Epidemiology and Social
No evidence of sexual transmission of Kaposi's sarcoma herpes virus in a heterosexual South African population
Malope, Babatyi Ia,b; MacPhail, Patricka; Mbisa, Georginac; MacPhail, Catherined; Stein, Larab; Ratshikhopha, Edith Mb; Ndhlovu, Lewise; Sitas, Freddyb,f; Whitby, Denisec
From the aClinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
bCancer Epidemiology Research Group, National Health Laboratory Services, Johannesburg, South Africa
cViral Oncology Section, AIDS Vaccine Program, SAIC-Frederick, NCI-Frederick, Frederick MD, USA
dReproductive Health Research Unit, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
ePopulation Council, Johannesburg, South Africa
fResearch and Registers Division, The Cancer Council, New South Wales, Australia.
Received 5 July, 2007
Revised 30 October, 2007
Accepted 7 November, 2007
Correspondence to Denise Whitby, Viral Oncology Section, AIDS Vaccine Program, SAIC-Frederick, NCI-Frederick, Frederick MD, USA. Tel: +1 301 846 1714; fax: +1 301 846 7119; e-mail: firstname.lastname@example.org
Background: The transmission of Kaposi's sarcoma herpes virus (KSHV) in men who have sex with men is clearly associated with sexual risk factors, but evidence of heterosexual transmission of KSHV is conflicting.
Methods: Sera were obtained from 2103 South African individuals (862 miners, 95 sex workers, 731 female and 415 male township residents; mean age 33.2 years; ± 10.1). All sera were tested for antibodies to KSHV lytic K8.1 and latent Orf73, HIV, gonococcus, herpes simplex virus type 2 (HSV-2), syphilis and chlamydia. Information on social, demographic and high-risk sexual behavior was linked to laboratory data, to evaluate risk factors, expressed as odds ratios (95% confidence interval) for KSHV.
Results: Overall KSHV and HIV prevalences were 47.5 and 40%, respectively (P = 0.43). The risk of HIV infection was highest in sex workers then female residents and miners, compared with male residents (P < 0.001). HSV-2 infection was highly prevalent (66%) and lower, but still substantial, prevalences (6–8%) were observed for other sexually transmitted infections (STI). No significant difference in KSHV infection was observed among the residential groups (P > 0.05). KSHV was not associated with any of the STI or any measures of sexual behavior (P > 0.05).
Conclusion: The pattern of HIV and STI in sex workers suggests high rates of high-risk sexual behavior in this population. The lack of association with high-risk sexual behavior, particularly in sex workers, and with any markers of STI strongly suggest that the sexual mode does not play a significant role in KSHV transmission in this South African population.
Kaposi's sarcoma herpes virus (KSHV), also known as human herpes virus 8, is the causative agent of Kaposi's sarcoma [1,2] and is also associated with primary effusion lymphoma  and multicentric Castleman's disease . Kaposi's sarcoma occurs more commonly in immunosuppressed individuals especially those with HIV infection . In AIDS patients, Kaposi's sarcoma occurs rarely in those who acquired HIV via parenteral routes leading to the suggestion, even before the discovery of KSHV, that the causative agent must be sexually transmitted .
Studies of risk factors for KSHV infection in men who have sex with men (MSM) demonstrate an association with markers of sexual activity including the number of partners, unprotected sexual practices and markers of sexually transmitted infections (STI) [6–9]. Many studies have tried to identify specific sexual practices associated with the transmission of KSHV among MSM with little success, possibly because most MSM will report multiple sexual practices [8–10]. KSHV can be detected in the semen of infected subjects [11,12], but detection is less common than in saliva  indicating that infected saliva is the most likely source of KSHV during transmission between MSM .
Evidence for the heterosexual transmission of KSHV is less convincing. In the United Kingdom and the United States KSHV is more common among sexually transmitted disease clinic attendees than among blood donors [15,16], and some groups have reported an association of KSHV infection and sexual risk factors [17–19]. Other studies have reported a lack of evidence for heterosexual transmission [7,20].
In African and Mediterranean countries where KSHV is endemic, KSHV infection is common in children, and there is good evidence for the non-sexual horizontal transmission of KSHV [21–24]. Evidence for sexual transmission of KSHV in endemic countries is conflicting. In a South African study KSHV was marginally associated with increased numbers of sexual partners, but not with HIV . Also, several reports have shown associations between KSHV, STI and HIV in Ugandan and Zambian populations [26,27]. Other studies conducted in the same African countries have not, however, shown these associations [28–30].
In this study we evaluated risk factors for KSHV infection in a South African community with a high prevalence of HIV and other STI . We postulate that such a setting, where both KSHV infection and high-risk sexual behavior are prevalent, provides a unique opportunity to gain insight into the sexual transmission of KSHV, particularly when compared with HIV and other STI in which sexual transmission is firmly established.
Materials and methods
Sera obtained from 2103 individuals aged between 16 and 63 years were included in this study. The subjects were initially recruited in 2001 for a longitudinal study examining lifestyle changes, sexual behavior and STI associated with a community-based HIV prevention intervention (the Mothusimpilo Project) in the vicinity of Carletonville, a mining town on the borders of Gauteng and North West provinces, South Africa. The mines employ workers from the surrounding townships, neighbouring towns and from other parts of southern Africa.
Study subjects included 862 mineworkers residing in mine hostels, 95 female sex workers, and 415 male and 731 female residents of the nearby Khutsong township. The method of selection of subjects was based on randomly selected houses or index rooms in mine hostels within clusters and is described in detail elsewhere [32–34]. Recruitment of subjects was done during the day and in the case of township residents some of the working population may have been missed, which may bias socioeconomic measurements. Refusal to participate and absence of people in the household over a 5-day period for inclusion in the study was estimated at 11%.
Permission to conduct the study was obtained from the University of the Witwatersrand Research Ethics Committee (Medical). Permission was also obtained from the National Health Laboratory Services, Sexually Transmitted Infection Group, Population Council and the Mothusimpilo group.
A detailed questionnaire initially adapted from UNAIDS and modified to suit the local setting was used, as described elsewhere [31,35]. A one-on-one interview was conducted by trained interviewers in the language of preference of the participants. Available information on social and demographic factors, as well as sexual and risk behavior for HIV and STI was used to determine risk factors for KSHV in the community. A signed informed consent was obtained from all study subjects.
All sera were stored at −20°C. Laboratory analysis for HIV and STI were performed at the National Health Laboratory Services, Johannesburg, South Africa. The following STI were tested: gonococcal infection, herpes simplex virus type 2 (HSV-2), syphilis and chlamydia. A single Capillus HIV-1/HIV-2 IgG latex aggregation test (Cambridge Biotech Corporation, Galway, Ireland), with sensitivity and specificity greater than 99.9% and 99.6%, respectively, was subsequently used to screen for HIV infection. Syphilis serology was determined by a non-treponemal carbon antigen test to detect reagin antibodies (Immutrep RPR test; Omega Diagnositcs, Alloa, Scotland, UK). Qualitative enzyme-linked immunosorbent assay (ELISA) testing was used to detect HSV-2 type-specific IgG antibodies (MRL Diagnostics, Los Angeles, California, USA). Neisseria gonorrhoea and Chlamydia trachomatis-specific DNA sequences were detected in urine samples using ligase chain reactions (Abbott Laboratories, North Chicago, Illinois, USA). KSHV serology was performed at the Viral Oncology Section, AVP, NCI-Frederick. The detection of antibodies to lytic K8.1 and latent Orf73 KSHV antigens were determined as detailed previously . Collected questionnaire data, laboratory HIV and STI results were anonymously linked to the KSHV data using unique participant identification numbers.
Sexually transmitted infections
A very high prevalence of HIV and STI in the Carletonville community has been described before  and is also reflected in this study. To assess the overall impact of STI in this population, subjects were grouped into those with and without laboratory evidence of STI. For this grouping, participants serologically positive to IgG HSV-2 were excluded, as antibodies to HSV-2 were detected in more than 65% of all subjects including almost all sex workers (95.8%).
Descriptive statistical analysis and measures of association were performed using SAS 9.1 and SAS Enterprise Guide 3.0 statistical software (SAS Institute Inc., Cary, North Carolina, USA). Comparisons of means were performed using the Bonferroni adjusted student t-test between groups or analysis of variance among multiple groups. Odds ratios (OR) and 95% confidence intervals (CI) for human herpes virus 8 seropositivity among the subjects were calculated by fitting logistic regression models. Multivariate analysis included adjustment for age groups 25 years and less, 26–35 years, 36–45 years, and 46 years and older, community groups, HIV or other STI. Chi-square tests for binary measures, chi-square tests for trend, chi-square tests for homogeneity were recorded and two-sided P values were always used as a measure of significance of the associations. Selected factors thought to be possible risk factors for KSHV were included in an initial multivariate model; factors used to explain risk factors for HIV and other STI were also included. Factors with closely related features (i.e. residential groups and sex) were not put in the same model to avoid redundancy. Subsequently, all factors that remained significant at P ≤ 0.1 were identified and included in the next model, and factors significant at P < 0.05 were considered possible risk factors and included in the final model. Pearsons correlation was used as a parametric measure of correlation between the optical densities of the two assays and kappa statistic as a measure of agreement.
Table 1 shows the demography of the groups in the study and the prevalence of known STI and KSHV-positive serology. The mean age (± SD) for all the subjects was 33.2 years (10.1) and non-township residents were significantly older (P < 0.0001). An analysis of variance showed a significant difference in the ages of the various communities (P < 0.0001); the largest difference being between mineworkers and male township residents (P < 0.05).
HIV is associated with social and sexual behavior factors and other sexually transmitted infections
Table 1 shows that the prevalence of STI, including HIV, was high in all sections of the community. Serology for HSV-2 was positive in 65.7%, and 48.5% had at least one other STI. The prevalence of STI was highest in sex workers (85.3%), then female township residents, miners and male residents (OR 11.7, 95% CI 6.9–19.8; OR 3.3, 95% CI 2.5–4.3; and OR 2.0, 95% CI 1.5–2.6, respectively; P < 0.0001). Overall, HIV prevalence was 39.6% and was highest in sex workers (76.8%), followed by female township residents (48.3%), mineworkers (36.5%), and male township residents (22.2%; P < 0.0001). Significant differences were seen mostly between sex workers and other groups. Sex workers were 29.3 times more likely to be infected with STI, followed by a 4.1-fold risk in female township residents and then a 1.2-fold non-significant risk in mineworkers (OR 29.3, 95% CI 7.1–121.1; OR 4.1, 95% CI 3.1–5.6; and OR 1.2, 95% CI 0.9–1.6; P < 0.01; results not shown in tables).
Table 2 shows social factors and indicators of sexual behavior likely to impact the prevalence of HIV and syphilis. The profile of risk for these follows the expected pattern of an STI. The age group 26–35 years were at greatest risk (OR 3.1, 95% CI 2.4–3.9). Compared with male residents, sex workers and female residents were at greatest risk of HIV and syphilis (11.7 and 3.9-fold). The risk of HIV infection, adjusted for age and other STI was sevenfold, 2.4-fold and twofold higher in sex workers, female township residents and miners (OR 7.0, 95% CI 4.0–12.0; OR 2.4, 95% CI 1.8–3.2; OR 2.0, 95% CI 1.5–2.7; P < 0.001, respectively; results not shown in Table 2). Sexual intercourse and the number of sexual partners were both strong risk factors for HIV and syphilis. Drinking alcohol was associated with a high risk of both syphilis and HIV infection. In men, circumcised subjects appeared to be protected from HIV infection compared with those who were not circumcised (OR 0.8, 95% CI 0.6–1.0). Positive serology for another STI was a strong risk factor for HIV infection (Table 3). The risk of HIV infection was two to 3.5-fold higher in subjects with evidence of gonococcal, syphilitic or HSV-2 infection. The risk associated with chlamydial infection was not significant.
Kaposi's sarcoma herpes virus is not associated with sexually transmitted infections, HIV and sexual behavior
The overall prevalence of KSHV (seropositive to lytic KSHV K8.1 or latent KSHV Orf73) was 47.5% (Table 1). Although the prevalence of KSHV was highest in sex workers (50.5%), in contrast to the prevalence of HIV and other STI, this was not significantly different to that in mineworkers (48.4%), male township residents (47.5%) and female township residents (46.0%) (chi-square 3 df 1.3; P > 0.73).
In contrast to HIV and syphilis the prevalence of KSHV did not follow the pattern expected of an STI (Table 2). The age group most at risk was over 46 years (OR 1.4, 95% CI 1.0–1.8) and the area of residence had no impact on the prevalence of KSHV. Sexual intercourse and the number of sexual partners were not risk factors for KSHV. In contrast to HIV, positive serology for another STI had no impact on the risk of KSHV infection (Table 3). KSHV prevalence was similar between HIV-positive (48.5%) and HIV-negative (46.8%) subjects (P = 0.44). The prevalence of KSHV was also similar in those with no STI (46.1%) compared with those with STI (47.9%; P > 0.48).
Some social factors were associated with an increased risk of KSHV infection (Table 2). Subjects who had been married or were living as married were 1.2-fold more likely to be KSHV seropositive than if never married (OR 1.2, 95% CI 1.0–1.4). Those who were married at a later age (> 36 years) or were unmarried appeared to be protected from KSHV infection than if married at an early age (< 18 years). KSHV was also associated with drinking alcohol at least once a day (OR 1.4, 95% CI 1.0–2.1). Unexpectedly, male subjects who were circumcised were at a 1.3-fold risk of being KSHV infected than uncircumcised men (OR 1.3, 95% CI 1.0–1.6).
Lytic and latent Kaposi's sarcoma herpes virus antibodies
The mean antibody titre (± SD) for K8.1 was similar among all non-township and township community groups [mean antibody titre (± SD) 0.61 (0.52) versus 0.44 (0.49), respectively; P > 0.05]. For Orf73 the mean antibody titre (± SD) was significantly higher in sex workers than in any other community group (P < 0.05), but was similar among mineworkers, female township residents and male township residents (P > 0.05).
Seropositivity to K8.1 antibodies (43.0%) was significantly higher than seropositivity to Orf73 antibodies (28.5%; P < 0.0001). Seropositivity to K8.1 antibodies was similar among all the community groups, ranging from 41.6% in female township residents to 47.4% in sex workers (P = 0.22; chi-square 3 df 1.2; P = 0.75). No increased risks for K8.1 antibodies were noted in any of the community groups compared with male township residents (P > 0.25). The prevalence of K8.1 antibodies was similar between those with or without evidence of an STI, HSV-2 and HIV (P > 0.5). No increased risks for K8.1 antibodies were observed for HIV or any STI (P > 0.16).
Seropositivity to Orf73 was highest in sex workers (40.0%) compared with male township residents (27.7%), female township residents (27.4%), and mineworkers (28.7%; chi-square 3 df 6.7; P = 0.08). The risk of seropositivity to Orf73 was 1.7-fold higher in sex workers compared with male township residents (OR 1.7, 95% CI 1.1–2.8), and similar in mineworkers (OR 1.0, 95% CI 0.8–1.3) and female township residents (OR 1.0, 95% CI 0.7–1.3), compared with male township residents (OR 1). No differences in the prevalences of latent KSHV seropositivity were noted when subjects where divided by HIV status and other STI (P > 0.3).
A total of 506 subjects(24.1%) tested seropositive to both lytic K8.1 and latent KSHV Orf73 antibodies, 398 (18.9%) and 94 (4.5%) were seropositive to only lytic KSHV K8.1 or latent KSHV Orf73, respectively (κ = 0.50). A significant correlation between the optical density of the lytic K8.1 and latent KSHV Orf73 assays was noted (r = 0.53; P < 0.0001). Risk factors for being positive on both assays were similar to being positive on either assay. Being positive on both assays was not associated with STI or other measures of sexual behavior. Sex workers and those residing in hotspots were, however, more likely to be positive for both assays (OR 1.7, 95% CI 1.1–2.9 and OR 2.0, 95% CI 1.2–3.4).
As expected from previous work [36,37], the high prevalence of HIV infection in Carletonville was significantly associated with other STI, measures of sexual behavior and being a sex worker. In marked contrast, none of the factors associated with these known sexually transmitted agents was applicable to KSHV infection. The prevalence of KSHV infection was nearly as common as HIV infection (47.5 versus 40%) in this community. In agreement with other reports, KSHV infection was associated with an increase with age , whereas HIV infection was highest in 26–35 year olds, a pattern well defined in South Africa . Although still high, the prevalence of other STI in this study was up to sixfold lower than the prevalence of HIV infection (Table 1). This may be a reflection of ongoing intervention programmes in the Carletonville area aimed at reducing STI through syndromic treatment and other preventive measures . Defining modes of transmission of KSHV remains a challenge, especially in African endemic countries, where contrasting information existing for sexual transmission and non-sexual modes of transmission is common. In this study we were able to compare the well-known pattern of sexually related risk factors for HIV, with that seen for KSHV in a community at risk of both. The presence of other STI in this study was clearly associated with an increased risk of HIV infection.
In contrast, KSHV seropositivity in this population was not associated with the presence of chlamydia, gonococcal, syphilitic or HSV-2 infection (Table 3). This is in agreement with a study in Uganda that showed no association between STI and KSHV . In our study, KSHV infection did not differ significantly by HIV status. This was in contrast to a recent study in South African children, in which HIV co-infection was associated with KSHV seropositivity . KSHV infection was not associated with any measures of sexual activity, including the number of lifetime sexual partners. Most significantly, being a sex worker carried no greater risk of KSHV infection than other township residents, a finding supported by work in Djibouti . This lack of association between KSHV, STI and measures of sexual behavior in this population indicates that sexual transmission is not an important transmission route in the Carletonville population. This may be attributed to the existing high background of KSHV exposure in the population before sexual activity, thus masking the role of sexual transmission. KSHV is, however, prevalent to a similar degree in MSM in the United States and United Kingdom, where a clear role for sexual risk factors has been reported [6,7].
Evidently, in this population and other African and Mediterranean populations, non-sexual modes of transmission play an important role in KSHV infection [38,41,42]. In this study, a number of interesting associations have emerged. Whereas the reduced risk of HIV infection conferred by circumcision shown in this study (OR 0.8, 95% CI 0.6–1.0) is well recognized [43,44], circumcision appeared to carry a significant risk of KSHV infection (OR 1.3, 95% CI 1.0–1.6). This is contrary to a previous report from Kenya . In our study, circumcision was related to the home language, with most of the circumcised subjects speaking isiXhosa (70%) or Sesotho (50%) and only approximately 20% of those speaking isiZulu, Setswana and other languages. In South Africa, these languages are indicative of different social practices and geographical origins. Unexpectedly, the risk of KSHV infection was significant if the home language was isiZulu compared with Setswana, and no association was noted with other languages (Table 2). It follows that the association with circumcision found in this study may have more to do with geographical and cultural factors than with the absence of a foreskin. Other associations are difficult to explain. Drinking alcohol was a risk factor for both HIV and KSHV, and although this may be linked to sexual behavior it could also be related to the common practice of sharing drinking vessels and KSHV transmission via saliva, which is thought to be an important route of KSHV infection [13,23,46,47].
The highest prevalence of latent KSHV Orf73 antibody was seen in sex workers who also had a very high prevalence of HIV infection, an association not seen for lytic KSHV K8.1. Sex workers also had the highest latent Orf73 KSHV antibody titres compared with any other community group and were also more likely to express both lytic and latent antibodies together. The biological significance of this finding is unclear.
The risk factors relating to the transmission of KSHV in African populations require considerable further study. Having an infected family member, especially an infected mother, is clearly an important risk factor [22–24,47,48]. A role for environmental risk factors, such as the source of household water and insect vectors, has been proposed [49–51]. The role of HIV infection in facilitating the transmission of KSHV needs careful study because changes in the prevalence of KSHV as a result of the HIV epidemic will have important public health implications. Further longitudinal epidemiological studies specifically designed to identify risk factors for KSHV are required in African populations.
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