1. Clinical epidemiology and biostatistics, including HIV-TB diagnostic research
This focus will provide clinicians early in their research careers with a solid foundation in clinical epidemiology and biostatistics, upon which to develop capacity to respond to emerging questions in HIV-TB co-infection, and a path toward research in epidemiology, diagnostics, translational research and clinical trials.
Training in TB diagnostic research will cover HIV-TB diagnosis and specific challenges of diagnosing sputum-scarce and extra-pulmonary TB.
2. Advanced epidemiology and modelling of HIV-TB epidemic and interventions
Trainees will be equipped to better understand and model the HIV-TB epidemics and interventions to address them, especially in the context of changing guidelines: universal testing and treatment for HIV, shorter course TB treatments, wider and changing use of preventive therapies for both diseases, and constantly evolving interaction between the dual epidemics. Course participants will understand the HIV-TB epidemics and their associated interventions in defined communities, and apply these learnings to mathematical modelling of population-level impacts of different interventions.
3. Pharmacokinetics, pharmacogenetics and genetic epidemiology of HIV and TB drugs
Pharmacogenomics seeks to identify genetic risks for drug toxicity, reduced response to therapy, and relevant drug-drug interactions. Given the immense burden of HIV-TB, the fact that genetic polymorphisms profoundly affect many TB and HIV drugs, that polymorphism frequencies vary markedly with ancestry, and that South Africans are understudied, there is clear need to train future leaders in pharmacogenomics research in SA.
4. Translational studies of the immunopathogenesis of HIV-TB co-infection and disease
HIV impairs immunity to Mycobaterium tuberculosis (Mtb) via CD4 T-cell depletion and functional effects on innate and adaptive responses. HIV infection of macrophages impairs phagocytosis, antigen presentation, intracellular pathogen clearance and cytokine responses. HIV infection also alters the nature of the T-cell response to Mtb. Such functional deficits are seen even in HIV-infected patients with preserved CD4 counts and explain the 2-fold greater risk of TB in the 1st year of HIV infection. In advanced HIV, the annual risk of TB is ~30-fold greater than in HIV-uninfected individuals. Antiretroviral therapy (ART) reduces this risk by 65%, but studies in Cape Town suggest that the risk of TB in patients with reconstituted CD4 counts remains 4-fold elevated compared with HIV-uninfected people. The persistence of immune deficits and susceptibility to TB while on ART requires further investigation.
5. Clinical epidemiology and molecular/immune pathogenesis of HIV-TB drug hypersensitivity
Clinical and basic research in drug allergy has been identified as a priority research area, with key areas of need being:
standardized and validated phenotyping of drug-induced allergic reactions;
establishing the major types of HLA-restricted allergies (in different ethnic groups); and
identifying molecular mechanisms that contribute to HLA-restricted allergies or that do not have HLA associations.
The final goal is to develop predictive biomarkers and therapies. HIV-infected patients have >10-fold increased susceptibility to drug hypersensitivity reactions (HSRs) and are exposed to many drugs simultaneously. The spectrum of TB-associated drug HSRs varies from minor to life threatening. The incidence of adverse drug reactions in HIV may be as high as 30%, with mortality of toxic epidermal necrolysis as high as 40%. Withdrawal of the offending drug improves outcomes, but identifying the offending drug with in vivo, in vitro and provocation testing, exclusion of the offending drug, and delabelling of drugs is a major challenge, especially in populations with the major burden of disease. Clinical and basic research is needed to address the many gaps.