Abstract

BackgroundThe aim of the present study was to estimate the prevalence of Kaposi sarcoma–associated herpesvirus (KSHV) in the female general population, to define geographic variation in and heterosexual transmission of the virus

MethodsThe study included 10,963 women from 9 countries for whom information on sociodemographic characteristics and reproductive, sexual, and smoking behaviors were available. Antibodies against KSHV that encoded lytic antigen K8.1 and latent antigen ORF73 were determined

ResultsThe range of prevalence of KSHV (defined as detection of any antigen) was 3.81%–46.02%, with significant geographic variation noted. In Nigeria, the prevalence was 46.02%; in Colombia, 13.32%; in Costa Rica, 9.81%; in Argentina, 6.40%; in Ho Chi Minh City, Vietnam, 15.50%; in Hanoi, Vietnam, 11.26%; in Songkla, Thailand, 10%; in Lampang, Thailand, 8.63%; in Korea, 4.93%; and in Spain, 3.65%. The prevalence of KSHV slightly increased with increasing age among subjects in geographic areas where the prevalence of KSHV was high, such as Nigeria and Colombia, and it significantly decreased with increases in the educational level attained by subjects in those areas. KSHV was not statistically associated with age at first sexual intercourse, number of sex partners, number of children, patterns of oral contraceptive use, presence of cervical human papillomavirus DNA, or smoking status

ConclusionsThe study provides comparable estimates of KSHV prevalence in diverse cultural settings across 4 continents and provides evidence that sexual transmission of KSHV is not a major source of infection in the general population

Kaposi sarcoma–associated herpesvirus (KSHV), which is also known as “human herpesvirus 8” (HHV-8), has been shown to be causally associated with Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease [1–3]. Data on the non–HIV-infected population indicate that there is wide geographic variability in KSHV infection. The prevalence of KSHV was estimated in series of healthy individuals from different parts of the world and was found to be 1.3%–4.4% in Southeast Asia and the Caribbean regions and >40% in Africa [4–6]. In Europe, the prevalence of KSHV was found to be lowest in Spain or Greece (6%–8%) and highest in Italy (20.4%) [7–11]. Approximately 50% of the adult population of Brazilian Amerindians was reported to have antibodies to KSHV [12], compared with only 11% of HIV-negative injection drug users in Argentina [13]. When the same detection assay was used but the cutoff point for positive findings was changed, the range of estimates of prevalence in the US general population was found to be 1.5%–7% [14, 15]

The natural history of KSHV and its routes of transmission are not well understood. Routes of transmission may vary in relation to the background prevalence of KSHV in the general population [16]. Nonsexual transmission of KSHV may be important in those countries where the prevalence of KSHV is high and where infection in children has been reported. In countries with a low to intermediate background prevalence of KSHV, sexual transmission, at least among men who have sex with men (MSM), may be predominant. Evidence for heterosexual transmission of KSHV is conflicting. The prevalence of KSHV has been reported to be higher among heterosexual individuals attending a sexual transmitted diseases (STDs) clinic than among blood donors in the United States and the United Kingdom, as has also been seen for other STDs and hepatitis B [17, 18]. However, no clear association with other sexual transmitted infections (STIs) or with the lifetime number of sex partners has been observed in the US general population [14] or in South Africa, a country where KSHV is endemic [17, 19]

There is no reference standard assay for estimating the prevalence of KSHV, and because assays have demonstrated little agreement, especially among asymptomatic subjects [15], comparing estimates between different studies is highly problematic. Methods of recruiting subjects for studies are also highly variable and can affect the resulting prevalence estimate. In the present study, we were able to assess a large number of subjects who were recruited using similar protocols and tested by means of well-established assays conducted by a single operator

The aim of the study was to use the data from the International Agency for Research on Cancer (IARC) International Human Papillomavirus (HPV) Prevalence Surveys study and the National Cancer Institute (NCI)–Costa Rica HPV Natural History Study to provide reliable and comparable estimates of KSHV prevalence and to evaluate the role of heterosexual transmission of KSHV by comparing the seroresponse to KSHV with questionnaire data on lifetime sexual activity and detection of cervical HPV DNA

Methods

Since 1998, the IARC has coordinated a study aimed at estimating the prevalence of genital HPV in countries with contrasting cervical cancer incidence rates. The study has been completed in Argentina (Concordia), Thailand (Lampang and Songkla), Vietnam (Hanoi and Ho Chi Mihn City), Nigeria (Ibadan), Spain (Barcelona), Republic of Korea (Busan), and Colombia (Bogotá). In Guanacaste, Costa Rica, the study was nested in the recruitment phase of a cohort study conducted using a comparable protocol. Each participating center recruited a random sample of the female general population. Participants were stratified into 11 age groups ranging in age from <20 years up to 75 years. As stated in the study protocol, each specific country had to include around 100 women per age group, to result in a total of ∼1100 subjects per study site. The information was collected from a personal interview on sexual, reproductive, medical, and sociodemographic history, as well as tobacco and alcohol consumption. Women also contributed cervical cells and a blood sample that were used in testing for different sexually transmitted infections. The cities and/or countries participating in the study and their rates of participation were as follows: Lampang, Thailand, 71%; Hanoi, Vietnam, 94%; Ho Chi Minh City, Vietnam, 88%; Republic of Korea, 74%; Songkla, Thailand, 48%; Spain, 60%; Costa Rica, 91%; Colombia, 95%; Argentina, 50%; and Nigeria, 48.4% [20–22]. Of the 13,639 women initially selected for the study, 10,999 had blood samples available

Data sourcePlasma samples were shipped from the IARC to the Viral Oncology Section laboratory at the National Cancer Institute–Frederick (Frederick, MD) and were tested for antibodies against KSHV. Antibodies against K8.1 (a lytic antigen) were tested using an ELISA, largely as described elsewhere [7]. Antibodies against latency-associated nuclear antigen (LANA) open-reading frame 73 (ORF73) were tested by a similar ELISA using full-length baculo-expressed LANA as antigen and serum diluted 1:100. For both assays, 3 positive and 3 negative control samples were included on each plate and were used in the calculation of the cutoff value, to adjust for plate-to-plate variability. For the K8.1 ELISA, the cutoff value that was calculated was the average value for the negative control samples plus 0.75 for each plate. For the ORF73 ELISA, the cutoff value was determined by obtaining the mean value for the positive control samples and dividing it by 5

Statistical analysisThirty-six women (0.33%) were excluded from the statistical analysis because the results of testing for the presence of KSHV were indeterminate in both assays; therefore, a total of 10,963 women were included in the final analysis. Results of assays for K8.1 and ORF73 were evaluated separately and then combined. Two variables were created: any if results of testing for either the K8.1 antigen or the ORF73 antigen were positive, and both if results for K8.1 and ORF73 were positive. All analyses were conducted to determine the antibody response to K8.1, ORF73, both antigens, and any antigen. For reasons of simplicity, most of the results are presented for any antigen (i.e., detection of either the K8.1 or ORF73 antigen)

Unconditional logistic regression was used to estimate the prevalence of the odds ratio (POR) (and the corresponding 95% confidence interval [CI]) of being positive for KSHV on the basis of demographic characteristics, reproductive and sexual behaviors, oral contraceptive use, and smoking history. All PORs were finally adjusted for age group (<25 years, 25–34 years, 35–54 years, and >54 years of age), educational level (none, primary, secondary, or higher) and geographic area of recruitment

The heterogeneity of PORs between areas of recruitment was assessed using the likelihood ratio test. The model including the interaction term between the centers was compared with the exposure of interest to the model including the main effects

The κ index was used as a measurement of the presence of the 2 antigens. Positive results for the detection of K8.1 or ORF73 are reported in the text. All the analyses were performed using Stata software (version 10; Stata)

Protection of human subjectsThe general study has been approved by the institutional review boards of the local institutes and, specifically for this substudy, also by IARC and NCI institutions. Participants were requested to participate under noncoercive and nondiscriminatory practices. Women were interviewed, and biological samples were collected in private at the local gynecologic clinics. All data are preserved under rules of confidentiality. All women provided written informed consent, with there being no additional commitment to report back results in the aforementioned countries

Results

A total of 10,963 women were available for the final analysis. The mean age of the women was 40.96 years and varied from a mean of 32.1 years in Colombia to 45.7 years in Songkla, Thailand. Table 1 presents the prevalence of KSHV as stratified by geographic area of recruitment. The range of prevalence of KSHV was 1.76%–24.52% for K8.1, 1.85%–41.96% for ORF73, 3.81%–46.02% for any antigen, and 0.50%–15.84% for both antigens. The lowest prevalence of ORF73 was noted in Spain, and the lowest prevalence of K8.1 was noted in Songkla, Thailand. The highest prevalence of all antigens was noted in Nigeria. Figure 1 shows the prevalence of KSHV and the exact 95% CIs, based on detection of any of the antigens

Table 1

Prevalence of Kaposi sarcoma–associated herpesvirus (KSHV), by geographic area of recruitment

Table 1

Prevalence of Kaposi sarcoma–associated herpesvirus (KSHV), by geographic area of recruitment

Figure 1

Prevalence (95% exact confidence intervals) of Kaposi sarcoma–associated herpesvirus (KSHV), based on detection of antibodies to K8.1 or ORF73 in subjects in the geographic areas participating in the studies. *Vietnam; **Thailand

Figure 1

Prevalence (95% exact confidence intervals) of Kaposi sarcoma–associated herpesvirus (KSHV), based on detection of antibodies to K8.1 or ORF73 in subjects in the geographic areas participating in the studies. *Vietnam; **Thailand

For simplicity, hereafter, we will refer to the prevalence of KSHV by use of the “any antigen” category of reactivity to both antigen (tables 2 and 3). Other values are described in tables 4 and 5, which do not appear in the print version of the Journal and which appear only in the electronic version of the Journal

Table 2

Prevalence odds ratios (PORs) for Kaposi sarcoma–associated herpesvirus (KSHV)

Table 2

Prevalence odds ratios (PORs) for Kaposi sarcoma–associated herpesvirus (KSHV)

Table 3

Prevalence odds ratios (PORs) for Kaposi sarcoma–associated herpesvirus (KSHV), by sexual and reproductive activity, oral contraceptive use, and smoking history

Table 3

Prevalence odds ratios (PORs) for Kaposi sarcoma–associated herpesvirus (KSHV), by sexual and reproductive activity, oral contraceptive use, and smoking history

Table 2 describes the prevalence of KSHV and the POR for KSHV by area of recruitment, age at interview, and educational level. All areas of recruitment, with the exception of Korea, showed significantly higher PORs for KSHV than did Spain, the country in which the prevalence of KSHV was lowest. Women from Nigeria were 19 times more likely to be KSHV positive than were women from Spain. The estimate was statistically different from estimates noted for other countries (95% CI, 12.19–29.98). When all countries were considered together, detection of KSHV slightly increased with increasing age, although no significant linear trend was observed (P=.170, for linear trend). Figure 2 shows the prevalence of antibodies to KSHV by age group and area of recruitment. In Colombia and Nigeria, the prevalence of KSHV significantly increased with increasing age. This pattern was not observed in the remaining recruitment centers. In the adjusted model, detection of KSHV significantly decreased in association with an increasing educational level (P<.001, for linear trend). Women with secondary or higher educational level had a lower POR than did those who had never attended school (POR, 0.65; 95% CI, 0.53–0.80) (table 2)

Figure 2

Prevalence of antibodies to Kaposi sarcoma–associated herpesvirus, by age group and geographic area of recruitment. Graphics in each row show the prevalence of antibodies to K8.1 (A) ORF73 (B) either antigen (C) and both antigens (D). *Vietnam. **Thailand

Figure 2

Prevalence of antibodies to Kaposi sarcoma–associated herpesvirus, by age group and geographic area of recruitment. Graphics in each row show the prevalence of antibodies to K8.1 (A) ORF73 (B) either antigen (C) and both antigens (D). *Vietnam. **Thailand

Table 3 presents the POR of KSHV according to sexual and reproductive behaviors. Women who were virgins had a lower prevalence of KSHV, although differences in findings for sexually active women were not statistically significant (data not shown). No statistically significant association was observed in association with age at the time of first sexual intercourse, lifetime number of sex partners, oral contraceptive use, or smoking history

A higher prevalence of KSHV was observed among women who were HPV DNA positive (prevalence, 18.18% among HPV-positive women and 13.37% among HPV-negative women), but adjustment for potential confounders removed any statistical significance (POR, 1.08; 95% CI, 0.90–1.29)

Discussion

To our knowledge, this is the largest study to date that has evaluated the prevalence of KSHV in the general female population of 8 countries. The study showed an 18-fold disparity in the prevalence of KSHV between Nigeria and Spain. Estimates of high prevalence were observed in Nigeria (46%), Vietnam (11.3%–15.5%), Colombia (13%), and Costa Rica (11.1%). Intermediate prevalence values were observed in Thailand (8.6%–10.0%) and Argentina (6.4%). Finally, the values noted in Spain and Korea were at the lower end of the range (3.8%–4.9%, respectively). Thus, the study confirms the important geographic variation associated with this oncogenic virus, as has been reported in other settings [10]. When the most stringent criterion for infection (i.e., detection of both antigens) was used, prevalence was very low (0.50%–15.84%) in most countries but remained high in Nigeria (15.84%), followed by Colombia (4.97%). A high prevalence of KSHV was expected in Nigeria, reflecting findings similar to those in other African countries and in developing countries. The relatively high prevalence observed in Colombia, especially among older women in the general population, is worthy of further study. Cancer registry findings suggest that Kaposi sarcoma is rarely reported (incidence, ⩽0.1 case/100,000 women) in all the areas included in the present study, except in the cancer registry of Colombia (0.2 case/100,000 women) and sub-Saharan Africa (>20 cases/100,000 women) [23]

It is unknown whether part of the observed geographic variation could be attributable to concomitant HIV infection, a correlate of KSHV, because women could not be tested for the presence of HIV. The women included in the present study were a random sample of the general population in a given country, and, therefore, they should reflect variations in background infections due to HIV or HPV. The prevalence of KSHV in Nigeria was so high that the virus affected ∼1 in 2 women, a prevalence which is much higher than the expected prevalence of HIV infection in this setting, indicating that KSHV infection must be in part independent of HIV. The increasing prevalence of KSHV with increasing age in countries with a high prevalence of the virus, such as Nigeria and Colombia, is in agreement with transmission of KSHV through saliva from mother to child early in life and with the increasing prevalence of the virus from infancy to early adulthood [24, 25]. The association with age was clear for any measurement of KSHV infection selected, indicating a continuous acquisition of infection throughout life

Contrary to observations among MSM and HIV-infected populations, the data presented seem to indicate that there is no sexual transmission of KSHV among women in the general population. No association with age at the time of first sexual intercourse, lifetime number of sexual partners, or cervical HPV DNA was observed. We could not confirm the results of our previous preliminary research on the association between KSHV and HPV DNA among sex workers in Spain, although we were now using a much larger study [7]. However, these results are in agreement with previous reports in which the seroprevalence of KSHV among women was not significantly related to the duration of sexual activity, the lifetime number of sex partners, or coinfection with other STIs [14, 19], and they suggest other routes of transmission, such as through saliva [25–28] or blood contact [29]. However, the role of sexual behavior cannot be disregarded. The prevalence of KSHV has a geographic correlation with the prevalence of HPV. Furthermore, other potential aspects of sexual behavior have not been explored. For example, no data on the sexual behavior of the partner were available from this study or from other studies. The majority of recent studies have shown no association with sexual transmission among heterosexuals. This is not inconsistent with an association with the lifetime number of sex partners among high-risk groups, such as MSM

The incidence of AIDS-KS is very low in many of the countries included in the present study, and it has been speculated that this is the result of a very low prevalence of KSHV in the general population. This suggestion is not supported by our findings. The fact that the incidence of AIDS-KS is higher in the United States and Europe than in other societies with a similar prevalence of KSHV is probably a reflection of an important presence of risk groups, such as MSM, that constitute a large proportion of individuals with HIV infection [30]

It has been suggested that smoking interferes with protective humoral T helper 2–type and cell-mediated T helper 1–type equilibrium, which in turn may affect susceptibility to KSHV [31]. According to the data presented, smokers had a lower prevalence of KSHV, which is in agreement with the findings of reports published elsewhere [31, 32]. This association, after adjustment for educational levels, was of no statistical significance, and a detailed analysis of the type of tobacco used and whether a filter was used did not shed light on the association (data not shown)

KSHV is a γ-herpesvirus with a genetic organization similar to that of Epstein-Barr virus. The KSHV genome encodes >85 genes, of which >10 are known to be antigenic. Two major antigens are the subject of our investigation: ORF73, which encodes LANA, a protein with multiple viral functions expressed in latency, and K8.1, which encodes gpK8.1, a viral envelope glycoprotein. Testing for KSHV infection is challenging, because KSHV is not readily isolated in cell culture. KSHV DNA can be detected in all KS tumor biopsy specimens by means of polymerase chain reaction; however, viral DNA is detectable by nested or real-time polymerase chain reaction in the blood of only ∼50% of patients with KS and 10% of asymptomatically infected subjects, because few infected cells are present in peripheral blood. Serological assays are considerably more sensitive, but studies have shown poor agreement between tests in asymptomatically infected subjects

Longitudinal studies have shown that subjects may develop antibodies to lytic antigens several years before developing antibodies to latent antigens or vice versa. Therefore, it is important to use >1 antigen in cross-sectional studies such as this one. The assays used in the present study have been extensively used in previous studies of diverse populations, and they show excellent reproducibility and reliability supporting the prevalence estimates derived from this analysis [8, 14, 25]. The data from each assay have been presented separately and combined in more (i.e., positive results of both assays) or less (i.e., positive results of either assay) stringent ways. The major strength of this study is that the large number of subjects were recruited using a common protocol and tested using a common testing algorithm

The important geographic variation in and the high prevalence of KSHV observed in some countries reveal the need for further study of the risk factors for infection, to identify ways that lead to the prevention of the oncogenic consequences of this virus

Acknowledgments

We thank Gina Albero from the Catalan Institute of Oncology and Annie Arslan from the International Agency for Research on Cancer for data management and statistical contribution

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Potential conflicts of interest: none reported
Presented in part: 11th International Workshop on KSHV and Related Agents, 22–26 July 2008, Birmingham, United Kingdom (abstract 51; oral presentation in session 8: Epidemiologic and Clinical Research)
Financial support: National Cancer Institute, National Institutes of Health (contract N01-CO-12400); Spanish platform Centro de Investigación Biomédica en Red de Epidemiologia y Salud Pública (grant 06/0673)