Pediatric HIV: Immunologic and Virologic Response to Antiretroviral Therapy

Abstract

Background: Virologic and immunologic responses to antiretroviral treatment (ART) in infants may differ from older children and adults due to immunologic, clinical or epidemiologic characteristics. There are few longitudinal studies of immune activation and changes in immune phenotype among infants. Methods: Within a cohort of HIV-infected infants starting early ART in Nairobi, Kenya, longitudinal trajectories of HIV viral load and CD4 over two years of ART were modeled and compared to those of older children (Chapter 1). T-cell activation at baseline was measured using flow cytometry and its association with mortality and ART response quantified (Chapter 2). Changes in activation and T-cell memory subsets over two years of ART were described and compared among infants with good virologic and immunologic response to ART and those with discordant response (Chapter 3). Results: Chapter 1: Infants had higher viral loads at baseline pre-ART, a slower rate of suppression and a higher post-ART stabilized viral load than children. Infants were less likely than children to suppress HIV viral load to <250 copies/ml following 6 months (32% vs. 73%, infants vs. children p<0.0001) and 2 years (75% vs. 89%, infants vs. children p=0.007) of ART. Children had a significantly faster rate of CD4% reconstitution than infants, but failed to catch up to infant CD4% (CD4% at 24 months: 29% vs. 22%, infants vs. children p=0.04). Chapter 2: Among 75 infants, median CD8+ T-cell activation at baseline pre-ART was 16.5% (interquartile range [IQR] 9.9, 28.4). CD8+ T-cell activation was not correlated with pre-ART CD4%, HIV viral load or WHO stage. Low pre-ART CD8+ T-cell activation (<5%) was associated with mortality overall (Hazard ratio (HR)=3.5 [95% CI 1.3, 9.4]); and among those who survived to start ART (HR 5.8, 95% CI ). Pre-ART CD8+ T-cell activation >median was associated with slower CD4% recovery on ART. Chapter 3: Among infants who completed two years of ART, different viral/immune patterns were noted – those who had viral suppression and CD4 recovery (responders), CD4 recovery despite lack of viral suppression (discordant responders), and those with neither good viral suppression nor immune recovery (nonresponders). Overall, CD8+ T-cell activation decreased substantially in the first six months on ART, and naïve CD8+ T-cells increased. Naive CD4+ T-cells increased among concordant good responders only. Conclusion: Infants in this early ART cohort had high viral loads at baseline and failed to suppress virus or increase CD4% as efficiently as older children after ART initiation. In contrast to findings in adults, low CD8+ T-cell activation was associated with mortality and may be a marker of immune exhaustion and advanced HIV disease. Immune activation decreased and infant T-cell phenotype shifted toward a less differentiated phenotype with ART but was not restored to normal. Strategies to augment immune responses and improve ART specifically for infants are needed to improve outcomes in this vulnerable population.