OBJECTIVES:We utilize a large retrospective study cohort derived from electronic medical records to estimate the prevalence of long-term non-progression (LTNP) and determine the factors associated with progression among children infected with HIV in Botswana and Uganda.METHODS:Electronic medical records from large tertiary HIV clinical centers in Botswana and Uganda were queried to identify LTNP children 0-18 years enrolled between June 2003 and May 2014 and extract demographic and nutritional parameters. Multivariate subdistribution hazard analyses were used to examine demographic factors and nutritional status in progression in the pre-antiretroviral therapy era.RESULTS:Between the two countries, 14,246 antiretroviral therapy-naïve children infected with HIV were enrolled into clinical care. The overall proportion of LTNP was 6.3% (9.5% in Botswana vs 5.9% in Uganda). The median progression-free survival for the cohort was 6.3 years, although this was lower in Botswana than in Uganda (6.6 vs 8.8 years; P <0.001). At baseline, the adjusted subdistribution hazard ratio (aHRsd) of progression was increased among underweight children (aHRsd 1.42; 95% confidence interval [CI]: 1.32-1.53), enrolled after 2010 (aHRsd 1.32; 95% CI 1.22-1.42), and those from Botswana (aHRsd 2; 95% CI 1.91-2.10).CONCLUSIONS:In our study, the prevalence of pediatric LTNP was lower than that observed among adult populations, but progression-free survival was higher than expected. Underweight, year of enrollment into care, and country of origin are independent predictors of progression among children.

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.

In this study we determine the class I HLA alleles associated with HIV disease progression in Botswana and Uganda. From a cohort of about 12,000 children enrolled into pediatric HIV care centers in Uganda and Botswana since 2003, 1,000 participants were retrospectively recruited using the electronic medical records. They were stratified equally into two groups of rapid progression and LTNP according to the WHO classification of HIV disease progression. Class I HLA typing was done using HLAreporter that derives high-resolution allelotypes from whole exome sequence (WES) data. Of the 1,000, 850 participants had WES successfully done and class I HLA allele data was correctly typed for 800 participants. After adjusting for gender and country of origin, we identified HLA-B*57:03 (OR 3.21 95%CI 1.50-6.85, p=0.030) and C*03:02 (OR 4.49 95%CI 1.64-12.23, p=0.049) alleles that are associated with LTNP in children in Uganda and Botswana. In addition, we confirm earlier observations that HLA-B*15:10 (OR 0.46 95%CI 0.31-0.79, p=0.030) is associated with rapid HIV progression as seen in Caucasian populations. Consistent with previous studies, we identified a major role of HLA-B in HIV disease progression, as well as an unreported, uncommon HLA-C allele associated with HIV restriction in African pediatric populations.

Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana-a Southern African country that is regionally underrepresented in genomic databases. Using whole-exome sequencing data from 164 Batswana and comparisons with 150 similarly sequenced HIV-positive Ugandan children, we found that 13%-25% of variation observed among Batswana was not captured by public databases. Uncaptured variants were significantly enriched (p = 2.2 × 10-16) for coding variants with minor allele frequencies between 1% and 5% and included predicted-damaging non-synonymous variants. Among variants found in public databases, corresponding allele frequencies varied widely, with Botswana having significantly higher allele frequencies among rare (<1%) pathogenic and damaging variants. Batswana clustered with other Southern African populations, but distinctly from 1000 Genomes African populations, and had limited evidence for admixture with extra-continental ancestries. We also observed a surprising lack of genetic substructure in Botswana, despite multiple tribal ethnicities and language groups, alongside a higher degree of relatedness than purported founder populations from the 1000 Genomes project. Our observations reveal a complex, but distinct, ancestral history and genomic architecture among Batswana and suggest that disease mapping within similar Southern African populations will require a deeper repository of genetic variation and allelic dependencies than presently exists.

The aim of this study was to assess the level of availability of HIV prevention strategies in secondary schools in Kabarole district, Uganda in order to inform the design of interventions to strengthen HIV Prevention and psychosocial support. Quantitative and qualitative research methods were used in eight secondary schools in Kabarole district to establish available HIV prevention and psychosocial support services. Questionnaires were administered to 355 students 12-24 years old. In addition, 20 Key Informant interviews were held with education service providers. Quantitative data was analyzed using Epi-data and qualitative data were analyzed by thematic content analysis. Seven of the eight schools had at least one HIV prevention strategy. Two teachers in each of the five schools had been trained in HIV prevention. No school had a nurse trained in HIV prevention, care and support. Education service providers had limited knowledge of HIV prevention support and care of students living with HIV. We found out that students had knowledge on how one can acquire HIV. HIV prevention services reported by students in schools included: talks from teachers and guests (19%), drama with HIV prevention related messages (16%), peer education clubs (15%), workshops and seminars on HIV (8%), sensitization about HIV/AIDS (7%), guidance and counseling (6%), talking compounds- (5%), abstinence talks (6%), keeping students busy in sports (4%), straight talk (4%). Sixty three percent reported receiving HIV reading materials from various sources. Preventing HIV infection among students in schools is still demanding with limited interventions for students. Efforts to support school interventions should focus on including HIV Prevention in the school curriculum, working with peer educators as well as education service providers who spend much of the time with the students while at school.