Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial

Journal of the American Medical Association

Preliminary Communication | August 28, 2013

Anuoluwapo Osinusi, MD, MPH^1,2; Eric G. Meissner, MD, PhD¹; Yu-Jin Lee¹; Dimitra Bon, MS³; Laura Heytens, RN⁴; Amy Nelson, RN¹; Michael Sneller, MD¹; Anita Kohli, MD¹; Lisa Barrett, MD, PhD¹; Michael Proschan, PhD⁵; Eva Herrmann, PhD³; Bhavana Shivakumar, MS¹; Wenjuan Gu, PhD⁶; Richard Kwan, PAC⁴; Geb Teferi, MD⁷; Rohit Talwani, MD⁸; Rachel Silk, RN²; Colleen Kotb, RN²; Susan Wroblewski, RN¹; Dawn Fishbein, MD⁹; Robin Dewar, PhD⁶; Helene Highbarger, MS⁶; Xiao Zhang, MS¹; David Kleiner, MD¹⁰; Brad J. Wood, MD¹¹; Jose Chavez, MD⁷; William T. Symonds, PharmD¹²; Mani Subramanian, MD, PhD¹²; John McHutchison, MD¹²; Michael A. Polis, MD, MPH¹; Anthony S. Fauci, MD¹; Henry Masur, MD⁴; Shyamasundaran Kottilil, MD, PhD¹

[+-] Author Affiliations

¹Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
²Clinical Research Directorate/Clinical Monitoring Research Program, Science Applications International Corp (SAIC)–Frederick Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
³Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, Frankfurt, Germany
⁴Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, Maryland
⁵Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
⁶SAIC-Frederick Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
⁷Unity Health Care Inc, Washington, DC
⁸Department of Infectious Diseases, University of Maryland, Baltimore
⁹Department of Infectious Diseases, MedStar Washington Hospital Center, Washington, DC
¹⁰Department of Pathology, National Cancer Institute, Bethesda, Maryland
¹¹Center for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center and National Cancer Institute, Bethesda, Maryland
¹²Gilead Sciences, Foster City, California

JAMA. 2013;310(8):804-811. doi:10.1001/jama.2013.109309.

Abstract

Objective  To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics.

Design, Setting, and Patients  Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012).

Interventions  In the study’s first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks.

Main Outcomes and Measures  The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR₂₄]).

Results  In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR_24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR₂₄ rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.

Conclusion and Relevance  In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR₂₄ rates of 68% and 48%, respectively.

Trial Registration  clinicaltrials.gov Identifier: NCT01441180

Source

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