Acute hepatitis C: Current status and remaining challenges
Authors: Teresa Santantonio, Johannes Wiegand, J. Tilman Gerlach
Journal: Journal of Hepatology (2008)

The acute phase of hepatitis C virus (HCV) infection represents a key point in the evolution of hepatitis C. In some patients, the infection resolves spontaneously, whereas in others it develops into chronic disease. However, because acute hepatitis C is often asymptomatic, detection and diagnosis are usually difficult. What is more, there are no established treatment guidelines, leaving physicians to make several challenging decisions, such as whether to treat, when to treat and what treatment regimen to use. Pegylated interferon alfa monotherapy is most commonly used to treat patients with acute hepatitis C; the role of ribavirin has yet to be established. In this review, we discuss the epidemiology of acute hepatitis C, its risk factors and routes of transmission and current treatment practices. We also discuss data from published clinical studies and focus on unresolved issues for which additional studies are needed in order to establish standardized treatment guidelines for the management of acute hepatitis C. The acute phase of hepatitis C virus (HCV) infection represents a key point in the evolution of hepatitis C. In some patients, the infection resolves spontaneously, whereas in others it develops into chronic disease. However, because acute hepatitis C is often asymptomatic, detection and diagnosis are usually difficult. What is more, there are no established treatment guidelines, leaving physicians to make several challenging decisions, such as whether to treat, when to treat and what treatment regimen to use. Pegylated interferon alfa monotherapy is most commonly used to treat patients with acute hepatitis C; the role of ribavirin has yet to be established. In this review, we discuss the epidemiology of acute hepatitis C, its risk factors and routes of transmission and current treatment practices. We also discuss data from published clinical studies and focus on unresolved issues for which additional studies are needed in order to establish standardized treatment guidelines for the management of acute hepatitis C. 1. IntroductionIn the past decade, the introduction of pegylated interferons (PEG-IFNs) and the identification of host and viral factors that can predict sustained virological response (SVR) have improved the treatment of chronic hepatitis C. In contrast, because of the lack of a diagnostic marker for acute hepatitis C virus (HCV) infection and its relatively silent nature, prospective clinical investigations of acute hepatitis C have been difficult to conduct. In this review, we attempt to synthesize existing information on acute hepatitis C to provide a comprehensive overview of this condition, describe the natural history and epidemiology of the disease and discuss the best treatment practices.2. EpidemiologyPatients with acute HCV infection are generally asymptomatic, which renders diagnosis difficult and results in under-reporting [1Orland J.R. Wright T.L. Cooper S. Acute hepatitis C.Hepatology. 2001; 33: 321-327Crossref PubMed Scopus (187) Google Scholar, 2Blackard J.T. Shata M.T. Shire N.J. Sherman K.E. Acute hepatitis C virus infection: a chronic problem.Hepatology. 2008; 47: 321-331Crossref PubMed Scopus (96) Google Scholar]. Identification of patients with acute hepatitis C is also hindered because many patients are reluctant to divulge habits that may lead to infection. As a result, estimates of the incidence vary widely and are probably lower than the real figure. For example, in Italy, incidence estimates range from 1 to 14 cases per 100,000, according to whether the population evaluated included patients with acute HCV reported to the National Surveillance Agency [[3]Mele A. Tosti M.E. Marzolini A. Moiraghi A. Ragni P. Gallo G. et al.Prevention of hepatitis C in Italy: lessons from surveillance of type-specific acute viral hepatitis. SEIEVA collaborating Group.J Viral Hepat. 2000; 7: 30-35Crossref PubMed Scopus (49) Google Scholar], Italian blood donors, [[4]Tosti M.E. Solinas S. Prati D. Salvaneschi L. Manca M. Francesconi M. et al.An estimate of the current risk of transmitting blood-borne infections through blood transfusion in Italy.Br J Haematol. 2002; 117: 215-219Crossref PubMed Scopus (48) Google Scholar] or the general population [[5]Kondili L.A. Chionne P. Costantino A. Villano U. Lo Noce C. Pannozzo F. et al.Infection rate and spontaneous seroreversion of anti-hepatitis C virus during the natural course of hepatitis C virus infection in the general population.Gut. 2002; 50: 693-696Crossref PubMed Scopus (96) Google Scholar]. In the United States, the incidence of acute hepatitis C has declined in recent years [6Alter M.J. Kruszon-Moran D. Nainan O.V. McQuillan G.M. Gao F. Moyer L.A. et al.The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.N Engl J Med. 1999; 341: 556-562Crossref PubMed Scopus (2431) Google Scholar, 7Centers for Disease Control and PreventionRecommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease.MMWR Recomm Rep. 1998; 47: 1-39Google Scholar, 8Williams I. Epidemiology of hepatitis C in the United States.Am J Med. 1999; 107: 2S-9SAbstract Full Text Full Text PDF PubMed Google Scholar], with the Department of Health and Human Services Center for Disease Control and Prevention reporting 671 acute hepatitis C cases in 2005 for an overall national rate of 0.2 per 100,000. However, after accounting for under-reporting of asymptomatic infections, the estimated total was 20,000 new infections [[9]Centers for Disease Control and Prevention. Surveillance for acute viral hepatitis United States, 2005. 56th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2007. p. 1–24.Google Scholar].3. Risk factors, routes of transmission and diagnosisCurrently, intravenous drug use, unprotected sex with multiple partners, and viral exposure during medical procedures, such as surgery, dialysis and dental treatment, are factors associated with the highest degree of risk for HCV infection [9Centers for Disease Control and Prevention. Surveillance for acute viral hepatitis United States, 2005. 56th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2007. p. 1–24.Google Scholar, 10Santantonio T. Medda E. Ferrari C. Fabris P. Cariti G. Massari M. et al.Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy.Clin Infect Dis. 2006; 43: 1154-1159Crossref PubMed Scopus (96) Google Scholar, 11Corey K.E. Ross A.S. Wurcel A. Schulze Zur Wiesch J. Kim A.Y. Lauer G.M. et al.Outcomes and treatment of acute hepatitis C virus infection in a United States population.Clin Gastroenterol Hepatol. 2006; 4: 1278-1282Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 12Esteban J.I. Sauleda S. Quer J. The changing epidemiology of hepatitis C virus infection in Europe.J Hepatol. 2008; 48: 148-162Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 13Martinez-Bauer E. Forns X. Armelles M. Planas R. Sola R. Vergara M. et al.Hospital admission is a relevant source of hepatitis C virus acquisition in Spain.J Hepatol. 2008; 48: 20-27Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar]. Health care employees are at risk for acute hepatitis C through accidental exposure, such as needlestick injury; however, recent reports indicate that the risk for HCV transmission after needlestick injury is lower than that previously believed (mean value 0.75%; in Europe 0.42%; in Eastern Asia 1.5%) [[14]Kubitschke A. Bader C. Tillmann H.L. Manns M.P. Kuhn S. Wedemeyer H. Injuries from needles contaminated with hepatitis C virus: how high is the risk of seroconversion for medical personnel really?.Der Internist (Berl). 2007; 48: 1165-1172Crossref PubMed Scopus (34) Google Scholar]. Of note, risk factor patterns vary according to geography. For example, within many Western countries intravenous drug use is the greatest risk factor, with sexual transmission and medical practices representing other less common risk factors [10Santantonio T. Medda E. Ferrari C. Fabris P. Cariti G. Massari M. et al.Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy.Clin Infect Dis. 2006; 43: 1154-1159Crossref PubMed Scopus (96) Google Scholar, 11Corey K.E. Ross A.S. Wurcel A. Schulze Zur Wiesch J. Kim A.Y. Lauer G.M. et al.Outcomes and treatment of acute hepatitis C virus infection in a United States population.Clin Gastroenterol Hepatol. 2006; 4: 1278-1282Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 15Wiegand J. Buggisch P. Boecher W. Zeuzem S. Gelbmann C.M. Berg T. et al.Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study.Hepatology. 2006; 43: 250-256Crossref PubMed Scopus (211) Google Scholar]. Conversely, in Egypt, occupational exposure seems to be the greatest hazard, with intravenous drug use and sexual transmission less evident [16Kamal S.M. Fouly A.E. Kamel R.R. Hockenjos B. Al Tawil A. Khalifa K.E. et al.Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response.Gastroenterology. 2006; 130: 632-638Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 17Kamal S.M. Moustafa K.N. Chen J. Fehr J. Abdel Moneim A. Khalifa K.E. et al.Duration of peginterferon therapy in acute hepatitis C: a randomized trial.Hepatology. 2006; 43: 923-931Crossref PubMed Scopus (122) Google Scholar]. Although guidelines exist for the management of chronic hepatitis C [18Strader D.B. Wright T. Thomas D.L. Seeff L.B. Diagnosis, management, and treatment of hepatitis C.Hepatology. 2004; 39: 1147-1171Crossref PubMed Scopus (1576) Google Scholar, 19Dienstag J.L. McHutchison J.G. American Gastroenterological Association technical review on the management of hepatitis C.Gastroenterology. 2006; 130: 231-264Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar], they do not specifically address acute hepatitis C. Table 1 summarizes recommendations for persons who are at risk and should be tested for HCV infection.Table 1Relative risk for hepatitis C transmission and recommendations for testingAt-risk populationRecommendations for testingaTreatment guidelines recommend that patients suspected of having HCV infection should be tested for HCV antibodies; those with detectable HCV antibodies should undergo HCV RNA testing with use of a highly sensitive assay such as reverse transcription-polymerase chain reaction. Routine testing is recommended for patients with HIV infection and those with unexplained elevated aminotransferase levels.High riskInjection drug usersAll persons who have injected illicit drugs in the recent or remote past, including those who have injected only once and do not consider themselves to be drug usersBlood transfusion recipients or transplantation before 1992All patients who were notified that they received blood from a donor who later tested positive for HCVPersons who received transfused blood or blood products or transplanted organs before July 1992, including patients who received clotting factor concentrates before 1987Hemodialysis patientsAll patients with current or previous history of hemodialysisModerate riskHigh-risk sexual activitybSexual transmission of HCV is not clearly understood. However, certain high-risk sexual behaviors have been associated with HCV transmission, such as anal sex, sex with trauma, sex in the presence of a sexually transmitted disease, and sex without a condom.All sexual partners of HCV-infected patientsVertical transmission from mother to childAll children born to mothers infected with HCVLow riskOccupational exposureAll health care, emergency medical, and public safety workers after a needlestick injury or mucosal exposure to HCV-positive bloodSexual activity with long-term partnersbSexual transmission of HCV is not clearly understood. However, certain high-risk sexual behaviors have been associated with HCV transmission, such as anal sex, sex with trauma, sex in the presence of a sexually transmitted disease, and sex without a condom.All sexual partners of HCV-infected patientscAlthough the prevalence of infection is low, a negative test result in the partner provides reassurance, making testing of sexual partners beneficial in clinical practice.Very low risk/no riskCasual contactRoutine testing not requiredHousehold contactRoutine testing not requiredTable adapted from 2004 AASLD practice guidelines 18Strader D.B. Wright T. Thomas D.L. Seeff L.B. Diagnosis, management, and treatment of hepatitis C.Hepatology. 2004; 39: 1147-1171Crossref PubMed Scopus (1576) Google Scholar, 19Dienstag J.L. McHutchison J.G. American Gastroenterological Association technical review on the management of hepatitis C.Gastroenterology. 2006; 130: 231-264Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar.a Treatment guidelines recommend that patients suspected of having HCV infection should be tested for HCV antibodies; those with detectable HCV antibodies should undergo HCV RNA testing with use of a highly sensitive assay such as reverse transcription-polymerase chain reaction. Routine testing is recommended for patients with HIV infection and those with unexplained elevated aminotransferase levels.b Sexual transmission of HCV is not clearly understood. However, certain high-risk sexual behaviors have been associated with HCV transmission, such as anal sex, sex with trauma, sex in the presence of a sexually transmitted disease, and sex without a condom.c Although the prevalence of infection is low, a negative test result in the partner provides reassurance, making testing of sexual partners beneficial in clinical practice. Open table in a new tab After exposure to HCV, there is a window of 1–3 weeks before serum HCV RNA can be detected. In patients in whom symptoms are developing, the incubation period between exposure and appearance of symptoms can range from 2 to 12 weeks [[1]Orland J.R. Wright T.L. Cooper S. Acute hepatitis C.Hepatology. 2001; 33: 321-327Crossref PubMed Scopus (187) Google Scholar]. The most common symptoms are fatigue and jaundice, with dyspepsia and abdominal pain often reported [20World Health Organization. Hepatitis C. World Health Organization 2000 October [cited 2006 Apr 12];1-3.Google Scholar, 21Santantonio T. Sinisi E. Guastadisegni A. Casalino C. Mazzola M. Gentile A. et al.Natural course of acute hepatitis C: a long-term prospective study.Dig Liver Dis. 2003; 35: 104-113Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. Given that most symptoms are non-specific, many patients do not consult a physician and do not receive a diagnosis during the acute phase. The first indication of hepatic injury is an elevated alanine aminotransferase (ALT) level, which can occur 4–12 weeks after viral exposure [[22]Heathcote J, Elewaut A, Fedail S, Gangl A, Hamid S, Shah M, et al. WGO practice guideline: management of acute viral hepatitis. World Gastroenterology Organisation Web site 2003 December [cited 2007 Sep 14]. Available from: URL: http://www.worldgastroenterology.org/management-of-acute-viral-hepatitis.html.Google Scholar]. Fulminant liver injury is rare and occurs in less than 1% of patients.Diagnosis of acute HCV infection is confirmed by the detection of HCV RNA with documented anti-HCV antibody seroconversion (Table 2). Seroconversion may occur 4–10 weeks after exposure to HCV [23Mondelli M.U. Cerino A. Cividini A. Acute hepatitis C: diagnosis and management.J Hepatol. 2005; 42: S108-S114Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 24Pawlotsky J.M. Use and interpretation of virological tests for hepatitis C.Hepatology. 2002; 36: S65-S73Crossref PubMed Google Scholar]. Other criteria that can aid in diagnosing HCV infection include significantly elevated ALT levels (>10× ULN or >20× ULN), known or suspected exposure to HCV and increasing numbers of reactive proteins in a recombinant immunoblot assay confirmation test [23Mondelli M.U. Cerino A. Cividini A. Acute hepatitis C: diagnosis and management.J Hepatol. 2005; 42: S108-S114Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 25Heller T. Rehermann B. Acute hepatitis C: a multifaceted disease.Semin Liver Dis. 2005; 25: 7-17Crossref PubMed Scopus (61) Google Scholar].Table 2Proposed criteria for diagnosis of acute hepatitis C infectionPrimary criteriaPresence of HCV RNA in serum of a previously HCV-negative patient. Seroconversion from anti HCV-negative to anti HCV-positiveSecondary criteriaElevated transaminase level ⩾10 to 20 times the upper limit of normalKnown or suspected exposure to HCV within the preceding 6 monthsAll other causes of acute liver damage excludedAdditional considerationsSudden onset of liver diseaseRepetition of recombinant immunoblot assay testing to demonstrate eventual increase in the number of reactive proteins Open table in a new tab 4. Spontaneous resolution of acute hepatitis CAn average of 26% of patients with acute hepatitis C (range 20–67%) experience spontaneous clearance of the virus, an event that occurs primarily during the first 3 months after clinical onset of disease [10Santantonio T. Medda E. Ferrari C. Fabris P. Cariti G. Massari M. et al.Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy.Clin Infect Dis. 2006; 43: 1154-1159Crossref PubMed Scopus (96) Google Scholar, 11Corey K.E. Ross A.S. Wurcel A. Schulze Zur Wiesch J. Kim A.Y. Lauer G.M. et al.Outcomes and treatment of acute hepatitis C virus infection in a United States population.Clin Gastroenterol Hepatol. 2006; 4: 1278-1282Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 21Santantonio T. Sinisi E. Guastadisegni A. Casalino C. Mazzola M. Gentile A. et al.Natural course of acute hepatitis C: a long-term prospective study.Dig Liver Dis. 2003; 35: 104-113Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 26Micallef J.M. Kaldor J.M. Dore G.J. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.J Viral Hepat. 2006; 13: 34-41Crossref PubMed Scopus (646) Google Scholar, 27Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.-C. Ulsenheimer A. et al.Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, 28Hofer H. Watkins-Riedel T. Janata O. Penner E. Holzmann H. Steindl-Munda P. et al.Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load.Hepatology. 2003; 37: 60-64Crossref PubMed Scopus (184) Google Scholar]. If viremia persists for more than 6 months, chronic disease should be considered. Several host and viral factors, such as HLA, HCV genotype, co-infection with human immunodeficiency virus (HIV), gender, race and advanced age seem to influence the clinical course of disease [[29]Lehmann M. Meyer M.F. Monazahian M. Tillmann H.L. Manns M.P. Wedemeyer H. High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection.J Med Virol. 2004; 73: 387-391Crossref PubMed Scopus (91) Google Scholar], but none of these parameters can accurately predict spontaneous resolution [[2]Blackard J.T. Shata M.T. Shire N.J. Sherman K.E. Acute hepatitis C virus infection: a chronic problem.Hepatology. 2008; 47: 321-331Crossref PubMed Scopus (96) Google Scholar]. However, it seems that spontaneous resolution occurs more frequently in the presence of symptomatic disease [10Santantonio T. Medda E. Ferrari C. Fabris P. Cariti G. Massari M. et al.Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy.Clin Infect Dis. 2006; 43: 1154-1159Crossref PubMed Scopus (96) Google Scholar, 21Santantonio T. Sinisi E. Guastadisegni A. Casalino C. Mazzola M. Gentile A. et al.Natural course of acute hepatitis C: a long-term prospective study.Dig Liver Dis. 2003; 35: 104-113Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 27Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.-C. Ulsenheimer A. et al.Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, 30Kamal S.M. Ismail A. Graham C.S. He Q. Rasenack J.W. Peters T. et al.Pegylated interferon α therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics.Hepatology. 2004; 39: 1721-1731Crossref PubMed Scopus (164) Google Scholar]. Interestingly, several reports have now stated that a strong and multispecific cellular immune response is an important host factor for spontaneous viral eradication [31Diepolder H.M. Zachoval R. Hoffmann R.M. Wierenga E.A. Santantonio T. Jung M.C. et al.Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection.Lancet. 1995; 346: 1006-1007Abstract PubMed Scopus (568) Google Scholar, 32Gerlach J.T. Diepolder H.M. Jung M.C. Gruener N.H. Schraut W.W. Zachoval R. et al.Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C.Gastroenterology. 1999; 117: 933-941Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 33Gruner N.H. Gerlach T.J. Jung M.C. Diepolder H.M. Schirren C.A. 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Al Tawil A. et al.Cellular immune responses in seronegative sexual contacts of acute hepatitis C patients.J Virol. 2004; 78: 12252-12258Crossref PubMed Scopus (73) Google Scholar, 38Lucas M. Ulsenheimer A. Pfafferot K. Heeg M.H. Gaudieri S. Gruner N. et al.Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection.PLoS ONE. 2007; 2: e649Crossref PubMed Scopus (61) Google Scholar].Follow-up testing of HCV RNA levels in patients who experience spontaneous resolution is highly recommended because a late relapse may occur after the initial HCV RNA clearance [[27]Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.-C. Ulsenheimer A. et al.Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar]; therefore, HCV RNA should be monitored for a period of at least 6 months with 2–3 consecutive tests, and subsequent testing if ALT elevation is observed. Ultimately, comparison of rates of spontaneous viral clearance across studies of acute hepatitis C natural history will be possible only with the introduction of standardized definitions and methodologies [[39]Amin J. Law M.G. Micallef J. Jauncey M. Van B.I. Kaldor J.M. et al.Potential biases in estimates of hepatitis C RNA clearance in newly acquired hepatitis C infection among a cohort of injecting drug users.Epidemiol Infect. 2007; 135: 144-150Crossref PubMed Scopus (21) Google Scholar].5. Treatment of acute hepatitis CClinical trials focusing on the treatment of acute hepatitis C are hindered by the difficulties in its diagnosis. Many patients who might otherwise be candidates for treatment manifest high-risk behavior, such as ongoing intravenous drug abuse, and are thus unsuitable for clinical trials. As a result, most studies of acute hepatitis C are open-label, non-comparative investigations with small patient populations that differ widely with respect to design, patient population and treatment regimens; therefore, discerning the most effective intervention remains difficult. The lack of comparative studies has precluded the possibility that any one treatment regimen can become a gold standard.5.1 Conventional interferon-alfaTreatment of acute hepatitis C patients with conventional (non-pegylated) interferon (IFN) alfa has been investigated in several small clinical trials, which typically used 3–6 million units (MU) IFN alfa administered three times weekly for 4–24 weeks. These studies examined biochemical and virological response rates, and the results have been summarized in several meta-analyses (Fig. 1). Overall, 32–52% of patients treated with IFN alfa attained SVR (defined as undetectable HCV RNA 24 weeks after completing therapy) compared with only 4–11% of untreated patients [40Myers R.P. Regimbeau C. Thevenot T. Leroy V. Mathurin P. Opolon P. et al.Interferon for acute hepatitis C (review).The Cochrane Library. 2002; : CD000369Google Scholar, 41Cammà C. Almasio P. Craxı` A. Interferon as treatment for acute hepatitis C: a meta-analysis.Dig Dis Sci. 1996; 41: 1248-1255Crossref PubMed Scopus (94) Google Scholar, 42Poynard T. Leroy V. Cohard M. Thevenot T. Mathurin P. Opolon P. et al.Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration.Hepatology. 1996; 24: 778-789Crossref PubMed Google Scholar]. The most recent meta-analysis by Licata et al. [[43]Licata A. Di Bona D. Schepis F. Shahied L. Craxı` A. Cammà C. When and how to treat acute hepatitis C?.J Hepatol. 2003; 39: 1056-1062Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar] showed that IFN treatment significantly increased SVR rates (risk difference, 49%; 95% CI, 32.9–65%) compared with untreated control patients. Moreover, SVR rates increased with higher weekly doses of IFN. Thus, higher IFN dosages during the first month appear to be the best treatment option. In fact, an induction regimen of IFN alfa-2b (5 MU/day for 4 weeks, followed by 5 MU three times weekly for another 20 weeks) was shown to be highly effective in treating patients with acute hepatitis C [[44]Jaeckel E. Cornberg M. Wedemeyer H. Santantonio T. Mayer J. Zankel M. et al.Treatment of acute hepatitis C with interferon alfa-2b.N Engl J Med. 2001; 345: 1452-1457Crossref PubMed Scopus (760) Google Scholar]. In this study, 43 of 44 (98%) patients attained SVR, with a mean time of 3.2 weeks from initiation of treatment to undetectable HCV RNA. Twenty-four of these patients were followed up for a median of 135 weeks; all had undetectable HCV RNA and no evidence of liver disease [[45]Wiegand J. Jackel E. Cornberg M. Hinrichsen H. Dietrich M. Kroeger J. et al.Long-term follow-up after successful interferon therapy of acute hepatitis C.Hepatology. 2004; 40: 98-107Crossref PubMed Scopus (80) Google Scholar].Other studies have evaluated the efficacy of early treatment intervention with high-dose IFN alfa and shorter treatment durations (Fig. 1). In two studies, SVR was reported in 21 of 28 (75%) patients receiving high-dose regimens of IFN alfa (5 MU/day) for 8 weeks [[46]Delwaide J. Bourgeois N. Gerard C. De Maeght S. Mokaddem F. Wain E. et al.Treatment of acute hepatitis C with interferon α-2b: early initiation of treatment is the most effective predictive factor of sustained viral response.Aliment Pharmacol Ther. 2004; 20: 15-22Crossref PubMed Scopus (54) Google Scholar] and in 20 of 24 (83%) patients treated with 10 MU IFN alfa administered daily until normalization of ALT levels [[47]Vogel W. Graziadei I. Umlauft F. Datz C. Hackl F. Allinger S. et al.High-dose interferon-α2b treatment prevents chronicity in acute hepatitis C: a pilot study.Dig Dis Sci. 1996; 41: 81S-85SCrossref PubMed Google Scholar]. In a separate study, administration of intramuscular human lymphoblastoid IFN alfa (6 MU/day) for 4 weeks resulted in SVR in 13 of 15 (87%) patients [[48]Nomura H. Sou S. Tanimoto H. Nagahama T. Kimura Y. Hayashi J. et al.Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial.Hepatology. 2004; 39: 1213-1219Crossref PubMed Scopus (160) Google Scholar]. Two patients with detectable HCV RNA at the end of the treatment subsequently attained SVR when treated with IFN alfa (6 MU three times weekly) for an additional 20 weeks [[48]Nomura H. Sou S. Tanimoto H. Nagahama T. Kimura Y. Hayashi J. et al.Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial.Hepatology. 2004; 39: 1213-1219Crossref PubMed Scopus (160) Google Scholar]. In addition, Nomura and colleagues also compared the response rate achieved with early initiation of treatment (8 weeks after disease onset) with a delayed treatment strategy and demonstrated that therapy initiated after one year is clearly less effective [[48]Nomura H. Sou S. Tanimoto H. Nagahama T. Kimura Y. Hayashi J. et al.Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial.Hepatology. 2004; 39: 1213-1219Crossref PubMed Scopus (160) Google Scholar]. Similarly, in the meta-analysis by Licata et al. delaying initiation of therapy until 60 days after onset of disease did not compromise the probability of a favorable response [[43]Licata A. Di Bona D. Schep