1 Predictors of Cardiac Dysfunction among Children and Adolescents Perinatally-Infected with HIV-1. Kunjal Patel, Murray A. Mittleman, Steven D. Colan, James M. Oleske, Keyoor Patel, Russell B. Van Dyke and George R. Seage III, for the International Maternal Pediatric Adolescent AIDS Clinical Trials 219/219C Study Team.

2 HIV-associated Cardiomyopathy (CM) First pediatric cases reported in the late 1980s among children with AIDS. – –Presented with congestive heart failure or signs and symptoms of cardiovascular compromise. (Steinherz et al. 1986, Joshi VV et al. 1988) – –Left ventricular dysfunction and dilatation on echocardiography or autopsy. Added as a CDC Category B diagnosis in the 1994 revised classification for HIV infection in children < 13 years of age.

3 Cardiomyopathy (CM) Pathogenesis Direct infection of cardiac myocytes by HIV. (Grody et al. 1990) HIV replication in myocardial inflammatory cells cytokine production apoptosis of cardiomyocytes. (Monsuez et al. 2007) Nucleoside Reverse Transcriptase Inhibitor (NRTI) induced mitochondrial toxicity. –Selective inhibition of DNA polymerase . –Potency of inhibition: (Birkus et al. 2002) DDC>DDI>D4T>ZDV>3TC=ABC=TDF

4 Studies of Cardiac Structure and Function in HIV-infected Children US: Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P 2 C 2 ) and Children’s Hospital Boston –5-year cumulative incidence of cardiac dysfunction (Left Ventricular Fractional Shortening (LVFS) ≤25%, use of cardiac medications, heart failure): 18-39% –Associated with an increased risk of mortality Uganda (Mulago Hospital): 17% with LVFS<28% South Africa: 17% LVFS≤25%

5 Antiretroviral Therapy and CM P 2 C 2 Study (Lipshultz et al. 2000) –382 children followed for 14 months. –Exposure to ZDV in the perinatal period not associated with LV dysfunction. NCI Study (Domanski et al. 1995) –137 children followed for mean of 2 yrs. –Odds of CM (ZDV + vs. -): 8.4 (1.7, 4.2). –No association with DDI.

6 Specific Aims of Present Study Determine the effect of HAART on the incidence of cardiac dysfunction (CM and/or use of cardiac medications). Identify predictors of cardiac dysfunction among HAART users.

7 Pediatric AIDS Clinical Trials Group (PACTG) Protocol 219/219C Prospective cohort study of HIV-exposed children (infected and uninfected) from >80 clinical sites in the US including Puerto Rico. –Assess the long-term effects of HIV infection and in utero and postnatal exposure to antiretroviral therapy. Extensive clinical, neuropsychological, and laboratory evaluations.

8 Study Population and Exposure 3,107 perinatally HIV-infected children followed in PACTG 219/219C from : –Prevalent cases of cardiac dysfunction noted and then excluded. –Children with diabetes or those who had undergone cardiotoxic chemotherapy excluded. HAART defined as using ≥3 drugs from ≥2 different classes of HIV therapy (NRTIs, NNRTIs, or PIs). –Once initiating HAART, subjects were assumed to remain on HAART for the duration of follow-up.

9 Outcome – “Cardiac Dysfunction” CM diagnosis extracted from medical records and reported on diagnosis forms. –Study Definition: Left or right ventricular diastolic/systolic dimensions ≥ 2 SD from the mean for body surface area OR Abnormal fractional shortening index ≥ 2 SD from the mean. Use of cardiac medications: –Digoxin or Dobutamine.

10 Follow-up and Analytic Approach Study participants were followed to the date of CM diagnosis, initiation of cardiac medication, death, or the last study visit before May 31, 2007 (date of closure of PACTG 219/219C), whichever came first. Cox Regression Model with time-varying treatment (HAART vs. Non-HAART regimens). –Age, birth cohort, gender, race/ethnicity, in-utero ART exposure, in-utero exposure to illicit drugs, alcohol, or tobacco, birthweight, CD4%, CDC clinical category, (viral load). –Time-varying DDC use, DDI use, D4T use, ZDV use.

11 Results (1) 136 prevalent cases of cardiac dysfunction identified at baseline: –Prevalence = 4.2% (95% CI: 3.5, 4.9). –Median age at diagnosis/cardiac medication initiation = 4.5 years (Q1, Q3: 1.8, 7.2). Baseline characteristics of 3,107 followed for incident analyses: –43% ≤ 5 years of age, 82% born before –51% Female, 57% Black, 27% Hispanic. –17% with CD4<15%, 26% with CDC C disease. ► Median length of follow-up = 5.4 years (Q1, Q3: 2.8, 7.7).

12 Results (2) By end of follow-up: –102 incident cases of cardiac dysfunction. 16 with diagnosis and medication use 81 with diagnosis only 5 with medication use only –5.7 per 1000 person-years (95% CI: 4.7, 7.0). –Median age at diagnosis/medication initiation = 9.5 years (Q1, Q3: 6.1, 12.8). –Deaths among incident cases: N=38. Proportion of incident cases who died during follow-up: 37%.

HR* (95% CI)p-value Antiretroviral Therapy HAART regimens Non HAART regimens 0.4 (0.3, 0.7) Referent DDC use No DDC use 1.9 (1.2, 3.1) Referent Baseline CD4% <15% 15-24% ≥25% 4.0 (2.4, 6.6) 1.7 (1.0, 2.9) Referent < CDC clinical stage at Baseline Stage C Stage N/A/B 1.7 (1.1, 2.6) Referent *Hazard ratio also adjusted for birth cohort, gender, race/ethnicity, in-utero ART exposure, time-varying ZDV and D4T use. (p<0.05) 13 Estimated Effect of HAART on Cardiac Dysfunction

14 Predictors of Cardiac Dysfunction among HAART initiators HR (95% CI)p-value Age at HAART initiation (years) ≤ > 10 Referent 3.8 (1.3, 11.1) 4.2 (1.3, 13.3) Lowest CD4% after HAART initiation <15% 15-24% ≥ 25% 5.4 (1.6, 18.0) 2.5 (0.7, 9.1) Referent DDC use prior to HAART initiation Yes No 2.2 (1.0, 4.7) Referent

15 Limitations Survivor cohort – children were not followed from birth: –Generalizability of incidence estimate. Viral load not available for most children in earlier years – unable to adjust. Outcome misclassification possible: –Echocardiographic confirmation of recorded diagnoses not available.

16 Conclusions HAART regimens associated with a decreased risk of cardiac dysfunction among HIV-infected children. –reduction in viral load direct infection of cardiac myocytes or pro-inflammatory cytokines? This benefit overwhelms any potential mitochondrial toxicity associated with NRTIs included in HAART regimens? Vigilance for cardiac dysfunction in the HAART era essential, especially if poor immune status, prior DDC exposure and HAART started at an older age.

17 Acknowledgements Children and Families of IMPAACT (formerly PACTG) 219/219C. PACTG/IMPAACT 219/219C Team and Participating Institutions. Funded by US National Institutes of Health (NIAID, NICHD: U01 AI068632, #5 U01 AI41110, #1 U01 AI068616).

Frequency of Incident Cases by Calendar Year of Diagnosis 18

Derivation of Study Population 19 N=3555 infected children in P219/219C N=3277 perinatally-infected children N=3268 excluded inadvertent enrollees N=3252 excluded children who took chemotherapy (adriamycin, daunorubicin, epirubicin, mitoxantrone, and radiation therapy) N=3243 excluded children who had a diagnosis of diabetes