The Gambia Hepatitis Intervention Study
The Gambian Hepatitis Intervention Study (GHIS) is a collaborative project undertaken by the IARC, the Government of The Republic of The Gambia, and the Medical Research Council, UK. The GHIS was initiated in 1986 to evaluate the effectiveness of Hepatitis B virus (HBV) vaccination in childhood for the prevention of infection, chronic liver disease, and hepatocellular carcinoma (HCC) in adulthood in a high-risk population. The GHIS is a high profile project of the Agency, led by the Director’s Office.
The project involves three phases. During Phase I (1986-1990), HBV vaccine was phased into the Gambian Expanded Programme on Immunization (EPI) using a stepped-wedge design over a 4-year period (Hall et al., Cancer Res. 47: 5782, 1987). The unit of randomization was the EPI team, stratified according to four ecological zones. In total, 124,577 children were recruited, around half of whom received all EPI vaccines and half all vaccines plus HBV. In Phase II (1991-1997), the efficacy of the vaccine against infection and chronic carriage was estimated. Phase III (initiated in 1998) involves the long-term follow-up of the children in the trial through cancer registration, using HCC as the primary endpoint.
Three methods were established for the long-term identification of subjects. First, at recruitment personal details of children were recorded, such as name, parents’ name, birth date, sex, etc. Second, at the age of 4 months or older, palm- and footprints of each child were taken. Third, the usual site of the BCG vaccination and the resulting scar were altered for children in the study.
At the beginning of GHIS, a population-based National Cancer Registry (NCR) was established. Cases are identified through public health facilities and private clinics. Confirmation of clinical diagnosis is supported by the histopathology unit of the National Health Laboratory Services (NHLS). For HCC diagnosis, clinical criteria, ultrasound and alpha-fetoprotein are used in combination. Both the NCR and the NHLS have received long-term support from IARC, the former representing one of the only population-based cancer registries in sub-Saharan Africa.
In Phase I, vaccine efficacy was shown to be 84% against infection and 94% against chronic carriage at 9 years of age (Fortuin et al., Lancet 341: 1129, 1993; Viviani et al., Vaccine, 17: 2946, 1999). These results demonstrate the protection conferred by the HBV vaccine against chronic infection.
The final outcome of GHIS will be evaluated through record linkage between HCC cases in the NCR and the GHIS database of vaccinated and unvaccinated children. The latest estimates (Viviani et al., Cancer Epi. Bio. Prev. 17: 3216, 2008) indicate that the number of cases needed to detect a significant difference between vaccinated and unvaccinated groups will be reached when GHIS subjects are around 30 years old. Overall, between 30 and 35 years of total follow-up will be necessary to obtain unequivocal results. Therefore, the final outcome of GHIS should be measurable between 2017 and 2020.
Public health value of GHIS
The GHIS is the only randomized trial of HBV vaccine in Africa and one of only two world-wide examining chronic liver disease and HCC as outcomes. The study has demanded a long-term commitment from its partners over a 30-40 year period in order to achieve these goals.
Through improving the understanding of the risk factors for HCC and the clinical presentation of the disease in West Africa, this study will provide a framework to develop recommendations and guidelines for effective reduction of the burden of liver cancer in high-incidence areas of Africa. These include the development of interventions aimed at improving early diagnosis, controlling viral replication in chronically infected subjects, managing chronic liver disease and, whenever feasible, proposing appropriate treatment to liver cancer patients.
The strategy adopted for the GHIS provides a model for the evaluation of the introduction of new vaccines or other prevention strategies in sub-Saharan African countries and other low-resource regions world-wide. The value and feasibility of population-based cancer registration as an integral part of routine medical and hospital practice in order to assess the long-term effect of interventions is evident. In addition, the training of staff to implement the intervention, in this case in the Gambian EPI, in the NCR and in the NHLS, has added capacity to the delivery of public health services.