Chronic morbidities in perinatally HIV-acquired adolescents on antiretroviral therapy

Doctoral Thesis


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of children perinatally infected with HIV, with an increasing number surviving into adolescence, accompanied by the development of chronic comorbidities. However, there is limited knowledge on the spectrum of comorbidities, determinants, and risk factors among youth living with perinatally acquired HIV (YLPHIV) especially in sub-Saharan Africa, with most data from high-income countries. There is a critical need for data on health and chronic comorbidities among YLPHIV from countries with a high HIV prevalence. Aim: To investigate the spectrum and determinants of HIV-associated comorbidities among YLPHIV on ART in Cape Town, South Africa. Specific objectives were to investigate cardiovascular, musculoskeletal, mental health and metabolic outcomes in YLPHIV compared to HIV-uninfected adolescents. Method: In a prospective study YLPHIV on ART were enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC) from seven health-care sites in Cape Town, South Africa, between July 2013 – April 2015. Eligibility criteria were adolescents, 9-14 years old, with perinatally acquired HIV, been on ART for at least six months, and who were aware of their HIV status. A control group of HIVuninfected adolescents' frequency-matched by age and sex was also enrolled. The cohort was longitudinally followed for development or progression of comorbidities with clinical and laboratory measurements. Comorbidities assessed included: (1) cardiovascular health: echocardiography was used to investigate cardiac structure and endothelial peripheral arterial tonometry technique (EndoPAT) was used for endothelial function. The pathobiological determinants of atherosclerosis in youth (PDAY) risk score was used to assess long-term cardiovascular risk for atherosclerotic disease at the coronary artery (CA) and abdominal aorta (AA). A PDAY score ≥1 was regarded as elevated; (2) bone health: quantitative ultrasound was used to evaluate calcaneal stiffness index (SI); (3) mental health: the Child Behavior Checklist (CBCL) and BECK youth inventories were utilised. The association of mental health with metabolic abnormalities was investigated. Statistical analyses included descriptive data and regression modelling analysis, using the software, Stata® 14.2 to 16 (Stata Corp LP. College Station, Texas, USA). Results: Overall, 515 YLPHIV and 110 HIV-uninfected participants with median age 12.0 years (IQR 11.9, 10.7) and 11.8 years (IQR 11.7, 10.0) were enrolled; YLPHIV with median duration of ART of 7.6 years (IQR: 4.6–9.2), also had a median CD4 cell count of 713 cells/mm3 (IQR: 561.0–957.5), and 387 (75%) had a viral load (VL) of 500 cell/mm3 (RR 1.04, p=0.76), VL (RR 1.01, p=0.78) or current ART class (protease inhibitor-based vs non-nucleoside inhibitor-based, RR 0.90, p=0.186) were not associated with ED after adjustment. At 48 months of follow-up, among YLPHIV, 8% (n=17) had sustained viraemia, and 54% (n=118) had transient viraemia through this period. The median duration on ART was 12 years (IQR 8-14); 57% (n=124) were on a non-nucleoside reverse transcriptase inhibitor-based ART, while the rest received protease inhibitor-based ART. Few YLPHIV met the criteria for hypertension (2%, n=4) or hyperglycaemia (0.5%, n=1). None of the HIV-uninfected youth had hypertension or hyperglycaemia. Fewer YLPHIV smoked compared to the uninfected youth (15.6% vs 11.5%, p=0.50. Elevated PDAY scores for CA (30.3% [n=66] vs 31.3% [n=10], p=0.74) and AA (18.4% [n=40] vs 21.9% [n=7], p=0.20), respectively among YLPHIV and HIV-uninfected adolescents differed slightly but did not reach statistical significance. Among YLPHIV, sustained viraemia [adjusted odds ratio (aOR)=18.4, p50 copies/ml (OR=2.06, p=0.023) were associated with an increased risk of low SI, while the use of efavirenz (OR=0.41, p=0.009) was associated with a decreased risk of low SI. YLPHIV had more impairment in mental health in several domains: functional competence (40% vs 25%, p=0.02), self-concept (23% vs 9%, p=0.03), higher depression (6% vs 2%, p< 0.01), anger (6% vs 2%, p=0.04), and disruptive behaviour (4% vs 0%, p p<0.01). Among YLPHIV, higher levels of anger were associated with increased total cholesterol and low-density lipoprotein (LDL) levels (ß=0.010, p=0.041 and ß=0.012, p=0.048, respectively), higher disruptive behaviour with increased LDL levels (ß=0.010, p=0.043), and severer CBCL-internalizing problems with low albumin levels (ß=-0.067, p=0.052) after adjusting for age, sex, and BMI z-score. Conclusion: YLPHIV are at higher risk of having subclinical cardiac structural abnormality and ED compared to uninfected adolescents. Both groups had a substantial proportion with high PDAY scores reflecting increased aggregate atherosclerotic risk. Bone health was worse among YLPHIV. HIV-related factors such as ART initiation at an older age, advanced clinical disease, and specific ARTs were significant risk factors for these conditions. Mental health impairment was common and associated with increased lipid concentration in YLPHIV. These data highlight a high prevalence of chronic comorbidities in YLPHIV, specific risk factors associated with these and provide information for strengthened strategies to prevent or monitor HIV-associated illnesses.