Prevention of Liver Fibrosis and Cancer in Africa (Prolifica)

By Professor Simon Taylor-Robinson and Professor Mark Thursz

Hepatocellular carcinoma survival rates are still low, even in the developed world, because patients often present late, when tumours are too large for curative treatment. With early diagnosis, HCC is curable by surgery or chemoembolization and many deaths are preventable. However, current gold-standard screening tests for HCC diagnosis are expensive, only have 75–80% sensitivity and specificity, and are not performed routinely in primary care.

Professor Taylor-Robinson’s innovative research aims to build on new proof-of-concept data to develop a revolutionary screening technology which uses urine testing via a dipstick to rapidly diagnose HCC. The testing would provide a practical, low-cost test which is easy to use primary care. Clinically and economically, such a simple approach would have a global impact, not only in the developed economies of Europe and North America but also in severely resource-limited settings, such as sub-Saharan Africa. It would help to save thousands of pounds and thousands of lives.

To realise this goal funding is required to enable studies which will use metabolic profiling to detect a panel of suitable biomarkers for the early detection of HCC. Ultimately, Professor Taylor-Robinson and his team aim to use the biomarkers in laboratories worldwide and in a ground-breaking urinary dipstick which will diagnose HCC.

Professor Taylor-Robinson works in the Department of Cancer and Surgery at Imperial. He holds many senior board memberships in the field of liver studies and is a fellow and international director of the Royal College of Physicians of London. He has led numerous initiatives in Africa, including training programmes for doctors across the continent.

The problem

Liver cancer is one of the leading causes of mortality worldwide, with an estimated annual mortality rate of 500,000 with a survival rate of less than 5%.

Cirrhosis (scarring of the liver as a result of continuous, long-term liver damage) is the primary risk factor for the development of liver cancer in developing countries, such as in West Africa, where viral hepatitis B is the leading cause of cirrhosis.

Late presentation of patients with liver cancer results in a bad prognosis, due mainly to insufficient and lack of affordable screening tools for early tumour detection. In resource-poor settings, procedures such as ultrasounds are not available and population mass-screening is often not practicable.

Our solution

Since February 2011, we have been working on a five-year translational clinical research project, funded by the European Union Framework 7 (www.prolifica.eu).  The aim of the project is to reduce the incidence of liver cancer in three West African countries – Gambia, Nigeria and Senegal. In particular, hepatocellular carcinoma: (HCC), is the most common cause of death in these countries. The project will also seek to identify biomarkers (measurable indicators of the severity or presence of the disease) for the development of simple diagnostics for detecting cancer in resource-poor countries.

The project aim is to identify urinary biomarkers of liver cancer in West African populations with viral hepatitis B, specifically in Senegal, Gambia and Nigeria. These will be used to develop a urinary diagnostic for early liver cancer that can be used for screening in resource-poor rural communities, who otherwise present too late for medical attention.

Additionally, it will investigate if the treatment of chronic hepatitis B virus infection is an effective method of reducing the incidence of liver cancer in resource-poor settings.

Objectives

The key aims of the project are:

• To identify the main risk factors for liver cancer (HCC) in a West African population
• To demonstrate that the treatment of chronic hepatitis B virus infection is feasible and an effective method of reducing the incidence of liver cancer in resource-poor settings
• To show that liver cancer can be detected early and treated effectively in patients
• To train local medical staff and scientists in the procedures required, such that the project is undertaken efficiently and technology transfer and capacity building are established in these countries.

The project began with a visit to Gambia to initiate public health teaching on hepatitis B. Also, to provide initial training to local staff responsible for collecting biological samples from patients in both village and hospital settings. Staff from Imperial conducted workshops to train local staff in the following activities:

• How to conduct their studies ethically and to comply with Good Clinical Practice
• How to ensure that volunteer patients are well informed of the study requirements, such that they may make an independent decision on consenting to take part
• How to collect the biological samples to a particular protocol
• How to store the samples for future research analysis
• The collection of epidemiological information to help facilitate the identification of the main reasons for the incidence of liver cancer (e.g. diet, living standards, illness).

Protocols for the above activities were created (i.e. consent forms, study information, laboratory procedures and epidemiological questionnaire) to ensure that the local staff understood how to carry out the procedures effectively. In particular, ensuring that the volunteer patients were well informed of the project aims and why their blood and urine samples were required. Also, how the samples would be used to provide information on hepatitis B and liver cancer and how outcomes will affect their own and their families' future health.

Imperial visited Gambia a second time to characterise and verify samples collected by the Gambian and Senegalese collaborators.  All samples taken from patients require being transferred from the villages and hospitals to the laboratory within a short timeline, to be viable for research purposes. Protocols for this purpose were provided and a method was devised to ensure that samples were transported and remained viable, given the practical limitations of a hot climate with underlying transport, including facilities for mobile cold storage, both during collection and transport.

In the laboratory, the Imperial team trained local staff in the processing of samples and correct storage in -80^oC freezers before analysis. They also oversaw the transfer of patient urine and blood samples back to the UK for metabonomic analysis at Imperial. The tests were to remain frozen throughout the journey to the UK, so it was important to show local staff how to pack and send samples such that they stayed frozen throughout the trip, arriving intact and frozen at Imperial.

The Imperial team also contributed to the training of Nigerian project staff in ethical patient recruitment (Good Clinical Practice). Also, they facilitated the setting up of their laboratory and the processing and storage of biological samples.

The outcome

At the end of year one, all Gambian and Senegalese staff were fully trained and competent in all activities involved in the collecting of biological samples (including informing patients and processing of the samples for research analysis). As such, local staff were able to undertake and manage the activities without supervision.

During the second year, Imperial visited both Gambia and Senegal.  Their trip to Gambia was to support the local staff and help solve any problems that may have arisen with the process of sample collection. 

During this time, they also visited Senegal to train staff in the use of a Fibroscan provided by the project.  The particular ‘ultrasound-like’ piece of equipment, specifically devised to non-invasively assess the presence of liver cancer in patients, was successfully achieved and the machine is currently being used to confirm the presence of liver cancer in Senegalese patients recruited to the project. Gambian staff had previous experience of using the Fibroscan and did not require training.

Imperial visited both centres in Senegal, Le Dantec hospital and Thies hospital, where the majority of patients are recruited for the project. In Thies, the majority of patients are recruited from a local factory and the surrounding villages. As this is very different to that in Gambia and Nigeria (where recruitment is mainly from villages and hospitals), the Imperial team also ensured that the factory medical staff responsible for recruiting the facility patients understood the recruitment and sample collection procedures. Also, that they were trained to the same standard as those in Gambia and Nigeria.

The Imperial team also helped the three centres with blood pressure monitoring, documentation storage and study procedures information (Good Laboratory Practice).

Going forward

The team continues to help solve sample collection issues arising from the study and to monitor progress in Gambia, Nigeria and Senegal. The above activities have been instrumental in ensuring that the project has been initiated effectively and ethically.

All staff involved in both patient recruitment and sample collection currently work to standard protocols and procedures, ensuring that the collected data is of high quality and will provide informative insights into liver cancer and hepatitis B in West Africa. It will also facilitate the identification of key liver cancer biomarkers for the development of diagnostics for the early detection of the disease in resource-poor settings.

Importantly, the activities undertaken have provided the basis for transferring new skills and building the capacity for providing adequate liver cancer healthcare in West Africa.

Dr Nathalie MacDermott is undertaking a PhD looking at genetic susceptibility to infection with and outcome from Ebola virus disease. Recent studies have demonstrated that the genetics of our host immune system impacts on how it interacts with infecting pathogens. Studies have demonstrated the impact of host genetics in relation to meningococcal infection, HIV, herpes simplex encephalitis, mycobacterial infection and fungal infections. Understanding genetic differences in susceptibility to pathogens and severity of illness helps to further understand the way the pathogen invades the body and interacts with the immune system.

The West African Ebola epidemic of 2013-2015 resulted in over 28,000 infections and 11,000 deaths. It caused untold disruption to health services in the region and the economic impacts will be long-lasting. It was apparent during the epidemic that some patients succumbed to very severe disease while yet others had a much milder disease and went on to survive. Studying the genetics of groups of individuals infected with Ebola virus, but who had different outcomes, will help us to understand how Ebola virus invades cells and causes disease. Identifying a genetic susceptibility to disease from Ebola virus may help us to identify a target for new treatments or vaccines. This means that for the next epidemic, wherever that may be, a treatment which either slows the disease process or kills the virus may be available. This would mean improved survival of patients and may assist in preventing an epidemic of Ebola virus reaching the scale of the 2013-2015 epidemic.

Relevant publications:

1. MacDermott NE, De S & Herberg J.  Viral haemorrhagic fever in children.  Archives of Disease in Childhood. 2016;101(5):461-8. doi: 10.1136/archdischild-2014-307861

2. Hartley L, Evans J & MacDermott NE.  Management and outcome in viral meningo-encephalitis.  Paediatrics and Child Health.  2011. 21(11); pp488-494