Treatment Outcomes and Adverse Drug Effects of Ethambutol, Cycloserine, and Terizidone for the Treatment of Multidrug-Resistant Tuberculosis in South Africa

ABSTRACTTreatment outcomes among multidrug-resistant tuberculosis (MDR-TB) patients receiving ethambutol, cycloserine, or terizidone as part of a standardized regimen were compared, determining occurrence of serious adverse drug events (SADEs). Newly diagnosed adult MDR-TB patients were enrolled between 2000 and 2004, receiving a standardized multidrug regimen for 18 to 24 months, including ethambutol, cycloserine, or terizidone. Cycloserine and terizidone were recorded individually. SADEs and factors associated with culture conversion and unfavorable treatment outcomes (default, death, treatment failure) were determined. Of 858 patients, 435 (51%) received ethambutol, 278 (32%) received cycloserine, and 145 (17%) received terizidone. Demographic and baseline clinical data were comparable. Successful treatment occurred in 56%, significantly more in patients receiving cycloserine (60%) and terizidone (62%) than in those receiving ethambutol (52% [P = 0.03]). Defaults rates were 30% in ethambutol patients versus 15% and 11% for cycloserine and terizidone patients, respectively. Terizidone was associated with fewer unfavorable outcomes (adjusted odds ratio [AOR], 0.4; P = 0.008; 95% confidence interval [CI], 0.2 to 0.8). Patients receiving cycloserine were more likely to achieve culture conversion than those receiving ethambutol or terizidone (AOR, 2.2; P = 0.02; 95% CI, 1.12 to 4.38). Failure to convert increased the odds of unfavorable outcomes (AOR, 23.7; P < 0.001; 95% CI, 13 to 44). SADEs were reported in two patients receiving ethambutol, seven patients receiving cycloserine, and three receiving terizidone (P = 0.05). Ethambutol was associated with high culture conversion and default rates. Cycloserine achieved higher culture conversion rates than terizidone. Fewer patients on terizidone experienced SADEs, with lower default rates. The differences that we observed between cycloserine and terizidone require further elucidation.

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Effectiveness and Safety of Bedaquiline-containing Regimens for Treatment on Patients With Refractory Rifampicin/multidrug-resistant Tuberculosis: A Retrospective Cohort Study in East China

10.21203/rs.3.rs-833736/v1 ◽

2021 ◽

Author(s):

Shao-Jun Zhang ◽

Yan Yang ◽

Wen-Wen Sun ◽

Zhong-Shun Zhang ◽

He-ping Xiao ◽

...

Keyword(s):

Treatment Outcomes ◽

Treatment Success ◽

Multidrug Resistant ◽

East China ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Conversion Rates ◽

Mdr Tb ◽

Culture Conversion ◽

Closing Rate

Abstract Objective: To compare the effectiveness and safety of bedaquiline-containing and bedaquiline-free regimens for treatment of patients with refractory rifampicin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB).Methods: Patients with refractory RR/MDR-TB receiving bedaquiline-containing regimens (bedaquiline group, n=102) and bedaquiline-free regimens (non-bedaquiline group, n=100) were included in this retrospective historical control study across East China. The culture conversion, end-of-treatment outcomes, cavity closing rate, and adverse events (AEs) were compared between the two groups. Univariate and multivariate analyses were performed to identify independent predictors of treatment success and culture reversion.Results: The baseline characteristics of the patients were well balanced between the two groups. The culture conversion rates in the bedaquiline group at month 3 (89.2% vs. 66.0%), month 6 (90.2% vs. 72.0%), month 9 (91.2% vs. 66.0%), and month 12 (94.1% vs. 65.0%) were all significantly higher than those in the non-bedaquiline group (all p<0.001). Similar results were observed in the cavity closing rate at month 9 (19.6% vs. 8.0%, p=0.017) and month 12 (39.2% vs. 15.0%, p<0.001). Patients receiving bedaquiline-containing regimens had more treatment success than those receiving bedaquiline-free regimens (p<0.001; cure rate, 69.6% vs. 45.0%; complete the treatment, 22.5% vs. 18.0%; treatment success, 92.2% vs. 63.0%). The use of bedaquiline was identified as an independent predictor of both treatment success (OR=7.356, 95% CI: 2.920–18.530, p<0.001) and culture reversion (OR=0.124, 95% CI: 0.035–0.452, p<0.001). AEs were similarly reported in 26.5% of patients in the bedaquiline group and 19.0% in the non-bedaquiline group (p=0.206).Conclusions: Bedaquiline-containing regimens resulted in better treatment outcomes and similar safety relative to bedaquiline-free regimens for patients with refractory pulmonary RR/MDR-TB.

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An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis

European Respiratory Journal ◽

10.1183/13993003.00803-2016 ◽

2017 ◽

Vol 49 (3) ◽

pp. 1600803 ◽

Cited By ~ 36

Author(s):

Mayara Lisboa Bastos ◽

Zhiyi Lan ◽

Dick Menzies

Keyword(s):

Systematic Review ◽

Treatment Outcomes ◽

Multidrug Resistant ◽

Current Evidence ◽

Aminosalicylic Acid ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

End Of Treatment ◽

Mdr Tb ◽

Culture Conversion

This systematic review aimed to update the current evidence for multidrug-resistant tuberculosis (MDR-TB) treatment.We searched for studies that reported treatment information and clinical characteristics for at least 25 patients with microbiologically confirmed pulmonary MDR-TB and either end of treatment outcomes, 6-month culture conversion or severe adverse events (SAEs). We assessed the association of these outcomes with patients' characteristics or treatment parameters. We identified 74 studies, including 17 494 participants.The pooled treatment success was 26% in extensively drug-resistant TB (XDR-TB) patients and 60% in MDR-TB patients. Treatment parameters such as number or duration and individual drugs were not associated with improved 6-month sputum culture conversion or end of treatment outcomes. However, MDR-TB patients that received individualised regimens had higher success than patients who received standardised regimens (64% versus 52%; p<0.0.01). When reports from 20 cohorts were pooled, proportions of SAE ranged from 0.5% attributed to ethambutol to 12.2% attributed to para-aminosalicylic acid. The lack of significant associations of treatment outcomes with specific drugs or regimens may reflect the limitations of pooling the data rather than a true lack of differences in efficacy of regimens or individual drugs.This analysis highlights the need for stronger evidence for treatment of MDR-TB from better-designed and reported studies.

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Time to sputum culture conversion and its predictors among patients with multidrug resistant tuberculosis in Hangzhou, China: a retrospective cohort study

10.21203/rs.2.13140/v1 ◽

2019 ◽

Author(s):

Qingchun Li ◽

Min Lu ◽

Evelyn Hsieh ◽

Limin Wu ◽

Yifei Wu ◽

...

Keyword(s):

Cohort Study ◽

Treatment Outcomes ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Multidrug Resistant ◽

Sputum Culture Conversion ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Culture Conversion

Abstract Background To investigate the time to initial sputum culture conversion (SCC) and its predictors among multidrug-resistant tuberculosis (MDR-TB) patients in Hangzhou, China.Methods A retrospective cohort study was conducted among patients initiating treatment for MDR-TB from 2011-2015 in Hangzhou, China. Time to initial SCC was analyzed using the Kaplan-Meier method, and Cox proportional hazards regression was used to identify predictors of SCC.Results Among 384 patients enrolled with MDR-TB, 359 (93.5%) successfully achieved initial SCC after a median of 85 days (inter-quartile range, 40-112 days). A higher rate of SCC was observed in participants with successful treatment outcomes than those with poor treatment outcomes (P<0.01). Multivariate analysis showed that age 25-64 years (adjusted odds ratio [AOR], 0.7; 95% confidence interval [CI], 0.5-0.9; P<0.01), age ≥65 years (AOR, 0.5; 95%CI, 0.3-0.8; P<0.01) and household registration in Hangzhou (AOR, 1.3; 95%CI, 1.0-1.5; P<0.05) were found to be associated with SCC.Conclusions Although high SCC and treatment success rates were observed among MDR-TB patients in Hangzhou, the prolonged duration to initial SCC underscores the importance of emphasizing measures for infection control. A new policy of shifting outpatient treatment to inpatient treatment in China may reduce the risk of transmission from patients in the time window prior to SCC.

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Genotypic Resistance of Pyrazinamide but Not Minimum Inhibitory Concentration Is Associated With Longer Time to Sputum Culture Conversion in Patients With Multidrug-resistant Tuberculosis

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1509 ◽

2020 ◽

Author(s):

Johanna Kuhlin ◽

Lina Davies Forsman ◽

Mikael Mansjö ◽

Michaela Jonsson Nordvall ◽

Maria Wijkander ◽

...

Keyword(s):

Treatment Outcome ◽

Minimum Inhibitory Concentration ◽

Inhibitory Concentration ◽

Multidrug Resistant ◽

Sputum Culture ◽

Sputum Culture Conversion ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Culture Conversion

Abstract Background Pyrazinamide (PZA) resistance in multidrug-resistant tuberculosis (MDR-TB) is common; yet, it is not clear how it affects interim and treatment outcomes. Although rarely performed, phenotypic drug susceptibility testing (pDST) is used to define PZA resistance, but genotypic DST (gDST) and minimum inhibitory concentration (MIC) could be beneficial. We aimed to assess the impact of PZA gDST and MIC on time to sputum culture conversion (SCC) and treatment outcome in patients with MDR-TB. Methods Clinical, microbiological, and treatment data were collected in this cohort study for all patients diagnosed with MDR-TB in Sweden from 1992–2014. MIC, pDST, and whole-genome sequencing of the pncA, rpsA, and panD genes were used to define PZA resistance. A Cox regression model was used for statistical analyses. Results Of 157 patients with MDR-TB, 56.1% (n = 88) had PZA-resistant strains and 49.7% (n = 78) were treated with PZA. In crude and adjusted analysis (hazard ratio [HR], 0.49; 95% conficence interval [CI], .29-.82; P = .007), PZA gDST resistance was associated with a 29-day longer time to SCC. A 2-fold decrease in dilutions of PZA MIC for PZA-susceptible strains showed no association with SCC in crude or adjusted analyses (HR, 0.98; 95% CI, .73–1.31; P = .89). MIC and gDST for PZA were not associated with treatment outcome. Conclusions In patients with MDR-TB, gDST PZA resistance was associated with a longer time to SCC. Rapid PZA gDST is important to identify patients who may benefit from PZA treatment.

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Treatment outcomes in multidrug-resistant tuberculosis according to pyrazinamide susceptibility

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.19.0314 ◽

2020 ◽

Vol 24 (2) ◽

pp. 233-239

Author(s):

S. Park ◽

K-W. Jo ◽

T. S. Shim

Keyword(s):

Success Rate ◽

Treatment Outcomes ◽

Treatment Success ◽

Multidrug Resistant ◽

Treatment Success Rate ◽

Aminosalicylic Acid ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Effective Drugs

BACKGROUND: Pyrazinamide (PZA) is an important anti-tuberculosis drug for multidrug-resistant tuberculosis (MDR-TB). However, PZA has recently been demoted within the hierarchy of TB drugs used for MDR-TB.METHODS: We conducted a retrospective cohort study to investigate treatment outcomes for simple MDR-TB (susceptible to both second-line injectable drugs and fluoroquinolones) according to PZA susceptibility.RESULTS: Among 216 pulmonary MDR-TB patients included in the study, 68 (31.5%) were PZA-resistant (PZA-R). The mean age was 41.8 years, and 63.4% were male. Baseline characteristics such as comorbidity, previous TB history, acid-fast bacilli (AFB) smear positivity and cavitation were similar in PZA-susceptible (PZA-S) and PZA-R patients. The number of potentially effective drugs was slightly higher among PZA-S patients than among the PZA-R (5.1 vs. 4.8, respectively; P = 0.003). PZA was more frequently used in PZA-S patients (73.0%) than in the PZA-R (14.7%), while para-aminosalicylic acid was more frequently used in PZA-R than in PZA-S patients (76.5% vs. 50.7%). The treatment success rate was similar in PZA-S (77.7%) and PZA-R (75.0%) patients. PZA resistance was not associated with treatment success in multivariate analysis.CONCLUSIONS: PZA-resistant simple MDR-TB patients had the same treatment success rate as the PZA-susceptible group even without using novel anti-TB drugs.

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Analysis of Smear Microscopy and Culture Conversion Results in Multidrug-Resistant Tuberculosis Patients with and without Type 2 Diabetes Mellitus

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v26i3.1590 ◽

2020 ◽

Vol 26 (3) ◽

Author(s):

Henny Fauziah ◽

Aprianti S. ◽

Handayani I. ◽

Kadir NA

Keyword(s):

Diabetes Mellitus ◽

Multidrug Resistant ◽

World Health ◽

Smear Microscopy ◽

Tuberculosis Patients ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Significant Difference ◽

Mdr Tb ◽

Culture Conversion

The World Health Organization (WHO) recommended microscopic AFB smear examination and culture as follow-ups to the response of MDR TB therapy. Analyzed the results of microscopic AFB smear and culture conversion as well as treatment outcome in Multidrug-Resistant Tuberculosis (MDR-TB) patients with and without Diabetes Mellitus (DM). This is a retrospective study involved 70 MDR-TB patients with (27 patients) with DM and without DM (43 patients) who had microscopic AFB smear and culture results at the start of the follow-up therapy. This research was conducted at Labuang Baji Regional Public Hospital, Makassar, from June to July 2019, used medical records of MDR-TB patients the period of June 2016 to December 2017. The results showed that 52 out of 70 MDR-TB patients had microscopic AFB smear and culture conversion in MDR-TB with DM (21 patients) and without DM (31 patients). The duration of microscopic AFB smear conversion in MDR TB patients with DM (3.33±0.54 months) was longer than patients without DM (2.07±0.05 months), p=0.001. While in culture conversion, there was no significant difference between MDR-TB with DM (1.28±0.64 months) and without DM (1.25±0.59), p=0.648. The recovery outcome between MDR-TB with (48.1%) and without DM (48.8%) was not significantly different. However, the output of treatment failure was greater in DM (11.2%) than without DM (2.3%), although statistically, there was no significant difference (p=0.568). Multidrug-resistant tuberculosis patients with DM experienced slower microscopic AFB smear conversion than MDR-TB patients without DM. However, in culture, there was no significant difference in the conversion period between the two groups. MDR-TB patients, both of with and without DM, had the same chance of recovery.

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Treatment Outcome of a Shorter Regimen Containing Clofazimine for Multidrug-resistant Tuberculosis: A Randomized Control Trial in China

Clinical Infectious Diseases ◽

10.1093/cid/ciz915 ◽

2019 ◽

Vol 71 (4) ◽

pp. 1047-1054 ◽

Cited By ~ 1

Author(s):

Yadong Du ◽

Chao Qiu ◽

Xiaohong Chen ◽

Jing Wang ◽

Wei Jing ◽

...

Keyword(s):

Multidrug Resistant ◽

Sputum Culture ◽

Control Group ◽

Sputum Culture Conversion ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Significant Difference ◽

Mdr Tb ◽

Experimental Group ◽

Culture Conversion

Abstract Background The emergence of multidrug-resistant tuberculosis (MDR-TB) poses a serious obstacle to global TB control programs. Methods We carried out a prospective, randomized, multicenter study in China that was focused on the potential of a shorter regimen containing clofazimine (CFZ) for the treatment of MDR-TB. There were 135 MDR-TB cases that met eligibility requirements and were randomly stratified into either the control group or experimental group. Patients in the control group received an 18-month treatment regimen, whereas patients in the experimental group received a 12-month treatment regimen containing CFZ. Results At the completion of the treatment period, the difference in sputum-culture conversion rates between the experimental group and the control group was not significant. Notably, by the end of 3 months of treatment, 68.7% patients receiving the experimental regimen had sputum-culture conversion, as compared with 55.9% of those receiving the control regimen; this was a significant difference, suggesting an early sputum conversion (P = .04). There were 67 adverse events reported in 56 patients in this study, including 32 in the control group and 35 in the experimental group. No significant difference in the overall incidences of adverse events was observed between the 2 groups. Conclusions The MDR-TB patients treated with the shorter regimen containing CFZ had a comparable successful outcome rate when compared to those with the standard regimen. The patients assigned to the experimental group achieved more rapid sputum-culture conversion, reflecting superior antimicrobial activity against MDR-TB. Clinical Trials Registration Chinese Clinical Trial Registry ChiCTR 1800020391.

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Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00962-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 5928-5932 ◽

Cited By ~ 25

Author(s):

Chawangwa Modongo ◽

Jotam G. Pasipanodya ◽

Beki T. Magazi ◽

Shashikant Srivastava ◽

Nicola M. Zetola ◽

...

Keyword(s):

Characteristic Curve ◽

Multidrug Resistant ◽

Sputum Culture ◽

Classification And Regression Tree ◽

Fiber System ◽

Sputum Culture Conversion ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Culture Conversion

ABSTRACTAminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0–24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0–24, and trough concentrations. The primary node for failure had two competing variables,Cmaxof <67 mg/liter and AUC0–24of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R2= 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacinCmaxof ≥67 mg/liter versus 3/15 (20%) in those with aCmaxof <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacinCmaxand AUC0–24below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.

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Adverse treatment outcomes in multidrug resistant tuberculosis go beyond the microbe-drug interaction: Results of a multiple correspondence analysis.

Biomédica ◽

10.7705/biomedica.5072 ◽

2020 ◽

Vol 40 (4) ◽

pp. 616-625

Author(s):

Ángela Tobón ◽

Johana Rueda ◽

Diego H. Cáceres ◽

Gloria I. Mejía ◽

Elsa M. Zapata ◽

...

Keyword(s):

Treatment Outcomes ◽

Treatment Success ◽

Multidrug Resistant ◽

Chronic Obstructive ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Poor Outcomes ◽

Lost To Follow Up

Introduction: Multidrug-resistant tuberculosis treatment is effective in 50% of patients due to several factors including antibiotic susceptibility of the microorganism, adverse treatment reactions, social factors, and associated comorbidities.Objectives: In this study, we describe the demographics, clinical characteristics, and factors associated with treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) patients in Medellín, Colombia.Materials and methods: We conducted a retrospective analysis using data from patients diagnosed with MDR-TB attending Hospital La María in Medellín, Colombia, for treatment between 2010 and 2015. Patients were categorized as having successful (cured) or poor (failure, lost to follow-up, and death) treatment outcomes. Associations between demographic, clinical factors, laboratory results, treatment outcomes, and follow-up information were evaluated by univariate, multivariate, and multiple correspondence analyses.Results: Of the 128 patients with MDR-TB, 77 (60%) had successful outcomes. Of those with poor outcomes, 26 were lost to follow-up, 15 died, and 10 were treatment failures. Irregular treatment, the presence of comorbidities, and positive cultures after more than two months of treatment were associated with poor outcomes compared to successful ones (p<0.05 for all). The multiple correspondence analyses grouped patients who were lost to follow-up, had HIV, and drug addiction, as well as patients with treatment failure, irregular treatment, and chronic obstructive pulmonary disease.Conclusion: The recognition of factors affecting treatment is essential and was associated with treatment outcomes in this series of patients. Early identification of these factors should increase the rates of treatment success and contribute to MDR-TB control.

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Treatment outcomes and antiretroviral uptake in Multidrug-Resistant Tuberculosis and HIV coinfected Patients in Sub Saharan Africa. A Systematic Review and Meta-Analysis

10.21203/rs.2.10131/v1 ◽

2019 ◽

Author(s):

Elvis Dzelamonyuy Chem ◽

Marie Claire Van Hout ◽

Vivian Hope

Keyword(s):

Treatment Outcomes ◽

Meta Analysis ◽

Multidrug Resistant ◽

Pooled Analysis ◽

Sub Saharan Africa ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Sub Saharan ◽

Hiv Negative

Abstract Background Multidrug-resistant tuberculosis (MDR-TB) in HIV endemic settings is a major threat to public health. MDR-TB is a substantial and underreported problem in Sub-Saharan Africa (SSA), with recognised cases projected to increase with advancement in diagnostic technology. There is paucity of review evidence on treatment outcomes and antiretroviral (ART) uptake among MDR-TB patients with HIV in SSA. To address this gap a review of treatment outcomes in HIV patients co-infected with MDR-TB in the SSA region was undertaken. Methods Three databases (Medline, Web of Science, CINHAL), Union on Lung Heath conference proceedings and grey literature were searched for publications between January 2004 and May 2018. Records were assessed for eligibility and data extracted. Random effect meta-analysis was conducted using STATA and Cochrane’s review manager. Results A total of 271 publications were identified of which nine fulfilled the inclusion criteria. Data was collected from 3,368 MDR-TB and HIV co-infected patients from four SSA countries; South Africa (6), Lesotho (1), Botswana (1) and Ethiopia (1). The most common outcome was cure (34.9% cured in the pooled analysis), this was followed by death (18.1% in pooled analysis). ART uptake was high, at 83% in the pooled analysis. Cure ranged from 22.2% to 57.7% among patients on ART and from 28.6% to 54.7% among those not on ART medication. MDR-TB and HIV coinfected patients were less likely to be successfully treated than HIV negative MDR-TB patients (Risk Ratio = 0.87, 95% CI 0.97, 0.96). Conclusion Treatment outcomes for MDR-TB and HIV coinfected patients do not vary widely from those reported globally. However, treatment success was lower among HIV positive MDR-TB patients compared to HIV negative MDR-TB patients. Prompt antiretroviral initiation and interventions to improve treatment adherence are necessary.

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