Since the first pediatric cases of HIV-associated cardiomyopathy were reported in the late 1980s, cardiomyopathy has been the leading noninfectious cause of death among HIV-infected children [1–4]. It is a Centers for Disease Control and Prevention (CDC) category B condition and a WHO HIV clinical stage 4 disease [5,6].
Numerous studies have evaluated cardiac function among HIV-infected children [7–18]. The US-based Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study (P2C2) reported an incidence of poor left ventricular function, heart failure, and/or use of cardiac medications, of 18–30% [11–15]. This is similar to the prevalence of cardiac dysfunction found among HIV-infected children from Uganda, Nigeria, and South Africa [17–19]. Although symptomatic cardiac dysfunction was rarely diagnosed among the P2C2 children, mild left ventricular dysfunction was associated with mortality [12,15].
Several mechanisms of HIV-associated cardiomyopathy have been proposed. The presence of HIV within the heart initially suggested that cardiac damage resulted from direct infection of cardiac myocytes [20–22]. HIV, however, does not replicate within myocytes [23,24]. Increased production of pro-inflammatory cytokines by infected inflammatory cells within the myocardium may be an alternative mechanism. Cytokine activation results in cardiomyocyte apoptosis, eventually leading to ventricular remodeling [24–26]. Another proposed mechanism for cardiomyopathy is nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity [27–29]. NRTIs, which inhibit HIV reverse transcriptase, also inhibit DNA polymerase-γ, the enzyme responsible for mitochondrial DNA (mtDNA) replication [27–34]. NRTIs inhibit DNA polymerase-γ in varying degrees within different human tissues [30–34]. The rank order of the effects of NRTIs on mitochondria, however, is relatively consistent, with zalcitabine (ddC), an NRTI that is no longer in use, associated with the greatest degree of mitochondrial toxicity, followed by didanosine (ddI), stavudine (D4T), and zidovudine (ZDV) [30–34]. Lamivudine (3TC), abacavir (ABC), and tenofovir have relatively limited effects on mitochondria [30,31]. However, an adult study did find an association between current ABC use and left ventricular hypertrophy .
NRTIs constitute the backbone of HAART. Survival among perinatally infected children has increased with HAART , generating questions about the long-term effect of HAART on cardiac disease. A few studies have examined the association between antiretroviral use and cardiac function among HIV-infected children, but they were all conducted in the pre-HAART era [8,10,13]. Two studies found no toxicity with ZDV [8,13], whereas one found an eight-fold increased risk of cardiomyopathy with ZDV . With these conflicting results and increased HAART use, including ZDV, among HIV-infected children, there is a need to assess the effect of HAART on cardiomyopathy. We described the incidence of cardiomyopathy from 1993 to 2007 in a large US-based cohort of perinatally HIV-infected children, and evaluated the effects of HAART and specific NRTIs (ddC, ddI, D4T, ZDV, and ABC) on cardiomyopathy incidence. We also identified predictors of cardiomyopathy among HAART initiators and the effect of HAART on survival after cardiomyopathy development. Finally, we examined the clinical significance of cardiomyopathy by estimating its effect on overall survival.
The eligible study population included 3209 perinatally HIV-infected children enrolled in Pediatric AIDS Clinical Trials Group (PACTG) protocols 219 and 219C, which were consecutive prospective studies evaluating the long-term effects of HIV infection and antiretroviral drugs. HIV-infected and HIV-exposed but uninfected children were enrolled between 1993 and 2006 from more than 80 study sites across the USA and Puerto Rico. The protocols were approved by Human Subjects Review Boards at each participating institution and written informed consent was obtained from each child's parent or legal guardian.
At each study visit, sociodemographic and clinical characteristics were collected. HIV-RNA quantification was not routinely performed before 2000 and, thus, viral loads were available for only 59% of our incident study population. Nadir CD4% and peak viral load were defined as the lowest CD4% and the highest viral load documented prior to and at study entry.
HAART was defined as concomitant use of at least three drugs from at least two classes of antiretroviral drugs. The calendar years prior to 1996 were considered to be the pre-HAART era, as this time span predates protease inhibitor use in clinical practice. The HAART era included all calendar years from 1996 onwards. In analyses, once a child initiated HAART, they were assumed to remain on HAART. A similar approach was used to estimate effects of ddC, ddI, D4T, ZDV, and ABC. Medication start and stop dates were unavailable within PACTG 219. Therefore, the midpoint between the first visit at which treatment was documented and the preceding visit was considered the date of treatment initiation .
Cardiomyopathy was defined as having a diagnosis based on clinician report of meeting the criteria for cardiomyopathy or initiating digoxin. The study specified criteria for cardiomyopathy were having ventricular diastolic/systolic dimensions of at least 2 SDs above the mean for body surface area or abnormal fractional shortening index of 2 SDs or less below the mean. No validation with actual echocardiogram results was conducted. For analyses, the date of cardiomyopathy was defined as the earliest of the date of cardiomyopathy diagnosis or date of initiation of digoxin.
Prevalent cases of cardiomyopathy were identified at entry and excluded from subsequent analyses. For incident cardiomyopathy, children were followed from entry to cardiomyopathy, death, or their last visit, whichever came first. For incident cardiomyopathy among HAART initiators, children were followed from HAART initiation to cardiomyopathy, death, or their last visit. Children who initiated HAART prior to entry were followed from entry. For survival after cardiomyopathy, children were followed from their cardiomyopathy date to their date of death or censored at their last visit. For overall survival, all children were followed from entry to their date of death, or censored at their last visit.
An extended Cox regression model was used to estimate the effects of time-varying HAART, ddC, ddI, D4T, ZDV, and ABC on cardiomyopathy incidence. Age at entry, birth cohort, sex, race/ethnicity, maternal antiretroviral drug use during pregnancy, birth weight, CDC clinical category at entry, nadir CD4%, and peak viral load were considered as potential confounders. All confounders of the association between any of the antiretroviral drug of interest and cardiomyopathy were included in the final multivariable model. A Cox regression model was used to identify predictors of cardiomyopathy among those receiving HAART. Age at HAART initiation, sex, race/ethnicity, CDC clinical category at HAART initiation, nadir CD4%, peak viral load, use of individual NRTIs prior to HAART initiation and in the first HAART regimen were considered as potential predictors. All univariable predictors of cardiomyopathy at P value less than the 0.05 significance level were included in the final multivariable model. Given our prior hypothesis that nadir CD4% (as a proxy for pro-inflammatory response to viral load) and ZDV would be associated with cardiomyopathy via different pathogenic mechanisms, we additionally evaluated their potential interaction. To further explore the effects of ZDV, we also compared incidence rates by ZDV use prior to HAART initiation and initiating ZDV-containing HAART. Extended Cox regression models were also used to estimate the effect of time-varying HAART use on survival after cardiomyopathy diagnosis and the effects of time-varying HAART and cardiomyopathy on overall survival. Analyses were conducted using SAS version 9 (SAS Institute, Cary, North Carolina, USA).
Of the 3209 perinatally infected children enrolled in PACTG 219 and 219C, seven immediately went off-study and were excluded. Thirteen children exposed to doxorubicin, two who underwent radiation therapy, 10 diabetic children, and eight with Kawasaki disease were further excluded due to their independent risk of cardiomyopathy. No children were identified with hyperthyroidism, Barth syndrome, or muscular dystrophy. Of the 3169 children remaining in the study population, 134 entered PACTG 219 or 219C with cardiomyopathy, resulting in a prevalence of 4.2% [95% confidence interval (CI): 3.6%, 5.0%]. Their median age at cardiomyopathy diagnosis was 4.5 years. Seventy-two percent of the cases had initiated antiretroviral drugs prior to diagnosis, but only 12% had initiated HAART. There were 18 deaths (13.0%) observed among the prevalent cases with a median time from diagnosis to death of 1.8 years.
Table 1 outlines characteristics of the 3035 children followed for incident cardiomyopathy. At entry, 44% were 5 years of age or less (81% born prior to 1996), 26% were CDC category C, and 27% had a nadir CD4 percentage < 15%. Of the 1795 children with viral load information, 34% had a peak viral load of at least 100 000 copies/ml at entry. The children exposed to HAART were more likely to be born in the HAART era, more likely to be black, and more likely to be exposed to antiretroviral drugs in utero than children who never initiated HAART.
Over a median of 5.5 years of follow-up, 99 incident cases of cardiomyopathy were observed, yielding an incidence rate of 5.6 cases per 1000 person-years (95% CI: 4.6, 6.8; 17 603 person-years). The majority (80%) of the incident cases had only on a clinical diagnosis of cardiomyopathy. Five (5%) of the incident cases only had exposure to digoxin, and 15 (15%) of the incident cases had both a clinical diagnosis of cardiomyopathy and exposure to digoxin. The median age at diagnosis of cardiomyopathy was 9.4 years and increased in the HAART era compared with the pre-HAART era (pre-HAART era, 6.7 years; HAART era, 10.3 years; P = 0.005). Sixty-three percent of the incident cases were male. The incidence of cardiomyopathy decreased substantially over time from 25.6 cases per 1000 person-years in the pre-HAART era to 3.9 cases per 1000 person-years in the HAART era (Fig. 1). In more recent years (2001–2005), the incidence of cardiomyopathy ranged from 0.5 to 4.8 cases per 1000 person-years.
In multivariable analyses, HAART was associated with a 50% lower rate of cardiomyopathy compared to no HAART (Table 2). In contrast, the rate of cardiomyopathy was 1.8 times higher among children exposed to ddC. Although none of the other NRTIs were significantly associated with cardiomyopathy, there was a suggestion of an almost two-fold higher rate of cardiomyopathy with any use of ZDV.
Among the 2515 children exposed to HAART in the study population, the median age at HAART initiation was 6.1 years. Over a median of 5.1 years, 45 (1.8%) HAART initiators developed cardiomyopathy. In multivariable analyses (Table 3), significant predictors of cardiomyopathy development during HAART included older age at HAART initiation, male sex, Hispanic ethnicity, ddC use prior to HAART initiation, first initiating a HAART regimen containing ZDV, and a lower nadir CD4%. There was a multiplicative interaction between initiating a HAART regimen containing ZDV and nadir CD4%. Children who first initiated ZDV-containing HAART and had a nadir CD4 percentage less than 15% had a substantially higher subsequent incidence of cardiomyopathy compared with children with either of these exposures alone (i.e. children who initiated HAART not containing ZDV but had a nadir CD4 percentage less than 15% and children who did first initiate ZDV-containing HAART but had a nadir CD4 percentage of at least 15%) (Table 3).
Table 4 compares the crude incidence rates of cardiomyopathy by exposure to ZDV prior to HAART and initiating HAART including ZDV among the 2515 children exposed to HAART in the study population. Children exposed to ZDV prior to HAART with continued exposure through initiation of a HAART regimen including ZDV, and children who initiated HAART including ZDV, had substantially higher rates of cardiomyopathy compared with children who discontinued ZDV exposure by initiating a HAART regimen without ZDV and children who were not exposed to ZDV prior to or with HAART. The majority of the cases who were exposed to ZDV prior to HAART and initiated HAART including ZDV (n = 25) were on a protease inhibitor-based HAART regimen (72%), whereas the majority of cases who were not exposed to ZDV prior to HAART but initiated HAART including ZDV (n = 10) were on a non-nucleoside reverse transcriptase inhibitor-based HAART regimen (60%). Seven of the eight (88%) cases exposed to ZDV prior to HAART and initiated a HAART regimen without ZDV were on a protease inhibitor-based HAART regimen including D4T and 3TC. Both of the cases who were never exposed to ZDV initiated a protease inhibitor-based HAART regimen including D4T.
Over a median follow-up of 5.6 years from entry until death, an overall mortality rate of 12.1 per 1000 person-years (95% CI: 10.6, 13.8; 219 deaths; 18 060 person-years) was observed. Thirty-six deaths occurred among the 99 incident cases of cardiomyopathy with a median time from diagnosis to death of 0.8 years and a mortality rate after diagnosis of 78.7 per 1000 person-years (95% CI: 55.1, 108.9; 458 person-years). In multivariable analyses, having a diagnosis of cardiomyopathy was significantly associated with a six-fold higher rate of mortality compared with not having a diagnosis of cardiomyopathy (95% CI: 4.0, 8.8), whereas HAART use was associated with 60% lower rate of mortality compared with no HAART exposure (95% CI: 50%, 70%). In contrast, there was no association between HAART and survival after cardiomyopathy development (hazard ratio 1.3; 95% CI: 0.6, 2.7).
We found a six-fold decrease in the incidence of cardiomyopathy among children perinatally infected with HIV in the HAART era (1996–2007) compared with the pre-HAART era (1993–1995), likely reflecting improved virologic control with HAART reducing the risks of opportunistic infections and cytokine activation leading to cardiomypathy. However, the observed annual incidence of cardiomyopathy in recent years ranged from 0.5 to 4.8 per 1000 children, over 40 times higher than the reported annual incidence of 1.13 per 100 000 children from the US-based Pediatric Cardiomyopathy Registry . Although the definition of cardiomyopathy in the Pediatric Cardiomyopathy Registry was more specific, the substantially increased incidence among perinatally infected children suggests that even with HAART, HIV infection and/or its treatment still increases the risk of cardiomyopathy in children.
While HAART was associated with a significantly lower rate of cardiomyopathy, ddC use was associated with an 80% higher rate of cardiomyopathy. This may be due to the effect of ddC on the mitochondria of cardiomyocytes, similar to the effect of ddC on mtDNA of nerve cells leading to peripheral neuropathy . Advanced HIV infection, as indicated by a nadir CD4 percentage less than 15%, was also independently associated with a higher rate of cardiomyopathy. Again, activation of a pro-inflammatory cytokines in response to viral infection of lymphocytes within the heart may be the mechanism by which HIV causes cardiomyopathy [24–26]. Similar to the effects observed in the Pediatric Cardiomyopathy Registry, we found males to have a higher rate of cardiomyopathy than females. Our observed higher rate of cardiomyopathy among Hispanics compared with white children also seems to be consistent with results from the Pediatric Cardiomyopathy Registry, although a formal comparison of Hispanics to whites could not be conducted within the registry population .
Stronger associations of male sex, Hispanic ethnicity, and use of ddC prior to HAART with cardiomyopathy were observed among children who initiated HAART. An older age at HAART initiation was also associated with a higher rate of cardiomyopathy, perhaps indicating the effects of greater exposure to replicating virus during prior nonsuppressive therapy or a longer duration of exposure to NRTIs. Although ever having received ZDV was not significantly associated with cardiomyopathy in our entire study population, among those who initiated HAART, continued or new exposure to ZDV as a component of HAART was associated with a higher rate of cardiomyopathy. There was a multiplicative interaction between this association and nadir CD4%, supporting the theory of a multifactorial pathogenesis of HIV-associated cardiomyopathy, combining inflammatory mediators and NRTI-associated cardiac damage perhaps mediated through mtDNA depletion .
Our reported incidence of cardiomyopathy may be underestimated if young children with cardiomyopathy died prior to enrolling in PACTG 219 or 219C. The greater median age of the incident cases of cardiomyopathy compared with the median age of the prevalent cases identified at entry suggest that a ‘survivor’ cohort of children may have been followed for incident analyses. The majority of our prevalent cases were diagnosed in the pre-HAART era. If covariate information prior to entry were available, inclusion of all prevalent cases in incident analyses would likely have strengthened our observed association of HAART use with cardiomyopathy. As viral load information was missing for 59% of the study population, we were not able to adjust for it in our analyses. Sensitivity analyses conducted among the subset of children with viral load information, however, suggest that stronger associations of HAART and cardiomyopathy with survival would be observed with adjustment for viral load. Lack of sufficient viral load data also limited our ability to explore the mechanisms underlying our observed association between ZDV as a component of HAART and rate of cardiomyopathy. The specific hypothesis of mitochondrial toxicity associated with ZDV exposure leading to cardiomyopathy was, therefore, not tested. There may be an alternative mechanism explaining the observed association between HAART with ZDV and cardiomyopathy. Echocardiographic studies were not recorded and kept as part of PACTG 219 and 219C, so cardiomyopathy classification could not be confirmed. There may, therefore, be some misclassification of our cardiomyopathy outcome. Assuming that this misclassification is nondifferential with respect to treatment, our observed associations of HAART and individual NRTIs with incidence of cardiomyopathy are likely conservative.
In conclusion, we found a strong protective association of HAART with cardiomyopathy among children and adolescents perinatally infected with HIV. We also demonstrated that early initiation of HAART is associated with a lower incidence of cardiomyopathy, adding to earlier studies showing the benefits of early HAART initiation on maintaining immunocompetence among perinatally infected children . In choosing therapy, however, the benefit of specific medications must be weighed against their potential toxicities . Our study is the first to see a multiplicative effect of a low nadir CD4% and initiating a ZDV-containing HAART regimen on cardiomyopathy. This association needs to be confirmed in future studies, but it is consistent with the theory of a multifactorial pathogenesis of HIV-associated cardiac damage [27–29]. Even with the significant declines in mortality observed with improved antiretroviral therapy, this study highlights the ongoing problem of cardiomyopathy among HIV-infected children. ZDV may cause progression to cardiomyopathy and, thus, its risks and benefits should be carefully balanced for each child, and alternative NRTIs may be considered. Additionally, long-term monitoring of cardiac function among HIV-infected children may be warranted.
K.P. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design was performed by K.P., R.B.VD., M.A.M., S.D.C., J.M.O., and G.R.S.
Acquisition of data was done by R.B.VD. and J.M.O.
Analysis and interpretation of data was done by K.P., R.B.VD., M.A.M., S.D.C., J.M.O, and G.R.S.
Drafting of the manuscript was done by K.P., R.B.VD., and G.R.S.
Critical revision of the manuscript for important intellectual content was done by K.P., R.B.VD., M.A.M., S.D.C., J.M.O., and G.R.S.
Statistical analysis was performed by K.P. and G.R.S.
Funding was obtained by J.M.O., R.B.VD., and G.R.S.
Administrative, technical, or material support was provided by G.R.S.
Study supervision was provided by K.P., R.B.VD., M.A.M., S.D.C., J.M.O., and G.R.S.
The authors thank the children and families for their participation in PACTG 219C, and the individuals and institutions involved in the conduct of 219C as well as the leadership and participants of the P219/219C protocol team. We are grateful for the contributions of Joyce Kraimer, Barbara Heckman, Shirley Traite, and Nathan Tryon. The authors also thank the individual staff members and sites who have participated in the conduct of this study.
The National Institute of Allergy and Infectious Diseases and the National Institute of Child Health and Human Development were involved in the design, data collection, and conduct of protocol 219/219C but were not involved in the present analysis, the interpretation of the data, the writing of the manuscript, or decision to submit for publication.
Leadership: J.M.O., MD, MPH; Founding Chair; R.B.VD., MD; Chair; Mark Abzug, MD; John Farley, MD, Mary G. Fowler, MD, MPH, Michael Brady, MD, and Wayne Dankner, MD.
Protocol Team Members (versions 1 and 2 of PACTG-219): Mary Culnane, MS, CRNP; Elizabeth Hawkins; Lynne Mofenson, MD; Yvonne J. Bryson, MD; Edward M. Connor, MD; Lawrence D’Angelo, MD, MPH; Mark Mintz, MD; Karen J. O’Donnell, PhD; Margaret Oxtoby, MD; Andrea R. Hale, RN, MPH; Richard D. Gelber, PhD; Steven Gortmaker, PhD; William Lenderking, PhD; Lynn Marrow; Christina Joy, RN, MSM; Colleen Clark, MPH; Bethann Cunningham, MS; Rhoda Sperling, MD; Gwendolyn B. Scott, MD; Courtney Fletcher, PharmD; Blake Caldwell, MD; Dianne Donovan,
Protocol Team Members (versions 3 and 4 of PACTG-219C): Elizabeth Smith, MD; Anne Fresia; Gregory Ciupak; Michelle Eagle, PA; Dorothy R. Smith, MS; CPNP; Paul Palumbo, MD; John Sleasman, MD; James Connor, MD; Michael Hughes, PhD; Rebecca Oyomopita, MSc; George Johnson, MD; Andrew Wiznia, MD; Nancy Hutton, MD; Andrea Kovacs, MD; Mary Sawyer, MD; Martin Anderson, MD; Audrey Rogers, PhD, MPH; William Borkowsky, MD; Jane Lindsey, ScD; Jack Moye, MD; Myron Levin, MD; Marilyn Crain, MD, MPH; Paul Britto, MS; Ruth Toumala, MD; Joseph Cervia, MD; Eileen Monagham, Kenneth Dominguez, MD, Melody Higgins, RN, MS, G.R.S. DSc; MPH, Denise Gaughan, MPH; Phil Gona, PhD; William Shearer, MD, PhD; Lois Howland, DPH, MS, RN; Deborah Storm, PhD, RN; Kathleen Malee, PhD; Wendy Mitchell, MD; Carol Gore; Eve Powell; Michelle McConnell, MD; Newana Beatty; Susan Brogly, PhD; Jennifer Bryant, CRA; Miriam Chernoff, PhD; Barbara Heckman, BS; Dawn English; Edward Handelsman, MD; Patrick Jean-Philippe, MD; Kathleen Kaiser; Joyce Kraimer, MS; Linda Millar; Shirley Traite, MSW; Paige Williams, PhD; Elizabeth Woods, MD, MPH; and Carol Worrell, MD.
Participating institutions and clinical site investigators in the US-based multisite cohort study, PACTG 219/219C:
University of New Jersey Medical and Dental School - Department of Pediatrics, Division of Allergy, Immunology and Infectious Diseases: Dr Arlene Bardeguez, Dr Arry Dieudonne, Linda Bettica, Juliette Johnson; Boston Medical Center, Division of Pediatric Infectious Diseases: Dr Stephen I. Pelton, Dr Ellen R. Cooper, Lauren Kay, Ann Marie Regan, Med; Children's Hospital LA - Department of Pediatrics, Division of Clinical Immunology and Allergy: Dr Joseph A. Church, Theresa Dunaway; Long Beach Memorial Medical Center, Miller Children's Hospital: Dr Audra Deveikis, Dr Jagmohan Batra, Susan Marks, Ilaisanee Fineanganofo; Harbor - UCLA Medical Center - Department of Pediatrics, Division of Infectious Diseases: Dr Margaret A. Keller, Dr Nasser Redjal, Spring Wettgen, Sheryl Sullivan; Johns Hopkins Hospital and Health System - Department of Pediatrics, Division of Infectious Diseases: Dr Nancy Hutton, Beth Griffith, Mary Joyner, Carolyn Keifer; University of Maryland Medical Center, Division of Pediatric Immunology and Rheumatology: Dr Douglas Watson, Dr John Farley; Texas Children's Hospital, Allergy and Immunology Clinic: Dr Mary E. Paul, Chivon D. Jackson, Faith Minglana, Dr Heidi Schwarzwald; Cook County Hospital: Dr Kenneth M. Boyer, Dr Jamie Martinez, Dr James B. McAuley, Maureen Haak; Children's Hospital of Columbus, Ohio: Dr Michael Brady, Dr Katalin Koranyi, Jane Hunkler, Charon Callaway; University of Miami Miller School of Medicine, Division of Pediatric Immunology and Infectious Disease: Dr Gwendolyn B. Scott, Dr Charles D. Mitchell, Dr Claudia Florez, Joan Gamber; University of California San Francisco School of Medicine, Department of Pediatrics: Dr Diane W. Wara, Dr Ann Petru, Nicole Tilton, Mica Muscat; Children's Hospital and Research Center Oakland, Pediatric Clinical Research Center and Research Lab: Dr Ann Petru, Teresa Courville, Karen Gold, Katherine Eng; University of California San Diego Mother, Child and Adolescent HIV Program: Dr Stephen A. Spector, Dr Rolando M. Viani, Mary Caffery, Kimberly Norris; Duke University School of Medicine - Department of Pediatrics, Children's Health Center: Margaret Donnelly, Dr Kathleen McGann, Carole Mathison, John Swetnam; University of North Carolina at Chapel Hill School of Medicine - Department of Pediatrics, Division of Immunology and Infectious Diseases: Dr Tom Belhorn, Jean Eddleman, Betsy Pitkin; Schneider Children's Hospital: Dr Vincent R. Bonagura, Dr Susan Schuval, Dr Blanka Kaplan, Dr Constance Colter; Harlem Hospital Center: Dr Elaine J. Abrams, Maxine Frere, Delia Calo; New York University School of Medicine, Division of Pediatric Infectious Diseases: Dr William Borkowsky, Nagamah Deygoo, Maryam Minter, Seham Akleh; Children's National Medical Center, ACT: Diana Dobbins, Deidre Wimbley, Dr Lawrence D’Angelo, Hans Spiegel; University of Washington School of Medicine - Children's Hospital and Regional Medical Center: Dr Ann J. Melvin, Kathleen M. Mohan, Michele Acker, Suzanne Phelps; University of Illinois College of Medicine at Chicago, Department of Pediatrics: Dr Kenneth C. Rich, Dr Karen Hayani, Julia Camacho; Yale University School of Medicine - Department of Pediatrics, Division of Infectious Disease: Dr Warren A. Andiman, Leslie Hurst, Dr Janette de Jesus, Donna Schroeder; SUNY at Stony Brook School of Medicine, Division of Pediatric Infectious Diseases: Denise Ferraro, Jane Perillo, Michele Kelly; Howard University Hospital, Department of Pediatrics and Child Health: Dr Sohail Rana, Dr Helga Finke, Patricia Yu, Dr Jhoanna Roa; LA County/University of Southern California Medical Center: Dr Andrea Kovacs, Dr James Homans, Dr Michael Neely, Dr LaShonda Spencer; University of Florida Health Science Center Jacksonville, Division of Pediatric Infectious Disease and Immunology: Dr Mobeen H. Rathore, Dr Ayesha Mirza, Kathy Thoma, Almer Mendoza; North Broward Hospital District, Children's Diagnostic and Treatment Center: Dr Ana M. Puga, Dr Guillermo Talero, James Blood, Stefanie Juliano; University of Rochester Medical Center, Golisano Children's Hospital: Dr Geoffrey A. Weinberg, Barbra Murante, Susan Laverty, Dr Francis Gigliotti; Medical College of Virginia: Dr Suzanne R. Lavoie, Tima Y. Smith; St. Jude Children's Research Hospital, Department of Infectious Diseases: Dr Aditya Gaur, Dr Katherine Knapp, Dr Nehali Patel, Marion Donohoe; University of Puerto Rico, U. Children's Hospital AIDS: Dr Irma L. Febo, Dr Licette Lugo, Ruth Santos, Ibet Heyer; Children's Hospital of Philadelphia, Center for Pediatric and Adolescent AIDS: Dr Steven D. Douglas, Dr Richard M. Rutstein, Carol A. Vincent, Patricia C. Coburn; St. Christopher's Hospital for Children/Drexel University College of Medicine: Dr Jill Foster, Dr Janet Chen, Dr Daniel Conway, Dr Roberta Laguerre; Bronx-Lebanon Hospital Center, Infectious Diseases: Dr Emma Stuard, Caroline Nubel, Dr Stefan Hagmann, Dr Murli Purswani; New York Medical College/Metropolitan Hospital Center: Dr Mahrukh Bamji, Dr Indu Pathak, Dr Savita Manwani, Dr Ekta Patel; University of Massachusetts Memorial Children's Medical School, Department of Pediatrics: Dr Katherine Luzuriaga, Dr Richard Moriarty; Baystate Health, Baystate Medical Center: Dr Barbara W. Stechenberg, Dr Donna J. Fisher, Dr Alicia M. Johnston, Maripat Toye; Connecticut Children's Medical Center: Dr Juan C. Salazar, Kirsten Fullerton, Gail Karas; Medical College of Georgia School of Medicine, Department of Pediatrics, Division of Infectious Disease: Dr Stuart Foshee, Dr Chitra S. Mani, Dr Denis L. Murray, Dr Christopher White; University of South Alabama College of Medicine, Southeast Pediatric ACTU: Dr Mary Y. Mancao, Dr Benjamin Estrada; LSU Health Sciences Center: Dr Ronald D. Wilcox; Tulane University Health Sciences Center: Dr Margarita Silio, Dr Thomas Alchediak, Cheryl Borne, Shelia Bradford; St Josephs Hospital and Medical Center, Cooper University Hospital - Children's Hospital Boston, Division of Infectious Diseases, David Geffen School of Medicine at UCLA - Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Orange County, Children's Memorial Hospital - Department of Pediatrics, Division of Infectious Disease, University of Chicago - Department of Pediatrics, Division of Infectious Disease, Mt. Sinai Hospital Medical Center - Chicago, Women's and Children's HIV Program, Columbia University Medical Center, Pediatric ACTU, Incarnation Children's Center, Cornell University, Division of Pediatric Infectious Diseases and Immunology, University of Miami Miller School of Medicine - Jackson Memorial Hospital, Bellevue Hospital (Pediatric), San Francisco General (Pediatric), Phoenix Children's Hospital, Metropolitan Hospital Center (N.Y.), University of Cincinnati, SUNY Downstate Medical Center, Children's Hospital at Downstate, North Shore University Hospital, Jacobi Medical Center, University of South Florida - Department of Pediatrics, Division of Infectious Diseases, Cornell University, Oregon Health and Science University - Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of the King's Daughters, Infectious Disease, Lincoln Medical and Mental Health Center, Mt. Sinai School of Medicine, Division of Pediatric Infectious Diseases, Emory University Hospital, San Juan City Hospital, UMDNJ - Robert Wood Johnson, Ramon Ruiz Arnau University Hospital, Medical University of South Carolina, SUNY Upstate Medical University, Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan, Children's Hospital at Albany Medical Center, Children's Medical Center of Dallas, Children's Hospital - University of Colorado at Denver and Health Sciences, Center, Pediatric Infectious Diseases, Columbus Children's Hospital, University of Florida College of Medicine - Department of Pediatrics, Division of Immunology, Infectious Diseases and Allergy, University of Mississippi Medical Center, Palm Beach County Health Department, Children's Hospital LA - Department of Pediatrics, Division of Adolescent Medicine, Vanderbilt University Medical Center, Division of Pediatric Infectious Diseases, Washington University School of Medicine at St. Louis, St. Louis Children's Hospital, Children's Hospital and Medical Center, Seattle ACTU, Oregon Health Sciences University, St. Luke's-Roosevelt Hospital Center, Montefiore Medical Center - Albert Einstein College of Medicine, Children's Hospital, Washington, D.C., Children's Hospital of the King's Daughters, University of Alabama at Birmingham, Department of Pediatrics, Division of Infectious Diseases, Columbus Regional HealthCare System, The Medical Center, Sacred Heart Children's Hospital/CMS of Florida, Bronx Municipal Hospital Center/Jacobi Medical Center.
Financial disclosures: None reported.
Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). Additional data for a subset of the study population was collected under the Eunice Kennedy Shriver National Institute of Child Health and Human Development cooperative agreement #3 U01 HD052102-06S3 with the Pediatric HIV/AIDS Cohort Study Data and Operations Center (PHACS-DOC).
Conflicts of interest
There are no conflicts of interest.
1. Steinherz LJ, Brochstein JA, Robins J. Cardiac involvement in congenital acquired immunodeficiency syndrome
. Am J Dis Child
2. Joshi VV, Gadol C, Connor E, Oleske JM, Mendelson J, Marin-Garcia J. Dilated cardiomyopathy in children with acquired immunodeficiency syndrome: a pathologic study of five cases
. Hum Pathol
3. Johann-Liang R, Cervia JS, Noel GJ. Characteristics of human immunodeficiency virus-infected children at time of death: an experience in the 1990s
. Pediatr Infect Dis J
4. Brady MT, Oleske JM, Williams PL, Elgie C, Mofenson LM, Dankner WM, et al. Declines in mortality rates and changes in causes of death in HIV-1-infected children during the HAART era
. J Acquir Immune Defic Syndr
5. Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age.
MMWR Morb Mortal Wkly Rep
6. World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children.
Geneva, Switzerland: WHO Press; 2007.
7. Lipshultz SE, Chanock S, Sanders SP, Colan SD, Perez-Atayde A, McIntosh K. Cardiovascular manifestations of human immunodeficiency virus infection in infants and children
. Am J Cardiol
8. Lipshultz SE, Orav EJ, Sanders SP, Hale AR, McIntosh K, Colan SD. Cardiac structure and function in children with human immunodeficiency virus infection treated with zidovudine
. N Engl J Med
9. Luginbuhl LM, Orav EJ, McIntosh K, Lipshultz SE. Cardiac morbidity and related mortality in children with HIV Infection
10. Domanski MJ, Sloas MM, Follmann DA, Scalise PP, Tucker EE, Egan D, Pizzo PA. Effect of zidovudine and didanosine treatment on heart function in children infected with human immunodeficiency virus
. J Pediatr
11. Starc TJ, Lipshultz SE, Kaplan S, Easley KA, Bricker JT, Colan SD, et al. Cardiac complications in children with human immunodeficiency virus infection
12. Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, et al. Cardiac dysfunction and mortality in HIV-infected children: the prospective P2C2 HIV multicenter study
13. Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, et al. Absence of cardiac toxicity of zidovudine in infants
. N Engl J Med
14. Starc TJ, Lipshultz SE, Easley KA, Kaplan S, Bricker JT, Colan SD, et al. Incidence of cardiac abnormalities in children with human immunodeficiency virus infection: the prospective P2C2 HIV study
. J Pediatr
15. Fisher SD, Easley KA, Orav EJ, Colan SD, Kaplan S, Starc TJ, et al. Mild dilated cardiomyopathy and increased left ventricular mass predict mortality: the prospective P2C2 HIV multicenter study
. Am Heart J
16. Al-Attar I, Orav EJ, Exil V, Vlach SA, Lipshultz SE. Predictors of cardiac morbidity and related mortality in children with acquired immunodeficiency syndrome
. J Am Coll Cardiol
17. Lubega S, Zirembuzi GW, Lwabi P. Heart disease among children with HIV/AIDS attending the paediatric infectious disease clinic at Mulago Hospital
. Afr Health Sci
18. Brown SC, Schoeman CJ, Bester CJ. Cardiac findings in children admitted to a hospital general ward in South Africa: a comparison of HIV-infected and uninfected children
. Cardiovasc J S Afr
19. Okoromah CA, Ojo OO, Ogunkunle OO. Cardiovascular dysfunction in HIV-infected children in a sub-Saharan African country: comparative cross-sectional observational study
. J Trop Pediatr
20. Calabrese LH, Proffitt MR, Yen-Lieberman B, Hobbs RE, Ratliff NB. Congestive cardiomyopathy and illness related to the acquired immunodeficiency syndrome (AIDS) associated with isolation of retrovirus from myocardium
. Ann Intern Med
21. Grody WW, Cheng L, Lewis W. Infection of the heart by the human immunodeficiency virus
. Am J Cardiol
22. Lipshultz SE, Fox CH, Perez-Atayde AR, Sanders SP, Colan SD, McIntosh K, Winter HS. Identification of human immunodeficiency virus-1 RNA and DNA in the heart of a child with cardiovascular abnormalities and congenital acquired immune deficiency syndrome
. Am J Cardiol
23. Twu C, Liu NQ, Popik W, Bukrinsky M, Sayre J, Roberts J, et al. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways
. Proc Natl Acad Sci U S A
24. Fiala M, Popik W, Qiao JH, Lossinsky AS, Alce T, Tran K, et al. HIV-1 induces cardiomyopathy by cardiomyocyte invasion and gp120, Tat, and cytokine apoptotic signaling
. Cardiovasc Toxicol
25. Monsuez JJ, Escaut L, Teicher E, Charniot JC, Vittecoq D. Cytokines in HIV-associated cardiomyopathy
. Int J Cardiol
26. Satoh M, Minami Y, Takahashi Y, Nakamura M. Immune modulation: role of the inflammatory cytokine cascade in the failing human heart
. Curr Heart Fail Rep
27. Lewis W, Papoian T, Gonzalez B, Louie H, Kelly DP, Payne RM, et al. Mitochondrial ultrastructural and molecular changes induced by zidovudine in rat hearts
. Lab Invest
28. Lewis W. Cardiomyopathy in AIDS: a pathophysiological perspective
. Prog Cardiovasc Dis
29. Lewis W. Mitochondrial DNA replication, nucleoside reverse-transcriptase inhibitors, and AIDS cardiomyopathy
. Prog Cardiovasc Dis
30. Burkis G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors
. Antimicrob Agents Chemother
31. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway
32. Benbrik E, Chariot P, Bonavaud S, Ammi-Saïd M, Frisdal E, Rey C, et al. Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells
. J Neurol Sci
33. Medina DJ, Tsai CH, Hsiung GD, Cheng YC. Comparison of mitochondrial morphology, mitochondrial DNA content, and cell viability in cultured cells treated with three antihuman immunodeficiency virus dideoxynucleosides
. Antimicrob Agents Chemother
34. Saitoh A, Fenton T, Alvero C, Fletcher CV, Spector SA. Impact of nucleoside reverse transcriptase inhibitors on mitochondria in human immunodeficiency virus type 1-infected children receiving highly active antiretroviral therapy
. Antimicrob Agents Chemother
35. Mondy KE, Gottdiener J, Overton ET, Henry K, Bush T, Conley L, et al. High prevalence of echocardiographic abnormalities among HIV-infected persons in the era of highly active antiretroviral therapy
. Clin Infect Dis
36. Gortmaker SL, Hughes M, Cervia J, Brady M, Johnson GM, Seage GR, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1
. N Engl J Med
37. Lipshultz SE, Sleeper LA, Towbin JA, Lowe AM, Orav EJ, Cox GF, et al. The incidence of pediatric cardiomyopathy in two regions of the United States
. N Engl J Med
38. Dalakas MC, Semino-Mora C, Leon-Monzon M. Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2’3’-dideoxycytidine (ddC)
. Lab Invest
39. Patel K, Hernán MA, Williams PL, Seeger JD, McIntosh K, Dyke RB, et al. Long-term effects of highly active antiretroviral therapy on CD4 evolution among children and adolescents infected with HIV: five years and counting
. Clin Infect Dis
40. Van Dyke RB, Wang L, Williams PL. Toxicities associated with dual nucleoside reverse transcriptase inhibitor regimens in HIV-infected children
. J Infect Dis