• Adapting the DOTS framework for tuberculosis control to the management of non-communicable diseases in sub-Saharan Africa

      Harries, A D; Jahn, A; Zachariah, R; Enarson, D; Clinical HIV Unit, Ministry of Health, Lilongwe, Malawi; Family Health International, Malawi Country Office, Lilongwe, Malawi; London School of Hygiene and Tropical Medicine, London, United Kingdom; Lighthouse Trust, Lilongwe, Malawi; International Training and Education Center on HIV, University of Washington, Seattle, WA; Médecins Sans Frontières, Operational Research Medical Department, Luxembourg; International Union against Tuberculosis and Lung Disease, Paris, France (Public Library of Science (PLoS), 2008-06-10)
    • Building clinical trials capacity for tuberculosis drugs in high-burden countries

      Schluger, N; Karunakara, U; Lienhardt, C; Nyirenda, T E; Chaisson, R; Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University, New York, NY, USA; Campaign for Access to Essential Medicines, Médecins Sans Frontières, Geneva, Switzerland; Clinical Trial Division, International Union Against Tuberculosis and Lung Disease, Paris, France; European and Developing Countries Clinical Trials Partnership, Cape Town, South Africa; Center for TB Research, Johns Hopkins University, Baltimore, MD, USA (2007-11-06)
    • Impact of Xpert MTB/RIF for TB Diagnosis in a Primary Care Clinic with High TB and HIV Prevalence in South Africa: A Pragmatic Randomised Trial

      Cox, H; Mbhele, S; Mohess, N; Whitelaw, A; Muller, O; Zemanay, W; Little, F; Azevedo, V; Simpson, J; Boehme, C C; et al. (Public Library of Science, 2014-11-25)
      Xpert MTB/RIF is approved for use in tuberculosis (TB) and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert under routine conditions in settings with high TB burden.
    • Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

      Ahuja, S D; Ashkin, D; Avendano, M; Banerjee, R; Bauer, M; Bayona, J N; Becerra, M C; Benedetti, A; Burgos, M; Centis, R; et al. (2012-08)
      Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.
    • New approaches to filling the gap in tuberculosis drug discovery.

      Casenghi, M; Cole, S; Nathan, C F; Médecins Sans Frontières, Campaign for Access to Essential Medicines, Geneva. martina.casenghi@geneva.msf.org (Public Library of Science, 2007-11-06)
    • Randomized trials to optimize treatment of multidrug-resistant tuberculosis

      Mitnick, C D; Castro, K G; Harrington, M; Sacks, L V; Burman, W; Harvard Medical School, Boston, MA, USA; Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA, USA; Treatment Action Group, New York, NY, USA; Food and Drug Administration, Rockville, MD, USA; Denver Public Health and University of Colorado Health Sciences Center, Denver, CO, USA (2007-11-06)
    • Risk score for predicting mortality including urine lipoarabinomannan detection in hospital inpatients with HIV-associated tuberculosis in sub-Saharan Africa: Derivation and external validation cohort study.

      Gupta-Wright, A; Corbett, EL; Wilson, D; van Oosterhout, JJ; Dheda, K; Huerga, H; Peter, J; Bonnet, M; Alufandika-Moyo, M; Grint, D; et al. (Public Library of Science, 2019-04-01)
      The prevalence of and mortality from HIV-associated tuberculosis (HIV/TB) in hospital inpatients in Africa remains unacceptably high. Currently, there is a lack of tools to identify those at high risk of early mortality who may benefit from adjunctive interventions. We therefore aimed to develop and validate a simple clinical risk score to predict mortality in high-burden, low-resource settings. A cohort of HIV-positive adults with laboratory-confirmed TB from the STAMP TB screening trial (Malawi and South Africa) was used to derive a clinical risk score using multivariable predictive modelling, considering factors at hospital admission (including urine lipoarabinomannan [LAM] detection) thought to be associated with 2-month mortality. Performance was evaluated internally and then externally validated using independent cohorts from 2 other studies (LAM-RCT and a Médecins Sans Frontières [MSF] cohort) from South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. The derivation cohort included 315 patients enrolled from October 2015 and September 2017. Their median age was 36 years (IQR 30-43), 45.4% were female, median CD4 cell count at admission was 76 cells/μl (IQR 23-206), and 80.2% (210/262) of those who knew they were HIV-positive at hospital admission were taking antiretroviral therapy (ART). Two-month mortality was 30% (94/315), and mortality was associated with the following factors included in the score: age 55 years or older, male sex, being ART experienced, having severe anaemia (haemoglobin < 80 g/l), being unable to walk unaided, and having a positive urinary Determine TB LAM Ag test (Alere). The score identified patients with a 46.4% (95% CI 37.8%-55.2%) mortality risk in the high-risk group compared to 12.5% (95% CI 5.7%-25.4%) in the low-risk group (p < 0.001). The odds ratio (OR) for mortality was 6.1 (95% CI 2.4-15.2) in high-risk patients compared to low-risk patients (p < 0.001). Discrimination (c-statistic 0.70, 95% CI 0.63-0.76) and calibration (Hosmer-Lemeshow statistic, p = 0.78) were good in the derivation cohort, and similar in the external validation cohort (complete cases n = 372, c-statistic 0.68 [95% CI 0.61-0.74]). The validation cohort included 644 patients between January 2013 and August 2015. Median age was 36 years, 48.9% were female, and median CD4 count at admission was 61 (IQR 21-145). OR for mortality was 5.3 (95% CI 2.2-9.5) for high compared to low-risk patients (complete cases n = 372, p < 0.001). The score also predicted patients at higher risk of death both pre- and post-discharge. A simplified score (any 3 or more of the predictors) performed equally well. The main limitations of the scores were their imperfect accuracy, the need for access to urine LAM testing, modest study size, and not measuring all potential predictors of mortality (e.g., tuberculosis drug resistance). This risk score is capable of identifying patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions, although further prospective validation studies are necessary. Given the scale of HIV/TB morbidity and mortality in African hospitals, better prognostic tools along with interventions could contribute towards global targets to reduce tuberculosis mortality.
    • Translational Research for Tuberculosis Elimination: Priorities, Challenges, and Actions

      Lienhardt, C; Lönnroth, K; Menzies, D; Balasegaram, M; Chakaya, J; Cobelens, F; Cohn, J; Denkinger, C M; Evans, T G; Källenius, G; et al. (Public Library of Science, 2016-03-02)
      Christian Lienhardt and colleagues describe the research efforts needed to end the global tuberculosis epidemic by 2035.
    • Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis

      Harausz, EP; Garcia-Prats, AJ; Law, S; Schaaf, HS; Kredo, T; Seddon, JA; Menzies, D; Turkova, A; Achar, J; Amanullah, F; et al. (Public Library of Science, 2018-07-11)
      An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children.
    • Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance.

      Cox, H; Kebede, Y; Allamuratova, S; Ismailov, G; Davletmuratova, Z; Byrnes, G; Stone, C; Niemann, S; Rüsch-Gerdes, S; Blok, L; et al. (PLoS, 2006-10)
      BACKGROUND: The DOTS (directly observed treatment short-course) strategy for tuberculosis (TB) control is recommended by the World Health Organization globally. However, there are few studies of long-term TB treatment outcomes from DOTS programs in high-burden settings and particularly settings of high drug resistance. A DOTS program was implemented progressively in Karakalpakstan, Uzbekistan starting in 1998. The total case notification rate in 2003 was 462/100,000, and a drug resistance survey found multidrug-resistant (MDR) Mycobacterium tuberculosis strains among 13% of new and 40% of previously treated patients. A retrospective, observational study was conducted to assess the capacity of standardized short-course chemotherapy to effectively cure patients with TB in this setting. METHODS AND FINDINGS: Using routine data sources, 213 patients who were sputum smear-positive for TB, included in the drug resistance survey and diagnosed consecutively in 2001-2002 from four districts, were followed up to a median of 22 months from diagnosis, to determine mortality and subsequent TB rediagnosis. Valid follow-up data were obtained for 197 (92%) of these patients. Mortality was high, with an average of 15% (95% confidence interval, 11% to 19%) dying per year after diagnosis (6% of 73 pansusceptible cases and 43% of 55 MDR TB cases also died per year). While 73 (74%) of the 99 new cases were "successfully" treated, 25 (34%) of these patients were subsequently rediagnosed with recurrent TB (13 were smear-positive on rediagnosis). Recurrence ranged from ten (23%) of 43 new, pansusceptible cases to six (60%) of ten previously treated MDR TB cases. MDR M. tuberculosis infection and previous TB treatment predicted unsuccessful DOTS treatment, while initial drug resistance contributed substantially to both mortality and disease recurrence after successful DOTS treatment. CONCLUSIONS: These results suggest that specific treatment of drug-resistant TB is needed in similar settings of high drug resistance. High disease recurrence after successful treatment, even for drug-susceptible cases, suggests that at least in this setting, end-of-treatment outcomes may not reflect the longer-term status of patients, with consequent negative impacts for patients and for TB control.
    • XDR-TB in South Africa: detention is not the priority.

      Goemaere, E; Ford, N; Berman, D; McDermid, C; Cohen, R; PLOS Medicine (2007-04)