Stratified Medicine to Optimise Treatment for Hepatitis C Virus Infection

Stratified Medicine is a type of personalised medicine where treatments are directed specifically at people who are most likely to respond to them, often using detailed information about individuals. We believe that the treatment of patients with hepatitis C virus (HCV) would benefit enormously from this approach.

About 300,000 people in the UK are infected with HCV, only half of whom have been diagnosed as carrying the virus. The virus has a high tendency to persist as the body's immune system is usually unable to clear infection. HCV infects the liver, causing liver cirrhosis (scarring), liver failure and liver cancer. HCV exists in different genetic forms called genotypes. In the UK, most infections are caused by either genotype 1 or 3, which occur at about equal frequency.

Treatment for HCV has consisted of two drugs interferon and ribavirin. Approximately half of patients receiving treatment respond and are successfully cured of infection. Until recently, no additional drugs were available to treat those who failed treatment. The number of people who develop severe liver disease from HCV is expected to continue to rise over the next two decades. Those who develop liver failure can be given a transplant but the transplanted organ is rapidly infected with the virus and often becomes diseased within a few years.

New drugs, which directly act against the virus (called DAAs), are being used in combination with interferon and ribavirin in NHS patients for the first time in the clinic in 2012. DAA drugs increase the cure rate to 70%. However, there are drawbacks: the drugs are very expensive costing in excess of £20,000 per patient; the virus can become resistant to new drugs, rendering them useless and increasing the frequency of resistant strains in the community; the first wave of new drugs are effective against genotype 1 but not genotype 3 strains; additional side effects can be associated with the new drugs, so that treatment may be stopped before the virus is eliminated.

We have developed a team of experts in the clinical care of HCV patients, who will work with HCV scientists, in partnership with industry. Combining expertise in this way should serve to benefit patients. The group is already working well together collecting blood samples and information from 10,000 people across the UK into a single bio-bank, supported by government infrastructure. We aim to assess the genetic make up of both the virus and the infected person. We will also look at the way in which the immune system responds to the virus, and measure protein markers in the blood. We will assess these in patients receiving therapy and also in those with serious liver disease to try to work out in advance who will develop further complications of their disease. A unique feature of our group will be the ability to draw all these strands together.

We will develop new technologies so that we rapidly obtain the host and viral sequence in thousands of infected people. In this way we hope to improve treatment options for patients so that the right therapies are given to patients who are most likely to benefit from them. We will focus our efforts especially on HCV genotype 3, which is a particular problem in UK patients, and also on patients with more serious liver disease, who are more difficult to treat with the new therapies. Ultimately we hope to predict the likelihood of treatment response in individuals, and possibly through our investigations develop new therapies. This could bring considerable cost-savings to the NHS and means that drugs are given to HCV-infected people who are most likely to respond to them.

HCV infects 300,000 people within the UK and is an MRC priority research area. We have developed a flexible and dynamic UK wide consortium(STOP-HCV) that will use patient stratification to optimise treatment of infected patients. The consortium builds on existing cutting edge clinical and scientific expertise, in genuine partnership with industry, supported by NIHR infrastructure.
Our overarching aim is to define and develop a deeper understanding of patient strata and to develop prognostic models so that rational treatment strategies can be deployed. In a new era of novel Directly Acting Antiviral (DAA) therapies, treating only a subset of patients with DAA will cost the NHS an estimated £96 million/year with an expected overall treatment failure rate of 30%. Moreover, 40% of patients receiving DAAs would respond to current cheaper therapies. Therefore, refined patient stratification will be of enormous clinical and economic benefit. A focus of our program will be study of HCV genotype-3 infection, highly prevalent in the UK, with a characteristic clinical phenotype, and a high relapse rate with standard therapy. We will also focus on difficult-to-treat patient groups such as those with cirrhosis and those co-infected with HIV, where optimal management pathways will be of particular benefit in patients.
Our consortium is underpinned by HCV Research UK, a network of 18 UK centres biobanking samples from 10,000 HCV infected patients, linked to a state-of-the-art clinical database. The consortium has been purposefully constructed to support rational enquiry and will be divided into integrated themes including cohort development, host and viral genomics, immune phenotyping and biomarker evaluation. The program is supported by health economic, methodological, statistical, and bioinformatics expertise. The STOP-HCV consortium draws together UK expertise in collaborative working to ensure stratification at a national level for the optimal treatment of patients with HCV

The economic and societal impacts of our consortium will be far reaching:

Enhancing the quality of life, health and well- being: Our overarching aim is to use stratification to enhance clinical decision-making and thereby achieve maximum effectiveness and cost-effectiveness of therapeutic regimens for hepatitis C virus (HCV) infection. We also aim to understand disease mechanisms that define patient strata so that new rational therapeutic approaches can be developed and deployed. We will focus on patients that are difficult to treat with advanced disease, and those with genotype-3 infection a strain that is particularly common in the UK. To achieve this we have developed a consortium in partnership with industry that unites academics from different disciplines, and clinicians at the forefront of the field. Impact on society will be achieved through direct health benefits to the 300,000 patients infected with HCV within the UK, many of whom develop liver cirrhosis, liver failure and hepatocellular cancer.

Contributing towards evidence based policy-making: Through integration between scientists, clinicians, statisticians and health economics, our consortium will drive national guidelines for the treatment of HCV.

Economic impacts: New directly acting antivirals (DAAs) are now available at a cost of >£20,000/treatment course. Treating only 1% of infected people will cost the NHS £96 million. With effective stratification these therapies will be given to those people most likely to obtain maximum benefit with direct economic savings to the NHS.

Economic prosperity:
Our program of work involves the identification and integrated analysis of host and viral genomic markers and other biomarkers of disease progression and treatment response. This work may enhance UK competitiveness and prosperity (i) through the commercialisation and exploitation of predictive models of clinical outcomes, (ii) the development of high throughput assays for in-vitro assays of drug resistance testing, and (iii) high throughput integrative genomics. (vi) innovative statistical methodology that may be commercially exploited.
Furthermore, New insights into disease biology may lead to the development of novel therapeutic avenues and early phase clinical studies.
Our work will increase innovative research capacity within academic organisations that seek to develop new therapies and diagnostic tools.

Industry: Our consortium has been developed in alignment with industry needs in the arenas of both HCV pharama and diagnostics, and the industrial sector will benefit directly from our consortium.

Voluntary sector: The hepatitis C Trust, a charity run by patients for patients is represented on the STOP-HCV steering committee. One additional direct spin-off from the consortium will be an increased participation of UK patients in clinical trials - an area in which historically, the UK has performed very badly.

Technological advances: Society will also benefit through technological advances made within the strategic aims of the projects. This will include the deployment and high throughput of novel genetic sequencing technologies and integrative platforms for host and viral genomics, immune phenotyping, and biomarkers.

Realistic time scales for benefits to be achieved is 5 years.