Antiretroviral therapy (ART) adherence among people living with HIV AIDS (PLHIV) in the north of vietnam a multi method approach

ANTIRETROVIRAL THERAPY ART ADHERENCE among People Living with HIV/AIDS PLHIV in the North of Vietnam: a Multi-method Approach Hoa Mai Do MD, MPH A thesis submitted for the degree of D

ANTIRETROVIRAL THERAPY (ART) ADHERENCE among People Living with HIV/AIDS (PLHIV)

in the North of Vietnam: a Multi-method Approach

Hoa Mai Do

MD, MPH

A thesis submitted for the degree of Doctor of Philosophy at the School of Public Health, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology

2011

ABSTRACT

The antiretroviral therapy (ART) program for People Living with HIV/AIDS (PLHIV) in Vietnam has been scaled up rapidly in recent years (from 50 clients in 2003 to almost 38,000 in 2009) ART success is highly dependent on the ability of the patients to fully adhere to the prescribed treatment regimen Despite the remarkable extension of ART programs in Vietnam, HIV/AIDS program managers still have little reliable data on levels of ART adherence and factors that might promote or reduce adherence Several previous studies in Vietnam estimated extremely high levels of ART adherence among their samples, although there are reasons

to question the veracity of the conclusion that adherence is nearly perfect Further, no study has quantitatively assessed the factors influencing ART adherence In order to reduce these gaps, this study was designed to include several phases and used a multi-method approach to examine levels of ART non-adherence and its relationship to a range of demographic, clinical, social and psychological factors

The study began with an exploratory qualitative phase employing four focus group discussions and 30 in-depth interviews with PLHIV, peer educators, carers and health care providers (HCPs) Survey interviews were completed with 615 PLHIV in five rural and urban out-patient clinics

in northern Vietnam using an Audio Computer Assisted Self-Interview (ACASI) and clinical records extraction The survey instrument was carefully developed through a systematic procedure to ensure its reliability and validity Cultural appropriateness was considered in the design and implementation of both the qualitative study and the cross sectional survey

The qualitative study uncovered several contrary perceptions between health care providers and HIV/AIDS patients regarding the true levels of ART adherence Health care providers often stated that most of their patients closely adhered to their regimens, while PLHIV and their peers reported that “it is not easy” to do so The quantitative survey findings supported the PLHIV and their peers’ point of view in the qualitative study, because non-adherence to ART was relatively common among the study sample Using the ACASI technique, the estimated prevalence of one-

month non-adherence measured by the Visual Analogue Scale (VAS) was

24.9% and the prevalence of four-day not-on-time-adherence using the modified Adult AIDS Clinical Trials Group (AACTG) instrument was 29% Observed agreement between the two measures was 84% and kappa coefficient was 0.60 (SE=0.04 and p<0.0001) The good agreement between the two measures in the current study is consistent with those found in previous research and provides evidence of cross-validation of the estimated adherence levels

The qualitative study was also valuable in suggesting important variables for the survey conceptual framework and instrument development The survey confirmed significant correlations between two measures of ART adherence (i.e dose adherence and time adherence) and many factors identified in the qualitative study, but failed to find evidence of significant correlations of some other factors and ART adherence Non-adherence to ART was significantly associated with untreated depression, heavy alcohol use, illicit drug use, experiences with medication side-effects, chance health locus of control, low quality of information from HCPs, low satisfaction with received support and poor social connectedness No multivariate association was observed between ART adherence and age, gender, education, duration of ART, the use of adherence aids, disclosure

of ART, patients’ ability to initiate communication with HCPs or distance between clinic and patients’ residence

This is the largest study yet reported in Asia to examine non-adherence to ART and its possible determinants The evidence strongly supports recent calls from other developing nations for HIV/AIDS services to provide screening, counseling and treatment for patients with depressive symptoms, heavy use of alcohol and substance use Counseling should also address fatalistic beliefs about chance or luck determining health outcomes The data suggest that adherence could be enhanced by regularly providing information on ART and assisting patients to maintain social connectedness with their family and the community This study highlights the benefits of using a multi-method approach in examining complex barriers and facilitators of medication adherence It also demonstrated the utility of the ACASI interview method to enhance open disclosure by people living with HIV/AIDS and thus, increase the veracity

of self-reported data

TABLE OF CONTENT

KEYWORDS i

ABSTRACT iii

TABLE OF CONTENT v

LIST OF FIGURES xi

LIST OF APPENDICES xii

LIST OF ABBREVIATION xiii

STATEMENT OF ORIGINAL AUTHORSHIP xvi

RELATED PRESENTATIONS AND PAPERS xvii

ACKNOWLEDGMENT xviii

CHAPTER 1: THESIS OVERVIEW 1

1.1 Background of the Study 1

1.2 Purpose of the Study 3

1.3 Significance of the Study 4

1.4 Structure of the Thesis 4

CHAPTER 2: LITERATURE REVIEW 7

2.1 HIV/AIDS, Antiretroviral Therapy (ART) and Its Treatment Outcomes 7

2.2 Challenges of ART Program, the High Level of ART Adherence Required and the Consequences of Poor ART Adherence 10

2.3 Measurement of Adherence and the Prevalence of ART Adherence 13

2.4 Factors Associated with ART Adherence 16

2.4.1 Contextual factors 17

2.4.2 Individual factors 22

2.5 Research on ART Adherence in Resource-poor Countries and Asia 26

2.6 The Situation of HIV/AIDS and Research on ART Adherence in Viet Nam 31

2.6.1 HIV/AIDS in Viet Nam 31

2.6.2 ARV treatment, care and support programs for PLHIV in Viet Nam 35

2.6.3 Research on ART adherence in Viet Nam 39

2.7 Where to from Here: Research Questions, Survey Conceptual Framework, Objectives and Hypotheses 41

CHAPTER 3 METHODOLOGY 45

3.1 Study Design 45

3.2 Study Sites 48

3.2.1 Dong Da hospital (provincial level) 48

3.2.2 Dong Anh outpatient clinic (district level) 49

3.2.3 Hai Duong provincial AIDS center (provincial level) 49

3.2.4 Chi Linh and Kinh Mon out-patient clinics (district level) 49

3.3 Study Population, Sample Size and Data Collection Methods 50

3.3.1 Exploratory qualitative research 50

3.3.2 Cross-sectional survey 53

3.4 Survey Instrument Development 56

3.4.1 Expert consensus panel and individual feedback 56

3.4.2 Focus group discussion with HIV/AIDS patients 59

3.4.3 ACASI software development 60

3.4.4 Pilot study 60

3.5 Survey Variable Measurement 62

3.5.1 Outcome variables 62

3.5.2 Independent variables 64

3.6 Measurement Quality of the Survey Instrument 67

3.6.1 Test-retest reliability 67

3.6.2 Internal consistency 71

3.6.3 Construct validity 73

3.7 Data Analysis and Management 74

3.7.1 Exploratory qualitative data analysis 74

3.7.2 Survey data analysis 75

3.8 Ethical Considerations 78

CHAPTER 4: QUALITATIVE FINDINGS 81

4.1 Socio-demographic Characteristics of the Respondents 81

4.2 Qualitative Data Analysis Framework 84

4.3 How do HIV/AIDS Patients Adhere to Their Regimen? 85

4.4.1 Adherent aids 90

4.4.2 Adjust schedule of taking medication 90

4.4.3 Inappropriate behaviors 91

4.5 Factors Influencing ART Adherence among PLHIV 91

4.5.1 Gender and personal characteristics 91

4.5.2 Depression 93

4.5.3 Illicit drug use 93

4.5.4 Alcohol use 95

4.5.5 Treatment related factors 95

4.5.6 Health service issues 97

4.5.7 Social and family factors 100

CHAPTER 5: SURVEY FINDINGS 111

5.1 Characteristics of Study Participants 112

5.1.1 Socio-demographic characteristics 112

5.1.2 Characteristics of drug and alcohol use 114

5.1.3 Treatment and clinical characteristics 114

5.1.4 The use of adherent aids 116

5.1.5 Respondents’ experiences with side-effects 117

5.1.6 Descriptive statistics for depression and Chance Health Locus of Control (HLC) Scales 119

5.1.7 Social and family characteristics 120

5.2 Level of Non-adherence to ART Among the Sample 124

5.3 Factors Associated with ART Dose Non-adherence 130

5.3.1 Univariate analysis 130

5.3.2 Multivariate logistic regression model of factors associated with dose non-adherence 134

5.4 Factors Associated with Time Non-adherence 137

5.4.1 Univariate analysis 137

5.4.2 Multivariate logistic regression model of factors associated with time non-adherence 142

CHAPTER 6: DISCUSSION AND CONCLUSION 149

6.1 Level of ART Non-adherence and the Use of ACASI Technique 149

6.2 Factors Associated with ART Adherence 151

6.2.1 Psychological and individual factors 152

6.2.2 Clinical and treatment related factors 156

6.2.3 Family and social factors 160

6.3 Limitations of the Study 163

6.4 Significance and Implications of the Study 165

6.4.1 Study significance and implications for future studies 165

6.4.2 Public health and clinical practice 169

REFERENCES 173

APPENDICES 184

LIST OF TABLES

CHAPTER 2

Table 2.1 Summary Literature Review of Quantitative Study on ART Adherence

Conducted in Asian Countries……… 28

CHAPTER 3 Table 3.1: Matrix for Sampling in Qualitative Research……… 51

Table 3.2 Survey Sampling Process……… 55

Table 3.3 Prevalence and Test-retest Reliability of Outcome and Categorical Variables……… 69

Table 3.4 Test-retest Reliability of Self-reported Continuous Independent Variables……… 70

Table 3.5 Cronbach alpha of Continuous Variables……… 72

Table 3.6 Summary of the Fit Statistics of Models……… 73

CHAPTER 4 Table 4.1: Socio-demographic Characteristics of Respondents……… 83

CHAPTER 5 Table 5.1 Characteristics of the Sample 113

Table 5.2 Alcohol & Drug Use……… 114

Table 5.3 Treatment Characteristics of the Sample 115

Table 5.4 Clinical Characteristics of the Sample 116

Table 5.5 The Use of Adherence Aids……… 117

Table 5.6 Experiences of Side-effects of the Sample……… 118

Table 5.7 Experience with Depression Symptom among the Sample 119

Table 5.8 Descriptive Statistics of Chance Health Locus of Control 120

Table 5.9 Categorical Family and Social Factors……… 121

Table 5.10 Continuous Family and Social Factors……… 122

Table 5.11 Descriptive Statistics of Friendship Scale……… 123

Table 5.12 Descriptive Statistics of Modified Patient Reactions Assessment (PRA) Scale 124

Table 5.13 Agreement between Two Measures of ART adherence……… 127

Table 5.14 Characteristics of ART adherence among sample……… 128

Table 5.15 Reasons for not taking medication on time or missing doses 129

Table 5.16 Univariate analysis of socio-demographic factors by dose

non-adherence 130Table 5.17 Univariate analysis of clinical and treatment factors by dose non-

adherence 131Table 5.18 Univariate analysis of alcohol and drug use by dose non-

adherence 132Table 5.19 Univariate analysis of depression, side–effect experience and health locus of control by ART dose non-adherence 133Table 5.20 Univariate analysis of continuous social factors by dose non-

adherence 134Table 5.21 Multivariate analysis of factors associated with dose non-adherence measured by VAS ……… 136Table 5.22 Univariate analysis of socio-demographic factors by time non-

adherence 138Table 5.23 Univariate analysis of clinical and treatment factors by time non-

adherence 139Table 5.24 Univariate analysis of alcohol and drug use by time non-

adherence 140Table 5.25 Univariate analysis of depression, experience of side –effects and

health locus of control by time non-adherence 141Table 5.26 Univariate analysis of involvement in PLHIVs’ groups by time non-

adherence 141Table 5.27 Univariate analysis of social factors by time non-adherence 142Table 5.28 Multivariate analysis of factors associated with time non-adherence measured by AACTG……… 143Table 5.29 Summary of the factors associated with ART non-adherence by two measurements in multivariate analysis 146

LIST OF FIGURES

CHAPTER 2

Figure 2.1 Estimated number of AIDS-related deaths with and without

antiretroviral therapy globally, 1996-2008……… 9Figure 2.2 Estimated number of life-years added due to antiretroviral therapy by

region, 1996-2008 10Figure 2.3 Price of ARVs in Viet Nam in 2008……… 12Figure 2.4: Literature Mapping on ART Adherence among PLHIV……… 18Figure 2.5 Reported Cumulative HIV Infections, AIDS Cases, and AIDS Deaths,

1995-2009………

32Figure 2.6 Distribution of reported HIV cases by sex and by year, 1993-

2009………

33Figure 2.7 Distribution of reported HIV cases by age group and by year,

Figure 2.8 HIV prevalence among IDUs in Viet Nam 1996-2009……… 34Figure 2.9 HIV prevalence among female sex worker in Viet Nam 1996- 2009 34Figure 2.10 National spending on HIV/AIDS by categories, 2007-2009……… 37Figure 2.11 The Number of Adults and Children on ART in Viet Nam, 2006-2009…

………

38Figure 2.12 Survey Conceptual Framework……… 42

LIST OF APPENDICES

1 Appendix A Viet Nam at a Glance……… 185

2 Appendix B Viet Nam Map and Location of Study Sites……… 17

3 Appendix C Guideline for exploratory qualitative……… 189

4 Appendix D List of international and national expert providing feedback

5 Appendix E Final Survey Questionnaire ……… 207

6 Appendix F Bland – Altman Plots……… 229

7 Appendix G Ethical Approval from Queensland University of

9 Appendix I NVivo software tree node ……… 241

10 Appendix K Pictures of ACASI instruments, study sites, and data

collection………

243

LIST OF ABBREVIATION

AACTG Adult AIDS Clinical Trials Group

ACASI Audio Computer-Assisted Self-Interview

ACSPRI Australian Consortium for Social and Political Research

Incorporated

AIDS Acquired Immune Deficiency Syndrome

AMOS Analysis of Moment Structure

ANOVA Analysis Of Variance

ART Antiretroviral Therapy

ARV Antiretroviral

AZT Zidovudine (formerly called azidothymidine)

BA Bachelor of Art

BDI Beck’s Depression Inventory

CDC Center for Disease Control and Prevention

CES-D Center for Epidemiological Studies Depression

CFA Confirmatory Factor Analysis

CFI Comparatives Fit Index

CHLC Chance Health Locus of Control

CI Confidence Interval

CPCRA Community Programs for Clinical Research on AIDS

DNA Deoxyribonucleic acid

DOT Direct Observed Treatment

EDM Electronic Drug Monitoring

ESTHER The Ensemble pour une Solidarité Thérapeutique Hospitalière

FGD Focus Group Discussion

FHI Family Health International

FSWs Female Sex Workers

GFATM The Global Fund for AIDS, Tuberculosis and Malaria

GFI Goodness of Fit Index

GIPA Greater Involvement of People with HIV/AIDS

HAART Highly Active Antiretroviral Therapy

HIV Human Immunodeficiency Virus

HLC Health Locus of Control

HSPH Hanoi School of Public Health

IBBS Integrated Biological and Behavioral Surveillance

ICC Intraclass correlation coefficients

IDUs Injecting Drug Users

IHBI Institute of Health and Biomedical Innovation

IHLC Internal Health Locus of Control

IMB Information, Motivation and Behavioral skills

IRIS Introduction Research for International Students

KAP Knowledge Attitude and Practice

LIFE-GAP Leadership and Investment in Fighting an Epidemic –

Global AIDS Program MBBS Bachelor of Medicine, Bachelor of Surgery

MD Medical Doctor

MHLC Multidimensional Health Locus of Control

ML Maximum Likelihood

MOH Ministry of Health

MOU Memorandum Of Understanding

MPH Master of Public Health

MSM Men who have Sex with Men

NAP The National AIDS Program

NCADPPC The National Committee for AIDS, Drug and Prostitution

Prevention and Control NGOs Non-Government Organizations

NNR TIs Non-Nucleoside Reverse Transcriptase Inhibitors

NRTIs Nucleoside Reverse Transcriptase Inhibitors

OIs Opportunistic Infections

PAI Patient Affective Index

PCI Patient Communication Index

PEPFAR The President's Emergency Plan for AIDS Relief

PhD Doctor of Philosophy

PHLC Powerful Others Health Locus of Control

PII Patient Information Index

PIs Protease Inhibitors

PLHIV People Living with HIV/AIDS

PRA Patient Reaction Assessment

QUT Queensland University of Technology

RMSEA Root-Mean-Square Error of Approximation

SD Standard Deviations

SDT Self-Determination Theory

SPSS Statistical Package for the Social Sciences

SST Self Supervised Treatment

TB Tuberculosis

UNAIDS The United Nations Joint Program on HIV/AIDS

USA The United States of America

VAAC The Viet Nam Administration of AIDS Control

VAS Visual Analogue Scale

VCT Voluntary Counseling and Testing

WHO World Health Organization

STATEMENT OF ORIGINAL AUTHORSHIP

The work contained in this thesis has not been previously submitted to meet requirement for an award at this or any other higher education institution To the best of my knowledge and belief, this contains no material previously published

or written by another person except where due reference is made

Hoa Mai Do

Date: February 18th 2011

RELATED PRESENTATIONS AND PAPERS

Conference Papers

Hoa Do, Michael Dunne, Masaya Kato, Kinh Nguyen Antiretroviral Therapy

Adherence among People Living with HIV/AIDS in the North of Vietnam: A qualitative study (The 4th International Conference on HIV Treatment Adherence, Miami, USA, April 5th-7th, 2009)

Hoa M Do, Michael P Dunne, Cuong V Pham, Masaya Kato Non-adherence to

Antiretroviral Therapy in Viet Nam: Prevalence and clinical, social and psychological correlates (The 18th International AIDS Conference, Vienna, Austria, July 18th-23th, 2010)

Papers

D.M.Hoa, L.B Chau, P.T Linh et al Model of care and support for people living

with HIV/AIDS in Hai Chau district, Da Nang city Vietnam Journal of Public

Health 2009 12(6)

B.T.Mai, D.M.Hoa, L.B Chau et al Care and support for people living with

HIV/AIDS in Hai Chau and Thanh Khe district in Danang city in 2006 Vietnam

Journal of Public Health 2007 3(9)

Linh Cu Le, Robert W Blum, Robert Magnani, Paul C Hewett, and Hoa Mai Do

A pilot of audio computer-assisted self-interview (ACASI) for youth reproductive

health research in Vietnam Journal of Adolescent Health, 38 2006: 740-747

ACKNOWLEDGMENT

I would like to express my gratitude to all who have helped me to accomplish this thesis and my study at the Queensland University of Technology (QUT) First and foremost I would like to thank Prof Michael Dunne, my principal supervisor, for his interest in this study, his excellent ideas, and his dedication to reading and providing comments on multiple drafts of my thesis He also encouraged and guided me to be able to steer my academic study and professional development throughout my PhD program I would also like to thank Prof Gerard Fitzgerald and Dr Nguyen Van Kinh, my Associate Supervisors, for their time and great comments on this thesis I would like to express my gratitude

to Dr Masaya Kato from World Health Organization Representative Office in Vietnam, who provided me a realistic perspective to my thesis and his continuous expertise throughout this process I would like to extend my appreciation and thanks to Dr Pham Viet Cuong, Prof Everarda Cunningham, Dr Diana Batistutta and Dr Cameron Hurst, for their statistical supports Special appreciation and thanks to Sonja Firth, who has spent time and effort providing editorial support I

am also very thankful to Jill Nalder for helping, encouraging, and sharing emotions during my study at QUT

This study would have never happened without the support of the Hanoi School of Public Health (HSPH), and I appreciate the contributions from the Dean, Prof Le Vu Anh, and my colleagues at the HSPH who helped make the

research a success Thanks to Dr Masami Fujita, Dr Julian Elliott, Dr Rachel

Burdon, Prof Krishna Poudel, Dr Do Thi Thanh Nhan, Ass.Prof Le Cu Linh, Dr

Nguyen Thanh Huong, Dr Do Duy Cuong, Dr Vu Thi Bich Diep, Dr Cao Thi Thanh Thuy, Ms Nguyen Thi Minh Thu for their constructive comments on the questionnaire, protocol and manuscripts I wish to thank Tran Hong Quang and Pham Thuy Linh for their helps in developing the ACASI software Special thanks

to my research assistants, Le Minh Hai, Nguyen Minh Hoang, Le Thi Thu Huyen, Nguyen Thi Hoang Nga, Le Bao Chau, Le Thi Thu Ha for their assistance in data collection To all the faculty, staff and PhD colleagues at the QUT and the HSPH whom I could not possibly mention in detail, a big thank you for your supports

This study will not be successful without the cooperation of many kinds of souls Special thanks are due to all committed directors and dedicated staff in five out-patient clinics for their cooperation and facilitations to smoothly complete

my fieldwork portion of this study There were many people in Hanoi and Hai Duong whom I would like to thank for their willingness, patience and time to participate in this study

I would like to thank the Australian Leadership Awards (ALA) Scholarship

of the Australian Agency for International Development (AusAID), the World Health Organization (WHO) Representative Office in Vietnam, and the Hanoi School of Public Health (HSPH) for their financial supports that made this study possible The ALA Scholarship has offered educational experiences on research and leadership training that has allowed me to both shape my career path and become friends with some of the most interesting and admirable people I have ever known

Last but certainly not least, to my family, I would like to thank my parents, sisters and brothers for their continuing support in countless ways, as well as my friends who understood and put up with me during this stressful time period To

my husband, Cuong, I am grateful for his unending support and patience throughout the implementation of this thesis and my education Without his emotional and mental support, I could not have successfully completed my PhD degree Bim and Chick, my lovely son and little daughter, I am done and I am coming home I love you so much and I am proud of you both

CHAPTER 1: THESIS OVERVIEW

1.1 Background of the Study

The1 increased availability of treatment has dramatically improved survival rates

and lowered the incidence of opportunistic infections in People Living with HIV/AIDS (PLHIV) 2 Antiretroviral Therapy (ART) has been shown to successfully decrease viral loads and increase CD4 cell count 3-5 A dramatic reduction in HIV related morbidity and mortality has been observed in countries where ART has been made widely available 6, 7 Whilst there are many benefits

to ART, there are also many challenges caused by this therapy One of these challenges is that very high levels of adherence to ART (at least 95%) are needed to ensure optimal benefits 3, 7, 8 Many studies have revealed that poor adherence can lead to failure to reduce viral load, the evolution of drug resistance and subsequent immunological and clinical failure 3, 4, 6

Although the measurement of ART adherence is critically important in both ART interventions and clinical research, there is no “gold standard” by which to measure adherence to medication 9-12 While adherence can only be ensured by

directly observed treatment, this is not practical for daily therapy which has to be

taken for the whole of a patient’s life As a result, levels of adherence can only be

estimated by use of indirect measures 13 These measures include self-reporting

tools (such as questionnaires and visual analogue), pill counts, pharmacy refill records and electronic drug monitoring devices However, all methods have strengths and weaknesses 9-12 The most common approach is to elicit the information by self-report, in which participants describe their adherence over a specified time interval It appears that self-report methods may lead to an overestimation of medication adherence, but they are often used because they are inexpensive and feasible in a wide variety of settings 14 More importantly, many studies have shown that self-report assessment, visual analogue scale, electronically monitored doses, and pill count lead to similar estimates of the relationship between adherence and viral suppression and adherence is a strong

predictor of viral load 3, 15, 16

Most of the studies on ART adherence have been conducted in North America, Europe and African countries, but not many have been conducted in Asia There are considerable variations in ART adherence levels between countries as well

as within a country A meta-analysis conducted by Mills et al (2008) for 31 studies (17 573 patients total) conducted in North America indicated a pooled estimate of 55% (range: 26%-86%) of the population achieving adequate levels

of adherence, while the result of the analysis of 27 studies (12 116 patients total) conducted in sub-Saharan Africa indicated a pooled estimate of 77% (range: 30%-100%), indicating a significantly (P<0.001) higher level of adherence in Africa 17 The literature review of this current study (Chapter 2) found that the proportion of PLHIV who achieve optimal adherence in Asia was even higher than in Africa 18, 19 The potential reasons for the high level of adherence in Asia are discussed, including biases caused by the influence of healthcare providers

20, 21 and the fear by patients that their treatment will be interrupted if they admit

to poor adherence practice22 Current studies in Viet Nam have also highlighted these problems 23 and drawn attention to the need for a better approach to data collection A method such as Audio Computer-Assisted Self-Interview (ACASI), that maximizes patients’ anonymity, minimizes the influence of health care providers in the data collection process and eases patients’ concerns about the impact of the interview on their treatment 14, might be appropriate

Researchers have identified numerous factors influencing ART adherence among PLHIV17 There are different ways to group the factors that influence adherence to ART The simplest way distinguishes between individual and contextual factors The contextual factors include treatment related issues (complexity of regimen side-effects, accessibility, patient-provider relationship, quality of services, etc.), and social interaction (disclosure, types of support, sources of support, satisfaction level, social capital, etc.) On the other hand, many individual factors were reported to be important in influencing adherence to ART These factors comprise socio-demographic characteristics and risk behaviors such as drug use, alcohol use and mental health problems Understanding the factors that influence adherence to ART is essential for designing strategies to optimize adherence The evidence has been growing

lacking in Viet Nam Despite the remarkable scaling up of ART programs in Viet Nam 24, HIV/AIDS program managers still have little reliable data on levels of ART adherence and factors that might facilitate or impede adherence to ART Three studies on ART in Viet Nam estimated extremely high levels of ART adherence among their samples (from 85% to 100% of participants were optimal

ART adherers)22, 23, 25 Official reports from out-patients clinics also generally underestimated ART non-adherent practice due to factors that inhibit patients’ honesty in reporting their non-adherent practices (fear of consequences) and failure of professionals to recognize and report non-adherence Further, no study

has quantitatively assessed the factors influencing ART adherence Hence, this study aims to partially fill the gaps in the literature on adherence to ART Specifically, the result of this doctoral study should increase the level of understanding of ART adherence and its associated factors among PLHIV in the

North of Viet Nam

1.2 Purpose of the Study

This study was conducted across several phases and used a multi-method approach First, a qualitative study employed 4 focus group discussions and 30

in-depth interviews with HIV/AIDS patients, peer educators, carers and medical staff Second, a survey was used to collect data from 615 HIV/AIDS patients on ART in five rural and urban out-patient clinics in Viet Nam using an Audio Computer Assisted Self-Interview (ACASI) and clinical record extraction This study aims to answer the following questions:

1 To what extent do PLHIV in the North of Viet Nam adhere to their

Antiretroviral (ARV) regimens?

2 What individual, family and clinical factors influence ART adherence

among PLHIV in the North of Viet Nam?

3 What are the practical implications for intervention programs to improve

ART adherence?

1.3 Significance of the Study

This study contributes to the field of HIV/AIDS treatment and care in Viet Nam in several ways So far, there has been no systematic study on ART adherence among HIV/AIDS patients in Viet Nam To design effective ART interventions for HIV/AIDS patients, it is necessary to measure sub-optimal ART adherence and explore factors that facilitate or impede optimal adherence with ART 10, 12

This new study can also contribute to the international literature To date, few studies on ART adherence have used a multi-method approach, despite the acknowledged value of combining research methods in behavioral and social studies 26-28 This study used a combination of research methods including exploratory qualitative research and a cross-sectional survey with clinical record extraction to capture perspectives from HIV/AIDS patients, health care providers, peer educators and HIV/AIDS patients’ supporters This work should provide a comprehensive picture of the cultural and structural context of the ART programs

in Viet Nam The triangulation between various research methods significantly enhances the understanding of how to promote and increase the efficiency and effectiveness of HIV/AIDS treatment and care programs As the number of PLHIV receiving ART is on the increase, this proposed study benefits policy makers and program managers as they strive to develop effective and appropriate ARV treatment interventions in Viet Nam

1.4 Structure of the Thesis

The thesis is comprised of 6 chapters

Chapter 1 provides the background, purpose, significance and structure of the study

Chapter 2 reviews relevant literature related to ART adherence among PLHIV This chapter starts with a review of the HIV/AIDS epidemic and the implementation and outcomes of ART programs worldwide This is followed by a review of the challenges of ART, the requirement for a high level of ART adherence and consequences of poor ART adherence and explains why ART adherence is so important Level of ART adherence and associated factors

research on ART adherence conducted in Asia and Viet Nam and other rationales for this study This chapter concludes with an introduction to the study

aims including research questions, conceptual framework and hypotheses

Chapter 3 describes the methods and instruments employed in this study First, the study design used, the research process, descriptions of the study sites, the

target population, the sample size, data collection, and development of research

instruments are described in detail Second, the results of the pilot survey as well

as the reliability and validity of the survey instruments used in this study are presented Finally, this chapter describes the process of data management and analysis and ethical considerations

Chapter 4 presents the results from the exploratory qualitative study, which describes how HIV/AIDS patients adhere to their regimens, and the facilitators and barriers of their adherent behaviors The main purpose of this qualitative component was to gain a deep understanding of ART adherence from the point

of view of PLHIV, their family members, their peers, and health care providers and identify important factors that should be included in the survey

Chapter 5 reports the results from the survey of 615 PLHIV The characteristics

of the study sample are first described This is followed by estimates of the level

of non-adherence to ART among the sample, measured by two international standard instruments (i.e VAS and AACTG) The results of statistical tests examining a range of factors associated with the two types of ART non-

adherence are then presented

Chapter 6 starts with a discussion on the triangulation between qualitative study

and cross-sectional survey findings and consideration of these findings within the

context of other research The strengths and limitations of this study are then discussed Lastly, this chapter delineates implications for future research and recommendations for clinical and public health practice

CHAPTER 2: LITERATURE REVIEW

INTRODUCTION

This chapter reviews relevant literature regarding adherence to ART and factors that influence ART adherence among PLHIV It is comprised of seven sections The first section describes the HIV/AIDS epidemic and the implementation and outcomes of ART programs worldwide The second section examines the challenges for HIV/AIDS treatment programs, the requirement for a level of ART

adherence and the consequences of poor adherence The next section explores

how ART adherence among PLHIV has been defined and evaluated across the world Factors influencing ART adherence are discussed in section four Section

five focuses on the research related to ART adherence conducted in developing

and Asian countries The following section describes the HIV/AIDS epidemic in the Vietnamese context, the response to this epidemic including HIV/AIDS care and treatment programs, and the gaps in the research on ART adherence in Viet

Nam The chapter concludes by discussing the focus, research questions, and conceptual framework of this study

2.1 HIV/AIDS, Antiretroviral Therapy (ART) and Its

Treatment Outcomes

It has been nearly three decades since scientists identified the first case of HIV/AIDS in 1981 Since that time, almost 60 million people have been infected with HIV HIV/AIDS has become one of world’s leading cause of death killing approximately 25 million people 29 In 2008 alone, it is estimated that 33.4 million

people worldwide were living with HIV, 2.7 million people were newly infected with the virus and 2 million died of AIDS 29 Among those living with HIV/AIDS globally, more than 97% are in low- and middle-income countries

The introduction of Antiretroviral (ARV) medication for treating AIDS patients in the 1990s brought new hope to affected people Prior to 1996, mono-therapy (e.g AZT) was the treatment of choice used to interfere with HIV-related production of DNA needed for cell replication However, because HIV has an extremely short life cycle (approximately ten billion particles are produced and destroyed daily), viral replication occurs quickly as does mutation 6 Consequently, while mono-therapy could temporarily slow viral replication, clinical benefits were short lived, and this treatment approach was quickly rendered ineffective due to the likelihood of drug resistance developing within weeks or months 30

The international treatment guidelines now indicate that optimal treatment for HIV involves a combination consisting of different kinds of ARVs, which attack the virus in different ways The most commonly used are from three classes: Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non Nucleoside Reverse Transcriptase Inhibitors (NNR TIs) and Protease Inhibitors (PIs) This combination, referred to as ART, is highly effective at interfering with HIV replication in both early and late stages in the viral replication cycle Nowadays, several ARVs are often combined in a single tablet, which ensures that patients always take multiple doses together 6

Globally there has been a rapid increase in access to ART in the last 5 years More than 4 million people in poor-resource countries had access to HIV treatment at the end of 2008, up from 3 million at the end of 2007 This represents an increase of 36% in one year and a 10-fold increase over five years

29 An estimated 700 thousand people received treatment in high-income countries in 2008, bringing the global total to at least 4.7 million 29 Despite considerable progress, global coverage remains low The proportion of those in need of treatment that had access to ARV in 2007 and 2008 was 35% and 42% respectively

The increased availability of treatment has dramatically improved survival rates and lowered the incidence of opportunistic infections in people with AIDS 2

virus, and can even reduce the level of the virus to a point where it is no longer possible to detect any HIV in the blood These medicines prevent HIV from multiplying rapidly and, at the same time, boost the body’s immune system Therefore, ART has been shown to successfully decrease viral loads and increase CD4 cell count 3-5 A dramatic reduction in HIV related morbidity and mortality has been observed in countries where ART has been made widely available 6, 7 Figure 2.1 shows the globally estimated number of AIDS-related deaths with and without antiretroviral therapy in the period between 1996 and

2008 During the same period, Figure 2.2 shows the UNAIDS’s estimated number of life-years added due to antiretroviral therapy by region This illustrates

that ART can increase the length and quality of life and enable people to lead full

and productive lives 2

Figure 2.1 Estimated Number of AIDS-related Deaths with and without ART

Globally, 1996–2008 (Source from AIDS Epidemic Update 2009 by UNAIDS, 2009)

2.2 Challenges of ART Program, the High Level of ART

Adherence Required and the Consequences of Poor ART

Adherence

Whilst there are many benefits to ART, there is also many challenges caused by this therapy The first challenge for patients on ART is side-effects All ARVs have different side-effects and these can have an impact both on how the medicines will be used and how patients take them People on ARV medications frequently report severe and disabling physical symptoms The most common side-effects are nausea, vomiting, allergy, fatigue, diarrhea, and more chronic problems such as peripheral neuropathy, oral numbness, and metallic taste 2 Nowadays, though newer first line ART formulation (e.g replacement of D4T with Tenofovia-based first line regimen) or the fixed-dose combination of Tenofovia, Emtricitabine (FTC), and Efavrienz helped to reduce side-effects and increase tolerance among PLHIV on ART 31, adverse effects were claimed as barriers of ART adherence 32, 33,

Figure 2.2 Estimated Number of Life-years Added due to ART by Region, 1996-2008 (Source from AIDS Epidemic Update 2009 by UNAIDS, 2009)

In addition, ARV medications must be taken in accordance with strict dietary guidelines and therefore can greatly interfere with lifestyle and secrecy concerning HIV status For example, once patients decide to take ARVs, they are

required to take the medicines daily at specific times of the day with fixed intervals between doses, for the rest of their life 6, 28 Very high levels of adherence to ART (at least 95%) are needed to ensure optimal benefits 3, 7, 8

Many studies have revealed that poor adherence can lead to failure to reduce viral load, the evolution of drug resistance and subsequent immunological and clinical failure 3, 4, 6

Drug-resistance is a well-recognized biological phenomenon occurring with infectious organisms including bacteria, viruses and parasites When an infectious organism is exposed to an antibiotic, or an antiviral agent, some of the

organisms will be very sensitive to the agent while some will be partially resistant, due to genetic variation When patients interrupt taking their drugs or reduce the dose, those organisms that were sensitive will have been killed, while

the more resistant organisms will have survived and can replicate 13 Viral replication occurring in the presence of the drug selection pressure will ultimately

select for new viral variants that are drug-resistant Therefore, patients who often

experience suboptimal drug levels have an increased chance of drug resistance and failure of therapy 13 When a specific failing ART regimen is continued, an accumulation of variation will occur, leading to greater cross-resistance to other members of the drug class The transmission of the resistant virus may then also

confer limitations in treatment options for those newly infected 34

If an individual develops resistance to ARVs, two problems occur First, the

first-line ARVs will no longer work and the individual will start to suffer from multiple opportunistic infections Second, the individual may transmit the drug-resistant virus to their contacts and when those individuals go for treatment they will discover that their virus does not respond to the first-line therapy 2, 6 Once a person develops resistance to first-line medicines she/he will need to change to second-line ARVs 6 However, at present these products are substantially more expensive than the first-line ARVs and have a different range of side-effects 2

Moreover, the decision to change a person from first-line to second-line therapy

is a difficult one to make, especially if CD4 and viral load testing equipment is not

available Figure 2.3 shows that the cost of second-line therapy is about 10 times more than first-line therapy in Viet Nam 6 The danger is that if too many patients progress to second-line therapy, the increased costs involved will limit access to treatment for many people who would benefit from first-line therapy Every effort should be made to ensure a high level of adherence (at least 95%)

to the first-line ARVs in order to delay the emergence of drug-resistance and enable individuals to be treated for many years with first-line ARVs 2, 7, 35 In addition, it is evidenced that adherence to ARV medication is critical in order to gain optimal viral suppression 4, 6 and to increase the CD4 lymphocyte count 3-5

Figure 2.3 Price of ARVs in Viet Nam in 2008

(Source: Supply Chain Management System) Note:

First line ARVs: d4T: stavudine; 3TC: lamivudine; NVP: nevirapine; EFV:

efavirenz; AZT: zidovudine

Second line ARVs: ABC: Abacavir; ddI: Videx (brand name); LPV/r: Lopinavir/

ritonavir

2.3 Measurement of Adherence and the Prevalence of ART

Adherence

More than ten years ago, the term “compliance” was used almost interchangeably with the term “adherence” Recently, the term “adherence” has replaced the term “compliance” 4 This occurred, because both terms describe the same behavior, yet implied a different motivation for it Compliance typically refers to the extent to which a patient obeys the advice and directive of a doctor,

and implies a somewhat passive role on the part of the patient, and overly authoritative role for the doctor 36 Furthermore, “compliance” is viewed as value-

laden and containing a directional bias that assumes that physician guidelines are accurate and that patient behavior should be measured in accordance with these guidelines 4 Adherence on the other hand, is less value-laden, suggests a

more collaborative relationship between provider and patient, and promotes a more comprehensive study of variables that affect adherence (e.g regimen, context, etc.) Adherence therefore is defined as the extent to which patients follow the instructions they are given for prescribed treatments 36

Medication adherence is a complex term referring to a variety of distinct adherence behaviors, beginning with picking up a prescription and ending with consumption of the medication 36 In the case of adherence to ART, full adherence requires keeping appointments with health care providers, refilling a prescription, correctly counting the medications to be taken, and ensuring that medications are taken at the right time of day and in accordance with dietary guidelines Therefore, ART adherence is made up of different types of adherence, such as measure of dose adherence, schedule adherence, adherence with dietary guidelines, and adherence to keeping appointments with providers This may lead to confusion surrounding what is actually being measured in adherence studies 36

There are two measures that are frequently used to report adherence to ART The first is the overall adherence, recorded as the number of tablets taken correctly as a proportion of those which were prescribed The second measure is

the percentage of patients taking at least 95% of their tablets correctly While the

first measure is important for the clinical evaluation of individual patients and

counseling purposes, the second one is essential for programmatic or public health planning and evaluation, since it is one of the most important requirements for the success of ART programs 13

Adherence can be analyzed as a continuous variable or as a categorical variable that distinguishes “optimal” from “suboptimal” adherence Studies have traditionally used a threshold of 95% or more to distinguish between optimal and suboptimal adherence 10, 14, 37 This threshold was based on evidence that near perfect adherence (95% or more) to existing regimens is needed to achieve optimal patient and clinic outcomes, such as lower risk of virological failure, increased CD4 lymphocyte count and lower hospitalization rates 35, 38 Early unboosted protease inhibitors (PIs)-based cART regimens required about more than 95% adherence to be consistently effective 35, but today’s non-nucleoside reverse transcriptase inhibitors (NNRTIs) and boosted protease inhibitors (PIs)-based cART can achieve virologic suppression at moderate adherence (70-90%), although optimal outcomes can require maximum adherence 394040, 41

While adherence is best measure by direct observation, this is not practical for daily therapy which has to be taken for the whole of a patient’s life As a result, levels of adherence can only be estimated by use of indirect measures 13 These measures include self-reporting tools (such as questionnaires and visual analogue scales), pill counts, pharmacy refill records and Electronic Drug Monitoring (EDM) devices However, all methods have strengths and weaknesses 9-12 For example, though pill count and pharmacy refill are useful and low cost tools to measure ART adherence 42, 43, they are considered a crude method that overestimates actual adherence because some patients come to clinics to get the medications but do not really take them at home Measuring adherence by EDM devices, which monitors the number of times the cap of a pill container is removed, is generally considered a reliable method because of its advantages such as objectivity, minimal patient bias, and recording of precise dose timing 41 However, EDM is quite expensive and logistically challenging to use, especially in limited resource settings 41 In addition, there are still problems with measuring adherence using electronic drug monitors Bangsberg et al (2000) found in his study that ART patients open the pill boxes out of curiosity

by self-report, in which participants describe their adherence over a specified time interval14 It appears that the self-report methods may lead to an overestimation of medication adherence14, but they are often used because they are inexpensive and feasible in a wide variety of settings 14 More importantly, several studies have shown that self-report assessment, visual analogue scale, electronically monitored doses, and pill count lead to similar estimates of the relationship between adherence and viral suppression and adherence is a strong

predictor of viral load 3, 15, 16

Most of the studies on ART adherence have been conducted in North America, Europe and African countries, but not many have been conducted in Asia There

are considerable variations of ART adherence levels between countries as well

as within a country A meta-analysis conducted by Mills et al (2006) for 31 studies (17 573 patients total) conducted in North America indicated a pooled estimate of 55% (range: 26%-86%) of the populations achieving adequate levels

of adherence, while the analysis result of 27 studies (12 116 patients total) conducted in sub-Saharan Africa indicated a pooled estimate of 77% (range: 30%-100%), indicating a significantly (P<0.001) higher level of adherence in Africa 17 Many reasons have been reported to explain this disparity Adherence

success in sub-Saharan Africa can be explained by the role of social capital, where prioritization of adherence is complemented through resources and help made available by treatment partners, other family members, friends, and health

care providers Helpers expect adherence and make their expectations known, creating a responsibility on the part of patients to adhere Patients adhere to promote good will on the part of helpers, thereby ensuring help will be available when future need arises 44 Another reason for higher ART adherence level in resource-poor countries is that there are still substantial barriers to accessing ART In order to access ARVs from health care and treatment programs supported by either government or other donors in resource-poor countries, patients need to show good evidence that they are able to strictly follow the therapies For example, in Vietnam, each patient needs to have at least one family member to assist and remind her/him to take the medications, and both patient and this family member have to go through several education sessions on

ART run by clinics prior to receiving medication2322 Another study in Africa noted

that limited access to ARTs in poor-resource countries may be an important motivating factor 45 However, the great variability in the measures of ART

adherence level (i.e methods, instruments, response format, and the recall period, etc) should also be considered in these settings The lack of standardized measures makes it difficult to evaluate any particular measure or to compare measures across studies 14

Measuring adherence to medications is not a simple task No single measure is appropriate for all settings It has been found that the use of more than one measure of adherence allows the strength of one method to compensate for the weakness of the other and to more accurately capture the information needed to determine adherence levels 10, 46 Therefore, this current research tried to assess different aspects of the ART adherence level among AIDS patients in the north of Viet Nam, including dose adherence (i.e visual analogue scale), time adherence (i.e AACTG modified instrument), adherence during the weekend, and dietary adherence

2.4 Factors Associated with ART Adherence

Researchers have identified numerous factors influencing treatment adherence including the medication adherence of PLHIV There are different ways to group the factors that influence adherence to ART, ranging from conceptual frameworks that simply distinguish between individual and contextual factors, to those frameworks that include more detailed categories A systemic review of ART adherence found over 200 separate variables associated with HIV medication adherence 47 This section focuses on the literature addressing ART adherence factors which summarized in the Figure 2.4 These factors can be divided into two levels, The first level is the individual level, including socio-demographic characteristics, personal perceptions, beliefs, and attitudes toward ART, risk behaviors, personal ability and behavior skills, physical and mental status This level directly shapes PLHIV’ adherence behavior to ART The second level includes contextual factors such as ART treatment related factors, health services, family and social support, which directly or indirectly influences their adherence behavior through individual factors

2.4.1 Contextual Factors

Treatment related issues

Illness characteristics influence level of adherence in several ways Most notably,

patients with short-term illnesses tend to be more adherent than patients with chronic illnesses 36 Additionally, patients are more likely to be adherent when symptomatic, and when symptoms are relieved quickly following treatment 36

Considering these points, it is clear that the characteristics of HIV/AIDS make adherence to treatment challenging HIV/AIDS is a chronic illness and treatment

does not always provide immediate relief Symptoms may stimulate the use of medications by acting as a reminder or reinforcing beliefs about the necessity for

treatment As mentioned earlier, HIV/AIDS treatment needs to last for the whole life of anyone who has commenced ART, even when all of their symptoms disappear However, some patients stop taking their medications when they feel

better and no longer have any symptoms This situation happens in many cases

with patients on ART 3, 36

Illness severity has been found to be associated with adherence to ART, although the results have been mixed in terms of the strength and direction of the

association 36, 48 For example, Gao et al (1999) studied adherence to ART among 72 AIDS patients at various stages of illness and found that adherence was highest among patients who previously had AIDS-related complications In a

longitudinal study involving 46 HIV-positive patients, Singh et al (1996) found that illness severity, as indicated by CD4 count and number of opportunistic infections, did not discriminate adherents from non-adherent patients 49

Treatment regimens include the number of pills prescribed, the complexity of the

regimen (dosing frequency and dietary instruction), and the specific type of ARV

and medication side-effects Many studies have found that side effects are associated with ART adherence In a study of adherence to ART involving 109 AIDS patients in Botswana, Weiser et al (2003) found that 9% of the cohort reported missing doses due to side-effects 50 Likewise, Nachega et al (2009) reported that ART medications can cause side effects, including metabolic complications that can impact patients’ adherence levels 51 5 In a qualitative

study of adherence to ART among HIV-infected women, Roberts and Mann

(2000) found that side-effects were reported by participants as a main barrier to

adherence 52

Figure 2.4 Literature Mapping on ART Adherence among PLHIV

- Dose adherence: Self-report, VAS,

MEMS

- Schedule Adherence

- Dietary Instruction Adherence

- Clinical and Pharmaceutical

Record Review: Pill Count, Pill

Pick-up, Appointment Keeping

- Composite Index: CAS, CASE

Treatment Outcomes

CD4 counts, Quality of Life, Mental and Health Status, Viral Load, Drug Resistant, Morbidity, Mortality

ART Adherence

High-risk Behaviors (Illicit Drug and Alcohol Abuse)

Mental Health Problems (Depression, Anxiety, Stress)

Individual Factors

Health Locus of Control

(Internal, Chance, & Other Power)

Socio-demographic Characteristics

(Socio-economic status, Gender,

Age, Ethnicity, Education, Job)

Treatment Related

- Illness characteristics & severity:

history of HIV (+), treatment duration,

health state at initiation of therapy,

progress of disease over time, CD4

count, opportunistic infections, TB

infection & other diseases functional

status, clinical stage

- Regimen: complexity, dosage level,

side-effects

Contextual Factors

Family and Social Support

- Marital status, # of children

- Disclosure of ART status

- Discrimination, Fear of Abandonment,

Stigma

- Kinds of assistance: tangibles,

emotion,

- Exposure to the community-based

programs: peer education, home

based-care support, etc

- Trust in & Satisfaction w/ health

services, social and family supports

Health Services

- Availability: supply continuity,

working hour

- Accessibility: cost, time, distance

- Clinical Settings: equipment, facilities,

guidelines, etc

- Relationships b/w Health Providers and

Patients

- Adherence Support & Follow-up (e.g

counseling, home visits, DOT)

- Special Services: Methadol