The TB research group at OUCRU works in close collaboration with Pham Ngoc Thach hospital and Benh Vien Nhiet Doi to conduct research aimed at improving outcome for patients with tuberculous meningitis and pulmonary tuberculosis. Tuberculous meningitis is a devastating condition with 25% mortality in HIV-negative patients and over 60% mortality in those with HIV co-infection. Many survivors are left with severe neurological disability. We have recently completed a trial of immediate versus deferred antiretroviral drugs for those presenting with TB meningitis and HIV disease and the results will be published this year. Our next randomised control trial will begin shortly to compare standard treatment for TB meningitis with a regimen boosted with a fluoroquinolone and high-dose rifampicin in all patients with TB meningitis. We are also conducting a program of research on the pharmacokinetics of TB drugs in children with TB meningitis led by Dr Nguyen Duc Bang and Dr Thomas Pouplin as children may be under-dosed using current WHO treatment guidelines. The results of this study will be used to guide the design of an intervention trial to improve treatment in children.
In addition to clinical research on TB meningitis, we conduct studies on novel diagnostics for TB meningitis, pulmonary TB and multi-drug resistant tuberculosis. We have recently completed a large evaluation of the MODS technique led by Dr Dang Thi Minh Ha, for rapid early diagnosis of TB in children, HIV patients, TB meningitis and for identification of multi-drug resistance. The results of this study in children have been published and other publications will follow soon. (Ha, D.T., et al., PLoS One, 2009. 4(12): p. e8341.)
Drug resistant pulmonary TB presents many challenges for clinicians in National TB Programs. We are conducting a large prospective study of factors influencing treatment failure and relapse in isoniazid-resistant tuberculosis patients, led by Dr Phan Vuong Khac Thai.
Our basic science research has made exciting progress on drug resistance determinants (Duong, D.A., et al., AAC, 2009. 53(11): p. 4835-9.), pathogen virulence factors and the interaction between pathogen and host genetic susceptibility factors. We have identified an interaction between the host susceptibility polymorphism, TLR2 T597C, and the Beijing genotype of TB which influences the clinical disease phenotype (Caws, M., et al., PLoS Pathog, 2008. 4(3): p. e1000034). This is the first time such as an association has been demonstrated in tuberculosis and research continues to elucidate the underlying mechanisms responsible for this observed association. Dr Sarah Dunstan is investigating the contribution of human genetics to TB, with a focus to further understand why people progress to active disease, and/ or severe disseminated disease. We are using genome wide expression and genetic variation approaches to identify TB susceptibility genes. One study used gene expression profiles in human macrophages to identify novel candidates genes. To our knowledge, this was the first identification of CCL1 as a gene involved in host susceptibility to TB and the first study to combine microarray and DNA polymorphism studies to identify genes associated with TB susceptibility (Thuong, NTT., et al PLosPathof, 2008 4(12):e1000229). Our recent publication in Cell, in collaboration with the University of Washington describes a protective variant of the leukotriene A4 hydrolase (LTA4H) gene in patients with TB in Vietnam and leprosy in Nepal which modulates TNF-alpha production. (Tobin, D.M., et al., Cell. 2010 140(5): p. 717-30.)
Overall, our TB research programme aims to address questions of treatment and prevention in this long-neglected disease, to generate an evidence-base for policy improvement in National TB Programs, while conducting basic science research to contribute to understanding of pathogenesis and susceptibility in human populations. We look forward to an exciting year of further advances in these areas.