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

描述（由申请人提供）：东西伯利亚伊尔库茨克州的艾滋病毒/耐多药结核病（MDR-TB）流行可以说是世界上最严重的。我们发现，在伊尔库茨克结核病防治站，该州的转诊医院，所有艾滋病毒和原发性耐多药结核病患者（没有结核病治疗史）在住院治疗期间死亡。我们还发现，基因型耐药突变只能部分解释伊尔库茨克如此普遍的表型耐药程度。次优的血清抗结核药物浓度放大了这种表型耐药性，我们在其他环境中的工作已经证明了优化药物敏感结核病药代动力学的重要性。在抗结核/抗逆转录病毒药物浓度方面，用于治疗耐多药结核的药物缺乏这种基础性工作，艾滋病毒感染人群也缺乏这种基础性工作。此外，我们发现伊尔库茨克的HIV感染与北京结核基因型有关，通常发现为MDR，但死亡率在M。结核病亚系北京MIT 17.因此，综合考虑，我们假设伊尔库茨克早期HIV/TB高死亡率是由于（1）复杂MDR和广泛耐药（XDR）-TB未得到完全诊断和治疗，（2）抗TB/抗逆转录病毒药代动力学不良导致疗效低下，（3）高传播性和毒性M循环增加。结核亚系。我们将通过对在伊尔库茨克结核病防治站开始治疗的HIV感染患者进行抗结核和抗逆转录病毒药物的药代动力学采样来研究这些假设。我们还将在伊尔库茨克艾滋病中心的抗逆转录病毒初治患者中加强病例发现工作。他们的痰液将接受TB（GeneXpert）筛查，阳性标本将接受常规方法的培养和药物敏感性检测，然后与定量敏感性（MIC检测）进行比较，对耐药突变进行测序，然后进行基因分型以进行亚系鉴定和传播性分析。该提案将利用与流行病学和微生物学研究所/俄罗斯医学科学院以及伊尔库茨克结核病防治站与弗吉尼亚大学的密切合作。我们汇集了来自俄罗斯和美国的HIV/TB专家团队，他们在TB基因分型（伊尔库茨克）、TB分子诊断和测序（伊尔库茨克/弗吉尼亚大学）以及HIV/TB药代动力学（弗吉尼亚大学）方面具有长期经验。该提案的完成将为更好的诊断战略和初步治疗方案提供信息，以应对这一双重流行病的早期和压倒性死亡率。

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.