Clinical Risk Assessment Tools for the Characterization of Early Warning Indicators of HIV Virologic Failure on First-Line Antiretroviral Therapy in an Urban Clinic in KwaZulu-Natal, South Africa Public

Abstract

Objective: HIV virologic failure (VF), the inability achieve or maintain suppression of viral replication, is associated with increased morbidity, early mortality, and has been causally-linked to the acquisition of HIV drug resistance. In addition to institutional and community-level influences, there are a number of individual-level risk factors associated with a patient's likelihood of failing virologically. Here, a series of risk indices were developed in order to provide a practical risk characterization tool, implementable in clinical settings.

Design and Methods: Findings from the Risk Factors for Virologic Failure (RFVF) study conducted in an urban clinic in KwaZulu-Natal, South Africa were utilized to develop indices characterizing individual risk of VF at initiation of ART as well as after at least five months on treatment. Indices were based on multivariate models where statistically significant demographic, socioeconomic, psychosocial, and clinical/laboratory-related predictors of VF were identified. Baseline, RFVF (full), and Restricted RFVF (parsimonious) Indices were comprised of point values derived from model output. Assessments were conducted of the fit statistics and predictive discrimination of the models from which the point-based indices were derived as well as of models from which index-derived patient scores were the sole predictors of VF.

Results: Patients' risk of VF was characterized as a "score" expressed as a percentage of the total theoretical maximum risk of VF for each index. Model assessments revealed that both the RFVF and Restricted Indices provided more robust predictions of VF as compared to the Baseline Index. Univariate analysis of risk scores also revealed that while both the Restricted and RFVF Indices outperformed the Baseline Index, the Restricted Index was comparable to the RFVF (ROC curve AUC of 0.848 versus 0.847, respectively).

Conclusions: The Baseline Index provides a means for characterizing an individual's risk of VF based on measurable factors present at ART initiation. The Restricted RFVF Index provides risk characterization with equal utility to that of the full, RFVF Index but with a limited, and therefore more feasible, number of predictors. These prognostic indices and their methodologic derivations may serve as useful foundational work for the application and implementation of such rapid, risk quantification tools in future research and clinical care settings.

Table of Contents

Chapter I: Background and Literature Review .............................................1

Introduction ............................................................................................2

Historical Context of the HIV Epidemic in South Africa ...............................2

HIV in KwaZulu-Natal, South Africa ...........................................................7

KZN HIV Epidemiology by Race, Gender, and Age ........................................8

At Risk Populations ..................................................................................10

Global Treatment Guidelines ....................................................................11

Virologic Failure ......................................................................................14

Viral Load Monitoring in KZN ...................................................................16

Acquired HIV Drug Resistance...................................................................19

Causes and Risk Factors of Virologic Failure ...............................................21

Risk Factors .............................................................................................23

Demographic Risk Factors .........................................................................23

Clinical Risk Factors .................................................................................25

Psychological/Social Risk Factors ...............................................................26

Early Warning Indicators ...........................................................................26

Study Justification .....................................................................................28

Study Setting ............................................................................................29

Study Summary and Findings .....................................................................29

Use of Predictive Risk Indices in Clinical Practice.........................................30

Chapter II: Manuscript ..............................................................................33

Introduction ............................................................................................34

Methodology ...........................................................................................35

RFVF Study Methods: ...............................................................................35

Clinical Setting ........................................................................................35

Study Participants ...................................................................................36

Study Design...........................................................................................36

Data Collection .......................................................................................37

Primary Statistical Analysis......................................................................38

Risk Score Index Methods: .......................................................................39

Construction of Indices ...........................................................................41

Assessment of Indices .............................................................................42

Instruments ...........................................................................................43

Ethical considerations ............................................................................44

Results ..................................................................................................44

Cohort description-Univariate Analysis ...................................................44

Multivariate Model Assessment ..............................................................45

Risk Indices Comparisons .......................................................................46

Discussion .............................................................................................48

Strengths ...............................................................................................51

Limitations ............................................................................................52

Future Studies .......................................................................................55

Public Health Implications .....................................................................56

Conclusion ............................................................................................57

Appendix A ...........................................................................................59

Adapted Quantitative Measures Used in RFVF Study.................................59

Appendix B ...........................................................................................60

Tables and Figures .................................................................................60

Table 1: Cohort characteristics of 458 RFVF participants ..........................60

Figure 1: Diagram illustrating the methodological flow of patient-based

information from which the risk indices are derived .................................62

Figure 2: Schema depicting the social, behavioral, and clinical factors ..............63

Table 2: Baseline, RFVF, and Restricted predictive model characteristics ............64

Figure 3a Baseline Model ROC curve .......................................................65

Figure 3b RFVF ROC curve .....................................................................65

Figure 3c Restricted Model ROC curve ....................................................65

Table 3: Adjusted odds ratios and point values for Baseline, RFVF, and

Restricted indices derived from logistic regression models .........................66

Table 4: Baseline, RFVF, and Restricted predictive characteristics of VF as an outcome

for every one unit increase in cumulative score percentage .......................68

Figure 4a Baseline Index ROC curve ........................................................69

Figure 4b RFVF Index ROC curve.............................................................69

Figure 4c Restricted Index ROC curve.......................................................69

Table 5: RFVF Study cohort risk characterization Classifications using score quintiles

derived from the Baseline, RFVF, and Restricted Indices ...........................70

Figure 5 RFVF Study Population Risk Characterization Distributions derived from

Baseline, RFVF, and Restricted Indices ....................................................71

References ............................................................................................72

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, Medicine and Surgery Health Sciences, Epidemiology
Mot-clé	HIV clinical risk score virologic failure South Africa
Committee Chair / Thesis Advisor	Castro, Kenneth G, Emory University Marconi, Vincent, Emory University
Partnering Agencies	Emory University schools, faculty or affiliated programs University, college or educational institution (other than Emory)

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