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Isoniazid-monoresistant tuberculosis is associated with poor treatment outcomes in Durban, South Africa.
van der Heijden YF, Karim F, Mufamadi G, Zako L, Chinappa T, Shepherd BE, Maruri F, Moosa MS, Sterling TR, Pym AS
(2017) Int J Tuberc Lung Dis 21: 670-676
MeSH Terms: Adult, Antitubercular Agents, Drug Resistance, Bacterial, Female, HIV Infections, Humans, Isoniazid, Logistic Models, Longitudinal Studies, Male, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Retrospective Studies, South Africa, Treatment Failure, Treatment Outcome, Tuberculosis
Show Abstract · Added March 14, 2018
SETTING - A large tuberculosis (TB) clinic in Durban, South Africa.
OBJECTIVE - To determine the association between isoniazid (INH) monoresistant TB and treatment outcomes.
DESIGN - We performed a retrospective longitudinal study of patients seen from 2000 to 2012 to compare episodes of INH-monoresistant TB with those of drug-susceptible TB using logistic regression with robust standard errors. INH-monoresistant TB was treated with modified regimens.
RESULTS - Among 18 058 TB patients, there were 19 979 TB episodes for which drug susceptibility testing was performed. Of these, 557 were INH-monoresistant and 16 311 were drug-susceptible. Loss to follow-up, transfer, and human immunodeficiency virus (HIV) co-infection (41% had known HIV status) were similar between groups. INH-monoresistant episodes were more likely to result in treatment failure (4.1% vs. 0.6%, P < 0.001) and death (3.2% vs. 1.8%, P = 0.01) than drug-susceptible episodes. After adjustment for age, sex, race, retreatment status, and disease site, INH-monoresistant episodes were more likely to have resulted in treatment failure (OR 6.84, 95%CI 4.29-10.89, P < 0.001) and death (OR 1.81, 95%CI 1.11-2.95, P = 0.02).
CONCLUSION - INH monoresistance was associated with worse clinical outcomes than drug-susceptible TB. Our findings support the need for rapid diagnostic tests for INH resistance and improved treatment regimens for INH-monoresistant TB.
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17 MeSH Terms
Fluoroquinolones for the treatment and prevention of multidrug-resistant tuberculosis.
Sterling TR
(2016) Int J Tuberc Lung Dis 20: 42-47
MeSH Terms: Antitubercular Agents, Clinical Trials as Topic, Dose-Response Relationship, Drug, Fluoroquinolones, Humans, Levofloxacin, Moxifloxacin, Treatment Outcome, Tuberculosis, Multidrug-Resistant
Show Abstract · Added March 14, 2018
Although fluoroquinolones (FQs) play an important role in the treatment of multidrug-resistant tuberculosis (MDR-TB), there are several issues that need to be addressed to optimize their effectiveness and minimize toxicity. This includes identification of the optimal dose of FQs such as levofloxacin (LVX) and moxifloxacin, and the optimal role of FQs in combination with other anti-tuberculosis drugs, particularly those with overlapping toxicity, such as QT prolongation. While the ability of FQs to penetrate into cavities and granulomas is likely beneficial, suboptimal sensitivity of genotypic tests to detect FQ resistance could negatively affect treatment outcomes of FQ-containing regimens. Several trials are underway to evaluate the safety and effectiveness of FQs as part of combination MDR-TB therapy; there are also two planned studies of LVX to prevent tuberculosis among close contacts of MDR-TB.
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9 MeSH Terms
Factors associated with non-completion of follow-up: 33-month latent tuberculous infection treatment trial.
Moro RN, Sterling TR, Saukkonen J, Vernon A, Horsburgh CR, Chaisson RE, Hamilton CD, Villarino ME, Goldberg S
(2017) Int J Tuberc Lung Dis 21: 286-296
MeSH Terms: Adult, Antitubercular Agents, Directly Observed Therapy, Female, Follow-Up Studies, Homeless Persons, Humans, Isoniazid, Latent Tuberculosis, Male, Medication Adherence, Multivariate Analysis, Proportional Hazards Models, Risk Factors, Sex Factors, Time Factors
Show Abstract · Added March 14, 2018
SETTING - A post-hoc exploratory analysis of a randomized, open-label clinical trial that enrolled 8053 participants from the United States, Canada, Brazil, and Spain.
OBJECTIVE - To assess factors associated with non-completion of study follow-up (NCF) in a 33-month latent tuberculous infection treatment trial, PREVENT TB.
DESIGN - Participants were randomized to receive 3 months of weekly directly observed therapy vs. 9 months of daily self-administered therapy. NCF was defined as failing to be followed for at least 993 days (33 months) from enrollment. Possible factors associated with NCF were analyzed using univariate and multivariate regression via Cox proportional hazard model.
RESULTS - Of 7061 adults selected for analysis, 841 (11.9%) did not complete study follow-up. Homelessness, young age, low education, history of incarceration, smoking, missing an early clinic visit, receiving isoniazid only, and male sex were significantly associated with NCF. Similar results were found in the North American region (United States and Canada) only. In Brazil and Spain, the only significant factor was missing an early clinic visit.
CONCLUSIONS - Study subjects at higher risk for NCF were identified by characteristics known at enrollment or in early follow-up. Evaluation of follow-up in other trials might help determine whether the identified factors consistently correlate with retention.
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16 MeSH Terms
Pediatric multidrug-resistant tuberculosis clinical trials: challenges and opportunities.
McAnaw SE, Hesseling AC, Seddon JA, Dooley KE, Garcia-Prats AJ, Kim S, Jenkins HE, Schaaf HS, Sterling TR, Horsburgh CR
(2017) Int J Infect Dis 56: 194-199
MeSH Terms: Adult, Antitubercular Agents, Child, Clinical Trials as Topic, Humans, Tuberculosis, Multidrug-Resistant, Tuberculosis, Pulmonary
Show Abstract · Added March 14, 2018
On June 17, 2016, RESIST-TB, IMPAACT, Vital Strategies, and New Ventures jointly hosted the Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Meeting in Arlington, Virginia, USA. The meeting provided updates on current multidrug-resistant tuberculosis (MDR-TB) trials targeting pediatric populations and adult trials that have included pediatric patients. A series of presentations were given that discussed site capacity needs, community engagement, and additional interventions necessary for clinical trials to improve the treatment of pediatric MDR-TB. This article presents a summary of topics discussed, including the following: current trials ongoing and planned; the global burden of MDR-TB in children; current regimens for MDR-TB treatment in children; pharmacokinetics of second-line anti-tuberculosis medications in children; design, sample size, and statistical considerations for MDR-TB trials in children; selection of study population, design, and treatment arms for a trial of novel pediatric MDR-TB regimens; practical aspects of pediatric MDR-TB treatment trials; and strategies for integrating children into adult tuberculosis trials. These discussions elucidated barriers to pediatric MDR-TB clinical trials and provided insight into necessary next steps for progress in this field. Investigators and funding agencies need to respond to these recommendations so that important studies can be implemented, leading to improved treatment for children with MDR-TB.
Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.
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7 MeSH Terms
Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries.
Getahun H, Matteelli A, Abubakar I, Aziz MA, Baddeley A, Barreira D, Den Boon S, Borroto Gutierrez SM, Bruchfeld J, Burhan E, Cavalcante S, Cedillos R, Chaisson R, Chee CB, Chesire L, Corbett E, Dara M, Denholm J, de Vries G, Falzon D, Ford N, Gale-Rowe M, Gilpin C, Girardi E, Go UY, Govindasamy D, D Grant A, Grzemska M, Harris R, Horsburgh CR, Ismayilov A, Jaramillo E, Kik S, Kranzer K, Lienhardt C, LoBue P, Lönnroth K, Marks G, Menzies D, Migliori GB, Mosca D, Mukadi YD, Mwinga A, Nelson L, Nishikiori N, Oordt-Speets A, Rangaka MX, Reis A, Rotz L, Sandgren A, Sañé Schepisi M, Schünemann HJ, Sharma SK, Sotgiu G, Stagg HR, Sterling TR, Tayeb T, Uplekar M, van der Werf MJ, Vandevelde W, van Kessel F, van't Hoog A, Varma JK, Vezhnina N, Voniatis C, Vonk Noordegraaf-Schouten M, Weil D, Weyer K, Wilkinson RJ, Yoshiyama T, Zellweger JP, Raviglione M
(2015) Eur Respir J 46: 1563-76
MeSH Terms: Antirheumatic Agents, Antitubercular Agents, Coinfection, Comorbidity, Disease Management, Drug Users, Emigrants and Immigrants, Evidence-Based Medicine, HIV Infections, Health Personnel, Homeless Persons, Humans, Interferon-gamma Release Tests, Isoniazid, Kidney Failure, Chronic, Latent Tuberculosis, Mass Screening, Practice Guidelines as Topic, Prisoners, Public Health, Radiography, Thoracic, Renal Dialysis, Rifampin, Risk Assessment, Silicosis, Substance-Related Disorders, Transplant Recipients, Tuberculin Test, Tumor Necrosis Factor-alpha, World Health Organization
Show Abstract · Added February 17, 2016
Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.
Copyright ©ERS 2015.
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30 MeSH Terms
Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI.
Bliven-Sizemore EE, Sterling TR, Shang N, Benator D, Schwartzman K, Reves R, Drobeniuc J, Bock N, Villarino ME, TB Trials Consortium
(2015) Int J Tuberc Lung Dis 19: 1039-44, i-v
MeSH Terms: Adult, Antitubercular Agents, Aspartate Aminotransferases, Brazil, Canada, Case-Control Studies, Chemical and Drug Induced Liver Injury, Drug Administration Schedule, Drug Therapy, Combination, Female, Hepatitis C, Humans, Isoniazid, Latent Tuberculosis, Male, Middle Aged, Multivariate Analysis, Rifampin, Risk Factors, Spain, United States
Show Abstract · Added February 17, 2016
SETTING - Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear.
OBJECTIVES - To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity.
DESIGN - Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV.
RESULTS - Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors.
CONCLUSION - The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.
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21 MeSH Terms
Four-month fluoroquinolone-containing regimens are inferior to standard 6-month tuberculosis treatment.
Sterling TR
(2015) Evid Based Med 20: 128-9
MeSH Terms: Antitubercular Agents, Female, Fluoroquinolones, Humans, Male, Mycobacterium tuberculosis, Tuberculosis, Pulmonary
Added February 17, 2016
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7 MeSH Terms
Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study.
Sterling TR, Moro RN, Borisov AS, Phillips E, Shepherd G, Adkinson NF, Weis S, Ho C, Villarino ME, Tuberculosis Trials Consortium
(2015) Clin Infect Dis 61: 527-35
MeSH Terms: Adolescent, Adult, Antitubercular Agents, Drug-Related Side Effects and Adverse Reactions, Female, Humans, Isoniazid, Latent Tuberculosis, Male, Middle Aged, Prospective Studies, Respiratory Tract Diseases, Rifampin
Show Abstract · Added February 17, 2016
BACKGROUND - Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome.
METHODS - We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study.
RESULTS - Among 7552 persons who received ≥ 1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥ 35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1).
CONCLUSIONS - SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear.
CLINICAL TRIALS REGISTRATION - NCT00023452.
Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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13 MeSH Terms
Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study.
Luetkemeyer AF, Rosenkranz SL, Lu D, Grinsztejn B, Sanchez J, Ssemmanda M, Sanne I, McIlleron H, Havlir DV, Haas DW, Adult AIDS Clinical Trials Group A5221 and A5243 Study Teams
(2015) Clin Infect Dis 60: 1860-3
MeSH Terms: Antitubercular Agents, Arylamine N-Acetyltransferase, Benzoxazines, Cytochrome P-450 CYP2B6, Female, Genotype, HIV Infections, Humans, Male, Peru, Pharmacogenetics, Rifampin, South Africa, Tuberculosis, Uganda
Show Abstract · Added March 13, 2015
In STRIDE, slow metabolizer CYP2B6 and NAT2 genotypes were each associated with increased plasma efavirenz concentrations during antituberculosis therapy. Concentrations were greater on therapy than off therapy in 58% with CYP2B6 and 93% with NAT2 slow metabolizer genotypes. Individuals with slow metabolizer genotypes in both genes had markedly elevated concentrations.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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15 MeSH Terms
Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid.
Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, Nachman S, Oliveira R, Moro RN, Shang N, Goldberg SV, Sterling TR, International Maternal Pediatric and Adolescents AIDS Clinical Trials Group, Tuberculosis Trials Consortium
(2015) JAMA Pediatr 169: 247-55
MeSH Terms: Adolescent, Antitubercular Agents, Child, Child, Preschool, Drug Therapy, Combination, Female, Humans, Isoniazid, Latent Tuberculosis, Male, Rifampin, Treatment Outcome
Show Abstract · Added February 17, 2016
IMPORTANCE - Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.
OBJECTIVES - To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.
DESIGN, SETTING, AND PARTICIPANTS - A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.
INTERVENTIONS - Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.
MAIN OUTCOMES AND MEASURES - We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.
RESULTS - Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.
CONCLUSIONS AND RELEVANCE - Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.
TRIAL REGISTRATION - clinicaltrials.gov Identifier: NCT00023452.
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12 MeSH Terms