Effects of Highly Active Anti-Retroviral Therapy on Cardiovascular Health in Infants of HIV-Infected Mothers

BACKGROUND: HIV-infected pregnant women frequently receive HAART, which is associated with reduced maternal-fetal transmission of HIV infection. This has resulted in a rapidly increasing number of seroreverters (HIV-uninfected infants born to HIV-infected women), representing the majority of infants in the United States exposed to HAART. Long-term consequences and toxicities associated with this exposure are not known, but severe cardiotoxicity is suggested in animal models. This study will utilize HIV seroreverter cohorts from the NIH-sponsored Women and Infants Transmission Study (WITS) and Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infections Study (P2C2) to determine how left ventricular (LV) structure and function, serum cardiac troponin T (cTnT), serum pro brain natriuretic peptide (proBNP), and serum high sensitivity C reactive protein (hsCRP) are affected by HAART exposure. In P2C2, patients were recruited from May 1990 to January 1994 from five clinical centers in the United States. This study was initiated in 2002 in response to a 'Request for Applications' on HAART cardiovascular toxicities. DESIGN NARRATIVE: This study will utilize HIV seroreverter cohorts from the NIH-sponsored WITS and P2C2 cohorts to determine how LV structure and function, cTnT, proBNP, and hsCRP are affected by HAART exposure. The p2C2 seroreverter cohort has been exposed to no antiretroviral therapy or zidovudine alone (without HAART) and has persistent significantly depressed LV contractility in comparison to normal with up to 5 years of follow-up. The WITS seroreverter cohort has been exposed mostly to HAART. This cohort will determine the incremental effect of HAART on LV structure and function by following the P2C2 protocol for assessment of LV structure and function. This study will test three hypotheses: 1) that HAART exposure results in fetal and neonatal myocardiocyte injury and death (by serial assessment of cTnT \[a biomarker of acute myocardial injury\] in both seroreverter cohorts); 2) that HAART exposure results in impaired myocardiocyte mitochondrial function resulting in LV dysfunction (by serial assessment of proBNP \[a biomarker related to LV dysfunction\], LV volume and pressure increases resulting in LV stretch, and neurohormonal activation); and 3) that HAART exposure results in accelerated atherosclerosis (by serial assessment of hsCRP \[a biomarker of generalized inflammation predictive of increased subsequent coronary artery disease\]). This study will determine the cardiovascular effects of HAART in seroreverters and the need for future cardiovascular follow-up and cardiovascular preventive and therapeutic trials in this rapidly expanding population.