Since its identification in 1990, hepatitis C virus (HCV), now estimated to infect 130 million persons worldwide, has emerged as a major etiological agent of liver disease, accounting for up to 27% of cirrhosis and 25% of hepatocellular carcinoma [1,2]. In the United States, recent data show that 4 million persons have been infected  and the Centers for Disease Control and Prevention estimated 24 000 new HCV infections in 2004, the majority of which were attributed to injection drug use (IDU) . However, both the number of acute infections and the proportion attributed to IDU are likely to be significant underestimates, owing to substantial underreporting of both risk and acute infection. In this issue of AIDS, Garfein et al.  report on a large and noteworthy HCV prevention trial in young IDU, a population with very high risk for HCV [The Drug Users Intervention Trial (DUIT)]. Between 2002 and 2004, 854 young IDU in five cities in the United States were enrolled in a randomized trial designed to determine whether a peer education intervention, based on cognitive–behavioral theory and incorporating education and skills building, could reduce injection and sexual behavioral risk and HCV incidence. This study is significant in its scope, rigorous methodology, and measures, and especially in assessing HCV as a biological endpoint. Injection risk outcomes were assessed from self-report, both individually and as a composite summary variable, including injecting with previously used syringes; splitting/dividing drugs; sharing cookers, cotton filters, and rinse water with other IDU; and, the number of injection partners. Sexual risk was assessed based on sexual act (vaginal and anal), type and number of partners, and condom use. After 6 months, investigators found greater declines in composite injection risk in the peer education intervention arm compared with the control arm, but not in any of the six individually reported injection risk outcomes. Of the three sexual behavior outcomes, one, anal sex with casual/sex trade partners, declined significantly in association with the intervention. Despite the fact that both intervention and control groups reported declines in behavioral risk, HCV incidence did not differ, at 18% in both groups.
HCV infection among IDU has declined since the late 1980s . In earlier work, Garfein et al.  found that HCV infection was prevalent in two-thirds (64.7%) of injectors with 1 year or less of injection exposure. Ten years later, Hahn et al.  found lower HCV prevalence: 50% of young IDU were likely to be infected after 5 years of injecting. It is possible, and even likely, that HIV prevention programs have contributed to decreasing HCV risk and infection; HIV prevalence is lower in areas where needle exchange is available . However, the impact of needle and paraphernalia sharing is far greater for HCV transmission than HIV . The incidence of HCV remains extremely high, even in settings where HIV incidence is low, and further decreases in HCV are unlikely to continue in the absence of large-scale and effective interventions. In San Francisco, HCV incidence among the young (under 30 years of age) IDU we have studied was 25.1/100 person years  in 2001; with recent estimates (2006) at 29.3/100 person years . By comparison, HIV incidence has been stable since 1990 and low (< 1%) . This contrast of high HCV incidence and low HIV incidence highlights the high infectiousness of HCV; even infrequent injecting poses too great a risk to prevention of HCV transmission.
The DUIT study is ground breaking as it is the first randomized controlled trial of a intervention based on cognitive–behavioral theory and targeted at young IDU specifically for the prevention of HCV infection. Previous studies, principally observational, have examined the effects of exposure to preventive services on HCV, including needle exchange, drug treatment, harm reduction and education programs, and bleach disinfection; none has provided conclusive evidence of significant impact on HCV incidence (reviewed by Wright and Tompkins ). Given the significant ‘window of opportunity’ to prevent HCV in young or new IDU , more intervention studies of these and other preventive approaches are needed in this population.
HCV prevention science is in a young but evolving stage. Much remains to be learned regarding HCV transmission that can be translated into effective prevention. Intervention strategies and prevention tools are needed from diagnostic, biological, behavioral, and social sciences. We also need research to determine how these multiple disciplines may interact and complement each other. For example, it is plausible that the period of acute HCV infection, during which both high viremia and high-risk behavior may be occurring, contributes substantially both to increased infectivity and to transmission (similar to acute HIV infection). Detection of acute HCV is currently feasible, and under the scenario of increased infectivity of acute HCV, new diagnostic methods could lead to novel interventions incorporating effective testing and counseling programs. Serodiscordant-partner studies are also needed to gain better understanding of the infectivity and transmission dynamics of HCV in IDU and to inform interventions that might address risk that occurs in intimate partnerships. Research into potential biological interventions that reduce infectivity, such as clinical treatment of acute HCV infection to reduce the expanding pool of infection among IDU, should also be conducted. Results from several studies now show that very early treatment for acute HCV is highly effective, eliminating persistent infection in up to 90% of patients . Making treatment for acute (and chronic) infection feasible for IDU requires further research to identify modifiable behaviors, conditions, and clinical factors that will improve treatment candidacy . Effective treatment interventions for substance use, to reduce the frequency and duration of injecting behavior, also have important implications for reducing new HCV infections. Despite the paucity of results from the few studies that have assessed associations between methadone treatment and HCV infection, enormous potential exists in this area for risk reduction and HCV prevention. Since many young IDU report difficulty accessing or participating in strictly regulated narcotic treatment programs, innovative models for the delivery of effective opioid agonist therapies, such as buprenorphine, and new pharmacotherapies for methamphetamine dependence are excellent candidates for investigation.
Lastly, multidisciplinary research to produce and test a safe and effective HCV vaccine is urgently needed. HCV vaccine trials should be designed to enroll and retain young IDU as the population most at risk for HCV. This group, however, is also likely to be the most difficult to retain in longitudinal studies, owing to their high mobility (J. Hahn, unpublished data). As young IDU may distrust vaccines and their vaccinators, methods to maximize vaccine trial acceptability and adherence will be critical. Social and behavioral research is needed to inform and facilitate vaccine trial readiness and trial operations. For instance, novel methods must be developed to improve retention and adherence to multidose vaccine regimens, and inform or design alternative delivery schemes. Preventive vaccine trials enrolling young IDU will require that the best preventive ‘standard of care’ be provided to participants. The best currently available standard of care for HCV prevention includes provision of good prevention information, sterile injecting equipment, and access to drug treatment. The DUIT Study adds a new approach to the current prevention ‘toolbox’ against HCV, using social systems to effect risk reduction. However, since this new tool, like the aforementioned methods, still ‘misses the mark’ with respect to preventing HCV infection, we agree with Garfein and coworkers that risk reduction is not enough.
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