Title: Stratified Treatment OPtimisation for HCV-1 (STOP-HCV 1)
Funder: Department of Health and Social Care

Abstract: New interferon free, low toxicity, orally administered direct acting antiviral therapies (DAAs) are set to revolutionise chronic hepatitis C virus (HCV) treatment. Initial Phase II/III data with interferon-free combinations of novel DAAs from three randomised-controlled trials (RCT) show very high treatment responses (>90% cure) with only 12 weeks of treatment, and excellent tolerability [Refs 9,10,11,12,14,15,16]). However, DAA treatments are very expensive (~£35,000 for 12 weeks) and even though required treatment courses are much shorter than previous standard-of care, many patients, particularly disadvantaged populations, will still find it hard to adhere to therapy for this duration. Stratification is already part of routine HCV treatment with choice and duration of treatment determined by viral genotype and sub-genotyping. The overarching aim of this work is to evaluate further stratification rules for HCV treatment to provide high probability of cure with much shortened courses of new, interferon-free DAA HCV treatment which are coming into NHS practice. It is clear from the limited number of Phase II studies exploring shortened durations of DAA therapy that a high proportion of individuals can be cured with treatment durations shorter than the 12 week courses for which approvals have been granted. Three key combinations where there has been limited investigation of shorter treatments are (i) paritaprevir/ritonavir/ombitasvir/dasabuvir/ribavirin (A3D) combination included in the first part of this study (ii) sofosbuvir/ledipasvir/ribavirin (SOF/LDV) which is used here as retreatment and (iii) the combination of elbasvir/grazeoprevir for which market approval is expected in late 2015. Such studies have been relatively small as shorter duration therapies have not been pushed for approval by the originator companies. Overall cure rates with 8/52 of A3D were 88% (N=80)(18), 67% with 6 weeks of SOF/LDV(19), 39% (N=31) and 84% (N=31) with 4 and 6 weeks of grazeoprevir/elbasvir/sofosbuvir in non-cirrhotic genotype 1 infection(20) and 80% in HIV co-infected individuals receiving 8 weeks of grazeoprevir/elbasvir(21). Robust data to predict which patients will respond effectively to these shortened courses will reduce the cost-per-cure and improve access to new treatment. We would anticipate these outputs to begin to inform clinical practice very soon after the grant period given the current barriers to treatment. This study design is open label randomized control trial. At enrolment, participants will be randomised 1:1 to HCV RNA guided duration of 4-6 weeks A3D v 8 weeks A3D (control), with/without ribavirin (using weight- based dosing), in a factorial design. Because of varying durations, the interventions will not be blinded. Cure will be determined using the standard definition, Sustained Virological Response at 12 weeks (SVR12). Participants not achieving SVR12 (or with failure to suppress or relapse prior to 12 weeks after the end of treatment) will rollover into a re-treatment of 12 weeks of an alternative DAA combination (sofosbuvir/ledipasvir with weight based ribavirin). Mechanistic work using the well characterized samples from this study will be embedded in the MRC HCV Stratified Medicine Consortium to understand the biological mechanisms which determine cure (including host genetics, full viral sequencing and immune reponses).

Lay abstract: STOP-HCV-1 (Stratified Treatment OPtimisiation for Hepatitis C) What is changing in hepatitis C treatment? We are at the beginning of a new era in the treatment of hepatitis C (HCV). While it has been possible to treat HCV for some years, treatments that include interferon are long (6-12 months), toxic and have limited cure rates even in those who tolerate them for the full course. The new oral direct acting antiviral (DAA) treatments are taken for shorter duration (12 weeks or less), are well tolerated and offer a much better chance of cure. However, three months of therapy is still a lot for many patients and, as the cost of these drugs is currently very high (over £25,000 for 12 weeks’ treatment), it’s more difficult to access them. What is the question we are testing in patients with Hepatitis C genotype 1 and mild liver disease? We are using two NICE approved DAA treatment combinations (DAA combination 1 is ombitasvir/dasabuvir/paritaprevir/ritonavir; DAA combination 2 is sofosbuvir/ledipasvir). Both of these DAA combinations have been safe, well tolerated and very effective in the thousands of patients worldwide who have been treated with them. We know these DAAs can be effective at curing HCV genotype 1 when given for between 8 and 12 weeks; importantly, some smaller studies have suggested that even shorter courses could be used and still achieve HCV cure. We are aiming to discover which patients may be cured by shorter courses (for some as short as 4 weeks) of therapy and how we might use new techniques in molecular medicine to predict this. We will also be testing whether the addition of another, older drug (ribavirin) has value in short course treatment. If we show that very short courses of DAA can cure the majority of patients with HCV this will be a great advance, as it will avoid unnecessary cost and inconvenience to both patients and those providing care. The safeguards in the study include a retreatment phase with DAA combination 2 (as listed above). So for patients who don’t achieve HCV cure after completing the first round of treatment, they will be guaranteed to receive further treatment with sofosbuvir/ledipasvir/ribavarin for 12 weeks (study design). How many patients will take part? We expect to recruit just over 400 patients (HCV-monoinfected and HCV/HIV co-infected) to allow us to answer our main question. We anticipate opening centres for recruitment in England in the first quarter of 2016 and are in discussion with centres in Wales and Scotland to join later this year. Link to URL http://www.stop-hcv.ox.ac.uk/stop-hcv-1-trial

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION