Publications by authors named "Iqbal Master"

20 Publications

  • Page 1 of 1

Effectiveness and cardiac safety of bedaquiline-based therapy for drug-resistant tuberculosis: a prospective cohort study.

Clin Infect Dis 2021 Apr 21. Epub 2021 Apr 21.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Bedaquiline improves treatment outcomes in patients with rifampin-resistant TB (RR-TB) but prolongs the QT-interval and carries a black-box warning by the U.S. Food and Drug Administration. The World Health Organization recommends that all patients with RR-TB receive a regimen containing bedaquiline, yet a phase 3 clinical trial demonstrating its cardiac safety has not been published.

Methods: We conducted an observational cohort study of RR-TB patients from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, including electrocardiograms (ECGs) performed in triplicate at four time points during bedaquiline therapy. Participants were followed until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT-prolongation, defined as any QTcF>500 ms or an absolute change from baseline (△ QTcF) >60 ms.

Results: We enrolled 195 eligible participants, of whom 40% had extensively drug-resistant (XDR) TB. Most participants (97%) received concurrent clofazimine. 74% of participants were cured or successfully completed treatment, and outcomes did not differ by HIV status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase of 23.7 (SD 22.7) ms from baseline to month 6. Four participants experienced a QTcF>500 ms and 19 experienced a △QTcF>60 ms. Older age was independently associated with QT-prolongation. QT-prolongation was neither more common nor severe in participants receiving concurrent lopinavir-ritonavir.

Conclusions: Severe QT-prolongation was uncommon and did not require permanent discontinuation of either bedaquiline or clofazimine. Close QT-monitoring may be advisable in older patients.
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http://dx.doi.org/10.1093/cid/ciab335DOI Listing
April 2021

Responding to SARS-CoV-2 in South Africa: what can we learn from drug-resistant tuberculosis?

Eur Respir J 2020 07 23;56(1). Epub 2020 Jul 23.

Dept of Medicine and Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.

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http://dx.doi.org/10.1183/13993003.01369-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257618PMC
July 2020

Maternal and Infant Outcomes Among Pregnant Women Treated for Multidrug/Rifampicin-Resistant Tuberculosis in South Africa.

Clin Infect Dis 2021 04;72(7):1158-1168

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, South Africa.

Background: Data on safety and efficacy of second-line tuberculosis drugs in pregnant women and their infants are severely limited due to exclusion from clinical trials and expanded access programs.

Methods: Pregnant women starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa, from 1 January 2013 to 31 December 2017, were included. We conducted a record review to describe maternal treatment and pregnancy outcomes, and a clinical assessment to describe infant outcomes.

Results: Of 108 pregnant women treated for MDR/RR-tuberculosis, 88 (81%) were living with human immunodeficiency virus.. Favorable MDR/RR-tuberculosis treatment outcomes were reported in 72 (67%) women. Ninety-nine (91%) of the 109 babies were born alive, but overall, 52 (48%) women had unfavorable pregnancy outcomes. Fifty-eight (54%) women received bedaquiline, and 49 (45%) babies were exposed to bedaquiline in utero. Low birth weight was reported in more babies exposed to bedaquiline compared to babies not exposed (45% vs 26%; P = .034). In multivariate analyses, bedaquiline and levofloxacin, drugs often used in combination, were both independently associated with increased risk of low birth weight. Of the 86 children evaluated at 12 months, 72 (84%) had favorable outcomes; 88% of babies exposed to bedaquiline were thriving and developing normally compared to 82% of the babies not exposed.

Conclusions: MDR/RR-tuberculosis treatment outcomes among pregnant women were comparable to nonpregnant women. Although more babies exposed to bedaquiline were of low birth weight, over 80% had gained weight and were developing normally at 1 year.
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http://dx.doi.org/10.1093/cid/ciaa189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028100PMC
April 2021

The Impact of Concurrent Antiretroviral Therapy and MDR-TB Treatment on Adverse Events.

J Acquir Immune Defic Syndr 2020 01;83(1):47-55

Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.

Background: South Africa has among the highest incidence of multidrug-resistant tuberculosis (MDR-TB) and more than 70% of patients are HIV co-infected. MDR-TB treatment is associated with frequent adverse events (AEs). Although guidelines recommend concurrent treatment of MDR-TB and HIV, safety data on concurrent therapy are limited.

Methods: We conducted a prospective observational study of MDR-TB patients with and without HIV-coinfection in South Africa between 2011 and 2015. Participants received standardized MDR-TB and HIV regimens. Participants were followed monthly for the duration of MDR-TB therapy and screened for clinical and laboratory AEs. Audiometry was performed monthly during the intensive phase; color discrimination testing was performed every 2 months.

Results: We enrolled 150 HIV-infected and 56 HIV-uninfected participants. Nearly all experienced at least one clinical (93%) or laboratory (96%) AE. The most common clinical AEs were peripheral neuropathy (50%) and difficulty sleeping (48%); the most common laboratory AEs were hypokalemia (47%) and decreased creatinine clearance (46%). Among 19 clinical and lab AEs examined, there were no differences by HIV status, except for diarrhea (27% HIV-infected vs. 13% HIV-uninfected, P = 0.03). Hearing loss was experienced by 72% of participants (8% severe loss). Fourteen percent experienced color discrimination loss (4% severe loss). There were no differences in frequency or severity of hearing or vision loss by HIV status.

Conclusions: AEs were common, but not more frequent or severe among MDR-TB/HIV co-infected participants receiving concurrent antiretroviral therapy. Given the favorable treatment outcomes associated with concurrent treatment, antiretroviral therapy initiation should not be delayed in MDR-TB patients with HIV-coinfection.
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http://dx.doi.org/10.1097/QAI.0000000000002190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903405PMC
January 2020

Spatiotemporal Clustering of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Is Associated With Human Immunodeficiency Virus Status and Drug-Susceptibility Patterns in KwaZulu-Natal, South Africa.

Clin Infect Dis 2020 05;70(10):2224-2227

Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Medical Center, New York, New York, USA.

Using an open-access spatiotemporal analytics program, we mapped spatiotemporal heterogeneity loci in tuberculosis (TB) cases (clusters) and dynamic changes, and characterized the drug-resistant TB clustering risk using routine microbiological data from KwaZulu-Natal, South Africa. The data may provide insight into transmission dynamics and support efficient deployment of public health resources.
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http://dx.doi.org/10.1093/cid/ciz913DOI Listing
May 2020

A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.

N Engl J Med 2019 03 13;380(13):1201-1213. Epub 2019 Mar 13.

From the Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL), London (A.J.N, P.P.J.P., S.K.M., K.S.), and the Liverpool School of Tropical Medicine, Liverpool (S.B.S.) - both in the United Kingdom; International Union against Tuberculosis and Lung Disease (the Union), Paris (C.-Y.C., A.D., I.D.R.); the Department of Internal Medicine, Wanfang Hospital, and School of Medicine, Taipei Medical University (C.-Y.C.) - both in Taipei, Taiwan; the University of Witwatersrand, Faculty of Health Sciences, Johannesburg (F.C.), King Dinizulu Hospital Complex, Kwazulu Natal (I.M., N.N.), and Think TB and HIV Investigative Network, Durban (R.M.) - all in South Africa; National Center for Communicable Diseases (D.D.) and the Mongolian Tuberculosis Coalition (B.T.) - both in Ulaanbaatar, Mongolia; the Institute of Tropical Medicine, Antwerp, Belgium (A.D., G.T.); Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam (P.-T.D., N.L.); Armauer Hansen Research Institute (T.M.), and St. Peter's Tuberculosis Specialized Hospital and Global Health Committee (D.M.) - all in Addis Ababa, Ethiopia; the Division of Research and Development, Vital Strategies, New York (I.D.R.); and the Dalla Lana School of Public Health, University of Toronto, Toronto (I.D.R.).

Background: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.

Methods: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority.

Results: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.

Conclusions: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).
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http://dx.doi.org/10.1056/NEJMoa1811867DOI Listing
March 2019

High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen.

Eur Respir J 2018 12 20;52(6). Epub 2018 Dec 20.

University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa.

South African patients with rifampicin-resistant tuberculosis (TB) and resistance to fluoroquinolones and/or injectable drugs (extensively drug-resistant (XDR) and preXDR-TB) were granted access to bedaquiline through a clinical access programme with strict inclusion and exclusion criteria.PreXDR-TB and XDR-TB patients were treated with 24 weeks of bedaquiline within an optimised, individualised background regimen that could include levofloxacin, linezolid and clofazimine as needed. 200 patients were enrolled: 87 (43.9%) had XDR-TB, 99 (49.3%) were female and the median age was 34 years (interquartile range (IQR) 27-42). 134 (67.0%) were living with HIV; the median CD4 count was 281 cells·μL (IQR 130-467) and all were on antiretroviral therapy.16 out of 200 patients (8.0%) did not complete 6 months of bedaquiline: eight were lost to follow-up, six died, one stopped owing to side effects and one was diagnosed with drug-sensitive TB. 146 out of 200 patients (73.0%) had favourable outcomes: 139 (69.5%) were cured and seven (3.5%) completed treatment. 25 patients (12.5%) died, 20 (10.0%) were lost from treatment and nine (4.5%) had treatment failure. 22 adverse events were attributed to bedaquiline, including a QT interval corrected using the Fridericia formula (QTcF) >500 ms (n=5), QTcF increase >50 ms from baseline (n=11) and paroxysmal atrial flutter (n=1).Bedaquiline added to an optimised background regimen was associated with a high rate of successful treatment outcomes for this preXDR-TB and XDR-TB cohort.
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http://dx.doi.org/10.1183/13993003.01528-2018DOI Listing
December 2018

Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study.

Lancet Respir Med 2018 09 11;6(9):699-706. Epub 2018 Jul 11.

Right to Care, Johannesburg, South Africa; University of Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa.

Background: 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.

Methods: In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment.

Findings: 24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28-0·46) and extensively drug-resistant tuberculosis (0·26, 0·18-0·38) compared with standard regimens.

Interpretation: Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(18)30235-2DOI Listing
September 2018

MDR-TB patients in KwaZulu-Natal, South Africa: Cost-effectiveness of 5 models of care.

PLoS One 2018 18;13(4):e0196003. Epub 2018 Apr 18.

Health Systems Research Unit, South African Medical Research Council, Cape Town, South Africa.

Background: South Africa has a high burden of MDR-TB, and to provide accessible treatment the government has introduced different models of care. We report the most cost-effective model after comparing cost per patient successfully treated across 5 models of care: centralized hospital, district hospitals (2), and community-based care through clinics or mobile injection teams.

Methods: In an observational study five cohorts were followed prospectively. The cost analysis adopted a provider perspective and economic cost per patient successfully treated was calculated based on country protocols and length of treatment per patient per model of care. Logistic regression was used to calculate propensity score weights, to compare pairs of treatment groups, whilst adjusting for baseline imbalances between groups. Propensity score weighted costs and treatment success rates were used in the ICER analysis. Sensitivity analysis focused on varying treatment success and length of hospitalization within each model.

Results: In 1,038 MDR-TB patients 75% were HIV-infected and 56% were successfully treated. The cost per successfully treated patient was 3 to 4.5 times lower in the community-based models with no hospitalization. Overall, the Mobile model was the most cost-effective.

Conclusion: Reducing the length of hospitalization and following community-based models of care improves the affordability of MDR-TB treatment without compromising its effectiveness.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196003PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906004PMC
July 2018

Improved Survival and Cure Rates With Concurrent Treatment for Multidrug-Resistant Tuberculosis-Human Immunodeficiency Virus Coinfection in South Africa.

Clin Infect Dis 2018 04;66(8):1246-1253

Rollins School of Public Health, Emory University, Atlanta, Georgia.

Background: Mortality in multidrug-resistant (MDR) tuberculosis-human immunodeficiency virus (HIV) coinfection has historically been high, but most studies predated the availability of antiretroviral therapy (ART). We prospectively compared survival and treatment outcomes in MDR tuberculosis-HIV-coinfected patients on ART to those in patients with MDR tuberculosis alone.

Methods: This observational study enrolled culture-confirmed MDR tuberculosis patients with and without HIV in South Africa between 2011 and 2013. Participants received standardized MDR tuberculosis and HIV regimens and were followed monthly for treatment response, adverse events, and adherence. The primary outcome was survival.

Results: Among 206 participants, 150 were HIV infected, 131 (64%) were female, and the median age was 33 years (interquartile range [IQR], 26-41). Of the 191 participants with a final MDR tuberculosis outcome, 130 (73%) were cured or completed treatment, which did not differ by HIV status (P = .50). After 2 years, CD4 count increased a median of 140 cells/mm3 (P = .005), and 64% had an undetectable HIV viral load. HIV-infected and HIV-uninfected participants had high rates of survival (86% and 94%, respectively; P = .34). The strongest risk factor for mortality was having a CD4 count ≤100 cells/mm3 (adjusted hazards ratio, 15.6; 95% confidence interval, 4.4-55.6).

Conclusions: Survival and treatment outcomes among MDR tuberculosis-HIV individuals receiving concurrent ART approached those of HIV-uninfected patients. The greatest risk of death was among HIV-infected individuals with CD4 counts ≤100 cells/mm3. These findings provide critical evidence to support concurrent treatment of MDR tuberculosis and HIV.
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http://dx.doi.org/10.1093/cid/cix1125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888963PMC
April 2018

Dilemma of managing asymptomatic children referred with 'culture-confirmed' drug-resistant tuberculosis.

Arch Dis Child 2016 07 4;101(7):608-13. Epub 2016 Apr 4.

Department of Medicine, Montefiore Medical Center & Albert Einstein College of Medicine, Bronx, New York, USA.

Background: The diagnosis of drug-resistant tuberculosis (DR-TB) in children is challenging and treatment is associated with many adverse effects.

Objective: We aimed to assess if careful observation, without initiation of second-line treatment, is safe in asymptomatic children referred with 'culture-confirmed' DR-TB.

Setting: KwaZulu-Natal, South Africa-an area with high burdens of HIV, TB and DR-TB.

Design, Intervention And Main Outcome Measures: We performed an outcome review of children with 'culture-confirmed' DR-TB who were not initiated on second-line TB treatment, as they were asymptomatic with normal chest radiographs on examination at our specialist referral hospital. Children were followed up every other month for the first year, with a final outcome assessment at the end of the study.

Results: In total, 43 asymptomatic children with normal chest radiographs were reviewed. The median length of follow-up until final evaluation was 549 days (IQR 259-722 days); most (34; 83%) children were HIV uninfected. Resistance patterns included 9 (21%) monoresistant and 34 (79%) multidrug-resistant (MDR) strains. Fifteen children (35%) had been treated with first-line TB treatment, prior to presentation at our referral hospital. At the final evaluation, 34 (80%) children were well, 7 (16%) were lost to follow-up, 1 (2%) received MDR-TB treatment and 1 (2%) died of unknown causes. The child who received MDR-TB treatment developed new symptoms at the 12-month review and responded well to second-line treatment.

Conclusions: Bacteriological evaluation should not be performed in the absence of any clinical indication. If drug-resistant Mycobacterium tuberculosis is detected in an asymptomatic child with a normal chest radiograph, close observation may be an appropriate strategy, especially in settings where potential laboratory error and poor record keeping are constant challenges.
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http://dx.doi.org/10.1136/archdischild-2015-310186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996348PMC
July 2016

Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

J Acquir Immune Defic Syndr 2015 Aug;69(5):536-43

*Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NY; †Department of Epidemiology, Columbia Mailman School of Public Health, New York, NY; ‡Centre for AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa; §Department of Microbiology, National Health Laboratory Service (NHLS), Durban, South Africa; ‖Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; ¶DR-TB Department, King Dinuzulu Hospital, Department of Health, Sydenham, South Africa; and #Department of Epidemiology, Boston University School of Public Health, Boston, MA.

Background: Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug-susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed patients with XDR-TB in KwaZulu-Natal, South Africa.

Methods: Retrospective cohort study of consecutive patients with XDR-TB admitted to a TB referral hospital without previous XDR-TB treatment. A subset of isolates had extended DST (including capreomycin), mutational analysis, and IS6110 restriction fragment length polymorphism assays.

Results: A total of 216 eligible patients with XDR-TB were identified. The majority were treated with capreomycin (72%), were young (median age: 35.5 years), and were female (56%). One hundred five (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. A total of 47/52 (90.4%) patients with XDR-TB were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible, although this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin-resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%).

Conclusions: Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly because of ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all patients with XDR-TB. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.
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http://dx.doi.org/10.1097/QAI.0000000000000650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501864PMC
August 2015

Surgical treatment of complications of pulmonary tuberculosis, including drug-resistant tuberculosis.

Int J Infect Dis 2015 Mar;32:61-7

Division of Therapeutic Immunology, TIM, Dept of Laboratory Medicine, Karolinska Institutet; Center for allogeneic stem cell transplantation (CAST), Karolinska Hospital, Stockholm, Sweden. Electronic address:

Surgery for drug-resistant tuberculosis has been shown to be safe and effective, with similar level of mortalities associated with surgical intervention observed with that for lung cancer. While surgery has been an option to treat TB in the pre-antibiotic era, it is now increasingly used to treat complications of pulmonary TB, particularly in patients with drug-resistant TB who do not respond to medical treatment. The two most frequent indications for lung resection in drug- resistant TB, are i) failed medical treatment with persistent sputum positivity or ii) patients who have had medical treatment and are sputum negative, but with persistent localized cavitary disease or bronchiectasis. Massive hemoptysis is a potentially life-threatening complication of TB. Lung resection is potentially curative in patients with massive hemoptysis and cavitary or bronchiectatic disease. Bronchial artery embolization in these patients has a high success rate but bears also the risk of recurrence. Lung resection can be safely undertaken in selected patients with HIV co-infection and pulmonary complications of TB. Ambulatory drainage is a novel, safe, affordable and effective method of draining a chronic TB associated empyema thoracis. We review here the current surgical treatment of the complications of pulmonary TB and discuss the experience from the Durban Cardiothoracic Surgery Unit for the surgical treatment of patients with complicated pulmonary TB.
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http://dx.doi.org/10.1016/j.ijid.2015.01.019DOI Listing
March 2015

Cellular therapy in tuberculosis.

Int J Infect Dis 2015 Mar;32:32-8

Therapeutic Immunology Division, Dept of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Center for allogeneic stem cell transplantation (CAST), Karolinska Hospital, Stockholm, Sweden. Electronic address:

Cellular therapy now offer promise of potential adjunct therapeutic options for treatment of drug-resistant tuberculosis (TB). We review here the role of Mesenchymal stromal cells, (MSCs), as well as other immune effector cells in the therapy of infectious diseases with a focus on TB. MSCs represent a population of tissue-resident non-hematopoietic adult progenitor cells which home into injured tissues increase the proliferative potential of broncho-alveolar stem cells and restore lung epithelium. MSCs have been shown to be immune-modulatory and anti-inflammatory mediated via cell-cell contacts as well as soluble factors. We discuss the functional profile of MSCs and their potential use for adjunct cellular therapy of multi-drug resistant TB, with the aim of limiting tissue damage, and to convert unproductive inflammatory responses into effective anti-pathogen directed immune responses. Adjunct cellular therapy could potentially offer salvage therapy options for patients with drug-resistant TB, increase clinically relevant anti-M.tuberculosis directed immune responses and possibly shorten the duration of anti-TB therapy.
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http://dx.doi.org/10.1016/j.ijid.2015.01.016DOI Listing
March 2015

Association between health systems performance and treatment outcomes in patients co-infected with MDR-TB and HIV in KwaZulu-Natal, South Africa: implications for TB programmes.

PLoS One 2014 9;9(4):e94016. Epub 2014 Apr 9.

Discipline of Public Health Medicine, University of KwaZulu-Natal, Durban, South Africa.

Objective: To improve the treatment of MDR-TB and HIV co-infected patients, we investigated the relationship between health system performance and patient treatment outcomes at 4 decentralised MDR-TB sites.

Methods: In this mixed methods case study which included prospective comparative data, we measured health system performance using a framework of domains comprising key health service components. Using Pearson Product Moment Correlation coefficients we quantified the direction and magnitude of the association between health system performance and MDR-TB treatment outcomes. Qualitative data from participant observation and interviews analysed using systematic text condensation (STC) complemented our quantitative findings.

Findings: We found significant differences in treatment outcomes across the sites with successful outcomes varying from 72% at Site 1 to 52% at Site 4 (p<0.01). Health systems performance scores also varied considerably across the sites. Our findings suggest there is a correlation between treatment outcomes and overall health system performance which is significant (r = 0.99, p<0.01), with Site 1 having the highest number of successful treatment outcomes and the highest health system performance. Although the 'integration' domain, which measured integration of MDR-TB services into existing services appeared to have the strongest association with successful treatment outcomes (r = 0.99, p<0.01), qualitative data indicated that the 'context' domain influenced the other domains.

Conclusion: We suggest that there is an association between treatment outcomes and health system performance. The chance of treatment success is greater if decentralised MDR-TB services are integrated into existing services. To optimise successful treatment outcomes, regular monitoring and support are needed at a district, facility and individual level to ensure the local context is supportive of new programmes and implementation is according to guidelines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094016PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981751PMC
June 2015

Treatment outcomes for extensively drug-resistant tuberculosis and HIV co-infection.

Emerg Infect Dis 2013 Mar;19(3):416-24

Albert Einstein College of Medicine, Bronx, NY 10461, USA.

High mortality rates have been reported for patients co-infected with extensively drug-resistant tuberculosis (XDR-TB) and HIV, but treatment outcomes have not been reported. We report treatment outcomes for adult XDR TB patients in KwaZulu-Natal Province, South Africa. Initial data were obtained retrospectively, and outcomes were obtained prospectively during 24 months of treatment. A total of 114 XDR TB patients were treated (median 6 drugs, range 3-9 drugs); 82 (73%) were HIV positive and 50 (61%) were receiving antiretroviral therapy. After receiving treatment for 24 months, 48 (42%) of 114 patients died, 25 (22%) were cured or successfully completed treatment, 19 (17%) withdrew from the study, and 22 (19%) showed treatment failure. A higher number of deaths occurred among HIV-positive patients not receiving antiretroviral therapy and among patients who did not show sputum culture conversion. Culture conversion was a major predictor of survival but was poorly predictive (51%) of successful treatment outcome.
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http://dx.doi.org/10.3201/eid1903.120998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647656PMC
March 2013

Survival from XDR-TB is associated with modifiable clinical characteristics in rural South Africa.

PLoS One 2012 6;7(3):e31786. Epub 2012 Mar 6.

Department of Medicine, Section of Infectious Diseases, AIDS Program, Yale University, School of Medicine New Haven, Connecticut, United States of America.

Background: Drug-resistant tuberculosis (TB) is a major threat to global public health. Patients with extensively drug-resistant TB (XDR-TB), particularly those with HIV-coinfection, experience high and accelerated mortality with limited available interventions. To determine modifiable factors associated with survival, we evaluated XDR-TB patients from a community-based hospital in rural South Africa where a large number of XDR-TB cases were first detected.

Methodology/principal Findings: A retrospective case control study was conducted of XDR-TB patients diagnosed from 2005-2008. Survivors, those alive at 180 days from diagnostic sputum collection date, were compared with controls who died within 180 days. Clinical, laboratory and microbiological correlates of survival were assessed in 69 survivors (median survival 565 days [IQR 384-774] and 73 non-survivors (median survival 34 days [IQR 18-90]). Among 129 HIV+ patients, multivariate analyses of modifiable factors demonstrated that negative AFB smear (AOR 8.4, CI 1.84-38.21), a lower laboratory index of routine laboratory findings (AOR 0.48, CI 0.22-1.02), CD4>200 cells/mm(3) (AOR 11.53, 1.1-119.32), and receipt of antiretroviral therapy (AOR 20.9, CI 1.16-376.83) were independently associated with survival from XDR-TB.

Conclusions/significance: Survival from XDR-TB with HIV-coinfection is associated with less advanced stages of both diseases at time of diagnosis, absence of laboratory markers indicative of multiorgan dysfunction, and provision of antiretroviral therapy. Survival can be increased by addressing these modifiable risk factors through policy changes and improved clinical management. Health planners and clinicians should develop programmes focusing on earlier case finding and integration of HIV and drug-resistant TB diagnostic, therapeutic, and preventive activities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031786PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295798PMC
August 2012

Extensively drug-resistant tuberculosis in women, KwaZulu-Natal, South Africa.

Emerg Infect Dis 2011 Oct;17(10):1942-5

Albert Einstein College of Medicine, Bronx, New York, USA.

To determine whether women in KwaZulu-Natal, South Africa, with drug-resistant tuberculosis (TB) were more likely than men to have extensively drug-resistant TB, we reviewed 4,514 adults admitted during 2003-2008 for drug-resistant TB. Female sex independently predicted extensively drug-resistant TB, even after we controlled for HIV infection. This association needs further study.
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http://dx.doi.org/10.3201/eid1710.110105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310667PMC
October 2011

High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers.

Ann Intern Med 2010 Oct;153(8):516-22

Boston University School of Medicine and School of Public Health, Boston, Massachusetts, USA.

Background: Nosocomial transmission has been described in extensively drug-resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden.

Objective: To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among health care workers in KwaZulu-Natal, South Africa.

Design: Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy.

Setting: A public tuberculosis referral hospital in KwaZulu-Natal, South Africa.

Participants: 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment.

Measurements: Hospital admission rates and hospital admission incidence rate ratios.

Results: Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001).

Limitation: The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis.

Conclusion: Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection-control programs.
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http://dx.doi.org/10.7326/0003-4819-153-8-201010190-00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074259PMC
October 2010