Research ArticleSofosbuvir/velpatasvir for 12 vs. 6 weeks for the treatment of recently acquired hepatitis C infection
Graphical abstract
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
References (30)
- et al.
Efficacy of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance
J Hepatol
(2005) - et al.
Factors associated with uptake of treatment for recent hepatitis C virus infection in a predominantly injecting drug user cohort: the ATAHC Study
Drug Alcohol Depend
(2010) - et al.
Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study
Lancet Infect Dis
(2017) - et al.
Ledipasvir-sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial
Lancet Gastroenterol Hepatol
(2017) - et al.
Treatment of acute hepatitis C genotypes 1 and 4 with 8 weeks of grazoprevir plus elbasvir (DAHHS2): an open-label, multicentre, single-arm, phase 3b trial
Lancet Gastroenterol Hepatol
(2019) - et al.
Four weeks of ledipasvir/sofosbuvir and ribavirin with or without pegylated interferon for chronic hepatitis C in non-cirrhotic people who inject drugs. A randomized trial
J Hepatol
(2018) - et al.
THU-193-4 week treatment for hepatitis C. A randomised controlled trial (4RIBC)
J Hepatol
(2019) - et al.
High incidence of HCV in HIV-negative men who have sex with men using pre-exposure prophylaxis
J Hepatol
(2020) - et al.
Effective treatment of injecting drug users with recently acquired hepatitis C virus infection
Gastroenterology
(2010) - et al.
Twelve-week treatment of acute hepatitis C virus with pegylated interferon- alpha -2b in injection drug users
Clin Infect Dis
(2007)