Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study

Author(s): Kohli A, Kapoor R2, Sims Z3, Nelson A4, Sidharthan S3, et al.

Abstract

Background: Worldwide, although predominantly in low-income countries in the Middle East and Africa, up to 13% of hepatitis C virus (HCV) infections are caused by HCV genotype 4. For patients with HCV genotype 1, the combination of ledipasvir and sofosbuvir has been shown to cure high proportions of patients with excellent tolerability, but this regimen has not been assessed for the treatment of HCV genotype 4. We assessed the efficacy, safety, and tolerability of 12 weeks of combination therapy with ledipasvir and sofosbuvir for patients with chronic HCV genotype 4 infections.

Methods: In this single-centre, open-label cohort, phase 2a trial, patients with HCV genotype 4 who were treatment naive or interferon treatment experienced (HIV-negative) were sequentially enrolled at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA. We gave patients 12 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) as a single combination tablet once per day. The primary efficacy endpoint was sustained viral response at 12 weeks (SVR12), as measured by the proportion of patients with HCV RNA concentrations less than the lower limit of quantification (COBAS TaqMan HCV test, version 1.0, 43 IU/mL). The primary safety endpoint was the frequency and severity of adverse events. We did our analyses on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01805882.

Findings: Between Sept 16, 2013, and Nov 2, 2014, we recruited 21 patients. 20 (95%) of 21 patients completed 12 weeks of treatment and achieved SVR12 (95% CI 76-100), including seven patients with cirrhosis. One patient was non-adherent to study drugs and withdrew from the study, but was included in the intention-to-treat analysis. No patients discontinued treatment because of adverse events and no grade 3 or 4 adverse events occurred that were related to study medications. The most common adverse events were diarrhoea (two patients), fatigue (three patients), nausea (two patients), and upper respiratory infections (two patients).

Interpretation: Ledipasvir and sofosbuvir treatment for 12 weeks was well tolerated by patients with HCV genotype 4 and resulted in 100% SVR for all patients who received all 12 weeks of study drugs, irrespective of previous treatment status and underlying liver fibrosis. This is the first report of a single-pill, all-oral, interferon-free, ribavirin-free treatment for patients with HCV genotype 4.

Funding: NIAID, National Cancer Institute and Clinical Center Intramural Program. The study was also supported in part by a Cooperative Research and Development Agreement between NIH and Gilead Sciences.

Similar Articles

Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome

Author(s): Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, et al.

Global burden of disease (GBD) for hepatitis C

Author(s): Global Burden Of Hepatitis C Working Group

The hepatitis C virus life cycle as a target for new antiviral therapies

Author(s): Pawlotsky JM, Chevaliez S, McHutchison JG

Global distribution and prevalence of hepatitis C virus genotypes

Author(s): Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, et al.

HCV genotypes among 1013 Saudi nationals: a multicenter study

Author(s): Al Traif I, Al Balwi MA, Abdulkarim I, Handoo FA, Alqhamdi HS, et al.

Genetic epidemiology of hepatitis C virus throughout egypt

Author(s): Ray SC, Arthur RR, Carella A, Bukh J, Thomas DL

Telaprevir activity in treatment-naive patients infected hepatitis C virus genotype 4: a randomized trial

Author(s): Benhamou Y, Moussalli J, Ratziu V, Lebray P, De Backer K, et al.

Socioeconomic status in HCV infected patients - risk and prognosis

Author(s): Omland LH, Osler M, Jepsen P, Krarup H, Weis N, et al.

Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4

Author(s): Hasan F, Asker H, Al-Khaldi J, Siddique I, Al-Ajmi M, et al.

Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4

Author(s): El Makhzangy H, Esmat G, Said M, Elraziky M, Shouman S, et al.

Response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C due to genotype 4

Author(s): Martín-Carbonero L, Puoti M, García-Samaniego J, De Luca A, Losada E, et al.

Sofosbuvir for previously untreated chronic hepatitis C infection

Author(s): Lawitz E, Mangia A Wyles D, Rodriguez-Torres M, Hassanein T, et al.

Efficacy and safety of sofosbuvir-based triple therapy in hepatitis C genotype 4 infection

Author(s): Wehmeyer MH, Jordan S, Lüth S, Hartl J, Stoehr A, et al.

Daclatasvir plus peginterferonalfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

Author(s): Hézode C, Hirschfield GM, Ghesquiere W, Sievert W, Rodriguez-Torres M, et al.

Daclatasvir and asunaprevir plus peginterferonalfa and ribavirin in HCV genotype 1 or 4 non-responders

Author(s): Jensen D, Sherman KE, Hézode C, Pol S, Zeuzem S, et al.

Hepatitis C virus treatment in the real world: optimising treatment and access to therapies

Author(s): Zoulim F, Liang TJ, Gerbes AL Aghemo A4, Deuffic-Burban S5, et al.

Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4

Author(s): Doss W, Shiha G, Hassany M, Soliman R, Fouad R, et al.

Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection

Author(s): Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, et al.

Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection

Author(s): Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, et al.