Title: Optimising the clinical and cost effectiveness of therapy for chronic hepatitis C virus infection. Strategies to identify patients who require modified treatment regimes.
Funder: Department of Health and Social Care

Abstract: Chronic hepatitis C virus (HCV) infection causes liver cirrhosis and cancer, but viral eradication reduces morbidity and mortality. Until recently, treatment of patients with advanced cirrhosis was limited by the poor response and tolerability to therapy with interferon. The recent development of interferon-free options consisting of potent new antivirals thus represents an important opportunity to cure HCV and improve liver function in patients with cirrhosis. NHS England has funded these new antivirals for 1000 patients with advanced cirrhosis through the English Expanded Access Program (EAP). A further 5000 patients with cirrhosis will be offered therapy in 2015. Treatment is with a drug combination of sofosbuvir with either ledipasvir or daclatasvir and ribavirin, for 12 weeks at a cost of 35,000. For difficult-to-treat patients, the drug licenses recommend 24 weeks therapy (at a cost of 70,000), but it is unclear which patients require this, rather than standard 12 weeks. The ability to identify patients who require the longer, very expensive therapy is therefore pertinent on both clinical and economic grounds. My research will address this critical unmet need. I will focus on genotypes 1 and 3 infections - the commonest subtypes of HCV in the UK. Patients with cirrhosis are at higher risk of treatment failure compared to those without cirrhosis. Within the EAP to date, approximately 10% of patients have failed to respond to 12 weeks of treatment, and will be considered for longer durations of therapy. My aim is to identify such patients before treatment is initiated. Genotype 3 HCV is particularly challenging to cure, with resistance to ledipasvir demonstrated in vitro. Such patients may require daclatasvir, but this antiviral agent costs an additional 20,000 per course. I hypothesise that a group of patients with HCV cirrhosis respond poorly to treatment, and that modifying treatment (either by changing drug regimes or extending the duration) will improve response rates. By optimising the use of available therapies, patients will benefit from better chance of cure, and the overall NHS costs of HCV treatment will reduce. I will identify patients with poor treatment response by analysing the national database of all patients who received treatments on the EAP. I speculate that a combination of patient and viral characteristics will be predictive of treatment failure. In parallel, I will determine if virus phenotyping improves treatment response prediction. I will study virus from patients on the EAP using a viral phenotyping assay, which was recently developed by my supervisor's research group through NIHR-funded work, to determine whether the assay identifies patients with genotypes 1 and 3 HCV who are at high likelihood of treatment failure. This will therefore extend the clinical applicability of the assay to the latest available treatment. Finally, for those patients with genotype 1 infection predicted to have poor response on standard treatment duration, I will conduct a clinical trial to study if extended-duration therapy improves response rates. For patients with genotype 3 infection who are predicted to respond poorly to treatment, I will examine in vitro responses to alternative drugs, to determine whether these patients retain sensitivity to alternative (albeit more expensive) therapeutic agents.I speculate that these strategies of pre-treatment response prediction will identify patients who are most likely to fail standard HCV therapy, and require modified, more expensive therapy. Conversely, patients with predicted favourable response can be treated with a standard course, sparing the side effects and costs of prolonged therapy. This approach can improve the clinical and cost effectiveness of new HCV therapies, offering huge benefits to patients as well as informing disease management guidelines and NHS funding policy.

Lay abstract: Hepatitis C is a virus which infects the human liver and can cause long-term damage, with liver scarring , development of cirrhosis and liver cancer, leading to premature death. Treatment to clear the virus infection can stop ongoing liver damage. For many years, treatment of hepatitis C virus (HCV) has been with a combination of a weekly injection called interferon, together with tablet medications, for up to 48 weeks. This treatment has unpleasant side effects and is often ineffective in patients with cirrhosis, the most severe stage of liver disease . Recently, new treatments which involve a combination of tablet medications for only 12 weeks have been developed. These are highly effective with fewer side effects, but are expensive (over 35,000 per course), and some patients may need more than 12 weeks treatment. I want to find out if I can identify which patients need a longer, and more expensive, course of therapy to get rid of their infection. In England an early treatment program (funded by NHS England) is currently treating 1000 patients with liver cirrhosis with these new treatments, offering a chance to cure HCV infection and improve liver disease. Treatment involves a medication called sofosbuvir, combined with another medication which is either daclatasvir or ledipasvir. My aim is to find ways to predict if viral treatment is likely to be successful, before a patient starts treatment. This allows doctors to consider longer courses or alternative treatments, for those with low likelihood of success. By using treatments with the best chance of response, patients can avoid taking unsuccessful treatments, and will also lead to cost-saving for the NHS. I will find out what factors relating to the patient or the virus infection are associated with a low chance of responding to HCV treatments. I will do this by analysing data collected from all patients in England who have been treated with the drugs sofosbuvir and daclatasvir or ledipasvir. I will apply a new technology, developed by the research group I work with at Queen Mary University of London, to test the virus within patient blood. This allows prediction of the likelihood that the patient will respond successfully to anti-HCV drugs. I will carry out a clinical trial to test whether for patients who are predicted to have low likelihood of response, the chance of success will improve on using 24 weeks treatment, compared to using the standard 12-week course. If this is true, doctors will know which patients are best treated with the longer, more expensive treatment, and which patients do not require it. I believe this research will guide doctors to the best of use of the latest available treatments, and benefit many patients who suffer with liver disease due to HCV infection.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION