Editorial Commentary: Acute‐Phase Hepatitis C Virus Infection: Implications for Research, Diagnosis, and Treatment

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 resource-limited 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, >80% of primary infections are asymptomatic, and 70%–80% of these occult infections become chronic, leading to significant long-term 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, community-acquired 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 issue of Clinical Infectious Diseases offers further insights into the kinetics of viremia and seroconversion in IDUs. The study cohort of 179 HCV antibody-negative IDUs was followed up with use of RNA and antibody screening. Despite risk-reduction counseling, 62 (34%) of the subjects experienced acute-phase HCV infections, most of which were detected before seroconversion by means of the frequent RNA screening. The median time to seroconversion after the first HCV RNA-positive sample was obtained was 36 days, although 1 patient with an unusual case had a specimen with a low HCV RNA level that was obtained 434 days before seroconversion (a case similar to the intermittent viremia discussed above, although the virus was detected at a lower frequency in this instance) [8, 9]. Acute infection resulted in few clinical findings, with no cases of jaundice and only slight elevations of ALT and bilirubin levels during the viremic, pre-seroconversion period. For 20 subjects with frequent serial samples in whom the course of viremia and seroconversion and the outcome of infection were followed closely, viremia patterns were highly variable, with little correlation between viral load profiles and subsequent resolution of viremia. Although the viral load stabilized in most cases of persistent infection within several months of infection, several cases that evolved to chronic infection showed fluctuation in viral loads, including intermittent negative HCV RNA test results, for >1 year after initial viremia. In subjects who eventually experienced clearance of viremia, HCV became undetectable within 3 months after infection in some cases, although 1 patient did not experience eradication of infection until almost 2 years after viremia was initially detected. These data indicate that clearance of acute-phase viremia can occur much later than has been observed in transfusion recipients. This is consistent with results from a recent retrospective study of 57 HCV-infected IDUs in Australia, which documented clearance rates of 23%, 38%, and 40% at 6, 12, and 24 months after diagnosis of acute infection, respectively [11]. Research involving these various populations has identified numerous factors associated with viral resolution, including mode of acquisition, inoculation dose, viral genotype, rate of viral evolution following acute-phase infection, HCV quasi species complexity in the inoculum, age at acquisition of infection, host HLA and other genetic polymorphisms, race/ethnicity, sex, and, as mentioned above, clinical manifestations of acute disease [12–22]. The effectiveness of the host's immune response, which is largely determined by host genetics in the context of specific viral populations, is probably the major determinant of spontaneous viral clearance [12–15, 17–19, 23–25]. The rapid replication and mutation rates of HCV permit the selection of immune response escape variants during the acute phase of infection. In the majority of cases that evolve to the chronic phase, viral species evolve that are able to adapt to the initial innate and adaptive (i.e., neutralizing antibody and cytotoxic T cell) immune responses, resulting in an increasingly genetically diverse quasi species. This has led to intense interest in studying persons with acute-phase infection to understand the immune responses that may be responsible for a self-limited course of infection [3]. Insights from such studies could contribute to the development of prophylactic or therapeutic vaccines, although hope for the successful development of HCV vaccines has been tempered by observations that persons who have experienced resolution of a previous infection receive only partial protection from HCV reinfection [26], as well as the observation of frequent superinfection in highly exposed carriers of chronic infection [27]. These recent findings indicate that even highly robust immune responses induced by natural infection are minimally protective, reducing the promise that recombinant HCV antigen-based vaccines, which are generally less immunogenic, will prove to be protective. Interest in primary HCV infection has been further stimulated by recent studies suggesting that treating patients soon after seroconversion results in significantly increased rates of viral clearance. Recently, Nomura et al. [28], with use of a randomized, controlled design, compared short-term IFN-α treatment (6 million units administered during a 4-week period) as an early intervention (within 8 weeks after infection) with the same treatment as a late intervention (after ⩾1 year of infection) in 30 patients identified with symptomatic acute-phase HCV infection. Thirteen (87%) of 15 patients who received early intervention with short-term therapy showed sustained virologic response (SVR), compared with 40% of those who received late-intervention treatment. After further follow-up therapy (of 20 weeks' duration) for patients who did not experience viral clearance, 100% of those in the early intervention group showed successful SVR, compared with 57% of those in the late intervention group. These findings corroborate those of an uncontrolled study of early treatment for HCV infection in Germany that also showed a high rate of SVR (98%) among 44 patients treated within 112 days after infection with a 24-week course of IFN-α [29]. These studies have important implications for clinicians. First, although HCV RNA screening can detect acute-phase HCV infections that would be missed by serological testing, these assays are expensive, and the yield and predictive value will depend on risk in the screened population and frequency of testing. Second, determination of resolution status is difficult because of fluctuating viremia in both patients with resolution of infection and those with chronic infection during the year after seroconversion. A role for routine HCV RNA (or HCV antigen) screening outside of the context of donor screening and research protocols is probably premature in light of these issues and the controversy over the merits of early treatment. Very importantly, there are still gaps in the current literature to guide recommendations for management of acute-phase HCV infection, including recommendations regarding the timing of treatment initiation, the duration of treatment, and the optimal regimen (the majority of studies of acute-phase HCV infection have used different forms of IFN-α monotherapy, rather than combination therapy with ribavirin), as well as data on the effects of early treatment on the patient's own immune response. The most recent guidelines from the American Association for the Study of Liver Disease provide an excellent summary of these issues with respect to treatment of acute-phase HCV infection and concludes that no definitive recommendations can be made regarding early detection and treatment [30]. Clinical decisions regarding early versus late treatment are therefore reasonably consigned to individualized assessments of risks and benefits, including waiting 2–4 months to see whether infection resolves spontaneously. Potential conflicts of interest. M.P.B. and K.A.P.S.: no conflicts.