Utilizing genotypic mutations to determine treatment effectiveness among MDR and XDR TB patients in KwaZulu-Natal, SouthAfrica Open Access

Abstract

Introduction. Tuberculosis (TB) remains the second leading cause of infectious disease death worldwide, and TB drug resistance is associated with dramatically worse treatment outcomes. South Africa's KwaZulu-Natal Province has among the highest caseloads of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB globally. Regimens require at least four likely effective drugs to improve treatment outcomes; yet without sufficient lab capacity, phenotypic drug susceptibility testing is impractical. Genotypic susceptibility testing can fill this need. We utilized sequencing data to estimate susceptibility for drugs used in standardized MDR and XDR regimens, and to examine whether treatment outcomes vary based on different numbers of likely effective drugs.

Methods. We used isolates and data from two studies in KwaZulu-Natal to characterize the frequencies of resistance-conferring mutations among MDR and XDR TB participants. We calculated the number of likely effective drugs that subjects received. In a subset of MDR participants, we examined the association between number of effective drugs and treatment outcomes. We also described the frequency of adverse events, and estimated the odds of unsuccessful treatment using multivariate analysis.

Results. We analyzed sequencing data for 90 MDR and 363 XDR participants (n=453 total). Resistance-conferring mutations were most frequent in the pncA (74%) and inhA (39%) genes among MDR participants. Over 88% of XDR participants exhibited resistance-conferring mutations for each gene examined. 90% of the MDR, but only 23% of XDR participants received ≥ 4 effective drugs. There was no significant association between the number of effective drugs and treatment outcomes in the subset of MDR participants. The number of adverse events experienced was significantly associated with treatment outcome (aOR=4.1, 95CI 1.3 - 12.9).

Conclusions. Genotypic mutations conferring resistance to antituberculosis drugs were common, and the vast majority of MDR and XDR participants received at least one drug providing no clinical benefit. There was no association between the number of effective drugs and outcomes among MDR patients. However, similar analyses should be performed among XDR populations, where only 23% received at least four effective drugs. The frequency of adverse events was associated with outcomes, and further efforts are needed to minimize their frequency and impact.

Table of Contents

Chapter 1.Introduction. 1

Introduction and Rationale. 1

Problem Statement. 2

Purpose of this Study. 2

Research Questions. 3

Significance of this Study. 3

Definition of Terms. 4

Chapter 2. Comprehensive Review of the Literature. 6

Tuberculosis Epidemiology. 6

Global Tuberculosis Epidemiology. 6

Global Drug-Resistant Tuberculosis Epidemiology. 6

South Africa Drug-Resistant Tuberculosis Epidemiology. 8

Drug Resistance in Tuberculosis. 9

Overview of Drug Resistance. 10

Understanding Acquired Resistance. 10

Understanding Resistance in Practice. 11

TB Drugs and Resistance. 15

Treatment and Outcomes in Multidrug-Resistant Tuberculosis. 20

MDR TB Treatment Outcomes. 20

Approaches to Treatment and Management of MDR TB. 22

Rationale for this Study and Research Questions. 24

Rationale for Completing this Study. 24

Research Questions for this Study. 25

Chapter 3. Manuscript. 26

Contribution of Student to Manuscript. 27

Abstract. 28

Introduction. 29

Methods. 30

Setting and Standardized TB Treatment. 31

Study Population and Data Sources. 31

Statistical Analysis and Definition of Terms. 32

Results. 34

Frequency of mutations. 34

Maximum number of Likely Effective Drugs. 35

Treatment Outcomes and Adverse Events. 35

Increased Resistance. 36

Discussion. 37

Tables and Figures. 42

Table 1. Demographic and clinical characteristics of participants with multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB at baseline (n=603). 42

Table 2. Frequency of genotypic mutations conferring resistance to antituberculosis drugs among MDR and XDR TB participants. 42

Table 3. Maximum number of likely effective drugs received by XDR and XDR TB participants, based on genotypic resistance. 43

Table 4. Baseline demographic and clinical characteristics associated with treatment outcomes among participants with MDR TB. 44

Table 5. Odds of unsuccessful treatment among MDR TB participants. 45

Chapter 4. Conclusions and Recommendations. 46

Adequacy of Standardized TB Treatment Regimens. 46

MDR TB Standardized Regimen. 46

XDR TB Standardized Regimen. 46

Optimizing Standardized Regimens. 47

Number of Effective Drugs and Treatment Outcomes among MDR TB Participants. 48

Accessibility of Susceptibility Testing Technologies. 48

Adverse Events. 49

Conclusion. 51

References. 52

About this Master's Thesis

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School	Rollins School of Public Health
Department	Hubert Department of Global Health
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Keyword	Tuberculosis Drug resistance Sequencing
Committee Chair / Thesis Advisor	Gandhi, Neel R, Emory University
Partnering Agencies	University, college or educational institution (other than Emory) Hospital or other health care provider

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