Postdischarge interventions for children hospitalized with severe acute malnutrition: a systematic review and meta-analysis.

BACKGROUND: Children hospitalized with severe acute malnutrition (SAM) have poor long-term outcomes following discharge, with high rates of mortality, morbidity, and impaired neurodevelopment. There is currently minimal guidance on how to support children with SAM following discharge from inpatient treatment. OBJECTIVES: This systematic review and meta-analysis aimed to examine whether postdischarge interventions can improve outcomes in children recovering from complicated SAM. METHODS: Systematic searches of 4 databases were undertaken to identify studies of interventions delivered completely or partially after hospital discharge in children aged 6-59 mo, following inpatient treatment of SAM. The main outcome of interest was mortality. Random-effects meta-analysis was undertaken where ≥2 studies were sufficiently similar in intervention and outcome. RESULTS: Ten studies fulfilled the inclusion criteria, recruiting 39-1781 participants in 7 countries between 1975 and 2015. Studies evaluated provision of zinc (2 studies), probiotics or synbiotics (2 studies), antibiotics (1 study), pancreatic enzymes (1 study), and psychosocial stimulation (4 studies). Six studies had unclear or high risk of bias in ≥2 domains. Compared with standard care, pancreatic enzyme supplementation reduced inpatient mortality (37.8% compared with 18.6%, P < 0.05). In meta-analysis there was some evidence that prebiotics or synbiotics reduced mortality (RR: 0.72; 95% CI: 0.51, 1.00; P = 0.049). Psychosocial stimulation reduced mortality in meta-analysis of the 2 trials reporting deaths (RR: 0.36; 95% CI: 0.15, 0.87), and improved neurodevelopmental scores in ≥1 domain in all studies. There was no evidence that zinc reduced mortality in the single study reporting deaths. Antibiotics reduced infectious morbidity but did not reduce mortality. CONCLUSIONS: Several biological and psychosocial interventions show promise in improving outcomes in children following hospitalization for SAM and require further exploration in larger randomized mortality trials. This study was registered with PROSPERO as CRD42018111342 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=111342)

"I don't feel shy because I will be among others who are just like me…": The role of support groups for children perinatally infected with HIV in Zimbabwe.

As access to paediatric antiretroviral therapy (ART) continues to improve in sub-Saharan Africa, a new historically specific cohort of HIV-perinatally infected children surviving into adolescent has emerged. Although remarkable successes have been made clinically in keeping this cohort alive and in reasonable health, their social support experiences are still unknown. The research being reported here sought to explore peer social support experiences of HIV-perinatally infected children in Harare, Zimbabwe. In this article, we draw on 56 repeat in-depth interviews (IDIs) conducted in three phases and two focus group discussions (FGDs) with HIV-infected children (11-13 years). Additional interviews were held with 10 carers. Study findings suggested that both children and carers perceive support groups as a safe social space for learning and acquiring HIV information as well as gaining confidence. Additionally, findings highlighted the importance of consistency of participation. Structural and personal barriers to access and participation in support group were also identified. We conclude that support groups are a useful resource for HIV-infected children and therefore should be supported by stable funding

Rheumatic fever and rheumatic heart disease among children presenting to two referral hospitals in Harare, Zimbabwe

Background. Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain significant causes of morbidity and mortality in resource-limited settings. In Zimbabwe ARF/RHD characteristics have not been systematically documented.Objectives. To document cases of ARF/RHD among children presenting at referral hospitals in Harare, Zimbabwe, determine their clinical and echocardiographic characteristics, and identify opportunities for improving care.Methods. A cross-sectional survey was carried out in which consecutive children aged 1 - 12 years presenting with ARF/RHD according to the 2002/3 World Health Organization modified Jones criteria were enrolled.Results. Out of 2 601 admissions and 1 026 outpatient visits over 10 months, 50 children were recruited, including 31 inpatients with ARF/RHD and 19 outpatients with chronic RHD. Among inpatients, 9 had ARF only, 7 recurrent ARF with RHD, and 15 RHD only. The commonest valve lesions were mitral regurgitation (26/31) and aortic regurgitation (11/31). The commonest reason for admission was cardiac failure (22/31). The proportion of ARF/RHD cases among inpatients aged 1 - 12 years was 11.9/1 000. Of the 22 with RHD, 14 (63.6%) presented de novo and 1 had bacterial endocarditis. Among the outpatients, 15 had  cardiac failure while echocardiographic findings included mitral regurgitation (18/19) and aortic regurgitation (5/19). At presentation, 18/26 known cases were on oral penicillin prophylaxis and 7 on  injectable penicillin. Of those on secondary prophylaxis, 68.0% reported taking it regularly.Conclusion. ARF/RHD remains a major problem and cause of hospital admissions in Harare, Zimbabwe. Children often present late with established RHD and cardiac failure. With the majority on oral penicillin, secondary prophylaxis was suboptimal in a resource-limited setting unable to offer valve replacement surgery

EXPLORING BIOGRAPHIES: THE EDUCATIONAL JOURNEY TOWARDS BECOMING INCLUSIVE EDUCATORS OF CHILDREN WITH DISABILITIES

The current study explored the formative processes of twelve student teachers constructing role understandings in the context of their experiences and interactions with people with disabilities. In particular, it examined the participants’ changing notions of self-as-teacher and their unfolding perceptions of an inclusive educator’s role in teaching children with disabilities. The research aimed to investigate personal and professional forms of knowledge linked with the prior subjective life experiences of the student teachers and those arising from their interactions in situated learning experiences in community settings. The contextual framework of the study focused on the development of the student teachers’ unique understandings and awareness of people with disabilities through processes of biographical situated learning. The investigation examined participants’ voluntary out-ofcourse experiences with people with disabilities across three community settings for the ways in which these experiences facilitated the participants’ emerging role understandings. These settings included respite experiences in families’ homes of young children with disabilities receiving early intervention, an after-school recreational program for primary and secondary aged children and adolescents with disabilities, and an independent living centre providing post-school options and activities for adults with disabilities. ii Two groups participated in the current study, each consisted of six student teachers in the Bachelor of Education Course at the Bathurst campus of Charles Sturt University. Group One participants were in the second year compulsory inclusive education subject and Group Two participants were in the third year elective early intervention subject. The investigation examines the nature of reflexive and reflective processes of the student teachers from subjective, conflict realities in an attempt to link community experiences with real-life issues affecting inclusive educational practices. The voluntary community experiences engaged the research participants in multi-faceted interactions with people with disabilities, providing thought-provoking contexts for their reflections on observations, responses and reactions to situations, such as critical incidents. The participants engaged in reflexive and reflective processes in records made in learning journals and in semi-structured interviews conducted throughout the investigation. Results were analysed from a constructivist research paradigm to investigate their emerging role understandings. Prior to this study there had been few practical components in the compulsory undergraduate inclusive education subject which meant that previously student teachers gained theoretical knowledge without the opportunity to apply their learning. Many student teachers had expressed their feelings of anxiety and uneasiness about what they should do and say to a person with a disability. Thus, the community experiences were selected in order to give a specific context for student teachers’ learning and to provide participants with expanded opportunities to consider their professional identity, social awareness and acceptance of people with disabilities. iii An analysis of the data demonstrated the centrality of reflection within a situated teaching and learning framework. Understandings of prior experiences and motivation were shown to interact with the outcomes of the community experiences through an on-going process of reflection and reflexivity. This reconstructing process encouraged learners to reflect on past, present and projected future experiences and reframe actions from multiple perspectives as a way of exploring alternatives within broader contexts. The data reveal the participants’ engagement in the community experiences facilitated their awareness of wider socio-cultural educational issues, while focusing their attention on more appropriate inclusive teaching and learning strategies. The reflective inquiry process of identifying diverse issues led participants to consider other possible alternatives to current community practices for better ways to support their changing perspectives on ideal inclusive classroom practices. The dialogic nature of participants’ on-going deliberations contributed to the construction of their deeper understandings of an inclusive educator’s role. The findings of the study identified external environmental and internal personal factors as contributing biographical influences which shaped the student teachers’ emerging role understandings. The results emphasised the value of contextual influences in promoting desirable personal and professional qualities in student teachers. Importantly, situated learning enhanced participants’ unique interpretations of their prospective roles. As a result of analysing their insights from interactions in community contexts, the student teachers had increased their personal and professional understandings of individuals with disabilities and broadened their perceptions of their roles as inclusive educators. Thus, the study found that encouraging a biographical reflexive and reflective orientation in participants was conducive iv to facilitating changes in their understandings. Overall, the outcomes had benefits for student teachers and teacher educators in finding innovative ways for integrating biographical perspectives into situated teaching and learning approaches. The study showed that contextual influences facilitated deeper understanding of role identity and produced new ideas about the nature of reflexivity and reflection in guiding student teachers’ learning. (Note: Appendices not included in digital version of thesis

Opportunities for improving the efficiency of paediatric HIV treatment programmes

Objectives: To conduct two economic analyses addressing whether to: routinely monitor HIV-infected children on antiretroviral therapy (ART) clinically or with laboratory tests; continue or stop cotrimoxazole prophylaxis when children become stabilized on ART. Design and methods: The ARROW randomized trial investigated alternative strategies to deliver paediatric ART and cotrimoxazole prophylaxis in 1206 Ugandan/Zimbabwean children. Incremental cost-effectiveness and value of implementation analyses were undertaken. Scenario analyses investigated whether laboratory monitoring (CD4 tests for efficacy monitoring; haematology/biochemistry for toxicity) could be tailored and targeted to be delivered cost-effectively. Cotrimoxazole use was examined in malaria-endemic and non-endemic settings. Results: Using all trial data, clinical monitoring delivered similar health outcomes to routine laboratory monitoring, but at a reduced cost, so was cost-effective. Continuing cotrimoxazole improved health outcomes at reduced costs. Restricting routine CD4+ monitoring to after 52 weeks following ART initiation and removing toxicity testing was associated with an incremental cost-effectiveness ratio of $6084 per quality-adjusted life-year (QALY) across all age groups, but was much lower for older children (12+ years at initiation; incremental cost-effectiveness ratio =$769/QALY). Committing resources to improve cotrimoxazole implementation appears cost-effective. A healthcare system that could pay $600/QALY should be willing to spend up to$12.0 per patient-year to ensure continued provision of cotrimoxazole. Conclusion: Clinically driven monitoring of ART is cost-effective in most circumstances. Routine laboratory monitoring is generally not cost-effective at current prices, except possibly CD4 testing amongst adolescents initiating ART. Committing resources to ensure continued provision of cotrimoxazole in health facilities is more likely to represent an efficient use of resources

Marginal structural models for repeated measures where intercept and slope are correlated: An application exploring the benefit of nutritional supplements on weight gain in HIV-infected children initiating antiretroviral therapy

BackgroundThe impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear.MethodsIn the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications.ResultsIn simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction.DiscussionThis study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures

Evaluation of weight-based prescription of antiretroviral therapy in children.

OBJECTIVES: The aim of the study was to investigate the extent of and factors associated with incorrect dosing of antiretroviral therapy (ART) in HIV-infected children in Harare, Zimbabwe. METHODS: All children aged 0-10 years and children aged 11-17 years who weighed < 35 kg and taking ART were recruited from the paediatric HIV clinic at Harare Hospital. Their current doses of ART drugs were compared against doses recommended by the national guidelines. RESULTS: Among 309 children recruited [55% male; median age 7 years (interquartile range (IQR) 5-10 years)], the median CD4 count was 899 cells/μL and the median duration of their current ART regimen was 11.2 months (IQR 4.9-17.1 months). Overall, 110 (35.6%) children were prescribed incorrect doses of at least one drug component within their ART regimen; 64 (20.7%) under-dosed and 49 (15.9%) over-dosed on at least one drug. Children receiving a higher than recommended dose of at least one drug were younger compared with correctly dosed children (median 6 versus 7 years, respectively; P = 0.001), had been on their current ART regimen for a shorter time (median 7.2 versus 13 months, respectively; P = 0.003) and were less likely to be receiving a three-drug fixed-dose combination (FDC; 42.9 versus 63.3%, respectively; P = 0.009). Those who were under-dosed were also less likely to be on a three-drug FDC (25 versus 63.3%, respectively; P < 0.001). CONCLUSIONS: Over a third of children were prescribed incorrect doses of ART. Children taking triple-drug FDCs were likely to be correctly dosed. Our study highlights the importance of weight monitoring at each clinical contact, training of health care providers on paediatric drug dosing and the need for wider availability of FDCs for children

Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial

BACKGROUND: Dolutegravir (DTG), combined with a backbone of two NRTIs, is currently the preferred first-line treatment for HIV in childhood. CHAPAS4 is an ongoing randomized controlled trial (#ISRCTN22964075) investigating second-line treatment options for children with HIV. We did a nested PK substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food, as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4-trial to participate in this PK substudy. Children weighing 14-19.9 kg took 25 mg DTG as dispersible tablets (DT) and children ≥20 kg took 50 mg film-coated tablets (FCT). Steady-state 24 h DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 h after observed DTG intake with food. Reference adult PK data and paediatric data from the ODYSSEY-trial was used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L. RESULTS: 39 children on DTG were included in this PK substudy. The Geometric Mean (GM), (CV%) AUC0-24h was 57.1 h*mg/L (38.4%) which was approximately 8% below the average AUC0-24h in children in the ODYSSEY-trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%) which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY-trial and adult references

Optimizing Clinical Trial Design to Maximize Evidence Generation in Pediatric HIV.

For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in "basket" trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis

Risk factors for postdischarge mortality following hospitalization for severe acute malnutrition in Zimbabwe and Zambia.

BACKGROUND: Children discharged from hospital following management of complicated severe acute malnutrition (SAM) have a high risk of mortality, especially HIV-positive children. Few studies have examined mortality in the antiretroviral therapy (ART) era. OBJECTIVES: Our objectives were to ascertain 52-wk mortality in children discharged from hospital for management of complicated SAM, and to identify independent predictors of mortality. METHODS: A prospective cohort study was conducted in children enrolled from 3 hospitals in Zambia and Zimbabwe between July 2016 and March 2018. The primary outcome was mortality at 52 wk. Univariable and multivariable Cox regression models were used to identify independent risk factors for death, and to investigate whether HIV modifies these associations. RESULTS: Of 745 children, median age at enrolment was 17.4 mo (IQR: 12.8, 22.1 mo), 21.7% were HIV-positive, and 64.4% had edema. Seventy children (9.4%; 95% CI: 7.4, 11.7%) died and 26 exited during hospitalization; 649 were followed postdischarge. At discharge, 43.9% had ongoing SAM and only 50.8% of HIV-positive children were receiving ART. Vital status was ascertained for 604 (93.1%), of whom 55 (9.1%; 95% CI: 6.9, 11.7%) died at median 16.6 wk (IQR: 9.4, 21.9 wk). Overall, 20.0% (95% CI: 13.5, 27.9%) and 5.6% (95% CI: 3.8, 7.9%) of HIV-positive and HIV-negative children, respectively, died [adjusted hazard ratio (aHR): 3.83; 95% CI: 2.15, 6.82]. Additional independent risk factors for mortality were ongoing SAM (aHR: 2.28; 95% CI: 1.22, 4.25), cerebral palsy (aHR: 5.60; 95% CI: 2.72, 11.50) and nonedematous SAM (aHR: 2.23; 95% CI: 1.24, 4.01), with no evidence of interaction with HIV status. CONCLUSIONS: HIV-positive children have an almost 4-fold higher mortality than HIV-negative children in the year following hospitalization for complicated SAM. A better understanding of causes of death, an improved continuum of care for HIV and SAM, and targeted interventions to improve convalescence are needed