A systematic review of risk factors for death in adults during and after tuberculosis treatment

BACKGROUND: Despite effective anti-tuberculosis chemotherapy, case-fatality rates of up to 25% are described in both industrialised and resource-poor settings. An understanding of the factors predisposing to poor outcome may allow the development of adjunctive treatment strategies or closer clinical monitoring in high-risk individuals. OBJECTIVES: To describe the definitions and timing of deaths due to tuberculosis (TB), and the reported range of risk factors for death. METHODS: All electronically available studies investigating risk factors for death in TB patients from 1966 to 2010 were analysed. Included were peer-reviewed reports of cohort, case control or cross-sectional studies with the primary objective of determination of quantitative effect estimates of the relationship between risk factors and death in adults treated for TB. Many studies were limited by their retrospective design, reliance on data from registries and charts, and risk of reporting bias. RESULTS: Most studies reported risk factors for all-cause mortality throughout anti-tuberculosis treatment. In the context of high TB incidence and human immunodeficiency virus (HIV) prevalence, risk factors for death are HIV positivity, advancing immunosuppression, smear-negative disease and malnutrition. In regions of low TB incidence and HIV prevalence, risk factors include non-infective comorbidities, sputum smear-positive disease and alcohol and substance misuse. CONCLUSIONS: There remains a need for prospective clinical studies, particularly with a focus on deaths occurring during the first months of anti-tuberculosis treatment. Qualitative research should be used to further explore the relationship between sex and health-seeking behaviour, and to optimise delivery of health care to socially marginalised groups

Optimizing Pharmacology Studies in Pregnant and Lactating Women Using Lessons from HIV: A Consensus Statement

Information on the extent of drug exposure to mothers and infants during pregnancy and lactation normally becomes available years after regulatory approval of a drug. Clinicians face knowledge gaps on drug selection and dosing in pregnancy and infant exposure during breastfeeding. Physiological changes during pregnancy often result in lower drug exposures of antiretrovirals, and in some cases a risk of reduced virologic efficacy. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network and the World Health Organization (WHO)–convened Pediatric Antiretrovirals Working Group collaboratively organized a workshop of key stakeholders in June 2019 to define key standards to generate pharmacology data for antiretrovirals to be used among pregnant and lactating women; review the antiretroviral product pipeline; describe key gaps for use in low-income and middle-income countries; and identify opportunities to undertake optimal studies allowing for rapid implementation in the clinical field. We discussed ethical and regulatory principles, systemic approaches to obtaining data for pregnancy pharmacokinetic/pharmacodynamic (PK/PD) studies, control groups, optimal sampling times during pregnancy, and pharmacokinetic parameters to be considered as primary end points in pregnancy PK/PD studies. For lactation studies, the type of milk to collect, ascertainment of maternal adherence, and optimal PK methods to estimate exposure were discussed. Participants strongly recommended completion of preclinical reproductive toxicology studies prior to phase III, to allow study protocols to include pregnant women or to allow women who become pregnant after enrolment to continue in the trial. The meeting concluded by developing an algorithm for design and interpretation of results and noted that recruitment of pregnant and lactating women into clinical trials is critical