Neurodevelopmental Status and in utero Antiretroviral Exposure in HIV-Exposed Uninfected Infants

1. Neurodevelopmental Status and in utero Antiretroviral Exposure in HIV-Exposed Uninfected Infants Paige Williams Miguel Marino, Kay Malee, Susan Brogly, Michael Hughes and Lynne Mofenson, for the IMPAACT 219/219C Team August 4, 2008 International AIDS Conference Mexico City

2. Background Despite the great success of antiretroviral treatment (ART) in PMTCT, concerns remain regarding the safety of these drugs in HIV-uninfected ART-exposed infants, and safety data are relatively limited: • Animal studies: have suggested increased risks of congenital malformations, carcinogenic effects, and mitochondrial toxicity • Human studies: have generally been reassuring, but there have been reported effects on birth weight, anemia, and other hematological measures. • Mitochondrial toxicity: Some studies indicate potential associations withcertain nucleoside analogs, particularly zidovudine plus lamivudine (ZDV+3TC).

3. Studies of Neurodevelopmental Functioning in HIV-exposed Uninfected Children • Few studies have evaluated cognitive and motor functioning in uninfected children • Most have focused on comparisons with HIV-infected children: • Women and Infants Transmission Study (WITS):(Chase et al, 2000) • PACTG 219/219C Cohort:(Lindsey et al, 2007) • One recent study specifically evaluated the effect of HAART in 39 uninfected subjects versus 24 unexposed controls (Alimenti et al, 2006)

4. OUR STUDY OBJECTIVE: To evaluate whether HIV-uninfected children exposed in utero to ART have different neurodevelopmental functioning than those without ART exposure • controlling for many possible confounders • based on >1800 uninfected children born to HIV-infected mothers enrolled in the PACTG 219/219C prospective cohort study

5. Methods • Patients:1840 HIV-exposed uninfected children enrolled in PACTG 219/219C, who had a valid Bayley test of infant development. • Study background: PACTG 219/219C was a prospective cohort study which followed over 5000 children born to HIV-infected mothers between 1993-2006 at >80 sites in the US and Puerto Rico, for long-term outcomes of HIV exposure and ART (~2300 uninfected). • ART Exposure for Uninfected:Collected at birth or within the first year of life, supplemented with perinatal treatment trials data.

6. Neurodevelopmental Assessments • Bayley Scales of Infant Development: considered the standard for measuring cognitive and motor development in children under 3 years of age. • Bayley Outcomes: • Cognitive: Mental Developmental Index (MDI) • Motor:Psychomotor Developmental Index (PDI) • Each standardized to have mean 100 and SD=15 in the normal U.S. population • We selected assessment closest to 2 years of age (measured every ~6 months). • Change in Test Version: The Bayley II test was implemented around 1995-1996, and tended to yield lower test scores.

7. Statistical Methods Linear Regression Models: Used to evaluate the association of in utero ART exposure on MDI and PDI scores in HIV-uninfected children at age 2, controlling for potential confounders • Sensitivity analysis by Bayley test version: since shift in version coincided with increased use of ART (N=449 on VI, N=1391 on V2) • Subgroup analyses:includes those with • maternal viral load data (N=936, 51%) • maternal substance use data (N=1162, 63%)

8. Covariates Included in Analyses • Age at test • Gender • Race/Ethnicity (White, Black, Hispanic) • Primary language (English, not English) • Primary caregiver (biological parent or not) • Primary caregiver education level (< HS, HS Grad, College/Technical School, College Grad, other) • Low birth weight (<2500 g) • BAYLEY Test Version (I vs II) • Site characteristics (geographic region; urban/rural) • (Maternal substance use, maternal viral load)

9. Results

10. Study Population Characteristics for HIV-uninfected Children (N=1840) • 50% female, 55% Black, 32% Hispanic • 26% non-English primary language • 65% of caregivers had graduated high school • 16% born at low birth weight (LBW: < 2500g) • 8% unexposed in utero to antiretrovirals (n=146) • Demographic and caregiver characteristics did not differ significantly by prenatal ART exposure, but exposed were more likely to be born after 1994, and more likely to be assessed by Bayley II.

11. Mean Mental Developmental Index (MDI), Adjusted for All Potential Confounders Among HIV-uninfected children, ART-exposed had marginally higher cognitive scores than unexposed after adjustment for all other covariates.

12. Mean Psychomotor Developmental Index (PDI), Adjusted for All Potential Confounders There was no difference in the adjusted mean motor scores between ART-exposed and unexposed HIV-uninfected children.

13. ART Exposure by Birth Weight Interaction • We identified a significant interaction (p=0.003) between ART exposure and low birth weight (LBW) • Among LBW infants, ART-exposed had significantly higher cognitive and motor scores, by 10-12 points Adjusted Mean Bayley Score Low Birth Weight P=0.73 P=0.76 P=0.01 P<0.01

14. Bayley Test Version • To ensure previous results were not confounded by Bayley test version, separate models were fit for each version (V1: N=449, V2: N=1391). • Within each test version, adjusted means for exposed were within 2-4 points of those for unexposed (all NS). Adjusted Mean Bayley Score ---- Bayley I ---- ---- Bayley II ----

15. Effects of Specific ART Regimens • We considered many classifications of prenatal ART exposure: • (ZDV+3TC) vs (other ART) vs (not exposed) • HAART vs (non-HAART ART) vs (not exposed) • Duration of exposure (0, 1-13, 13-27, 27-40 wks) • Exposure by trimester • None of these analyses suggested lower cognitive or motor functioning with higher levels of in utero ART exposure

16. Maternal Substance Use (N=1162) • Maternal substance use (heroin, cocaine, or stimulants) was reported for 17% of the children. • There was no difference in adjusted MDI or PDI scores by ART exposure in this subgroup, and no difference by maternal substance use.

17. Maternal Viral Load (N=936) Adjusted Mean Bayley Score • Studies have identified an effect of mother’s health status on birth weight and other key developmental outcomes. • We observed a slight decreasing trend in scores with increasing viral load, but no effect of maternal ART controlling for viral load. P=0.09 P=0.03 Viral Load (copies/mL)

18. Limitations & Conclusions • Limitations: Our study suffers from usual biases inherent in an observational study. • In particular, there may be residual confounding by socioeconomic status or access to prenatal care. • Maternal substance use was self-reported, and did not take into account frequency or trimester of use. • Strengths: This is the largest study evaluating cognitive and motor development in prenatally ART-exposed but uninfected children. • Conclusions: We found similar cognitive and motor scores between those exposed prenatally to ART vs unexposed, after adjustment for a large number of covariates.

19. Conclusions, continued • Adjustment for maternal substance use and viral load confirmed these results. We observed no effect of maternal substance use, consistent with several other studies(Chase et al. 2000; MacMillan et al. 2001; Mellins et al 2003; Lindsey et al 2007) • Separate analyses by Bayley Test Version also confirmed that cognitive and motor scores were similar for ART-exposed and unexposed. • However, among LBW infants, ART-exposed had significantly higher cognitive and motor scores. Since prenatal ART exposure may be associated with LBW, the need to adjust for LBW is unclear.

20. Conclusions, continued • We also found that those with prenatal ART exposure did not have higher rates of severe cognitive impairment (MDI<70, 13%) or motor impairment (PDI<70, 10%; results not shown). • Overall, the HIV-uninfected children in our study scored significantly below US norms, and thus may require continued follow-up.

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

22. Extra slides for questions

23. Effects of Other Covariates On Mental and Motor Scores • Significantly higher mental and motor scores: for females, those of normal birth weight, more highly educated caregivers, tested with Bayley I (vs Bayley II) • Significantly higher mental (but not motor) scores:forthose withEnglish as primary language, Whites, those born after 1994. • Marginal effect on motor (but not mental) scores: for type of primary caregiver (biological parent vs not). • Significant variation across sites: by geographic region, urban/rural, site size

24. Example: Effects of ZDV+3TC vs other prenatal exposure Those exposed to ZDV+3TC have slightly higher adjusted mental development scores as compared to unexposed, but no difference in motor scores.