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Occurrence and clinical management of moderate-to-severe adverse events during drug-resistant tuberculosis treatment: a retrospective cohort study.

ABSTRACT: OBJECTIVES: To determine the incidence of symptomatic moderate-to-severe adverse events during treatment of drug-resistant tuberculosis, and to compare their risk and outcomes by patients' human immunodeficiency virus (HIV) co-infection status. METHODS: We conducted a retrospective cohort analysis of patients treated for drug-resistant tuberculosis between January 2008 and February 2010. Routinely, clinicians monitored and managed patients' response to treatment until its completion. Any symptomatic adverse event observed by the clinician or reported by the patient was recorded in the standard patient treatment booklet of the National Tuberculosis and Leprosy Programme. There were 18 symptomatic adverse events routinely monitored. Depending on the nature of the medical intervention needed, each was graded as mild, moderate or severe. Data were extracted from the patient treatment booklet using a structured form, then descriptive, bivariate and Cox proportional hazard analysis performed, stratified by patients' HIV infection status. Statistical associations were done at the 5% level of significance and reported with 95% confidence intervals. RESULTS: Fifty seven (57) patients with drug-resistant tuberculosis were identified, 31 (53%) of whom were HIV co-infected. The cumulative incidence of moderate-to-severe adverse events was 46 events in 100 patients. HIV co-infected patients experienced more moderate-to-severe adverse events compared with the HIV uninfected patients (median 3 versus 1 events, p?=?0.01). They had a four-fold increase in the cumulative hazard of moderate-to-severe adverse events compared with the HIV uninfected patients (HR?=?4.0, 95% CI 1.5 - 10.5). Moderate-to-severe adverse events were the main determinant of a clinician's decision to reduce the dose or to stop the suspected offending medicine (RR?=?3.8, 95% 1.2-11.8). CONCLUSIONS: Moderate-to-severe adverse events are common during drug-resistant tuberculosis therapy. They are more likely to occur and to persist in HIV co-infected patients than in HIV uninfected patients. Clinicians should employ various strategies for preventing drug-induced patient discomfort and harm, such as reducing the dose or stopping the suspected offending medicine. Managers of tuberculosis control programmes should strengthen pharmacovigilance systems. We recommend a more powered study for conclusive risk-factor analysis.

SUBMITTER: Sagwa EL

PROVIDER: S-EPMC4219090 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Occurrence and clinical management of moderate-to-severe adverse events during drug-resistant tuberculosis treatment: a retrospective cohort study.

Sagwa Evans L EL Mantel-Teeuwisse Aukje K AK Ruswa Nunurai C NC

Journal of pharmaceutical policy and practice 20141021 1

<h4>Objectives</h4>To determine the incidence of symptomatic moderate-to-severe adverse events during treatment of drug-resistant tuberculosis, and to compare their risk and outcomes by patients' human immunodeficiency virus (HIV) co-infection status.<h4>Methods</h4>We conducted a retrospective cohort analysis of patients treated for drug-resistant tuberculosis between January 2008 and February 2010. Routinely, clinicians monitored and managed patients' response to treatment until its completion ...[more]

PMID: 25383192

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Project description:BackgroundTreatment 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.MethodsWe 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.Findings58 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.InterpretationFluoroquinolones, 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.FundingCanadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

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Occurrence and clinical management of moderate-to-severe adverse events during drug-resistant tuberculosis treatment: a retrospective cohort study.

Publications

Occurrence and clinical management of moderate-to-severe adverse events during drug-resistant tuberculosis treatment: a retrospective cohort study.

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