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  • Bedaquiline overdose: A case report

    Telnov, O; Alvarez, V; Gragila, E; Molfino, L; du Cros, P; Rich, M (Elsevier, 2019-04-02)
    We present a case report describing outcomes in a 21 year old HIV-negative man who received treatment with bedaquiline. Due to error, dosage received comprised 4 pills of 100 mg every second day in the 60 days following the first two weeks of 4 pills of 100 mg every day. On detection, treatment was continued as per standard dosing of 200 mg given three times per week, with enhanced monitoring of ECG and liver function. The man was asymptomatic, with no signs of jaundice, abdominal pain, or abnormal heart rhythm. Toxic effects at this dosage were therefore not observed.
  • 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; Lawn, SD; Fielding, K (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.
  • Treatment outcomes of patients switching from an injectable drug to bedaquiline during short standardized MDR-TB treatment in Mozambique

    Bastard, M; Molfino, L; Mutaquiha, C; Galindo, MA; Zindoga, P; Vaz, D; Mahinca, I; du Cros, P; Rusch, B; Telnov, A (Oxford University Press, 2019-03-11)
    Bedaquiline was recommended by WHO as the preferred option in treatment of MDR-TB patients with long regimen. However, no recommendation was given for the short MDR-TB regimen. Data from our small cohort of patients who switched injectable dug to bedaquiline suggest that bedaquiline based short regimen is effective and safe.
  • Countries are out of step with international recommendations for tuberculosis testing, treatment, and care: Findings from a 29-country survey of policy adoption and implementation

    Saran, K; Masini, T; Chikwanha, I; Paton, G; Scourse, R; Kahn, P; Sahu, S; Perrin, C; Ditiu, L; Lynch, S (bioRxiv, 2019-02-01)
    Background: Tuberculosis (TB) poses a global health crisis requiring robust international and country-level action. Adopting and implementing TB policies from the World Health Organization (WHO) is essential to meeting global targets for reducing TB burden. However, many high TB burden countries lag in implementing WHO recommendations. Assessing the progress of implementation at national level can identify key gaps that must be addressed to expand and improve TB care. Methods: In 2016/2017, Médecins Sans Frontières and the Stop TB Partnership conducted a survey on adoption and implementation of 47 WHO TB policies in the national TB programs of 29 countries. Here we analyze a subset of 23 key policies in diagnosis, models of care, treatment, prevention, and drug regulation to provide a snapshot of national TB policy adoption and implementation. We examine progress since an analogous 2015 survey of 23 of the same countries. Results: At the time of the survey, many countries had not yet aligned their national guidelines with all WHO recommendations, although some progress was seen since 2015. For diagnosis, about half of surveyed countries had adopted the WHO-recommended initial rapid test (Xpert MTB/RIF). A majority of countries had adopted decentralized models of care, although one-third of them still required hospitalization for drug-resistant (DR-)TB. Recommended use of the newer drugs bedaquiline (registered in only 6 high-burden TB countries) and delamanid (not registered in any high-burden country) was adopted by 23 and 18 countries, respectively, but short-course (9-month) and newer pediatric regimens by only 13 and 14 countries, respectively. Guidelines in all countries included preventive treatment of latent TB infection for child TB contacts and people living with HIV/AIDS, but only four extended this to adult contacts. Conclusion: To reach global TB targets, greater political will is needed to rapidly adopt and implement internationally recognized care guidelines.
  • Demanding an end to tuberculosis: treatment of tuberculosis infection among persons living with and without HIV

    Fargher, J; Reuter, A; Furin, J (Lippincott, Williams & Wilkins, 2019-01-01)
    More than two billion people are infected with Mycobacterium tuberculosis and few of them are ever offered therapy in spite of such treatment being associated with reduced rates of morbidity and mortality. This article reviews the current recommendations on the diagnosis and treatment of TB infection (or what is commonly referred to as 'prophylaxis' or 'preventive therapy' of latent TB) and discusses barriers to implementation that have led to low demand for this life-saving therapeutic intervention.
  • Beyond 'cure' and 'treatment success': quality of life of patients with multidrug-resistant tuberculosis

    Laxmeshwar, C; Stewart, A G; Dalal, A; Kumar, A M V; Kalaiselvi, S; Das, M; Gawde, N; Thi, S S; Isaakidis, P (International Union Against Tuberculosis and Lung Disease, 2019-01-01)
    Two drug-resistant tuberculosis (DR-TB) sites (MSF Clinic, Jupiter Hospital) in Mumbai, India.
  • Field Evaluation of Near Point of Care Cepheid GeneXpert HIV-1 Qual for Early Infant Diagnosis

    Opollo, VS; Nikuze, A; Ben-Farhat, J; Anyango, E; Humwa, F; Oyaro, B; Wanjala, S; Omwoyo, W; Majiwa, M; Akelo, V; Zeh, C; Maman, D (Public Library of Science, 2018-12-27)
    Access to point-of-care HIV testing shortens turn-around times, time to diagnosis and reduces loss to follow-up hence minimizing barriers to early linkage to care and treatment among HIV infected infants. Currently samples for early infant HIV diagnosis are sent to centralized testing facilities which are few and located only at specific regions in Kenya. However, there are Point of Care (POC) early infant diagnosis [EID] technologies elsewhere such as SAMBA and ALERE-Q that are yet to be evaluated in Kenya despite the urgent need for data to inform policy formulation regarding EID. The Cepheid GeneXpert HIV-1 Qual (GeneXpert) technology for POC EID offers a great opportunity to minimize HIV associated morbidity, mortality and loss to follow-up through decentralization of early infant HIV testing to the clinics. This technology also allows for same-day results thus facilitating prompt linkage to care.
  • High Prevalence of Infection and Low Incidence of Disease in Child Contacts of Patients with Drug-resistant Tuberculosis: a Prospective Cohort Study

    Huerga, H; Sanchez-Padilla, E; Melikyan, N; Atshemyan, H; Hayrapetyan, A; Ulumyan, A; Bastard, M; Khachatryan, N; Hewison, C; Varaine, F; Bonnet, M (BMJ, 2018-12-06)
    We aimed to measure the prevalence and incidence of latent tuberculosis infection (LTBI) and tuberculosis (TB) disease in children in close contact with patients with drug-resistant TB (DR-TB) in a country with high DR-TB prevalence.
  • High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen

    Ndjeka, N; Schnippel, K; Master, I; Meintjes, G; Maartens, G; Romero, R; Padanilam, X; Enwerem, M; Chotoo, S; Singh, N; Hughes, J; Variava, E; Ferreira, H; Te Riele, J; Ismail, N; Mohr, E; Bantubani, N; Conradie, F (European Respiratory Society, 2018-10-25)
    Background: South African patients with rifampicin-resistant tuberculosis and resistance to fluoroquinolones and/or injectables (pre/XDR-TB) were granted access to bedaquiline through a Clinical Access Programme with strict inclusion and exclusion criteria.Methods: Pre/XDR-TB and XDR-TB patients were treated with 24 weeks bedaquiline within an optimised, individualised background regimen that could include levofloxacin, linezolid and clofazimine as needed.Results: 200 patients were enrolled: 87 (43.9%) with XDR-TB, 99 (49.3%) were female, median age 34 years (IQR 27, 42). 134 (67.0%) were living with HIV; median CD4+ 281 (IQR 130; 467) and all on antiretroviral therapy.16/200 patients (8.0%) did not complete 6 months of bedaquiline of which 8 were lost to follow up, 6 died, 1 stopped for side effects and 1 patient was diagnosed with drug-sensitive TB.146/200 (73.0%) patients had favourable outcomes: 139/200 were cured (69.5%) and 7 completed treatment (3.5%). 25 died (12.5%), were lost from treatment (10.0%), 9 had treatment failure (4.5%).22 adverse events were attributed to bedaquiline: including QTcF >500 ms (n=5), QTcF increase >50 ms from baseline (n=11), paroxysmal atrial flutter (n=1).Conclusion: Bedaquiline added to an optimised background regimen was associated with a high rate of successful treatment outcomes for this MDR-TB and XDR-TB cohort.
  • Model of care and risk factors for poor outcomes in patients on multi-drug resistant tuberculosis treatment at two facilities in eSwatini (formerly Swaziland), 2011–2013

    Verdecchia, M; Keus, K; Blankley, S; Vambe, D; Ssonko, C; Piening, T; Casas, EC (Public Library of Science, 2018-10-17)
  • "Life continues": Patient, health care and community care workers perspectives on self-administered treatment for rifampicin-resistant tuberculosis in Khayelitsha, South Africa

    Mohr, E; Snyman, L; Mbakaz, Z; Caldwell, J; DeAzevedo, V; Kock, Y; Trivino Duran, L; Venables, E (Public Library of Science, 2018-09-14)
    Self-administered treatment (SAT), a differentiated model of care for rifampicin-resistant tuberculosis (RR-TB), might address adherence challenges faced by patients and health care systems. This study explored patient, health-care worker (HCW) and community care worker (CCW) perspectives on a SAT pilot programme in South Africa, in which patients were given medication to take at home with the optional support of a CCW.
  • Alternative sputum collection methods for diagnosis of childhood intrathoracic tuberculosis: a systematic literature review

    Ioos, V; Cordel, H; Bonnet, M (BMJ Journals, 2018-08-20)
    Diagnosis of intrathoracic tuberculosis (ITB) is limited in children partly by their difficulty to produce sputum specimen.
  • 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; Barry, P; Becerra, M; Chan, ED; Chan, PC; Ioana Chiotan, D; Crossa, A; Drobac, PC; Fairlie, L; Falzon, D; Flood, J; Gegia, M; Hicks, RM; Isaakidis, P; Kadri, SM; Kampmann, B; Madhi, SA; Marais, E; Mariandyshev, A; Méndez-Echevarría, A; Moore, BK; Nargiza, P; Ozere, I; Padayatchi, N; Ur-Rehman, S; Rybak, N; Santiago-Garcia, B; Shah, NS; Sharma, S; Shim, TS; Skrahina, A; Soriano-Arandes, A; van den Boom, M; van der Werf, MJ; van der Werf, TS; Williams, B; Yablokova, E; Yim, J; Furin, J; Hesseling, AC (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.
  • 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; Te Riele, J; Conradie, F (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.
  • Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia

    Hewison, C; Bastard, M; Khachatryan, N; Kotrikadze, T; Hayrapetyan, A; Avaliani, Z; Kiria, N; Yegiazaryan, L; Chumburidze, N; Kirakosyan, O; Atshemyan, H; Qayyum, S; Lachenal, N; Varaine, F; Huerga, H (International Union Against Tuberculosis and Lung Disease, 2018-07-01)
    Bedaquiline (BDQ) was initially only available through compassionate use programmes.
  • Impact of pyrazinamide resistance on multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan

    Kuhlin, J; Smith, C; Khaemraev, A; Tigay, Z; Parpieva, N; Tillyashaykhov, M; Achar, J; Hajek, J; Greig, J; du Cros, P; Moore, D (International Union Against Tuberculosis and Lung Disease, 2018-05-01)
    The World Health Organization (WHO) recommends the inclusion of pyrazinamide (PZA) in treatment regimens for multidrug-resistant tuberculosis (MDR-TB) unless resistance has been confirmed.
  • Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high HIV and tuberculosis burden countries: a systematic review

    Atwine, D; Bonnet, M; Taburet, AM (Wiley-Blackwell, 2018-04-06)
    Efavirenz (EFV) and Rifampicin-Isoniazid (RH) are cornerstone drugs in HIV-tuberculosis (TB) co-infection treatment but with complex drug interactions, efficacy and safety challenges. We reviewed recent data on EFV and RH interaction in TB/HIV high-burden countries.
  • Breast tuberculosis in men: A systematic review

    Quaglio, G; Pizzol, D; Bortolani, A; Manenti, F; Isaakidis, P; Putoto, G; Olliaro, PL (Public Library of Science, 2018-04-03)
    Breast tuberculosis in male is a rarely reported and poorly described condition.
  • Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis

    Cox, V; Brigden, G; Crespo, RH; Lessem, E; Lynch, S; Rich, ML; Waning, B; Furin, J (International Union Against Tuberculosis and Lung Disease, 2018-04-01)
    The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.

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