Whom? When? How? Another piece of evidence for early treatment of acute hepatitis C
Authors: Heiner Wedemeyer, Elmar Jäckel, Johannes Wiegand, Markus Cornberg, Michael P. Manns
Journal: Hepatology (2004)

HCV, hepatitis C virus; aHCV-ab, anti–hepatitis C virus-antibodies. Management of acute infection with the hepatitis C virus (HCV) is still a matter of debate and different treatment algorithms have been proposed in recent years. The 2002 NIH consensus conference was rather cautious in recommending therapy for patients with acute hepatitis C,1 while the recently updated French, Swedish, and German consensus guidelines suggested early treatment with interferon alfa.2-4 The need for additional trials, however, has been highlighted throughout the debate. Thus, where are we now, almost two years after the NIH conference? Undoubtedly, the evolution to chronicity of an acute infection with HCV should be avoided, considering the potential risk for the development of liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis C.5 In addition, HCV infection can be associated with extrahepatic manifestations, as well as result in significant social and legal consequences, especially for medical health professionals. Fortunately, acute hepatitis C has become a quite uncommon disease, although new infections still occur. As the majority of acute HCV cases nowadays affect IV drug addicts, treatment trials have become difficult to perform, with most studies on acute hepatitis C being of limited size or rigor. Well-performed trials are, however, urgently needed, since there is still no prophylactic vaccine available for HCV. Thus, whom do we really have to treat? If we treat, when to start? Is interferon monotherapy sufficient, or do we need combination with ribavirin? How long to treat? Are there differences among HCV genotypes, patients with high or low viral load, the sexes, or different ethnic backgrounds? A major problem for the design of treatment trials in acute hepatitis C is the variable course of the infection between individuals as well as its different stages (Fig. 1). Furthermore, very few randomized trials have compared different treatment strategies. The study by Nomura and colleagues from Japan6 is therefore of importance and quite unique, since the investigators prospectively randomized patients for early intervention or observation. Schematic course of acute hepatitis C virus infection. Patients may present at different phases during the infection. Phase A: postexposure. Phase B: asymptomatic viremic patients with normal liver enzymes 2–6 weeks postexposure before the onset of symptoms. Phase C: acute hepatitis with different levels of alanine aminotransferase elevations; symptoms may vary significantly between patients. Phase C1: early acute hepatitis phase. Phase C2: late acute hepatitis phase. Phase D: spontaneous recovery or partial tolerization—establishment of persistent viremia. Phase E: chronic hepatitis C after more than 6 months of infection. aHCV-ab, anti–hepatitis C virus-antibodies. Thirty-nine Japanese patients with acute hepatitis C were evaluated, and 5 individuals had to be excluded from the study because of hepatitis B coinfection or alcohol abuse. The remaining patients were followed for 2 months after presentation before they were randomized for early treatment or 1 year of observation. Importantly, the rate of spontaneous HCV clearance during the first 2 months was rather low—only 12%. In addition, none of the 15 patients in the observation group subsequently cleared HCV. Only 3 out of 34 had significantly elevated bilirubin levels (above 3 mg/dL). After randomization, Nomura and colleagues treated their patients with daily injections of 6 million units of interferon alfa for only 4 weeks. This short therapy was sufficient to prevent chronicity in 13 out of 15 patients. The 2 remaining individuals cleared HCV after 5 additional months of interferon alfa thrice weekly, leading to an overall sustained response of 100% in the early intervention group. In contrast, when treatment was initiated after 1 year, only 40% of patients responded to the 4 weeks of interferon induction, and only 2 additional patients responded to additional 20 weeks of interferon therapy. Thus, the Nomura data adds another piece of evidence to support early treatment of acute hepatitis C. However, the study has some limitations, and the results from Japan may not necessarily fit with American and European experiences. It should also be noted that delayed therapy was performed with interferon alfa alone, since the trial was initiated in the mid 1990s. Nowadays, treatment with pegylated interferon and ribavirin would be the treatment of choice, most likely leading to higher response rates in the observation group. So how to combine the different pieces of the puzzle? Antiviral therapy of acute hepatitis C is based on the use of interferon alfa. Since this drug is associated with significant side effects and costs, a careful selection of patients is required.7 Because in many cases the source of infection is IV drug abuse, only a minor percentage of all individuals with acute hepatitis C will be eligible for antiviral treatment. It will be very important to identify factors associated with spontaneous clearance to avoid unnecessary treatment. Host factors such as ethnic background, sex, human leukocyte antigen types, and cytokine polymorphisms have been studied extensively for possible associations with spontaneous recovery from HCV infection.8 However, none of these factors is useful yet for the decision to start or withhold therapy. Although frequent quantification of HCV-RNA during the early course of the disease might help to identify individuals able to clear the infection,9 this approach is not very applicable for routine clinical practice. In addition, symptomatic icteric patients usually recover without treatment more often than to asymptomatic individuals with acute hepatitis C,10, 11 a finding also supported by the Nomura data. Finally, the likelihood of clearing HCV may be higher for patients infected with the HCV genotype 3 than for patients infected with genotype 1, although in our experience about two-thirds of asymptomatic young, male, HCV genotype 3 patients developed a chronic course of the infection.12 Thus, early treatment should be recommended, especially for less-symptomatic patients infected with HCV genotype 1. Whether antiviral therapy can be withheld safely at early stages for icteric non-genotype 1 patients still remains an open question. Acute hepatitis C is usually diagnosed when patients visit their doctors because of symptoms of hepatitis (Fig. 1, phase C). After needle-stick injury, HCV infection may be diagnosed earlier in the asymptomatic phase due to systematic screening (phase B). A postexposure prophylactic administration of interferon (phase A) is currently not justified by any data, considering the relatively low infectivity of HCV, the high treatment success of acute hepatitis C, and the slow progression of chronic hepatitis C. Unfortunately, no data are available on the treatment of early asymptomatic phase B acute HCV infection, while most studies enrolled patients in phase C. There has been some concern that treatment initiation in the asymptomatic phase B could be too early, since antiviral cellular immunity does not emerge before 8 to12 weeks of infection.13 However, early reduction of viral load should prevent exhaustion of antiviral immune responses14 and prevent functional impairment of HCV-specific T cells.15, 16 In the German Acute Hepatitis C Study-I, performed between 1998 and 2000 and resulting in a sustained virological response of 98% after 24 weeks of interferon monotherapy,17 the average time from infection to first symptoms was 54 days. Therapy was started after an average of 89 days of infection. Spontaneous HCV clearance, however, often occurs earlier, as shown by the Nomura data and also in the Hofer study from Austria in which patients were already HCV-RNA-negative after 75 days.9 Thus, a good time to start therapy might be between days 70 and 100 after exposure, corresponding to days 20 to 50 after onset of symptoms (Fig. 1, phase C1). Additional problems of the Nomura study were that the time of exposure was known only for a minority of patients and that the initiation of therapy in those patients was rather late even in the "early" intervention group, with an average of 150 days (Fig. 1, phase C2). Several different treatment regimes have been explored in patients with acute hepatitis C. In the case series by Vogel et al., patients were treated until normalization of alanine aminotransferase levels with high doses of daily interferon (10 million units per day).18 Nomura et al. treated their patients for only 4 weeks with daily infections of 6 million units of interferon alfa, and additional therapy for 5 months with a thrice-weekly regimen was necessary only in 2 out 15 patients.6 However, Japanese patients usually show better responses to antiviral therapy of HCV infection than do Caucasian or African-American patients; thus, this short course of interferon may not be as efficient in Western countries. The Jaeckel study also used an induction phase of daily interferon followed by 20 weeks of thrice-weekly dosing.17 Importantly, virological response to this treatment regimen was durable for up to 4 years after the end of therapy, and no late relapse occurred.19 First data on the German follow-up study using pegylated interferon alfa-2b for 24 weeks showed similar sustained virological response rates of >90%.20 A study from Belgium suggests that an even shorter course of daily injections of interferon alfa-2b for only 2 months may be very effective in the majority of patients.21 Taking all these data together, the "hit early and hard" strategy seems to be successful in most cases. Importantly, ribavirin is not needed if therapy is started early. Half a year of therapy, however, may be unnecessary for most patients, and individualization of treatment according to host as well as viral factors should be the goal of future studies.22 The good news of the Nomura study is that the risk for developing chronic hepatitis C after needle-stick injury is very low if antiviral therapy with interferon alfa alone is initiated within 3 to 4 months after infection. Treatment should be recommended especially for less-symptomatic patients infected with HCV genotype 1, while the "wait and see" strategy seems to be reasonable for individuals with genotype 2 or 3 infection. The bad news is that we still do not know the optimal interferon dose and treatment duration for patients in Western countries. The story continues!