1Department of Infectious Disease, Imperial College London, London, W2 1NY, UK.
2NIHR Biomedical Research Centre, Imperial College NHS Trust, London, W2 1NY, UK.
3MRC Clinical Trials Unit, University College London Medical School, London, UK.
4Mortimer Market Centre, Central and North West London NHS Foundation Trust, London, UK.
5Institute of Global Health, University College London Medical School, London, UK.
6Hepatology, Brighton and Sussex Medical School, Brighton, UK.
7Hepatology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
8Hepatology, John Radcliffe Hospital, Oxford, UK.
9Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK.
10Clinical and Experimental Medicine, University of Surrey, Guilford, UK.
11Infectious Diseases, Royal Free Hampstead NHS Trust Hospital, London, UK.
12HIV Medicine, Chelsea & Westminster NHS Trust, London, UK.
13Swansea Bay University Health Board, Swansea, UK.
14Infectious Diseases, Sheffield Teaching Hospitals Nhs Foundation Trust, Sheffield, UK.
15Infectious Diseases, University Hospitals of Leicester NHS Trust, Leicester, UK.
16Hepatology, St George's Hospital, London, London, UK.
17Heaptology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle, UK.
18Hepatitis C Trust, London, UK.
19Peter Medawar Buildling for Pathogen Research, Oxford, UK.
20Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK.
Background: The World Health Organization (WHO) has identified the need for a better understanding of which patients with hepatitis C virus (HCV) can be cured with ultrashort course HCV therapy. Methods: A total of 202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks' sofosbuvir/ledipasvir/ribavirin. The primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment. Results: All evaluable participants achieved SVR12 overall (197/197, 100% [95% CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95% CI -3.8%, +3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91% [86%-97%] (92/101) for fixed-duration vs 48% [39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall, first-line SVR12 was 72% [65%-78%] (70/101) without ribavirin and 68% [61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01). Conclusions: Unsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy. ISRCTN Registration: 37915093 (11/04/2016).