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Towards control of mortality from HCC in developing countries

With liver cancer cases in Africa expected to double by 2050, established solutions for screening, early detection and treatment are desperately needed. The PROLIFICA project has made a case for such developments thanks to a large case study conducted in West Africa. The team is now working on the development of biomarkers for a dipstick test.

Some 25 to 30 % of the 250 million individuals affected by Chronic ‘Hepatitis B virus’ (HBV) infection are expected to die from ‘hepatocellular carcinoma’ (HCC). This situation is of particularly high concern for developing countries like those in West Africa, where HCC is a leading cause of premature death, ageing is expected to double its incidence, access to screening and treatment programmes is severely limited, and tailored HBV treatment guidelines don’t exist. The EU-backed PROLIFICA (Prevention of Liver Fibrosis and Cancer in Africa) project sought to evaluate the burden of liver disease and liver cancer from HBV infection in this region and to demonstrate that community-based screening and treatment are feasible, effective and cost-efficient. To do this, the project team conducted a study on over 9 000 patients in The Gambia, Senegal and Nigeria with three main objectives in mind: identifying the main risk factors for HCC in a West African population using a case control clinical study design; demonstrating that the treatment of chronic HBV infection is feasible and effective; and providing evidence that HCC can be detected early and treated effectively thanks to simple diagnostic tests. Prof. Mark Thursz of the Imperial College of Science Technology and Medicine, UK, who coordinated the project, details the main project findings. Why did you choose to focus your project on Africa? Africa is one of the areas of the world with the highest prevalence of chronic hepatitis B virus infection and consequently the highest incidence of hepatocellular carcinoma. I have collaborated with investigators in West Africa for many years on projects looking at the natural history of hepatitis B virus infection and genetic factors that influence the outcome of this infection. Treatment for hepatitis B virus infection is widely available in Europe and America but there were no treatment programmes in Africa. We were motivated to explore whether it would be feasible to set up a programme to screen and treat hepatitis B in order to prevent patients from progressing to end-stage liver disease. PROLIFICA was set up with two platforms: the first was a case control study in hepatocellular carcinoma which was designed to provide samples and data for biomarker development. The second was a population-based screening programme to determine whether we could effectively identify people infected with hepatitis B and provide them with treatment to prevent complications in the infection. You aimed to show that HBV, a major cause of liver cancer, can be detected early and treated efficiently. How did you achieve that? The main objective was to look at the efficacy and cost-effectiveness of detecting chronic hepatitis B virus infection at an early stage so that treatment of the infection would prevent liver cancer. As the infection is invariably asymptomatic until end-stage liver disease occurs, we needed to go out into the community to perform screening using a point-of-care test for HBsAg — a serum marker for chronic infection. Patients who tested positive were then invited for full assessment, and treatment was provided for those who met international criteria. You have screened over 9 000 patients from The Gambia and Senegal. What are the most important things you learned from that work? No previous study has looked at the uptake of screening in the community for viral hepatitis. We were pleased to see that the uptake of screening was around 70 % and that those who tested positive were effectively linked into care. We were surprised to find that only 5 % of patients with chronic hepatitis B virus infection actually needed treatment. This is probably good news as the number of people with this infection worldwide is daunting at over 250 million. If only 5 % require treatment, this makes it a much more manageable number. We have also shown that screening and treatment turns out to be cost effective. This data has been shared with the HIV & Hepatitis group at the World Health Organisation and will form the basis of future recommendations on population screening. How would you proceed to reduce the number of cancer cases in Africa? We have now used the data from PROLIFICA to model the impact of various interventions to control hepatitis B virus infection and to reduce the number of deaths from hepatocellular carcinoma. The models verify how effective hepatitis B vaccination programmes have been in preventing new infections, but this has had no impact on the deaths from end-stage liver disease. In fact the results show us that cancer deaths will continue to climb and persist at high levels for another 30 years without alternative interventions. Screening and treatment for hepatitis B virus infection would result in a major reduction in the number of cancer cases within five years. How do you expect your project to impact local policies? Initially we expect a limited uptake of the screen and treat strategy as there is little political momentum to tackle hepatitis B when there is still a focus on HIV, TB and malaria. However, some governments in Africa have expressed an interest in introducing public health measures to control hepatitis B in order to reduce the rate of liver cancer. What would you say are the most interesting biomarkers you identified and why? We identified a number of patients with hepatocellular carcinoma in our clinics and obtained biological samples for proteomic and metabonomic analyses. The proteomic analysis identified four proteins with changes in serum levels in hepatocellular carcinoma. We are now waiting for further analyses to determine how useful these might be in screening or diagnosis. We have also identified and verified a panel of metabolites in urine which are modified in patients with hepatocellular carcinoma. These are particularly interesting because they may, in the future, provide us with a simple urine dipstick test to identify patients with a high risk of disease. In addition, some of the metabolites such as acetylcarnitine indicate a potential therapeutic target for future drug discovery. What are your next plans now that the project has been completed? Further work is required to develop the urinary metabolite panel into a practical test. At the moment we have set up a mass spectrometer in the MRC’s Laboratories in The Gambia to measure metabolites and see if we can provide ‘real-time’ diagnostic information. If this is validated, then we would look to see how the format of the test could be simplified and potentially even turned into a dipstick test. With regard to the screen and treat strategy for hepatitis B, we are beginning to look for funding to do a full-scale country-wide demonstration project to definitively demonstrate the impact on cancer and cirrhosis-related deaths. PROLIFICA Funded under FP7-HEALTH project page on CORDIS PROLIFICA website

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