Fat and lean mass predict time to hospital readmission or mortality in children treated for complicated severe acute malnutrition in Zimbabwe and Zambia.

HIV and severe wasting are associated with post-discharge mortality and hospital readmission among children with complicated severe acute malnutrition (SAM); however, the reasons remain unclear. We assessed body composition at hospital discharge, stratified by HIV and oedema status, in a cohort of children with complicated SAM in three hospitals in Zambia and Zimbabwe. We measured skinfold thicknesses and bioelectrical impedance analysis (BIA) to investigate whether fat and lean mass were independent predictors of time to death or readmission. Cox proportional hazards models were used to estimate the association between death/readmission and discharge body composition. Mixed effects models were fitted to compare longitudinal changes in body composition over 1 year. At discharge, 284 and 546 children had complete BIA and skinfold measurements, respectively. Low discharge lean and peripheral fat mass were independently associated with death/hospital readmission. Each unit Z-score increase in impedance index and triceps skinfolds was associated with 48 % (adjusted hazard ratio 0·52, 95 % CI (0·30, 0·90)) and 17 % (adjusted hazard ratio 0·83, 95 % CI (0·71, 0·96)) lower hazard of death/readmission, respectively. HIV-positive v. HIV-negative children had lower gains in sum of skinfolds (mean difference -1·49, 95 % CI (-2·01, -0·97)) and impedance index Z-scores (-0·13, 95 % CI (-0·24, -0·01)) over 52 weeks. Children with non-oedematous v. oedematous SAM had lower mean changes in the sum of skinfolds (-1·47, 95 % CI (-1·97, -0·97)) and impedance index Z-scores (-0·23, 95 % CI (-0·36, -0·09)). Risk stratification to identify children at risk for mortality or readmission, and interventions to increase lean and peripheral fat mass, should be considered in the post-discharge care of these children.

Recovery of children following hospitalisation for complicated severe acute malnutrition.

Nutritional recovery and hospital readmission following inpatient management of complicated severe acute malnutrition (SAM) are poorly characterised. We aimed to ascertain patterns and factors associated with hospital readmission, nutritional recovery and morbidity, in children discharged from hospital following management of complicated SAM in Zambia and Zimbabwe over 52-weeks posthospitalization. Multivariable Fine-Gray subdistribution hazard models, with death and loss to follow-up as competing risks, were used to identify factors associated with hospital readmission; negative binomial regression to assess time to hospitalisation and ordinal logistic regression to model factors associated with nutritional recovery. A total of 649 children (53% male, median age 18.2 months) were discharged to continue community nutritional rehabilitation. All-cause hospital readmission was 15.4% (95% CI 12.7, 18.6) over 52 weeks. Independent risk factors for time to readmission were cerebral palsy (adjusted subhazard ratio (aSHR): 2.96, 95% CI 1.56, 5.61) and nonoedematous SAM (aSHR: 1.64, 95%CI 1.03, 2.64). Unit increases in height-for-age Z-score (HAZ) (aSHR: 0.82, 95% CI 0.71, 0.95) and enrolment in Zambia (aSHR: 0.52, 95% CI 0.28, 0.97) were associated with reduced subhazard of time to readmission. Young age, SAM at discharge, nonoedematous SAM and cerebral palsy were associated with poor nutritional recovery throughout follow-up. Collectively, nonoedematous SAM, ongoing SAM at discharge, cerebral palsy and low HAZ are independent risk factors for readmission and poor nutritional recovery following complicated SAM. Children with these high-risk features should be prioritised for additional convalescent care to improve long-term outcomes.

Sustainable HIV treatment in Africa through viral-load-informed differentiated care.

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

Monovalent Rotavirus Vaccine Effectiveness Against Rotavirus Hospitalizations Among Children in Zimbabwe.

BACKGROUND: Rotavirus is a leading cause of mortality among children <5 years old. We evaluated monovalent rotavirus vaccine effectiveness (VE) under conditions of routine use at 2 surveillance sites in Harare, Zimbabwe, after vaccine introduction in May 2014. METHODS: Children aged <5 years hospitalized or treated in the accident and emergency department (A&E) for acute watery diarrhea were enrolled for routine surveillance. Copies of vaccination cards were collected to document vaccination status. Among children age-eligible to receive rotavirus vaccine, we estimated VE, calculated as 1 - odds ratio, using a test-negative case-control design. RESULTS: We included 903 rotavirus-positive cases and 2685 rotavirus-negative controls in the analysis; 99% had verified vaccination status. Rotavirus-positive children had more severe diarrhea than rotavirus-negative children; 61% of cases and 46% of controls had a Vesikari score ≥11 (P < .01). Among cases and controls, 31% and 37%, respectively, were stunted for their age (P < .01). Among children 6-11 months old, adjusted 2-dose VE against hospitalization or treatment in A&E due to rotavirus of any severity was 61% (95% confidence interval [CI], 21%-81%) and 68% (95% CI, 13%-88%) against severe rotavirus disease. Stratified by nutritional status, adjusted VE was 45% (95% CI, -148% to 88%) among stunted infants and 71% (95% CI, 29%-88%) among infants with a normal height for age. CONCLUSIONS: Monovalent rotavirus vaccine is effective in preventing hospitalizations due to severe rotavirus diarrhea among infants in Zimbabwe, providing additional evidence for countries considering rotavirus vaccine introduction that live, oral rotavirus vaccines are effective in high-child-mortality settings.

Development of a neonatal curriculum for medical students in Zimbabwe - a cross sectional survey.

BACKGROUND: Calls have been made to reassess the curricula of medical schools throughout the world to adopt competence-based programs that address the healthcare needs of society. Zimbabwe is a country characterized by a high neonatal mortality rate of 24 per 1000 live births. The current research sought to determine the content and appropriate teaching strategies needed to guide the development of an undergraduate neonatal curriculum map for medical students at the University of Zimbabwe College of Health Sciences. METHODS: We surveyed faculty (n = 8) and non-faculty pediatricians (n = 5), senior resident medical officers (N = 26) using a self-administered questionnaire, and completed one focus group discussion with midwives (n = 11). We asked respondents their expectations regarding knowledge, psychomotor skills, competencies, and teaching strategies in a basic newborn curriculum for medical students. Relevant policy and curricula documents were reviewed to assess newborn health needs and the current training. A group of faculty educationists (n = 11) collated and finalized the findings from the document review, survey, and focus group using descriptive statistics and thematic analysis. RESULTS: The document review revealed three key neonatal health objectives according to the current national maternal and neonatal health road map. These objectives are to be met using a four tier approach comprising (i) family planning (ii) focused antenatal care (iii) clean and safe delivery and (iv) basic and comprehensive emergency obstetric & neonatal care. Existing curriculum has 15 newborn topics taught in lecture style during the pediatric rotations, and five newborn care skills to be learned through observation. The existing curriculum is silent on desired competencies. In the current study 19 cognitive areas, 17 psychomotor skills and six competency domains were identified for an ideal neonatal curriculum for undergraduate students. A combination of teaching strategies including classroom, simulation and a clinical rotation were recommended. CONCLUSION: This study revealed a significant gap between the existing neonatal curriculum and the ideal curriculum as recommended by broad stakeholders in the context of national health care needs. Next steps are to complete the development and implementation of the proposed curriculum map to better align with the ideal state.

Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition.

Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM (n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia. Compared with adequately nourished controls (n = 173), we found that at baseline, complicated SAM was characterized by systemic, endothelial, and intestinal inflammation, which was exacerbated by HIV infection. This persisted over 48 weeks despite nutritional recovery and was associated with children's outcomes. Baseline plasma concentrations of vascular endothelial growth factor, glucagon-like peptide-2, and intestinal fatty acid-binding protein were independently associated with lower mortality or hospital readmission over the following 48 weeks. Following principal components analysis of baseline biomarkers, higher scores of a component representing growth factors was associated with greater weight-for-height z score recovery and lower mortality or hospital readmission over the 48 weeks. Conversely, components representing higher gut and systemic inflammation were associated with higher mortality or hospital readmission. These findings highlight the interplay between inflammation, which damages tissues, and growth factors, which mediate endothelial and epithelial regeneration, and support further studies investigating interventions to reduce inflammation and promote epithelial repair as an approach to reducing mortality and improving nutritional recovery.

Renal abnormalities among HIV-infected, antiretroviral naive children, Harare, Zimbabwe: a cross-sectional study.

BACKGROUND: Data on the prevalence of renal and urine abnormalities among HIV-infected children in Sub-Saharan Africa are limited. We set out to determine the prevalence of proteinuria; low estimated glomerular filtration rate (eGFR), urinary tract infection and associated factors among HIV-infected antiretroviral therapy (ART) naive children, aged 2-12 years, attending the paediatric HIV clinic at a tertiary hospital in Harare. METHODS: Consecutive ART naive children attending the clinic between June and October 2009 were recruited. Detailed medical history was obtained and a complete physical examination was performed. Children were screened for urinary tract infection and for significant persistent proteinuria. Serum creatinine was used to estimate GFR using the modified Counahan-Barratt formula. The Student's t-test was used to analyse continuous variables and the chi-square or Fisher's exact test was used to analyse categorical data. Logistic regression was performed to assess the relationship between study factors and urine abnormalities, persistent proteinuria and the eGFR. RESULTS: Two hundred and twenty children were enrolled into the study. The median age was 90 months (Q1=65.5; Q3=116.5). The prevalence of urinary tract infection was 9.5%. Escherichia coli was the predominant organism. There was uniform resistance to cotrimoxazole. Persistent proteinuria (urine protein to creatinine ratio greater than 0.2, a week apart) was found in 5% of the children. Seventy-five children (34.6%) had mild to moderate renal impairment shown by a low eGFR (30 to <90 ml/min/1.73 m2). Persistent proteinuria was more likely to be found in children who were wasted, weight-for-height (WHZ) z-score <-2 (p=0.0005). Children with WHO clinical stage 4 were more likely to have a low eGFR than children with less advanced stages (OR 2.68; CI 1.24-5.80). Urine abnormalities were more likely to be observed in children with WHO clinical stages 3 and 4 (OR 2.20; CI 1.06-4.60). CONCLUSION: There is significant renal impairment among HIV-infected, ART naive children aged 2-12 years attending the outpatient paediatric HIV clinic at Harare Central Hospital. The abnormalities are more likely to occur in children with advanced HIV/AIDS. Screening for renal impairment and urinary tract infections in HIV-infected children before initiation of ART and regularly thereafter would be helpful in their management. KEYWORDS: HIV, renal disease, persistent proteinuria, glomerular filtration rate, urinary tract infection.

Brief Report: Suboptimal Lopinavir Exposure in Infants on Rifampicin Treatment Receiving Double-dosed or Semisuperboosted Lopinavir/Ritonavir: Time for a Change.

BACKGROUND: Although super-boosted lopinavir/ritonavir (LPV/r; ratio 4:4 instead of 4:1) is recommended for infants living with HIV and receiving concomitant rifampicin, in clinical practice, many different LPV/r dosing strategies are applied due to poor availability of pediatric separate ritonavir formulations needed to superboost. We evaluated LPV pharmacokinetics in infants with HIV receiving LPV/r dosed according to local guidelines in various sub-Saharan African countries with or without rifampicin-based tuberculosis (TB) treatment. METHODS: This was a 2-arm pharmacokinetic substudy nested within the EMPIRICAL trial (#NCT03915366). Infants aged 1-12 months recruited into the main study were administered LPV/r according to local guidelines and drug availability either with or without rifampicin-based TB treatment; during rifampicin cotreatment, they received double-dosed (ratio 8:2) or semisuperboosted LPV/r (adding a ritonavir 100 mg crushed tablet to the evening LPV/r dose). Six blood samples were taken over 12 hours after intake of LPV/r. RESULTS: In total, 14/16 included infants had evaluable pharmacokinetic curves; 9/14 had rifampicin cotreatment (5 received double-dosed and 4 semisuperboosted LPV/r). The median (IQR) age was 6.4 months (5.4-9.8), weight 6.0 kg (5.2-6.8), and 10/14 were male. Of those receiving rifampicin, 6/9 infants (67%) had LPV Ctrough <1.0 mg/L compared with 1/5 (20%) in the control arm. LPV apparent oral clearance was 3.3-fold higher for infants receiving rifampicin. CONCLUSION: Double-dosed or semisuperboosted LPV/r for infants aged 1-12 months receiving rifampicin resulted in substantial proportions of subtherapeutic LPV levels. There is an urgent need for data on alternative antiretroviral regimens in infants with HIV/TB coinfection, including twice-daily dolutegravir.

Risk factors for inpatient mortality among children with severe acute malnutrition in Zimbabwe and Zambia.

BACKGROUND/OBJECTIVES: Malnutrition underlies 45% of deaths in children under-5 years annually. Children hospitalised with complicated severe acute malnutrition (SAM) have unacceptably high mortality. We aimed to identify variables from early hospital admission (baseline factors) independently associated with inpatient mortality in this cohort to identify those most at risk. SUBJECTS/METHODS: Observational study of 745 children aged 0-59 months admitted with complicated SAM at three hospitals in Zimbabwe/Zambia. Children underwent anthropometry and clinical assessment by a study physician within 72 h of enrolment, and caregivers provided sociodemographic data. Children were followed-up daily until discharge/death. A multivariable survival analysis identified the baseline factors independently associated with mortality. RESULTS: 70/745 (9.4%) children died in hospital. Age between 6-23 months [aHR 6.53, 95%CI 2.24-19.02], higher mid-upper arm circumference [aHR 0.73, 95%CI 0.59-0.89], presence of oedema [aHR 2.22, 95%CI 1.23-4.05], shock [aHR 8.18, 95%CI 3.79-17.65], sepsis [aHR 3.13, 95%CI 1.44-6.80], persistent diarrhoea [aHR 2.27, 95%CI 1.18-4.37], lack of a toilet at home [aHR 4.35, 95%CI 1.65-11.47], and recruitment at one Harare site [aHR 0.38, 95%CI 0.18-0.83] were all independently associated with inpatient mortality. Oedematous children had a significantly higher birthweight [2987 g vs 2757 g, p < 0.001] than those without oedema; higher birthweight was weakly associated with mortality [aHR 1.50 95%CI 0.97-2.31]. CONCLUSIONS: Children with oedema, low MUAC, baseline infections, shock and lack of home sanitation had a significantly increased risk of inpatient mortality following hospitalisation for complicated SAM. Children with high-risk features may require additional care. A better understanding of the pathophysiology of SAM is needed to identify adjunctive interventions.

First-Line Antituberculosis Drug Concentrations in Infants With HIV and a History of Recent Admission With Severe Pneumonia.

Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants.

Ethical and legal constraints to children's participation in research in Zimbabwe: experiences from the multicenter pediatric HIV ARROW trial.

BACKGROUND: Clinical trials involving children previously considered unethical are now considered essential because of the inherent physiological differences between children and adults. An integral part of research ethics is the informed consent, which for children is obtained by proxy from a consenting parent or guardian. The informed consent process is governed by international ethical codes that are interpreted in accordance with local laws and procedures raising the importance of contextualizing their implementation. FINDINGS: In Zimbabwe the parental informed consent document for children participating in clinical research is modeled after Western laws of ethics and requires that the parent or legally authorized representative provide consent on behalf of a minor. This article highlights the experiences and lessons learnt by Zimbabwean researchers in obtaining informed consent from guardians of orphaned children participating in a collaborative HIV clinical trial involving the Medical Research Council, United Kingdom and four centers, three of which are in Uganda. Researchers were faced with a situation where caregivers of orphaned children were not permitted to provide informed consent for trial participation. The situation contrasted with general clinical practice where consent for procedures on orphans is obtained from their caregivers who are not legal guardians. CONCLUSION: The challenges faced in obtaining informed consent for orphans in this clinical trial underscores the need for the Zimbabwe ethics committee to develop an ethical and legal framework for pediatric research that is based on international guidelines while taking into account the cultural context. The Medical Research Council of Zimbabwe has since started the process that is expected to involve critical stakeholders namely the community including children, ethicists, the legal fraternity and researchers.

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial.

BACKGROUND: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. METHODS: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (≥14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127. FINDINGS: Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1·4 years (IQR 0·6-2·0) and median weight 8·1 kg (5·4-10·0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112-137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was -10% (95% CI -19% to -2%; p=0·020), demonstrating superiority of dolutegravir. The frequentist estimated difference was -18% (-36% to 2%; p=0·057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1·08 [95% CI 0·47-2·49]; p=0·86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0·93 [0·50-1·74]; p=0·83). No events were considered related to dolutegravir. INTERPRETATION: Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

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.

Brief Report: Cessation of Long-Term Cotrimoxazole Prophylaxis in HIV-Infected Children Does Not Alter the Carriage of Antimicrobial Resistance Genes.

BACKGROUND: Cotrimoxazole (CTX) is a broad-spectrum antimicrobial, combining trimethoprim and sulfamethoxazole. CTX prophylaxis reduces mortality and morbidity among people living with HIV in regions with high prevalence of bacterial infections and malaria. The Antiretroviral research for Watoto trial evaluated the effect of stopping versus continuing CTX prophylaxis in sub-Saharan Africa. METHODS: In this study, 72 HIV-infected Zimbabwean children, on antiretroviral therapy, provided fecal samples at 84 and 96 weeks after randomization to continue or stop CTX. DNA was extracted for whole metagenome shotgun sequencing, with sequencing reads mapped to the Comprehensive Antibiotic Resistance Database to identify CTX and other antimicrobial resistance genes. RESULTS: There were minimal differences in the carriage of CTX resistance genes between groups. The dfrA1 gene, conferring trimethoprim resistance, was significantly higher in the continue group (P = 0.039) and the tetA(P) gene conferring resistance to tetracycline was significantly higher in the stop group (P = 0.013). CTX prophylaxis has a role in shaping the resistome; however, stopping prophylaxis does not decrease resistance gene abundance. CONCLUSIONS: No differences were observed in resistance gene carriage between the stop and continue groups. The previously shown multi-faceted protective effects of CTX in antiretroviral research for Watoto trial clinical outcomes are not outweighed by the risk of multi-drug resistance gene selection due to prophylaxis. These findings are reassuring, given current recommendations for long-term CTX prophylaxis among children living with HIV in sub-Saharan Africa to decrease mortality and morbidity.

Cost estimates of diarrhea hospitalizations among children <5 years old in Zimbabwe.

INTRODUCTION: Diarrhoea is a leading killer of children <5 years old, accounting for 480,000 deaths in 2017. Zimbabwe introduced Rotarix into its vaccination program in 2014. In this evaluation, we estimate direct medical, direct non-medical, and indirect costs attributable to a diarrhea hospitalization in Zimbabwe after rotavirus vaccine introduction. METHODS: Children <5 years old admitted to Harare Central Hospital from June 2018 to April 2019 with acute watery diarrhea were eligible for this evaluation. A 3-part structured questionnaire was used to collect data by interview from the child's family and by review of the medical record. A stool specimen was also collected and tested for rotavirus. Direct medical costs were the sum of medications, consumables, diagnostic tests, and service delivery costs. Direct non-medical costs were the sum of transportation, meals and lodging for caregivers. Indirect costs are the lost income for household members. RESULTS: A total of 202 children were enrolled with a median age of 12 months (IQR: 7-21) and 48 (24%) had malnutrition. Children were sick for a median of 2 days and most had received outpatient medical care prior to admission. The median monthly household income was higher for well-nourished children compared to malnourished children (p < 0.001). The median total cost of a diarrhea illness resulting in hospitalization was $293.74 (IQR: 188.42, 427.89). Direct medical costs, with a median of $251.74 (IQR: 155.42, 390.96), comprised the majority of the total cost. Among children who tested positive for rotavirus, the median total illness cost was $243.78 (IQR: 160.92, 323.84). The median direct medical costs were higher for malnourished than well-nourished children (p < 0.001). CONCLUSION: Direct medical costs are the primary determinant of diarrhea illness costs in Zimbabwe. The descriptive findings from this evaluation are an important first step in calculating the cost effectiveness of rotavirus vaccine.

Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM): rationale and methods of a longitudinal observational study.

INTRODUCTION: Mortality among children hospitalised for complicated severe acute malnutrition (SAM) remains high despite the implementation of WHO guidelines, particularly in settings of high HIV prevalence. Children continue to be at high risk of morbidity, mortality and relapse after discharge from hospital although long-term outcomes are not well documented. Better understanding the pathogenesis of SAM and the factors associated with poor outcomes may inform new therapeutic interventions. METHODS AND ANALYSIS: The Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM) study is a longitudinal observational cohort that aims to evaluate the short-term and long-term clinical outcomes of HIV-positive and HIV-negative children with complicated SAM, and to identify the risk factors at admission and discharge from hospital that independently predict poor outcomes. Children aged 0-59 months hospitalised for SAM are being enrolled at three tertiary hospitals in Harare, Zimbabwe and Lusaka, Zambia. Longitudinal mortality, morbidity and nutritional data are being collected at admission, discharge and for 48 weeks post discharge. Nested laboratory substudies are exploring the role of enteropathy, gut microbiota, metabolomics and cellular immune function in the pathogenesis of SAM using stool, urine and blood collected from participants and from well-nourished controls. ETHICS AND DISSEMINATION: The study is approved by the local and international institutional review boards in the participating countries (the Joint Research Ethics Committee of the University of Zimbabwe, Medical Research Council of Zimbabwe and University of Zambia Biomedical Research Ethics Committee) and the study sponsor (Queen Mary University of London). Caregivers provide written informed consent for each participant. Findings will be disseminated through peer-reviewed journals, conference presentations and to caregivers at face-to-face meetings.

Medical Education Partnership Initiative (MEPI) in Zimbabwe: Outcomes and Challenges.

BACKGROUND: Sub-Saharan Africa has an inadequate number of health professionals, leading to a reduced capacity to respond to health challenges, including HIV/AIDS. From 2010 to 2015, the Medical Education Partnership Initiative (MEPI)-sponsored by the U.S. Presidents Emergency Plan for AIDS Relief (PEPFAR) and the National Institutes of Health (NIH)-was enthusiastically taken up by the University of Zimbabwe College of Health Sciences (UZCHS) and 12 other sub-Saharan African universities to develop models of training to improve medical education and research capacity. In this article, we describe the outcomes and challenges of MEPI in Zimbabwe. METHODS: UZCHS in partnership with the University of Colorado, Denver; Stanford University; University of Cape Town; University College London; and King's College London designed the Novel Education Clinical Trainees and Researchers (NECTAR) program and 2 linked awards addressing cardiovascular disease and mental health to pursue MEPI objectives. A range of medical education and research capacity-focused programs were implemented, including faculty development, research support, mentored scholars, visiting professors, community-based education, information and technology support, cross-cutting curricula, and collaboration with partner universities and the ministries of health and education. We analyzed quantitative and qualitative data from several data sources, including annual surveys of faculty, students, and other stakeholders; workshop exit surveys; and key informant interviews with NECTAR administrators and leaders and the UZCHS dean. FINDINGS: Improved Internet connectivity and electronic resource availability were early successes of NECTAR. Over the 5-year period, 69% (115 of 166) of faculty members attended at least 1 of 15 faculty development workshops. Forty-one faculty members underwent 1-year advanced faculty development training in medical education and leadership. Thirty-three mentored research scholars were trained under NECTAR, and 52 and 12 in cardiovascular and mental health programs, respectively. Twelve MEPI scholars had joined faculty by 2015. Full-time faculty grew by 36% (122 to 166), annual postgraduate and medical student enrollment increased by 61% (75 to 121) and 71% (123 to 210), respectively. To institutionalize and sustain MEPI innovations, the Research Support Center and the Department of Health Professions Education were established at UZCHS. CONCLUSION: MEPI has synergistically revitalized medical education, research capacity, and leadership at UZCHS. Investments in creating a new research center, health professions education department, and, programs have laid the foundation to help sustain faculty development and research capacity in the country.

Child mortality according to maternal and infant HIV status in Zimbabwe.

BACKGROUND: HIV causes substantial mortality among African children but there is limited data on how this is influenced by maternal or infant infection status and timing. METHODS: Children enrolled in the ZVITAMBO trial were divided into 5 groups: those born to HIV-negative mothers (NE, n = 9510), those born to HIV-positive mothers but noninfected (NI, n = 3135), those infected in utero (IU, n = 381), those infected intrapartum (IP, n = 508), and those infected postnatally (PN, n = 258). Their mortality was estimated. RESULTS: Two-year mortality was 2.9% (NE infants), 9.2% (NI), 67.5% (IU), 65.1% (IP), and 33.2% (PN). Between 8 weeks and 6 months, mortality in IU infants quintupled (from 309 to 1686/1000 c-y). The median time from infection to death was 208, 380, and >500 days for IU, IP, and PN infants, respectively. Among NI children, advanced maternal disease was predictive of mortality. Acute respiratory infection was the major cause of death. CONCLUSIONS: Perinatally infected infants are at particular risk of death between 2 and 6 months: cotrimoxazole prophylaxis and early pediatric HAART should be scaled up. Uninfected infants of infected mothers have at least twice the mortality risk of infants born to uninfected mothers: all HIV-exposed infants should be targeted with child survival interventions. HIV-positive mothers with more advanced disease are not only more likely to infect their infants, but their infants are more likely to die, whether infected or not: provision of antiretroviral treatment to pregnant and lactating women is an urgent need for both mothers and their children.

The impact of safer breastfeeding practices on postnatal HIV-1 transmission in Zimbabwe.

OBJECTIVES: We assessed the association between exposure to an educational intervention that emphasized safer breastfeeding practices and postnatal HIV transmission among 437 HIV-positive mothers in Zimbabwe, 365 of whom did not know their infection status. METHODS: Mothers were tested for HIV and were encouraged--but not required--to learn their HIV status. Intervention exposure was assessed by a questionnaire, Turnbull methods were used to estimate postnatal HIV transmission, and multivariate Cox proportional hazard models were constructed to assess the association between intervention exposure and postnatal HIV transmission. RESULTS: Cumulative postnatal HIV transmission was 8.2%; each additional intervention contact was associated with a 38% reduction in postnatal HIV transmission. HIV-positive mothers who were exposed to both print and video materials were 79% less likely to infect their infants compared with mothers who had no exposure. These findings were similar for mothers who did not know their HIV status. CONCLUSIONS: The promotion of exclusive breastfeeding has the potential to reduce postnatal HIV transmission among women who do not know their HIV status, and child survival and HIV prevention programs should support this practice.

Reference intervals of serum transferrin receptors in pre-school children in Zimbabwe.

In laboratory medicine an observed value of a biological analyte may be compared with previously observed values from an appropriate reference population. A reference range for serum transferrin receptor concentration has not been established for Zimbabwean children. We prospectively studied 208 children aged 3-60 months who were residents of Harare, a non-malaria and non-hookworm endemic area, and who attended a well-child clinic. Anthropometric measurements were calculated, complete blood counts performed and serum concentrations of ferritin and transferrin receptors determined. A final group of 83 pre-school children with no apparent illness was used to determine the serum transferrin receptor concentration reference interval after excluding individuals with abnormal clinical and laboratory investigations. The central 95 percentile interval for transferrin receptors after eliminating factors that are known to affect serum transferrin receptors was 3.9-9.5 mg/L. Children, aged < or =24 months had a lower reference range than children >24 months old. This study provides an estimate of the serum transferrin receptor reference intervals in African children using the Ramco Laboratories, Stafford, TX assay kit.