Rachel C. Vreeman

A systematic review of pediatric adherence to antiretroviral therapy in low- and middle-income countries.

Background: Sustaining antiretroviral therapy (ART) adherence requires accurate, consistent monitoring, a particular challenge for low-income countries. The optimal strategy to measure pediatric adherence remains unclear. Objective: To conduct a systematic review of pediatric ART adherence measurement techniques, adherence estimates, and clinical correlates in low- and middle-income countries to inform ART adherence monitoring. Methods: We searched online bibliographic databases, including MEDLINE and EMBASE, using systematic criteria. Two reviewers selected all descriptive or interventional studies involving nonpregnant, HIV-positive individuals ≤18 years old that measured ART adherence in low- or middle-income countries as defined by World Bank criteria. Data were extracted regarding sample characteristics, study setting, measurement strategy, adherence estimate, and adherence correlates. Results: The search yielded 1566 titles, of which 17 met selection criteria. Adherence measurement strategies included self- or proxy-report measures (14 studies), pill counts (4 studies), pharmacy records, drug levels, clinic adherence, and directly observed therapy (1 study each). The self- or proxy-report measures were heterogeneous, and few employed validation strategies. Caregiver-reported adherence was generally higher than self-report estimates. Pill counts revealed lower adherence estimates. Estimates of ART adherence ranged from 49% to 100%, with 76% of articles reporting >75% adherence. Factors related to family structure, socioeconomic status, disclosure, and medication regimen were all significantly associated with ART adherence. Conclusions: Pediatric HIV care programs in low- and middle-income countries use heterogeneous methods to measure ART adherence. Adherence estimates vary substantially, but most studies from low- and middle-income countries report >75% adherence, whereas most studies from high-income countries report <75% adherence.

Disclosure of HIV status to children in resource-limited settings: a systematic review

Informing children of their own HIV status is an important aspect of long‐term disease management, yet there is little evidence of how and when this type of disclosure takes place in resource‐limited settings and its impact.

‘Wamepotea’ (They have become lost): Outcomes of HIV-positive and HIV-exposed children lost to follow-up from a large HIV treatment program in western Kenya

Objective:The objective of this study was to identify the vital status and reasons for children becoming loss to follow-up (LTFU) from a large program in western Kenya. Methods:This was a prospective evaluation of a random sample of 30% of HIV-exposed and HIV-positive children LTFU from either an urban or rural HIV Academic Model Providing Access to Healthcare clinic. LTFU is defined as absence from clinic for >6 months if on combination antiretroviral therapy and > 12 months if not. Experienced community health workers were engaged to locate them. Results:There were 97 children sampled (78 urban, 19 rural). Of these, 82% were located (78% urban, 100% rural). Among the HIV positive, 16% of the children were deceased, and 16% had not returned to clinic because of disclosure issues/discrimination in the family or community. Among the HIV exposed, 30% never returned to care because their guardians either had not disclosed their own HIV status or were afraid of family/community stigma related to their HIV status or that of the child. Among children whose HIV status was unknown, 29% of those found had actually died, and disclosure/discrimination accounted for 14% of the reasons for becoming LTFU. Other reasons included believing the child was healed by faith or through the use of traditional medicine (7%), transport costs (6%), and transferring care to other programs or clinics (8%). Conclusion:After locating >80% of the children in our sample, we identified that mortality and disclosure issues including fear of family or community discrimination were the most important reasons why these children became LTFU.

Association of antiretroviral and clinic adherence with orphan status among HIV-infected children in Western Kenya.

Background:Pediatric adherence to antiretroviral therapy (ART) is not well studied in resource-limited settings. Reported ART adherence may be influenced by contextual factors, such as orphan status. Objectives:The objectives of this study were to describe self- and proxy-reported pediatric ART adherence in a resource-limited population and to investigate associated contextual factors. Patients and Methods:This was a retrospective study involving pediatric, HIV-infected patients in Western Kenya. We included patients aged 0-14 years, who were on ART and had at least 1 adherence measurement (N = 1516). We performed logistic regression to assess the association between orphan status and odds of imperfect adherence, adjusting for sex, age, clinic site, number of adherence measures, and ART duration, stratified by age and ART duration. Results:Of the 1516 children, only 33% had both parents living when they started ART. Twenty-one percent had only father dead, 28% had only mother dead, and 18% had both parents dead. Twenty-nine percent reported imperfect ART adherence. The odds of ART nonadherence increase for children with both parents dead. Fifty-seven percent of children had imperfect clinic adherence. There was no significant association between orphan status and imperfect clinic adherence. Conclusions:The majority of pediatric patients in this resource-limited setting maintained perfect ART adherence, though only half kept all scheduled clinic appointments. Understanding contextual factors, such as orphan status, will strengthen adherence interventions.

Patient-Reported Barriers to Adherence to Antiretroviral Therapy: A Systematic Review and Meta-Analysis

Background Maintaining high levels of adherence to antiretroviral therapy (ART) is a challenge across settings and populations. Understanding the relative importance of different barriers to adherence will help inform the targeting of different interventions and future research priorities. Methods and Findings We searched MEDLINE via PubMed, Embase, Web of Science, and PsychINFO from 01 January 1997 to 31 March 2016 for studies reporting barriers to adherence to ART. We calculated pooled proportions of reported barriers to adherence per age group (adults, adolescents, and children). We included data from 125 studies that provided information about adherence barriers for 17,061 adults, 1,099 children, and 856 adolescents. We assessed differences according to geographical location and level of economic development. The most frequently reported individual barriers included forgetting (adults 41.4%, 95% CI 37.3%–45.4%; adolescents 63.1%, 95% CI 46.3%–80.0%; children/caregivers 29.2%, 95% CI 20.1%–38.4%), being away from home (adults 30.4%, 95% CI 25.5%–35.2%; adolescents 40.7%, 95% CI 25.7%–55.6%; children/caregivers 18.5%, 95% CI 10.3%–26.8%), and a change to daily routine (adults 28.0%, 95% CI 20.9%–35.0%; adolescents 32.4%, 95% CI 0%–75.0%; children/caregivers 26.3%, 95% CI 15.3%–37.4%). Depression was reported as a barrier to adherence by more than 15% of patients across all age categories (adults 15.5%, 95% CI 12.8%–18.3%; adolescents 25.7%, 95% CI 17.7%–33.6%; children 15.1%, 95% CI 3.9%–26.3%), while alcohol/substance misuse was commonly reported by adults (12.9%, 95% CI 9.7%–16.1%) and adolescents (28.8%, 95% CI 11.8%–45.8%). Secrecy/stigma was a commonly cited barrier to adherence, reported by more than 10% of adults and children across all regions (adults 13.6%, 95% CI 11.9%–15.3%; children/caregivers 22.3%, 95% CI 10.2%–34.5%). Among adults, feeling sick (15.9%, 95% CI 13.0%–18.8%) was a more commonly cited barrier to adherence than feeling well (9.3%, 95% CI 7.2%–11.4%). Health service–related barriers, including distance to clinic (adults 17.5%, 95% CI 13.0%–21.9%) and stock outs (adults 16.1%, 95% CI 11.7%–20.4%), were also frequently reported. Limitations of this review relate to the fact that included studies differed in approaches to assessing adherence barriers and included variable durations of follow up. Studies that report self-reported adherence will likely underestimate the frequency of non-adherence. For children, barriers were mainly reported by caregivers, which may not correspond to the most important barriers faced by children. Conclusions Patients on ART face multiple barriers to adherence, and no single intervention will be sufficient to ensure that high levels of adherence to treatment and virological suppression are sustained. For maximum efficacy, health providers should consider a more triaged approach that first identifies patients at risk of poor adherence and then seeks to establish the support that is needed to overcome the most important barriers to adherence.

The epidemiology of substance use among street children in resource-constrained settings: a systematic review and meta-analysis

AIMS To compile and analyze critically the literature published on street children and substance use in resource-constrained settings. METHODS We searched the literature systematically and used meta-analytical procedures to synthesize literature that met the reviews inclusion criteria. Pooled-prevalence estimates and 95% confidence intervals (CI) were calculated using the random-effects model for life-time substance use by geographical region as well as by type of substance used. RESULTS Fifty studies from 22 countries were included into the review. Meta-analysis of combined life-time substance use from 27 studies yielded an overall drug use pooled-prevalence estimate of 60% (95% CI = 51-69%). Studies from 14 countries contributed to an overall pooled prevalence for street childrens reported inhalant use of 47% (95% CI = 36-58%). This review reveals significant gaps in the literature, including a dearth of data on physical and mental health outcomes, HIV and mortality in association with street childrens substance use. CONCLUSIONS Street children from resource-constrained settings reported high life-time substance use. Inhalants are the predominant substances used, followed by tobacco, alcohol and marijuana.

Factors Sustaining Pediatric Adherence to Antiretroviral Therapy in Western Kenya

Antiretroviral therapy (ART) requires nearly perfect adherence to be effective. Although 90% of HIV-infected children live in Africa, there are limited data on pediatric adherence from this multicultural continent.We conducted a qualitative study to identify key factors contributing to pediatric ART adherence. Ten focus group discussions (N = 85) and 35 individual interviews were conducted with parents and guardians of HIV-infected children receiving ART in western Kenya. Interviews covered multiple aspects of the experience of having children take ART and factors that inhibited or facilitated medication adherence. Constant comparison, progressive coding, and triangulation methods were used to arrive at a culturally contextualized, conceptual model for pediatric ART adherence derived from the descriptions of the lived experience in this resource-limited setting. Child care, including sustained ART adherence, depends on interacting cultural and environmental determinants at the levels of the individual child, parent/caregiver, household, community, health care system, and society.

The clinical burden of tuberculosis among human immunodeficiency virus-infected children in Western Kenya and the impact of combination antiretroviral treatment.

Context: The burden of tuberculosis (TB) disease in children, particularly in HIV-infected children, is poorly described because of a lack of effective diagnostic tests and the emphasis of public health programs on transmissible TB. Objectives: The objectives of this study were to describe the observed incidence of and risk factors for TB diagnosis among HIV-infected children enrolled in a large network of HIV clinics in western Kenya. Design: Retrospective observational study. Setting: The USAID-Academic Model Providing Access to Healthcare (AMPATH) Partnership is Kenya’s largest HIV/AIDS care system. Since 2001, the program has enrolled over 70,000 HIV-infected patients in 18 clinics throughout Western Kenya. Patients: This analysis included all HIV-infected children aged 0 to 13 years attending an AMPATH clinic. Main Outcome Measure: The primary outcome was a diagnosis of any TB, defined either by a recorded diagnosis or by the initiation of anti-TB treatment. Diagnosis of TB is based on a modified Kenneth Jones scoring system and is consistent with WHO case definitions. Results: There were 6535 HIV-infected children aged 0 to 13 years, eligible for analysis, 50.1% were female. Of these, 234 (3.6%) were diagnosed with TB at enrollment. There were subsequently 765 new TB diagnoses in 4368.0 child-years of follow-up for an incidence rate of 17.5 diagnoses (16.3–18.8) per 100 child-years. The majority of these occurred in the first 6 months after enrollment (IR: 106.8 per 100 CY, 98.4–115.8). In multivariable analysis, being severely immune-suppressed at enrollment (Adjusted Hazard Ratio [AHR]: 4.44, 95% CI: 3.62–5.44), having ever attended school AHR: 2.65, 95% CI: 2.15–3.25), being an orphan (AHR: 1.57, 95% CI: 1.28–1.92), being severely low weight-for-height at enrollment (AHR: 1.46, 95% CI: 1.32–1.62), and attending an urban clinic (AHR: 1.39, 95% CI: 1.16–1.67) were all independent risk factors for having an incident TB diagnosis. Children receiving combination antiretroviral treatment were dramatically less likely to be diagnosed with incident TB (AHR: 0.15, 95% CI: 0.12–0.20). Conclusions: These data suggest a high rate of TB diagnosis among HIV-infected children, with severe immune suppression, school attendance, orphan status, very low weight-for-height, and attending an urban clinic being key risk factors. The use of combination antiretroviral treatment reduced the probability of an HIV-infected child being diagnosed with incident TB by 85%.

A Cross-Sectional Study of Disclosure of HIV Status to Children and Adolescents in Western Kenya

Introduction Disclosure of HIV status to children is essential for disease management but is not well characterized in resource-limited settings. This study aimed to describe the prevalence of disclosure and associated factors among a cohort of HIV-infected children and adolescents in Kenya. Methods We conducted a cross-sectional study, randomly sampling HIV-infected children ages 6–14 years attending 4 HIV clinics in western Kenya. Data were collected from questionnaires administered by clinicians to children and their caregivers, supplemented with chart review. Descriptive statistics and disclosure prevalence were calculated. Univariate analyses and multivariate logistic regression were performed to assess the association between disclosure and key child-level demographic, clinical and psychosocial characteristics. Results Among 792 caregiver-child dyads, mean age of the children was 9.7 years (SD = 2.6) and 51% were female. Prevalence of disclosure was 26% and varied significantly by age; while 62% of 14-year-olds knew their status, only 42% of 11-year-olds and 21% of 8-year-olds knew. In multivariate regression, older age (OR 1.49, 95%CI 1.35–1.63), taking antiretroviral drugs (OR 2.27, 95%CI 1.29–3.97), and caregiver-reported depression symptoms (OR 2.63, 95%CI 1.12–6.20) were significantly associated with knowing one’s status. Treatment site was associated with disclosure for children attending one of the rural clinics compared to the urban clinic (OR 3.44, 95%CI 1.75–6.76). Conclusions Few HIV-infected children in Kenya know their HIV status. The likelihood of disclosure is associated with clinical and psychosocial factors. More data are needed on the process of disclosure and its impact on children.

Impact of the Kenya post-election crisis on clinic attendance and medication adherence for HIV-infected children in western Kenya

BackgroundKenya experienced a political and humanitarian crisis following presidential elections on 27 December 2007. Over 1,200 people were killed and 300,000 displaced, with disproportionate violence in western Kenya. We sought to describe the immediate impact of this conflict on return to clinic and medication adherence for HIV-infected children cared for within the USAID-Academic Model Providing Access to Healthcare (AMPATH) in western Kenya.MethodsWe conducted a mixed methods analysis that included a retrospective cohort analysis, as well as key informant interviews with pediatric healthcare providers. Eligible patients were HIV-infected children, less than 14 years of age, seen in the AMPATH HIV clinic system between 26 October 2007 and 25 December 2007. We extracted demographic and clinical data, generating descriptive statistics for pre- and post-conflict antiretroviral therapy (ART) adherence and post-election return to clinic for this cohort. ART adherence was derived from caregiver-report of taking all ART doses in past 7 days. We used multivariable logistic regression to assess factors associated with not returning to clinic. Interview dialogue from was analyzed using constant comparison, progressive coding and triangulation.ResultsBetween 26 October 2007 and 25 December 2007, 2,585 HIV-infected children (including 1,642 on ART) were seen. During 26 December 2007 to 15 April 2008, 93% (N = 2,398) returned to care. At their first visit after the election, 95% of children on ART (N = 1,408) reported perfect ART adherence, a significant drop from 98% pre-election (p < 0.001). Children on ART were significantly more likely to return to clinic than those not on ART. Members of tribes targeted by violence and members of minority tribes were less likely to return. In qualitative analysis of 9 key informant interviews, prominent barriers to return to clinic and adherence included concerns for personal safety, shortages of resources, hanging priorities, and hopelessness.ConclusionDuring a period of humanitarian crisis, the vulnerable, HIV-infected pediatric population had disruptions in clinical care and in medication adherence, putting children at risk for viral resistance and increased morbidity. However, unique program strengths may have minimized these disruptions.