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.

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

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-alpha(PEG-IFN-alpha)-induced thrombocytopenia may become a limiting factor for continuation of therapy, the present study investigated if EPO can alleviate PEG-IFN-alpha 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 x/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-alpha-induced vWF-increase were not different between study groups. CONCLUSIONS: Treatment with EPO alleviated the decrease in hemoglobin but worsened PEG-IFN-alpha 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.

Antiviral therapy decreases GpIIb/IIIa activation of platelets in patients with chronic hepatitis C.

Interferon alpha (IFN-alpha) is used to treat haematological and solid malignancies and is the gold standard therapy for chronic hepatitis C infection in combination with ribavirin. It has a well known platelet lowering effect and was recently shown to impair platelet aggregation in the presence of various agonists and has been accused to increase patients' bleeding risk during IFN-alpha therapy. Thus, we hypothesised that antiviral treatment decreases GpIIb/IIIa activation and affects global platelet function. In a prospective clinical trial, we examined the effects of combination therapy with pegylated IFN-alpha 2a (PegIFN-alpha 2a) and ribavirin on platelet GpIIb/IIIa activation and platelet secretion in 20 patients with chronic hepatitis C at week 2, 4, 8 and 12 after the beginning of therapy. In addition, we determined global platelet function (CEPI-CT) with the PFA-100 and vWF-Ag levels. Antiviral therapy significantly decreased GpIIb/IIIa activation in a time dependent manner, whereas markers of platelet secretion (P-selectin, beta-thromboglobulin) remained unchanged. Despite a marked elevation of vWF-Ag levels, CEPI-CT did not change compared to baseline levels. Antiviral therapy significantly decreases GpIIb/IIIa activation in patients with chronic hepatitis C, while vWG-Antigen levels are markedly increased and alpha-granule secretion is not affected. This does not result in an alteration of global platelet function as assessed by the PFA-100, because elevated vWF-Antigen levels might compensate for the acquired defect.

Prospective study of viral clearance and CD4(+) T-cell response in acute hepatitis C primary infection and reinfection.

BACKGROUND: The outcome of acute hepatitis C is determined by early host-virus interactions, particularly involving the antiviral T-cell response. OBJECTIVES: To identify early prognostic markers of spontaneous resolution of acute hepatitis C by performing a comprehensive analysis of viral and immunological factors during the natural course of acute HCV infection and reinfection. STUDY DESIGN: 20 patients were investigated prospectively during acute HC or confirmed reinfection and 18 of them during follow up after spontaneous or treatment-induced elimination of the virus and resolution of the disease. Multiparameter flow cytometry was used to functionally characterize virus-specific CD4(+) T-cell responses relative to the virologic outcome. RESULTS: Parallel immunologic and virologic monitoring of patients with acute HC identified distinct patterns of host-virus interaction related to HCV persistence or clearance. The highest frequency of antiviral Th1 cytokine-producing CD4(+) T-cells was observed in patients with HCV reinfection, preceding rapid viral clearance within 3 weeks after disease onset. In all patients who subsequently cleared viremia, CD4(+) T-cells produced Th1 cytokines following stimulation with non-structural HCV antigens (NS3 and NS4). In contrast, a chronic course of disease was associated with the absence of antiviral Th1 cytokine producing cells from the first weeks after onset of disease (acute persistent HC), or with fluctuating RNA levels (yo-yo pattern) and gradual waning of antiviral Th1 cells. CONCLUSIONS: The results highlight the variability of immune response pattern in acute hepatitis C. Most importantly, "acute persistent hepatitis C" and a lack of TH1 effector cells within the first months of acute hepatitis C represent efficacious predictors of viral persistence and could thus be used as criteria in selecting candidates for early antiviral treatment.

Tongue and skin hyperpigmentation during PEG-interferon-alpha/ribavirin therapy in dark-skinned non-Caucasian patients with chronic hepatitis C.

Various skin disorders may occur during antiviral therapy with interferon (IFN) and ribavirin (RBV) for chronic hepatitis C. This article describes to our knowledge the first report of lingual hyperpigmentation during pegylated (PEG)-IFN/RBV combination therapy in five dark-skinned hepatitis C virus (HCV) patients. Lingual pigmentation during antiviral therapy was not associated with age, gender, HCV genotype, doses of RBV, or duration of the treatment or treatment outcome. Since IFN increases the expression of alpha-melanocyte-stimulating hormone (MSH) surface receptors, the use of PEG-IFN having a longer plasma half-life may even increase incidence for such cutaneous side effects particularly in dark-skinned HCV patients.

Randomized, double-blind, placebo-controlled study of peginterferon alfa-2a (40KD) plus ribavirin with or without amantadine in treatment-naïve patients with chronic hepatitis C genotype 1 infection.

BACKGROUND/AIMS: Amantadine may augment virological response rates to interferon-based therapy in chronic hepatitis C patients. Using a novel design, amantadine was studied in naïve genotype 1 patients treated in combination with peginterferon alfa-2a (40KD)/ribavirin. METHODS: Patients enrolled in this randomized, placebo-controlled multicenter trial were stratified by single-dose interferon sensitivity (stratum I, 24-h HCV-RNA decline >1.4-log10; II, 0.8-1.39-log10; III, <0.8-log10; a reliable means of identifying nonresponders to interferon/ribavirin) and fibrosis grade (F0/1/2 vs. F3/4) at baseline. All patients received peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 1000-1200 mg/day and were randomized to receive amantadine 100 mg twice daily (N = 114) or placebo (N = 95) for 48 weeks. RESULTS: Week-24 virological response rates in strata II and III, the primary outcome, were similar in patients treated with amantadine (63.7%) or placebo (65.7%), as were sustained virological response rates at week 72 (46.5 and 51.6%, respectively). Adverse event profiles were similar and amantadine did not improve health-related quality of life compared with placebo. Interferon sensitivity was the only significant predictor of treatment outcome. CONCLUSIONS: Adding amantadine to peginterferon alfa-2a (40KD)/ribavirin combination therapy does not augment virological response rates in genotype 1 patients. Virological response was almost exclusively determined by interferon sensitivity at baseline.

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)-alpha2 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 microg PEG-IFN alpha2a (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.

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.

The impact of positive peritoneal washings and serosal and adnexal involvement on survival in patients with stage IIIA uterine cancer.

OBJECTIVE: The aim of this study was to determine the prognostic significance of serosal involvement (SER), adnexal involvement (ADN), and positive peritoneal washings (PPW) in patients with Stage IIIA uterine cancer. We also sought to determine patterns of recurrence in patients with this disease. METHODS: The records of 136 patients with Stage IIIA uterine cancer treated at the Queensland Centre for Gynecological Cancer between March 1983 and August 2001 were reviewed. One hundred thirty-six patients underwent surgery and 58 (42.6%) had full surgical staging. Seventy-five patients (55.2%) had external beam radiotherapy and/or brachytherapy postoperatively. Overall survival was the primary statistical endpoint. Statistical analysis included univariate and multivariate Cox models. RESULTS: Forty-six patients (33.8%) had adnexal involvement, 23 (16.9%) had serosal involvement, and 40 (29.4%) had positive peritoneal washings. Median follow-up was 55.1 months (95% confidence interval, 36.9 to 73.4 months) after which time 71 patients (52.2%) remained alive. For patients with endometrioid adenocarcinoma, ADN and SER were associated with impaired survival on multivariate analysis (odds ratio 2.8 and 3.2, respectively). In the subgroup of patients with high-risk tumors (including papillary serous carcinomas, clear cell carcinomas, and uterine sarcomas), neither ADN, nor SER, nor PPW influenced survival. CONCLUSION: Patients with Stage IIIA uterine cancer constitute a heterogeneous group. For patients with endometrioid adenocarcinoma, both ADN and SER, but not PPW, were associated with impaired prognosis. For patients with high-risk histological types, prognosis is poor for all three factors.