Antiretroviral choice and severe disease predict poorer neuropsychological outcomes in HIV+ children from Africa.

Background: The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1104s study evaluated neuropsychological outcomes over 96 weeks in children living with HIV (CLHIV) aged 5-11 years at 6 Sub-Saharan African sites to explore associations between HIV-illness related biomarkers and neuropsychological outcomes. Methods: Children living with HIV had participated in IMPAACT P1060, which compared efficacy of nevirapine versus lopinavir/ritonavir in children initiating ART at <3 years of age. At age 5-11, neuropsychological evaluations of KABC cognitive ability, TOVA attention-impulsivity and BOT-2 motor domains were assessed and repeated after 48 and 96 weeks. Clinical, antiretroviral therapy (ART) and laboratory (immunological and virological) parameters were used to predict neuropsychological outcomes using linear mixed-effects multivariable regression models, controlling for child and caregiver characteristics. Results: 246 CLHIV (45% male, mean age at initial neuropsychological evaluation 7.1 yrs [SD 1.2]) began ART at a median age 14.9 months (IQR 8.2, 25.2). Nadir CD4 percentage was 14.7% (IQR 11.0, 19.5); the median peak viral load (VL) was 750 000 copies/ml (IQR 366 000, 750 000) and 63% had ≥WHO stage 3 clinical disease; 164 (67%) were on lopinavir/ritonavir, 71 (29%) were on nevirapine and 7 (3%) were on efavirenz. Other antiretrovirals were similar. Nevirapine at P1104s study start or later was associated with poorer neuropsychological scores across all domains except Global Executive Composite, even when controlling for nadir CD4 percent and time-varying HIV VL. Other predictors of poorer scores in KABC domains included low birth weight, WHO stage 4 disease and serious illness history and elevated VL was associated with worse BOT-2 scores. Conclusion: Children receiving nevirapine had poorer neuropsychological scores than those on lopinavir/ritonavir. Antiretroviral choice might adversely impact neuropsychological performance. In addition, low birth weight and markers of severe HIV disease: advanced WHO clinical HIV disease, history of serious illness and an elevated VL, were associated with lower neuropsychological scores.

Malaria Transmission Intensity Likely Modifies RTS, S/AS01 Efficacy Due to a Rebound Effect in Ghana, Malawi, and Gabon.

BACKGROUND: RTS,S/AS01 is the first malaria vaccine to be approved and recommended for widespread implementation by the World Health Organization (WHO). Trials reported lower vaccine efficacies in higher-incidence sites, potentially due to a "rebound" in malaria cases in vaccinated children. When naturally acquired protection in the control group rises and vaccine protection in the vaccinated wanes concurrently, malaria incidence can become greater in the vaccinated than in the control group, resulting in negative vaccine efficacies. METHODS: Using data from the 2009-2014 phase III trial (NCT00866619) in Lilongwe, Malawi; Kintampo, Ghana; and Lambaréné, Gabon, we evaluate this hypothesis by estimating malaria incidence in each vaccine group over time and in varying transmission settings. After estimating transmission intensities using ecological variables, we fit models with 3-way interactions between vaccination, time, and transmission intensity. RESULTS: Over time, incidence decreased in the control group and increased in the vaccine group. Three-dose efficacy in the lowest-transmission-intensity group (0.25 cases per person-year [CPPY]) decreased from 88.2% to 15.0% over 4.5 years, compared with 81.6% to -27.7% in the highest-transmission-intensity group (3 CPPY). CONCLUSIONS: These findings suggest that interventions, including the fourth RTS,S dose, that protect vaccinated individuals during the potential rebound period should be implemented for high-transmission settings.

Chest radiography in children aged 2-59 months enrolled in the Innovative Treatments in Pneumonia (ITIP) project in Lilongwe Malawi: a secondary analysis.

BACKGROUND: Pneumonia is the leading infectious cause of death in children aged under 5 years in low- and middle-income countries (LMICs). World Health Organization (WHO) pneumonia diagnosis guidelines rely on non-specific clinical features. We explore chest radiography (CXR) findings among select children in the Innovative Treatments in Pneumonia (ITIP) project in Malawi in relation to clinical outcomes. METHODS: When clinically indicated, CXRs were obtained from ITIP-enrolled children aged 2 to 59 months with community-acquired pneumonia hospitalized with treatment failure or relapse. ITIP1 (fast-breathing pneumonia) and ITIP2 (chest-indrawing pneumonia) trials enrolled children with non-severe pneumonia while ITIP3 enrolled children excluded from ITIP1 and ITIP2 with severe pneumonia and/or selected comorbidities. A panel of trained pediatricians classified the CXRs using the standardized WHO CXR research methodology. We analyzed the relationship between CXR classifications, enrollee characteristics, and outcomes. RESULTS: Between March 2016 and June 2018, of 114 CXRs obtained, 83 met analysis criteria with 62.7% (52/83) classified as having significant pathology per WHO standardized interpretation. ITIP3 (92.3%; 12/13) children had a higher proportion of CXRs with significant pathology compared to ITIP1 (57.1%, 12/21) and ITIP2 (57.1%, 28/49) (p-value = 0.008). The predominant pathological CXR reading was "other infiltrates only" in ITIP1 (83.3%, 10/12) and ITIP2 (71.4%, 20/28), while in ITIP3 it was "primary endpoint pneumonia"(66.7%, 8/12,; p-value = 0.008). The percent of CXRs with significant pathology among children clinically cured (60.6%, 40/66) vs those not clinically cured (70.6%, 12/17) at Day 14 was not significantly different (p-value = 0.58). CONCLUSIONS: In this secondary analysis we observed that ITIP3 children with severe pneumonia and/or selected comorbidities had a higher frequency of CXRs with significant pathology, although these radiographic findings had limited relationship to Day 14 outcomes. The proportion of CXRs with "primary endpoint pneumonia" was low. These findings add to existing data that additional diagnostics and prognostics are important for improving the care of children with pneumonia in LMICs. TRIAL REGISTRATION: ITIP1, ITIP2, and ITIP3 were registered with ClinicalTrials.gov ( NCT02760420 , NCT02678195 , and NCT02960919 , respectively).

Pharmacokinetics and Safety of 3 Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women.

BACKGROUND: Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy. METHODS: IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics. RESULTS: Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P < .001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg × hour/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (P < .001), resulting in lower AUCss (522 mg × hour/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or tuberculosis cases in women or infants. CONCLUSIONS: 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT02651259.

Impacts of Ecology, Parasite Antigenic Variation, and Human Genetics on RTS,S/AS01e Malaria Vaccine Efficacy.

PURPOSE OF REVIEW: Global malaria elimination has little chance of success without an effective vaccine. The first malaria vaccine, RTS,S/AS01e, demonstrated moderate efficacy against clinical malaria in phase III trials and is undergoing large-scale effectiveness trials in Africa. Importantly, the vaccine did not perform equally well between phase III study sites. Though reasons for the moderate efficacy and this variation are unclear, various mechanisms have been suggested. This review summarizes the recent literature on such mechanisms, with a focus on those involving landscape ecology, parasite antigenic variation, and human host genetic differences. RECENT FINDINGS: Transmission intensity may have a role pre- and post-vaccination in modulating immune responses to the vaccine. Furthermore, malaria incidence may "rebound" in vaccinated populations living in high transmission intensity settings. There is growing evidence that both genetic variation in the parasite circumsporozoite protein and variation of human host genetic factors affect RTS,S vaccine efficacy. These genetic factors may be interacting in complex ways to produce variation in the natural and vaccine-induced immune responses that protect against malaria. SUMMARY: Due to the modest efficacy of RTS,S/AS01e, the combinations of factors (ecological, parasite, human host) impacting its effectiveness must be clearly understood, as this information will be critical for implementation policy and future vaccine designs.

Prospective Newborn Screening for Sickle Cell Disease and Other Inherited Blood Disorders in Central Malawi.

Objectives: Newborn screening in the United States and Europe allows early identification of congenital disorders but does not yet exist in most low-resource settings, especially in sub-Saharan Africa. Newborn screening can identify multiple inherited hematological disorders, but feasibility and effectiveness for Africa are not fully determined. Methods: Surplus dried blood spot collected in Central Malawi through the HIV Early Infant Diagnosis surveillance program were repurposed and tested by isoelectric focusing for sickle cell disease and trait. Additional genetic testing identified G6PD deficiency and alpha thalassemia. Results: Testing of 10,529 cards revealed an overall sickle cell trait prevalence of 7.0% (range 3.9-9.7% by district); 10 of 14 infants identified with sickle cell disease (prevalence 0.1%) were located and received care at a specialized clinic. Subsequent testing of 1,329 randomly selected cards identified alpha thalassemia trait in 45.7% of samples, and G6PD deficiency in 20.4% of males and 3.4% of females, with 29.0% of females as heterozygous carriers. Conclusion: Inherited hematological disorders are common in Central Malawi; early identification through newborn screening can improve clinical outcomes and should be supported throughout Africa.

Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092.

BACKGROUND: Severe acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM. MATERIALS AND METHODS: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC0-12h) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts. RESULTS: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) -3.4 (IQR -4.0, -3.0) and 27 non-SAM had median WHZ -1.0 (IQR -1.8, -0.1). No significant differences in mean AUC0-12h or CL/F were observed (P ≥ 0.09) except for lower 3TC AUC0-12h (GMR, 0.60; 95% CI, 0.4-1.0; P = 0.047) at week 12, higher ZDV AUC0-12h (GMR, 1.52; 1.2-2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%). CONCLUSION: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.

IMPAACT 2016: Operationalizing HIV Intervention Adaptations to Inform the Science and Outcomes of Implementation.

Introduction: Uptake of evidence-based interventions for adolescents and young adults living with HIV (AYA-LWH) in sub-Saharan Africa (SSA) is complex, and cultural differences necessitate local adaptations to enhance effective implementation. Few models exist to guide intervention tailoring, yet operationalizing strategies is critical to inform science and implementation outcomes, namely acceptability, appropriateness, feasibility, fidelity, and sustainability. This paper describes operationalizing the ADAPT-ITT framework applied to a manualized trauma-informed cognitive behavioral therapy (TI-CBT) intervention addressing mental and sexual health for AYA-LWH in SSA in preparation for a randomized controlled trial (RCT). Methods: Phase 1 of the RCT focused on operationalizing ADAPT-ITT steps 3-7 to tailor the intervention for use in eight sites across Botswana, Malawi, South Africa, and Zimbabwe. Well-defined processes were developed to supplement the general guidelines for each step to provide clear, consistent direction on how to prepare and conduct each step, including documenting, assessing, and determining adaptations, while maintaining intervention fidelity. The processes provided efficient standardized step-by-step progression designed for future replication. All sites participated in Phase 1 using the created tools and strategies to translate and present the TI-CBT to community stakeholders for feedback informing local adaptations. Results: The research team developed and operationalized materials guiding adaptation. A translation review process verified local adaptability, maintained core concepts, and revealed differing interpretations of words, idioms, and culturally acceptable activities. Strategically designed tools comprised of feedback and translation verification forms resulted in meticulous management of adaptations. Robust collaborations between investigators, research managers, site personnel, and topical experts maximized multidisciplinary expertise, resulting in ~10-15 personnel per site facilitating, collecting, assessing, and integrating local feedback. Processes and tools operationalized in steps 3-7 effectively addressed implementation outcomes during community engagements (n = 108), focus groups (n = 5-8 AYA-LWH and caregivers per group), and strategic training of youth leaders. Discussion: This paper offers a novel generalizable approach using well-defined processes to guide intervention adaptation building on the ADAPT-ITT framework. The processes strengthen the science of implementation and provide much-needed specificity in adaptation steps to optimize and sustain real-world impact and help researchers and community stakeholders maximize existing infrastructure, culture, and resources to inform implementation strategies.

Environmental modifiers of RTS,S/AS01 malaria vaccine efficacy in Lilongwe, Malawi.

BACKGROUND: RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009-2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted. METHODS: We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6-12 weeks) and children (5-17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation. RESULTS: Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner. CONCLUSIONS: Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called "dambos" which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context. TRIAL REGISTRATION: Efficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.

Case reduction and cost-effectiveness of the RTS,S/AS01 malaria vaccine alongside bed nets in Lilongwe, Malawi.

BACKGROUND: RTS,S/AS01, the most advanced vaccine against malaria, is now undergoing pilot implementation in Malawi, Ghana, and Kenya where an estimated 360,000 children will be vaccinated each year. In this study we evaluate RTS,S/AS01 alongside bed net use and estimate cost-effectiveness. METHODS: RTS,S/AS01 phase III trial and bed net prevalence data were used to determine the effect of vaccination in the urban/periurban and rural areas of Lilongwe, Malawi. Cost data were used to calculate the cost-effectiveness of various interventions over three years. FINDINGS: Since bed nets reduce malaria incidence and homogeneous vaccine efficacy was assumed, participants without bed nets received greater relative benefit from vaccination with RTS,S/AS01 than participants with bed nets. Similarly, since malaria incidence in rural Lilongwe is higher than in urban Lilongwe, the impact and cost-effectiveness of vaccine interventions is increased in rural areas. In rural Lilongwe, we estimated that vaccinating one child without a bed net would prevent 2·59 (1·62 to 3·38) cases of malaria over three years, corresponding to a cost of $10·08 (7·71 to 16·13) per case averted. Alternatively, vaccinating one child with a bed net would prevent 1·59 (0·87 to 2·57) cases, corresponding to $16·43 (10·16 to 30·06) per case averted. Providing RTS,S/AS01 to 30,000 children in rural Lilongwe was estimated to cost $782,400 and to prevent 58,611 (35,778 to 82,932) cases of malaria over a three-year period. Joint interventions providing both vaccination and bed nets (to those without them) were estimated to prevent additional cases of malaria and to be similarly cost-effective, compared to vaccine-only interventions. INTERPRETATION: To maximize malaria prevention, vaccination and bed net distribution programs could be integrated. FUNDING: Impacts of Environment, Host Genetics and Antigen Diversity on Malaria Vaccine Efficacy (1R01AI137410-01).

Association between caregiver depression symptoms and child executive functioning. Results from an observational study carried out in four sub-Saharan countries.

Depressive symptoms among HIV-positive (HIV+) women may negatively impact their health and possibly that of their young children through risk of compromised caregiving. We evaluated how depression symptoms in predominantly (97%) female caregivers relate to neurodevelopmental outcomes in their HIV affected children. Data come from the IMPAACT P1104s Study, an observational cohort across six sites in four countries: Zimbabwe, South Africa, Uganda and Malawi. Participants (n = 611) were 5-11-year-old children with HIV (HIV), HIV exposed uninfected (HEU), or HIV unexposed uninfected (HUU). Primary caregivers were assessed for depression with the Hopkins Symptom Checklist (HSCL) and children with Behavior Rating Inventory for Executive Function (BRIEF) parent-report, Kauffman Assessment Battery for Children II (KABC), Bruininks-Oseretsky Test of Motor Proficiency 2nd Ed. (BOT-2), Test of Variables of Attention (TOVA), Multiple Indicators Cluster Survey, Child Disability and Development scales (MICS-4). Caregivers with higher depression scores (>1.75 mean HSCL score) reported more executive function problems in their children, regardless of HIV status. All executive function scores were significantly (p < 0.001) associated with depressive symptomatology at baseline and across time. Caregiver depressive symptomatology was not associated with other assessed neurocognitive outcomes. These results highlight the potential impact of caregiver depression on child behavioral outcomes.

Safety and immunogenicity of the RTS,S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa.

BACKGROUND: We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries. METHODS: Infants 6-12 weeks and children 5-17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anti-circumsporozoite (CS) antibodies were assessed. RESULTS: Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1-97.8) in the R3R, 85.2% (72.9-93.4) in the R3C and 87.5% (74.8-95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccination-related. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p = 0.0001). CONCLUSIONS: The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00866619.

African Multi-Site 2-Year Neuropsychological Study of School-Age Children Perinatally Infected, Exposed, and Unexposed to Human Immunodeficiency Virus.

BACKGROUND: Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART). METHODS: We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child's age and sex, and selected personal/family control variables. RESULTS: The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF. CONCLUSIONS: Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence.

Real-world experience using hydroxyurea in children with sickle cell disease in Lilongwe, Malawi.

INTRODUCTION: Sickle cell disease (SCD) is among the most common inherited hematologic diseases in sub-Saharan Africa (SSA). Historically, hydroxyurea administration in SSA has been restricted due to limited region-specific evidence for safety and efficacy. METHODS: We conducted a prospective observational cohort study of pediatric patients with SCD in Malawi. From January 2015 to November 2017, hydroxyurea at doses of 10-20 mg/kg/day was administered to children with clinically severe disease (targeted use policy). From December 2017 to July 2018, hydroxyurea was prescribed to all patients (universal use policy). RESULTS: Of 187 patients with SCD, seven (3.7%) died and 23 (12.3%) were lost to follow-up. The majority (135, 72.2%) were prescribed hydroxyurea, 59 (43.7%) under the targeted use policy and 76 (56.3%) under the universal use policy. There were no documented severe toxicities. Under the targeted use policy, children with SCD demonstrated absolute decreases in the rates of hospitalization (-4.1 per 1000 person-days; -7.2, -1.0; P = .004), fevers (-4.2 per 1000 person-days; -7.2, -1.1; P = .002), transfusions (-2.3 per 1000 person-days; 95% confidence interval: -4.9, 0.3; P = .06), and annual school absenteeism (-51.2 per person-year; -60.1, -42.3; P < .0001) within 6 months of hydroxyurea commencement. CONCLUSION: We successfully implemented universal administration of hydroxyurea to children with SCD at a tertiary hospital in Malawi. Similar to recently reported trials, hydroxyurea was safe and effective during routine programmatic experience, with clinical benefits particularly among high-risk children. This highlights the importance of continued widespread scale-up of hydroxyurea within SCD programs across SSA.

Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa.

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score ≤2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

Building capacity in neurodevelopment assessment of children in sub-Saharan Africa: A quality assurance model to implement standardized neurodevelopment testing.

Compromised neurodevelopment (ND) among infants and children is prevalent in sub-Saharan Africa. Standardized testing of ND is frequently prohibitive in these contexts, as tests require skilled staff for their application. In this paper, we present a quality assurance (QA) model (QualiND) for standardized ND testing, discussing findings and implications from our experience applying the Kaufman Assessment Battery for Children second edition (KABC-II). The QualiND model was implemented within IMPAACT P1104s study, a multisite, prospective study including 615 children affected by HIV. From 2014 to 2016, the QualiND managed 18 testers across 6 sites located in 4 African countries applying the KABC-II in 9 local languages. The QualiND is a multilevel, video-assisted iterative model incorporating remote evaluation, feedback, and supervision roles. Using an ad hoc rubric, videos of test application were evaluated by experienced staff in a centralized QA center. At each study site, testers and supervisors reviewed feedback from videos received via email from the QA center and devised an action plan to address testing errors and deficiencies. There were few instances of invalid tests and few barriers to test completion. Over 97% of KABC-II tests across sites were considered to be valid by the QA center. Overall, the QualiND model was a useful platform for remote supervision to nonspecialist and minimally trained research staff. The QualiND model may be useful to researchers and organizations involved in measuring early child development using standardized tests in low and middle-income countries.

Validity of Neuropsychological Testing in Young African Children Affected by HIV.

INTRODUCTION: Western-constructed neuropsychological tests have been used in low and middle income countries to assess the impact of HIV/AIDS and other chronic illnesses. We explore using such instruments cross-culturally in a sub-Saharan Africa setting. METHODS: IMPAACT P1104S was a two-year observational study carried out at six clinical sites (South Africa- 3 sites, Malawi, Uganda and Zimbabwe) to assess and compare neuropsychological outcomes in three cohorts of children 5-11 years of age: HIV-infected (HIV), HIV-exposed but uninfected (HEU) and HIV unexposed and uninfected (HU). Descriptive statistics compared socio-demographic characteristics among children at sites. Instruments included the KABC-II cognitive ability, TOVA attention/impulsivity, BOT-2 motor proficiency tests, and BRIEF executive function problems. Test characteristics were assessed using intraclass and Spearman non-parametric correlations, linear regression and principal factor analyses. RESULTS: Of the 611 participants, 50% were male and mean age ranged from 6.6 to 8 years. In Malawi, Uganda and Zimbabwe, substantial proportions of families lived in rural settings in contrast to the South African sites. Intraclass correlation coefficients between weeks 0 and 48 were highest for the KABC scores, ranging between 0.42 to 0.71.Correlations among similar test domains were low to moderate but significant, with positive correlation between KABC Sequential and TOVA scores and negative correlation between BRIEF and KABC scores. TOVA response time scores correlated negatively with the BOT-2 Total points score. Strong and significant associations between individual measures of growth, disability and development with all test scores were observed. Performance-based measures were markedly lower for HIV compared to HEU and HU participants, even after controlling for age, sex and site. Factor analyses confirmed the underlying theoretical structure of the KABC scaled item scores. CONCLUSION: The KABC, TOVA, BRIEF and BOT-2 were valid and reliable tools for assessing the neuropsychological impact of HIV in four sub-Saharan African countries.