Sexually Transmitted Diseases:
Correlates of Human Herpesvirus-8 Seropositivity Among U.S. Military Members Recently Infected With Human Immunodeficiency Virus
Crum, Nancy F. MD, MPH*; Wallace, Mark R. MD*; Stephan, Kevin MD†; Blazes, David L. MD, MPH†; Aronson, Naomi MD§; Tasker, Sybil A. MD†; Thomas, Anne G. PhD∥; Wegner, Scott MD¶; Casper, Corey MD, MPH**; Wald, Anna MD, MPH‡; Corey, Lawrence MD‡; Brodine, Stephanie K. MD∥
From the *Department of Medicine, Infectious Diseases Division, Naval Medical Center San Diego, San Diego, California; †Infectious Diseases Division, Wilford Hall Medical Center, Lackland Air Force Base, Texas; †Infectious Diseases Service, National Naval Medical Center and the Uniformed Services University of the Health Sciences, Bethesda, Maryland; §Infectious Diseases Division, Walter Reed Army Medical Center, Washington, DC, and the Uniformed Services University of the Health Sciences, Bethesda, Maryland; ∥Naval Health Research Center, San Diego, California; ¶U.S. Military HIV Research Program, Rockville, Maryland, and the Uniformed Services University of the Health Sciences, Bethesda, Maryland; the **Department of Medicine, Infectious Diseases Division, University of Washington, Seattle, Washington; the ‡Departments of Medicine, Epidemiology, and Laboratory Medicine, University of Washington, Seattle, Washington; and the ‡Departments of Medicine, Laboratory Medicine, and Program in Infectious Disease, Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, Washington
The authors thank Joyce Gilcrest and Brandie Pope for their assistance with the U.S. military HIV database, and Heather Taylor and Anne Cent for their assistance with the HHV-8 serologic assays.
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of the Army, Department of the Air Force, Department of Defense, or the United States Government.
Financial support provided by the U.S. Military HIV Research Program, Rockville, Maryland, NIH Grants P01 AI-30731 and U19 AI-31448, and the Joel Meyer Infectious Disease Scholarship Grant.
A subset of data in this article was presented at the 40th Annual Meeting of the Infectious Diseases Society of America, October 24-27, 2002, Abstract #511.
Correspondence: Nancy F. Crum, c/o Clinical Investigation Department (KCA), Naval Medical Center San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134-1005. E-mail: email@example.com
Received January 23, 2003,
revised April 25, 2003, and accepted May 7, 2003.
Background: Human herpesvirus 8 (HHV-8), the cause of Kaposi's sarcoma, is common among HIV-infected persons. The exact route of transmission of HHV-8 in various populations is still debated.
Goal: The goal was to define the correlates of HHV-8 infection among men recently infected with human immunodeficiency virus.
Study Design: Three hundred forty-two HIV-infected U.S. military men were evaluated using a questionnaire regarding potential risk factors and laboratory data, including HHV-8, herpes simplex virus 2 (HSV-2), syphilis, hepatitis B, and hepatitis C serologies.
Results: The seroprevalence of HHV-8 was 32%. HHV-8 was significantly associated with hepatitis B seropositivity (odds ratio [OR], 2.44; 95% confidence interval [CI], 1.5–4.1), and black ethnicity was negatively associated with HHV-8 (OR, 0.6; 95% CI, 0.3–0.9) in the multivariate analysis. HHV-8 was not associated with drug use or hepatitis C seropositivity. Among men who have sex with men (MSM), HHV-8 infection correlated with hepatitis B seropositivity (OR, 2.2; 95% CI, 1.1–4.3) and HSV-2 (OR, 2.6; 95% CI, 1.4–4.9). Among heterosexuals, the correlates of HHV-8 were different; blacks as compared with whites (OR, 0.3; 95% CI, 0.1–0.8) and married versus single status (OR, 0.4; 95% CI, 0.2–0.9) were associated with a lower rate of HHV-8 infection. Among heterosexuals, hepatitis B, HSV-2, and sexual behaviors were not associated with HHV-8.
Conclusion: This study suggests that the seroprevalence of HHV-8 is increased in both MSM and heterosexual men with HIV infection, and that the route(s) of HHV-8 acquisition might be different between MSM and heterosexuals.
SINCE THE DISCOVERY OF human herpesvirus 8 (HHV-8) in 1994 and its subsequent identification as the causative agent of Kaposi's sarcoma, efforts to determine the route of transmission have been ongoing. Much of what is known about the epidemiology of HHV-8 is inferred from prevalence rates in various groups. The prevalence of HHV-8 in blood donors in the U.S. population is thought to be between 1% and 5%. 1 Among HIV-infected heterosexuals of both sexes, the rates range from 5% to 20%, whereas HIV-infected men who have sex with men (MSM) have rates of 30% to 45%. 2-5 Studies examining specific risk factors associated with HHV-8 acquisition have been inconclusive. Some studies have suggested that a history of sexually transmitted infections (STIs), including herpes simplex virus 2 (HSV-2), higher numbers of sexual partners, and high-risk sexual behaviors, might be associated with HHV-8 seropositivity. 5-7 Others, however, have implicated deep kissing or illicit drug use as risk factors. 2,4,8,9 Lack of agreement in study results could be the result of several factors, including the heterogeneity of the populations studied, the sensitivity and specificity of diagnostic assays, and the timing of risk factor assessment in relation to HHV-8 acquisition. Better understanding of the specific route(s) of HHV-8 transmission might allow for the development of preventive strategies designed to reduce the risk of HHV-8 infection.
We examined the HHV-8 seroprevalence and its correlates in U.S. military members who were recently infected with HIV. This unique group consisted of persons who had acquired HIV almost exclusively from sexual contact. Our population of military men afforded us the opportunity to closely evaluate potential risk factors for HHV-8 infection in a cohort of men with a wide variety of ages, sexual behaviors, and ethnicities.
Current or retired U.S. military men with documented HIV seroconversion within 3 years before study enrollment were enrolled in an HIV seroepidemiologic study conducted from February 1997 to March 2001. 10 All participants in this study had signed an informed consent allowing the use of stored blood samples for sexually transmitted infection research. Enrollees were from geographically diverse locations throughout the United States and were evaluated at a tertiary-care military hospital. Participants completed a 16-page, self-administered questionnaire regarding demographic information, military deployments, and potential risk factors, including sexual activities and parenteral exposures during the HIV seroconversion window. The questionnaire included a variety of sexual activities, including age of first intercourse, number of lifetime partners, number of male and female partners during the seroconverting window, HIV-infected partners, partners in foreign countries, and locations of meeting sexual partners. Participants also reported if they engaged in anal intercourse, vaginal intercourse, oral-receptive sex, and how often a condom was used during these sexual activities. Based on answers regarding their history of sexual intercourse with men and/or women in the HIV seroconversion window, each participant was categorized as heterosexual (reporting sex only with women) or men who have sex with men (reporting at least one male sexual partner in the seroconversion interval). Questionnaire data were confidentially maintained to protect the military members participating in the study.
Blood was used for determination of lymphocyte subset analysis by flow cytometry, plasma HIV-1 RNA viral load by a quantitative reverse transcriptase PCR assay (Amplicor HIV-1 Monitor assay, Roche Molecular Systems, Branchburg, NJ), syphilis serology (microhemagglutination-Treponema pallidum testing), and hepatitis B serology. Of the 564 persons in the original study, 342 (61%) had blood available for HHV-8 determination. HHV-8 serologic testing was performed using stored serum (n = 266) or plasma (n = 76) samples by HHV-8 whole virus enzyme immunoassay (EIA), with the selected use of immunofluorescence assay (IFA) at the University of Washington as described previously. 11 HSV-2 antibody testing was performed by Focus HerpeSelect EIA at the University of Washington.
As a result of changes in laboratory procedures, some of the original study participants did not have blood available for HHV-8 testing. We compared the demographics of our subgroup with blood available to the original study population and found no differences except that our subgroup was slightly older (30 vs. 28 y) (P <0.05). In addition, plasma samples were used for participants who did not have serum available. However, we found no significant differences in HHV-8 seroprevalence between tests performed with serum and plasma (32.7% vs. 30.3%, P = 0.69).
Descriptive analysis of demographics, potential risk behaviors, and laboratory results were performed. Univariate analyses were conducted to compare HHV-8-seropositive and -seronegative persons by logistic regression. Continuous variables were assessed to determine their appropriate form by a 2-step process. First, each variable was evaluated in a linear form with and without a quadratic form and then as a categorical variable using biologically important intervals and median values. Multivariate analyses were performed using logistic regression with backward stepwise deletion with a threshold for inclusion of a P value of ≤0.10 and/or biologic significance (SAS, 8e, 2001, Cary, NC). Separate analyses were also performed stratified by sexual orientation and ethnicity. All significant variables were examined for interaction and confounding.
The mean age of our study population was 30 years (range, 18–57 y), with 44% whites, 42% blacks, and 14% other. The mean CD4 count was 496 cells/mm3 (range, 12–1077 mm3), and 45% were Centers for Disease Control and Prevention stage A1. Fifty-nine percent reported sex with men, whereas 41% were heterosexual. Forty-six percent reported an STI during their HIV seroconversion window, and the median number of lifetime partners was 24 (range, 1–500). Heterosexuals, compared with MSM, were more likely to report a history of genital herpes and to be HSV-2-seropositive. Oral and anal sexual activity, bleeding during sexual activities, group sex, more than one current sexual partner, and nitrate use were reported significantly more often by MSM than heterosexuals (P <0.05). In addition, MSM were more likely to be hepatitis B-seropositive in a univariate analysis (Tables 1, 2, 3, and 4). Whites and blacks in our study population were compared by all variables listed within the tables (data not shown), and we found that whites were statistically more likely than blacks to engage in anal intercourse, report a known HIV-infected partner, and use nitrates. In addition, whites were more likely to be men who had sex with men. Blacks were more likely to be heterosexual and had a significantly higher rate of syphilis by history.
A total of 342 blood specimens were available for HHV-8 testing, and 110 (32.2%) were positive. The seroprevalence of HHV-8 was higher in MSM (35.0%) than in heterosexual men (26.5%), although this was not statistically significant (P = 0.13). Demographic information, sexual behaviors, parenteral exposures, and laboratory values are shown in Tables 1, 2, 3, and 4.
Correlates of HHV-8 Infection
Hepatitis B seropositivity (odds ratio [OR], 2.50; 95% confidence interval [CI], 1.51–4.13) was significantly correlated with HHV-8-seropositive status in the univariate analysis (P <0.001). No statistically significant relationships were found between HHV-8 serostatus and any demographic or sexual history variables, including number of lifetime sexual partners, history of STIs, receptive oral or anal intercourse, HSV-2 seropositivity, reporting sex with a known HIV-infected sexual partner, bleeding or condom use during sexual activities. Furthermore, there was no association of HHV-8 seropositivity and injection drug use, other drug use, including nitrates, a history of tattoos or body piercing, needlestick injuries, or hepatitis C seropositivity. In a multivariate analysis adjusted for age, ethnicity, education, HIV-infected sexual partner, hepatitis B serostatus, and HSV-2 serostatus, HHV-8 seropositivity was associated with hepatitis B (OR, 2.44; 95% CI, 1.45–4.11); blacks had a significantly lower rate of HHV-8 seropositivity than whites (OR, 0.55; 95% CI, 0.33–0.93;Table 5). There was no evidence of confounding between variables in the multivariate model. Interactions between sexual orientation and ethnicity, sexual orientation and oral sex, sexual orientation and anal sex, and sexual orientation and self-reported bleeding were assessed with no statistically significant findings.
Because sexual behaviors that might predispose to HHV-8 infection varied by sexual preference in our univariate analyses and previous studies, the participants were divided into heterosexual and MSM groups (Table 6). Among MSM, both hepatitis B (OR, 2.52; 95% CI, 1.33–4.78) and HSV-2 (OR, 2.64; 95% CI, 1.42-4.91) were strongly associated with HHV-8 in univariate analyses. A history of STIs other than HSV-2 was associated with an elevated risk of HHV-8 infection, although this finding was not statistically significant (OR, 1.68; 95% CI, 0.92-3.08). In a multivariate model adjusted for age, STIs during lifetime, hepatitis B, and HSV-2, both HSV-2 (OR, 2.60; 95% CI, 1.38-4.89) and hepatitis B (OR, 2.17; 95% CI, 1.10-4.29) remained significantly related to HHV-8 in MSM. The correlates of HHV-8 infection were different between heterosexual men and MSM. Univariate analyses among heterosexuals showed that blacks (OR, 0.32; 95% CI, 0.13-0.75) and married persons were less likely to have serologic evidence of HHV-8 infection (OR, 0.43; 95% CI, 0.18-0.99), whereas persons reporting a higher level of education (OR, 4.67; 95% CI, 1.31-16.62) were more likely to be HHV-8-seropositive. In the multivariate analysis adjusted for age, ethnicity, marital status, and education, being married as compared with being single (OR, 0.38; 95% CI, 0.15-0.97) and black ethnicity (OR, 0.30; 95% CI, 0.11-0.79) were associated with lower HHV-8 seroprevalence. Among heterosexuals, a history of STIs, including HSV-2 and hepatitis B serostatus, was not related to HHV-8 infection.
We identified a high seroprevalence (32%) of HHV-8 infection among recently HIV-infected U.S. military men. Our study population of recently HIV-infected military men was identified by periodic HIV screening with a mean length of HIV infection at study enrollment of 11 months. This is the first study to examine HHV-8 seroprevalence and its correlates among U.S. military personnel.
Although the study population included approximately equal numbers of heterosexuals and MSM, the overall seroprevalence of this group is similar to that found in other studies among HIV-infected MSM. 2-6 The prevalence of HHV-8 infection among this cohort of U.S. men reporting heterosexual behavior is significantly higher than that reported in previous studies, although, to our knowledge, no previous studies have looked at HHV-8 seroprevalence among men who acquired HIV through heterosexual sex. HHV-8 infection among this group was 5 to 25 times that seen in random U.S. blood donors, suggesting that there might be common risk factors for the acquisition of HIV and HHV-8 in this population. 1
The risk factors for HHV-8 infection differed between MSM and heterosexual men, despite their being from the same general population of HIV-infected military personnel. Among MSM, both hepatitis B and HSV-2 were associated with HHV-8 seropositivity, and no association was found between hepatitis C and HHV-8. These data, consistent with previous studies, 5-7 suggest that HHV-8 is likely to be transmitted by sexual activity among MSM. Although our study examined a wide variety of sexual behaviors, we did not identify any specific sexual behavior, including anal sex, oral sex, bleeding during sex, or having an HIV-infected partner, that was associated with HHV-8 infection. Of note, our study did not examine the frequency of oral-receptive sex or kissing in relation to HHV-8; a prior study found that exposure to saliva is associated with HHV-8 infection. 8 Among heterosexuals, hepatitis B and HSV-2 were not associated with HHV-8 seropositivity. Smith et al. showed that in MSM, HHV-8 was associated with STIs, but found that in heterosexual men, there was no evidence for sexual transmission. 5 Taken together, these findings suggest that the mode of transmission of HHV-8 might be somewhat different between MSM and heterosexual men. Salivary transmission of HHV-8 could conceivably reconcile the disparities in correlates of infection between diverse populations.
We found that blacks had a lower seroprevalence of HHV-8 than whites. The blacks in our population were more likely to be heterosexual and were less likely to report nitrate use, anal intercourse, or sex with a known HIV-infected partner. However, when we examined only heterosexuals, the negative association between black ethnicity and HHV-8 remained. A positive association between blacks and HHV-8 has been noted in women 2,12; however, no association has previously been noted in men. 4,13,14 The reason that heterosexual black U.S. military men have a lower rate of HHV-8 than whites is unclear. Black heterosexuals in our study reported more high-risk sexual behaviors and had a higher rate of hepatitis B and HSV-2 seropositivity than whites; these findings are supported by other studies. 15-17 HHV-8 seroprevalence varies significantly among well-defined demographic groups. In the United States, infection rates are highest among MSM, a group that is largely comprised of whites. Blacks in the military might lack exposure to persons from demographic groups that are likely to be infected with HHV-8.
The relationship between marital status and HHV-8 infection has not previously been reported in the published literature. The reason that heterosexual men who are married (as compared with single persons) have a lower seroprevalence of HHV-8 is unknown, but could be related to fewer lifetime or high-risk partners.
There were a number of limitations to our study. Like with any study that assesses exposure status through the use of a self-reported study instrument, the validity of survey responses could not be verified. However, although the official military policy against drug use or homosexual behavior could bias the responses to our questionnaire, a substantial number of men did report MSM behavior and drug use. The low reported rate of injection drug use is supported by the lack of hepatitis C seropositivity in our group. In addition to questionnaire data regarding risk factors, biologic outcomes to determine sexual exposures such as HSV-2, hepatitis B, and syphilis serologies were also measured. This study was designed to assess risk factors associated with HIV seroconversion; therefore, it might have failed to collect specific correlates of HHV-8 infection. In addition, as a result of the cross-sectional study design, we could not evaluate the temporal relationship between a specific behavior and acquisition of HHV-8 infection. Although several specific risk behaviors were assessed, the duration and frequency of these behaviors were not ascertained. Future studies should focus on incident risk factors with quantitative questions regarding potential risk factors.
Based on the findings of this study, HHV-8 is a commonly acquired infection among both MSM and heterosexual men with HIV infection; this suggests that behaviors that place men at risk for HIV might also be associated with acquisition of HHV-8. The U.S. military population is not at increased risk for HHV-8 in general because HHV-8 seroprevalence rates in our population were similar to other studies examining HIV-infected persons. HHV-8 seropositivity is highly associated with STIs such as HSV-2 and hepatitis B in MSM but not in heterosexuals. Safer sexual practices are recommended to reduce the incidence of HHV-8 infections in HIV-infected MSM 18; it is unclear whether such strategies would be efficacious in heterosexual men, because sexual risk factors were not correlated with HHV-8 infection in this study. Furthermore, the high rate of HHV-8 infection among HIV-positive heterosexual men and the low rate of infection among blacks suggests that much has yet to be learned about the seroprevalence of HHV-8 infection among persons not traditionally considered to be at high risk for the development of Kaposi's sarcoma. Studies aimed at determining the correlates of incident HHV-8 infection among broader populations of HIV-infected individuals are now warranted and will help to define the mode of HHV-8 transmission in areas where the virus is not endemic.
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