Faculty Bibliography

Within the last year, the landscape of therapy for genotype 1 chronic hepatitis C virus (HCV) has changed dramatically as 2 much-anticipated protease inhibitors became available for use. These agents, telaprevir and boceprevir, when used in combination with pegylated interferon and ribavirin, offer patients an improved chance of cure and the opportunity for a shorter duration of therapy. Although these medications represent a significant achievement in the battle against HCV, they do not represent the final phase in the evolution of HCV therapy. Many other direct-acting antiviral agents representing several classes, as well as agents that act via host-mediated pathways, are in development. Recent proof of concept studies demonstrating the capacity to eradicate HCV without interferon signal the potential for yet another quantum leap in the field.

The aim of this study is to review clinical trial data on the newly approved protease inhibitors boceprevir and telaprevir to develop consensus recommendations on the optimal use of these agents for the treatment of patients with chronic hepatitis C virus (HCV) infection. An expert panel of seven leading authorities in viral hepatitis was convened to establish and disseminate a practical guide on best practices for incorporating boceprevir and telaprevir into therapy for HCV infection in both treatment-naive and treatment-experienced patients. The topics covered include selecting candidates for boceprevir- or telaprevir-based treatments, predictors of response and early viral kinetics, response-guided therapy approaches, on-treatment management strategies to optimize the likelihood of response and minimize the risk of drug resistance, management of adverse effects during therapy and key considerations for special populations. The expert panel incorporated the best available clinical evidence into recommendations on how boceprevir and telaprevir should be used in the clinical setting. They indicated how treatment regimens may differ according to the baseline factors, such as presence of cirrhosis and when therapy may need to be modified or stopped altogether because of adverse events or poor virologic response. This practical guide will serve as a valuable resource for clinicians embarking on the new treatment paradigm of boceprevir or telaprevir in combination with peginterferon/ribavirin for chronic genotype 1 HCV infection.

Albinterferon alfa-2b (albIFN) is a fusion protein of recombinant human albumin/recombinant interferon (IFN)-alpha-2b, with approximately 200-h half-life. Safety/efficacy of albIFN q4wk was evaluated in 391 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 2/3. Patients were randomized 3:4:4:4 to one of four open-label treatment groups: pegylated IFN (Peg-IFN)-alpha-2a 180 mug qwk or albIFN 900, 1200 or 1500 mug q4wk, plus oral ribavirin 800 mg/day, for 24 weeks. Primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <20 IU/mL 24 weeks post-treatment). SVR rates were as follows: 85%, 76%, 76% and 78% with Peg-IFNalpha-2a and albIFN 900, 1200 and 1500 mug, respectively (P = NS); corresponding rapid virologic response rates (HCV RNA <43 IU/mL at week 4) were as follows: 78%, 49% (P < 0.001), 60% (P = 0.01) and 71%. SVR rates were not influenced by interleukin 28B genotype, although rapid virologic response rates were greater with interleukin 28B CC (P = NS). Serious adverse event rates were as follows: 4%, 11%, 3% and 3% with Peg-IFNalpha-2a and albIFN 900, 1200 and 1500 mug, respectively. No increase in serious/severe respiratory events was noted with albIFN. Fewer absolute neutrophil count reductions <750/mm(3) occurred with albIFN (P = 0.03), leading to fewer IFN dose reductions. Haemoglobin reductions <10 g/dL were less frequent with albIFN 900 and 1200 mug vs 1500 mug and Peg-IFNalpha-2a (P = 0.02), leading to fewer ribavirin dose reductions. albIFN administered q4wk produced fewer haematologic reductions than Peg-IFNalpha-2a, but had numerically lower SVR rates (P = NS) in patients with chronic HCV genotype 2/3.

BACKGROUND & AIMS: Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection. METHODS: We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 x 10(-5) from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance. RESULTS: In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P(combined) = 8.9 x 10(-9) and 1.1 x 10(-9), respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (P(combined) = 5.4 x 10(-7)), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages. CONCLUSIONS: Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.

BACKGROUND: Shortened courses of treatment with pegylated interferon alfa and ribavirin for patients with hepatitis C virus infection who experience rapid virologic response can be effective in appropriately selected patients. The cost-effectiveness of truncated therapy is not known. OBJECTIVE: To assess the cost-effectiveness of response-guided therapy versus standard-duration therapy on the basis of best available evidence. METHODS: We developed a decision model for chronic hepatitis C virus infection representing two treatment strategies: 1) standard-duration therapy with pegylated interferon alfa and ribavirin for 48 weeks in patients with genotype 1 or 4 and for 24 weeks in patients with genotype 2 or 3 and 2) truncated therapy (i.e., 50% decrease in treatment duration) in patients with rapid virologic response. Patients for whom truncated therapy failed began standard-duration therapy guided by genotype. We used a Markov model to estimate lifetime costs and quality-adjusted life-years. RESULTS: In the base-case analysis, mean lifetime costs were $46,623 +/- $2,483 with standard-duration therapy and $42,354 +/- $2,489 with truncated therapy. Mean lifetime quality-adjusted life-years were similar between the groups (17.1 +/- 0.7 with standard therapy; 17.2 +/- 0.7 with truncated therapy). Across model simulations, the probability of truncated therapy being economically dominant (i.e., both cost saving and more effective) was 78.6%. The results were consistent when we stratified the data by genotype. In one-way sensitivity analyses, the results were sensitive only to changes in treatment efficacy. CONCLUSION: Truncated therapy based on rapid virologic response is likely to be cost saving for treatment-naive patients with chronic hepatitis C virus infection. Cost-effectiveness varied with small changes in relative treatment efficacy.