Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alpha-2a and ribavirin.

UNLABELLED: Treatment response remains suboptimal for many patients with chronic hepatitis C, particularly those with genotype 1 and high levels of viremia. The efficacy of high-dose regimens of peginterferon alfa-2a and ribavirin was compared with conventional dose regimens in patients with features predicting poor treatment responses. Eligible treatment-naïve adults with genotype 1 infection, hepatitis C virus (HCV) RNA >800,000 IU/mL and body weight >85 kg were randomized to double-blind treatment with peginterferon alfa-2a at 180 or 270 microg/week plus ribavirin at 1200 or 1600 mg/day for 48 weeks (four regimens were evaluated). The primary endpoint was viral kinetics during the first 24 weeks of therapy. Among patients receiving peginterferon alfa-2a (270 microg/week) the magnitude of HCV RNA reduction was significantly greater than for patients randomized to the conventional dose of peginterferon alfa-2a (180 microg/week) for the pairwise comparison for ribavirin at 1600 mg/day (P = 0.036) and numerically greater for the pairwise comparison for ribavirin at 1200 mg/day (P = 0.060). Patients randomized to the highest doses of peginterferon alfa-2a (270 microg/week) and ribavirin (1600 mg/day) experienced the numerically highest rates of sustained virologic response (HCV RNA < 50 IU/mL) and the lowest relapse rate (47% and 19%, respectively). The arm with the higher doses of both drugs was less well-tolerated than the other regimens. CONCLUSION: Higher fixed doses of peginterferon alfa-2a (270 microg/week) and ribavirin (1600 mg/day) may increase sustained virologic response rates compared with lower doses of both drugs in patients with a cluster of difficult-to-treat characteristics.

Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.

BACKGROUND: Hepatitis C virus (HCV) infection is highly prevalent and is associated with substantial morbidity and mortality among persons infected with the human immunodeficiency virus (HIV). We compared the efficacy and safety of pegylated interferon alfa-2a (peginterferon alfa-2a) plus either ribavirin or placebo with those of interferon alfa-2a plus ribavirin for the treatment of chronic HCV infection in patients who were also infected with HIV. METHODS: A total of 868 persons who were infected with both HIV and HCV and who had not previously been treated with interferon or ribavirin were randomly assigned to receive one of three regimens: peginterferon alfa-2a (180 microg per week) plus ribavirin (800 mg per day), peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU three times a week) plus ribavirin. Patients were treated for 48 weeks and followed for an additional 24 weeks. The primary end point was a sustained virologic response (defined as a serum HCV RNA level below 50 IU per milliliter at the end of follow-up, at week 72). RESULTS: The overall rate of sustained virologic response was significantly higher among the recipients of peginterferon alfa-2a plus ribavirin than among those assigned to interferon alfa-2a plus ribavirin (40 percent vs. 12 percent, P<0.001), or peginterferon alfa-2a plus placebo (40 percent vs. 20 percent, P<0.001). Among patients infected with HCV genotype 1, the rates of sustained virologic response were 29 percent with peginterferon alfa-2a plus ribavirin, 14 percent with peginterferon alfa-2a plus placebo, and 7 percent with interferon alfa-2a plus ribavirin. The corresponding rates among patients infected with HCV genotype 2 or 3 were 62 percent, 36 percent, and 20 percent. Neutropenia and thrombocytopenia were more common among patients treated with regimens that contained peginterferon alfa-2a, and anemia was more common among patients treated with regimens containing ribavirin. CONCLUSIONS: Among patients infected with both HIV and HCV, the combination of peginterferon alfa-2a plus ribavirin was significantly more effective than either interferon alfa-2a plus ribavirin or peginterferon alfa-2a monotherapy.

Risk factors for hepatic decompensation in patients with HIV/HCV coinfection and liver cirrhosis during interferon-based therapy.

OBJECTIVE: Hepatic decompensation was reported from two recent trials (APRICOT and RIBAVIC) assessing interferon (IFN)-based treatment of hepatitis C virus (HCV) in HIV/HCV-coinfected patients. This paper identifies risk factors associated with hepatic decompensation in APRICOT. METHODS: APRICOT is a randomized, partially-blinded, controlled trial comparing treatment with peg-IFN alpha-2a 180 microg once weekly plus ribavirin/placebo 400 mg twice daily with IFN alpha-2a 3 million units three times weekly plus ribavirin 400 mg twice daily for 48 weeks in a total of 859 patients. Multiple logistic regression analysis was performed comparing the baseline characteristics of those cirrhotic patients who experienced decompensation with those of the other cirrhotic patients enrolled. RESULTS: Fourteen patients, all cirrhotic, experienced hepatic decompensation during the study. The incidence in the cirrhotic subgroup of the study was 10.4% (14/134). Six of the 14 patients died as a result of hepatic decompensation. The risk factors associated with hepatic decompensation were increased bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelets, and treatment with didanosine. Markers of viral replication, histological activity, cellular immune status or HCV-therapy, treatment with ribavirin and pegylated versus non-pegylated IFN were not associated with hepatic decompensation. CONCLUSIONS: The results from APRICOT indicate that the overall risk of hepatic decompensation in HIV/HCV-coinfected patients without cirrhosis receiving IFN-based treatment is low. In contrast, patients with markers of advanced cirrhosis, despite the absence of a history of hepatic decompensation, should be monitored closely during IFN-based therapy, because they are at risk of hepatic decompensation. Treatment with antiretrovirals such as didanosine may increase the risk further.

Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin.

AIM: To assess the likelihood of a sustained virological response (SVR) vs. the likelihood of anaemia in patients with chronic hepatitis C. METHODS: Data from 1732 patients treated with peginterferon alfa-2a (40KD) plus ribavirin in two randomized, multinational studies were pooled. Probabilities of SVR and anaemia were modelled using the generalized additive logistic model, with numerous clinical variables considered for entry into the model. Baseline haemoglobin was only considered in the analysis for anaemia. RESULTS: The probability of anaemia increased from 6 to 16% as a function of the ribavirin dose kg(-1) (12-16 mg kg(-1)), whereas the relationship between SVR and ribavirin dose kg(-1) was influenced by hepatitis C virus (HCV) genotype. The probability of an SVR was not influenced by the ribavirin dose kg(-1) in patients with HCV genotype 2 or 3 infection, but increased as a function of ribavirin dose kg(-1) in patients with HCV genotype 1 infection (40-50% increase in probability of SVR for 12-16 mg kg(-1) dose ribavirin increase). The probability of an SVR in patients included with HCV genotype 1 decreased with increasing HCV RNA level to about 3 million copies ml(-1), but was relatively independent of increasing HCV RNA level thereafter. In addition, older age, a higher ribavirin apparent oral clearance and cirrhosis had a negative impact on achieving an SVR, but improved with increasing alanine aminotransferase (ALT) quotient. Sex and ribavirin dose kg(-1) were the most important prognostic factors for anaemia, followed by baseline haemoglobin, age, baseline ALT quotient and cirrhosis. CONCLUSION: This study supports individualizing ribavirin dosages by HCV genotype and body weight, and highlights several clinical variables that influence the likelihood of an SVR compared with anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin.

Pharmacokinetics of ribavirin in patients with hepatitis C virus.

AIM: A population pharmacokinetic analysis was performed using plasma concentration data (n = 7025) from 380 patients to examine the relationship between ribavirin dose and its pharmacokinetics. METHODS: Ribavirin pharmacokinetics were described by a three-compartment model with sequential zero-order and a first-order absorption processes. Interoccasion variability and food effects were included. RESULTS: Lean body weight (range 41-91 kg) was the only covariate with a clinically significant influence on ribavirin pharmacokinetics, affecting clearance (15.3-23.9 l h(-1)) and the volume of the larger peripheral compartment. CONCLUSION: The model provided a good description of the available data, confirmed by accurate estimates of parameter values and low residual variability (17%).