• Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis.

      Blanc, F-X; Sok, T; Laureillard, D; Borand, L; Rekacewicz, C; Nerrienet, E; Madec, Y; Marcy, O; Chan, S; Prak, N; et al. (2011-10-20)
      Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy.
    • Early Outcomes of Decentralized Care for Rifampicin-Resistant Tuberculosis in Johannesburg, South Africa: An Observational Cohort Study

      Berhanu, R; Schnippel, K; Mohr, E; Hirasen, K; Evans, D; Rosen, S; Sanne, I (PloS One, 2016-11-03)
      OBJECTIVE: We describe baseline characteristics, time to treatment initiation and interim patient outcomes at a decentralized, outpatient treatment site for rifampicin-resistant TB (RR-TB). METHODS: Prospective observational cohort study of RR-TB patients from March 2013 until December 2014. Study subjects were followed until completion of the intensive phase of treatment (6 months), transfer out, or a final outcome (loss from treatment (LFT) or death). RESULTS: 214 patients with RR-TB were enrolled in the study. Xpert MTB/RIF was the diagnostic test of rifampicin resistance for 87% (n = 186), followed by direct PCR on AFB positive specimen in 14 (7%) and indirect PCR on cultured isolate in 5 (2%). Median time between sputum testing and treatment initiation was 10 days (IQR 6-21). Interim outcomes were available in 148 patients of whom 78% (n = 115) were still on treatment, 9% (n = 13) had died, and 14% (n = 20) were LFT. Amongst 131 patients with culture positive pulmonary TB, 85 (64.9%) were culture negative at 6 months, 12 were still sputum culture positive (9.2%) and 34 had no culture documented or contaminated culture (26%). Patients who initiated as outpatients within 1 week of sputum collection for diagnosis of RR-TB had a significantly lower incidence of LFT (IRR 0.30, 95% CI: 0.09-0.98). HIV co-infection occurred in 178 patients (83%) with a median CD4 count 88 cells/ml3 (IQR 27-218). CONCLUSIONS: Access to decentralized treatment coupled with the rapid diagnosis of RR-TB has resulted in short time to treatment initiation. Despite the lack of treatment delays, early treatment outcomes remain poor with high rates of death and loss from care.
    • Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study

      Ferlazzo, G; Mohr, E; Laxmeshwar, C; Hewison, C; Hughes, J; Jonckheere, S; Khachatryan, N; De Avezedo, V; Egazaryan, L; Shroufi, A; et al. (Elsevier, 2018-02-13)
      Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.
    • Effect of Antiretroviral Therapy on the Diagnostic Accuracy of Symptom Screening for Intensified Tuberculosis Case Finding in a South African HIV clinic

      Rangaka, M X; Wilkinson, R J; Glynn, J R; Boulle, A; van Cutsem, G; Goliath, R; Mathee, S; Maartens, G; Centre for Infectious Disease Research and Epidemiology, School of Public Health and Family Medicine, University of Cape Town, South Africa. mxrangaka@yahoo.co.uk (Oxford University Press, 2012-12)
      Current symptom screening algorithms for intensified tuberculosis case finding or prior to isoniazid preventive therapy (IPT) in patients infected with human immunodeficiency virus (HIV) were derived from antiretroviral-naive cohorts. There is a need to validate screening algorithms in patients on antiretroviral therapy (ART).
    • Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study

      Schnippel, K; Ndjeka, N; Maartens, G; Meintjes, G; Master, I; Ismail, N; Hughes, J; Ferreira, H; Padanilam, X; Romero, R; et al. (Elsevier, 2018-07-09)
      Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline.
    • Effect of HIV-1 infection on T-Cell-based and skin test detection of tuberculosis infection

      Rangaka, M X; Wilkinson, K A; Seldon, R; Van Cutsem, G; Meintjes, G A; Morroni, C; Mouton, P; Diwakar, L; Connell, T G; Maartens, G; et al. (2007-12-07)
      RATIONALE: Two forms of the IFN-gamma release assay (IFNGRA) to detect tuberculosis infection are available, but neither has been evaluated in comparable HIV-infected and uninfected persons in a high tuberculosis incidence environment. OBJECTIVE: To compare the ability of the T-SPOT.TB (Oxford Immunotec, Abingdon, UK), QuantiFERON-TB Gold (Cellestis, Melbourne, Australia), and Mantoux tests to identify latent tuberculosis in HIV-infected and uninfected persons. METHODS: A cross-sectional study of 160 healthy adults without active tuberculosis attending a voluntary counseling and testing center for HIV infection in Khayelitsha, a deprived urban South African community with an HIV antenatal seroprevalence of 33% and a tuberculosis incidence of 1,612 per 100,000. MEASUREMENTS AND MAIN RESULTS: One hundred and sixty (74 HIV(+) and 86 HIV(-)) persons were enrolled. A lower proportion of Mantoux results was positive in HIV-infected subjects compared with HIV-uninfected subjects (p < 0.01). By contrast, the proportion of positive IFNGRAs was not significantly different in HIV-infected persons for the T-SPOT.TB test (52 vs. 59%; p = 0.41) or the QuantiFERON-TB Gold test (43 and 46%; p = 0.89). Fair agreement between the Mantoux test (5- and 10-mm cutoffs) and the IFNGRA was seen in HIV-infected people (kappa = 0.52-0.6). By contrast, poor agreement between the Mantoux and QuantiFERON-TB Gold tests was observed in the HIV-uninfected group (kappa = 0.07-0.30, depending on the Mantoux cutoff). The pattern was similar for T-SPOT.TB (kappa = 0.18-0.24). Interpretation: IFNGRA sensitivity appears relatively unimpaired by moderately advanced HIV infection. However, agreement between the tests and with the Mantoux test varied from poor to fair. This highlights the need for prospective studies to determine which test may predict the subsequent risk of tuberculosis.
    • Effect of multidrug resistance on global tuberculosis control.

      Cox, H; Hargreaves, S; Ismailov, G (Elsevier, 2003-11-29)
    • Effect of Previous Treatment and Sputum Quality on Diagnostic Accuracy of Xpert(®) MTB/RIF

      Acuña-Villaorduña, C; Orikiriza, P; Nyehangane, D; White, L F; Mwanga-Amumpaire, J; Kim, S; Bonnet, M; Fennelly, K P; Boum, Y; Jones-López, E C (International Union Against Tuberculosis and Lung Disease, 2017-04-01)
      In early studies, Xpert® MTB/RIF accurately detected culture-proven pulmonary tuberculosis (TB). Recent reports have, however, found a lower than expected specificity in previously treated TB patients.
    • Effect of Previous Treatment and Sputum Quality on Diagnostic Accuracy of Xpert(®) MTB/RIF

      Acuña-Villaorduña, C; Orikiriza, P; Nyehangane, D; White, L F; Mwanga-Amumpaire, J; Kim, S; Bonnet, M; Fennelly, KP; Boum, Y; Jones-López, EC (International Union Against Tuberculosis and Lung Disease, 2017-04-01)
      In early studies, Xpert® MTB/RIF accurately detected culture-proven pulmonary tuberculosis (TB). Recent reports have, however, found a lower than expected specificity in previously treated TB patients.
    • Effect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in South African adults with HIV-associated tuberculosis.

      Cohen, K; Van Cutsem, G; Boulle, A; McIlleron, H; Goemaere, E; Smith, P J; Maartens, G; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. karen.cohen@uct.ac.za (Oxford Journals, 2008-02)
      BACKGROUND AND OBJECTIVES: Nevirapine-containing antiretroviral therapy (ART) and rifampicin-based antitubercular therapy are commonly co-administered in Africa, where nevirapine is often the only available non-nucleoside reverse transcriptase inhibitor. Rifampicin induces the metabolism of nevirapine, but the extent of the reduction in nevirapine concentrations has varied widely in previous studies. We describe the steady-state pharmacokinetics of nevirapine during and after antitubercular therapy in South African patients. METHODS: Sixteen patients receiving ART including standard doses of nevirapine were admitted twice for intensive pharmacokinetic sampling: during and after rifampicin-based antitubercular therapy. RESULTS: Geometric mean ratios for nevirapine pharmacokinetic parameters during versus after antitubercular therapy were 0.61 [90% confidence interval (CI) 0.49-0.79] for Cmax, 0.64 (90% CI 0.52-0.80) for area under the curve up to 12 h (AUC(0-12)) and 0.68 (90% CI 0.53-0.86) for Cmin. Nevirapine Cmin was subtherapeutic (<3 mg/L) in six patients during antitubercular therapy (one of whom developed virological failure) and in none afterwards. There was no correlation between rifampicin concentrations and the degree of nevirapine induction assessed by the proportional change in nevirapine concentrations between the two admissions. The ratio of nevirapine AUC(0-12) to the AUC(0-12) of its 12-hydroxy metabolite was significantly lower in the presence of antitubercular therapy, consistent with induced metabolism. CONCLUSIONS: Nevirapine concentrations were significantly decreased by concomitant rifampicin-based antitubercular therapy and a high proportion of patients had subtherapeutic plasma concentrations. Further study in African patients is required to determine the implications for treatment outcomes.
    • Effectiveness and Safety of Standardised Shorter Regimens for Multidrug-Resistant Tuberculosis: Individual Patient Data and Aggregate Data Meta-Analyses

      Ahmad Khan, F; Salim, M; du Cros, P; Casas, E; Khamraev, A; Sikhondze, W; Benedetti, A; Bastos, M; Lan, Z; Jaramillo, E; et al. (European Respiratory Society, 2017-07-27)
      We assessed the effectiveness and safety of standardised, shorter multidrug-resistant tuberculosis (MDR-TB) regimens by pooling data from observational studies.Published studies were identified from medical databases; unpublished studies were identified from expert consultation. We conducted aggregate data meta-analyses to estimate pooled proportions of treatment outcomes and individual patient data (IPD) meta-regression to identify risk factors for unsuccessful treatment in patients treated with 9- to 12-month MDR-TB regimens composed of a second-line injectable, gatifloxacin/moxifloxacin, prothionamide, clofazimine, isoniazid, pyrazinamide and ethambutol.We included five studies in which 796 out of 1279 (62.2%) individuals with confirmed MDR-TB (98.4%) or rifampin-resistant TB (1.6%), and not previously exposed to second-line drugs, were eligible for shorter regimens. 669 out of 796 participants were successfully treated (83.0%, 95% CI 71.9-90.3%). In IPD meta-regression (three studies, n=497), failure/relapse was associated with fluoroquinolone resistance (crude OR 46, 95% CI 8-273), pyrazinamide resistance (OR 8, 95% CI 2-38) and no culture conversion by month 2 of treatment (OR 7, 95% CI 3-202). Two participants acquired extensive drug resistance. Four studies reported grade 3 or 4 adverse events in 55 out of 304 (18.1%) participants.Shorter regimens were effective in treating MDR-TB; however, there is uncertainty surrounding the generalisability of the high rate of treatment success to less selected populations, to programmatic settings and in the absence of drug susceptibility tests to key component drugs.
    • Effects of Treatment Interruption Patterns on Treatment Success Among Patients With Multidrug-Resistant Tuberculosis in Armenia and Abkhazia

      Bastard, M; Sanchez-Padilla, E; Hewison, C; Hayrapetyan, A; Khurkhumal, S; Varaine, F; Bonnet, M (Oxford University Press, 2014-10-13)
      The success of the current treatment regimen for multidrug-resistant tuberculosis (MDR-TB) is poor partly due to a high defaulter rate. Many studies explored predictors of poor outcomes, but very few assessed the impact of treatment interruptions on MDR-TB treatment outcomes.
    • Efficacy, Safety and Tolerability of Linezolid for the Treatment of XDR-TB: a Study in China

      Berry, C; Yates, TA; Seddon, JA; Phillips, PP; du Cros, P (European Respiratory Society, 2016-05-01)
    • Eligibility for the Shorter Multidrug-Resistant Tuberculosis Regimen: Ambiguities in the World Health Organization Recommendations

      Varaine, F; Guglielmetti, L; Huerga, H; Bonnet, M; Kiria, N; Sitienei, JK; Rich, M; Mitnick, CD (American Thoracic Society, 2016-10-15)
    • embCAB Sequence Variation Among Ethambutol-Resistant Mycobacterium Tuberculosis Isolates Without embB306 Mutation

      Plinke, C; Cox, H S; Zarkua, N; Karimovich, H A; Braker, K; Diel, R; Rüsch-Gerdes, S; Feuerriegel, S; Niemann, S; Molecular Mycobacteriology, Research Center Borstel, Germany; Macfarlane Burnet Institute for Medical Research and Public Health, Australia; Medecins Sans Frontieres, Uzbekistan; Ministry of Health, Uzbekistan; Medecins Sans Frontieres, Germany; Department of Pneumology, Medical School Hannover (MHH), Germany; National Reference Center for Mycobacteria, Research Center Borstel, Germany (2010-04-28)
      Mechanisms of resistance to ethambutol in Mycobacterium tuberculosis remain inadequately described. Although there is mounting evidence that mutations of codon 306 in embB play a key role, a significant number of phenotypically ethambutol-resistant strains do not carry mutations in this codon. Here, other mutations in the embCAB operon are suggested to be involved in resistance development.
    • Emergence of extensive drug resistance during treatment for multidrug-resistant tuberculosis.

      Cox, H; Sibilia, K; Feuerriegel, S; Kalon, S; Polonsky, J; Khamraev, A K; Rüsch-Gerdes, S; Mills, C; Niemann, S (Massachusetts Medical Society, 2008-11-27)
    • The emerging crisis of drug-resistant tuberculosis in South Africa: lessons from New York City.

      Murphy, R A; Division of Infectious Diseases, Massachusetts General Hospital and Brigham and Women's Hospital, Boston, Massachusetts, USA. richard.murphy@newyork.msf.org (2008-06-01)
      Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis have emerged as important infections in South Africa among patients infected with human immunodeficiency virus (HIV). In the face of this new epidemic, South Africa must rededicate itself to the task of tuberculosis control and treatment with a rapid, multifaceted approach. Priorities include expansion of second-line treatment capacity, investment in clinical laboratories, a system to ensure supervised treatment for all patients, and enhancement of infection control procedures. In New York City, where drug-resistant tuberculosis emerged 2 decades ago--also in the context of a large HIV-infected population and an underfunded public health infrastructure--similar steps were successful in leading to the rapid decrease in rates of drug resistance among tuberculosis isolates. With refinements based on local resource constraints, urgent measures could potentially arrest the alarming increase in multidrug-resistant and extensively drug-resistant tuberculosis cases in South Africa. Unlike many countries in sub-Saharan Africa, South Africa has the capacity to mount a rapid and large-scale response before drug-resistant tuberculosis envelops a much larger and far poorer region.
    • Ending Tuberculosis by 2030: Can We Do It?

      Suthar, A B; Zachariah, R; Harries, A D (International Union Against TB and Lung Disease, 2016-06-30)
      The Sustainable Development Goals aim to end tuberculosis (TB) related deaths, transmission and catastrophic costs by 2030. Multisectorial action to accelerate socio-economic development, a new vaccine and novel diagnostics and medicines for treatment are key advances needed to end TB transmission. Achieving 90-90-90 targets for TB (i.e., 90% of vulnerable populations screened, 90% diagnosed and started on treatment, and at least 90% cured) will help accelerate progress towards reductions in mortality; however, passive case detection strategies, multidrug-resistant TB, human immunodeficiency virus coinfection and outdated pathways to care need to be overcome. Ending the catastrophic costs associated with TB will require expansion of health insurance coverage, comprehensive coverage of TB services, and limited indirect costs by vulnerable and poor populations.
    • The endTB observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens.

      Khan, U; Huerga, H; Khan, AJ; Mitnick, CD; Hewison, C; Varaine, F; Bastard, M; Rich, M; Franke, MF; Atwood, S; et al. (BioMed Central, 2019-08-20)
      BACKGROUND: At a time when programs were struggling to design effective regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB), the marketing authorization of bedaquiline and delamanid was a critical development in the MDR-TB treatment landscape. However, despite their availability for routine programmatic use, the uptake of these drugs has remained slow; concerns included a lack of evidence on safety and efficacy and the need to protect the new drugs from the development of acquired resistance. As part of the endTB Project, we aimed to address these barriers by generating evidence on safety and efficacy of bedaquiline or delamanid based MDR-TB regimens. METHODS: This is a protocol for a multi-center prospective cohort study to enroll 2600 patients from April 2015 through September 2018 in 17 countries. The protocol describes inclusion of patients started on treatment with bedaquiline- or delamanid- containing regimens under routine care, who consented to participate in the endTB observational study. Patient follow-up was according to routine monitoring schedules recommended for patients receiving bedaquiline or delamanid as implemented at each endTB site. Therefore, no additional tests were performed as a part of the study. Data were to be collected in a customized, open-source electronic medical record (EMR) system developed as a part of the endTB Project across all 17 countries. DISCUSSION: The endTB observational study will generate evidence on safety and efficacy of bedaquiline- and delamanid-containing regimens in a large, extremely heterogeneous group of MDR-TB patients, from 17 epidemiologically diverse countries. The systematic, prospective data collection of repeated effectiveness and safety measures, and analyses performed on these data, will improve the quality of evidence available to inform MDR-TB treatment and policy decisions. Further, the resources available to countries through implementation of the endTB project will have permitted countries to: gain experience with the use of these drugs in MDR-TB regimens, improve local capacity to record and report adverse events (pharmacovigilance), and enhance significantly the body of data available for safety evaluation of these drugs and other novel treatments.