Although there was no consistent trend in the number of tests performed each year for HCV infection in the HOPS, the proportion of all HCV infection tests performed that were follow-up tests for patients with documented HCV-negative serostatus increased dramatically from 2.4% (3/124) in 1996 to 75.0% (417/556) in 2007.
From 1996 to 2007, there were a total of 1115 HCV infections identified among 4606 patients ever tested for HCV infection for an overall period prevalence of 24.2%. Among these 1115 infections, 805 were identified among patients whose HCV status was negative or unknown at HOPS enrollment and 310 represented patients known to have HCV infection at enrollment. The prevalence of HCV infection decreased from 36.7% in 1996 to 19.7% in 2007 (Fig. 1). Significant decreases (P < 0.01) were observed within most demographic and risk group strata from 1996 to 2000, with the exception of IDU (P = 0.32) and HRH (P = 0.36) patients (Fig. 3). Across the study period, prevalence of HCV infection remained consistently greater among patients ≥45 years old at HOPS entry compared with those aged 35-44 years and those aged <35 years at HOPS entry (41.5% vs. 40.3% and 31.9%, respectively, in 1996 and 24.2% vs. 22.0% and 13.8% in 2007), among females compared with males (29.9% vs. 22.5% for period 1996-2007), among blacks and Hispanics compared with whites (30.2% and 28.6% vs. 18.9% for 1996-2007), among IDU compared with HRH and MSM (80.8% vs. 18.1% and 10.2% for 1996-2007), and among publicly insured patients compared with privately insured patients (31.9% vs. 14.3% for 1996-2007).
To our knowledge, this study is the largest recent evaluation of trends in testing for and prevalence of HCV infection among a heterogeneous cohort of HIV-infected persons with long-term follow-up in the United States. We found that among patients active in the HOPS anytime from 1996 to 2007, the proportion of patients tested for HCV infection increased approximately 8-fold (from 10.7% to 76.6%) and the prevalence of HCV infection decreased almost 50% (from 36.7% to 19.7%). Patients were more likely to be tested for HCV infection if they were older than 35 years, were of nonwhite race or Hispanic ethnicity, were classified IDU or HRH, or had been followed more than 3 years in the HOPS. The increase in testing for HCV infection between 1996 and 2001 coincided with the 1999 release of guidelines that recommended universal testing of all HIV-infected persons; however, much of the increase actually occurred before their publication.31 Although recommendations for retesting known HCV-seronegative HIV-infected patients are not established, the fraction of all HCV tests performed annually in the HOPS for patients who had previously tested negative steadily increased from 1996 to 2007.
It remained concerning, however, that even in 2007, long after publication of the guidelines, nearly 1 of 4 HOPS patients went untested for HCV infection. As HOPS patients from sociodemographic groups traditionally at greater risk for HCV infection were more likely to be tested (e.g., IDU and blacks), it is possible that providers did not test some patients because they considered them at low risk for exposure to HCV (e.g., non-IDU MSM), although we have no definitive data to support this assertion. Recent data do suggest, however, that extensive sexual HCV transmission among HIV-infected MSM occurs.32,33 Regardless of perceived risk, it is important that all HIV-infected persons are tested for HCV infection so that coinfection can be identified as early as possible and prompt referral for treatment can occur.
In most serosurveys, the prevalence of HCV infection is driven primarily by the proportion of IDU in the cohort under study; the greater the fraction of IDU in the cohort, the greater the prevalence of HCV infection both in the general population13,34-37 and among HIV-infected persons.16,27,38,39 Whereas a recent study reported a decline in the incidence of HCV infection among IDUs from 1994 to 2004,40 we found that the prevalence of HCV infection among IDU patients did not decrease, in contrast to the pattern among the other demographic groups (Table 1, Fig. 2), and was consistently elevated at all time points. However, the fraction of all prevalent infections in the cohort attributable to IDU patients declined (Fig. 4), and that attributable to HRH and MSM patients increased, during the observation period.
The HOPS has seen an increase in median age across all demographic and risk groups; the increase was greatest among IDU patients (by 11 years compared with 6 years for other HIV risk groups). Our findings of relative aging of the IDU population are consistent with those in the national data and have been attributed to a cohort effect that coincided with the epidemic of IDU that began in the 1960s, peaked in the 1970s and 1980s, and decreased since then.41 Other surveys demonstrate that this age cohort, born between 1940 and 1960, is at greatest risk for HCV infection and that HCV infection incidence peaked in the mid-1980s and has been decreasing since then.12,14,42 The disproportionate increase in the median age of IDU patients in the HOPS suggests that, relative to patients from other risk groups, fewer young IDU patients were entering and/or more young IDUs were leaving the study. Nonetheless, the aging of the entire HOPS cohort is consistent with improvements in survival afforded by HAART, regardless of risk group. The relative reduction in the fraction of IDU patients and increase in the fraction of HRH and MSM patients among all prevalent HCV infections in the HOPS are consistent with the findings from the national surveillance data.43,44
Since 1996, proportionate mortality because of chronic liver disease has been increasing in the HOPS. In an analysis of 823 HOPS patients with and without HCV coinfection from 1996 to 2001, Tedaldi et al11 found disproportionately more deaths among HCV/HIV-coinfected patients, although HCV infection was not significantly associated with decreased survival. In other analyses, however, infection with HIV has been associated with higher HCV RNA viral load and more rapid progression of cirrhosis, liver failure, and hepatocellular carcinoma.2,45 Indeed, a recent analysis of mortality in the HOPS found that despite overall dramatic declines in mortality between 1996 and 2004, hepatic disease was the only reported cause of death for which absolute rates increased over time.46 The disproportionate liver-related mortality among patients coinfected with HCV may contribute to the reductions in HCV prevalence we observed over time.
Our findings are subject to limitations. First, data collected in the HOPS are not population based; therefore, trends and estimates derived from the study might not be representative of all HCV/HIV-coinfected persons in the United States. Second, we required only a single positive anti-HCV test for inclusion in the analyses because HCV confirmatory test results were not uniformly available or abstracted during the earlier part of the study period. Consequently, the true prevalence of chronic HCV infection in the HOPS is probably lower, given that 5-10% of HIV-infected persons seem to resolve HIV infection,47-49 although chronic seronegative HCV infection has been reported in as many as 13% of HIV-infected patients with advanced immunosuppression.50,51 Nonetheless, the effect of these factors should be modest and stable over time. The specificity of HCV EIA tests, however, has improved over time. Therefore, HCV EIA tests performed on HOPS patients in the 1990s were more likely to result in a false-positive test result than were such tests performed more recently.52 This may have lead to some overestimation of HCV prevalence in the earlier years of our observation period. Third, because subgroups of HOPS patients who were more likely to be tested (e.g., IDU, HRH, and patients of black and Hispanic ethnicity) also tended to have higher HCV coinfection rates, disparities in testing may have led us to overestimate the HCV prevalence in the HOPS population as a whole. Finally, because less than half of active patients in the cohort were tested for HCV infection before 2000, HCV infection prevalence estimates for earlier years may be less accurate, and some degree of bias in the temporal trends in HCV infection prevalence in HOPS over the study period cannot be ruled out.
In summary, we observed an overall decrease in the prevalence of HCV infection in the HOPS in recent years, associated with the reduction in the fraction of participating IDU patients, among whom HCV infection rates remained high and stable over time. Despite declining HCV prevalence, the overall rates we observed in the HOPS remained approximately 15-fold higher than HCV prevalence rates in the general US population (1.6%) estimated from the National Health and Nutrition Examination Survey (NHANES) during 1999 through 2002.14 Although the fraction of patients in the HOPS being tested (and retested) for HCV infection increased, a sizable portion of patients remained untested even in 2007. Testing all HIV-infected persons-irrespective of perception of risk-for HCV coinfection is imperative both to optimize patient management and to maximize opportunities to treat this potentially eradicable infection.
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APPENDIX: THE HOPS INVESTIGATORS
The HOPS Investigators currently include the following investigators and sites: John T. Brooks, Kate Buchacz, and Marcus Durham, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA; Kathleen C. Wood, Rose K. Baker, James T. Richardson, Darlene Hankerson, and Carl Armon, Cerner Corporation, Vienna, VA; Frank J. Palella, Joan S. Chmiel, Carolyn Studney, and Onyinye Enyia, Feinberg School of Medicine, Northwestern University, Chicago, IL; Kenneth A. Lichtenstein and Cheryl Stewart, National Jewish Medical and Research Center, Denver, CO; John Hammer, Benjamin Young, Kenneth S. Greenberg, Barbara Widick, and Joslyn D. Axinn, Rose Medical Center, Denver, CO; Bienvenido G. Yangco and Kalliope Halkias, Infectious Disease Research Institute, Tampa, FL; Douglas J. Ward and Jay Miller, Dupont Circle Physicians Group, Washington, DC; Jack Fuhrer, Linda Ording-Bauer, Rita Kelly, and Jane Esteves, State University of New York (SUNY), Stony Brook, NY; Ellen M. Tedaldi, Ramona A. Christian, Faye Ruley, and Dania Beadle, Temple University School of Medicine, Philadelphia, PA; and Richard M. Novak and Andrea Wendrow, University of Illinois at Chicago, Chicago, IL.