Faculty Bibliography

With an estimated prevalence of about 170 million people worldwide, chronic hepatitis C is an important cause of chronic liver disease associated with a substantial risk of cirrhosis and hepatocellular carcinoma. The recent past has borne witness to remarkable advancements in the treatment of chronic hepatitis C with the development of novel, effective, and well tolerated medications that have resulted in paradigm shifts in treatment approaches and may potentially affect the natural history of the disease. We provide a clinical review of current concepts and future developments in the management of chronic hepatitis C to aid in the understanding and individualization of chronic hepatitis C treatment. J. Med. Virol. 88:1844-1855, 2016. (c) 2016 Wiley Periodicals, Inc.

BACKGROUND & AIMS: The best regimen to re-treat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus genotype 1 infection. METHODS: We performed an open-label trial at 32 sites in the United States and at 2 sites in New Zealand of 197 patients with genotype 1 hepatitis C virus infection, with or without compensated cirrhosis, who were treatment-naive or were treated previously with a DAA. Between March 2, 2015, and September 1, 2015, patients received sofosbuvir-velpatasvir (400 mg/100 mg in a fixed-dose combination) plus GS-9857 (100 mg) once daily for 6-12 weeks, plus ribavirin for 1 treatment group consisting of treatment-naive patients with cirrhosis. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: Among treatment-naive patients without cirrhosis, 71% (24 of 34; 95% confidence interval [CI], 53-85) achieved SVR12 after 6 weeks of treatment and 100% (36 of 36; 95% CI, 90%-100%) achieved SVR12 after 8 weeks of treatment. Among treatment-naive patients with cirrhosis, 94% (31 of 33; 95% CI, 80-99) achieved SVR12 after 8 weeks of treatment and 81% (25 of 31; 95% CI, 63-93) achieved SVR12 after 8 weeks of treatment with ribavirin. Among DAA-experienced patients treated for 12 weeks, 100% without cirrhosis (31 of 31; 95% CI, 89-100) and 100% with cirrhosis (32 of 32; 95% CI, 89-100) achieved SVR12. The most common adverse events were headache, diarrhea, fatigue, and nausea. One patient (<1%) discontinued treatment because of adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found 8 weeks of treatment with sofosbuvir-velpatasvir plus GS-9857 to be safe and effective in treatment-naive patients; 12 weeks was safe and effective in patients previously treated with DAAs. The combination was safe and effective in patients with or without compensated cirrhosis. Clinicaltrials.gov no: NCT02378935.

BACKGROUND: Fibrosis progression varies markedly in hepatitis C virus (HCV)-infected individuals. We investigated factors that influence fibrosis progression in chronic HCV infection. METHODS: HCV-infected patients who underwent at least 2 liver biopsies were included in this study. Associations between fibrosis progression and epidemiologic, virologic, and disease-associated factors were analyzed using logistic regression and multistate Markov modeling. RESULTS: We analyzed 936 biopsy specimens obtained from 378 individuals. Mean age (+/-SD) at first biopsy was 48.3 +/- 9.3 years, 59.3% of patients were male, 59.9% were white, and 86.7% were infected with HCV genotype 1. Fibrosis progression and cirrhosis occurred in 57.4% and 5.8%, respectively. Fibrosis progression between the first and last biopsies was associated with lower fibrosis in the first biopsy specimen (P < .001) and with the occurrence of at least 1 flare in the alanine aminotransferase (ALT) level (>200 U/L; P = .007). We found the highest fibrosis progression rate between stages 0 and 1 and the lowest between stages 2 and 3. Increased necroinflammation and higher ALT level were associated with faster progression. HCV genotype 3-infected patients were more likely to progress to cirrhosis (P < .001). CONCLUSIONS: Fibrosis progression in HCV is not linear but varies according to stage, with the highest progression in patients with the lowest fibrosis severity. Patients who experience flares in the ALT level are also more likely to progress.