Predictors of Drug Resistance or Negative Culture at Baseline: Identifying Ineligible Patients in a Clinical Trial for Tuberculosis Treatment Pubblico

Abstract

Abstract

Setting: Tuberculosis (TB) control continues to be hindered by sluggish diagnostic tests. Delays
prevent patients from receiving appropriate treatment if infected with drug-resistant TB or
organisms other than TB. In research, eligibility often requires drug-sensitive TB infection, and
delays in identifying ineligible patients consume study resources. New rapid diagnostics are
available, but high cost often renders universal testing difficult. A risk-based approach to
prioritize testing may be more feasible.
Objective: Identify predictors associated with drug-resistance or a negative culture. Determine
the time required to identify these conditions.
Design: This is a secondary analysis of 432 patients enrolled domestically and internationally in
a Phase 2, randomized clinical trial testing a novel intensive phase TB regimen. Upon
enrollment, sputum specimens were cultured and tested for drug resistance. Participants with
resistance or negative cultures were deemed ineligible. Patient information collected at
enrollment was analyzed to identify associations.
Results: In univariate analyses, presence of nausea and Hispanic ethnicity were associated with
resistance in the US. Only Hispanic ethnicity (p-value 0.025) predicted resistance in multivariate
analyses. Age 30 years or older (p-value 0.025) was the only predictor outside the US.
Negative cultures were found among US non-Hispanic participants only. Univariate predictors
included increasing age, race, and presenting less than two of the three symptoms cough, sweats,
and loss of appetite. In multivariate analyses, Blacks and Asian/Pacific Islanders were less likely
to have negative cultures than whites (p-value 0.0077 and 0.027, respectively). Participants with
less than two of the three symptoms were more likely to produce negative cultures (p-value
0.017). Average time to determine ineligibility was 65 days.
Conclusion: The average time required to identify resistance or negative cultures went beyond
the duration of intensive phase therapy (54 days). Hispanic patients in the US and patients 30
years or older outside the US had higher levels of resistance. Patients with negative cultures
tended to be older non-Hispanic whites living in the US, with less than two of the three symptoms
cough, sweats, and loss of appetite. Clinical trial sites should consider taking advantage of new
rapid diagnostics by prioritizing testing for persons with these risk factors.

Table of Contents

TABLE OF CONTENTS

BACKGROUND ........................................................................................................................1
METHODS .............................................................................................................................9
RESULTS ..............................................................................................................................11
DISCUSSION .........................................................................................................................15

Strengths and Weaknesses ................................................................................................ 18
Future Directions ............................................................................................................. 19
REFERENCES ........................................................................................................................ 20
TABLES ............................................................................................................................... 25
Table 1: Summary of Ineligible Patients for Tuberculosis Trials Consortium Study 28 ..................... 25
Table 2: Univariate analyses for patients with resistant isolates, by site location ......................... 26
Table 3: Significant predictors of resistance in multivariate logistic regression, by site location ....... 29
Table 4: Univariate analyses for patients with cultures that were negative for tuberculosis, all patients and US non-Hispanic patients only ......................................................................................................................... 30
Table 5: Significant predictors of negative culture in multivariate logistic regression....................... 33
Table 6: Times to determination of ineligibility ........................................................................ 34
FIGURES ............................................................................................................................... 35
Figure 1: Times to determination of ineligibility for all ineligible patients ....................................... 35
Figure 2: Times to determination of ineligibility by reason: culture-negative for tuberculosis
or drug resistant...................................................................................................................... 36
Figure 3: Times to determination of resistance by site location .................................................. 37
Figure 4: Times to determination of ineligibility for all ineligible patients, excluding those
with fluoroquinolone monoresistance ........................................................................................... 38
Figure 5: Times to determination of ineligibility by reason, excluding those with
fluoroquinolone monoresistance .................................................................................................. 39
Figure 6: Times to determination of resistance by site location, excluding patients with
fluoroquinolone monoresistance .................................................................................................. 40
APPENDIX ............................................................................................................................... 41
IRB Exemption Letter .......................................................................................................... 41

About this Master's Thesis

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Rollins School of Public Health
Department	Epidemiology
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Parola chiave	screening clinical trial time to determination drug resistance tuberculosis diagnostics negative culture ineligibility
Committee Chair / Thesis Advisor	Spaulding, Anne C, Emory University
Committee Members	Bliven-Sizemore, Erin, CDC
Partnering Agencies	Emory University schools, faculty or affiliated programs CDC

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