SEARCH: SouthEast Asian Research Collaborative in Hepatitis

Lead Research Organisation: Imperial College London
Department Name: Infectious Disease

Abstract

Viral hepatitis leads to greater mortality each year than HIV, TB or malaria. It ranks 7th amongst the leading causes of death worldwide. Unusually for an infectious disease, the numbers of deaths are distributed quite evenly between richer and poorer countries.
The challenge of tackling viral hepatitis has not yet been embraced by the global health community in the same way as HIV, TB and malaria which has been supported by the Global Fund which provides funding for treatments in countries otherwise unable to afford them. But more recently, a recognition of the relative importance of viral hepatitis has informed an ambitious WHO strategy launched for 2016-21.The WHO goals are to reduce deaths from viral hepatitis by 10% by 2020 and 65% by 2030. To do this the ambition is to treat 3 million hepatitis C infected individuals by 2020 and 80% of eligible hepatitis C (HCV) infected individuals by 2030 (a global estimate of approximately 60 million individuals in the next 13 years). This will pose a major challenge, particularly to poorer countries with high burdens of infection, where costs of delivering treatment are prohibitive.
Vietnam is ranked 9th amongst countries for deaths caused by viral hepatitis and has one of the highest mortality rates from hepatitis C in the world with an estimated 1 million individuals infected. It is also classifed as low-middle income by the World Bank. Current treatment rates in Vietnam are relatively low and use interferon containing therapies which involve long courses (24-48 weeks) including weekly injections, a high rates of side effects and offer cure rates in the region of 70%. However, there are now newly approved tablet treatment regimens (without interferon) of between 12 and 24 weeks. These courses of interferon-free direct acting antivirals (DAAs) are highly effective, with far fewer side effects. However, they are currently very expensive and these costs are the limiting factor for treatment in both richer and poorer countries at present. In addition, whilst 12 weeks of therapy represents great progress, many patients will struggle to take a full course.
Despite these facts, recommended therapies will overtreat a high proportion of patients, and over 80% of patients are likely to be curable with two thirds of the recommended treatment duration. We lack are robust ways of predicting which patients these are and ensuring cure is achieved for the minimum price, inconvenience and toxicity. The proposed work aims to create a network and run studies to provide the data needed to inform how new treatments are used. This is particularly important in Vietnam as the type of hepatitis C circulating there is only rarely found in Europe and USA where most of the trials have been done to date. Genotype 6 hepatitis C, the most common genotype in Vietnam, has rarely been included in studies to date and may well differ in its responses to treatment compared to other genotypes.

Technical Summary

Novel interferon free treatments for hepatitis C have the potential to cure hepatitis C (HCV) and substantially reduce the resulting mortality from liver cancer and end stage liver disease. The WHO has set ambitious targets to treat 80% of those with active infection (over 70 million people) by 2030. However, access to new treatments is very limited , particularly by price. Vietnam (a low middle income country) has the 9th highest number of deaths attributed to viral hepatitis. An estimated 1 million people are infected with HCV in Vietnam, where the epidemic in Vietnam is unusually characterised by a prevalent circulating viral genotype (6), only seen at high levels in SE Asia.
The proposed work will study a new interferon free treatment combination, sofosbuvir (NS5B inhibitor) and ravidasvir (NS5a inhibitor). The optimum duration of therapy for sofosbuvir/ravidasvir is not known and there is very little data with this or any treatment combination in genotype 6 HCV infection (the only Phase III study completed was done in genotype 4 infection). It is likely that many patients can be cured with treatments shorter than the licensed durations, with the potential to significantly reduce treatment costs and complexity of care.
The work proposed will carry out two studies to evaluate the optimum duration of therapy (i) 60 patients (30 genotype 1, 30 genotype 6). Those whose virus is undetectable (<500 IU/ml) within 48 hours of starting treatment will receive 4 weeks of treatment; others will receive 6 weeks of therapy. All those failing treatment will receive 12 weeks of therapy (ii) in 43 cirrhotics with genotype 6 , patients achieving undetectable (<500 IU/ml) virus in blood at 2 weeks will received 12 weeks, all others 24 weeks. The studies will include full genome sequencing of isolates, pharmacokinetic studies of interactions in HIV drugs and collection of health economic data to inform clinical practice and policy in the scale up of the novel therapies

Planned Impact

Viral hepatitis leads to greater mortality each year than HIV, TB or malaria. It ranks 7th amongst the leading causes of death (Stanaway et al 2016). Unusually for a communicable disease, the burden of both mortality and morbidity is quite evenly distributed between high/upper-middle and low/lower-middle income countries (LMICs) (Stanaway et al 2016).

The challenge of tackling viral hepatitis has not yet been embraced by the global health community to the same extent as HIV, TB and malaria which are supported by the Global Fund. However, a increasing recognition of the relative importance of viral hepatitis has given impetus to global initiatives with an ambitious WHO strategy launched for 2016-21 and inclusion of viral hepatitis in the Sustainable Development goals (SDGs).

Rising mortality from hepatitis C is the greatest driver to the increase in mortality from viral hepatitis. East Asia is by far the most heavily affected region with an estimated 460 million attributed deaths each year. The WHO goals are to reduce mortality from viral hepatitis by 10% by 2020 and 65% by 2030. To do this, the ambition is to treat 3 million hepatitis C (HCV) infected individuals by 2020 and 80% of infected individuals by 2030 (a global estimate of approximately 70 million individuals in the next 13 years). Successful cure of HCV has been shown through many studies to significantly reduce the incidence of liver cancer, end stage liver disease (cirrhosis) and all-cause mortality (e.g. Simmons et al 2016).

Vietnam is ranked 9th in counties with deaths attributable to viral hepatitis and has one of the highest mortality rates from hepatitis C in the world (Gower 2014). Current treatment coverage is relatively low with the challenge of delivering interferon based treatments a major obstacle to providing successful therapy. New interferon free therapies have the potential to revolutionise the approach to HCV but are currently beyond the reach of many healthcare systems, particularly in low middle income countries (LMIC).

Meeting the challenges laid set by the WHO Strategy will rely on a range of approaches tackling market access and generic competition, but also in ensuring that (when treatment is purchased by the tablet) that individual patients only have the treatment they need to be cured. This is the aim of this work, to ensure that patients are able to be cured with the minimum amount of treatment they require. Approved treatment regimens of between 12 and 24 weeks of interferon free direct acting antivirals (DAAs) will overtreat a high proportion of patients, and over 80% of patients are likely to be curable with two thirds of the recommended treatment duration. What we lack are robust ways of predicting which patients these are and ensuring cure is achieved for the minimum price, inconvenience and toxicity. in addition to clinical outcomes, real world data and the economic burden of disease (both to the health system and to the patients) will play an important part in developing a policy capable of achieving substantially increased treatment coverage goals.

This programme of work will provide evidence to inform the scale up of treatment and develop the capacity for further, larger studies which will use both novel trial designs (MAMS) and state-of-the-art next generation sequencing technologies to develop algorithms for the management of hepatitis C in Vietnam (which need not involve complex infrastructure and support). The investigators aim to have data to inform the more cost-effective use of expensive medications by 2022. This is particularly important for Vietnam where the most prevalent viral genotype (6) has not been well studied in previous trials.

Publications

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Cooke GS (2019) Pricing viral hepatitis as part of universal health coverage. in The Lancet. Global health

 
Description Genotype 6 is the main lineage of Hepatitis C virus in Vietnam, but is rare outside South East Asia and there is limited evidence for how well new tablet drugs cure it. These drugs remain expensive and the World Health Organization has highlighted a need to find predictive factors for selecting persons who could be treated for a shorter duration.
In this study we proposed using the level of virus in blood after a period on treatment to determine which patients might be successfully treated with shorter duration of therapy. We used the cheapest, most widely available drug combination option, sofosbuvir and daclatasvir, for which regional guidelines recommend 12 weeks of treatment in individuals with mild liver disease and 24 weeks of therapy in individuals with liver cirrhosis, or 12 weeks with the addition of another antiviral drug with toxic side effects (ribavirin), to maximise chance of cure.
In patients with mild disease we showed that shortening therapy to 4 or 8 weeks of sofosbuvir and daclatasvir, on the basis of virus levels in blood after 2 days of therapy, resulted in a cure rate of just 75% overall, which is way below the expected cure rates of >95% with 12 weeks of treatment. However, all patients treated with 8 weeks of therapy were cured, suggesting that shorter durations of treatment may be appropriate with this drug combination in patients with mild disease. Reassuringly, 100% of the patients who failed therapy were cured when retreated with the normal duration of the same drug combination, suggesting that shortened treatment may not provoke significant drug resistance.
In patients with liver cirrhosis, we used virus levels at day 14 to determine which patients might be successfully treated with 12 weeks and which patients might require 24 weeks duration. All participants in the study had low levels of virus after 2 weeks and received 12 weeks of therapy. All were cured. These findings show that longer durations of therapy are not required to cure genotype 6 infection, despite the presence of cirrhosis. This has major consequences for public health policy in the region and could lead to change in regional guidelines.
This work represents the first clinical trial on treatment of genotype 6 infection with this drug combination. Ongoing genetic sequencing work will allow us to better understand the role of virus mutants in this under-studied genotype and their impact on treatment outcome.
Exploitation Route Response guided therapy warrants further study and is now being investigated as part of a larger multi-arm randomized clinical trial in Vietnam.
Further genetic sequencing work and pharmacokinetic analysis will be pursued by co-investigators.
Sectors Healthcare

 
Description Development of Microelimination targets for HCV
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact Using data collected through research and in collaboration with PHE, we drafted targets from BHIVA which have been adopted by clinics nationally to track progress
URL https://www.bhiva.org/BHIVA-calls-for-accelerated-efforts-to-prevent-and-cure-hepatitis-C-infection
 
Description Lancet Commission: Accelerating the Elimination of Viral Hepatitis
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact This comprehensive commission has outlined a number of key recommendations to accelerate the elimination of viral hepatitis. Some of these are already beginning - e.g. availablility of voluntary license for GLE/PIB and increase access to hepatitis B vaccine
URL https://www.sciencedirect.com/science/article/pii/S246812531830270X?via%3Dihub
 
Description Collaborative Award in Science
Amount £3,786,213 (GBP)
Funding ID UNS35328 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 02/2023
 
Description Global Challenges Research Fund
Amount £25,000 (GBP)
Organisation United Kingdom Research and Innovation 
Department Global Challenges Research Fund
Sector Public
Country United Kingdom
Start 12/2018 
End 03/2019
 
Description Hepatitis C Trust-STOP-HCV 
Organisation Hepatitis C Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Sharing of knowledge and expertise
Collaborator Contribution Sharing of knowledge and expertise
Impact Engagement with patient groups, patient perspective on clinical studies and policies related to STOP-HCV Consortium
Start Year 2013
 
Description Imperial - STOP-HCV-1 
Organisation Imperial College London
Department Imperial College Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Sharing of knowledge & expertise, intellectual input into study protocol for STOP-HCV-1 trial
Collaborator Contribution Sharing of knowledge & expertise, provision of samples and data from STOP-HCV-1 trial for analysis
Impact Trial in progress, actively recruiting patients
Start Year 2013
 
Description Imperial - STOP-HCV-1 
Organisation University of Oxford
Department Oxford Clinical Trials Unit (CTU)
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of knowledge & expertise, intellectual input into study protocol for STOP-HCV-1 trial
Collaborator Contribution Sharing of knowledge & expertise, provision of samples and data from STOP-HCV-1 trial for analysis
Impact Trial in progress, actively recruiting patients
Start Year 2013
 
Description MRC clinical trials unit 
Organisation Medical Research Council (MRC)
Department MRC Clinical Trials Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Leading design and delivery of the project
Collaborator Contribution Design and analysis of study protocol
Impact Data not yet emerging from existing projects
Start Year 2016
 
Title SEARCH-1 - Southeast Asian Research Collaborative in Hepatitis 
Description The aim of the Southeast Asian Research Collaborative in Hepatitis (SEARCH) project was to carry out a single arm, open label pilot clinical study with the objective of identifying successful strategies for shortening treatment for individuals chronically infected with hepatitis C based on their early response to therapy. This clinical study was funded by award from the UK MRC as part of the Global Challenge Research Fund calls GCRF FA 260. The study was a single arm, open label trial evaluating strategies for shortening treatment for individuals infected with hepatitis C virus (HCV) based on their early response to directly acting antiviral (DAA) therapy (Sofosbuvir/Daclatasvir). 103 Participants were stratified by stage of liver fibrosis to one of two strategies based on virological response at either 48 hours (mild disease)-STRATUM A or 14 days (cirrhosis)-STRATUM B of treatment. 147 patients were screened and 52 were enrolled to STRATUM A and 41 were enrolled to STRATUM B. HCV genotyping revealed that in STRATUM A , 44% of patients were genotype1 and 56% genotype 6, and in STRATUM B, 100% of patients were genotype 6. 96% of patients had detectable viral loads at at day 2 in STRATUM A and 46% of patients had detectable viral loads at 14 days in STRATUM B. SV12 following first line treatment only was seen in 74.5% patients in STRATUM A and 100% patients in STRATUM B. SV12 following first line treatment and retreatment was seen in 100% patients in STRATUM A. In STRATUM A, SV12 was seen in 61.8% (21/34 patients) with 4 weeks of Sofosbuvir/Daclatasvir treatment and SV12 was seen in 100% (17/17) pateints with 8 weeks treatment of Sofosbuvir/Daclatasvir. We hypothesize that Shortened HCV treatment courses based on early viral responses to sofosbuvir and daclatasvir therapy will achieve high rates of cure 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2020
Development Status Closed
Clinical Trial? Yes
Impact Trial has just started so no notable impacts have arisen 
URL http://www.isrctn.com/ISRCTN17100273
 
Description Coordination of The Lancet Gastroenterology & Hepatology's first Commission on accelerating the elimination of viral hepatitis. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This report assesses the global landscape of the Hepatitis C, and identifies priorities at a global, regional and national level that are key to its elimination. The focus of this article was on the challenges faced by high burden individual countries-20 high-burden countries have been defined that are home to over 75% of the burden of disease- and the recommendation is that all of these countries need to have funded national elimination plans by 2020.
Year(s) Of Engagement Activity 2019
URL https://www.thelancet.com/commissions/elimination-of-viral-hepatitis
 
Description World Hepatitis Day, 18th July 2017 (The John Radcliffe Hospital) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Questions and discussion
Year(s) Of Engagement Activity 2017