The Impact of HIV and Antiretroviral Therapy on the Cardiovascular System of HIV-infected Children

Background Cardiovascular disease is increased in HIV-infected adults but the underlying aetiology is incompletely understood. Pre-clinical changes in cardiovascular structure and arterial stiffness in HIV-infected children are described in mainly middle to high-income countries with minimal longitudinal data available. Limited cross-sectional data is available from Africa in settings where 90% of HIV-infected children live. Methods ART-naive and ART-experienced (on d4T+3TC+NNRTI for >2years, virologically suppressed at enrolment) HIV-infected children underwent serial assessment within the CHAPAS-3 trial (evaluating d4T vs ZDV vs ABC-based first line ART in Zambia/Uganda): extensive cardiovascular assessment of structure (carotid intimal medial thickness [cIMT] and arterial stiffness (pulse wave velocity [PWV]). Additionally markers of inflammation, disordered thrombogenesis, vascular damage and immune activation were measured. Age-matched HIV-uninfected controls had a single assessment. Baseline differences between ART-naive/experienced children vs controls, and longitudinal changes in HIV-infected children were assessed. Results In 208 ART-naive children with median age 2.9y (IQR 1.7–4.4), median CD4% 18% (11-23) and 209 HIV-uninfected controls median age 3.0y (2.1–4.1), mean(sd) cIMT was 0.46(0.04) v 0.44(0.04) mm respectively (p<0.001); PWV was 5.85(0.8) vs 5.67(0.74)m/sec respectively (p=0.05). Among 74 ART-experienced children on ART for a mean of 3.7y with a median age of 6.9y (5.9–8.50), median CD4% 33% (27-39) and 75 uninfected controls with median age 6.7y (5.6-8.6), the mean(sd) cIMT was 0.46(0.05) vs 0.45(0.04)mm respectively (p=0.09); PWV was 5.63(0.61) vs 5.69(0.68)m/s respectively (p=0.57). In ART naive children IMT and PWV significantly decreased from baseline (ART initiation) to week 96 mean(sd) cIMT -0.02(0.04)mm (p<0.001), PWV -0.37(0.82)m/s (p<0.001). In contrast whereas cIMT had significantly reduced by mean -0.2(0.06)mm (p=0.01) at week 96 in the ART experienced group PWV increased by 0.34(0.62)m/s (p<0.001). There was no evidence that the changes in IMT or PWV over 96 weeks differed by randomisation ART in either ART naive or ART experienced children (p≥0.27). Significant differences in a panel of 19 biomarkers and immunophenotyping (markers of activation and proliferation) were demonstrated between HIV infected ART naive children and healthy age matched HIV uninfected children. No significant relationship between any of the biomarkers, immunophenotyping markers and IMT or PWV was demonstrated. Conclusion In this large study of arterial structural and stiffness in HIV-infected children in Africa, ART-naive HIV-infected children had significantly poorer IMT and PWV than age-matched controls, with significant improvement seen after 96 weeks of ART. After a mean 3.7 years on ART, HIV-infected children had cIMT and PWV comparable to uninfected age-matched controls. IMT continued to improve after a further 96 weeks on ART. These findings illustrate that ART can reverse some of the structural/stiffness changes caused by HIV, strengthening the argument for early diagnosis and treatment of HIV-infected infants.