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RESEARCH AND PRACTICE |
Kimberly A. Page-Shafer is with the Center for AIDS Prevention Studies, Department of Medicine, University of California San Francisco, Calif. Barbara Cahoon-Young is with East Bay Liver Clinic, Oakland, Calif. Jeffrey D. Klausner is with the Division of STD Control, San Francisco Department of Public Health, San Francisco, Calif. Scott Morrow is with San Mateo County Department of Public Health, Redwood City, Calif. Fred Molitor and Juan Ruiz are with the Office of AIDS, HIV/AIDS Epidemiology Branch, California Department of Health Services, Sacramento, Calif. Willi McFarland is with the HIV Epidemiology Unit, San Francisco Department of Public Health, San Francisco, Calif.
Correspondence: Requests for reprints should be sent to Kimberly A. Page-Shafer, PhD, MPH, Center for AIDS Prevention Studies, UCSF, 74 New Montgomery St, Suite 500, San Francisco, CA 94105 (e-mail: kshafer{at}psg.ucsf.edu).
| ABSTRACT |
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Objectives. We evaluated risk for hepatitis C virus (HCV) infection in women residing in low-income neighborhoods of northern California.
Methods. A population-based sample of 1707 women, aged 18 to 29, were surveyed and screened for sexually transmitted infections and HCV.
Results. Women infected with HCV (2.5%) were more likely to have a history of injection and noninjection drug use, to exchange sex for money or drugs, and to have sexually transmitted infections. HCV was independently associated with history of injection drug use, herpes simplex virus type 2 (HSV-2) infection, and heroin and cocaine use.
Conclusions. Injection drug use is the highest risk exposure for HCV, but HSV-2 and noninjection drug use contribute significantly to increased risk. HCV prevention programs in impoverished areas should integrate drug treatment and sexually transmitted infection control.
| INTRODUCTION |
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HCV infection is most easily acquired parenterally. As a result, prevalence is highest among injection drug users (IDUs) and hemophiliacs.68 Nonparenteral transmission of HCV appears to be inefficient.714 Past research has documented the cofactor role of sexually transmitted infections in amplifying the acquisition and transmission of HIV and hepatitis B virus (HBV),1517 but this interrelationship has not been well examined for HCV. High rates of sexually transmitted infections and HCV coinfection among IDUs suggest that ulcerative or nonulcerative urogenital infections may be cofactors for HCV transmission. However, investigation of sexually transmitted infections as potential cofactors for sexual transmission of HCV is hampered by the confounding effects of concomitant high-risk sexual behavior and injection practices.18 Lack of data on the determinants of sexual transmission of HCV has limited the development of guidelines for sexual partners who may be at risk for transmitting or acquiring HCV.9,19
The current study examined HCV in the Young Women's Survey, a population-based sample of young women recruited in lowincome, multiethnic neighborhoods of northern California.20 Analysis focused on sexual behavior and sexually transmitted infections as risk factors for HCV and their associated population attributable fractions.
| METHODS |
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Study Subjects
The target population was young women residing in low-income neighborhoods. Eligibility criteria were being female, aged 18 to 29 years, fluent in English or Spanish, and a resident in the target area. The target area was defined as 1990 US census block groups below the 10th percentile for median household income. In the 4 counties included in the study of HCV, a total of 19 270 inhabited dwellings were enumerated in 276 randomly selected street blocks within the target area. Contact was made with a resident in each of 15 943 dwellings (82.7%). Of the 2828 eligible women identified, 2096 (74.1%) were enrolled from April 1996 to January 1998. Sera were available for 1707 (81.4%) of the women who were interviewed.
Measures
A structured interviewer-administered survey was conducted to gather data on sociodemographic characteristics, sexual behavior, substance use, medical history, and other health-related factors. Response rates for most variables were greater than 99%. Blood and urine samples were obtained to test for HIV, syphilis, herpes simplex virus types 1 and 2 (HSV-1, HSV-2), HBV, gonorrhea, and chlamydia.
Laboratory Methods
Antibody to HCV (anti-HCV) was detected with a third-generation enzyme immunoassay (EIA-3.0; Ortho Diagnostics Systems, Raritan, NJ). Specimens reactive by initial EIA-3.0 were confirmed with a strip recombinant immunoblot assay (RIBA 2.0; Chiron, Emeryville, Calif). Discrepant results (EIA+, RIBA) were considered negative. HIV testing was conducted with enzyme immunoassay (EIA; Abbott Laboratories, Abbott Park, Ill) and confirmed by immunofluorescent antibody (IFA; Neufeld, Vienna, Austria). Antibody to hepatitis B core antigen (anti-HBc) was detected by EIA (Abbott Laboratories, Abbott Park, Ill), and hepatitis B surface antigen (HBsAg) was detected by microparticle EIA (Abbott Laboratories, Abbott Park, Ill). HSV-1 and HSV-2 specific antibodies were differentiated based on recombinant antigen bands for gG1, gB1, gG2, and gD2 with a strip recombinant immunoblot assay (RIBA HSV Type 1/Type 2 SIA; Chiron, Emeryville, Calif). Blood samples were tested for syphilis by rapid plasma reagin or VDRL tests; reactive specimens were confirmed by microhemagglutination test for Treponema pallidum. Ligase chain reaction (LCx; Abbott Laboratories, Abbott Park, Ill) was used to detect gonococcal and chlamydial DNA in urine specimens.
Statistical Methods
To account for the single-stage, cluster-sample survey design, we used Stata, Version 6.0, Survey (SVY) procedures to construct point prevalences, 95% confidence intervals (CIs), and odds ratios (ORs).21 Ninety-five-percent confidence intervals were adjusted to account for homogeneity within the primary sampling units (i.e., city blocks). Because crude prevalence estimates in the sample differed from the survey-adjusted estimates, we present only weighted percentages.
Multiple logistic regression analysis, adjusting for the survey design, was used to identify independent correlates of HCV infection based on factors significant in bivariate analyses, a priori hypotheses (such as coinfection with HIV or HBV), and other variables of interest or potential confounders (such as age, race/ethnicity, and county). Models were examined with both a backward and a forward stepwise process. Variables were retained in the models if they reached a significance level of .05 or less. The final multiple logistic model and aflogit procedures21 employing Stata statistical software were used to obtain estimates of adjusted population attributable fraction and corresponding 95% confidence intervals with an approach based on unconditional logistic regression.22,23 The 95% confidence intervals associated with the population attributable fraction estimates were adjusted for probability weights but not for the cluster weights.
| RESULTS |
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Women for whom sera were not available did not differ significantly from women with sera with respect to age, education, income, or injection drug use history. However, women without sera available were more likely to be single and to have 2 or more male sex partners and less likely to be Latina (
2 test, P < .05). The latter finding resulted from sera not being available for a disproportionate number of subjects from San Joaquin County.
Prevalence of Anti-HCV, by Sexually Transmitted Infections and Sexual Behavior
Prevalence of HCV was significantly higher among women with serologic markers for infection with syphilis (18.3%; 95% CI = 0, 41.7), HSV-2 (4.2%; 95% CI = 1.9, 6.4), HBV (8.3%; 95% CI = 3.2, 13.5), and HIV (63.5%; 95% CI = 0.8, 119.5) (Table 2
). Prevalence of HCV increased with increasing number of lifetime male sexual partners, from 0.4% (95% CI = 0, 1.3) among women with 1 partner to 3.9% (95% CI = 2.2, 5.7) among women with 5 or more partners. Only 2 women (0.1%) reported no male sexual partners, and 1 of these women had HCV infection. Other sexual risk behaviors associated with increased HCV prevalence were sex with an IDU (12.6%; 95% CI = 7.2, 18.0), exchange sex (trading sex for money, drugs, or other needs) (13.6%; 95% CI = 5.6, 18.6), and ever having anal sex (4.5%; 95% CI = 2.1, 7.0).
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Independent Risk Factors for HCV Infection
In multivariate analyses (Table 4
), the strongest independent associations with HCV infection were history of injection drug use (adjusted OR = 4.9; 95% CI = 2.7, 9.2), serological evidence of HSV-2 infection (OR = 3.7; 95% CI = 1.2, 11.5), any use of heroin (OR = 5.6; 95% CI = 3.1, 10.2), any use of cocaine (OR = 3.4; 95% CI = 1.2, 9.5), and very low income (adjusted OR for income < $500 per month = 4.2; 95% CI = 1.2, 14.4) after adjustment for age. Sexual risk behavior did not reach statistical significance in the model. The associations found between HCV infection and race/ethnicity were confounded by income and reported sexual risk behavior. African American women were most likely to have HSV-2 infection, to have lower income, and to report a history of trading sex for drugs or money and thus were at highest risk for HCV infection. No significant interactions were found between age, racial/ethnic group, and sexual risk behaviors. HIV infection was a significant risk factor for HCV in this study but was excluded from the model because of small numbers and the observation that parameter estimates of the other variables were not significantly changed by its inclusion. The adjusted odds ratio for HCV infection associated with HIV infection was 7.5 (95% CI = 1.5, 37.0).
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| DISCUSSION |
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The independent association of anti-HCV with HSV-2 infection suggests a possible cofactor for sexual transmission or acquisition of HCV. As has been hypothesized with HIV, HSV-2 infection may serve to increase the efficiency of sexual acquisition of HCV infection through enhanced viral reproduction or by providing a portal of entry through ulceration or inflammation. The cross-sectional design of this study, however, precludes confirmation of this hypothesis and limits causal inference.
A similar association between HCV and HSV-2 was shown in a study of heterosexual couples who were HCV serodiscordant.24 Alter et al.1 found that HCV infection was associated with HSV-2 infection in the National Health and Nutrition Examination Survey III study in analyses controlling for age but not for drug use and high-risk sexual behaviors. Similarly, in a recent study among drug users in treatment, Hwang et al.25 found no association between HCV and HSV-2 after controlling for the confounding effects of injection history and sexual risk.
We recognize that HSV-2 seropositivity may simply serve as a biological marker for underreported sexual risk in our study. However, understanding the role HSV-2 plays in HCV infection could help reduce the potential sexual risk further and clarify prevention messages regarding sexual transmission.6,26 Furthermore, the high attributable risk suggests, first, that if a causal link is established, HSV-2 infection may be an important determinant of sexually acquired HCV, and second, that reducing exposure through condom use and treatment of symptomatic genital herpes infections could avert many infections.
Attributable fraction estimates, which combine information on the prevalence of the exposure with an associated measure of excess risk, provide an estimate of the potential effect of preventive interventions.27 Our study suggested that although injection drug use had a significant excess risk associated with HCV infection, the higher prevalence of HSV-2 infection and noninjection drug use resulted in a larger population attributable fraction estimate for these nonparenteral exposures. Results further implied that prevention and control of HCV infection must focus not only on reducing injection drug use, which has a moderately low prevalence, but also on reducing sexually transmitted infections and noninjection drug exposures. However, the etiologic interpretation of population attributable fraction estimates must be approached with caution because of the wide confidence intervals and potential noncausal associations. Given the modest sample size and the limited focus of the population under study (young women from low-income neighborhoods), the reader must not overinterpret the population attributable fraction estimates, which may be subject to both variability and the bias inherent in observational data. Measures of attributable risk provide an important tool for public health planning and should not be considered alternatives to measures of effect.27,28
We recognize other possible limitations of the data. Only women for whom sera were available were included in the analyses, and although these women constituted 81.4% of the participating sample, they represented only 60% of all the eligible women identified. No observations were made of nonparticipants; thus, nonresponse bias is possible. Comparisons of women with and without sera detected some differences; the most significant was due to lack of sera from some women from San Joaquin County. Nonetheless, omitting San Joaquin from the analyses did not substantially change the principal findings of the study. Readers are also cautioned not to overinterpret results based on 40 confirmed HCV infections.
Despite these limitations, our data provide rare population-based estimates of HCV prevalence and related risk factors among young, low-income women. Understanding the epidemiology of HCV infection among women in low-income neighborhoods is a critical first step in designing primary and secondary interventions to mitigate the morbidity and mortality of this emerging infection. The growing evidence linking HSV-2 to HIV and HBV1517,29 points to a potential role for HSV-2 as a cofactor in sexual transmission of HCV as well. Strong empirical evidence supports the efficacy of sexually transmitted infection control as a means of reducing HIV risk through clinical and behavioral intervention.15 Prevention of sexual transmission of HCV should be considered from a similar public health perspective. Although the per-contact likelihood of HCV transmission may be lower than through syringe sharing, a large and growing pool of carriers may generate significant numbers of new infections through sexual intercourse. Because many of the risk factors responsible for HCV infection are also related to risk of other adverse health outcomes, public health efforts aimed at reducing drug use and sexual risk vulnerability in very-low-income women should have multiple positive results.
| Acknowledgments |
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We would like to acknowledge the following people for their expert assistance with this project: Dr Estie Hudes, for her expert assistance with the population attributable fraction analyses, and Drs Michael Busch and Andrew Moss, for reviewing the manuscript and providing valuable comments. We thank the public health laboratory directors in the counties of Alameda, Contra Costa, San Francisco, San Mateo, and San Joaquin and the staff of the Viral and Rickettsial Disease Laboratory for performing specimen testing. We thank Dr Gail Bolan and Mr Harold Rasmussen for their support.
The Young Women's Survey Team also includes (in alphabetical order): Geneva Bell-Sanford, San Joaquin County Department of Public Health, Calif; Gail Bolan, San Francisco Department of Public Health, Calif; Cynthia Cossin, Viral and Rickettsial Disease Laboratory, Berkeley, Calif; Viva Delgado, San Francisco Department of Public Health, Calif; Carla Dillard Smith, CAL-PEP, Oakland, Calif; Maria Hernandez, San Francisco Department of Public Health, Calif; Tanya Holmes, Alameda County Department of Public Health, Calif; Martin Lynch, Contra Costa County Department of Public Health, Calif; Juan Reardon, Contra Costa County Department of Public Health, Calif; Charlotte Smith, San Mateo County Department of Public Health, Calif; Hypolitta Villa, San Joaquin County Department of Public Health, Calif; and Francis Wiser, San Mateo County Department of Public Health, Calif.
The California Department of Health Services Institutional Review Board and local institutional review boards, when available, approved all study protocols and materials.
| Footnotes |
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Accepted for publication September 30, 2001.
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