Contribution of genetic variation to pharmacokinetic variability and toxicity in patients undergoing multi-drug tuberculosis treatment in Sub-Saharan Africa (RAFAgene)

Principal Investigator:

Prof Dissou Affolabi

Scientific Description:

In 2010 there were an estimated 8.8 million incident cases of tuberculosis (TB) globally, with 2.3 million of these reported in Africa, 1.1 million deaths among HIV-negative cases of TB and an additional 0.35 million deaths among people who were HIV-positive. The complex relationship between TB pathogen, host, and drug exposure in the pathogenesis of TB is poorly understood. The treatment regimen that is currently recommended by WHO for new cases of drug-susceptible TB is highly efficacious, with cure rates of around 90% in HIV-negative patients. However, even if all new TB cases were treated and patients were adherent to the treatment, there would still be 10% of patients (i.e. 880,000 patients worldwide, 230,000 patients in Africa) who fail to respond to treatment. Even if adherent to treatment, a proportion of patients, with rifampicin sensitive TB, are slow to respond to medication or are non-responders. The problem is even more complex and serious in HIV infected patients where the efficacy of the current treatments appears to be lower. Still other patients can be treated successfully, but will experience toxicity and thus treatment interruptions. While several potential determinants of the variable response to drug treatment are recognised (e.g. sex, age, ethnicity), much of the variability in response to anti-tuberculosis drugs remains unexplained. In recent years there has been a rapid development in the understanding of the genetics underlying interindividual differences in drug metabolism and treatment efficacy. The field of pharmacogenetics encompasses the study of the heterogeneity in genes related to drug transporters, drug metabolising enzymes and drug targets, in the context of efficacy of treatment and adverse drug reactions. Few studies have been conducted to explore this field for TB disease. Through this study we aim to explore and determine host genetic factors contributing to pharmacokinetic (i.e. drug concentration) and dynamic (i.e. treatment outcome) variability in TB patients. The “RAFAgene” study is a 5 year project which will be nested within two multi-country randomised phase III tuberculosis treatment trials, the OFLOTUB and RAFA trials (reg numbers NCT00216385 and PACTR 201105000291300) conducted in Sub-Saharan Africa. Patients enrolled in the pharmacokinetic studies within these 2 trials will be sampled for genetic analysis (genome-wide and targeted SNPs screening with in vitro confirmation of the biological plausibility of the association between pharmacokinetic and genetic characteristics). The proposed project is led by Dr Dissou Affolabi at the National Hospital for TB and Pulmonary (NHTPD) with partners from the National TB program in Senegal, the University Ignace Deen in Guinea, the University of Cape Town (SA), the Medical Research Council in Durban (South Africa), the University of Liverpool UK and the London School of Hygiene and Tropical Medicine UK.

Lay Description: While potent drug treatments are available for tuberculosis, as many as 10% of patients are not cured by such treatments, and the cure rate achieved by the treatments is even lower in HIV-infected individuals. While much of the variability to anti-tuberculosis drugs remains unexplained, one likely reason is genetic, in other words that different people respond differently to a drug because of their gene differences. This is known to be the cases for other drugs in other diseases. In this study, Dr. Dissou Affolabi and colleagues at the National Hospital for TB and Pulmonary Diseases (NHTPD), and partners from the National TB program in Senegal, the University Ignace Deen in Guinea, the University of Cape Town (Republic of South Africa), the Medical Research Council in Durban (Republic of South Africa), the University of Liverpool (United Kingdom) and the London School of Hygiene and Tropical Medicine (United Kingdom), will study the role of host genetics in the success of TB treatment in sub-Saharan Africa.