Genotyping and Pharmacokinetics in the HIV/MDR-TB epidemic of Eastern Siberia

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DESCRIPTION (provided by applicant): The HIV/multidrug-resistant tuberculosis (MDR-TB) epidemic in the Irkutsk oblast of Eastern Siberia is arguably the most severe in the world. We have found that in the Irkutsk TB Dispensary, the referral hospital for the oblast, all patients wih HIV and primary MDR-TB (no prior history of TB treatment) died during the inpatient phase of treatment. We have also found that genotypic drug-resistance mutations only partially explain the extent of phenotypic resistance that is so widespread in Irkutsk. Suboptimal serum anti-TB drug concentrations amplify such phenotypic resistance and our work in other settings has demonstrated the importance of optimizing pharmacokinetics for drug-susceptible TB. Such foundational work in anti- TB/antiretroviral drug concentrations is lacking for drugs used in the treatment of MDR-TB, and absent in the HIV-infected population. Furthermore, we have found that HIV infection in Irkutsk to be associated with the Beijing TB genotype, commonly found to be MDR, but that mortality was more frequent in those with the M. tuberculosis sublineage Beijing MIT17. Thus taken together we hypothesize that the high early HIV/TB mortality in Irkutsk is due to a combination of (1) complex MDR and extensively drug resistant (XDR)-TB that is incompletely diagnosed and incompletely treated, (2) poor anti-TB/antiretroviral pharmacokinetics that lead to low efficacy and (3) increased circulation of hyper-transmissible and virulent M. tuberculosis sublineages. We will investigate these hypotheses by performing pharmacokinetic sampling of anti-TB and antiretroviral medications in HIV-infected patients initiating therapy at Irkutsk TB Dispensary. We will also perform intensified case-finding among antiretroviral na¿ve patients at the Irkutsk AIDS Centre. Their sputum will be screened for TB (GeneXpert) and positive specimens subjected to conventional methods of culture and drug-susceptibility testing, followed by comparison to quantitative susceptibility (MIC testing), sequencing for drug-resistance mutations, and then genotyping for sublineage identification and transmissibility analysis. This proposal will leverage a strong collaboration with the Institute Epidemiology and Microbiology/Russian Academy of Medical Sciences and the Irkutsk TB Dispensary with the University of Virginia. We bring together a team of HIV/TB experts from Russia and the U.S.A. with longstanding experience in TB genotyping (Irkutsk), molecular diagnostics and sequencing for TB (Irkutsk/University of Virginia) and HIV/TB pharmacokinetics (University of Virginia). Completion of the proposal will inform better diagnostic strategies and initial therapeutic regimens to combat the early and overwhelming mortality of this dual epidemic.