Faculty Bibliography

The HCV council 2011 convened 11 leading clinicians and researchers in hepatitis C virus from academic medical centers in the United States to provide a forum for the practical and comprehensive evaluation of current data regarding best practices for integrating new direct-acting antiviral agents into existing treatment paradigms. The council investigated 10 clinical practice statements related to HCV treatment that reflect key topical areas. Faculty members reviewed and discussed the data related to each statement, and voted on the nature of the evidence and their level of support for each statement. In this new era of DAAs, a comprehensive and critical analysis of the literature is needed to equip clinicians with the knowledge necessary to design, monitor, and modify treatment regimens in order to optimize patient outcomes.

Mericitabine (RG7128), an orally administered prodrug of PSI-6130, is the most clinically advanced nucleoside analogue inhibitor of the RNA-dependent RNA polymerase (RdRp) of HCV. This review describes what has been learnt so far about the resistance profile of mericitabine. A serine to threonine substitution at position 282 (S282T) of the RdRp that reduces its replication capacity to approximately 15% of wild-type is the only variant that has been consistently generated in serial in vitro passage experiments. To date, no evidence of genotypic resistance to mericitabine has been detected by population or clonal sequence analysis in any baseline or on-treatment samples collected from >600 patients enrolled in Phase I/II trials of mericitabine administered as monotherapy, in combination with pegylated interferon/ribavirin, or in combination with the protease inhibitor, danoprevir, for 14 days in the proof-of-concept study of interferon-free therapy.

BACKGROUND: Pegylated-interferon (PEG-IFN) and ribavirin (RBV), current standard treatment for hepatitis C virus (HCV) infection, are frequently associated with neutropenia and anemia, leading to high treatment discontinuation rates in HIV/HCV-coinfected patients. Our objective was to compare the effectiveness of intervening with hematologic growth factors versus dose reductions of standard HCV therapy for the management of treatment-induced hematologic disorders. METHODS: Ninety-two HIV/HCV-coinfected, therapy-naive subjects received PEG-IFN alfa-2b 1.5 mug.kg(1).wk(1) and RBV 13 +/- 2 mg.kg(1).d(1) for up to 48 weeks. Before treatment initiation, subjects were randomized to subsequently receive growth factors, recombinant human erythropoietin (rHuEPO) and/or granulocyte colony-stimulating factor, or dose reduction (RBV and/or PEG-IFN) for anemia and neutropenia management, respectively. We analyzed the ability of each management strategy to control anemia and neutropenia and the percentage of subjects who achieved a successful treatment outcome according to the different management strategies. RESULTS: During treatment, 43 subjects developed anemia (human erythropoietin, n = 24; dose reduction, n = 19), whereas 25 subjects developed neutropenia (granulocyte colony-stimulating factor, n = 10; dose reduction, n = 15). After the intervention, the increase in both hemoglobin and absolute neutrophil counts did not differ between the 2 side effect management strategies. Sustained response percentages were similar comparing anemic and neutropenic subjects regardless of management strategy (anemia: recombinant human erythropoietin, 29% versus dose reduction, 21%, P = 0.92; neutropenia: granulocyte colony-stimulating factor, 40% versus dose reduction, 20%, P = 0.46). CONCLUSIONS: Growth factor supplementation and dose reduction do not seem to differ as management strategies for anemia and neutropenia in HIV/HCV-coinfected individuals treated with PEG-IFN/RBV

New treatments for chronic hepatitis C combining direct-acting antivirals (DAAs) with pegylated interferon and ribavirin (PEG-IFN/RBV) have dramatically increased the number of patients whose viral load declines to undetectable levels early in treatment. Most go on to achieve a sustained virologic response, but some patients who maintain undetectable levels of virus throughout treatment later relapse during follow-up. These data suggest that hepatitis C virus (HCV) genomes may persist in form(s) that are refractory to eradication by DAAs and PEG-IFN/RBV. Here we examine the molecular biology of HCV replication and review the clinical virology of relapse for clues as to how the virus might survive months of antiviral therapy to later reappear when treatment is withdrawn.