Elisabeth Formann

Peginterferon Alfa-2a and Ribavirin for 24 Weeks in Hepatitis C Type 1 and 4 Patients With Rapid Virological Response

BACKGROUND & AIMS This analysis reports the rate of sustained virological response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 or 4 who were assigned to 24 weeks of treatment with pegylated interferon (peginterferon) alfa-2a 180 mug/wk plus ribavirin 1000/1200 mg/day after achieving a rapid virological response (RVR; HCV RNA level <50 IU/mL) at week 4 in a prospective trial investigating response-guided therapy. METHODS Non-RVR patients with an early virological response were randomized to 48 or 72 weeks of therapy (this is a still-ongoing trial). RESULTS A total of 150 of 516 patients (29%) had an RVR, 143 of whom completed 24 weeks of treatment. Younger patients, leaner patients, and those with an HCV RNA level </=400,000 IU/mL and HCV genotype 4 infection were more likely to achieve an RVR; however, among patients with an RVR, no baseline factor predicted SVR. The SVR rate was 80.4% (115/143; 95% confidence interval [CI], 72.9-86.6) in patients who completed 24 weeks of treatment. The SVR rate was 86.7% (26/30; 95% CI, 69.3%-96.2%) in patients infected with genotype 4 and 78.8% in those infected with genotype 1 (89/113; 95% CI, 70.1%-85.9%; intent to treat: 89/120; 74.2%; 65.4-81.7%). Treatment was well tolerated. CONCLUSIONS This prospective study confirms that a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000/1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy.

Twice-weekly administration of peginterferon-alpha-2b improves viral kinetics in patients with chronic hepatitis C genotype 1.

Summary.  The decline in hepatitis C viral load on treatment with peginterferon‐α‐2b is not continuous. The aim of this study was to investigate whether twice weekly dosing of peginterferon‐α‐2b may improve viral kinetics. Ten interferon‐naïve patients with chronic hepatitis C (genotype 1a or b) were randomized to receive either 1.0 μg/kg peginterferon‐α‐2b once (group A) or twice weekly (group B) for 4 weeks. Viral load and serum concentrations of peginterferon‐α‐2b were measured. Peginterferon‐α‐2b reached maximal blood concentrations 24 h after the first dose, followed by a linear decline during the subsequent days. On the day before administration of the next dose, peginterferon‐α‐2b was undetectable in nine patients in group A (once weekly dosing). The same pattern was observed during the next 3 weeks of therapy. In group B (twice weekly dosing) peginterferon‐α‐2b was detectable at any given time point and higher than in group A (P between 0.01 and <0.0001). Viral load decreased in all patients within 2 days after the first dose of peginterferon‐α‐2b, but increased again on day 3. In group A, it further increased until day 7. A similar pattern was observed in the second week. In contrast, in group B, viral load decreased again on day 4 and remained lower until the end of the study (P < 0.001). To achieve continuous drug exposure and to improve initial viral clearance, peginterferon‐α‐2b has to be given at least two times weekly.

Relative impact of fatigue and subclinical cognitive brain dysfunction on health-related quality of life in chronic hepatitis C infection.

Objectives:To assess the relative impact of fatigue and subclinical cognitive brain dysfunction on the impairment of health-related quality of life (HRQL) in hepatitis C virus (HCV) infection. Design and methods:We performed a cross-sectional study in 120 patients with untreated chronic HCV infection to test the hypothesis that the severity of fatigue had an independent effect on HCV-associated impairment of HRQL. Patients were investigated using the short-form-36 questionnaire, the fatigue impact scale, the brief fatigue inventory, and P300 event-related potentials, as an objective correlate of neurocognitive function. Patients with decompensated cirrhosis or clinical depression were excluded. Results:Relative to healthy controls, HCV-infected patients showed significant levels of fatigue (Fatigue Impact Scale, 49 versus 26 points, brief fatigue inventory, 3.0 versus 1.6 points, P < 0.001). Fatigue impact scale and brief fatigue inventory scores were highly correlated (r = 0.77, P < 0.001), demonstrating concurrent validity. Severity of fatigue and age were the only factors independently associated with the impairment of HRQL (P < 0.001). Fatigue was not related to the severity of hepatitis or the degree of subclinical brain dysfunction. Conclusion:In untreated patients with chronic HCV infection, fatigue severity and age but not neurocognitive dysfunction or hepatic function are independently associated with impaired HRQL. Both the fatigue impact scale and the brief fatigue inventory are suitable tools to assess the subjective burden of fatigue. Our findings stress the need for effective therapeutic interventions to reduce the burden of fatigue in patients with HCV infection.

Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin.

BACKGROUND:Sudden hearing loss has been reported on standard interferon (IFN)-α2 therapy. This is the first report on the occurrence of sudden hearing loss in six cases of chronic hepatitis C in temporal relation to treatment with pegylated (PEG)-IFN alfa2a or b/ribavirin combination therapy. Three patients were treated in an ongoing randomized placebo–controlled trial comparing the addition of 200 mg amantadine or placebo to the combination of 180 μg PEG-IFN α2a (PEGASYS®, Roche, Basel, CH)/wk and 1–1.2 g ribavirin/d (COPEGUS®, Roche, Nutley, USA) in de novo patients infected with HCV genotype 1. Sudden hearing loss and tinnitus developed on day 1 and after 4, 23, 25, 36, and 40 wk of treatment, respectively.CONCLUSIONS:Sudden hearing loss may occur in about 1% of patients on PEG-IFN/ribavirin combination therapy. This rate was not different to that observed in an untreated population. Possible mechanisms involved include direct ototoxicity of IFN, autoimmunity, and hematological changes. In contrast to published cases on auditory disability due to standard IFN, hearing loss did not fully resolve after discontinuation of therapy with PEG-IFN. On the other hand, symptoms did not worsen on continued treatment. Therefore, the decision whether to continue or to stop the treatment when signs of ototoxicity appear is based on the clinical judgment of the treating physician.

Erythropoietin Treatment Is Associated with More Severe Thrombocytopenia in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy

BACKGROUND:Erythropoietin (EPO) not only stimulates erythropoiesis but also thrombopoiesis. As pegylated-interferon-α(PEG-IFN-α)-induced thrombocytopenia may become a limiting factor for continuation of therapy, the present study investigated if EPO can alleviate PEG-IFN-α induced thrombocytopenia. Further, we hypothesize that EPO increases platelet reactivity and protease activated receptor 1 (PAR-1) expression during combination antiviral therapy.METHODS:Forty patients with chronic hepatitis C received either 10,000 IU EPO 3×/week or placebo in a randomized, placebo-controlled, double-blinded fashion for 4 wk and combination antiviral therapy with PEG-IFN-2a and ribavirin.RESULTS:EPO alleviated the decrease in hemoglobin during combination antiviral therapy with ribavirin (10% vs 20%, p < 0.0001). Platelet counts decreased stronger in EPO than in placebo group on day 28 (p = 0.007). EPO induced a 40% increase in PAR-1 (p < 0.0001), which was accompanied by 100% increase in platelet reactivity (p < 0.0001). PFA-100 platelet plug formation time and PEG-IFN-α-induced vWF-increase were not different between study groups.CONCLUSIONS:Treatment with EPO alleviated the decrease in hemoglobin but worsened PEG-IFN-α induced thrombocytopenia after the first 4 wk of combination therapy. EPO caused PAR-1 receptor upregulation on platelets, which promoted an increase in platelet reactivity without affecting PFA-100 platelet plug formation time. EPO is not a useful option for short-term support of platelet production during antiviral therapy.

Hepatitis C viral dynamics: basic concept and clinical significance

Viral dynamics is a concept analyzing the time course of treatment-induced changes in blood virion concentration (kinetics) to derive conclusions of where, when and how in the living organism virions are produced or eliminated. Originally applied to human immunodeficiency virus type 1 and hepatitis B virus, it has elucidated mechanisms of antiviral therapy in hepatitis C virus infection as well. This review summarizes key aspects of mathematical modeling as well as important clinical applications, namely induction therapy and prediction of virologic response to treatment. Furthermore, limitations of currently available quantitative assays will be discussed.

798 VERY EARLY VIRAL KINETICS ON INTERFERON TREATMENT IN CHRONIC HEPATITIS C VIRUS GENOTYPE 4 INFECTION

BACKGROUND Interferon (IFN)-resistant hepatitis C virus strains limit efficacy of antiviral combination therapy in patients infected with genotypes 1 and 4. A single test dose of IFN was useful to identify non-responders to IFN-alpha2b/ribavirin (RBV) or likely non-responders to pegylated (PEG)-IFN-alpha2a/RBV therapy in genotype 1 patients. Our aim was to investigate this approach in genotype 4 patients. METHODS Viral load was measured in 46 patients before and 24 h after 10 megaunits (MU) IFN-alpha2b, and before and during 2 weeks of daily 5 MU IFN-alpha2b administration. Thereafter, patients received 48 weeks combination therapy with either 180 microg PEG-IFN-alpha2a/week (n=33), 1.5 microg/kg PEG-IFN-alpha2b/week (n=7) or 5 MU IFN-alpha2b/2 days (n=6), along with 1-1.2g RBV/day. For prediction analysis the largest group (PEG-IFN-alpha2a) was evaluated only. RESULTS Median 24 h log10 change after 10 MU IFN-alpha2b was 1.15 (range 0.08-2.48) and after 5 MU IFN-alpha2b was 0.81 (-0.12-2.22; P<0.0001). Log10 changes after 2 weeks on 5 MU IFN-alpha2b daily and 24 h after 10 MU were the best predictors of early virological response (defined by negativity of a standard qualitative PCR) to PEG-IFN-alpha2a/RBV combination therapy (area under curve [AUC]=0.97; P<0.001, receiver operating characteristics), 24 h log10 change after 10 MU was the best predictor of sustained virological response (SVR; AUC=0.91, P=0.001). CONCLUSION As in genotype 1 patients, there is large variation in IFN responsiveness, including the presence of resistant strains, in genotype 4 patients. A 24 h log10 change after 10 MU IFN-alpha2b is an excellent predictor of SVR on PEG-IFNalpha2a/RBV combination therapy. This test may be useful to obtain homogeneous groups for clinical studies and could help in clinical decision making.