Factors Associated With Noncompletion of Latent Tuberculosis Infection Treatment: Experience From the PREVENT TB Trial in the United States and Canada

Abstract

Background: Overall rates of noncompletion of treatment (NCT) for latent tuberculosis infection (LTBI) in the PREVENT TB trial were 18% for 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus isoniazid (maximum dose, 900 mg) (3HP-DOT) and 31% for 9 months of daily self-administered isoniazid (maximum dose, 300 mg; 9H-SAT). NCT for LTBI reduces its effectiveness. The study objective was to assess factors associated with NCT for LTBI among adult participants enrolled at US and Canadian sites of the PREVENT TB trial.

Methods: This was a post hoc exploratory analysis of the randomized, open-label PREVENT TB trial. Factors were analyzed by univariate and multivariate logistic regression (with enrollment site as a random effect).

Results: From 6232 participants analyzed, 1406 (22.6%) did not complete LTBI treatment (317 NCT attributed to an adverse event [NCT-AE] and 1089 NCT attributed to reasons other than an adverse event [NCT-O]). The proportion of NCT-AE was similar with both regimens (3HP-DOT = 6.4% vs 9H-SAT = 5.9%; P = .23); NCT-O was higher among participants enrolled in 9H-SAT (9H-SAT = 24.5% vs 3HP-DOT = 12.7%; P = .02). Among those in the NCT-AE group, being non-Hispanic and receiving 3HP-DOT, having cirrhosis and receiving 9H-SAT, alcohol consumption among men, and use of concomitant medication were associated with NCT-AE. Among those in the NCT-O group, receiving 9H-SAT, missing ≥1 early visit, men receiving 9H-SAT, men with a history of incarceration, alcohol abuse, use ever of intravenous drugs, younger age receiving 9H-SAT, and smoking were associated with NCT-O.

Conclusions: Factors associated with NCT, such as missing a clinic visit early during treatment, might help identify persons for whom tailored interventions could improve completion of LTBI treatment.

Clinical trials registration: NCT00023452.

Keywords: medication adherence; patient compliance; treatment completion.

Conflict of interest statement

Potential conflicts of interest. R. N. M. and N. A. S. are employed by the CDC Foundation, which receives funds for rifapentine research from Sanofi. T. R. S. is a member of data safety monitoring board for a clinical trial sponsored by Otsuka. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Figures

Figure 1.

Flow chart of participants evaluated for factors associated with noncompletion of latent tuberculosis infection (LTBI) treatment in North America (PREVENT TB trial). This figure shows the number of participants who were enrolled in the trial, the groups that were excluded from the analysis, and the remaining cohort that was evaluated for factors associated with noncompletion of latent Mycobacterium tuberculosis infection treatment. Exclusion criteria include the following: current confirmed tuberculosis; suspected tuberculosis; tuberculosis resistant to isoniazid or rifampin in the source patient; history of treatment for >14 consecutive days with rifamycin or >30 consecutive days with isoniazid during the previous 2 years; documented history of completing adequate treatment for active tuberculosis or latent M. tuberculosis infection in a human immunodeficiency virus (HIV)–seronegative person; history of sensitivity/intolerance to isoniazid or rifamycin; serum aspartate aminotransferase (AST) >5 times the upper limit of normal if AST was determined; pregnant or lactating females; persons currently receiving or planning to receive HIV-1 therapy ≤90 days after enrollment; or weight <10.0 kg. aThis analysis includes enrollment sites from the United States and Canada. Enrollment sites from Brazil and Spain were excluded; bThis analysis considers adults aged ≥18 years only; cPREVENT TB trial reasons for ineligibility include source patient’s infection resistant to isoniazid/rifampin (50%) and source patient being culture negative (31%), or other (19%); dReasons for LTBI treatment (not mutually exclusive) include the following: contact with infectious tuberculosis patient (n = 4156), tuberculin skin test converter (n = 2205), HIV-positive (n = 140), or fibrosis (n = 181); eNoncompletion of treatment attributed to an adverse event (AE) was designated if participants discontinued treatment after experiencing an adverse drug reaction associated with either 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus isoniazid (maximum dose, 900 mg) (3HP-DOT) or 9 months of daily self-administered isoniazid (maximum dose, 300 mg; 9H-SAT) that was considered definitely, possibly, or probably related to the study drug(s) by the site investigators (n = 311); if participants discontinued the regimen because of the physician’s preference and had a related AE of grade 2 or higher ≤3 days after their last regimen dose; or if the participant experienced tuberculosis or died ≤7 days after the last study dose.

Figure 2.

Percentage of participants assigned to receive 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus isoniazid (maximum dose, 900 mg) (3HP-DOT) who did not complete latent tuberculosis infection (LTBI) treatment attributed to an adverse event (AE) and attributed to reasons other than an AE, by maximum number of doses taken (n = 3230). This figure shows that the combined proportion of participants who did not complete LTBI treatment attributed to an AE plus the proportion of those who did not complete treatment for reasons other than an AE decreased with an increase in the number of 3HP-DOT doses taken. Pearson correlation coefficient in a linear regression model = −0.93; P< .001; r2 = 0.86. a11 doses in <10 weeks (3 [0.1%]), 11 doses in >16 weeks (7 [0.2%]); b12 doses in <10 weeks (21 [0.7%]), 12 doses in >16 weeks (27 [0.8%]). Abbreviations: NCT-AE, non-completion of LTBI treatment attributed to an adverse event; NCT-O, non-completion of LTBI treatment attributed to reasons other than an adverse event.

Figure 3.

Percentage of participants assigned to receive 9 months of daily self-administered isoniazid (maximum dose, 300 mg) (9H-SAT) who did not complete latent tuberculosis infection treatment (LTBI) attributed to an adverse event (AE) and attributed to reasons other than an AE, by doses taken (n = 3002). This figure shows how the combined proportion of participants who did not complete LTBI treatment attributed to an AE plus the proportion of those who did not complete treatment for reasons other than an AE in the 9H-SAT regimen decreased after the first 30-dose interval and remained constant thereafter. 9H-SAT: ≥240 doses in ≥52 weeks (60 [2.0%]). Pearson correlation coefficient in a linear regression model = −0.68; P = .03; r2 = 0.46. Abbreviations: NCT-AE, non-completion of LTBI treatment attributed to an adverse event; NCT-O, non-completion of LTBI treatment attributed to reasons other than an adverse event.