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Antiretroviral treatment in Rwandan children living with HIV: Clinical and
psychosocial outcomes
Mutwa, R.
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2015
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Mutwa, R. (2015). Antiretroviral treatment in Rwandan children living with HIV: Clinical and
psychosocial outcomes.
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Antiretroviral Treatment in Rwandan Children
Living with HIV: Clinical and Psychosocial
Outcomes
Rwatana MUTWA
Antiretroviral Treatment in Rwandan Children
Living with HIV: Clinical and Psychosocial
Outcomes
Rwatana MUTWA
Antir
etr
o
vir
al T
rea
tment in R
w
andan Childr
en Living with HIV
:
Clinical and Psy
chosocial Outcomes
R
w
atana MUTWA
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Antiretroviral Treatment in Rwandan Children
Living with HIV: Clinical and Psychosocial
Outcomes
Rwatana Mutwa
Colofon
Copyright © 2015, Philippe, Rwatana Mutwa, Kigali, Rwanda.
“Antiretroviral Treatment in Rwandan Children Living with HIV: Clinical and Psychosocial Outcomes”.
Thesis University of Amsterdam (UvA)
http://dare.uva.nl/dissertaties
The studies included in this thesis were supported by INTERACT Project.
The printing of this thesis was financially supported by Academic Medical Center (AMC, Amsterdam, and the AIGHD, Amsterdam, The Netherlands.
Cover design: Henita Kuntawala
Lay out: AIGHD, Amsterdam, The Netherlands. Printing: Ipskamp Drukkers, Enschede
Reprints were made with permission from the publishers, where appropriate.
No part of the thesis may be reproduced, stored, or transmitted without the prior written permission of the author or, when appropriate, the publishers of the articles.
Antiretroviral Treatment in Rwandan Children
Living with HIV: Clinical and Psychosocial
Outcomes
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D. C. van den Boom ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op donderdag 29 oktober 2015, te 12:00 uur door Rwatana Mutwa
Promotiecommissie:
Promotor: Prof. dr. P. Reiss Universiteit van Amsterdam
Copromotores: Dr. S.P.M. Geelen Wilhelmina Kinderziekenhuis
Dr. K.R. Boer Koninklijk Instituut voor de Tropen
Overige leden: Prof. dr. F.G.J. Cobelens Universiteit van Amsterdam
Prof. dr. M. Boele van Hensbroek Universiteit van Amsterdam Prof. dr. A.P. Hardon Universiteit van Amsterdam Prof. dr. M.D. de Jong Universiteit van Amsterdam Prof. dr. D.M. Burger Radboud Universiteit Nijmegen Dr. T.F.W. Wolfs UMC Utrecht Faculteit der Geneeskunde
CONTENTS
ACRONYMS USED IN THIS THESIS ... 7 Chapter1. Pediatric and adolescent HIV care and services in Rwanda: achievements and challenges over 10 years. ... 10 Chapter 2. Safety and effectiveness of combination antiretroviral therapy during the first year of treatment in HIV‐1 infected Rwandan children: a prospective study. ... 38 Chapter 3. Long‐term Effectiveness of Combination Antiretroviral Therapy and Prevalence of HIV Drug Resistance in HIV‐1–infected Children and Adolescents in Rwanda ... 70 Chapter 4. Mid‐Dosing Interval Efavirenz Plasma Concentrations in HIV‐1–Infected Children in Rwanda: Treatment Efficacy, Tolerability, Adherence, and the Influence of CYP2B6 Polymorphisms ... 96 Chapter 5. Hepatitis B virus prevalence and vaccine response in HIV‐infected children and adolescents on combination antiretroviral therapy in Kigali, Rwanda. ... 111 Chapter 6. Living situations affect cART adherence in HIV‐infected adolescents in Rwanda; a qualitative study ... 135 Chapter 7. “Let's Talk about Sex”: A Qualitative Study of Rwandan Adolescents' Views on Sex and HIV ... 161 Chapter 8. GENERAL DISCUSSION, CONCLUSIONS AND RECOMMENDATIONS ... 181 SUMMARY/SAMENVATTING ... 196 AUTHORS AND AFFILIATIONS ... 204 ACKNOWLEDGMENTS ... 206 PhD PORTFOLIO ... 209 ABOUT THE AUTHOR ... 211HAART in Rwandan IHV‐Infected Children
HAART in Rwandan IHV‐Infected Children
ACRONYMS USED IN THIS THESIS
3TC: lamivudine 95%CI: 95% confidence interval ABC: abacavir AE: Adverse event AIDS: acquired immune deficiency syndrome ANC: Antenatal Care anti‐HBc: antibody to hepatitis B virus core antigen anti‐HBs: antibody to hepatitis B virus surface antigen ALT: Alanine Amino Transferase AST: Aspartate Amino Transferase ART: antiretroviral treatment AZT: zidovudine CA: California cART: combination antiretroviral therapy CYP2B6: cytochrome P450 (CYP) 2B6 CNS: Central Nervous system D4T: stavudine DAIDS: Division of AIDS DDI: Didanosine DNA: deoxyribonucleic acid DHS: Demographic and Health Survey EDPRS: Economic Development and Poverty Reduction Strategy EFV: efavirenz EMR: Electronic Medical Record eMTCT: elimination of Mother to Child Transmission FGD: focus group discussion GA: Georgia GEE: generalizing estimating equation HAART: Highly Active Antiretroviral Therapy HAZ: height‐for‐age HBsAg: hepatitis B virus surface antigen HBV: hepatitis B virus HIV‐1: human immunodeficiency virus type‐1 HSSPs: Health Sector Strategic Plans IDI: in‐depth interviews INTERACT: Infectious Diseases Network for Treatment and Research in Africa IQR: interquartile range IRIS: immune reconstitution inflammatory syndromeHAART in Rwandan IHV‐Infected Children LMIC: Low‐ and middle‐income countries LPV/r: lopinavir/ritonavir MeSH: Medical Subject Headings MTCT: Mother to Child Transmission NNRTI: non‐nucleoside reverse transcriptase inhibitor NPV: nevirapine NRTI: nucleoside reverse transcriptase inhibitor NSP: National Strategy Plan NRL: National Reference Laboratory OR: odds ratio PCR: Polymerase chain reaction PI: protease inhibitor PMTCT: prevention of mother to child transmission PRSPs: Poverty Reduction Strategy Papers RNA: Ribonucleic acid RNEC: Rwanda National Ethics Committee SD: standard deviations TAM: thymidine analogue mutation TB: Tuberculosis TDF: tenofovir TRACplus: Treatment and Research AIDS Center TX: Texas UNAIDS: Joint United Nations Programme on HIV/AIDS UNICEF: United Nations Children's Fund USA: United States of America US: United States USAID: United States Agency for International Development VL: Viral load WAZ: weight‐for‐age WHO: World Health Organization
HAART in Rwandan IHV‐Infected Children
Chapter1. Pediatric and adolescent HIV care and services in Rwanda: achievements and challenges over 10 years.
1,2Philippe R. MUTWA, 3Sabin Nsanzimana, 2,4Kimberly R. BOER, 2,5,6Janneke van de WIJGERT, 7Anita
ASSIMWE, 2,8Sibyl P.M. GEELEN.
1Kigali University Teaching Hospital, Department of Pediatrics, Kigali, Rwanda. 2Academic Medical
Centre, Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands. 3Rwanda Ministry of Health, Rwanda Biomedical Center. 4Royal
Tropical Institute, Biomedical Research, Epidemiology Unit, Amsterdam, The Netherlands.5University of Liverpool, Institute of Infection and Global Health, Liverpool, United of
Kingdoms. 6Rinda Ubuzima, Kigali, Rwanda. 7Ministry of Health of Rwanda. 8Wilhelmina Children’s
Hospital, University Medical Centre Utrecht (UMCU), Utrecht, The Netherlands. Submitted for publication
ABSTRACT:
For more than a decade, the Rwanda HIV program has targeted children to maximize the number of children born without HIV infection, and to ensure that HIV‐positive children live long and productive lives. This has resulted in fewer children born with HIV, lower mortality rates, and improved quality of life and life expectancy of children born with HIV. HIV‐positive children are now reaching adolescence and adulthood. Although much has been done, there is room for improvement: about half of HIV‐positive children are not linked to care, and non‐adherence to treatment and treatment failure are high compared to the adult population. Here we reflect on the lessons learned in implementing the pediatric HIV/AIDS program in Rwanda. We recommend that the Rwanda Ministry of Health increases efforts to reach HIV‐infected children that are currently not linked to care, establishes programs for adolescents to address their needs and ensure a smooth transition from pediatric to adult care programs, and scales up programs at the health centers’ level to promote HIV status disclosure, intensify adherence support, and improve monitoring of viral load and treatment side effects in children and adolescents. Keywords: Rwanda, Pediatric, Adolescents, HIV, Program.
INTRODUCTION
In Rwanda, it is estimated that nearly 20,000 children less than 15 years of age are living with HIV.1 This represents approximately ten percent of all people living with HIV in the
country.1
Before antiretroviral treatment became available, HIV‐infected children in resource limited settings had an extremely poor prognosis, with 50% of children dying before the age of 2 years.2,3 Pediatric antiretroviral treatment (ART) has brought an impressive
reversal of this situation, with HIV‐infected children on ART now growing into adolescence and adulthood.4 National data from Rwanda indicate that more than half
of the children presently enrolled in the HIV program are aged between ten and 15 years.5
Over the past ten years, Rwanda has made significant progress in the provision of care and support for people living with HIV, with special emphasis on pediatric HIV management.
Before 2002, HIV services were only available in two referral hospitals and a few private clinics. At that time, only a small group of HIV‐infected people were being treated, mostly adult patients living in Kigali city. 6 From 2002, with support from several
international donors, the national HIV program was strengthened and care and treatment services were scaled up.7,8
Currently, Rwanda is one of few sub‐Saharan African countries to achieve universal access to ART for adults.4 National data indicate that greater than 90% of eligible HIV‐
infected adults receive treatment.5 In addition, efforts to reduce HIV incidence in
pregnant women and prevention of HIV transmission to newborns have been very successful.5,9 However, pediatric access appears to be more challenging, as currently it
has been estimated that only 57% of HIV‐infected children are linked to care and about 58% of children in need of antiretroviral treatment receive it.1,5 This represents a public
for survival of infants, and children under the age of five years.10‐12 Specific policies that
focus on increased access to ART for children and adolescents, and further improvement of HIV care are still needed.
In this review we aim to systematically summarize the main achievements of the Rwandan pediatric and adolescent HIV program over the last decade, discuss its challenges, and lessons learned. We highlight best practices in the Rwanda HIV pediatric program, and identify areas for potential improvements.
METHODS
We conducted a manual search and review of relevant national health documents including Poverty Reduction Strategy Papers (PRSPs), Economic Development and Poverty Reduction Strategy (EDPRS), Health Sector Strategic Plans (HSSPs), National Strategy Plans (NSPs), Demographic and Health Survey (DHS), National Health Reports, Rwandan and World Health Organisation (WHO) HIV/AIDS guidelines, policies and strategy documents. We also conducted a review of publications in peer‐reviewed journals; articles were sought using Medline through PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). A combination of Medical Subject Headings (MeSH) and abbreviations related to the themes were used. Search terms referred to HIV infection, antiretroviral therapy, children, and resource‐limited settings. “P(a)ediatr*,” “child*,” “HIV OR human immunodeficiency,” “AIDS OR Acquired immunodeficiency syndrome” “HAART OR antiretroviral therapy OR ART OR anti‐ retroviral agents,” “treat* OR therapy” “Africa,” “resource‐limited,” “developing country,” “outcomes,” “mortality,” “efficacy,” “adheren* OR complian*” “disclos* “Adolesc* OR teen*”” “early antiretroviral therapy” “deferred antiretroviral therapy” “linkage to care” “lost to follow‐up” “linkage to treatment OR linkage to care”. This search strategy was supplemented by searching references in the bibliographies of articles. Articles were included if they were published from January 2002 (start of the comprehensive HIV program in Rwanda) to March 2014.
Quantitative and qualitative studies, and reviews were included if they investigated at least one main pediatric HIV topic (prevention of mother to child transmission (PMTCT), HIV management and treatment including ART/cART/HAART in children and or adolescents, linkages and retention in care). Pediatric studies from other resource limited settings were used for discussion. A study was excluded if it was an unsystematic observation (case reports and case series), based on secondary data sources (editorials and viewpoints), or of poor quality (i.e. outcome definition unclear and/or unreliable measurement tools used). We limited our search to articles written in English and French published in peer reviewed journals.
Additionally, publicly available conference abstracts about Rwanda, presented from 2003 onward at National, Regional, or International HIV, and infectious diseases conferences were reviewed.
ACCESS TO PEDIATRIC HIV SERVICES
In its Vision 2020 strategy for equitable social and economic development, developed in 2002, Rwanda recognized HIV/AIDS as a devastating disease impacting on economic growth.13 This was followed by the country’s commitment to engage different
stakeholders in the HIV control program, appointment of a national coordinating committee, and development of an HIV/AIDS National Strategic Plan (NSP) in 2005 (revised in 2009 and 2013). As part of the NSP, pediatric HIV care and treatment and PMTCT guidelines were developed and frequently updated based on new evidence.14‐19
PMTCT has been repeatedly determined as a priority by the Ministry of Health, HIV/AIDS Division. 20‐22 The National HIV plans also outlined strategies and guidance to ensure
earlier diagnosis for infants and children, and ongoing access to quality of care services.20‐22 As outlined in the most recent NSP, the National ART program aimed to
increase the number of children on ART and expand the geographic accessibility. By June 2014, 510 facilities throughout the country offered pediatric care and treatment services to more than 11,000 HIV infected children, including 8,000 children on ART. 5
Furthermore, 488 facilities offered PMTCT services to more than 90% of pregnant women in Rwanda. This number of sites is a great achievement and Rwanda’s pediatric coverage is higher than in most sub‐Saharan African countries .4 This has resulted in a
decline of morbidity and mortality rates for Rwandan HIV infected children.23 However,
universal access for the pediatric population has not yet been reached with an additional 8,000 or more HIV‐infected children in need of care and treatment who are not yet linked to HIV services.1 It is assumed that a substantial proportion of these children have
lost their parents and are living in orphanages or in foster families.24
Similar to other low‐ and middle‐income countries Rwanda faces a critical shortage of qualified health workers. In addition, the workload brought on by the HIV epidemic has over‐stretched the healthcare system. For instance, in 2012, health statistics estimated one physician per 17,000 inhabitants and one nurse per 1,300 inhabitants.25
Moreover, the majority of skilled professionals are concentrated in urban areas while up to 90% of the population lives in rural areas, where health services are primarily offered by nurse‐driven health centers.25,26
Following the results of a Rwandan study on task‐shifting from doctors to nurses,27 the
Rwandan government adopted this approach in 2010. Most HIV‐infected adults are nowadays served by nurses at primary health care facilities,25 and physicians focus on
patients with more complex medical problems. However, nurses are not yet certified to prescribe ART to HIV‐infected children and therefore that role is still managed by visiting medical doctors typically based at district hospitals. Recognizing the lack of skilled staff as a limitation of the pediatric program, the national HIV/AIDS program recently opted to train more nurses in pediatric ART, who could then work under supervision of specialized HIV teams from the district hospitals.28
This is seen as a critical approach to reach more children and provide more comprehensive pediatric HIV services.
For improved clinical monitoring of the program and patient management, the Ministry of Health established a web‐based system (TRACnet) at all HIV clinics, using cell phones and internet, and each health facility is staffed with a data manager. Monthly collection and reporting of all information related to HIV/AIDS has helped the country to successfully scale‐up ART services and has guided the central level in recognizing gaps in services.29 Specifically for patient management, the Electronic Medical Records (EMR)
system was introduced in 2008, about 63% of the HIV clinics are currently reporting through the EMR system.5 These systems have, in particular, supported the PMTCT
program by enabling better tracking of early infant diagnosis, and improved integration of mother, and baby services.
The 2013 HIV strategic plan also stipulates the use of community health workers in order to reach more children and link them to care and treatment.28 An active tracking system
is under development in combination with an electronic reporting system, which allows for improved communication between community, community health workers and health care clinics. In this model, health care providers, social workers, and health community workers will systematically stimulate parents in HIV care, community members hosting an orphaned child and managers of orphanages to have their children screened for HIV. This aims to improve the tracing of HIV exposed and infected children in the community that are less likely to reach the health clinics.
If successful, the system may also be used for further improvement of patient retention and monitoring of ART adherence, and for support of other issues that may affect families with HIV‐infected children such as nutritional issues, concomitant diseases or social deterrents to adherence.30‐32 At the health clinics, Rwanda aims to increase
awareness among healthcare providers to test children who present with certain clinical signs and symptoms, such as malnutrition, recurrent respiratory infections or diarrhea, for HIV.
PEDIATRIC HIV TREATMENT
Care and treatment for HIV‐infected children and adolescents comes with very different challenges compared to adult care. HIV infection in children is generally acquired vertically, through perinatal transmission or through breastfeeding, when the immune system of a child is still immature. If untreated, in many infants this typically causes severe immune dysfunction,33 rapid disease progression to AIDS and premature
death.11,34,35 Therefore, early treatment for HIV‐infected young children is critical for
their survival. However, as young children are completely reliant on their caregivers, pediatric outcomes are influenced not only by medical, but also by the child’s social circumstances.36,37 Although, autonomy increases as children get older and develop, the
social support network remains crucial for their well‐being and for treatment assistance.36,38 Moreover, treatment outcomes of infected children have also been
reported to be driven by characteristics of the health care system, including accessibility, availability of skilled staff, and funds to track and link children to health services.39‐41 In
the past decade the number of children on ART has increased, resulting in a decrease of AIDS‐related mortality and morbidity. Tene et al. recently reported the results of a Rwandan study including 2,035 children initiated on ART between 2004 and 2010. A 3% and 5% incidence of death was estimated after respectively 1 and 2 years on cART.42 Another multi‐country study, including Rwanda, demonstrated that around 5%
of children in HIV programs were known to have died following 12 months of treatment.43
Guidelines on treatment initiation and regimen
In 2003, the first Rwandan ART guidelines for the provision of comprehensive care to HIV‐infected adults and children were published.14 These pediatric guidelines
recommended treatment for children depending on clinical signs and age‐related CD4 cell values.15‐18
As emerging scientific evidence emphasized the crucial role of early initiated ART for pediatric survival, criteria for pediatric ART initiation in Rwanda were gradually improved. The current Rwandan pediatric guidelines recommend ART initiation for all children less than five years of age. For children above five years, ART is indicated when they present with pediatric WHO stage three or four, tuberculosis or hepatitis B co‐ infection, or with a CD4 count <500 cells/μL.19 In regard to pediatric drug regimens,
Rwanda has made a significant effort towards increasing availability. In the early years of the program, the majority of children used adult fixed‐drug combination tablets, which had to be broken into pieces for the younger patients. In 2005, a limited number of pediatric fixed‐dose tablets and syrups became available, whereas today, the majority of HIV‐ infected children older than three years are initiated on pediatric fixed dose tablets.
Originally, the first line ART regimen included two nucleoside reverse transcriptase inhibitors (NRTIs), either stavudine or zidovudine combined with lamivudine, and one non‐nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine or efavirenz.14 Since then, preferred regimens have been modified based on new data. Currently preferred pediatric NRTIs in first‐line regimens are abacavir plus lamivudine; for children above 12 years old, tenofovir plus lamivudine is also an option.19 Stavudine was phased out due to its association with lipoatrophy, and zidovudine has been moved to the second‐line as it is known to cause or aggravate anemia.19,28 Lopinavir/ritonavir has become
available for second line treatment following virologic failure and for children who are known to be pre‐exposed to single‐dose nevirapine during prevention of mother to child transmission of HIV. Recently, the national HIV program has also introduced atazanavir/ritonavir as a second line drug for children pretreated with lopinavir/ritonavir. Third line drugs that include etravirine, darunavir and raltegravir have been introduced and recommended by new ART guidelines for adults and children failing second line therapy. 19 Based on monthly patient data in TRACnet, children on second line ART currently represent 6∙4% of total
children on ART;5 no children on third line therapy have yet been reported. Notably,
with the country’s effort to provide ART drugs at large scale and availability of pediatric friendly drugs, Rwanda, as many other countries, continues to face challenges in pediatric ART dosing, as only a limited number of pediatric pharmacokinetic studies are available to inform pediatric dosing questions. 44‐48 Treating young children is also
challenging because of palatability issues with certain oral solutions, and difficulties in administration.
ART efficacy and failure
The goals of ART are to achieve and maintain viral suppression, improve immune function, and achieve clinical recovery whilst simultaneously remaining safe and tolerable in children. ART has been reported to be efficacious in children with improved clinical and biological outcomes which have translated into reductions in HIV morbidity, mortality, and improved quality of life. However, it has been shown that children remain susceptible to virologic failure.49‐51 In a Rwandan pediatric cohort, approximately 40%
of children and adolescents on ART for a median period of 3∙4 years presented with incompletely suppressed viral load, and one out of three children was resistant to first line ART drugs.52
Similar findings have been found in pediatric studies in other sub‐Saharan countries.53‐ 56 This proportion of children with virologic failure is higher than the 11% found in adults
from the same setting.57 It has been shown in children that severe immunosuppression
prior to ART initiation is strongly associated with virologic failure, suggesting that continued loss of immune function prior to initiation of ART results in the inability to suppress HIV‐RNA and subsequent increased risk of HIV resistance. 11,52,58
These findings support the current opinion that pediatric ART should be initiated timely to ensure adequate virologic, immunologic and clinical responses. At the same time, the introduction of routine regular HIV RNA viral load monitoring in Rwanda in 2009 has allowed for increased and earlier detection of virologic failure. Currently, viral load
assessment is recommended after six months of ART and repeated six months later if the viral load exceeds 1000 copies /mL; for those showing complete suppression, viral load testing is recommended every 12 months. However, intensified virologic monitoring for children with virologic failure would assist in appropriate management of this population.
Recently, laboratory infrastructure and staff has been improved allowing for genotypic resistance testing to be available in country at the national reference laboratory, making drug resistance monitoring more accessible for the HIV program.
Finally, before combination antiretroviral treatment during pregnancy was scaled up throughout the country, single dose nevirapine was used in Rwanda for PMTCT.14‐16 As
pre‐exposure to nevirapine during PMTCT is associated with virologic failure and drug resistance, the Rwandan pediatric ART guidelines have been adapted to recommend a protease inhibitor based first line regimen for those children exposed to single dose nevirapine during PMTCT.17 Treatment failure goes hand in hand with HIV drug resistance and poor adherence is the major cause59‐61. Therefore intensified adherence support and virologic monitoring in children and adolescents should have high priority. Adherence Children and adolescents have shown to have more difficulty in remaining adherent to ART than their adult counterparts.62 Studies from Rwandan children and adolescents found rates of treatment adherence ranging from 45‐85%, depending on the method of assessment used.47,52,63 A combination of the child’s medical, social and environmental factors were found to be correlated with poor adherence.64‐67 Biological factors that affect adherence include side effects of ART regimens; they are often a threat to adherence and can be a reason for switching or discontinuing treatment regimens.68,69 The use of national ART pharmacovigilance data would be of
importance to inform the HIV pediatric program on the incidence of ART toxicity, impact on ART adherence, and subsequent treatment failure. Recent data from Rwanda and Uganda suggest that about one in ten children on ART develop an associated side effect resulting in treatment cessation or modification,70,71 but this was not replicated in other
studies.70,72 Since the start of the Rwandan HIV program, strategies to assess and
monitor ART‐related side effects through patients’ self‐report, clinical, and laboratory assessment have been developed and improved over time. However, data on the nature, severity and the impact of ART side effects on adherence, and treatment responses are still not routinely collected.
Several other important factors play a role in the adherence of pediatric HIV patients. Adherence differences are related to age, with children under five and adolescents presenting with more adherence issues.63,73 But the issue of age and adherence is
confounded by several other factors, including delayed disclosure, changes or lack of guardianship, and living in boarding schools or in orphanages.
The government of Rwanda has tried to address some of these issues through clinic‐ based and community‐based interventions. Healthcare teams have been trained to identify children and adolescents at a high risk of poor adherence and to monitor them more closely. At the community level, these children and adolescents are linked with social workers, peer‐educators and nominated supporters (usually a family or household member), and home visits are organized if deemed necessary.19 Also, pediatric and adolescent discussion groups and peer counseling sessions for children of different ages are organized to support them to accept their HIV status, and remain adherent to their treatment. For example, motivated adolescents, educate their peers by sharing their health information, values and behaviors.
Studies in Rwanda and other countries have demonstrated that lack of disclosure contribute to poorer adherence to treatment.63,73 In a study from Zambia, children who
were unaware of their HIV diagnosis were at higher risk of treatment failure compared to children who knew their HIV status.67 And a study in Western African countries
showed adherence to treatment, retention in care, and viral suppression to be much better for children with disclosed HIV status than for those who were not informed.74 Therefore informing children about their HIV status is a very important aspect of care as it allows them to understand why they need to take medication and why they have to come to the clinic for check‐ups whilst feeling well. It allows them to assist in their own care. Disclosure has also been associated with a reduction in risk behavior.73,75,76 In
Rwanda, HIV disclosure is now recommended for children aged seven years and above, also depending on their socio‐emotional maturity, complexity of family circumstances and presence of support. As caregivers are often reluctant to discuss and disclose the nature of the HIV illness to their child or adolescent, in practice disclosure is primarily done within HIV clinics either in the presence of parents or guardians, or during group discussions with peers. During the disclosure sessions, children and adolescents receive age‐adapted information on the nature of their illness and discuss the responsibilities in caring for themselves. As for today, HIV disclosure to children and adolescents is mainly executed at referral and district hospitals by health care workers trained in pediatric and adolescent psychosocial issues. Hence the National policy adopted a scale‐up of the number of trained healthcare workers to enable and strengthen disclosure interventions at all health facilities levels.28 Being an orphan contributes to poor adherence to ART, as
studies in Rwanda, 63,73 Kenya,77 and Uganda78 have shown. As part of a larger
movement to improve the life of orphans and vulnerable children, the Rwanda Government together with UNICEF and USAID, has begun integrating orphaned children into families, often relatives.79 The Rwanda Government, through the Ministry of
Education, has integrated life skills education on HIV prevention and management (all age‐specific) into secondary schools and universities. These courses emphasize adherence support and address issues related to stigma.
Also, the use of pill boxes, administration of directly observed ART, conducting motivational interviews, and enhancing the use of health information technology (for example, mobile texting as a reminder) are considered to improve adherence.39,80,81 As adherence to treatment among children and adolescents remains a challenging field, an evaluation of these interventions, separately or combined, and treatment outcomes in the Rwandan setting is recommended.
ADOLESCENT CARE
Adolescent care bridges pediatric and adult care, and ensuring a continuum of care is challenging.82 In addition, adolescence is a turbulent stage in life with many physical and emotional changes that influence behavior and treatment responses. 40,83,84 Worldwide, 9% of those living with HIV are adolescents, constituting 11% of new infections, and 13% of HIV‐ related deaths.85 Globally, AIDS deaths are decreasing, with adolescents being the only age group in which AIDS deaths have risen in the last decade; mortality risk doubled compared to that of adults HIV patients.85 In sub‐Saharan Africa ART coverage for children and adolescents is substantially lower than for adults, with only 34% of children on treatment85 and dataon adolescents lacking. Retention in care, treatment adherence and virologic suppression have all shown to be challenging in this age group. Treatment adherence for adolescents at 12 months after start of treatment has in one study been estimated to be 21% and only 7% by 24 months.82
The situation of adolescents is often exacerbated by the loss of one or both parents due to HIV. As mentioned before, orphaned HIV‐infected children and adolescents have been shown to have less access to health care, and are more likely to fall through the established social networks which affects access and adherence to HIV testing, care and treatment. Thus, management of HIV‐infected adolescents comes with specific challenges and it is therefore particularly important to offer appropriate services to which adolescents respond.86 It is also imperative that healthcare workers facilitate a
smooth transition from their pediatric medical setting to adult care. Particular attention should be paid to those adolescents who lack support and care from parents or home; they should be supported through peer education programs.
In Rwanda, the majority of HIV‐infected adolescents were infected through vertical transmission during a time period when PMTCT was not readily available. However, with only the recent success of universal access to ART, and given adolescent care and treatment complexity, the scale up of ART for adolescents has not yet been completed. Currently many health care professionals have limited experience in addressing adolescent HIV issues. Another real challenge for HIV‐positive adolescents is becoming sexually active for the first time.52,71,87
In recent years Rwanda has developed and implemented youth‐friendly centers to improve quality of care specifically for adolescents. Currently, there are three sites in the country being piloted with a plan to scale up these centers for National coverage. Rather than focusing only on HIV survival and related illnesses, the youth‐friendly centers focus on comprehensive reproductive health issues, HIV prevention, HIV treatment and adherence, and future issues including school success, career choices, and plans for marriage.
TOWARDS THE ELIMINATION OF HIV IN CHILDREN
A successful pediatric HIV program largely depends on reducing vertical transmission of HIV and reducing the overall incidence of HIV in children. Following a successful PMTCT pilot in 1999, the national PMTCT program started in 2001 using single‐dose nevirapine as the preventive intervention at a limited number of sites in Kigali. Subsequently, the coverage of PMTCT services was expanded progressively to reach previously underserved pregnant HIV‐infected women. By the end of 2013, the number of health facilities providing routine comprehensive PMTCT services had increased more than eight fold as compared to 2003 when only 53 sites were accredited to provide PMTCT services. The prenatal HIV testing rate for pregnant women rose from 80% in 2005 to
98% in 2013; and about 90% of HIV‐infected women and 93% of their infants were receiving ART for prophylaxis as compared to only 51% of women in 2005.5
Over the past years, PMTCT regimens have advanced from single‐dose nevirapine to combination ART for life (WHO Option B+) in 2012.18 This resulted in improvements of
health outcomes in HIV‐infected women and their infants. For instance, new HIV infection rates among infants at 18 weeks post‐partum decreased from 13∙7% in 2006 to 3∙4% in 2011.5 A recent household survey indicated an HIV‐free survival of 92% in infants at 24 months of age.88 These successes of the Rwandan PMTCT program could only be achieved by a combination of a strong political will and commitment to invest in PMTCT care delivery, rapid adoption and translation of scientific developments into policies and guidelines, integration of PMTCT in antenatal care services, adoption and implementation of the eMTCT strategy. Additional successes of the program include the implementation of early infant diagnosis using HIV DNA‐PCR. The challenges with the current Rwandan PMTCT care may include difficulty in maintaining patients in care after delivery, and uptake for HIV baby testing after 18 months. To overcome these challenges, community health workers have been trained in tracing, counseling and linking pregnant women to health facilities that provide PMTCT services, and in retrieving women and their babies who are lost to follow‐up. If an exposed infant is not tested through PMTCT services, they can also be picked up at various other entry points in care, such as the immunization clinics, pediatric clinics, and through the community health workers network.
SUMMARY
In the past decade the Rwanda national HIV program has targeted pediatric HIV through two important strategies. Firstly, through prevention of new pediatric cases by scaling‐ up PMTCT option B+ programs and secondly, through pediatric care and treatment programs to ensure that HIV infected children are living long productive lives.
Rwanda’s PMTCT program has been successful in increasing women’s access to ANC clinics, integrating ANC and PMTCT and hence providing option B+ to more than 90% of HIV‐infected pregnant women in need nationwide. This has resulted in a decrease of incident pediatric HIV infections and will continue to do so, and also promote the health of mothers in the future. Rwanda has also been successful in increasing access to care and treatment for many children and adolescents, importantly improving their quality of life and life expectancy. This has been achieved through continuous efforts of the government, healthcare workers throughout the country, and support of international donors and other stakeholders in the clinics and communities. Rwanda’s pediatric ART coverage is, although only at 57%, higher than in most sub‐Saharan African countries, with viral load suppression and adherence showing mixed results. Therefore, based on the figures of virologic failure in children, intensified adherence support and virologic monitoring in children and adolescents should have high priority.
Despite these amazing advances, gaps in the program remain; attention needs to be focused on HIV infected children that are currently not reached and link them to care. Moreover, special attention should be given to adolescents, addressing their needs and ensuring a smooth transfer from pediatric to adult care programs. Therefore, Rwanda has planned to improve clinical management of pediatric and adolescent patients through training of staff in pediatric ART use and by incorporating pediatric treatment in task sharing. These trainings will include the importance of timely disclosure, improved management of side effects and adherence issues that are associated with ART. The relationship between the clinic and communities will be strengthened to improve regular follow‐up.
In summary, Rwanda has made advances and other countries can learn from its successes. Improvements can still be found and Rwanda aims to achieve these with their
third HIV National Strategic Plan launched in 2013, which aptly concentrates on pediatric care and treatment.
OUTLINE OF THE THESIS
This thesis comprises studies on clinical and psychosocial outcomes of HIV infected children and adolescents on antiretroviral treatment in Rwanda.
As an introduction to this thesis, chapter 1 includes a review of the Rwandan pediatric HIV program since its inception. Main achievements and challenges regarding the scaling up of pediatric HIV services, and different aspects of pediatric antiretroviral treatment and care for children and adolescents are addressed. (Chapter 1)
The study presented in chapter 2 prospectively assesses clinical, immunological and virological responses for 123 HIV‐infected children ≤15 years of age receiving antiretroviral treatment. Children were followed over a period ranging between 9 and 18 months to explore treatment responses over time and factors that influence treatment response at different time points. In this study we also explored the incidence and severity of adverse events of antiretroviral treatment and its impact on adherence and treatment responses. (Chapter 2).
Chapter 3 describes the results from a cross sectional study documenting the long term treatment outcome of 424 children receiving antiretroviral treatment for a period ranging from 1 to 8 years. Clinical, immunological and virological outcomes were assessed at a single‐study visit. The study evaluated factors that were associated with treatment responses, the diagnostic accuracy of clinical and immunologic criteria in identifying virologic failure and the prevalence and patterns of HIV‐1 drug resistance‐ associated mutations that were present in children experiencing treatment failure
Chapter 4 reports on pharmacokinetics and pharmacogenetics of efavirenz in 97 Rwandan children and adolescents aged 3 to 18 years, receiving efavirenz doses according to the national and WHO ART guidelines. The study evaluated the mid‐dosing interval efavirenz plasma concentrations and the influence of CYP2B6 polymorphisms in relation to treatment efficacy, tolerability and adherence (chapter 4). Chapter 5 examines hepatitis B prevalence among a group of HIV infected children and adolescents, on antiretroviral treatment. In this study we also evaluated the success rate of HBV vaccination in children found to be HBV negative. Eighty‐eight children and adolescents aged 8 to 17 years who had not previously been immunized through the national program, received 3 hepatitis B immunizations. The anti‐HBs titer was measured 4‐6 weeks after the last immunization (chapter 5).
The study in chapter 6 assesses facilitators and barriers of adherence to antiretroviral treatment in adolescents. Results from focus group discussions and in depth interviews with HIV infected adolescents on treatment and their caregivers are presented in this chapter. (Chapter 6).
The study in chapter 7 presents the results from discussions on sex, sexuality and reproductive health in HIV infected adolescents on antiretroviral treatment (chapter 7). Chapter 8, includes a summary and general discussion of the main findings of the studies presented in this thesis, as well as recommendations for practice and perspectives for further research (chapter 8).
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