Statistical Analysis Plan for Primary and Selected Secondary Health Endpoints of the SEARCH-Youth Study

This document provides the statistical analytic plan (SAP) for evaluating health outcomes in the SEARCH-Youth study, a cluster randomized trial designed to evaluate the effect of a combination intervention on HIV viral suppression among adolescents and young adults with HIV in rural Uganda and Kenya (Clinicaltrials.gov: NCT03848728). The SAP was locked prior to unblinding and effect estimation. This SAP was embargoed until November 04, 2022 when it was submitted to arXiv.Comment: 14 pages, 1 figur

The age-specific burden and household and school-based predictors of child and adolescent tuberculosis infection in rural Uganda.

BackgroundThe age-specific epidemiology of child and adolescent tuberculosis (TB) is poorly understood, especially in rural areas of East Africa. We sought to characterize the age-specific prevalence and predictors of TB infection among children and adolescents living in rural Uganda, and to explore the contribution of household TB exposure on TB infection.MethodsFrom 2015-2016 we placed and read 3,121 tuberculin skin tests (TST) in children (5-11 years old) and adolescents (12-19 years old) participating in a nested household survey in 9 rural Eastern Ugandan communities. TB infection was defined as a positive TST (induration ≥10mm or ≥5mm if living with HIV). Age-specific prevalence was estimated using inverse probability weighting to adjust for incomplete measurement. Generalized estimating equations were used to assess the association between TB infection and multi-level predictors.ResultsThe adjusted prevalence of TB infection was 8.5% (95%CI: 6.9-10.4) in children and 16.7% (95% CI:14.0-19.7) in adolescents. Nine percent of children and adolescents with a prevalent TB infection had a household TB contact. Among children, having a household TB contact was strongly associated with TB infection (aOR 5.5, 95% CI: 1.7-16.9), but the strength of this association declined among adolescents and did not meet significance (aOR 2.3, 95% CI: 0.8-7.0). The population attributable faction of TB infection due to a household TB contact was 8% for children and 4% among adolescents. Mobile children and adolescents who travel outside of their community for school had a 1.7 (95% CI 1.0-2.9) fold higher odds of TB infection than those who attended school in the community.ConclusionChildren and adolescents in this area of rural eastern Uganda suffer a significant burden of TB. The majority of TB infections are not explained by a known household TB contact. Our findings underscore the need for community-based TB prevention interventions, especially among mobile youth

Gaps in the Child Tuberculosis Care Cascade in 32 Rural Communities in Uganda and Kenya.

Background:Reducing tuberculosis (TB) deaths among children requires a better understanding of the gaps in the care cascade from TB diagnosis to treatment completion. We sought to assess the child TB care cascade in 32 rural communities in Uganda and Kenya using programmatic data. Methods:This is a retrospective cohort study of 160,851 children (ages <15 years) living in 12 rural communities in Kenya and 22 in Uganda. We reviewed national TB registries from health centers in and adjacent to the 32 communities, and we included all child TB cases recorded from January 1, 2013 to June 30, 2016. To calculate the first step of the child TB care cascade, the number of children with active TB, we divided the number of reported child TB diagnoses by the 2015 World Health Organization (WHO) child TB case detection ratio for Africa of 27%. The remaining components of the Child TB Care Cascade were ascertained directly from the TB registries and included: diagnosed with TB, started on TB treatment, and completed TB treatment. Results:In two and a half years, a total of 42 TB cases were reported among children living in 32 rural communities in Uganda and Kenya. 40% of the children were co-infected with HIV. Using the WHO child TB case detection ratio, we calculated that 155 children in this cohort had TB during the study period. Of those 155 children, 42 were diagnosed and linked to TB care, 42 were started on treatment, and 31 completed treatment. Among the 42 children who started TB treatment, reasons for treatment non-completion were loss to follow up (7%), death (5%), and un-recorded reasons (5%). Overall, 20% (31/155) of children completed the child TB care cascade. Conclusion:In 32 rural communities in Uganda and Kenya, we estimate that 80% of children with TB fell off the care cascade. Reducing morbidity and mortality from child TB requires strengthening of the child TB care cascade from diagnosis through treatment completion

Metagenomic next-generation sequencing of samples from pediatric febrile illness in Tororo, Uganda.

Febrile illness is a major burden in African children, and non-malarial causes of fever are uncertain. In this retrospective exploratory study, we used metagenomic next-generation sequencing (mNGS) to evaluate serum, nasopharyngeal, and stool specimens from 94 children (aged 2-54 months) with febrile illness admitted to Tororo District Hospital, Uganda. The most common microbes identified were Plasmodium falciparum (51.1% of samples) and parvovirus B19 (4.4%) from serum; human rhinoviruses A and C (40%), respiratory syncytial virus (10%), and human herpesvirus 5 (10%) from nasopharyngeal swabs; and rotavirus A (50% of those with diarrhea) from stool. We also report the near complete genome of a highly divergent orthobunyavirus, tentatively named Nyangole virus, identified from the serum of a child diagnosed with malaria and pneumonia, a Bwamba orthobunyavirus in the nasopharynx of a child with rash and sepsis, and the genomes of two novel human rhinovirus C species. In this retrospective exploratory study, mNGS identified multiple potential pathogens, including 3 new viral species, associated with fever in Ugandan children

Predictors of Neonatal Sepsis in Rural Karnataka, India

Background: Neonatal sepsis can present with subtle signs but have a fulminant and fatal course if not recognised and treated early. Many practitioners in resource-poor settings are forced to empirically manage infants at risk for sepsis without access to blood cultures. We sought to identify predictors of poor outcomes in infants with suspected sepsis at a hospital in rural Karnataka, India. Materials and Methods: This was an observational study of infants aged zero to 30 days who were admitted from January to December 2011 with a diagnosis of presumed bacterial sepsis. We extracted perinatal risk factors, gestational age, birth weight, history and physical exam at the time of admission, white blood cell count, C-reactive protein, duration of hospitalisation, disposition, and blood culture results from medical charts. Poor outcome was defined as death, positive blood culture, hospitalisation greater than five days, or transfer for higher level of care. We calculated predictive values and odds ratio for each variable using univariate logistic regression. Results: Seventy-nine infants were included; 58 (73.4%) experienced a poor outcome. Prematurity and temperature instability were significantly associated with poor outcome, with trends towards higher risk for those having very low birth weight, convulsions, a bulging fontanelle, or lethargy on admission. Nine blood cultures were positive, including seven with Staphylococcus. Conclusions: In a cohort of infants admitted for presumed sepsis in rural Karnataka, prematurity and temperature instability were associated with poor outcome. Larger studies are needed to evaluate bacterial aetiologies and determine the optimal antibiotic regimen

Impact of intermittent preventive treatment of malaria in pregnancy with dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine on the incidence of malaria in infancy: a randomized controlled trial.

BACKGROUND: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) significantly reduces the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (SP), the current standard of care, but its impact on the incidence of malaria during infancy is unknown. METHODS: We conducted a double-blind randomized trial to compare the incidence of malaria during infancy among infants born to HIV-uninfected pregnant women who were randomized to monthly IPTp with either DP or SP. Infants were followed for all their medical care in a dedicated study clinic, and routine assessments were conducted every 4 weeks. At all visits, infants with fever and a positive thick blood smear were diagnosed and treated for malaria. The primary outcome was malaria incidence during the first 12 months of life. All analyses were done by modified intention to treat. RESULTS: Of the 782 women enrolled, 687 were followed through delivery from December 9, 2016, to December 5, 2017, resulting in 678 live births: 339 born to mothers randomized to SP and 339 born to those randomized to DP. Of these, 581 infants (85.7%) were followed up to 12 months of age. Overall, the incidence of malaria was lower among infants born to mothers randomized to DP compared to SP, but the difference was not statistically significant (1.71 vs 1.98 episodes per person-year, incidence rate ratio (IRR) 0.87, 95% confidence interval (CI) 0.73-1.03, p = 0.11). Stratifying by infant sex, IPTp with DP was associated with a lower incidence of malaria among male infants (IRR 0.75, 95% CI 0.58-0.98, p = 0.03) but not female infants (IRR 0.99, 95% CI 0.79-1.24, p = 0.93). CONCLUSION: Despite the superiority of DP for IPTp, there was no evidence of a difference in malaria incidence during infancy in infants born to mothers who received DP compared to those born to mothers who received SP. Only male infants appeared to benefit from IPTp-DP suggesting that IPTp-DP may provide additional benefits beyond birth. Further research is needed to further explore the benefits of DP versus SP for IPTp on the health outcomes of infants. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02793622 . Registered on June 8, 2016

Growth Recovery Among HIV-infected Children Randomized to Lopinavir/Ritonavir or NNRTI-based Antiretroviral Therapy.

BACKGROUND: Diminished growth is highly prevalent among HIV-infected children and might be improved by antiretroviral therapy (ART). We examined growth recovery in a rural Ugandan cohort of HIV-infected children randomized to lopinavir/ritonavir (LPV/r) or non nucleoside reverse transcription inhibitor-based ART. METHODS: HIV-infected children 2 months to 6 years of age were randomized to LPV/r- or non nucleoside reverse transcription inhibitor-based ART. Changes in weight-for-age (WAZ), height-for-age (HAZ) and weight-for-height Z-scores for 24 months were evaluated using generalized linear repeated measures models. Recovery from being underweight (WAZ<-2), stunted (HAZ<-2) and wasted (weight-for-height <-2) to Z-scores greater than -2 was also compared by arm using Kaplan-Meier survival and Cox proportional hazard modeling. RESULTS: A total of 129 children with median age of 3 years initiated therapy; 64 received LPV/r-based and 65 non nucleoside reverse transcription inhibitor-based ART (nevirapine: 36 and efavirenz: 29). The median (interquartile range) difference in growth measures between baseline and 24 months for LPV/r (n = 45) versus non nucleoside reverse transcription inhibitor-based therapy (n = 40) were as follows: WAZ, 0.47 (0.10, 1.62) versus 0.53 (0.03, 1.14) (P = 0.59) and HAZ, median 1.55 (0.78, 1.86) versus 1.19 (0.62, 1.65) (P = 0.23), respectively. ART regimen was not predictive of change in WAZ (β: -0.02, 95% confidence interval: -0.25, 0.20) or HAZ (β: 0.05, 95% confidence interval: -0.10, 0.19). The presence of confirmed virologic failure was not associated with growth. CONCLUSIONS: Most ART-naive children experienced recovery of both WAZ and HAZ over the 24 months after ART initiation, with no significant difference between those receiving LPV/r versus non nucleoside reverse transcriptase inhibitor-based ART. However, the persistence of median Z-scores below 0 underscores the need for additional strategies to improve growth outcomes in HIV+ African children