Successful retreatment of chronic HCV genotype-1 infection with ledipasvir and sofosbuvir after initial short course therapy with direct-acting antiviral regimens

Eleanor M. Wilson, Sarah Kattakuzhy, Sreetha Sidharthan, Zayani Sims, Lydia Tang, Mary Mclaughlin, Angie Price, Amy Nelson, Rachel Silk, Chloe Gross, Elizabeth Akoth, Hongmei Mo, G. Mani Subramanian, Phillip S. Pang, John G. Mchutchison, Anu Osinusi, Henry Masur, Anita Kohli, Shyam Kottilil

Research output: Contribution to journalArticle

Abstract

Background. The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. Methods. In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. Results. Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 106 IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed. Conclusions. In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants.

Original languageEnglish (US)
Pages (from-to)280-288
Number of pages9
JournalClinical Infectious Diseases
Volume62
Issue number3
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

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Retreatment
Chronic Hepatitis C
Hepacivirus
Antiviral Agents
Genotype
Infection
Viral Load
Recurrence
Therapeutics
High-Throughput Nucleotide Sequencing
sofosbuvir drug combination ledipasvir
Liver Cirrhosis
Fibrosis
Technology
Safety

Keywords

  • direct-acting antiviral agents
  • hepatitis C
  • ledipasvir.
  • retreatment
  • sofosbuvir

ASJC Scopus subject areas

  • Infectious Diseases
  • Microbiology (medical)

Cite this

Successful retreatment of chronic HCV genotype-1 infection with ledipasvir and sofosbuvir after initial short course therapy with direct-acting antiviral regimens. / Wilson, Eleanor M.; Kattakuzhy, Sarah; Sidharthan, Sreetha; Sims, Zayani; Tang, Lydia; Mclaughlin, Mary; Price, Angie; Nelson, Amy; Silk, Rachel; Gross, Chloe; Akoth, Elizabeth; Mo, Hongmei; Subramanian, G. Mani; Pang, Phillip S.; Mchutchison, John G.; Osinusi, Anu; Masur, Henry; Kohli, Anita; Kottilil, Shyam.

In: Clinical Infectious Diseases, Vol. 62, No. 3, 01.02.2016, p. 280-288.

Research output: Contribution to journalArticle

Wilson, EM, Kattakuzhy, S, Sidharthan, S, Sims, Z, Tang, L, Mclaughlin, M, Price, A, Nelson, A, Silk, R, Gross, C, Akoth, E, Mo, H, Subramanian, GM, Pang, PS, Mchutchison, JG, Osinusi, A, Masur, H, Kohli, A & Kottilil, S 2016, 'Successful retreatment of chronic HCV genotype-1 infection with ledipasvir and sofosbuvir after initial short course therapy with direct-acting antiviral regimens', Clinical Infectious Diseases, vol. 62, no. 3, pp. 280-288. https://doi.org/10.1093/cid/civ874
Wilson, Eleanor M. ; Kattakuzhy, Sarah ; Sidharthan, Sreetha ; Sims, Zayani ; Tang, Lydia ; Mclaughlin, Mary ; Price, Angie ; Nelson, Amy ; Silk, Rachel ; Gross, Chloe ; Akoth, Elizabeth ; Mo, Hongmei ; Subramanian, G. Mani ; Pang, Phillip S. ; Mchutchison, John G. ; Osinusi, Anu ; Masur, Henry ; Kohli, Anita ; Kottilil, Shyam. / Successful retreatment of chronic HCV genotype-1 infection with ledipasvir and sofosbuvir after initial short course therapy with direct-acting antiviral regimens. In: Clinical Infectious Diseases. 2016 ; Vol. 62, No. 3. pp. 280-288.
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abstract = "Background. The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. Methods. In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. Results. Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 106 IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85{\%}) had NS5A-resistant variants. The SVR12 rate was 91{\%} (31/34; intention to treat, ITT) after retreatment. One patient relapsed. Conclusions. In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants.",
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AU - Wilson, Eleanor M.

AU - Kattakuzhy, Sarah

AU - Sidharthan, Sreetha

AU - Sims, Zayani

AU - Tang, Lydia

AU - Mclaughlin, Mary

AU - Price, Angie

AU - Nelson, Amy

AU - Silk, Rachel

AU - Gross, Chloe

AU - Akoth, Elizabeth

AU - Mo, Hongmei

AU - Subramanian, G. Mani

AU - Pang, Phillip S.

AU - Mchutchison, John G.

AU - Osinusi, Anu

AU - Masur, Henry

AU - Kohli, Anita

AU - Kottilil, Shyam

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N2 - Background. The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. Methods. In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. Results. Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 106 IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed. Conclusions. In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants.

AB - Background. The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. Methods. In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. Results. Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 106 IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed. Conclusions. In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants.

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