A new class of hepatitis C drugs can cure the infection in weeks, but the high cost and the difficulty some patients have finishing the full course mean doctors need a way to tell who can be cured with a shorter treatment. The problem is that current evidence for shorter courses comes from small studies, and no one knows which patients will respond to just four to six weeks of therapy instead of the standard eight to twelve weeks. This trial randomly assigns patients to a shorter, RNA-guided duration of a specific drug combination or to the standard eight-week course, with some also receiving ribavirin. If a patient is not cured, they move to a twelve-week retreatment with a different drug combination. The research also collects blood samples to study host genetics, viral sequences, and immune responses, aiming to uncover the biological reasons why some people clear the virus faster. If successful, this work could lower the cost per cure and expand access to treatment, particularly for disadvantaged populations who struggle with longer regimens.
View original technical description
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).
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know