Predictors of mortality in Ugandan children with TB, 2016-2021.

BACKGROUND: The burden of pediatric TB is high in Uganda. Our objective was to evaluate predictors of mortality during TB treatment among children at an urban and a rural referral hospital.METHODS: We designed a historical cohort study of TB cases at Mulago National Referral Hospital, Kampala; and Fort Portal Regional Referral Hospital, Fort Portal, Uganda, in children aged <15 years from 2016 to 2021. We used Kaplan-Meier models to estimate survival and fit multivariable Cox regression models to determine mortality hazards during TB treatment.RESULTS: We identified 1,658 children diagnosed with TB from 2016 to 2021. Of 1,623 children with known treatment outcomes, 127/1,623 (7.8%) died during TB treatment, 1,298/1,623 (78.3%) completed treatment, 150/1,623 (9.2%) were lost to follow-up, and two children failed treatment. Using Kaplan-Meier functions, the median time to death was 27 days following treatment initiation. In adjusted Cox models, predictors of mortality included HIV (aHR 1.68, 95% CI 1.01-2.81), moderate malnutrition (aHR 2.22, 95% CI 1.18-4.16), and severe malnutrition (aHR 2.92, 95% CI 1.75-4.87).CONCLUSION: Mortality was high at an urban and a rural referral hospital among children who initiated TB treatment from 2016 to 2021, with the majority of deaths occurring during the intensive phase of TB treatment. Malnutrition and HIV were significant predictors of death during treatment.

Decentralisation of child tuberculosis services increases case finding and uptake of preventive therapy in Uganda.

BACKGROUND: A lack of capacity to diagnose tuberculosis (TB) in children at peripheral health facilities and limited contact screening and management contribute to low case finding in TB-endemic settings. OBJECTIVE: To evaluate the implementation of a pilot project that strengthened diagnosis, treatment and prevention of child TB at peripheral health facilities in Uganda. METHODS: In June 2015, health care workers at peripheral health facilities were trained to diagnose and treat child TB. Community health care workers were trained to screen household TB contacts. Before-and-after analysis as well as comparisons with non-intervention districts were used to evaluate impact on caseload and treatment outcomes. RESULTS: By December 2016, the average number of children (age < 15 years) diagnosed with TB increased from 45 to 108 per quarter. The proportion of child TB among all TB cases increased from 8.8% to 15%, and the proportion completing treatment increased from 65% to 82%. Of 2270 child TB contacts screened, 55 (2.4%) were diagnosed with TB. Of 910 eligible child contacts, 670 (74%) started preventive therapy, 569 (85%) of whom completed therapy. CONCLUSION: The strengthening of child TB services at peripheral health facilities in Uganda was associated with increased case finding, improved treatment outcomes and the successful implementation of contact screening and management.

Improved Adherence to Antiretroviral Therapy Observed Among HIV-Infected Children Whose Caregivers had Positive Beliefs in Medicine in Sub-Saharan Africa.

A high level of adherence to antiretroviral treatment is essential for optimal clinical outcomes in HIV infection, but measuring adherence is difficult. We investigated whether responses to a questionnaire eliciting caregiver beliefs in medicines were associated with adherence of their child (median age 2.8 years), and whether this in turn was associated with viral suppression. We used the validated beliefs in medicine questionnaire (BMQ) to measure caregiver beliefs, and medication event monitoring system caps to measure adherence. We found significant associations between BMQ scores and adherence, and between adherence and viral suppression. Among children initiating Antiretroviral therapy (ART), we also found significant associations between BMQ 'necessity' scores, and BMQ 'necessity-concerns' scores, and later viral suppression. This suggests that the BMQ may be a valuable tool when used alongside other adherence measures, and that it remains important to keep caregivers well informed about the long-term necessity of their child's ART.

Pharmacokinetics of antiretroviral drug varies with formulation in the target population of children with HIV-1.

The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study in 19 HIV-1-infected Ugandan children (1.8-4 years of age, weight 12 to <15 kg) receiving zidovudine, lamivudine, and abacavir solutions twice a day for ≥24 weeks, the use of scored tablets allowed comparison of plasma pharmacokinetics of oral solutions vs. tablets. Samples were collected 0, 1, 2, 4, 6, 8, and 12 h after each child's last morning dose of oral solution before changing to scored tablets of Combivir (coformulated zidovudine + lamivudine) and abacavir; this was repeated 4 weeks later. Dose-normalized area under curve (AUC)(0-12) and peak concentration (C(max)) for the tablet formulation were bioequivalent with those of the oral solution with respect to zidovudine and abacavir (e.g., dose-normalized geometric mean ratio (dnGMR) (tablet:solution) for zidovudine and abacavir AUC(0-12) were 1.01 (90% confidence interval (CI) 0.87-1.18) and 0.96 (0.83-1.12), respectively). However, lamivudine exposure was ~55% higher with the tablet formulation (AUC(0-12) dnGMR = 1.58 (1.37-1.81), C(max) dnGMR = 1.55 (1.33-1.81)). Although the clinical relevance of this finding is unclear, it highlights the impact of the formulation and the importance of conducting bioequivalence studies in target pediatric populations.

Tuberculosis in human immunodeficiency virus infected Ugandan children starting on antiretroviral therapy.

OBJECTIVE: To identify the incidence of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children in a resource-limited setting before and after initiation of antiretroviral therapy (ART), and to assess the impact of TB screening by tuberculin skin testing and clinical history. METHODS: A retrospective cohort study of 1806 HIV-infected children and adolescents (age <18 years) initiating ART from 2003 to 1 July 2006 in Kampala, Uganda. A TB screening program was instituted clinic-wide in January 2006. RESULTS: Of 311 (17.2%) HIV-infected children, 171 had been diagnosed with TB before and 140 after ART initiation. During the first 100 days of ART, risk of a new TB diagnosis was 2.7-fold higher compared to the pre-ART period (RR 2.7, 95%CI 2.1-3.5, P < 0.001). After 100 days of ART, the TB incidence rate decreased to below pre-ART levels (RR 0.41, 95%CI 0.30-0.54, P = 0.002). After TB screening was instituted in 2006, the proportion of new TB cases diagnosed after starting ART decreased by 70% (95%CI 51-82, P < 0.001), abating the early excess risk. CONCLUSIONS: TB is common among African children and adolescents initiating ART in sub-Saharan Africa. More aggressive screening for active TB before starting ART can diminish the rate of TB during immune reconstitution. Future studies are needed to determine optimal screening practices for HIV-infected children.

Extensive polymorphism in Cryptosporidium parvum identified by multilocus microsatellite analysis.

Restriction fragment length polymorphism and DNA sequence analysis discern two main types of Cryptosporidium parvum. We present a survey of length polymorphism at several microsatellite loci for type 1 and type 2 isolates. A total of 14 microsatellite loci were identified from C. parvum DNA sequences deposited in public databases. All repeats were mono-, di-, and trinucleotide repeats of A, AT, and AAT, reflecting the high AT content of the C. parvum genome. Several of these loci showed significant length polymorphism, with as many as seven alleles identified for a single locus. Differences between alleles ranged from 1 to 27 bp. Karyotype analysis using probes flanking three microsatellites localized each marker to an individual chromosomal band, suggesting that these markers are single copy. In a sample of 19 isolates for which at least three microsatellites were typed, a majority of isolates displayed a unique multilocus fingerprint. Microsatellite analysis of isolates passaged between different host species identified genotypic changes consistent with changes in parasite populations.