Background: Despite encouraging results from clinical trials and in highincome countries, large-scale data on the effectiveness and safety of dolutegravir (DTG) in children and adolescents living with HIV (CALHIV) are lacking in low-and middle-income countries (LMICs). Methods: Retrospective analysis was performed among CALHIV 0-19 years old and weighing greater than or equal to 20 kg who received DTG from 2017 to 2020 at sites in Botswana, Eswatini, Lesotho, Malawi, Tanzania and Uganda to determine effectiveness, safety and predictors of viral load suppression (VLS) among CALHIV using DTG, including through single drug substitutions (SDS). Results: Among 9419 CALHIV using DTG, 7898 had a documented post-DTG VL, and VLS post-DTG was 93.4% (7378/7898). VLS for antiret-roviral therapy (ART) initiations was 92.4% (246/263), and VLS was maintained for the ART-experienced [92.9% (7026/7560) pre-vs. 93.5% (7071/7560) post-DTG; P = 0.14). Among previously unsuppressed, 79.8% (426/534) achieved VLS with DTG. Only 5 patients reported a Grade 3 or 4 adverse event (0.057 per 100 patient-years) requiring DTG discontinuation. History of protease inhibitor-based ART [odds ratio (OR) = 1.53; 95% confidence interval (CI): 1.16-2.03], care in Tanzania (OR = 5.45; 95% CI: 3.41-8.70), and being 15-19 years old (OR = 1.31; 95% CI: 1.03-1.65) were associated with gain of VLS post-DTG. Predictors of VLS on DTG included VLS before DTG (OR = 3.87; 95% CI: 3.03-4.95) and using the once-daily, single tab tenofovir-lamivudine-DTG regimen (OR = 1.78; 95% CI: 1.43-2.22). SDS maintained VLS [95.9% (2032/2120) pre-vs. 95.0% (2014/2120) post-SDS with DTG; P = 0.19], and 83.0% (73/88) of unsuppressed gained VLS using SDS with DTG. Conclusions: We found DTG to be highly effective and safe within our cohort of CALHIV in LMICs. These findings can empower clinicians to prescribe DTG confidently to eligible CALHIV.

Background: Although achievements have been made globally since the UNAIDS 90-90-90 targets were announced, paediatric data remain sparse. We describe achievements toward antiretroviral therapy (ART) uptake and viral load (VL) suppression, existing gaps, and potential best practices among children and adolescents living with HIV (CALHIV) across 6 Eastern and Southern African countries.

Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.

Background. Children living with HIV (CLWH) are at high risk of colonization and infection by bacterial respiratory pathogens. Microbes in the upper respiratory microbiome can prevent colonization by these pathogens. The impact of HIV infection on development of the upper respiratory microbiome during childhood is poorly understood. Methods. We enrolled healthy CLWH (<5 years) and age- and sex-matched HIV-exposed, uninfected (HEU) and HIV-unexposed, uninfected (HUU) children in a cross-sectional study conducted in Botswana. We used shotgun metagenomic sequencing to compare the nasopharyngeal microbiomes of children by HIV status. Findings. Of 143 children, 44 were CLWH, 49 were HEU, and 50 were HUU. Nasopharyngeal microbiome composition differed by HIV status (p=0.043, R2=0.019). The relative abundance of Corynebacterium pseudodiphtheriticum was lower in CLWH compared to HEU and HUU children (p=0.01). Among CLWH, a low (<25%) CD4+ cell percentage was associated with microbiome composition (p=0.009, R2=0.042) and lower relative abundances of Corynebacterium propinquum (p=0.003), C. pseudodiphtheriticum (p=0.007), and Dolosigranulum pigrum (p=0.004). The relative abundances of C. propinquum, C. pseudodiphtheriticum and D. pigrum in the nasopharyngeal microbiome were negatively correlated with the abundances of Streptococcus pneumoniae and Staphylococcus aureus. Interpretation. CLWH with HIV-associated immunosuppression have altered nasopharyngeal microbiome composition and lower abundances of bacterial species associated with respiratory health during childhood. These findings suggest that the upper respiratory microbiome may contribute to the high risk of bacterial respiratory infections among CLWH. Funding. National Institutes of Health, Duke Center for AIDS Research, Penn Center for AIDS Research.

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