Risk factors for human herpesvirus 8 seropositivity in the AIDS Cancer Cohort Study

doi:10.1016/j.jcv.2005.10.010

Journal of Clinical Virology

Volume 35, Issue 4, April 2006, Pages 442-449

https://doi.org/10.1016/j.jcv.2005.10.010 Get rights and content

Abstract

Background

Cigarette smoking has been associated with a decreased risk for AIDS-related and classical KS, but whether it is associated with decreased risk of human herpesvirus 8 (HHV-8) infection is unknown.

Study design

We evaluated factors associated with HHV-8 seropositivity in 2795 participants (132 with KS) in the National Cancer Institute AIDS Cancer Cohort, including 1621 men who have sex with men (MSM), 660 heterosexual men and 514 women. Odds ratios (OR) and 95% confidence intervals were estimated using logistic regression models.

Results

Among non-KS subjects, HHV-8 seropositivity was 6%, 13% and 29% among women, heterosexual men and MSM, respectively. HHV-8 seropositivity was decreased in heavier (≥1/2 pack/day) compared to lighter smokers among women (5% versus 8%; adjusted OR (aOR) 0.4; 95% CI 0.2–0.8) and MSM (27% versus 32%; aOR 0.7; 95% CI 0.6–1.0), but not among heterosexual men (12% versus 16%; aOR 0.7; 95% CI 0.4–1.2). HHV-8 seroprevalence was increased in heavier (≥1 drink/day) compared to lighter consumers of alcohol among women (16% versus 4%; adjusted OR 5.2; 95% CI 2.3–12), but not among MSM (33% versus 28%; aOR 1.2; 95% CI 0.9–1.6) or heterosexual men (13% versus 13%; aOR 1.1; 95% CI 0.6–2.0). In analyses adjusted for smoking and drinking, HHV-8 seropositivity was positively associated with chlamydia infection (OR = 4.3; 95% CI 1.2–13) and with marital status among women p_{heterogeneity} = 0.03, and with hepatitis (OR = 1.6; 95% CI 1.2–2.1), gonorrhea (OR = 1.5; 95% CI 1.1–1.9), genital warts (OR = 1.5; 95% CI 1.1–2.0) and nitrate inhalant use (OR = 1.7; 95% CI 1.3–2.3) among MSM.

Conclusions

Inverse association of HHV-8 seropositivity with cigarette smoking may indicate protective effect of tobacco smoke on HHV-8 infection, whereas positive associations with alcohol may reflect either behavioral factors or biological effects modulating susceptibility. Smoking and drinking may influence KS risk, at least in part, by altering the natural history of HHV-8 infection.

Introduction

Human herpesvirus 8 (HHV-8, also called Kaposi sarcoma-associated herpesvirus) is accepted as the infectious cause of Kaposi sarcoma (KS) (Boshoff and Weiss, 2001, Chang et al., 1994), the most common tumor among persons with AIDS (Frisch et al., 2001, Mbulaiteye et al., 2003b). HHV-8 seroprevalence is low (∼3%) in the United States (Pellett et al., 2003) except among men who have sex with men (MSM; ∼30%) who also have a high risk of AIDS-related KS (Martin et al., 1998). Seroprevalence is intermediate (5–10%) among HIV-positive heterosexual men, women and injection drug users (Lennette et al., 1996, Martin, 2003). HHV-8 seropositivity is variably associated, particularly among MSM, with sexual exposures, sexually transmitted disease (Martin et al., 1998), and injection and other drug use in some but not all studies (Renwick et al., 2002).

Cigarette smoking has been associated with decreased risks for AIDS-related KS in the U.S. (Hoover et al., 1993, Nawar et al., 2005) and classical KS in Italy (Goedert et al., 2002), suggesting that cigarette smoking may modulate the natural history of HHV-8 infection. However, findings were equivocal in two studies conducted in Uganda, where KS is more common but smoking is less prevalent (Ziegler et al., 2003, Ziegler et al., 1997). Whether cigarette smoking decreases the risk of HHV-8 infection is unknown. We therefore evaluated the association of various behavioral factors, including cigarette smoking, with HHV-8 seropositivity among persons with AIDS in the U.S.

Section snippets

Study population and serology methods

We studied 2795 patients with AIDS aged ≥18 years old participating in the National Cancer Institute's AIDS Cancer Cohort (NCI-ACC) study. The patients were enrolled at 24 AIDS treatment and clinical trial sites in the United States from October 1997 to January 2000. All patients met Centers the Disease Control and Prevention (CDC) criteria for AIDS diagnosis (1992). At enrollment, the median (inter-quartile range) CD4 lymphocyte count was 204 (82–281) cells/μL and HIV viral load was 32,759

Results

One hundred thirty two (4.7%) of the subjects had KS at or before enrollment, including 2 women, 6 heterosexual men and 124 MSM (Table 1). One hundred nine (83%) of the subjects with KS had HHV-8 antibodies, including both of the women, three of the six heterosexual men and 104 of the 124 MSM. Associations with asymptomatic HHV-8 seropositivity were evaluated among the 2663 subjects without KS, of whom 554 (21%) had HHV-8 antibodies.

Discussion

In the NCI-ACC study, HHV-8 seropositivity was inversely associated with cigarette smoking and positively associated with alcohol consumption among women and MSM. The associations, particularly among women, were independent of sexual and recreational drug exposures. The magnitudes of the associations between cigarette smoking and alcohol consumption with HHV-8 seropositivity were accentuated in analyses that adjusted one for the other, indicating negative confounding. The associations were

Acknowledgements

We are grateful to the study subjects and the staff at the clinics for participating. We also thank Tabitha Hendershot, Mary-Anne Ardini and Athan Gadonas for study management (Research Triangle Institute (RTI), Washington DC), Sylvia Cohn (RTI, Washington DC) for preparing the data files and to Christine Gamache (Science Applications International Corporation-Frederick) for running the serology assays. The Study was funded in part by Contracts N01-CP-81017 and N01-CO-12400 from the Intramural

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Lifestyle factors associated with sex differences in Kaposi sarcoma incidence among adult black South Africans: A case-control study
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Citation Excerpt :
The relationship between KS and alcohol consumption is complex as the behavioral patterns associated with alcohol consumption may influence the probability of exposure to KSHV as stated by Mbulaiteye et al. [44] In a case-control study of KS in HIV positive Ugandan patients, Ziegler et al. and Nansseu et al. found no associated risk between alcohol consumption and KS. [42,43] KSHV seropositivity was also not associated with alcohol consumption in the study of Ugandan HIV-negative KS patients.[44,45]. Other explanations for the KS sex differences include genetic make-up along with unmeasured hormonal differences [46] and immune system functions.[47]
Kaposi Sarcoma (KS) is endemic in several countries in Southern and Eastern Africa, relatively rare worldwide but a leading cancer among people living with HIV. KS has always been more common in adult males than females. We assessed the prevalence of known cancer modifying factors (parity, hormonal contraceptive use in females, sex-partners, smoking and alcohol consumption in both sexes), and their relationship to KS, and whether any of these could account for the unequal KS sex ratios. We calculated logistic regression case-control adjusted odds ratios (OR_adj), and 95% confidence intervals (95%CI), between KS and each of the modifying factors, using appropriate comparison controls. Controls were cancer types that had no known relationship to exposures of interest (infection or alcohol or smoking or contraceptive use). The majority of the 1275 KS cases were HIV positive (97%), vs. 15.7% in 10,309 controls. The risk of KS among those with HIV was high in males (OR_adj=116.70;95%CI=71.35–190.88) and females (OR_adj=93.91;95%CI=54.22–162.40). Among controls, the prevalence of smoking and alcohol consumption was five and three times higher in males vs. females. We found a positive association between KS and heavy vs. non-drinking (OR_adj=1.31;95%CI=1.03–1.67), and in current heavy vs. never smokers (OR_adj=1.82;95%CI=1.07–3.10). These associations remained positive for alcohol consumption (but with wider CIs) after stratification by sex, and restriction to HIV positive participants. We found no evidence of interactions of smoking and alcohol by sex. Smoking and alcohol consumption may provide a possible explanation for the KS sex differences, given both exposures are more common in men, but confounding and bias cannot be fully ruled out. The role smoking and alcohol play in relation to viral loads of HIV/KSHV, differences in immunological responses or other genetic differences between males and females warrant further studies.
Coxiella burnetii antibody seropositivity is not a risk factor for AIDS-related non-Hodgkin lymphoma
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Quantitative determinations of anti-Kaposi sarcoma-associated herpesvirus antibody levels in men who have sex with men
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It is possible that the LIPS antigen mixture approach may have missed many of the borderline samples or that additional epitopes present in the ELISA assay were better at detecting antibodies in the asymptomatic KSHV samples. As found in previous MSM studies (Casper et al., 2006; Casper et al., 2002; Engels et al., 2007; Guanira et al., 2008; Mbulaiteye et al., 2006), both the ELISA (OR, 10.9; 95% CI, 6.0–19.5) and LIPS (OR, 11.5; 95% CI, 5.6–23.5) showed that KSHV infection was strongly associated with HIV infection. It has been proposed that the increased frequency of KSHV infection in HIV individuals may be due to increased KSHV viral shedding in HIV individuals (Pauk et al., 2000).
Infection with Kaposi sarcoma–associated herpesvirus (KSHV; also called human herpesvirus-8) is common among men who have sex with men (MSM). Here, quantitative anti-KSHV antibody levels were measured using luciferase immunoprecipitation systems (LIPS) in an MSM cohort with and without HIV from the NIH Clinical Center. Antibodies were detected using a mixture of 4 KSHV antigens in the MSM cohort and in Kaposi sarcoma (KS) patients. Along with HIV status, these results were compared with K8.1 and ORF73 ELISA, PCR virus detection, and additional LIPS testing. LIPS revealed that 25% (76/307) of the MSM cohort were KSHV seropositive, including 59 HIV+ and 17 HIV− subjects. The anti-KSHV antibody levels detected by LIPS were not statistically different between the KSHV+/HIV+ and KSHV+/HIV− subgroups but were lower than the KS patients (P < 0.0001). ELISA analysis of the MSM cohort detected a 35.5% frequency of KSHV infection and showed agreement with 81% of the samples evaluated by LIPS. Further LIPS testing with v-cyclin, a second ORF73 fragment and ORF38 reconciled some of the differences observed between LIPS and the ELISA immunoassays, and the revised LIPS seroprevalence in the MSM cohort was increased to 31%. Additional quantitative antibody analysis demonstrated statistically lower KSHV antibody levels in MSM compared to KS patients, but no difference was found between KSHV infected with and without HIV coinfection. These findings also suggest that antibodies against v-cyclin and ORF38 are useful for identifying patients with asymptomatic KSHV infection.
Cancer and men who have sex with men: A systematic review
2012, The Lancet Oncology
Citation Excerpt :
The National Cancer Institute's AIDS cohort study22 reported a significantly greater prevalence of HHV-8 infection in MSM than in women and heterosexual men, and identified correlates of HHV-8 that differed according to sexual behaviour. In MSM, HHV-8 was significantly associated with hepatitis, gonorrhoea, genital warts, and nitrate inhalant use.22 Finally, a study of patients with AIDS and Kaposi's sarcoma in Brazil that characterised the strains of Kaposi's sarcoma-associated herpes virus reported significant associations of specific strains with sexual orientation.23
Disparities in cancer burden between specific populations are widely acknowledged, including differences associated with sexual orientation. We searched PubMed for articles about cancer in men who have sex with men. Of the 410 publications that we identified, 47 reports were eligible for inclusion and review. Most addressed issues of cancer prevention, followed by diagnosis, survivorship, detection, and cancer treatment. Disparities exist mainly in the prevalence of viruses linked to cancers. Knowledge about sexual orientation and cancer is skewed towards infection-related cancers, so information about the association between sexual orientation and other cancers, and social and cultural causes for disparities in cancer, is less available. Men who have sex with men are still a largely overlooked minority group in this respect. Future research should examine the effects of sexual orientation on cancer, from prevention to survivorship.
Clinical Remission of Classic Kaposi Sarcoma with Topical 5% Imiquimod
2010, Actas Dermo-Sifiliograficas
The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman's disease
2009, Annals of Oncology
In HIV cohorts with access to highly active antiretroviral therapy (HAART), the incidence of Kaposi’s sarcoma (KS) is falling; however, the incidence of multicentric Castleman’s disease (MCD) in HIV has not previously been described.
The incidence of HIV-associated MCD was calculated from a prospective HIV database with 56 202 patient-years of follow-up and compared with KS. Univariate and multivariate analyses were carried out to identify factors associated with MCD. Plasma human herpesvirus (HHV)-8 DNA levels were measured in HIV-seropositive individuals with newly diagnosed MCD (n = 24), KS (n = 72), HIV-associated lymphoma (n = 74) and HIV-positive controls (n = 53).
From 24 cases of HIV-associated MCD, the incidence measured 4.3/10 000 patient-years [95% confidence interval (CI) 2.7–6.4]. The incidence in the pre-HAART (1983–1996), early-HAART (1997–2001) and later HAART (2002–2007) eras were 2.3 (95% CI 0.02–4.2), 2.8 (95% CI 0.9–6.5) and 8.3 (95% CI 4.6–12.6), respectively, representing a statistically significant increase over time (P < 0.05). In contrast, from 1180 cases of KS, the incidence in this cohort decreased with time. Multivariate analysis demonstrated that a nadir CD4 count >200/mm³, increased age, no previous HAART exposure and non-Caucasian ethnicity were all associated with an increased risk of MCD. Plasma HHV-8 DNA levels were higher in patients with newly diagnosed MCD than with KS, lymphomas or HIV-positive controls (Mann–Whitney U-test, P < 0.0001).
The incidence of HIV-associated MCD is increasing. It appears to occur more frequently in older HIV-positive individuals with well-preserved immune function.

View all citing articles on Scopus

¹: Collaborators in the ACC Study are listed in Appendix A.

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Risk factors for human herpesvirus 8 seropositivity in the AIDS Cancer Cohort Study

Abstract

Background

Study design

Results

Conclusions

Introduction

Section snippets

Study population and serology methods

Results

Discussion

Acknowledgements

J Clin Epidemiol

Lancet

Clin Dermatol

Semin Hematol

Hematol Oncol Clin North Am

Atherosclerosis

1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults

MMWR Recomm Rep

Correlates of human herpesvirus 8 seropositivity among heterosexual men in Kenya

AIDS

Epidemiology and pathogenesis of Kaposi's sarcoma-associated herpesvirus

Philos Trans R Soc Lond B Biol Sci

Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma

Science

Identifying human herpesvirus 8 infection: performance characteristics of serologic assays

J Acquir Immune Defic Syndr

Association of cancer with AIDS-related immunosuppression in adults

JAMA