The role of nutrition as a determinant of clinical, immunological and pharmacological outcome in HIV-infected children in Uganda
Citation:
ORIKIIRIZA, JUDY TATWANGIRE, The role of nutrition as a determinant of clinical, immunological and pharmacological outcome in HIV-infected children in Uganda, Trinity College Dublin.School of Medicine, 2019Download Item:
Abstract:
Introduction: Perinatally acquired HIV infection and malnutrition remain major public health challenges for sub-Saharan Africa health systems. HIV and malnutrition result in 50% mortality. The introduction of antiretroviral therapy (ART) and ready to use therapeutic food (RUTF) have significantly reduced the morbidity and mortality rates, however, clinical, nutritional, immunological and pharmacological responses to treatment remains understudied.
Objectives: The studies included in this thesis were designed to document the effects of nutritional status and nutritional supplementation using RUTF. This was achieved by: 1) describing the clinical cohorts of HIV infected Ugandan children; 2) determining the nutritional status and outcomes including anthropometry, nutrition biomarkers and dietary analysis; 3) determining lymphocyte phenotypes and how they are affected by HIV, malnutrition, RUTF and ART, and in immunological and virological responders and non-responders; 4) determining pharmacological responses, specifically efavirenz (EFV) and nevirapine (NVP) drug levels, virological failure and 5) the knowledge, perceptions of the primary carers on use of ART and RUTF in their children.
Methods: This was a prospective cohort study involving a population of HIV infected children who were ART-experienced (ART-E) or ART-na?ve (ART-N) initiating ART and primary carers. It was a multi-center study involving pediatric HIV health facilities in the central region of Uganda. Study participants were followed-up for 12 weeks while on RUTF for those who were malnourished. HIV negative healthy controls were enrolled and sampled once for immunological comparisons. We aimed to examine the role of nutrition and nutritional supplementation on clinical, immunological and pharmacological outcomes in HIV infected children aged between 6 months and 12 years. At each visit, children had a complete clinical and anthropometric assessment. Biological samples were taken to measure markers indicative of nutritional, immunological and pharmacological responses at baseline and 12 weeks. Primary carers were interviewed using focus group discussions and key informant guide to explore processes that influence adherence and uptake of RUTF and ART in children in routine HIV care. This study was approved by the relevant ethical boards.
Results: A total of 278 HIV infected children were screened, of whom 156 fulfilled the study criteria, between January 2015 and December 2017. These included 66 ART-N and 90 ART-E HIV infected children. The age range of enrolled children was 9 months to 12 years and majority were between 5-12 years and this age category had the highest malnutrition burden. Overall, 41 of 66 (62.1%) ART-N children were moderately acutely malnourished (MAM) or severely acutely malnourished (SAM) and 48.9% of the ART-E children were MAM or SAM. The median length of time on ART at baseline for the ART-E children was 42 months (IQR: 15-66 months). The majority (85.5%) of the ART-N children had severe immunological suppression prior to ART initiation, with median CD4+ T cell percentage <30% and an absolute counts less than 1000 cells/ml and a median viral load of 240,753 viral copies/mL (IQR: 45,752-1,286,388). The majority of ART-E patients (54.1%) at baseline had a median CD4+ T cell percentage >30% and absolute cell counts less than 1000 cells/ml and a median viral load of 114 viral copies/mL. Virologic failure occurred in 80% of SAM, 58.5% of well-nourished (WN) and 50% of MAM patients. After 12 weeks virologic failure occurred in 54.6% of SAM, 26.7% of WN and 20.7% of MAM patients. The mortality rate was 5/156 (3.2%) in the 1st month of recruitment.
Anthropometrically, the HIV infected children added 2.3 kg, (P<0.0001) and the mid-upper-arm circumference (MUAC) of 1 cm (P<0.0001) by 12 weeks. The malnourished children added 2.5 kg, (P<0.0001) and 1.3 cm MUAC, (P<0.0001) after RUTF supplementation while WN children added 2 kg, (P=0.002) and 0.3 cm MUAC with no RUTF. Good adherence was reported in 24/50 (48%), moderate adherence in 1/50 (2%) while 26/50 (52%) were poorly adherent to RUTF. Overall there was high macronutrient consumption, however the malnourished children had reduced nutrient intake. ART impacted more significantly on lipid profile than did nutritional supplementation. Serum lipid levels (total cholesterol, high density lipoprotein and low density lipoprotein) were all low among ART-N compared to ART-E children at baseline (P<0.0001, P<0.0001 and P=0.0011 respectively). Inflammatory markers were higher in the WN children compared with the malnourished children. After 12 weeks follow up, they drastically decreased in the malnourished children but did not attain the expected normal levels.
Compared to HIV-negative children, ART-N children had significantly lower frequencies of circulating CD4+ T cells, natural killer (NK) cells, CD56+ T cells (natural T or NT cells), invariant natural killer T (iNK T) cells and higher frequencies of CD8+ T cells, CD4-CD8- (double negative or DN) T cells. The Vδ1 subset of γδ T cells was expanded in children with HIV whereas Vδ2 and Vδ3 subsets were unchanged. When ART-N children were compared according to nutritional status, Vδ1 T cells were expanded and NT cells were depleted in the SAM patients. At baseline, malnourished and WN ART-E patients had higher frequencies and numbers of CD4+ T cells compared to ART-N patients and lower frequencies and numbers of DN and Vδ1 T cells. Supplementation of malnourished ART-E children with RUTF for 12 weeks resulted in expansions of NK cells, DN T cells and Vδ2 T cells, but not CD4+ T cells, and depletions of CD8+ T cells but many of these changes were also seen in WN patients who were not given RUTF. Vδ1 T cell numbers were significantly higher in immunological and virological non-responders to ART, whereas Vδ2 T cell numbers were lower in the immunological responders and higher in the virological non-responders.
Children with sub-therapeutic and supra-therapeutic levels of plasma EFV and NVP were more common than those who had therapeutic levels at baseline and 12 weeks. However, 81/84 (96.4%) had a self-reported adherence score to ART.
Most of the primary carers expressed limited knowledge on nutritional rehabilitation using RUTF. The presence of malnutrition in the family and utilisation of RUTF in the community was associated with being HIV positive and carried stigma, hindering pursuit of nutritional support. On the contrary, carers attributed the challenge of food insecurity to poor adherence to ART.
Conclusion: There is high unmet need for effective and timely initiation of ART in pediatric programs, as children continue to access care late, often with AIDS defining illness, and with high rates of loss-to-follow once in care. Immune reconstitution was marginal with high virologic failure and high incidence of suboptimal and undetectable drug levels despite reported high ART adherence. Prompt therapeutic drug monitoring and ART switching to potentiate benefits of ART in pediatric HIV programs needs to be prioritized irrespective of nutritional status. Though ART leads to sustained expansion of CD4+ T cells in both malnourished and WN children with HIV infection, it may cause depletions of other cells and complete immune recovery is not achieved. ART may have adverse effects on innate T cell populations and NK cells. Since Vδ1 T and NK cells are expanded in HIV infection especially in those with SAM and Vδ1 T cells are reduced among immunological and virological responders. Immunotherapies using innate T cells and NK cells may potentiate ART effect to attain complete immune recovery, however further studies are urgently needed with the high level of incomplete immune reconstitution in the era of ART in the Pediatric HIV programs with high co-infection burden.
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Higher Education Authority (HEA)
Early career Thrasher Award
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:ORIKIIRJDescription:
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Author: ORIKIIRIZA, JUDY TATWANGIRE
Advisor:
Doherty, DerekMartina, Hennessy
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PhDPublisher:
Trinity College Dublin. School of Medicine. Discipline of ImmunologyType of material:
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