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Treatment of Acute Hepatitis C
Journal of Gastroenterology, Apr 2002

Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, Pastore G, Dietrich M, Trautwein C, Manns M, for the German Acute Hepatitis Study Group (Medizinische Hochschule Hannover, Hannover, Germany; University of Bari, Bari, Italy; Essex-Pharma, Munich, Germany; Bernhard-Nocht Institute, Hamburg, Germany). Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001;345:1452–1457.

Epidemiologic studies have suggested that the majority of patients with acute hepatitis C virus (HCV) infection develop chronic infection. Despite improvements in response rates, therapeutic options for chronic HCV infection remain suboptimal. Combination therapy with pegylated interferon (IFN)- and ribavirin for chronic HCV infection yields a sustained virologic response in only slightly greater than half of all patients (Lancet 2001;358:958–965, Gastroenterology 2001;120[suppl 1]:A55). This study therefore focused on the treatment of acute infection with the goal of preventing the development of chronic infection. This case series examined the treatment of 44 patients with acute HCV infection.

To attain this sample size, the authors advertised throughout Germany in hospitals, clinics, patient advocacy groups, and government offices related to work injuries. An infection was considered acute if the patient had any of the following: (1) known or suspected exposure within 4 months, (2) documented HCV antibody seroconversion, or (3) serum alanine aminotransferase (ALT) >350 U/L with documentation of a normal ALT in the preceding year. Subjects were also required to have detectable serum HCV RNA (by a polymerase chain reaction assay) and elevated serum ALT levels. Exclusion criteria included signs of decompensated liver disease, coinfection with human immunodeficiency virus (HIV) or hepatitis B, and contraindications to therapy with IFN-. The treatment regimen was IFN--2b monotherapy. Because of the rise in HCV RNA observed at 24 hours after an injection of IFN--2b (Hepatology 1997;26:226–231), the patients received 5 million units of IFN--2b daily for 4 weeks and then 5 million units 3 times a week for 20 weeks. The primary endpoint was the sustained virologic response, defined by undetectable serum HCV RNA 24 weeks after the end of treatment.

Between March 1998 and March 2001, 44 patients were treated at 24 centers throughout Germany. Thirty (68%) patients had a known or suspected exposure, and 17 of these patients also had documented seroconversion. Six patients had documented seroconversion but no known exposure, and 8 patients had neither an exposure nor seroconversion and had only a marked increase in their ALT with a history of normal ALT in the preceding year. Modes of infection included intravenous drug use in 9 (20%), needle-stick injury in 14 (32%), surgical procedure in 7 (16%), sexual contact with HCV-positive partners in 10 (23%), and unknown in 4 (9%). The average time from infection until the start of therapy was 89 days (range, 30–112). One patient discontinued treatment at 12 weeks because of side effects. No serious adverse events were reported during the study, and none of the patients completing therapy required dose modification.

Of the 43 patients who completed treatment, 42 (98%) had undetectable HCV RNA at the end of therapy and follow-up. HCV RNA became undetectable in all 44 patients at a mean of 3.2 weeks of therapy (range, 2–12 weeks), and the ALT became normal at a mean of 10.4 weeks into therapy (range, 2–48 weeks). Interestingly, the patient who discontinued therapy at 12 weeks had recurrent viremia at 20 weeks but later cleared the infection. HCV RNA was undetectable after 12 months of follow-up. The sole patient with positive HCV RNA at the end of treatment had received corticosteroids during the course of IFN--2b for a flare of multiple sclerosis.

Based on these impressive findings, the investigators concluded that early treatment with IFN--2b prevents chronic HCV infection in most patients. Given the poorer response rates for the treatment of chronic HCV infection, the authors recommend treatment of all patients with acute HCV infection.


Acute HCV infection generally has a mild course, and patients therefore rarely seek medical attention. For this reason, appropriate treatment strategies and the role of acute therapeutic intervention have not been well studied. In particular, postexposure prophylaxis has not been addressed in a rigorous fashion, and the U.S. Public Health Service does not currently recommend immune globulin or specific treatment after known HCV exposure (MMWR Morb Mortal Wkly Rep 2001;50:1–52). Furthermore, in the face of a lack of definitive evidence, acute treatment has also not previously received enthusiastic support (Hepatology 2001;33:321–327).

A major barrier to identification and treatment of HCV infection is its insidious nature. Most cases are asymptomatic, and acute HCV infection rarely leads to fulminant hepatic failure (Ann Intern Med 1991;115:111–112, Hepatology 1995;21:240–252). Because of screening of the blood supply and other strategies to combat the spread of HIV, cases of acute HCV infection seem to have dramatically decreased since the 1980s (Hepatology 1997;26:3[suppl 1]:62S–65S). When present, symptoms are similar to other forms of acute hepatitis and include malaise, anorexia, nausea, and fatigue. Early studies of post-transfusion non-A, non-B hepatitis found that less than 25% of patients developed jaundice (Gastroenterology 1983;85:439–462). A recent cohort study of 142 patients with a history of illicit drug use highlights the difficulty of detecting acute HCV (Hepatology 1999;29:908–914). These patients were followed every 6 months from 1988 through 1996, and 43 (30%) had HCV seroconversion during this time. However, only 14% of the patients reported jaundice within 6 months of seroconversion. In addition, the health care providers following these patients failed to identify any of these acute infections.

Previous studies of acute HCV treatment have yielded mixed results. It is important to emphasize that the infrequent nature of the acute presentation has made these studies difficult to perform on a large scale. Most studies have examined the use of IFN- monotherapy, although there has also been limited experience with IFN- (Lancet 1991;338:914–915, Nippon Rinsho 1994;52:1847–1851). In a systematic review of 6 controlled trials with IFN--2b with 3 millions units 3 times a week for 6–24 weeks (J Hepatol 1999;31(suppl 1):189–192), only 2 studies measured HCV RNA, and there seemed to be a slight benefit in favor of treatment with IFN--2b. In one of the larger reports, 22 patients received 10 million units of IFN--2b until normalization of aminotransferases. Twenty of 22 (91%) completed therapy, and 18 (82%) had sustained viral clearance (Dig Dis Sci 1996;41:12(suppl):81S–85S).

Although the previous studies have collectively suggested benefit for treatment of acute HCV infection, the study by Jaeckel et al. provides the most compelling evidence to date. HCV was eradicated in 98% of the patients who received the full course of treatment. Natural history data suggests that 70%–80% of patients with acute HCV infection ultimately develop chronic HCV infection (Ann Intern Med 2000;132:296–305). Thus, early treatment seems to significantly alter the course of the disease. These response rates are also significantly higher than those seen in the treatment of chronic infection, raising the possibility that the treatment may be more effective in the acute setting, before development of viral persistence. Although not completely understood, viral persistence during HCV infection is thought to be related to the development of a weak antiviral immune response to viral antigens plus inability to eradicate infected cells (Hepatology 1999;30:595–601).

A particularly noteworthy aspect of the study by Jaeckel et al. was the timing of treatment. The time from exposure to treatment was 89 days (mean, with a range from 30 to 112 days). Therefore, immediate treatment did not seem to be required to achieve this extremely high response rate. Although the kinetics of viral eradication and persistence remain unclear, this finding would suggest either slow development of viral persistence, or perhaps other unknown factors played a role in the high response rate.

Although the results of this current study seem to be impressive, this study has some important limitations. Most importantly, the study was a prospective case series without a control group. Selection bias therefore becomes an obvious concern. For example, we do not know the number of patients screened in this study and it is unknown whether patients who were poorer candidates for therapy were not invited to participate. In addition, the definition of acute HCV infection was broad. Eight of the 44 subjects had no known exposure or documentation of seroconversion, and the true diagnosis of acute infection in these patients is therefore in doubt.

It seems that the treatment of acute HCV infection has clear merit. However, it is unlikely to have a significant impact on the current HCV “epidemic.” This is due to the fact that rates of acute HCV infection seem to be decreasing, and patients with acute HCV infection rarely are identified by their physicians.

This study raises a number of important practical issues concerning the treatment of acute HCV infection. First, is there a way to select patients who will truly require therapy? Previous natural history data suggests that as many as 30% of patients with acute HCV infection will clear the virus spontaneously and thus not require IFN- treatment. This question is difficult to answer because there are no reliable predictors of HCV clearance. Second, the timing of treatment must also be considered. A recent preliminary report suggested that most patients clear the virus within the first 12 weeks (Hepatology 2001;34:341A). This finding would suggest that it is prudent to wait until 12 weeks and then consider treatment. Finally, the current best treatment is also not clear. This study also used IFN--2b monotherapy, whereas the best current therapy for chronic HCV infection is the combination of pegylated IFN- and ribavirin. Although it is difficult to imagine improving on a response rate of 98% through the use of the pegylated form of IFN- or the addition of ribavirin, the case series design may have overestimated the response rate, and there may be a role for other treatments.

Perhaps the most important question concerning this study is this: do we currently have enough evidence to justify treatment of all patients with acute HCV infection? Although a definitive randomized controlled trial would be ideal, this may be an unrealistic expectation. Indeed, logistical factors and the infrequent acute presentation of HCV are likely to make a large, randomized, controlled trial unlikely. This study required 24 centers and 3 years to recruit just 44 patients. In addition, it might be argued that at this point it would be unethical to perform a placebo-controlled trial. Thus, without a randomized controlled trial expected soon, what are we to recommend for patients presenting with acute HCV infection? More specifically, are the data from this study enough to recommend therapy for all patients? Although the apparent response rate (98% viral eradication) was impressive, selection bias remains a major concern. If provided information about the number of patients screened and excluded, we might have a better sense of this study group and its generalizability to other patient populations. Unless an extremely select group of patients was examined, these results are compelling. In summary, on those occasions when patients with acute HCV infection are identified, this study supports aggressive treatment with IFN- monotherapy.


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