Elsevier

The Lancet Infectious Diseases

Volume 15, Issue 9, September 2015, Pages 1049-1054
The Lancet Infectious Diseases

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

https://doi.org/10.1016/S1473-3099(15)00157-7Get rights and content

Summary

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.

Introduction

Roughly 185 million people worldwide are infected with hepatitis C virus (HCV), which is associated with progression to end-stage liver disease and hepatocellular carcinoma.1, 2 HCV genotype 4 accounts for about 8–13% of these infections, mainly concentrated in sub-Saharan Africa, northern Africa, the Middle East, and southeast Asia.3, 4 Within Europe, HCV genotype 4 is present in a substantial proportion of patients with HCV infections in countries including Belgium, France, and Greece.5 In Egypt, genotype 4 HCV is particularly common, and about 15% of the Egyptian population is infected with this subtype.3

Although the development of ribavirin-free and interferon-free regimens for HCV genotype 1 has progressed rapidly, simple well tolerated treatments for HCV genotype 4 are particularly crucial in view of the high concentration of this genotype in low-income countries, where laboratory monitoring for adverse events might not be feasible.4 In 2014, the directly acting antivirals sofosbuvir and simeprevir were introduced. Sofosbuvir or simeprevir in combination with pegylated interferon and ribavirin for 12 weeks substantially improved the proportion of patients with HCV genotype 4 achieving a sustained viral response (SVR).6 For patients who were ineligible for interferon treatment, sofosbuvir and ribavirin for 24 weeks was also recommended.6 Although these regimens are associated with high 59–100% SVR for patients who are treatment naive or treatment experienced, they include multiple pills, injections, and long treatment durations.6 Additionally, both interferon and ribavirin need frequent laboratory monitoring and are associated with toxic effects, including fatigue, anaemia, and teratogenicity.6

Research in context

Systematic review

We searched PubMed on Feb 11, 2015, for articles published between Jan 1, 2000, and Feb 11, 2015, using a combination of the MeSH search terms “HCV treatment”, “antiviral agent”, and “genotype 4” and consulted the hepatitis C virus (HCV) treatment guidelines for phase 2 or 3 clinical trials of treatments for patients with HCV genotype 4. We also searched the reference lists of articles from our search for additional reports that met our inclusion criteria of phase 2 and phase 3 clinical trials of interferon-free regimens for treatment of HCV genotype 4.

Four clinical trials have been reported (one journal article and four in abstract form) for interferon-free regimens for patients with HCV genotype 4. The results of these trials have shown promising safety and efficacy (sustained viral response at 12 weeks, 84–100%) with combination direct-acting antiviral drugs, with or without ribavirin for 12–24 weeks. Few patients with cirrhosis or who have previously been treated with interferon-containing regimens have been included.

Added value of this study

Although our study is small, we showed high rates of sustained viral response at 12 weeks with use of sofosbuvir and ledipasvir for 12 weeks, which supports the possibility that this simple regimen might be effective for some patients.

Implications of all the available evidence

Further development of this efficacious, simple, well tolerated regimen is warranted and studies in patients with cirrhosis and previously treated patients should be pursued.

Two directly acting antivirals, ledipasvir (an NS5A inhibitor) and sofosbuvir (a nucleotide polymerase inhibitor), have been approved in the USA for combination use for the treatment of HCV genotype 1. Results from studies of this combination, given as one pill per day for 12 weeks, have shown 91–100% SVR in patients with HCV genotype 1 who are treatment naive and treatment experienced, with few adverse events.7, 8 In vitro, both ledipasvir and sofosbuvir have anti-HCV activity against HCV genotype 4 that is similar to that noted against HCV genotype 1. However, the clinical efficacy of this regimen in vivo for HCV genotype 4 has not yet been established.

Historically, proportions of patients with HCV genotype 4 who achieve SVR when given interferon-containing treatments have been between those of patients with HCV genotype 1 and HCV genotypes 2 and 3.9, 10 Furthermore, the in-vitro efficacy of ledipasvir and sofosbuvir for HCV genotype 4 suggests that the combination of these potent directly acting antivirals without ribavirin for 12 weeks might be effective for the treatment of HCV genotype 4 in patients who are treatment naive or interferon treatment experienced. Therefore, we did a clinical trial to assess the two drug combination of ledipasvir and sofosbuvir for 12 weeks for the treatment of patients with HCV genotype 4.

Section snippets

Study design

In this single-centre, open-label cohort, non-randomised phase 2a trial, we sequentially enrolled patients with HCV genotype 4 at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA. The study was approved by the Institutional Review Board of the National Institute of Allergy and Infectious Diseases (NIAID) and was done in compliance with the Good Clinical Practice guidelines, the Declaration of Helsinki, and regulatory requirements. The Regulatory Compliance and Human

Results

We enrolled and followed up patients from Sept 16, 2013, to Nov 2, 2014. We screened 24 participants and 21 were enrolled in study (figure). Table 1 shows baseline characteristics of the study population.

20 (95%, 95% CI 76–100) of 21 patients treated with ledipasvir and sofosbuvir achieved SVR12, in accordance with our predefined criteria. One patient had an HCV RNA concentration of 1 533 291 IU/mL at week 4. On further questioning the patient reported taking only one dose of study drug by week

Discussion

In the present study, treatment with sofosbuvir and ledipasvir for 12 weeks resulted in 95% SVR12 in patients with chronic HCV genotype 4 infections who were treatment naive or interferon treatment experienced. The regimen was well tolerated, rapidly suppressed HCV viraemia, and substantially simplified treatment for HCV genotype 4. 100% of patients who received the full 12 weeks of therapy achieved SVR12.

Treatment for HCV infection is changing rapidly.9 Results from early studies showed that

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