Priority Activities in Child and Adolescent Tuberculosis to Close the Policy-Practice Gap in Low- and Middle-Income Countries.

Over the past 15 years, and despite many difficulties, significant progress has been made to advance child and adolescent tuberculosis (TB) care. Despite increasing availability of safe and effective treatment and prevention options, TB remains a global health priority as a major cause of child and adolescent morbidity and mortality-over one and a half million children and adolescents develop TB each year. A history of the global public health perspective on child and adolescent TB is followed by 12 narratives detailing challenges and progress in 19 TB endemic low and middle-income countries. Overarching challenges include: under-detection and under-reporting of child and adolescent TB; poor implementation and reporting of contact investigation and TB preventive treatment services; the need for health systems strengthening to deliver effective, decentralized services; and lack of integration between TB programs and child health services. The COVID-19 pandemic has had a significant negative impact on case detection and treatment outcomes. Child and adolescent TB working groups can address country-specific challenges to close the policy-practice gaps by developing and supporting decentral ized models of care, strengthening clinical and laboratory diagnosis, including of multidrug-resistant TB, providing recommended options for treatment of disease and infection, and forging strong collaborations across relevant health sectors.

Programmatic Implementation of Contact Investigation in Eight African Countries.

The objective was to implement CI under national tuberculosis programmatic conditions and to advocate for its scaling up. Contact investigation was implemented in 150 Basic Management Units identified across eight countries. The target populations (children <5 years and persons living with HIV (PLHIV)) were evaluated during home and clinic visits using standardized tools, clinical examinations and, according to each country, additional tests. Contacts with active TB received TB treatment and those eligible received TB preventive therapy (TPT). Data were collected each quarter using standardized forms. Meetings were organized with partners to share preliminary results and advocate for scaling up. From October 2020 to December 2021, 9049 home visits were performed. The proportions of children <5 years and PLHIV who were screened and diagnosed with active TB were, respectively, 2.6% and 10.1%. Ninety-three percent of children <5 years and 98% of PLHIV living at home received TPT or TB treatment, respectively. The scale-up for contact investigation partially or at national level in 2022 was effective in six of the eight countries included in the project. These results indicate that CI is feasible under programmatic conditions within the National TB Programs of African countries.

High levels of virological failure with major genotypic resistance mutations in HIV-1-infected children after 5 years of care according to WHO-recommended 1st-line and 2nd-line antiretroviral regimens in the Central African Republic: A cross-sectional study.

A large cohort of 220 HIV-1-infected children (median [range] age: 12 [4-17] years) was cared and followed up in the Central African Republic, including 198 in 1st-line and 22 in 2nd-line antiretroviral regimens. Patients were monitored clinically and biologically for HIV-1 RNA load and drug resistance mutations (DRMs) genotyping. A total of 87 (40%) study children were virological responders and 133 (60%) nonresponders. In children with detectable viral load, the majority (129; 97%) represented a virological failure. In children receiving 1st-line regimens in virological failure for whom genotypic resistance test was available, 45% displayed viruses harboring at least 1 DRM to NNRTI or NRTI, and 26% showed at least 1 major DRM to NNRTI or NRTI; more than half of children in 1st-line regimens were resistant to 1st-generation NNRTI and 24% of the children in 1st-line regimens had a major DRMs to PI. Virological failure and selection of DRMs were both associated with poor adherence. These observations demonstrate high rate of virological failure after 3 to 5 years of 1st-line or 2nd-line antiretroviral treatment, which is generally associated with DRMs and therapeutic failure. Overall, more than half (55%) of children receiving 1st-line antiretroviral treatment for a median of 3.4 years showed virological failure and antiretroviral-resistance and thus eligible to 2nd-line treatment. Furthermore, two-third (64%) of children under 2nd-line therapy were eligible to 3rd-line regimen. Taken together, these observations point the necessity to monitor antiretroviral-treated children by plasma HIV-1 RNA load to diagnose as early as possible the therapeutic failure and operate switch to a new therapeutic line.

Virological response and resistance profiles after 18 to 30 months of first- or second-/third-line antiretroviral treatment: a cross-sectional evaluation in HIV type 1-infected children living in the Central African Republic.

A total of 242 HIV-1-infected children were followed up at the Complexe Pédiatrique of Bangui, Central African Republic, including 165 receiving antiretroviral treatment in first- (n=150) or second-/third-line (n=15) regimens. They were prospectively included in a study, in 2009, to assess their virological status and prevalence of antiretroviral drug-resistance mutations in cases of virological failure, according to revised 2010 WHO criteria (e.g., HIV-1 RNA >3.7 log(10) copies/ml). Detectable plasma HIV-1 RNA was observed in 53% of children under first-line treatment, and virological failure was diagnosed in 40%, which was associated in 85% of cases with viruses harboring at least one drug-resistance mutation to nucleoside reverse transcriptase inhibitors (NRTI) or nonnucleoside reverse transcriptase inhibitors (NNRTI), and in 36% of cases with at least one major drug-resistance mutation to NRTI or NNRTI when excluding the M184V mutation. Overall, the proportion of children receiving a first-line regimen for a median of 18 months with virological failure associated with drug-resistance mutations, and thus eligible for a second-line treatment, was estimated at 34% of the whole cohort. In children under second-/third-line therapy, virological failure occurred in 47%, plus at least one major drug-resistance mutation to NRTI or NNRTI, though less commonly to protease inhibitors. Taken together, these findings argue in favor of the urgent need to improve distribution of pediatric antiretroviral drugs in the Central African Republic, to increase adherence by treated children, and to offer adequate HIV biological monitoring.

Surveillance of antiretroviral drug resistance mutations in untreated young children living in the Central African Republic.

BACKGROUND: A survey of drug resistance-associated mutations (DRMs) was conducted in 2009 among 77 vertically HIV-infected children not treated by antiretroviral drugs, followed up at the Complexe Pédiatrique of Bangui, (Bangui, Central African Republic), a country where HIV mother-to-child transmission is prevented by the wide use of single-dose nevirapine in delivering mother and neonate. METHODS: Protease and reverse transcriptase sequencing was performed using the ViroSeq HIV-1 genotyping system, and DRMs were identified according to the 2009 update surveillance of transmitted HIV-1 drug resistance. RESULTS: DRMs were detected in 6 out of 43 samples with interpretable genotypic resistance tests, leading to a 'moderate' DRM prevalence of 13.9% (95% CI 3.5-24.3). DRM to non-nucleoside reverse transcriptase inhibitors were found in 5 samples (11.6% [95% CI, 2.0-21.2]) involving K103N, Y181C and G190A mutations. DRMs to nucleoside reverse transcriptase inhibitors was found in 1 sample (2.3% [95% CI 0.0-6.8]), with the K219Q mutation. No DRMs to protease inhibitors was detected. CONCLUSIONS: This survey predicts a moderate (between 5% and 15%) prevalence of DRMs in the Central African HIV-infected paediatric population of Bangui. These observations highlight the need to make an early diagnosis of the possibility of virological failure in Central African children receiving their first-line antiretroviral regimen.

Usefulness of a genotypic resistance test using dried blood spot specimens in African HIV-infected children with virological failure according to the 2010-revised WHO criteria.

We compared paired plasma and dried blood spot (DBS) samples from 54 HIV-1-treated children living in Bangui, Central African Republic, for antiretroviral-resistance-associated mutations. All children displayed virological failure (HIV-1 RNA >3.70 log(10)copies/ml). Testing for resistance genotype was carried out in a reference laboratory in Paris, France. A successful test result was obtained in 54 (100%) plasmas and 25 DBSs (46%). Among the 732 resistance-associated mutations analyzed, 718 were identical, leading to a high concordance rate of 98.1%. Genotypic resistance tests on DBS samples were found to be highly feasible and accurate in a foreign reference laboratory, but with additional costs for shipping and decreased sensitivity.

First data on HIV-1 resistance mutations to antiretroviral drugs in Central African Republic.

In a background of high genomic HIV-1 variability with a predominance of CRF11_cpx and CRF22_01A1, we have studied the emergence of resistance mutations in isolates from Central African patients at failure of d4T-AZT/3TC/NVP-EFV plus two at failure of a PI-including regimen; the resistance mutations observed are those which are expected on HIV-1 subtype B.