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Highly active antiretroviral therapy (HAART) appears to preserve cardiac function in children and adolescents infected with HIV, researchers found.
Compared with HIV-infected youths treated during a period in which HAART was not widely used, those mostly treated with HAART had significantly better echocardiographic measures of heart structure and function, according to Steven Lipshultz, MD, of the University of Miami, and colleagues.
Some of the patients from the earlier cohort -- but none from the newer cohort -- developed clinical heart disease, the researchers reported online in JAMA Pediatrics.
"This finding suggests an overall cardioprotective effect of long-term HAART," the authors wrote. "Whether this effect is the result of better immunological health, more normal somatic growth, direct killing of intramyocardial HIV, or other mechanisms is unclear."
What the study doesn't show is "whether over time these patients on treatment are going to continue to improve or whether these patients are going to continue to get a little bit worse from a cardiac perspective," commented Elizabeth Lowenthal, MD, of the Children's Hospital of Philadelphia, who pointed to the cross-sectional nature of the data.
Before the development of contemporary antiretroviral therapies (ART), children infected with HIV were more likely to have abnormalities in left ventricular structure and function that were associated with an increased mortality risk. In the HAART era, however, the interactions between HIV, ART, and cardiac function in a pediatric patients remain unclear.
Lipshultz and colleagues examined three cohorts -- two from the Adolescent Master Protocol of the Pediatrics HIV/AIDS Cohort Study (PHACS) and one from the Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2-HIV) Study.
PHACS was conducted at 14 pediatric HIV clinics in the U.S. from March 2007 to November 2009, and included children ages 7 to 16. From that study, the researchers looked at data from 325 children who were infected with HIV perinatally and were receiving HAART -- defined as any regimen with at least three ART drugs from at least two ART drug classes -- and 189 children who were exposed to HIV but remained uninfected.
From P2C2-HIV, which was conducted from 1990 to 1997, the researchers looked at data from 70 children who were infected with HIV but who were mostly untreated with HAART (the historical controls).
Children in both studies underwent echocardiograms.
On average, the children in the older study were younger than those in PHACS (9.7 versus 13 in the HIV-infected cohort and 11 in the exposed but uninfected cohort).
Compared with the historical controls, the HIV-infected children in the newer study had less advanced disease, as indicated by lower viral loads (69% versus 8% had a count of 0 to 400 copies/mL) and higher CD4 counts (median 693 versus 178 cells/mm3), as well as a longer duration of ART (median 11.2 versus 4.5 years for any ART).
At the time of the echocardiograms, the percentage of children receiving HAART was significantly higher in the newer study (89% versus 17%, P<0.001). The patients in PHACS were also more likely to have received a protease inhibitor.
Cardiac function -- assessed using left ventricular fractional shortening z scores -- was significantly worse in the historical cohort compared with both the HIV-infected and the exposed but uninfected cohorts in PHACS (P<0.05).
In addition, patients from the historical cohort had the highest values for left ventricular mass, left ventricular end-diastolic dimension, and left ventricular end-systolic dimension z scores compared with the two contemporary cohorts. The lowest values were seen in the exposed but uninfected children.
End-diastolic septal wall thickness and left ventricular end-systolic wall stress z scores were highest in the historical cohort.
Overall, 44% of the patients in the earlier study met criteria for cardiomyopathy, significantly higher than the 3.7% and 1.6% in the HIV-infected and the exposed-but-uninfected PHACS cohorts, respectively (P<0.001).
In a multivariate analysis among the HIV-infected children pooled from both studies, lower nadir CD4 percentage and higher viral load were associated with significantly worse values on multiple measures of cardiac structure and function.
In the historical cohort, longer exposure to ART and a lower nadir CD4 percentage were associated with worse cardiac function. In the HIV-infected children from PHACS, however, cardiac function was relatively stable.
"We believe these differences suggest that some children in the P2C2-HIV cohort with evidence of substantial immunosuppression had already experienced substantial cardiac damage before they received effective ART regimens, if they received any ART at all," the authors wrote. "This conclusion is consistent with previous reports from the P2C2-HIV Study showing that many of the deleterious cardiac changes occurred in the first few years of life in children with marked immunosuppression without effective ART or multidrug therapy."
They acknowledged that the cross-sectional nature of the analysis precludes assessments of causality and that the study was limited by the lack of information on specific medications.
"Examining the associations between individual ART agents and combinations of ART might identify optimal ART regimens, both in terms of optimizing HIV outcomes and protecting long-term cardiac health, and represents a future research opportunity using this data set," they wrote.
From the American Heart Association:
The study and PHACS were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard School of Public Health and the Tulane University School of Medicine.
The authors reported that they had no conflicts of interest.
- Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
JAMA PediatricsSource Reference: Lipshultz S, et al "Cardiac status of children infected with human immunodeficiency virus who are receiving long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the multicenter Pediatric HIV/AIDS cohort study" JAMA Pediatr 2013; DOI: 10.1001/jamapediatrics.2013.1206.