Faculty Bibliography

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) alpha-2b or IFN alpha-2b. We conducted two phase 3b long-term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN alpha-2b and/or PEG-IFN alpha-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN alpha-2b and 366 with SVR following treatment with PEG-IFN alpha-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN alpha-2b and three patients treated with PEG-IFN alpha-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1-99.7%] for IFN alpha-2b and 99.4% (95% CI, 97.7-99.9%) for PEG-IFN alpha-2b. Successful treatment of hepatitis C with PEG-IFN alpha-2b or IFN alpha-2b leads to clinical cure of hepatitis C in the vast majority of cases.

Vaniprevir is a competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease that has potent anti-HCV activity in preclinical models. This placebo-controlled dose-ranging study assessed the safety, tolerability, and antiviral efficacy of vaniprevir monotherapy in patients with genotype 1 chronic HCV infection. Treatment-naive and treatment-experienced non-cirrhotic adult patients with baseline HCV RNA >10(6)IU/ml were randomized to receive placebo or vaniprevir at doses of 125 mg qd, 600 mg qd, 25mg bid, 75 mg bid, 250 mg bid, 500 mg bid, and 700 mg bid for 8 days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log(1)(0)IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg bid. The most commonly reported drug-related adverse events (AEs) were diarrhea (n=5) and nausea (n=5). No pattern of laboratory or ECG abnormalities was observed, all AEs resolved during the study, and there were no discontinuations due to AEs. No serious AEs were reported. Resistance-associated amino acid variants were identified at positions R155 and D168 in patients infected with genotype 1a virus. Vaniprevir monotherapy demonstrated potent antiviral activity in patients with chronic genotype 1 HCV infection, and was generally well tolerated with no serious AEs or discontinuations due to AEs. Further development of vaniprevir, including studies in combination with other anti-HCV agents, is ongoing.

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNalpha-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNalpha-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 mug q4wk or Peg-IFNalpha-2a 180 mug qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (>/=15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNalpha-2a and albIFN 1500 mug; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNalpha-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNalpha/ribavirin therapy and commonly persisted for >/=6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.

UNLABELLED: The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)-alpha-2a and ribavirin (RBV) in treatment-naive patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV. CONCLUSION: SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks.