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Acute-phase hepatitis C virus infection: implications for research, diagnosis, and treatment.

Received 21 December 2004; accepted 23 December 2004; electronically published 3 March 2005. Reprints or correspondence: Dr. Michael P. Busch, Blood Systems Research Institute, 270 Masonic Ave., San Francisco, CA 94118 (mpbusch@itsa.ucsf.edu). Clinical Infectious Diseases 2005; 40:959–61 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4007-0008$15.00 In the 15 years since its identification, hepatitis C virus (HCV) has emerged as a major etiological agent of liver disease throughout the world. Globally, there are an estimated 170 million infected people, including 4 million cases in the United States [1, 2]. Although the incidence of HCV infection has decreased in the United States during the past decade, there are still an estimated 36,000 new infections occurring annually, the vast majority of which occur among injection drug users (IDUs). Injection drug use is also the predominant route of infection in other developed countries, whereas in resourcelimited settings, extensive risk exists from a wide range of other parenteral exposures, including transfusions of unscreened blood components. Only 15%–30% of newly infected persons develop the acute hepatitis syndrome, which is generally mild, occurs within 5– 12 weeks after exposure (mean length of time, 8 weeks), and lasts 2–12 weeks [3, 4]. Of interest, symptomatic acute-phase infection has been associated with an increased rate of viral clearance, presumably reflecting more-effective host immune responses that eradicate the virus by killing infected hepatocytes, resulting in clinical manifestations. Unfortunately, 180% of primary infections are asymptomatic, and 70%–80% of these occult infections become chronic, leading to significant longterm morbidity and mortality, as well as secondary transmission. Until recently, most of what was known about the kinetics of viremia and seroconversion in very early–phase HCV infection was based on cases of infection in transfusion recipients or in experimentally infected chimpanzees [5, 6]. In both of these populations, HCV RNA is detectable within 2–14 days after exposure, and HCV-specific antibodies are detectable within 20–150 days (mean length of time, 60 days). Long-term viremia status (i.e., resolved vs. chronic infection) is generally established within 3–6 months after acute infection, although examples of delayed clearance have been reported in both chimps and transfusion recipients. Screening blood donors for HCV RNA began in 1999 and led to detection and study of asymptomatic, communityacquired infections. During the initial 3 years of screening the US blood supply, 170 HCV RNA–positive, antibody-negative donors were identified among 40 million screened donations, a rate of 1 case per 230,000 donations [7]. In 67 of these donors, the median time to seroconversion (i.e., time from the first HCV RNA– positive, antibody-nonreactive donation to seroconversion) was 35 days, consistent with a 70-day mean duration of viremia preceding seroconversion. Among 55 donors who experienced seroconversion, 47 remained viremic during continued follow-up, 3 had fluctuating viremia in the presence of HCV antibody, and 5 experienced resolution of infection after seroconversion. Two donors (3%) had abortive infections, in which HCV RNA could be repeatedly demonstrated shortly after enrollment but later could not be detected in the absence of HCV seroconversion. Lastly, 3 donors (5%) remained viremic without elevated ALT levels but did not experience seroconversion, even after 1.5–3 years of follow-up (i.e., they had so-called “immunosilent” infections). Unusual profiles, including intermittent low HCV RNA levels for months preceding “ramp-up” viremia, have also been detected by high-sensitivity RNA screening of frequently collected units from paid plasma donors [8]. Low-level viremia for months and even years prior to seroconversion has also been reported in a study of IDUs in Amsterdam, The Netherlands[9]. These findings indicate that the natural history of community-acquired HCV infection, mostly attributable to injection drug use, is more variable than has been reported in populations of infected transfusion recipients and chimpanzees. The study by Cox et al. [10] in the current