Elsevier

Journal of Hepatology

Volume 75, Issue 4, October 2021, Pages 829-839
Journal of Hepatology

Research Article
Sofosbuvir/velpatasvir for 12 vs. 6 weeks for the treatment of recently acquired hepatitis C infection

https://doi.org/10.1016/j.jhep.2021.04.056Get rights and content

Highlights

  • REACT is a randomised study of short course DAA therapy for recently acquired HCV.

  • 188 participants were treated with either 6 or 12 weeks sofosbuvir/velapatasvir.

  • The study population was predominantly cis-male and included a high proportion living with HIV.

  • The study was stopped early due to the high rate of virological relapse in the short course arm.

  • Six weeks of sofosbuvir/velapatasvir cannot be considered non-inferior to 12 weeks.

Background & Aims

Shortened duration therapy for acute and recent HCV infection has been shown to be highly effective in several small non-randomised studies with direct-acting antiviral regimens; however, large randomised studies are lacking.

Methods

REACT was an NIH-funded multicentre international, open-label, randomised, phase IV non-inferiority trial examining the efficacy of short course (6-week) vs. standard course (12-week) therapy with sofosbuvir-velpatasvir for recent HCV infection (estimated duration of infection ≤12 months). Randomisation occurred at week 6. The primary endpoint was sustained virological response 12 weeks after treatment end (SVR12) in the intention-to treat (ITT) population. A total of 250 participants were due to be enrolled, but on advice of the data safety and monitoring board the study was halted early.

Results

The primary analysis population consisted of 188 randomised participants at termination of study enrolment; short arm (n = 93), standard arm (n = 95). Ninety-seven percent were male and 69% HIV positive. ITT SVR12 was 76/93, 81.7% (95% CI 72.4–89.0) in the short arm and 86/95, 90.5% (95% CI 82.7–95.6) in the standard arm. The difference between the arms was -8.8 (95% CI -18.6 to 1.0). In modified ITT analysis, wherein non-virological reasons for failure were excluded (death, reinfection, loss to follow-up), SVR12 was 76/85, 89.4% (95% CI 80.8–95.0) in the short arm and 86/88, 97.7% in the standard arm (95% CI 92.0–99.7; difference -8.3%, p = 0.025).

Conclusions

In this randomised study in recent HCV infection, a 6-week course of sofosbuvir-velpatasvir did not meet the criteria for non-inferiority to standard 12-week therapy.

Lay summary

In this randomised trial, 188 people with recently acquired hepatitis C infection were randomly assigned to treatment using either a short 6-week course (93 people) or standard 12-week course (95 people) of the hepatitis C treatment sofosbuvir/velpatasvir. There were 9 cases of relapse after treatment with the short course and 2 following the standard course. A shortened course of 6-week therapy for hepatitis C infection appeared to be less effective than a standard 12-week course in people with recently acquired hepatitis C infection.

ClinicalTrials.gov Identifier

NCT02625909.

Introduction

Individuals identified in the ‘acute’ phase of HCV infection have historically responded better to therapy than individuals with chronic HCV infection. Several studies in the interferon based-therapy era confirmed that duration of therapy, if commenced early, could be shortened by as much as half, with equivalent or higher sustained virological response (SVR) or ‘cure’.[1], [2], [3] This was demonstrated irrespective of whether the infection was considered acute (within the prior 6 months) or recent (within the prior 1 year) at therapy commencement,4 and was true across at-risk populations including people who inject drugs (PWID)5 and people with HIV.6,7

With the advent of direct-acting antiviral (DAA) therapies, the paradigm of shortened treatment for those with acute or recent HCV infection has been further examined. Although studies with initial regimens (including sofosbuvir and ribavirin) were disappointing,8,9 several single arm studies with more potent regimens demonstrated encouraging results.[10], [11], [12] One of the largest studies, the Dutch Acute HCV in HIV (DAHHS2) study, reported an SVR of 99% in 80 individuals with genotype 1 or 4 using a shortened duration of 8 weeks of grazoprevir-elbasvir.13 Most recently, the first pan-genotypic study in recent HCV infection (TARGET3D) demonstrated an SVR of 96% (per protocol) in 30 individuals using 6 weeks of gleceprevir-pibrentasvir.14 Although encouraging, these studies are limited by the lack of a control group and small sample sizes, reflecting the difficulties of identifying and recruiting large numbers of individuals in early HCV infection.

Recruiting through a large international network, the Recently Acquired HCV Infection Trial (REACT) aimed to test the hypothesis that 6 weeks (short) of sofosbuvir-velpatasvir is non-inferior to 12 weeks (standard) of sofosbuvir-velpatasvir among people with recent HCV infection.

Section snippets

Study design and randomisation

In this open-label, international, multicentre phase III trial, adults with recent HCV were randomly assigned (1:1) to receive sofosbuvir-velpatasvir 400 mg-100 mg once daily for 6 or 12 weeks. Randomisation was performed at week 5 or 6 on treatment using a permutated block design, with a computer random number generator using fixed block sizes of 4, stratified according to site and HIV status. Block size was known only to the study statistician and clinical trial manager. Participation of

Baseline characteristics

Between March 2017 and July 2019, 277 individuals were assessed for eligibility. Of these, 196 were enrolled and randomised, 97 individuals into the short arm and 99 individuals into the standard arm (Fig. 1). Fifty-five individuals were excluded at screening, 38 (69%) of whom did not meet eligibility criteria, with most not meeting inclusion criteria for HCV RNA >10,000 IU/ml (Table S1). Twenty-six individuals were enrolled, but not randomised at week 6. In the majority (n = 21/26, 80%), the

Discussion

In this randomised study of shortened treatment duration for individuals with recent HCV, sofosbuvir-velpatasvir for 6 weeks failed to meet the pre-specified criteria for non-inferiority and the study was terminated early following the second DSMB review. The suboptimal efficacy in the short arm was driven largely by a higher post-treatment relapse, observed in 10% (n = 9) of participants compared with 2% (n = 2) of participants in the standard arm. The REACT study thus found that a 6-week

Financial support

The study was funded by National Institutes of Health (NIDA division). Study medication was provided by Gilead Sciences Inc. The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. Research reported in this publication was supported by NIH and Gilead Sciences Inc (study medication only).

Authors’ contributions

GVM and GJD designed and proposed the study, with study design contributions from SB, MVdV, JR, JF, AR, JB, AK, MH, EG, TA, JG, KP. GVM, GD, SB, MVdV, JR, JF, AR, CT, JB, AK, MH, EG, MR, PI were involved in participant recruitment and data collection. GVM, GD, SB, MVdV, JR, JF, AR, JB, AK, MH, EG, TA, JG, MM, PM, KP provided study governance through the Protocol Steering Committee. KP conducted the data analyses, with oversight from MM and GVM. GVM, MM and GJD drafted the manuscript, with input

Data availability statement

Due to the sensitive nature of some of the data, including that related to injecting drug use, data included in this manuscript has not been placed in an open access database. However, data is available to be shared on request to the protocol steering committee.

Role of the funding source

The study was funded by National Institutes of Health (NIDA division). Study medication was provided by Gilead Sciences Inc. The sponsor (The Kirby Institute, UNSW Sydney) collected the data, managed study samples, monitored study conduct, performed the statistical analysis, and drafted the manuscript.

Conflict of interest

GVM: grants from Gilead Sciences and AbbVie Inc, outside the submitted work; SB: grants from Gilead Sciences, outside the submitted work; personal fees for Advisory Boards and lectures/presentations from Gilead Sciences, outside the submitted work; MvDW: grants and personal fees from AbbVie, grants and personal fees from Gilead, grants and personal fees from Johnson & Johnson, grants and personal fees from MSD, grants and personal fees from ViiV, outside the submitted work; JR: personal fees

Acknowledgements

The REACT study group includes members of the Protocol Steering Committee; Coordinating Centre, The Kirby Institute, UNSW Sydney; and Study Site Principal Investigators.

Protocol Steering Committee – Marc van der Valk (Amsterdam University medical Centers, The Netherlands), Margaret Hellard (The Alfred Hospital and Burnet Institute, Melbourne, Australia), Ed Gane (Auckland City Hospital, Auckland, New Zealand), Andri Rauch (Bern Inselspital, Bern, Switzerland), Julie Bruneau (Centre Hospitalier

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