JAC Advance Access published online on September 5, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn346
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Leading article |
Treatment of acute hepatitis C: the success of monotherapy with (pegylated) interferon 
1 Department of Internal Medicine, Medical Clinic and Polyclinic II, University of Leipzig, Leipzig, Germany 2 Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany
* Corresponding author. Tel: +49-341-97-12226; Fax: +49-341-97-12228; E-mail: johannes.wiegand{at}medizin.uni-leipzig.de
accepted 5 August 2008
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Abstract |
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Top
Abstract
IntroductionEarly control in the acute phase of hepatitis C infection is an attractive therapeutic goal in order to shorten disease duration and infectivity, to prevent chronicity and progression to advanced liver disease and to avoid eventual therapeutic non-response in the later stages of chronic hepatitis C. Over the past decade, different interferon-based treatment options have been developed, which lead to sustained virological response rates of up to 98%. The present article summarizes the successful invention of immediate and delayed strategies in acute hepatitis C monoinfection, critically discusses potential limitations and illustrates the therapeutic challenges of the near future.
Key Words: antiviral therapy , hepatology , liver disease
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Introduction |
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Standardized therapeutic approaches in acute hepatitis C virus (HCV) infection are difficult to perform, because several clinical, diagnostic and social reasons lead to under-reporting and limited epidemiological data.1
Clinically, many patients are asymptomatic or develop only unspecific symptoms such as fatigue, low-grade fever, myalgia or nausea. Jaundice only occurs in 20% to 30% of the cases.2,3
The serological screening of HCV antibodies is not reliable during early infection because it can take up to 12 weeks after exposure until anti-HCV immunoglobulin M antibodies emerge. Thus, in up to 30% of patients analysis of HCV-RNA by PCR will be the only possibility to diagnose acute HCV infection.4,5
Moreover, identification of individuals with acute hepatitis C is hindered by their reluctance to divulge habits that lead to transmission of the disease. After the screening of blood products for HCV-RNA by PCR, transfusion-associated transmission is virtually non-existent in western countries anymore. Intravenous drug abuse has become the leading risk factor today.5–10 The incidence is up to 39 per 100 person-years in drug abusers,9,11 and the prevalence is at least 50% in many parts of the world.12 Other possible modes of acquisition are medical procedures, unprotected sexual intercourse with multiple partners or needle-stick injuries in healthcare professionals.9,10,13–16 Recent reports highlight potential sources of infection after hospital admission.13,17,18 In contrast, needle-stick injuries are associated with a much lower risk than previously reported (mean 0.75%; in Europe 0.42%, in Eastern Asia 1.5%).19
Overall, incidence estimates of acute HCV infection vary widely depending on the evaluation methods and the institution they are reported to. In Germany, incidence data on hepatitis C are based on serological results irrespective of the acuity of the disease. Thus, discrimination between an acute infection and a newly diagnosed chronic disease cannot be performed.9 In Italy, incidence ranges from 1 to 14 infections per 100 000 according to the national surveillance agency,20 the Italian blood donor programme21 or evaluation in the general population.22 In the USA, 671 confirmed cases with acute HCV infection were reported in 2005 (0.2 per 100 000 inhabitants); however, after accounting for under-reporting of asymptomatic infections, the estimated incidence was 20 000 new cases.16
Diagnosis of acute HCV infection is based on the detection of HCV-RNA by PCR with documented anti-HCV antibody seroconversion. In case anti-HCV seroconversion cannot be proved, additional criteria can support the suspected diagnosis: ALT levels >10–20 times the upper limit of normal, known or suspected exposure to the virus, or increasing numbers of reactive proteins in a recombinant immunoblot confirmation assay.5,6
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Principles of antiviral therapy in acute hepatitis C |
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In chronic hepatitis C, combination therapy of pegylated interferon
plus ribavirin has become the standard of care and has replaced monotherapy with conventional interferons or their combination with ribavirin.23–26 Treatment duration and efficacy are dependent on HCV genotype and kinetics of HCV-RNA decline during the first weeks of therapy. Therapeutic regimens may be individualized to shorter or prolonged treatment strategies in single patients; however, 85% of the cases will be treated according to the standard schedule.25–35 In contrast to chronic hepatitis C, a standard therapy has not been identified in the acute phase of the disease yet. Many important treatment aspects are currently under investigation. Nevertheless, the following principles have been identified so far.
- Both conventional and pegylated interferons can be used in acute hepatitis C.36–43
- Combination therapy with ribavirin is not necessary.36–43
- Treatment duration and sustained virological response (SVR) rates are independent of HCV genotypes.36–43
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Treatment of acute hepatitis C with conventional interferon
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The first strategies to treat acute hepatitis C were based on conventional non-pegylated interferons. A recent meta-analysis identified therapeutic principles after investigation of 16 heterogeneous clinical studies which treated 320 patients subcutaneously, intramuscularly or intravenously for a period of 4–24 weeks with different dosages of interferon
or β.44 Overall, interferon treatment significantly increased the SVR rates compared with untreated controls (risk difference 49%; 95% CI: 32.9–65). SVR rates increased with higher weekly interferon dosages. A high dose therapy during the first months of therapy appeared to be the best treatment option.
An Austrian pilot study treated 24 patients with daily 10 MU interferon -2b subcutaneously until the normalization of ALT values and obtained SVR in 75% of patients.36
The German acute hepatitis C I trial became the landmark study for conventional interferons treating 44 individuals with a standardized treatment duration of 24 weeks.37 After a 4 week induction dosing period with daily 5 MU interferon -2b subcutaneously, patients continued with 5 MU three times weekly subcutaneously for another 20 weeks. HCV-RNA was eliminated 3.2 weeks after treatment initiation, and 43 of the 44 cases (98%) obtained SVR. Importantly, there is no evidence for late relapse episodes within a follow-up period of up to 224 weeks after the end of therapy.45
More recent trials reported SVR rates of 75% (n = 21/28) after daily injection of 5 MU interferon -2b subcutaneously for 8 weeks38 and of 87% (n = 13/15) after daily 6 MU human lymphoblastoid interferon intramuscularly (im) for 4 weeks,39 respectively.
Overall, all studies indicate that early treatment strategies for 4–24 weeks with initial daily interferon injection can effectively prevent chronicity of acute hepatitis C infection (Table 1).
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Treatment of acute hepatitis C with pegylated interferon
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After pegylated interferons had become standard of care in chronic hepatitis C, they were also studied in the acute phase of the disease. Due to their long lasting half-life time, treatment protocols were designed with continuous dosing levels by once weekly injections which replaced the high-dose induction regimens performed with conventional interferons so far. Importantly, head-to head studies between monotherapies with pegylated and conventional interferons have not been conducted yet.
The concept of immediate therapy37 was transferred to pegylated interferon in the German HEP-NET Acute Hepatitis C II study.40 Patients were treated with pegylated interferon -2b 1.5 µg/kg once weekly subcutaneously for 24 weeks. In the total study population, 71% of patients achieved SVR. The SVR rate in individuals receiving 80% of the scheduled dosage within 80% of the study period was 89%. The difference in the response rates between the intent-to-treat and the per-protocol analysis was due to protocol violations, treatment failures and a substantial number of patients lost to follow-up.
Two Italian study groups investigated pegylated interferon -2b in the setting of immediate therapy of acute hepatitis C for a shorter treatment period of 12 weeks. An SVR was observed in 14 of 19 cases (74%) and 33 of 46 individuals (72%), respectively.41,42
In addition to the changed dosing regimens, another important therapeutical aspect of acute hepatitis C was considered after the invention of pegylated interferons: the idea of a delayed instead of an immediate therapy to investigate the optimal time point for the initiation of treatment.
In the trials with conventional interferons, therapy was initiated as early as possible. However, immediate treatment results in over-treatment of those patients, who would have cleared the infection spontaneously. Prompt therapy exposes these individuals unnecessarily to treatment-related adverse events and increases medical costs. Spontaneous clearance of acute hepatitis C occurs in 20% to 67% of cases primarily within the first 3 months after the clinical onset of the disease.3,8,14,46–48 If viraemia persists for more than 6 months, chronic infection must be considered. Unfortunately, there are no host or viral factors that can reliably predict spontaneous resolution in individual cases.3,14,47 In general, patients with symptomatic disease (i.e. jaundice or flu-like symptoms) seem to experience spontaneous viral clearance more often than asymptomatic individuals.3,47 Self-limited disease could be observed in up to 52% (n = 24/46) of symptomatic patients in contrast to none of the asymptomatic cases.47
The study by Gerlach et al.47 became the rationale for subsequent studies investigating delayed therapy of acute hepatitis C with pegylated interferons. Only the patients who did not resolve the infection spontaneously were treated with different interferon-based regimens (conventional and pegylated interferons, with or without ribavirin, different treatment durations) and attained SVR in 81% of cases. The overall response rate including self-limited infections and treatment induced viral clearance was 91%. This result was in the same range as the therapeutic approaches with immediate treatment.37,40
A recent Italian trial evaluated delayed therapy within a standardized study protocol treating patients with 1.5 µg/kg pegylated interferon -2b once weekly subcutaneously for 24 weeks after an initial observation period of 12 weeks. At the end, 94% (n = 15/16) of patients cleared the infection.43 Thus, delayed treatment strategies achieve similar results as the immediate treatment concepts (Table 2). The high SVR rates with both conventional and pegylated interferon monotherapies do not justify combination with ribavirin so far.
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Interestingly, if pegylated interferon
was used in acute hepatitis C infection, most studies investigated pegylated interferon -2b.40–43 Pegylated interferon -2a 180 µg once weekly subcutaneously was tested in a limited number of patients only and was mostly combined with ribavirin.46,49 Thus, SVR data with pegylated interferon -2a monotherapy in acute hepatitis C are based on single cases only. |
What is the optimal time point for treatment initiation? |
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The therapeutical concepts of immediate and delayed treatment have not been investigated head-to-head so far. Previous results indicate that the time between presentation and start of therapy can influence SVR rates.38 At present, the German Competence Network for Viral Hepatitis (HEP-NET)50 is conducting a randomized, controlled trial comparing immediate treatment versus delayed therapy after an observation period of 12 weeks. However, treatment should not be delayed for too long, because SVR dropped from 87% to 40% in the Japanese interferon trial, if therapy was initiated after an observation period of 1 year.39
In an attempt to define the optimal time point for treatment initiation, a recently published study randomized patients to observation periods of 8, 12 and 20 weeks, respectively.51 However, the study is limited by substantial methodological flaws which unfortunately prevent the validity of the results.52
In any case of an observation period prior to delayed antiviral therapy, repeated quantitative testing of HCV RNA levels in patients who experience spontaneous resolution is highly recommended because a late relapse may occur after temporary HCV RNA clearance. A single negative HCV RNA test result should not be considered as confirmation of self-limited acute hepatitis C.47 Frequent HCV-RNA determination within the first months of clinical symptoms may predict spontaneous resolution of the infection;53 however, this may not be feasible in everyday clinical practice. Thus, although evidence-based data on optimal follow-up measurements during an observation period are unknown so far, we recommend repeated tests at least every 4 weeks within the first 3–4 months.
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What is the optimal treatment duration? |
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The highest SVR rates have been described with the 24 week treatment schedule of Jaeckel et al.37 including daily induction dosing with 5 MU interferon
-2b subcutaneously during the first 4 weeks of therapy. Daily dosage of conventional interferon within shorter treatment schedules of 4 weeks39 and 8 weeks38 indicates that shorter treatment duration may be possible; however, the studies included only a small number of patients with different ethnicities. Monotherapies with pegylated interferon -2b in the Italian trials indicate that a 12 week treatment period can attain high virological response rates of 72% to 74%.41,42 However, randomized trials investigating 12 versus 24 weeks in the setting of immediate therapy of acute hepatitis C have not been performed. In contrast to chronic hepatitis C, duration of therapy should not be adjusted to baseline viral load or decline of HCV-RNA at week 4 and 12 so far, because data are not robust enough yet.40–42
In delayed therapy, another Italian large ongoing randomized trial is currently comparing a 12 versus a 24 week treatment period. In addition, this study also includes a third treatment arm consisting of pegylated interferon -2b plus ribavirin to verify whether combination therapy can reduce treatment duration to 12 weeks without compromising efficacy.
Results published so far investigating the optimal treatment duration in the setting of delayed therapy54 cannot be recommended for clinical practice because of inconsistencies in the study population and the interpretation of data.55
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What is the optimal interferon dosage? |
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The optimal dosage cannot be defined for either conventional or pegylated interferon
yet.
Using conventional interferon in an increasing weekly dosage within the first months of therapy increases the risk difference of an SVR from 5% to 90%.44 The different regimens with daily 5–6 MU interferon subcutaneously37 or im39 for 4 or 8 weeks,38 have not been compared head-to-head.
During immediate therapy with pegylated interferon -2b, the Italian results indicate that at least 1.2–1.33 µg/kg once weekly should be administered subcutaneously.41,42 SVR rates of 83% to 84% could be observed in patients receiving >1.2 µg/kg pegylated interferon -2b (n = 32/38)42 and could be increased to 100% in individuals infected with HCV genotype 1 (n = 5), if the dosage was >1.33 µg/kg.41 Importantly, the sub-analyses of these two studies confirmed the hypothesis that the success of immediate antiviral treatment is independent of HCV genotype40 and rather related to an optimal interferon dosage.41,42
In delayed treatment, attempts to treat patients with dosages other than 1.5 µg/kg pegylated interferon -2b subcutaneously once weekly have not been performed yet. Data that treatment results may be dependent on HCV genotypes do not exist so far. Although all individuals with relapse or non-response after delayed therapy in the studies of Gerlach (n = 5) and Santantonio (n = 1) were infected with genotype 1 or 4,43,47 it should be noted that the cases in the German trial were treated without induction therapy or daily administration of interferon like those in the studies of Jaeckel et al.37 and Nomura et al.39
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Who should be treated? |
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Patients with acute hepatitis C infection may be difficult to treat. As mentioned above, most of the cases are previous or current iv drug addicts. Although iv drug abusers can be effectively treated,38,42,56 other investigators observed a high number of psychiatric side effects leading to treatment discontinuation.57 Even after exclusion of patients with ongoing drug abuse, adherence to therapy is a crucial issue for the success of treatment. In the German HEP-NET Acute HCV II Study, SVR rates between individuals of the intend-to-treat and the per-protocol analysis differed by 18%. This difference was mainly due to patients lost to follow-up.40 Moreover, three serious adverse events occurred during the study period including one suicide related to pegylated interferon
-2b. Thus, indication for antiviral therapy must be discussed on an individual basis using an interdisciplinary approach, especially if drug abuse or psychological disorders are present. Response rates comparable to non-injecting drug users can be achieved in iv drug addicts in experienced centres with established multidisciplinary infrastructures and with directly observed therapy.58,59 However, such an approach may be limited to specialists and not practicable in the routine standard of care. |
Conclusions |
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Although the gold-standard therapy of acute hepatitis C has not been defined yet, the infection can be successfully treated with interferon-based monotherapies. Both conventional and pegylated interferon
can be effectively used. Combination therapy is not recommended so far, because of the high SVR rates achieved with interferon-based monotherapies. Therapy may be initiated as early as possible or after an observation period of up to 12 weeks. In both settings, treatment duration should be 24 weeks so far. According to the Italian experience, a shorter treatment duration of 12 weeks may be suitable in patients with side effects or difficult-to-treat individuals who become HCV-RNA negative within the first 4 weeks of therapy.41,42
If treatment initiation is prolonged for more than 3–4 months after the onset of clinical symptoms, the disease should be considered as chronic and treated for 24 or 48 weeks according to HCV genotype with a combination therapy of pegylated interferon plus ribavirin.
Importantly, the indication for therapy and the treatment schedule must be thoroughly discussed on an individual patient level. The benefit of an SVR has to be carefully balanced against potential treatment-related serious adverse events. If possible, patients with acute hepatitis C should be included in controlled clinical trials in order to answer the numerous open questions in the future.
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Transparency declarations |
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None to declare.
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