Safety of Tenofovir During Pregnancy: Association with Low Birth Weight and Infant Growth

1. Safety of Tenofovir During Pregnancy:Association with Low Birth Weight and Infant Growth G.K. Siberry, P.L. Williams, H. Mendez, G. Seage, D.L. Jacobson, R. Hazra, K. Rich, R. Griner, K. Tassiopoulos, D. Kacanek, L.M. Mofenson, D.H. Watts for the Pediatric HIV/AIDS Cohort Study (PHACS) XVIII International AIDS Meeting- WEAX0103 July 2010, Vienna

2. Tenofovirdisoproxilfumarate (TDF) • Adults: Therapy • First line: Clinical trial-demonstrated efficacy • Pregnant women: Therapy • First line: UK. Alternative: WHO, US • Pregnant women: PMTCT • First line: UK, WHO. Alternative: US • Adolescents: Therapy • US Adult vsPed Guidelines for adolescents in early puberty • 2010: FDA approval down to 12 yrs old • Infants/Children: Not first line • Limited formulation. Limited PK data. Bone concerns.

3. TDF: Concern in Pregnancy • Tenofovir studies in animals (Tarantal 2002; Van Rompay 2004; Van Rompay 2008) • TFV passes through placenta to fetus • Increased bone turnover in pregnant animals • Undermineralization of fetal bones • Fetal growth restriction • Effects may be related to high TFV doses • In humans, maternal TDF, converted to TFV, passes through placenta to fetus (Hirt 2009) • Increasing use of TDF during pregnancy (Griner CROI 2010) • Limited human data about infant outcomes after maternal TDF (Nurutdinova 2008) • 14 infants exposed to TDF in utero. All HIV neg. Normal Weight and Length and development at birth and 12 months old (chart review) • AIDS2010- THPE0148-Rosso et al. No effects on birthweight, 9 TDF exposed Thai infants

4. Study Objective • Evaluate association of maternal TDF use with growth measures (weight, length, head circumference) at birth and at one year of age.

5. Surveillance Monitoring for Antiretroviral Therapy Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network • “Dynamic” cohort • HIV-exposed (uninfected)infants enrolled by 2 wks old • Visits at entry (birth-2 wks), 12 mos, then year • “Static” cohort • HIV-exposed (uninfected) children enrolled at 12 mos – 12 yrs old • Visit at entry, then yearly Study Population

6. Growth measurement data • Dynamic cohort: Weight, length, head circumference (HC) and gestational age (GA) are collected at birth and growth measurements obtained annually. • Static cohort: Birth weight and GA collected retrospectively. Age 1 growth measures only collected if enrolled at age 1. • Standardized protocols for body measurements at study visits (each performed 3 times) • Maternal information collected from prior studies or chart review for Static cohort, prospectively for Dynamic cohort • Maternal Antiretroviral (ARV) use, CD4, viral load, substance use information (alcohol, tobacco, illicit drugs) • Other information collected by interview at enrollment (demographic, SES) Methods: Data Collection

7. Low birth weight (LBW) defined as <2.5 kg • Low z-scores for weight, length, and HC defined as those with z<-1.5 (~7th percentile) • CDC 2000 growth standards, Age and sex-adjusted • Length and HC at birth • Weight, length and HC at 1 year of age • Logistic regression models used to evaluate associations between in uteroTDF exposure and above 6 outcomes • Controlled for a wide range of potential confounders Statistical Outcomes and Methods

8. TDF exposure = TDF use at any time during pregnancy • Limited to women on HAART (≥3 drugs, ≥2 classes) • HAART with TDF vs HAART without TDF (primary) • Duration of TDF use during pregnancy (secondary) • Potential confounders • Sociodemographic factors (sex, race, ethnicity, income, caregiver education level, marital status) • Maternal health status (VL, CD4, genital infections) • Maternal substance use (alcohol, tobacco, illicit drugs) • Sensitivity analyses performed for confounders potentially on causal pathway (gestational age) or highly correlated with TDF exposure (birth year) Statistical Methods: Exposures

9. Results: Sample Size • Birth Weight: 1887 • Evaluated on all enrolled (Static + Dynamic) • Birth Length & HC: 739 • Available only from Dynamic cohort • Growth Measures at One Year: 532 • Weight, Length and HC • 356 Dynamic, 176 Static

10. Results: TDF Exposure and LBW • Maternal TDF Use • TDF use increased from 15% in 2003 to 39% in 2009 • Overall, 21% of participants were exposed to TDF • 12% used TDF from the 1st trimester • Low Birth Weight Outcome (LBW, <2.5kg) • 20% of infants had LBW • No difference by TDF exposure (20.7% vs 19.5%) • No increased risk of LBW in models adjusting for maternal high VL, low CD4, and alcohol or substance use (aOR: 1.03, 95% CI: 0.75-1.40, p=0.87)

11. RESULTS: Association of TDF HAART (vs non-TDF HAART) During Pregnancy and Growth Outcomes at BIRTH 2 Adjusted for covariates with p<0.10. -For LBW: high maternal VL, low maternal CD4, maternal alcohol or tobacco during pregnancy; -For short birth length: female sex, mother < 25 yrs old, and maternal alcohol or tobacco use during pregnancy; -For small HC: maternal use of illicit drugs, and low income level.

12. RESULTS: Association of TDF HAART (vs non-TDF HAART) During Pregnancy and Growth Outcomes at ONE YEAR 2 Adjusted for covariates with p<0.10. -For low weight at 1 year: no covariates identified as being associated; -For short length at 1 year: high maternal VL, low maternal CD4 percent; -For small HC at 1 year: high maternal VL, maternal use of illicit drugs.

13. Results: Additional Analyses • Sensitivity Analyses: Gestational age and year of birth were significantly associated with LBW, BUT minimal effect on association of TDF exposure and low weight • No association was observed with duration of TDF exposure (aOR for each additional month of exposure: 1.02, 95% CI: 0.97-1.07, p=0.46)

14. Summary • We observed NO association of in uteroTDF exposure with LBW. • There was NO significant increase in risk of short length or small HC at birth or at age 1 based on TDF exposure. • TDF exposure was associated with low weight at age 1. • Remained marginally significant after adjustment for GA • >99% infant took ZDV proph (10% with add’l ARV proph) • Potential for residual confounding • Reported delayed clinical effects after ARV exposure: • Lower CD8+ counts (Pacheco 2006); Mitochondrial dysfunction- neuro, developmental and growth (Blanche1999); Febrile seizures (Landreau 2002); Trend for CNS cancer (Benhammou 2008) • This association requires confirmation in further studies.

15. National Heart, Lung and Blood Institute National Institute of Allergy and Infectious Diseases National Institute on Deafness and Other Communication Disorders Acknowledgements PHACS is funded by the following Institutes: Under cooperative agreements 5U01HD052104-04 (Coordinating Center, Tulane University) and 1U01HD052102-04 (Data and Operations Center, Harvard School of Public Health). We would also like to thank the Study Participants, PHACS Community Advisory Board, Frontier Science Inc., and Westat.

16. Acknowledgements • The following institutions participated in conducting PHACS in 2009: • Baylor College of Medicine • Bronx Lebanon Hospital Center • Children's Diagnostic & Treatment Center • Children’s Hospital, Boston • Children’s Hospital of Philadelphia • Children’s Memorial Hospital • Jacobi Medical Center • New York University School of Medicine • St. Christopher’s Hospital for Children • St. Jude Children's Research Hospital • San Juan Hospital/Department of Pediatrics • SUNY Downstate Medical Center • SUNY Stony Brook • Tulane University Health Sciences Center • University of Alabama, Birmingham • University of California, San Diego • University of Colorado Health Sciences Center • University of Florida/Jacksonville • University of Illinois, Chicago • University of Maryland, Baltimore • University of Medicine and Dentistry of New Jersey • University of Miami • University of Southern California • University of Puerto Rico Medical Center