Associations of FGF21 and GDF15 with mitochondrial dysfunction in children living with perinatally-acquired HIV: A cross-sectional evaluation of pediatric AIDS clinical trials group 219/219C

Background In persons living with HIV, mitochondrial disease (MD) is difficult to diagnose, as clinical signs are non-specific with inconsistent patterns. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are mitokines elevated in MD patients without HIV, and associated with cardiometabolic comorbidities in adults living with HIV. We assessed relationships of these biomarkers with MD in children living with perinatally-acquired HIV infection (CPHIV). Setting Cross-sectional study of CPHIV from Pediatric ACTG 219/219C classified by Mitochondrial Disease Criteria (MDC) that defines scores 2–4 as “possible” MD. Methods Each case with MDC equaling 4 (MDC4; n = 23) was matched to one randomly selected control displaying no MDC (MDC0; n = 23) based on calendar date. Unmatched cases with MDC equaling 3 (MDC3; n = 71) were also assessed. Plasma samples proximal to diagnoses were assayed by ELISA. Mitokine distributions were compared using Wilcoxon tests, Spearman correlations were calculated, and associations with MD status were assessed by conditional logistic regression. Results Median FGF21 and GDF15 concentrations, respectively, were highest in MDC4 (143.9 and 1441.1 pg/mL), then MDC3 (104.0 and 726.5 pg/mL), and lowest in controls (89.4 and 484.7 pg/mL). Distributions of FGF21 (paired Wilcoxon rank sum p = 0.002) and GDF15 (paired Wilcoxon rank sum p<0.001) differed in MDC4 vs MDC0. Mitokine concentrations were correlated across all participants (r = 0.33; p<0.001). Unadjusted odds ratios of being MDC4 vs MDC0 were 5.2 [95% confidence interval (CI): 1.06–25.92] for FGF21 and 3.5 (95%CI: 1.19–10.25) for GDF15. Relationships persisted after covariate adjustments. Conclusion FGF21 and GDF15 levels may be useful biomarkers to screen for CPHIV with mitochondrial dysfunction.

Physical development and mental health in South African perinatally HIV-positive adolescents on antiretroviral therapy and their caregivers with and without household food insecurity

Background: Perinatally acquired HIV-infected (PHIV+) adolescents have shown impairments in neurocognitive function and mental health problems compared with their peers. The contribution of food insecurity to such impairments has not been explored.Objectives: The aim of this report has been to explore the contribution of food insecurity to neurocognitive impairment and mental health problems in adolescents with perinatally-acquired HIV infection.Method: A total of 248 PHIV+ adolescents and healthy controls aged between 9 and 12 years completed a neuropsychological battery, the Childhood Behaviour Checklist (CBCL) and the Becks Youth Inventory. Head circumference, body mass index (BMI), height for age (HAZ), Tanner pubertal staging, albumin, haemoglobin, CD4 and viral loads were also measured. Participants’ caregivers were interviewed about their mental health and household food security. T-tests were used to assess for differences in food secure and food insecure households.Results: Caregivers of PHIV+ adolescents reported higher levels of depressive symptoms and household food insecurity. Increased food insecurity was associated with more behavioural problems in adolescents, as well as lower haemoglobin and albumin levels, faster processing speed and increased Tanner staging in boys. Body mass index and HAZ were not affected by food insecurity.Conclusion: These findings suggest that household food insecurity is associated with some altered behavioural, physical and physiological outcomes, which could complicate and compound the existing difficulties in PHIV+ households.

Interactive Transition Support for Adolescents Living with HIV using Social Media (InTSHA): Research Protocol (Preprint)

BACKGROUND Adolescents living with perinatally-acquired HIV often have poor retention in care and viral suppression during the transition from pediatric to adult based care. OBJECTIVE To evaluate a mobile phone-based intervention, InTSHA: Interactive Transition Support for Adolescents Living with HIV using Social Media, among adolescents living with perinatally-acquired HIV as they transition from pediatric to adult care in South Africa. METHODS InTSHA uses encrypted, closed group chats delivered via WhatsApp to develop peer support and improve communication between adolescents, their caregivers, and healthcare providers. The intervention is based on formative work with adolescents, caregivers, and healthcare providers and builds on several existing adolescent support programs as well as the Socioecological Model for Adolescent and Young Adult Readiness to Transition (SMART). The final InTSHA intervention involves ten modules conducted weekly through moderated WhatsApp group chats with adolescents and separately with their caregivers. We will randomize 80 South African adolescents living with perinatally-acquired HIV who are aware of their HIV status and aged between 15 to 19 years to receive either the intervention (n=40) or standard of care (n=40). RESULTS We will measure acceptability of the intervention as primary outcome and evaluate feasibility and preliminary effectiveness for retention in care and viral suppression after completion of the intervention and at least six months after randomization. In addition, we will measure secondary outcomes evaluating the impact of the InTSHA intervention on peer support, self-esteem, depression, stigma, sexual education, connection to healthcare providers and transition readiness. CONCLUSIONS If successful, the intervention will be evaluated in a fully powered randomized controlled trial with a larger number of adolescents from urban and rural populations to further evaluate the generalizability of InTSHA. CLINICALTRIAL ClinicalTrials.gov Identifier: NCT03624413

Determinants of precocious B-cell aging in European adolescences living with perinatally acquired HIV-1 after over 10 years of suppressive therapy

HIV infection results in a state of chronic immune activation leading to premature immune aging, B-cells dysfunction, that persists despite prolonged virological suppression. In this scenario, adolescence living with perinatally acquired HIV (PHIV), deserve a peculiar attention since potentially exposed for their entire life to chronic immune activation. Here we identified determinants of precocious aging B cells in 40 PHIV undergoing suppressive antiretroviral therapy (ART) for median 13.5 years. All individuals started ART by 2 nd year of life and achieved virus suppression within the 1 st year of ART, with majority of patient maintaining suppression until analysis and 5/40 experiencing viral Spike (transient elevation of HIV-1 VL, 50-999 copies/ml). We employed a multi-omics approach including deep immunological B and T cell phenotype in PBMC, with aging B cells defined by the expression of T-bet and CD11c; plasma proteomics analysis by mass spectrometry and serum level of anti-measles antibodies as correlates of humoral response. We found that individuals with expansion of aging B cell, defined by the expression of T-bet+CD11c+, were those starting treatment later, presenting detectable levels of cell-associated HIV-1 RNA, history of Spikes, and a higher frequency of exhausted T-cells, including those expressing PD-1, LAG3, TIGIT. Accordingly, the proteomic analysis revealed that subjects with expansion of aging B cells and exhausted T cells had enrichment of proteins involved in immune inflammation and complement activation pathways, such as CLU and APCS which are also involved in tumor progression. Signs of precocious aging were associated with a reduced capacity to maintain virological memory against measles vaccination. To our knowledge, this is the first study focusing on precocious B-cell aging and dysfunctionality in PHIV with long-term virological suppression. Our experimental strategy enabled identification of clinical, viral, cellular and plasma soluble markers associated with B-cells aging. Our results pave the way to further define risk of disease progression or lymphoproliferative disorders in PHIV.

Earlier antiretroviral initiation is independently associated with better arterial stiffness in children living with perinatally acquired HIV with sustained viral suppression in Mozambique

Background: Cardiovascular disease is a major driver of morbidity and mortality in adults living with HIV. The drivers of cardiovascular disease in children living with perinatally acquired HIV (PHIV) with sustained HIV viral suppression are unclear.Objectives: We explored the contribution of HIV-specific risk factors to arterial stiffness independently of traditional risk factors (metabolic syndrome [MetS]) in prepubertal children with PHIV with sustained viral suppression in a low-income country in Africa.Method: For this cross-sectional analysis, arterial stiffness was assessed by pulse wave velocity z-score (PWVz), measured using a Vicorder device. Metabolic syndrome components were measured. We retrospectively collected the antiretroviral therapy (ART) exposures, HIV stage, CD4 count and HIV viral load. A multivariate linear regression model was constructed for MetS components, retaining age and gender as obligatory variables. We then added HIV-related metrics to assess whether these had an independent or additive effect.Results: We studied 77 virally suppressed children with PHIV without evidence of cardiovascular disease (from medical history and physical examination). In the initial model, the PWVz was independently associated with each MetS component. The PWVz was higher in participants with proportionally greater visceral fat (waist/height ratio), elevated lipids (triglyceride/high-density lipoprotein ratio) and insulin resistance (log homeostatic model assessment [HOMA]). The addition of age at ART initiation increased the model R2 value from 0.36 to 0.43. In the resulting model, younger age at ART initiation was independently associated with a better PWVz (P 0.001).Conclusion: Earlier ART initiation was independently associated with lower large artery stiffness. This effect was independent of the effect of elevated lipids, visceral fat and insulin resistance.