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Re-treatment of Chronic Hepatitis C Virus Genotype 1 Infection After Relapse: An Open-Label Pilot StudyRe-treatment of Chronic HCV Genotype 1 Infection After Relapse

Anu Osinusi, MD; Anita Kohli, MD; Miriam M. Marti, BS; Amy Nelson, RN; Xiaozhen Zhang, MS; Eric G. Meissner, MD, PhD; Rachel Silk, RN; Kerry Townsend, BA; Phillip S. Pang, MD, PhD; G. Mani Subramanian, MD, PhD; John G. McHutchison, MD; Anthony S. Fauci, MD; Henry Masur, MD; and Shyam Kottilil, MD, PhD
[+] Article, Author, and Disclosure Information

From the Institute of Human Virology, University of Maryland, Baltimore, Maryland; Laboratory of Immunoregulation, NIAID, NIH Clinical Center, Bethesda, Maryland; Leidos Biomedical Research and Frederick National Laboratory for Cancer Research, Frederick, Maryland; and Gilead Sciences, Foster City, California.

Presented in part at The International Liver Congress, European Association for the Study of the Liver, London, United Kingdom, 9–13 April 2014.

Note: Drs. Osinusi and Kottilil had full access to all data in the study and take responsibility for the integrity and accuracy of the data analysis. Drs. Kottilil, Osinusi, and Masur and Ms. Marti had unrestricted access to the data and wrote the manuscript. Subsequent drafts of the manuscript reflect comments from all coauthors. All authors reviewed and approved the final manuscript.

Disclaimer: The views or policies of the U.S. Department of Health and Human Services are not necessarily reflected in this article. The U.S. government does not endorse any trade names, commercial products, or organizations mentioned.

Acknowledgment: The authors thank Katie Watkins, BS, and Erin Rudzinski, BS (clinical monitoring support); Judith Starling, PharmD (pharmacy); Michelle Chakrabarti, BS, Jerome Pierson, PhD, and John Tierney, BSN, MPM (regulatory support); William Ronnenberg, JD/MIP, MS, Richard Williams, PhD, and Mike Mowatt, PhD (technology transfer support); Marc Teitelbaum, MD, CPI (sponsor medical monitor); John Powers, MD (oversight); Cathy Rehm, Sara Jones, David Wu, BS, Leighton Daigh, BS, Zayani Sims, BS, and Jessica Johl, BS (laboratory support); and Colleen Kotb, RN, NP, Chloe Gross, BSN, Angie Price, NP, Richard Kwan, PA, Tess Petersen, BS, Sreetha Sidharthan, BS, Olivia Fankuchen, BS, Michelle Espinosa, and Rama Kapoor, MD (clinical support).

Grant Support: In part by the National Cancer Institute, NIH (contract HHSN261200800001E), intramural programs of the NIH Clinical Center and NIAID, and a Collaborative Research and Development Agreement between the NIH and Gilead Sciences. The study was sponsored by the Regulatory Compliance and Human Participants Protection Branch of the NIAID. All study medications were provided by Gilead Sciences.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1211.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Kottilil (email, skottilil@niaid.nih.gov).

Requests for Single Reprints: Shyam Kottilil, MD, PhD, National Institutes of Health, 10/11N204, 9000 Rockville Pike, Bethesda, MD 20892; e-mail, skottilil@niaid.nih.gov.

Current Author Addresses: Drs. Osinusi, Pang, Subramanian, and McHutchison: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404.

Dr. Kohli: National Institutes of Health, 10/11C442, 9000 Rockville Pike, Bethesda, MD 20892.

Ms. Marti: 91 Huntington Avenue, LWR1, Buffalo, NY 14214.

Ms. Nelson and Ms. Zhang and Dr. Kottilil: National Institutes of Health, 10/11N204, 9000 Rockville Pike, Bethesda, MD 20892.

Dr. Meissner: 856 Parrott Creek Way, Charleston, SC 29412.

Ms. Silk: 5415 West Cedar Lane, Suite 203, Bethesda, MD 20814.

Ms. Townsend: University of Maryland Health Center, 725 West Lombard Street, Baltimore, MD 21201.

Dr. Fauci: National Institutes of Health, 31/7A03, 9000 Rockville Pike, Bethesda, MD 20892.

Dr. Masur: National Institutes of Health, 10/2C145, 9000 Rockville Pike, Bethesda, MD 20892.

Author Contributions:Conception and design: A. Osinusi, A. Kohli, J.G. McHutchison, A.S. Fauci, H. Masur, S. Kottilil.

Analysis and interpretation of the data: A. Osinusi, A. Kohli, M.M. Marti, E.G. Meissner, K. Townsend, P.S. Pang, G.M. Subramanian, J.G. McHutchison, A.S. Fauci, H. Masur, S. Kottilil.

Drafting of the article: A. Osinusi, A. Kohli, M.M. Marti, A.S. Fauci, H. Masur, S. Kottilil.

Critical revision of the article for important intellectual content: A. Osinusi, A. Kohli, E.G. Meissner, G.M. Subramanian, J.G. McHutchison, A.S. Fauci, H. Masur, S. Kottilil.

Final approval of the article: A. Osinusi, A. Kohli, P.S. Pang, G.M. Subramanian, J.G. McHutchison, A.S. Fauci, H. Masur, S. Kottilil.

Provision of study materials or patients: A. Kohli, H. Masur, S. Kottilil.

Statistical expertise: S. Kottilil.

Obtaining of funding: H. Masur, S. Kottilil.

Administrative, technical, or logistic support: A. Kohli, A. Nelson, E.G. Meissner, P.S. Pang, H. Masur, S. Kottilil.

Collection and assembly of data: A. Osinusi, A. Kohli, M.M. Marti, A. Nelson, X. Zhang, R. Silk, K. Townsend, A.S. Fauci, S. Kottilil.

Ann Intern Med. 2014;161(9):634-638. doi:10.7326/M14-1211
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Background: The interferon (IFN)–free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV) genotype 1 (GT-1) infection for patients ineligible for IFN. However, sofosbuvir plus ribavirin therapy is associated with relapse in 15% to 30% of patients with HCV GT-1. Neither the mechanism of relapse nor the optimal re-treatment strategy for these patients is defined.

Objective: To assess the safety and efficacy of sofosbuvir plus ledipasvir in patients with chronic HCV GT-1 that relapsed after sofosbuvir plus ribavirin therapy.

Design: Phase 2a, open-label study. (ClinicalTrials.gov: NCT01805882)

Setting: Single U.S site.

Patients: 14 patients with HCV GT-1 that relapsed after treatment with sofosbuvir plus ribavirin for 24 weeks were re-treated with sofosbuvir plus ledipasvir for 12 weeks.

Measurements: HCV RNA concentration and population sequencing to detect NS5B S282T mutations.

Results: All 14 patients treated with sofosbuvir plus ledipasvir for 12 weeks achieved a sustained virologic response, including 7 with advanced liver disease (Knodell Histology Activity Index score of 3 or 4) and 1 with a detectable NS5B S282T mutation after sofosbuvir plus ribavirin therapy. Sofosbuvir plus ledipasvir was well-tolerated with few adverse events. Four grade 3 events (elevated serum creatinine in a patient with baseline renal insufficiency, hypercholesterolemia, and hypophosphatemia) occurred. There were no grade 4 events or treatment discontinuations.

Limitation: Small sample size.

Conclusion: The fixed-dose combination of sofosbuvir plus ledipasvir was efficacious in a small cohort of patients with HCV GT-1 that relapsed after sofosbuvir plus ribavirin therapy, even in the setting of advanced liver disease. Larger studies are needed to confirm these preliminary efficacy results.

Primary Funding Source: National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Cancer Institute, and Gilead Sciences.





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