Publications by authors named "James C M Brust"

38 Publications

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciab335DOI Listing
April 2021

Clofazimine pharmacokinetics in patients with TB: dosing implications.

J Antimicrob Chemother 2020 11;75(11):3269-3277

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization.

Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients.

Patients And Methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L.

Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant.

Conclusions: Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jac/dkaa310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566350PMC
November 2020

Modeling Missing Cases and Transmission Links in Networks of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

Am J Epidemiol 2020 07;189(7):735-745

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

Patterns of transmission of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases worldwide in 2017. Modeling TB transmission networks can provide insight into drivers of transmission, but incomplete sampling of TB cases can pose challenges for inference from individual epidemiologic and molecular data. We assessed the effect of missing cases on a transmission network inferred from Mycobacterium tuberculosis sequencing data on extensively drug-resistant TB cases in KwaZulu-Natal, South Africa, diagnosed in 2011-2014. We tested scenarios in which cases were missing at random, missing differentially by clinical characteristics, or missing differentially by transmission (i.e., cases with many links were under- or oversampled). Under the assumption that cases were missing randomly, the mean number of transmissions per case in the complete network needed to be larger than 20, far higher than expected, to reproduce the observed network. Instead, the most likely scenario involved undersampling of high-transmitting cases, and models provided evidence for super-spreading. To our knowledge, this is the first analysis to have assessed support for different mechanisms of missingness in a TB transmission study, but our results are subject to the distributional assumptions of the network models we used. Transmission studies should consider the potential biases introduced by incomplete sampling and identify host, pathogen, or environmental factors driving super-spreading.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/aje/kwaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443195PMC
July 2020

Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med 2020 04 17;8(4):383-394. Epub 2020 Mar 17.

Montreal Chest Institute, McGill University Health Centre Research Institute, McGill University, Montreal, QC, Canada. Electronic address:

Background: Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.

Methods: We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.

Findings: 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.

Interpretation: Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.

Funding: Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(20)30047-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384398PMC
April 2020

Complications of Silicone Cosmetic Procedures Among Medical Tourists from the Bronx, New York: A Retrospective Analysis.

J Clin Aesthet Dermatol 2019 Oct 1;12(10):24-28. Epub 2019 Oct 1.

Dr. Zheng is with the Division of Infectious Diseases at Tulane University in New Orleans, Louisiana.

Hundreds of thousands of Americans travel abroad each year for medical care, such as cosmetic silicone procedures. However, medical tourists risk encountering unqualified providers and receiving injectable or implantable cosmetic materials of questionable purity. We performed a retrospective chart review of patients treated at a multisite academic center in the Bronx, New York, between the years 2008 and 2017, and identified 12 patients who developed complications following silicone procedures performed in a foreign country, Puerto Rico, or the United States by an unlicensed provider. Procedures included silicone injections or implants in the breasts, buttocks, and face. Destination countries included the Dominican Republic, Guatemala, Venezuela, and Mexico. The patients in our study suffered significant morbidity, with complications including infection, implant rupture, and silicone migration. Laboratory and radiographic findings demonstrated nonspecific markers of inflammation. The management of silicone complications can be difficult and prolonged, and can place a large financial burden on the healthcare system as well as have significant and long-term negative consequences for the patient. Clinicians should be aware of the risks for adverse events, such as the ones described here following silicone injection and/or implant procedures, in patients who, whether for financial, cultural, or other reasons, chose to undergo cosmetic procedures in another country or by an unlicensed practictioner in the US. It is important that clinicians recognize the considerable and diverse morbidity of such patients and treat them with sensitivity and empathy to ensure optimal outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937147PMC
October 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903405PMC
January 2020

Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa.

Proc Natl Acad Sci U S A 2019 11 28;116(46):23284-23291. Epub 2019 Oct 28.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032;

Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant () strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1906636116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859317PMC
November 2019

Treatment Adherence Among Persons Receiving Concurrent Multidrug-Resistant Tuberculosis and HIV Treatment in KwaZulu-Natal, South Africa.

J Acquir Immune Defic Syndr 2019 10;82(2):124-130

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.

Background: Success in multidrug-resistant tuberculosis (MDR-TB) and HIV treatment requires high medication adherence despite high pill burdens, frequent adverse events, and long treatment duration, which may jeopardize adherence. We prospectively compared MDR-TB/HIV-coinfected persons to those with MDR-TB alone to determine the impact of concurrent treatment on adherence and outcomes.

Methods: We assessed medication adherence monthly using 3-day recall, 30-day recall, and visual analog scale and examined adherence to monthly study visits (months 0-12). We determined the proportion of participants fully adherent (no reported missed doses) to MDR-TB vs. HIV treatment by each measure. We assessed the association of medication and clinic visit adherence with MDR-TB treatment success (cure or completion, 18-24 months) and HIV virologic suppression.

Results: Among 200 patients with MDR-TB, 63% were women, median age was 33 years, 144 (72%) were HIV-infected, and 81% were receiving antiretroviral therapy (ART) at baseline. Adherence to medications (81%-98% fully adherent across all measures) and clinic visits (80% missed ≤1 visit) was high, irrespective of HIV status. Adherence to ART was significantly higher than to MDR-TB treatment by all self-reported measures (3-day recall: 92% vs. 84%, respectively; P = 0.003). In multivariable analysis, the adjusted risk ratio of unsuccessful MDR-TB treatment increased with every missed visit: 1.50, 2.25, and 3.37 for unsuccessful treatment, for 1, 2, and ≥3 missed visits.

Conclusions: Adherence to ART was higher than to MDR-TB treatment among persons with MDR-TB/HIV coinfection. Missed clinic visits may be a simple measure for identifying patients at risk of unsuccessful MDR-TB treatment outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760842PMC
October 2019

Social Mixing and Clinical Features Linked With Transmission in a Network of Extensively Drug-resistant Tuberculosis Cases in KwaZulu-Natal, South Africa.

Clin Infect Dis 2020 05;70(11):2396-2402

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

Background: Tuberculosis (TB) is the leading infectious cause of death globally, and drug-resistant TB strains pose a serious threat to controlling the global TB epidemic. The clinical features, locations, and social factors driving transmission in settings with high incidences of drug-resistant TB are poorly understood.

Methods: We measured a network of genomic links using Mycobacterium tuberculosis whole-genome sequences.

Results: Patients with 2-3 months of cough or who spent time in urban locations were more likely to be linked in the network, while patients with sputum smear-positive disease were less likely to be linked than those with smear-negative disease. Associations persisted using different thresholds to define genomic links and irrespective of assumptions about the direction of transmission.

Conclusions: Identifying factors that lead to many transmissions, including contact with urban areas, can suggest settings instrumental in transmission and indicate optimal locations and groups to target with interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciz636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245156PMC
May 2020

Management of active tuberculosis in adults with HIV.

Lancet HIV 2019 07;6(7):e463-e474

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, South Africa; Division of Clinical Pharmacology, Department of Medicine, South Africa.

Every year, about 1 million people living with HIV worldwide develop tuberculosis. Although the drug regimens used to treat tuberculosis in these patients are the same as those used in HIV-negative patients, cotreatment of tuberculosis with antiretroviral therapy involves challenges including the optimal timing of antiretroviral initiation, drug-drug interactions, drug tolerability, and the prevention and treatment of tuberculosis-associated immune reconstitution syndrome. Furthermore, mortality is high in people with HIV who are diagnosed with tuberculosis during a hospital admission, and in those with tuberculous meningitis. Studies in this field have better characterised these challenges and informed optimal management and guideline revisions. In patients with tuberculosis, antiretroviral therapy improves survival, is well tolerated, and can be adjusted to manage drug-drug interactions with rifampicin. Prednisone is effective in both preventing and treating the paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3018(19)30154-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750245PMC
July 2019

Mutations Causing Discordant Rifampicin Susceptibility in : Retrospective Analysis of Prevalence, Phenotypic, Genotypic, and Treatment Outcomes.

Open Forum Infect Dis 2019 Apr 12;6(4):ofz065. Epub 2019 Feb 12.

Department of Medical Microbiology, KwaZulu-Natal Academic Complex, National Health Laboratory Service, Durban, South Africa.

Background: Discordant genotypic/phenotypic rifampicin susceptibility testing in is a significant challenge, yet there are limited data on its prevalence and how best to manage such patients. Whether to treat isolates with mutations not conferring phenotypic resistance as susceptible or multidrug-resistant tuberculosis (MDR-TB) is unknown. We describe phenotypic and genotypic characteristics of discordant isolates and clinical characteristics and treatment outcomes of affected patients in KwaZulu-Natal, South Africa.

Methods: We analyzed clinical isolates showing rifampicin resistance on GenoType MTBDR while susceptible on 1% agar proportion method. We measured rifampicin minimum inhibitory concentrations (MICs) using Middlebrook 7H10 agar dilution and BACTEC MGIT 960. Sensititre MYCOTB plates were used for drug-susceptibility testing, and gene sequencing was performed on all isolates. Local MDR-TB program data were reviewed for clinical information and patient outcomes.

Results: Discordant isolates constituted 4.6% (60) of 1302 rifampicin-resistant cases over the study period. Of these, 62% remained susceptible to isoniazid and 98% remained susceptible to rifabutin. Rifampicin MICs were close to the critical concentration of 1 µg/mL (0.5-2 µg/mL) for 83% of isolates. The most frequent mutations were Q513P (25.3%), D516V (19.2%), and D516Y (13.3%). Whereas 70% were human immunodeficiency virus infected, the mean CD4 count was 289 cells/mm and 87% were receiving antiretroviral therapy. Standard therapy for MDR-TB was used and 53% achieved successful treatment outcomes.

Conclusions: Rifampicin-discordant TB is not uncommon and sequencing is required to confirm results. The high susceptibility to rifabutin and isoniazid and poor treatment outcomes with the current regimen suggest a potential utility for rifabutin-based therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofz065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475586PMC
April 2019

Linezolid Pharmacokinetics in South African Patients with Drug-Resistant Tuberculosis and a High Prevalence of HIV Coinfection.

Antimicrob Agents Chemother 2019 03 26;63(3). Epub 2019 Feb 26.

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

The World Health Organization (WHO) recently recommended that linezolid be prioritized in treatment regimens for drug-resistant tuberculosis (TB), but there are limited data on its pharmacokinetics (PK) in patients with this disease. We conducted an observational study to explore covariate effects on linezolid PK and to estimate the probability of PK/pharmacodynamic target attainment in South African patients with drug-resistant TB. Consecutive adults on linezolid-based regimens were recruited in Cape Town and underwent intensive PK sampling at steady state. Noncompartmental analysis was performed. Thirty participants were included: 15 HIV positive, 26 on the initial dose of 600 mg daily, and 4 participants on 300 mg daily after dose reduction for linezolid-related toxicity. There was a negative correlation between body weight and exposure, with 17.4% (95% confidence interval [CI], 0.1 to 31.7) decrease in area under the concentration-time curve from 0 to 24 h (AUC) per 10-kg weight increment after adjustment for other covariates. Age was an independent predictor of trough concentration, with an estimated 43.4% (95% CI, 5.9 to 94.2) increase per 10-year increment in age. The standard 600-mg dose achieved the efficacy target of free AUC/MIC of >119 at wild-type MIC values (≤0.5 mg/liter), but the probability of target attainment dropped to 61.5% (95% CI, 40.6 to 79.8) at the critical concentration of 1 mg/liter. When dosed at 600 mg daily, trough concentrations were above the toxicity threshold of 2 mg/liter in 57.7% (95% CI, 36.9 to 76.6). This confirms the narrow therapeutic index of linezolid, and alternative dosing strategies should be explored.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.02164-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395899PMC
March 2019

A new era for treatment of drug-resistant tuberculosis.

Eur Respir J 2018 10 4;52(4). Epub 2018 Oct 4.

Division of Global HIV and Tuberculosis, US Centers for Disease Control and Prevention, Atlanta, GA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01350-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402770PMC
October 2018

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Lancet 2018 09;392(10150):821-834

Centre for Lung Infection and Immunity, Department of Medicine & UCT Lung Institute, University of Cape Town, Cape Town, South Africa.

Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis.

Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration.

Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses.

Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition.

Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(18)31644-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463280PMC
September 2018

Extensively drug-resistant tuberculosis in South Africa: genomic evidence supporting transmission in communities.

Eur Respir J 2018 10 18;52(4). Epub 2018 Oct 18.

School of Medicine, Emory University, Atlanta, GA, USA.

Despite evidence that transmission is driving an extensively drug-resistant TB (XDR-TB) epidemic, our understanding of where and between whom transmission occurs is limited. We sought to determine whether there was genomic evidence of transmission between individuals without an epidemiologic connection.We conducted a prospective study of XDR-TB patients in KwaZulu-Natal, South Africa, during the 2011-2014 period. We collected sociodemographic and clinical data, and identified epidemiologic links based on person-to-person or hospital-based connections. We performed whole-genome sequencing (WGS) on the isolates and determined pairwise single nucleotide polymorphism (SNP) differences.Among 404 participants, 123 (30%) had person-to-person or hospital-based links, leaving 281 (70%) epidemiologically unlinked. The median SNP difference between participants with person-to-person and hospital-based links was 10 (interquartile range (IQR) 8-24) and 16 (IQR 10-23), respectively. The median SNP difference between unlinked participants and their closest genomic link was 5 (IQR 3-9) and half of unlinked participants were within 7 SNPs of at least five participants.The majority of epidemiologically-unlinked XDR-TB patients had low pairwise SNP differences with at least one other participant, consistent with transmission. These data suggest that much of transmission may result from casual contact in community settings between individuals not known to one another.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.00246-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195447PMC
October 2018

Spatial Patterns of Extensively Drug-Resistant Tuberculosis Transmission in KwaZulu-Natal, South Africa.

J Infect Dis 2018 11;218(12):1964-1973

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

Background: Transmission is driving the global drug-resistant tuberculosis (TB) epidemic; nearly three-quarters of drug-resistant TB cases are attributable to transmission. Geographic patterns of disease incidence, combined with information on probable transmission links, can define the spatial scale of transmission and generate hypotheses about factors driving transmission patterns.

Methods: We combined whole-genome sequencing data with home Global Positioning System coordinates from 344 participants with extensively drug-resistant (XDR) TB in KwaZulu-Natal, South Africa, diagnosed from 2011 to 2014. We aimed to determine if genomically linked (difference of ≤5 single-nucleotide polymorphisms) cases lived close to one another, which would suggest a role for local community settings in transmission.

Results: One hundred eighty-two study participants were genomically linked, comprising 1084 case-pairs. The median distance between case-pairs' homes was 108 km (interquartile range, 64-162 km). Between-district, as compared to within-district, links accounted for the majority (912/1084 [84%]) of genomic links. Half (526 [49%]) of genomic links involved a case from Durban, the urban center of KwaZulu-Natal.

Conclusions: The high proportions of between-district links with Durban provide insight into possible drivers of province-wide XDR-TB transmission, including urban-rural migration. Further research should focus on characterizing the contribution of these drivers to overall XDR-TB transmission in KwaZulu-Natal to inform design of targeted strategies to curb the drug-resistant TB epidemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiy394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217717PMC
November 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/cix1125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888963PMC
April 2018

Spatial distribution of extensively drug-resistant tuberculosis (XDR TB) patients in KwaZulu-Natal, South Africa.

PLoS One 2017 13;12(10):e0181797. Epub 2017 Oct 13.

Departments of Epidemiology and Global Health, Emory University Rollins School of Public Health, Atlanta, Georgia, United States of America.

Background: KwaZulu-Natal province, South Africa, has among the highest burden of XDR TB worldwide with the majority of cases occurring due to transmission. Poor access to health facilities can be a barrier to timely diagnosis and treatment of TB, which can contribute to ongoing transmission. We sought to determine the geographic distribution of XDR TB patients and proximity to health facilities in KwaZulu-Natal.

Methods: We recruited adults and children with XDR TB diagnosed in KwaZulu-Natal. We calculated distance and time from participants' home to the closest hospital or clinic, as well as to the actual facility that diagnosed XDR TB, using tools within ArcGIS Network analyst. Speed of travel was assigned to road classes based on Department of Transport regulations. Results were compared to guidelines for the provision of social facilities in South Africa: 5km to a clinic and 30km to a hospital.

Results: During 2011-2014, 1027 new XDR TB cases were diagnosed throughout all 11 districts of KwaZulu-Natal, of whom 404 (39%) were enrolled and had geospatial data collected. Participants would have had to travel a mean distance of 2.9 km (CI 95%: 1.8-4.1) to the nearest clinic and 17.6 km (CI 95%: 11.4-23.8) to the nearest hospital. Actual distances that participants travelled to the health facility that diagnosed XDR TB ranged from <10 km (n = 143, 36%) to >50 km (n = 109, 27%), with a mean of 69 km. The majority (77%) of participants travelled farther than the recommended distance to a clinic (5 km) and 39% travelled farther than the recommended distance to a hospital (30 km). Nearly half (46%) of participants were diagnosed at a health facility in eThekwini district, of whom, 36% resided outside the Durban metropolitan area.

Conclusions: XDR TB cases are widely distributed throughout KwaZulu-Natal province with a denser focus in eThekwini district. Patients travelled long distances to the health facility where they were diagnosed with XDR TB, suggesting a potential role for migration or transportation in the XDR TB epidemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640212PMC
October 2017

Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.

PLoS One 2017 10;12(7):e0180916. Epub 2017 Jul 10.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, United States of America.

Background: Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa.

Methods: We conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion.

Results: Genomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29-42). Smoking was reported by 21% of subjects and most subjects had HIV (80%), were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17-114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14-0.67).

Conclusions: Polymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in South Africa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180916PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507304PMC
September 2017

pncA Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia.

Emerg Infect Dis 2017 03;23(3):491-495

Although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. We found polymorphisms in the pncA gene for 70% of multidrug-resistant and 96% of extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa and Georgia. Assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3201/eid2303.161034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382742PMC
March 2017

Transmission of Extensively Drug-Resistant Tuberculosis in South Africa.

N Engl J Med 2017 01;376(3):243-253

From the Emory University Rollins School of Public Health and School of Medicine (N.S.S., S.C.A., S.A., A.C., N.R.G.) and the Centers for Disease Control and Prevention (N.S.S.) - both in Atlanta; Albert Einstein College of Medicine and Montefiore Medical Center (N.S.S., J.C.M.B., N.R.G.), Columbia University Mailman School of Public Health (B.M., T.S.B.), and the American Museum of Natural History (A.N.) - all in New York; the National Institute for Communicable Diseases, Johannesburg (N.I., H.M., S.V.O.), University of KwaZulu-Natal and National Health Laboratory Service, Durban (P. Moodley, K.M., T.M., P. Mpangase), and the South African Medical Research Council, Cape Town (N.M., T.K.) - all in South Africa; and the Public Health Research Institute, New Jersey Medical School-Rutgers University, Newark (E.S., B.K.).

Background: Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions.

Methods: We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment-length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission.

Results: Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%).

Conclusions: The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1604544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330208PMC
January 2017

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/archdischild-2015-310186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996348PMC
July 2016

High Prevalence of inhA Promoter Mutations among Patients with Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

PLoS One 2015 2;10(9):e0135003. Epub 2015 Sep 2.

Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.

Background: Drug-resistant tuberculosis (TB) remains extremely difficult to treat because there are often few remaining active medications and limited diagnostic options to detect resistance. Resistance to isoniazid is typically caused by mutations in either katG or the inhA promoter. inhA mutations confer low-level resistance to isoniazid and cross-resistance to ethionamide while katG mutations confer high-level isoniazid resistance and no cross-resistance. Line Probe Assays (LPAs) that detect mutations in katG and inhA are currently performed on all positive TB cultures in KwaZulu-Natal province, South Africa, but the frequency of inhA mutations in drug-resistant TB patients has not been examined.

Methods: We sought to determine the proportion of patients who could potentially benefit from high-dose isoniazid and who may be resistant to ethionamide. We reviewed 994 LPA (Hain MTBDRplus) results at the TB reference laboratory in KwaZulu-Natal to determine the frequency of mutations in either katG or the inhA promoter. We stratified these results by drug-resistance category (i.e., MDR-TB, pre-XDR-TB, and XDR-TB) as determined by phenotypic drug-susceptibility testing.

Results: Among MDR- and XDR-TB isolates, the prevalence of inhA mutations without a concurrent katG mutation was 14.8% and 10.3% respectively. The prevalence of inhA mutations with OR without a katG mutation was 30.3% and 82.8%, respectively.

Conclusion: More than 10% of patients with MDR- and XDR-TB may benefit from high-dose isoniazid. Although ethionamide is empirically included in all MDR- and XDR-TB regimens, nearly a third of MDR-TB patients and a majority of XDR-TB patients likely have resistance to ethionamide. Laboratories performing line probe assays should report specific band patterns so that clinicians may adjust treatment regimens accordingly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135003PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557915PMC
May 2016

Incidence and Geographic Distribution of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal Province, South Africa.

PLoS One 2015 6;10(7):e0132076. Epub 2015 Jul 6.

Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.

South Africa is experiencing a widespread drug-resistant tuberculosis epidemic, although data are limited regarding the current situation. This study finds that the extensively drug-resistant tuberculosis (XDR-TB) incidence in KwaZulu-Natal increased to 3.5 cases/100,000 (776 cases) in 2011-2012. XDR-TB cases are widely distributed geographically, with the majority of districts experiencing a rise in incidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132076PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493033PMC
April 2016

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094016PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981751PMC
June 2015

Minimal diversity of drug-resistant Mycobacterium tuberculosis strains, South Africa.

Emerg Infect Dis 2014 Mar;20(3):426-33

Multidrug- (MDR) and extensively drug-resistant tuberculosis (XDR TB) are commonly associated with Beijing strains. However, in KwaZulu-Natal, South Africa, which has among the highest incidence and mortality for MDR and XDR TB, data suggest that non-Beijing strains are driving the epidemic. We conducted a retrospective study to characterize the strain prevalence among drug-susceptible, MDR, and XDR TB cases and determine associations between strain type and survival. Among 297 isolates from 2005-2006, 49 spoligotype patterns were found. Predominant strains were Beijing (ST1) among drug-susceptible isolates (27%), S/Quebec (ST34) in MDR TB (34%) and LAM4/KZN (ST60) in XDR TB (89%). More than 90% of patients were HIV co-infected. MDR TB and XDR TB were independently associated with mortality, but TB strain type was not. We conclude that, although Beijing strain was common among drug-susceptible TB, other strains predominated among MDR TB and XDR TB cases. Drug-resistance was a stronger predictor of survival than strain type.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3201/eid2003.131083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944869PMC
March 2014

Chest radiograph findings and time to culture conversion in patients with multidrug-resistant tuberculosis and HIV in Tugela Ferry, South Africa.

PLoS One 2013 6;8(9):e73975. Epub 2013 Sep 6.

Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, New York, United States of America.

Background: The majority of patients with multidrug-resistant tuberculosis (MDR-TB) in South Africa are co-infected with HIV, but the radiographic features of MDR-TB and their relationship with time to sputum culture conversion in the antiretroviral therapy era have not been described.

Methods: We reviewed baseline chest radiographs for 56 patients with MDR-TB from a rural area of South Africa. We analyzed the association of cavities, consolidation, pleural effusion and hilar lymphadenopathy with time to sputum culture conversion, adjusting for HIV status, baseline sputum smear and CD4 count.

Results: Of the 56 subjects, 49 (88%) were HIV-positive, with a median CD4 count of 136 cells/mm(3) (IQR 65-249). Thirty-two (57%) patients were sputum smear positive. Twenty-two (39%) patients had a cavity and 37 (66%) patients had consolidations. Cavitary disease and consolidations were each associated with longer time to culture conversion on bivariate analysis but not after adjusting for sputum smear status (aORs 1.79 [0.94-3.42] and 1.09 [0.67-1.78], respectively). Positive baseline sputum smear remained independently associated with longer time to conversion (aOR 3.45 [1.39-8.59]). We found no association between pleural effusion or hilar lymphadenopathy and time to conversion. Seventy-nine percent of patients were cured at the end of treatment.

Conclusions: Despite high rates of HIV co-infection and advanced immunodeficiency, the majority of patients had severe pathology on baseline chest radiograph. Nevertheless, culture conversion rates were high and treatment outcomes were favorable. Cavitation and consolidation do not appear to have an independent association with time to culture conversion beyond that of baseline sputum smear status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073975PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765317PMC
June 2014

Natural ventilation reduces high TB transmission risk in traditional homes in rural KwaZulu-Natal, South Africa.

BMC Infect Dis 2013 Jul 1;13:300. Epub 2013 Jul 1.

Yale University School of Medicine, AIDS Program, New Haven, CT, USA.

Background: Transmission of drug susceptible and drug resistant TB occurs in health care facilities, and community and households settings, particularly in highly prevalent TB and HIV areas. There is a paucity of data regarding factors that may affect TB transmission risk in household settings. We evaluated air exchange and the impact of natural ventilation on estimated TB transmission risk in traditional Zulu homes in rural South Africa.

Methods: We utilized a carbon dioxide decay technique to measure ventilation in air changes per hour (ACH). We evaluated predominant home types to determine factors affecting ACH and used the Wells-Riley equation to estimate TB transmission risk.

Results: Two hundred eighteen ventilation measurements were taken in 24 traditional homes. All had low ventilation at baseline when windows were closed (mean ACH = 3, SD = 3.0), with estimated TB transmission risk of 55.4% over a ten hour period of exposure to an infectious TB patient. There was significant improvement with opening windows and door, reaching a mean ACH of 20 (SD = 13.1, p < 0.0001) resulting in significant decrease in estimated TB transmission risk to 9.6% (p < 0.0001). Multivariate analysis identified factors predicting ACH, including ventilation conditions (windows/doors open) and window to volume ratio. Expanding ventilation increased the odds of achieving ≥12 ACH by 60-fold.

Conclusions: There is high estimated risk of TB transmission in traditional homes of infectious TB patients in rural South Africa. Improving natural ventilation may decrease household TB transmission risk and, combined with other strategies, may enhance TB control efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2334-13-300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716713PMC
July 2013