district in the south Indian state of Andhra Pradesh. This district and state have one of the highest burdens of HIV infection due to sexual transmission in India [14].

Of the final 13,838 15-49-year-olds sampled, 12,617 (91.2%) gave a blood sample and interview, 6% did not participate, and 2.8% provided an interview only. Of this final analytic sample 12,617 study participants who provided a blood sample, 6317 (50.1%) were rural residents, 6382 (50.6%) were women, 4582 (36.3%) <25 years of age, and 4310 (34.2%) had not had any schooling.

This report examines HSV-2 and syphilis seroprevalence and associated risk factors in a large population-based sample, with a high participation rate, in a high HIV prevalent district [22] within a high prevalence state [14] of India. Seroprevalence of HSV-2 and syphilis demonstrated rural urban and gender differences. Seroprevalence for both HSV-2 and syphilis was higher in urban areas, HSV-2 was higher amongst women and syphilis was slightly higher in men.

Though less information from population based studies exists on rates of syphilis infection, estimates suggest that South Asia has the highest number of cases in the world [23]. Moreover, the burden of HSV-2 and syphilis infection extrapolated from these rates is high and supports current national efforts to address STI disease in the country. In general terms while the overall prevalence of HSV-2 is significantly lower than many other countries in sub-Saharan Africa, the ratio of HSV-2/HIV seroprevalence at 2-3 is roughly similar between our study and HSV-2/HIV seroprevalence ratios found in other populations in Africa [24].

Marked heterogeneity in syphilis and HSV-2 at the district and state level can become apparent when comparing burden of STIs across studies despite treatment policies that often remain the same across geographic regions [25]. For example, syphilis seroprevalence in our study was about four times that found in another study in a district in the neighboring state Karnataka while HSV-2 in our district level population was nearly 1/3 of that found in the district in Karnataka [6]. HSV-2 and syphilis seroprevalence rates were higher in urban areas and rates of syphilis were higher in men than in women in our study, while opposite trends were found in the Karnataka study. However, testing algorithms and testing kits differed between the two studies as well. While some of the differences in seroprevalence rates may be methodological, the heterogeneous nature of the STI epidemic in India, could explain the differences in findings at the district level, warranting programmatic prevention and treatment programs to reflect local conditions.

Our finding of a positive relationship between circumcised status and HSV-2 seroprevalence differs from the inverse relationship between circumcision and HIV found in Indian populations described previously [26], and that of a randomized controlled trial [27]. Moreover, uncircumcised status demonstrated a strong positive association with HIV seroprevalence within this same cohort in data described elsewhere [21]. A positive association between HSV-2 and circumcision has also been described in other epidemiologic work [28], and a lack of association has also been reported [29]. Results from a randomized controlled trial in Uganda, demonstrate a protective effect of circumcision on HSV-2 [30], however, potentially less protection than has been previously been found for HIV [27]. The role of sexual partnering patterns at the population level may play a significant role for HSV-2 acquisition, with cumulative cases as an important HSV-2 risk factor. Observational studies examining circumcision and STIs in India should take into consideration potential sexual partnering differences between circumcised and uncircumcised members of the population, and residual confounding, which may have resulted in the positive association of male circumcision with HSV-2 seroprevalence in our cross-sectional study.

We found lower odds of HSV-2 in women who reported never using condom. The explanation could be a higher frequency of condom use currently by those who are at high risk of HSV-2 (risk compensation) and/or a bias towards higher reporting of condom use by those who are at higher risk of HIV/STI. We have previously reported a similar association between never using condom and low HIV among both men and women in this study [21].

This population level STI co-seroprevalence with HIV data highlights and builds upon existing data from STI clinics of high HIV/STI co-seroprevalence in India [31, 32]. Our finding that 23% of those seroprevalent for syphilis and 12% seroprevalent for HSV-2, were also found to be HIV infected has important implications for STI syndromic management and HIV testing strategies practiced in India. Because syndromic management is not based on a proven diagnosis, such population based data is needed to inform local treatment algorithms. For example in this district in Andhra Pradesh with potentially less HSV-2, syndromic management that utilizes less acyclovir therapy may be of higher priority than in a neighboring state or district. Refinement of syndromic management algorithms might include studies that examine the etiology of genital ulceration and rates of asymptomatic infection or viral shedding.

Furthermore, recent national guidelines for strengthening STI/RTI services within government institutions [33] have lacked any mention of HIV testing at these centers. In one recent study from an STI clinic in Pune India, the majority of cases where both syphilis and HIV were acquired were detected at the same follow up visit suggesting co-transmission of HIV and syphilis [5]. Current guidelines for the operational management of RTI/STI clinics suggest that patients seeking STI care and found to have an STI or with symptoms are to be referred to local Integrated Counseling and Testing Centers (ICTC) for HIV testing. However, evaluation of the potential effectiveness of this approach has not been done yet. While the numbers of ICTCs in Andhra Pradesh state has increased dramatically to 661 centers [34], quality and accessibility has not been documented publicly and barriers to seeking voluntary counseling and testing have been reported [35]. Additions to government STI syndromic management algorithms could include a longer duration and increased doses of penicillin in HIV infected persons, for example. Additionally, picking up acute or early HIV infection during this time is critical to following through with partner notification procedures. Improvements in sensitivity, specificity and a decrease in the window period with newer rapid third generation whole blood kits now commercially available in parts of the country, suggest that HIV testing during presentation with STI symptoms could be an ideal time to pick up new cases of HIV and prevent loss to follow-up of patients referred out for HIV testing.

There were several limitations of this study. The sampling frame was limited to one district within Andhra Pradesh and we are unable to extrapolate these findings to other geographic regions. However, this information is useful as it comes from a high HIV prevalent district within a high HIV prevalent state and demonstrates relatively low levels of HSV-2 and syphilis. Findings from local data can impact our understanding of disease at the national level as evidenced from the previously described HIV prevalence from this study [15] which played a major role in the downward estimation of HIV burden for the country [36]. Additionally, without further clinical history and non-specific syphilis testing, we were unable to determine whether results from syphilis IgG testing were consistent with active, incubating, treated or convalescent infection. However, the yield of active syphilis would be less helpful from a population-based study as active cases of syphilis would be even less frequent in such a setting. Also high titers would have been difficult to interpret without a clinical history given that untreated secondary or tertiary syphilis could be present, however, both conditions would be insignificant in relation to transmission dynamics as syphilis can be non-communicable after 1-4 years [16].

Herpes and syphilis suppression and control as HIV prevention interventions have not been found to be effective [7, 8, 37]. However, additional examination of this HIV prevention strategy continues given the strong relationship between these sexually transmitted infections and HIV. However, there may be specific situations where such control or suppression strategies are used, such as during pregnancy, to prevent the devastating potential sequelae of neonatal herpes infection or intrapartum syphilis infection. HSV-2 control may be less important in this setting as an HIV prevention strategy as the HIV epidemic has not spread widely and levels of HSV-2 infection in India are relatively low.

This study provides data on the burden of HSV-2 and syphilis at the population level and its associations in a high HIV prevalence part of India. The strong association between HSV-2, syphilis and HIV seroprevalence in this population-based study suggests that acceleration of direct linkages between STI testing and HIV counseling and testing would be useful in enhancing the control of STIs and HIV in India.