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Prior to the highly active antiretroviral therapy (HAART)I era, and currently in countries with limited access to care, up to 38% of adult asymptomatic human immunodeficiency virus (HIV)-infected persons had clinical and echocardiographic evidence of dilated cardiomyopathy associated with lower CD4 counts.1,2 In HIV-infected children, poor nutritional status was also associated with echocardiographic abnormalities that demonstrate decreased left ventricular (LV) systolic dysfunction.3 The pre-HAART era Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study (P2C2) looked at longitudinal changes in LV structure and function and mortality in 193 children perinatally infected with HIV enrolled between May 1990 and April 1993.4 Serial cardiac data including echocardiograms were obtained from 0.1 to 10 years of age. This greatly extended our understanding of the incidence of systolic LV dysfunction during long-term follow-up of perinatally infected children, with 18% experiencing mild LV dysfunction and progressive increase in LV mass, associated with increased mortality over time.5 Surprisingly, children with what would be classified as only mild systolic LV dysfunction had a 12% 5-year cumulative incidence of symptomatic congestive heart failure and higher risk of all-cause mortality than patients without LV dysfunction.5 In a report from the Pediatric AIDS Clinical Trail group Protocols 219 and 219C which enrolled children with HIV or exposed perinatally to HIV from 1993 to 2006, Patel et al. found that 4.2% of 3,169 perinatally-infected children (83% exposed to HAART) had a clinical diagnosis of cardiomyopathy based on echocardiographic evidence at enrollment (median age at enrollment was 9.4 years). The incidence of cardiomyopathy in the HAART era was 3.9 cases per 1,000 person years, much lower than the incidence in the pre-HAART era (25.6 cases per 1,000 person years).6
HAART has changed the course of HIV infection, such that both adults and children are now surviving longer. However, the risk of premature cardiovascular disease has been associated with specific antiretroviral therapies.7 Nucleoside reverse transcriptase inhibitors (NRTIs) have been associated with mitochondrial toxicity,8 although a study in both HIV-infected and HIV-exposed uninfected infants whose HIV-infected mothers received zidovudine during pregnancy to prevent transmission showed no adverse cardiac effects in the first 10 to 14 months of life.9 Protease inhibitors (PIs) have been implicated in adversely affecting cardiac function and atherogenic risk in both adults and children.10–12 PI-containing regimens specifically have been associated with an increase in LV mass and with diastolic dysfunction in adults.13
The Adolescent Master Protocol (AMP) of the National Institutes of Health-funded Pediatric HIV/AIDS Cohort Study is a prospective cohort conducted at 14 US sites, designed to evaluate the impact of HIV infection and ART on the development of children and adolescents with perinatal HIV. The study enrolled children aged 7 to 16 years between March 2007 and November 2009, and also enrolled HIV-exposed but uninfected children over the same time period to serve as a comparison group. One analysis compared the HAART-treated AMP cohort to the prior pre-HAART P2C2 HIV- infected group.14 In P2C2 HIV-infected children, 44% (31 of 70) met the definition for cardiomyopathy (either a z score less than −2 for LV fractional shortening or greater than 2 for LV dimension) as compared to 4% (12 of 325) of the AMP HIV-infected children.
In HAART-treated AMP HIV-infected children (n = 325) compared to pre-HAART P2C2 (n = 70) HIV-infected children, viral load suppression (less than 400 copies/mL) was achieved in 69% vs 8% of children respectively, and the AMP children had better cardiac function (fractional shortening z = 0.10 compared with z = −1.94). However, LV structural measures, while significantly different between the cohorts, were within the normal range (LV end diastolic dimension z = −0.13 compared with z = 0.39 and LV mass z = −0.22 compared with z = 0.20).14
In adults, the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN Study), a prospective, observational cohort of 656 HAART-exposed HIV-infected participants who underwent echocardiography between 2004 and 2006 showed one patient with severe systolic dysfunction and 18% with mild systolic dysfunction.15 Factors significantly associated with LV systolic dysfunction were history of myocardial infarction, elevated high-sensitivity C-reactive protein level, and current tobacco smoking.
These data illustrate a clear decrease in clinical cardiomyopathy and related mortality despite persistent subclinical structural abnormalities in HAART treated patients in both adult and pediatric populations.3 Improvement in incidence and prevalence of cardiomyopathy with treatment of HIV has not previously been demonstrated and suggests that HAART therapy and viral suppression helps to prevent clinical cardiomyopathy. Nutritional status and overall health of the patient may play a significant role in the translation of structural cardiac abnormalities to clinical heart failure and mortality and may play a significant role in preventing heart failure in this and in other vulnerable populations. Cell-based research also may guide understanding and further therapies of cardiomyopathy with a recent study suggesting that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway.16 This pathway or other mechanisms of negative remodeling and fibrosis could explain clinical cardiomyopathy and improvement with HAART therapy.
The mechanism of cardiac protection in the HAART era is not clear and may be related to reduced virus levels and cytotoxic cytokines or an improved immune state and better nutritional status. Research looking at mechanisms of apoptosis and blocking apoptosis may further heart failure prevention and care. Future data should look for evidence of LV remodeling with immune reconstitution. Biomarkers and imaging may be most sensitive in demonstrating and monitoring clinical cardiomyopathy and effects of treatment. In patients perinatally infected with HIV, HAART therapy has clearly improved cardiac structure and decreased incidence of clinical congestive heart failure over time. This finding has not been previously demonstrated and may apply to other types of viral and immune mediated cardiomyopathies with available effective treatments.
The authors would like to thank the Pediatric HIV/AIDS Cohort Study network for their logistical support of this work.
IHighly active antiretroviral therapy (HAART) is defined as the concomitant use of three or more antiretroviral drugs from at least two classes.
Conflicts of Interest: All authors have reported that they have no relationships relevant to the contents of this paper to disclose.