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Ucapan Terima Kasih

First I would like to say thanks to my first Supervisor Prof Dr. dr. Tuti

Parwati Merati Sp. PD for guidance and her input on the thesis. Also I would like

to thank my second supervisor dr. A.A. Sawitri, for her encouragement, guidance

and support during the learning process, during this thesis but beyond.

Next I would like to thank each member of the examination comity Prof.

dr. D.N. Wirawan MPH, Dr. dr. Dyah Pradnyaparamita Duarsa MSi and dr. Pande

Putu Januaraga M.Kes Dr.PH for their input and corrections of this thesis. Also I

would like to thank the entire mentor Field Research Training Program (FRTP)

for their guidance and support during this.

Special thanks also to Dr. Ketut Dewi Kumara Wati, Sp. A(K) for her help

and the patience to answer all my questions.

Next I would like to thank my fellow FRTP colleges and friends as well as

everybody from the MIKM batch VI.

Finally I would like to thank my family, my husband and my kids, for

their support and for always believing in me.

Thank you.

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ABSTRACT

PREDICTORS OF LOST TO FOLLOW UP AND MORTALITY IN CHILDREN ≤ 12 YEARS OLD RECEIVING ANTIRETROVIRAL THERAPY IN SANGLAH GENERAL HOSPITAL, DENPASAR ,

BETWEEN 2010-2015

Background: Very little is known about predictors of LTFU and mortality in children in Asia. Many HIV-infected children in Bali have started antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. LTFU and mortality in children receiving ART is different and more complex compared to adults, since they dependent on their caregivers. Method: The study design was a retrospective survival analysis using secondary data of 138 HIV positive children receiving ARV treatment in Sanglah General Hospital, Bali between January 2010 till December 2015. Kaplan-Meier analysis was used to describe incidence rate and median time to LTFU/mortality and Cox Proportional Hazard Model was used to identify its predictors. Analyzed variables were socio-demographic characteristics, birth history, primary care giver and clinical characteristics at first hospital visit and/or at ART initiation.

Result/ Discussion: The overall mean age when starting ART was 3.21 years old, indicating an early diagnostic response. A total of 25% experienced LTFU/death by 9.1 month resulting in an incidence rate of 3.28/100 child-month. The higher the WHO stage, when stating the ARV therapy, the trend shows a higher risk for LTFU/mortality as well as low body weight (AHR 0.90 95%CI 0.82-0.99). A majority of the children received breast milk during the first 6 month and 73.19% were born vaginally which might lead to the assumption of low HIV testing during ANC.

Conclusion: The study found that only clinical characteristics can be used as predictors for LTFU/mortality and not socio-demographic characteristics, birth history and primary care giver.

Key words: LTFU, mortality, pediatric, ART, Indonesia

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ABSTAKT

PREDIKTOR LOST TO FOLLOW UP DAN KEMATIAN PADA ANAK-ANAK ≤ 12 TAHUN, YANG MENERIMA ANTIRETROVIRAL TERAPI

DI RUMAH SAKIT UMUM PUSAT, DENPASAR, PERIODE TAHUN 2010-2015

Latar belakang: Banyak anak yang terinfeksi HIV sudah mulai memperoleh terapi ant-iretroviral (ART) di Bali, akan tetapi Loss to follow up (LTFU) masih cukup substensial. LTFU dan kematian pada anak yang sedang dalam terapi ART berbeda dan lebih kompleks dibandingkan dengan dewasa. Selain karakteristik klinis, pasien anak-anak memiliki ketergantunga pada pengasuh mereka. Terdapat sedikit informasi mengenai prediktor pada anak-anak untuk LTFU atau kematian di Asia Metode: Desain penelitian adalah penelitian survival analysis retrospektif dengan menggunakan data sekunder dari 138 anak-anak HIV positif yang menerima pengobatan ARV di Rumah Sakit Umum Sanglah, Bali antara Januari 2010 sampai Desember 2015. Analisis Kaplan-Meier digunakan untuk menggambarkan tingkat kejadian dan waktu median untuk kematian. Cox Proportional Hazard Model digunakan untuk mengidentifikasi prediktornya. Variabel yang dianalisa adalah karakteristik sosio-demografis pasien, riwayat persalinan, pengasuh, dan karakteristik klinis saat kunjungan pertama dan/atau pada saat muali ART. Hasil / Diskusi: Keseluruhan rata-rata usia ketika anak-anak mulai terapi ARV adalah 3.2 tahun yang menunjukkan tindakan diagnostik yang cukup cepat. Dari semua pasien yang menerima ART, 25% mengalami LTFU kematian sebesar 9,1 bulan sehingga tingkat kejadian 3,28 /100 anak-bulan. Stadium WHO yang lebih tinggi, dan berat badad (AHR 0.90 95%CI 0.82-0.99) saat memulai ART, semakin tinggi risiko untuk LTFU dan atau kematian pada penelitian ini. Di sisi lain sebagian besar anak-anak mendapatkan ASI selama 6 bulan pertama dan 73,19% lahir per vaginal yang dapat menyebabkan asumsi bahwa tes HIV rendah selama ANC. Kesimpulan: Program harus lebih fokus pada anak-anak dengan stadium WHO 3 atau 4, serta anak-anak kekurangan gizi untuk kepatuhan yang lebih baik. Kata kunci: loss to follow up, kematian, anak, ARV, Indonesia

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TABLE OF CONTENT Page FRONT COVER i MAIN COVER ii PREREQUISITES DEGREE (PRASYARAT GELAR) ………………………………………………………

iii

SUPERVISORS APPROVAL SHEET (LEMBAR PERSETUJUAN PEMBIMBING)………………………….

iv

EXAMINATION COMITTEE (PENETAPAN PANITIA PENGUJI)…………………………………..

v

NOTE OF THANKS (UCAPAN TERIMA KASIH)……………………………………....………

vii

ABSTRACT………………………………………………………………… viii ABSTRAK. …………………………………………………………………. ix TABLE OF CONTENT……………………………………………….. x LIST OF FIGURES …………………………………………………... ix LIST OF TABLES ……………………………………………………. ix LIST OF APPENDIX ………………………………………………. x LIST OF ABBREVIATIONS………………………………………...

xi

CHAPTER I – FORWARD …………………………………………... 1 1.1 Background ……………………………………………. 1 1.2 Research Question …………………………………….. 4 1.3 Research Objectives …………………………………… 4 1.3.1 General Objectives ………………………………. 4 1.3.2 Specific Objectives ……………………………… 4 1.4 Relevance of Study ………………………………….. 6 CHAPTER II- LITERATURE REVIEW …………………………….. 7 2.1 ARV Therapy in Children ……………………………. 7 2.2 Primary Care Giver …………………………………… 8 2.3 Predictors for LTFU and Mortality …………………… 9 2.4 Predictors found which have influenced Program

Development …………………………………………..

12

CHAPTER III- CONCEPTUAL FRAMEWORK AND RESEARCH HYPOTHESIS ……………………………………………………..

13

3.1 Conceptual Framework ………………………………... 13 3.2 Research Hypothesis ………………………………….. 15 CHAPTER IV – METHOD……… …………………………………. 16 4.1 Study Design ………………………………………….. 16 4.2 Place and Time of Research …………………………… 16 4.3 Study Population ………………………………………. 16 4.3.1 Inclusion Criteria …………………………... 16

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4.3.2 Exclusion Criteria ………………………….. 16 4.4 Variables ………………………………………………. 17 4.5 Data Extraction and Data Collection ………………… 20 4.5.1 Instrument ……………………………………. 20 4.6 Data Processing ……………………………………….. 20 4.7 Data Analysis …………………………………………. 21 4.7.1 Univariate Analysis ………………………….. 21 4.7.2 Bivariate Analysis ……………………………. 21 4.7.3 Multivariate Analysis ………………………… 21 4.8 Ethical Consideration ………………………………….. 22 CHAPTER V – RESULTS ………………………………………….. 23 5.1 Eligible Sample …….. ………………………………… 21 5.2 Characteristics of Children …………………………… 25 5.2.1 Socio-demographic Characteristics ………….. 25 5.2.2 Birth History and PCG ………………………. 27 5.2.3 Clinical Presentation/Examinations…………. 29 5.3 Bivariate Analysis …………………………………….. 31 5.3.1 Bivariate Analysis of Socio-Demographic

Characteristics ………………………………...

31 5.3.2 5.3.2 Bivariate Analysis of Birth History and

PCG Characteristics …………………………..

32 5.3.3 Bivariate Analysis of Clinical Presentation/

Examination ………………………………….

33 5.4 Multivariate Analysis ………………………………... 35 CHAPTER VI – DISCUSSION ……………………………………… 37 6.1 Discussion …………………………………………….. 37 6.2 Weakness of the Study ………………………………… 48 CHAPTER VII- CONCLUSION AND SUGGESTIONS …………… 49 7.1 Conclusion …………………………………………….. 49 7.2 Suggestion …………………………………………….. 50 REFERENCE …………………………………………………………. 51 APPENDIX ………………………………………………………… 56

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LIST OF FIGURES

Page Figure 3.1 Conceptual Framework of predators of LTFU/Mortality

in Children ≤ 12 years old receiving ART in Bali (2010-2015) ……………………………………………………

12 Figure 5.1 Eligible Sample …………………………………………. 24 Figure 5.2 Number of Children starting ART per year (2010-2015) 26 Figure 5.3 Kaplan-Meier Survival Estimate ………………….…... 27 Figure 6 Map of Bali Districts ……………………..…………… 47

LIST OF TABLES

Page Table 5.1 Socio-Demographic Characteristics of Children receiving

ART in Bali between (2010-2015) ……………………..

26 Table 5.2 Birth History of children and PCG characteristics

receiving ART in Bali (2010-2015) ……… ………….…

28 Table 5.3 Clinical Characteristics of the Children ………………… 30 Table 5.4 Underlying Health Conditions in Children receiving ART

in Bali (2010-2015) …… ……………..............................

31 Table 5.5 Significacy of Socio-demographic characteristics of

children towards LTFU and/ or mortality ………... …….

32 Table 5.6 Significacy of Birth history and PCG characteristics of

children towards LTFU and/ or mortality ……..………

33 Table 5.7

Significacy of WHO staging and clinical characteristics of children towards LTFU and/ or mortality …………..

34

Table 5.8 Significacy of underlying health conditions of children towards LTFU and/ or mortality …… …...……………..

35

Table 5.9 Multivariate Analysis of Predictors for LTFU/Mortality in Children receiving ART in Bali Hospital (2010-2015) .

36

Table 6 WHO Classification of Immunodeficiency HIV by CD4 . 40

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LIST OF APPENDIX

Page Appendix 1 Data Extraction Sheet ………………………….…... 56 Appendix 2a Life table (month) …………………………………… 59 Appendix 2b Life table (years) ……………………………………… 59 Appendix 3 Starting Year of ART of children in Bali (2010-2015) . 59 Appendix 4 List of Main Complain of Children receiving ART in

Bali (2010-2015) …….. ……………………………..

59 Appendix 5 Reason for HIV testing in Children …………………. 60 Appendix 6a Comparing WHO Staging at First Visit to when

Starting ART ………………………………………..

60 Appendix 6b WHO!staging!by!event!………………………………………… 60 Appendix 7 Type of OI in Children receiving ART in Bali (2010-

2015)…………………………………………………..

61 Appendix 8 Bivariate analysis of OI OI in children receiving ART

in Bali (2010-2015) …………………………………..

62 Appendix 9 WHO clinical staging of HIV disease in adults,

adolescents and children ……………………………..

63 Appendix 10 Frequency of birth year of Children receiving ARV

therapy at Sanglah General Hospital between 2010-2015 ………………………………………………….

65 Appendix 11 Appendix 11: Birth process per birth year of children

receiving ART in Bali (2010-2015)…… …………….

65

Appendix 12 Breast -feeding per birth year of children receiving ART in Bali (2010-2015) ……………………………

65

Appendix 13 Ethical clearance approval …………………………. 66

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LIST OF ABBREVIATIONS

AIDS : Acquired Immune Deficiency Syndrome

ART : Antiretroviral Therapy

ARV : Antiretroviral

BMI : Body Mass Index

CD4 : Cluster Difference 4

FTT : Failure to thrive

HAART : Highly Active Antiretroviral Therapy

HIV : Human Immunodeficiency Virus

LTFU : Loss to Follow Up

NRTI : Nucleoside Reverse Transcriptase Inhibitor

NTB : West Nusa Tenggara

NTT : East Nusa Tenggara

PCG : Primary Care Giver

PLWHA : People Living With HIV/AIDS

PMTCT : Prevention of Mother To Child Transmission

PPIA : Pencegahan Penularan HIV dari Ibu ke Anak (= Prevention of

Mother to Child transmission)

TB :Tuberculosis

UNAIDS : United Nation AIDS

WHO : World Health Organization

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CHAPTER I Forward

1.1 Background

At the end of 2013, 35 (33.2–37.2) million people are living with HIV

according to an estimate by WHO. Of those 35 million people, 80% (28 million

people) are eligible for antiretroviral (ARV) therapy, under the WHO 2013 joined

ARV guidelines. However less than half (11.7 million people) had access to

antiretroviral therapy in low and middle-income countries (WHO 2014a; WHO

2014b), such as Indonesia. Sadly also 3.2million (2.9-3.5) children (<15 years

old) live with HIV in 2013 (UNAIDS 2014).

In the UNAIDS report of 2014 Indonesia is listed with concern since there has

been an increase of 48% of new HIV infections since the past 10 years (UNAIDS

2014). The provinces of Jakarta, Riau, Bali, West Java and East Java provinces

are classified as areas with concentrated epidemic, where as Tanah Papua has a

widespread (generalized) epidemic. Every 25 minutes, one person is newly

infected with HIV in Indonesia (Unicef Indonesia 2014). One out of every five

newly infected people is below the age of 25 years (Unicef Indonesia 2014). The

UNAIDS 2013 report estimates that there are 25,000 (16,000 - 37,000) children

aged 0-14 living with HIV in Indonesia in 2013 (UNAIDS 2013). Long-term

follow-up of persons living with HIV/AIDS (PLWHA) is vital to optimize clinical

outcomes (Blutinger et al. 2014).

Since drug treatment has no definite timeframe, PLWHA will probably have

to take the medication for the rest of their lives, which could contribute to their

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lost to follow up (LTFU) (Schilkowsky et al. 2011). Yet, limited data on the rates

of LTFU from HIV care and factors associated with LTFU especially from

resource-limited settings exists (Blutinger et al. 2014). The LTFU of patients

consuming antiretroviral therapy can cause serious consequences such as

interruption of treatment and increased risk of death (Dalal et al. 2008; Zhou et al.

2012). In resource-limited settings, where treatment has become rapidly available

following the accessibility of antiretroviral therapy, LTFU presents an even more

challenging obstacles that require special consideration and approaches (Zhou et

al. 2012).

The situation of LTFU in children is different and more complex compared to

adults: children dependent on their caregivers, also the child’s outcome may be

linked to those of the parent. Despite the fact that the caregivers are motivated to

support children to adhere to ART, they themselves may alternate frequently due

to sickness, death or adult migration (Fenner et al. 2010).

A high mortality rate, especially in the first 3 months of ART initiation, is

caused by the fact that children start treatment at an advanced stage of illness in

resource-poor settings. Such death might be misclassified as early LTFU if not

reported. The predictors of LTFU in the first year and second year of ART

initiation may also vary. Therefore it is vital to explore the predictors of LTFU in

the first year of on ART and examine whether these differ with risk factors of

LTFU after surviving the first year on ART. This is potentially useful in making

recommendations for patient retention in pediatric HIV care programs (Sengayi et

al. 2013).

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Denpasar is the capital of the province Bali. The island of gods is well known

for its beauty spectacular mountain scenery and beautiful beaches with warm and

friendly people, a vibrant culture and out of this world resorts (Ministry of

Tourism 2013). With 850.600 inhabitants in 2013 it is the most populated district

in Bali with a population density of 6.657 per km2 (Dinas Kesehatan Kota

Denpasar 2014). The first case of AIDS was reported in 1987 in Bali. The number

of new cases since then has been increasing. In 2014 alone from the 17.084 people

that went to one of the 18 Voluntary Counseling and Testing (VCT) centers, 1.036

were newly HIV positive cases (Dinas Kesehatan Kota Denpasar 2014).

The majority of research regarding LTFU and mortality in HIV-infected

patients receiving ARV therapy in resource-limited settings has been studies in the

sub-Saharan Africa region. Therefore this study will be the first to explore LTFU

and mortality among HIV positive children in Denpasar, Bali. The study will be

conducted in Sanglah General Hospital which is also the central referral hospital

for the province of Bali as well as for other provinces that lie to the east of Bali

such as NTB and NTT. Also Sanglah General Hospital is the only location in

whole of Bali that is able to provide ARV therapy to children.

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1.2 Research Question

Based on the data above the following research problems can be formulated:

Can the child’s demographic characteristics and clinical condition at baseline be

used as predictors for LFTU and/or mortality during ARV therapy in Sanglah

General Hospital?

1.3 Research Objectives 1.3.1 General Objective:

The purpose of the present study is to determine and analyze the

characteristics (demographic and clinically) of children, as well as their care

givers, which are LTFU from ART or have passed away during the first year of

ART at Sanglah General Hospital between 2010 and 2015 and their predictors.

1.3.2 Specific Objectives

The specific objectives are to determine:

a. the incidence rate of LTFU and/or mortality in children receiving ARV

therapy at Sanglah General Hospital between 2010 and 2015.

b. the demographic, clinical and socioeconomic characteristics of children

≤12 years old that have received ART at Sanglah General Hospital

between 2010 and 2015.

c. if the child’s demographic factors can be used as predictors for LTFU

and mortality in children receiving ARV therapy at Sanglah General

Hospital between 2010 and 2015.

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d. if the child’s caregiver’ characteristic can be used as predictors for LTFU

and mortality in children receiving ARV therapy at Sanglah General

Hospital between 2010 and 2015.

e. if the delivery history (weight at birth, birth helper, delivery process)and

breast feeding history can be used as predictors for LTFU and mortality

in children receiving ARV therapy at Sanglah General Hospital between

2010 and 2015.

f. if the clinical condition (WHO Stage at first visit/at ARV initiation,

weight at baseline, CD4 percentage, CD4 count, hemoglobin level and

type of opportunistic infections/underlying health condition) at baseline

can be used as predictors for LTFU and/or mortality in children receiving

ARV therapy at Sanglah General Hospital between 2010 and 2015.

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1.4 Relevance of study

1.4.1 Academic Relevance

The results of this study will increase the knowledge of

characteristics and the incidence rate of children, which are LTFU and or

died during ARV therapy.

1.4.2 Practical Relevance

The identification of factors associated with the LTFU and/or

mortality in ARV treatment could open up new alternatives that would

enable the health team (doctors, nurses, volunteers) to work preventively

on the aspects raised, and thus avoid the lost to follow up before it happens

and therefore prevent the unfavorable outcome of death.

Another relevant point of this study would be with the prevention

of LTFU, ARV multi residency can be prevent.