JAC Advance Access originally published online on January 5, 2006
Journal of Antimicrobial Chemotherapy 2006 57(2):360-363; doi:10.1093/jac/dki458
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Dose-dependent and genotype-independent sustained virological response of a 12 week pegylated interferon alpha-2b treatment for acute hepatitis C
Department of Infectious Diseases, University of Turin, Turin, Italy
* Correspondence address. Ospedale Amedeo di Savoia, Corso Svizzera 164, 10149 Turin, Italy. Tel: +39-011-4393926; Fax: +39-011-4393882; E-mail: francescogiuseppe.derosa{at}unito.it
Received 27 April 2005; returned 6 July 2005; revised 10 October 2005; accepted 20 November 2005
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Abstract |
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Objectives: The optimal regimen for acute hepatitis C (AHC) is considered to be a 24 week treatment with interferon (IFN) alpha-2b. A 24 week treatment with pegylated IFN (PEG-IFN) alpha-2b is also effective. This study was designed to assess response rates to a 12 week regimen of PEG-IFN alpha-2b.
Patients and methods: Patients with AHC were treated with PEG-IFN alpha-2b for 12 weeks in an open, non-randomized, prospective cohort study. Diagnosis of AHC was made with positive serum HCV RNA and elevated alanine aminotransferase (ALT) levels with a documented seroconversion or a known risk factor in the preceding 6 months. Treatment was administered within a median of 31 days (range 0–116) of the ALT level peak at a dosage varying from 1.06 to 1.66 µg/kg/week. The primary end-point was a sustained virological response (SVR).
Results: Nineteen patients were treated, of whom 11 patients (57.9%) had HCV genotype 1. Fourteen patients were asymptomatic. An SVR was achieved in 74% of patients and the SVR rate was 100 and 83.3%, respectively, in genotype 1 and non-1 infected patients treated with a dosage 
1.33 µg/kg, compared with 40 and 50%, respectively, in those who received a lower dosage. An SVR was significantly associated by multivariate analysis only with PEG-IFN dosage 1.33 µg/kg/week. No significant association was found with any viral genotype.
Conclusions: The rate of SVR was independent of the HCV genotype and was significantly associated by multivariate analysis only with the higher PEG-IFN dosage. Early identification and treatment of AHC is likely to decrease the burden of chronic hepatitis, especially when caused by HCV genotype 1.
Keywords: hepatitis C virus , acute hepatitis , interferon treatment , IFN , HCV
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Introduction |
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Interferon (IFN) treatment of acute hepatitis caused by hepatitis C virus (HCV) has been associated with response rates higher than those recorded in chronic C hepatitis. In the largest series so far described a sustained viral response (SVR) was achieved in 98% of the patients treated with a 24 week course of IFN alpha-2b.1 While the available evidence consistently depicts a rather promising outlook for the treatment of acute hepatitis C (AHC), much work remains to be done to identify the most appropriate IFN regimen, treatment duration and timing for intervention, as spontaneous clearance of HCV infection is possible, especially in symptomatic patients.2
The development of slow-releasing pegylated formulations of IFN (PEG-IFN) has made it possible to treat chronic HCV infection with both a simpler and more acceptable dosing frequency and significantly greater pharmacological exposure, with better treatment outcomes than those achieved with non-pegylated forms of IFN. The efficacy of a 24 week course of PEG-IFN alpha-2b was documented in two studies, and an SVR was achieved in 80 and 94% of patients.3,4 We describe here a series of 19 patients with AHC treated with a 12 week course of PEG-IFN alpha-2b.
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Materials and methods |
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The study was carried out at the ‘Amedeo di Savoia’ Hospital (Turin, Italy). Further to being a regional reference centre and the only infectious diseases facility in Turin province (population = 4 200 000), this centre serves as a reference point for a provincial network of outpatient facilities for drug abusers. In this setting, a programme of active surveillance of patients at high risk of blood-borne infections [such as HCV, hepatitis B virus (HBV) and HIV] was instituted 3 years ago with the purpose of offering free routine and prospective medical evaluations as well as specific counselling to intravenous drug users (IVDUs), healthcare workers with needlestick injuries, and sexual partners of HCV- and HIV-infected individuals.
Diagnosis of AHC was on criteria similar to those adopted by Jaeckel et al.,1 such as increased alanine aminotransferase (ALT) levels and positive serum HCV RNA with either documented recent seroconversion for anti-HCV antibodies or recently introduced relevant risk factors (sexual contact with HCV-infected partner, intravenous drug abuse, occupational exposure through needlestick injury). Cases of acute hepatitis caused by hepatitis A virus or HBV infection were excluded. HIV-positive patients were included only if the CD4+ T-lymphocyte count was higher than 400 cells/mm3 and if they had never received antiretroviral therapy. Laboratory evaluations were performed at diagnosis, at onset of therapy, at week 4, at week 12 and 24 weeks after the end of treatment. Viral parameters were analysed by a quantitative branched DNA assay (bDNA 3.0, Versant, Bayer) and a qualitative RT–PCR (Cobas Amplicor HCV test version 2.0, Roche), with lower detection limits of 615 and 50 IU/mL, respectively. Genotypes were studied by Line Probe Assay (HCV Genotype Assay LiPA, Bayer). Viral loads were tested at diagnosis, at onset of therapy and thereafter according to the study protocol.
The primary end-point was an SVR, defined as a negative RT–PCR 24 weeks after the end of treatment. The protocol was approved by the Regional Ethics Committee and patients gave signed informed consent.
PEG-IFN alpha-2b (PegIntron, Schering-Plough) was administered at a dosage varying from 1.06 to 1.66 µg/kg/weekly. The intended dosage of 1.5 µg/kg/weekly was not routinely administered because only 80 and 100 µg vials of PEG-IFN alpha-2b were available for outpatient treatment at the time the study was performed.
The Mann–Whitney U-test and contingency tables were used for continuous and categorical variables, respectively. Multiple regression analysis was performed with a logistic regression model. All P values were two-tailed with a 0.05 significance value.
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Results |
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Nineteen patients were treated (13 males and 6 females): median age 26 years (range 17–61). Diagnosis was made with elevated ALT levels and positive HCV RNA together with a documented seroconversion for anti-HCV antibodies in seven patients, and with the evidence of a new risk factor in the preceding 6 months in 12 patients (Table 1). Five patients (26%) had a mild dyspeptic syndrome (nausea, upper abdominal discomfort) and three of them (16%) had jaundice. The diagnosis was made in the asymptomatic patients by active surveillance related to high-risk behaviours (IVDUs, sexual transmission and occupational exposure). Demographic, virological and clinical criteria are summarized in Table 1.
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The median ALT value at diagnosis was 627 IU/mL (range 67–3249 IU/mL, normal value <37 IU/mL). The median interval between diagnosis and treatment was 31 days (range 0–116 days).
Eleven patients had genotype 1 (58%). Other present genotypes were 3a (six patients) and 2 (two patients). The median plasma HCV RNA level at onset of therapy was 1 x 105 IU/mL (range 615–7.7 x 106). Three patients had HIV infection. The median CD4+ T cell count was 580 cells/mm3, and the median HIV RNA load was 39 000 copies/mL (Cobas Amplicor HIV-1 Monitor Test, V 1.5, Roche Molecular Systems, Switzerland). No HIV-infected patient was undergoing antiretroviral treatment. At the fourth week the proportion of patients with negative bDNA and RT–PCR assays was 84% (16/19) and 74% (14/19), respectively. All patients received >80% of the scheduled dose.
Fourteen patients achieved an SVR (74%), which was significantly associated by univariate analysis with PEG-IFN dosage 1.33 µg/kg/week (P = 0.026), and lower HCV RNA levels at onset of therapy (P = 0.017). By a logistic regression model, only PEG-IFN dosage 1.33 µg/kg/weekly was significantly associated with an SVR (P = 0.0379; OR 14.7; 95% CI 1.16–185.2). No significant association was found with viral genotype, risk factor, symptoms at diagnosis, interval between diagnosis and treatment and HCV RNA level at onset of therapy. At the fourth week of treatment negative bDNA and RT–PCR had positive predictive values of 87.5 and 93%, respectively (P = 0.001), for achieving an SVR. The negative predictive values of positive bDNA and RT–PCR were 100 and 80%, respectively.
As evidenced in Table 1, patient no. 1 had a viral load just above the detection limit of the bDNA assay at diagnosis and at the onset of treatment, and patient no. 10 had a significant decrease in HCV RNA from 1 076 880 IU/mL at diagnosis to 626 IU/mL at onset of therapy, and both these patients had a genotype 1 infection. If we exclude these two patients from the analysis presented so far, an SVR was achieved in 67% of patients with genotype 1 (6 out of 9), and in 75% (6 out of 8) of patients with the other genotypes. However, this does not affect the genotype-independent rate of SVR or the significant association of an SVR with higher PEG-IFN dosage (P = 0.026). In fact, the SVR rate was 100 and 83% in patients with genotype 1 and non-genotype 1, respectively, who received 1.33 µg/kg/week, and 40 and 50%, respectively, in patients with genotype 1 and non-genotype 1 who received <1.33 µg/kg/weekly (difference not significant).
The genotype-independent rate of SVR did not change even after stratifying data according to the presence of seroconversion or of a new risk factor. Amongst patients treated with PEG-IFN above 1.33 µg/kg and diagnosed with evidence of seroconversion, the SVR rate was 100 and 67% in patients with genotype 1 and non-genotype 1, respectively, and it was 100% in patients diagnosed with a new risk factor.
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Discussion |
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In this non-controlled study, we confirmed that a better outcome is achievable by approaching HCV infection in its acute rather than in its chronic phase. Although the study design and its size do not allow for any definitive conclusion, these are findings which deserve consideration in the perspective of standardizing the treatment of AHC.
In our study PEG-IFN was administered for 12 weeks for several reasons. First, in patients with chronic hepatitis, the weekly administration of PEG-IFN is at least as effective as the daily administration of IFN, allowing a higher and more constant exposure to the drug. Second, the longer the duration of treatment proposed to IVDUs, the lower is the acceptance rate, as reported in a recent Swiss study where PEG-IFN was proposed for 24 weeks in the setting of AHC.5 Moreover, IVDUs are aware of the longer duration and the need for combination treatment in the setting of chronic HCV disease, especially when caused by HCV genotype 1. Third, only a minority of our patients had clinical predictors of a high rate of spontaneous clearance, such as jaundice (16%).
The SVR rate achieved in our study was 74% and was significantly associated by multivariate analysis only with PEG-IFN 1.33 µg/kg/weekly (P = 0.0379). There was no significant association with viral genotype. Viral load at onset of therapy was significantly associated with an SVR only by univariate analysis (P = 0.017). Our results confirm that harbouring a genotype 1 infection is not a predictor of treatment failure and that treatment of AHC with PEG-IFN is associated with a better outcome as compared with that achievable in chronic hepatitis. Particularly in genotype-1-infected patients, this might be taken as a further good reason for treating AHC.
Our study was designed to address the efficacy of a 12 week regimen in AHC, and PEG-IFN was administered without waiting for spontaneous clearance of HCV infection. With this bias, patients in the process of spontaneously clearing the infection may be wrongly considered as responders, overestimating the SVR rate. As presented in the Results section, the exclusion of two patients who may have been in the process of spontaneously eliminating the virus did not affect the genotype-independent rate of SVR and the significant association with the PEG-IFN dosage 1.33 µg/kg.
In this study we applied the same diagnostic criteria used by Jaeckel et al.1 and we recognize that the diagnosis of AHC may be difficult to prove without the evidence of seroconversion. However, in our study the results did not change even after stratifying data according to the presence of seroconversion or of a new risk factor: in particular, an SVR of 100% was achieved in patients with genotype 1 treated with a dosage 1.33 µg/kg/weekly, independent of the presence of seroconversion.
Our study has two major limitations: the variable dosages of PEG-IFN administered and the early treatment. The SVR rate achieved is lower in our study than that achieved by IFN alpha-2b (98%)1 and PEG-IFN administered for 24 weeks (80 and 94%)3,4 after excluding patients with possible spontaneous clearance, and it may be difficult to understand whether this is due to the shorter duration of treatment or the variable PEG-IFN dosage. However, an SVR in 86.6% of patients was reported with a 4 week course of natural IFN-alpha (6 MU daily), demonstrating the efficacy of shorter treatment courses.6 Moreover, the efficacy of the shorter duration of treatment with PEG-IFN alpha-2b is highlighted in our study by the fact that an SVR was achieved in 11 out of 12 patients (92%) treated with the higher dosage.
With such increasing evidence of better therapeutic outcome in acute as compared with chronic HCV infection, efforts must be undertaken for the earliest identification of newly infected patients in order to provide a chance of sustained cure which is almost double that achievable by treating chronic hepatitis C. Early treatment of patients with AHC, especially when infected with genotype 1, may reduce the burden of chronic HCV infection. Efforts should be made to diagnose AHC, and to optimize the dosage of PEG-IFN.
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No declarations were made by the authors of this paper.
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Acknowledgements |
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We gratefully acknowledge all colleagues from the Provincial network of outpatient facilities for intravenous drug abusers for referring their patients. We did not have any financial support.
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References |
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1. Jaeckel E, Cornberg M, Wedemeyer H et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001; 345: 1452–7.
2. Santantonio T, Sinisi E, Guastadisegni A et al. Natural course of acute hepatitis C: a long-term prospective study. Dig Liver Dis 2003; 35: 104–13.[CrossRef][Web of Science][Medline]
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Kamal S, Ismail A, Graham C et al. Pegylated interferon 
therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics. Hepatology 2004; 39: 1721–31.[CrossRef][Web of Science][Medline]
4. Santantonio T, Fasano M, Sinisi E et al. Efficacy of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance. J Hepatol 2005; 42: 329–33.[CrossRef][Medline]
5. Broers B, Helbling B, Francois A et al. Barriers to interferon-alpha therapy are higher in intravenous drug users than in other patients with acute hepatitis C. J Hepatol 2005; 42: 323–8.[Medline]
6. Nomura H, Sou S, Tanimoto H et al. Short-term interferon-alfa therapy for acute hepatitis C: a randomized control trial. Hepatology 2004; 39: 1213–9.[CrossRef][Medline]
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