What Is Pharmacovigilance and Why I s I t I mportant? Margarett Davis

1. What Is Pharmacovigilanceand Why Is It Important?Margarett Davis, MD, MPHCenters for Disease Control and PreventionAtlanta, GeorgiaART in Pregnancy, Breastfeeding, and BeyondJohannesburg, Republic of South Africa18-20 June, 2012

2. Who we are and what we will cover • What Is Pharmacovigilance and Why Is It Important? • Margarett Davis • Public Health Birth Defects Surveillance • Diana Valencia • WHO Pregnancy Registry: Pilot findings • Francoise Renaud-Thery • PEPFAR Expectations • Lara Stabinski

3. Pharmacovigilance (PV) is the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term side effects of medicines. • Birth defects surveillance Pharmacovigilance

4. Why is PV Important Now? Summary • There are approximately 4 million people on lifesaving antiretrovirals, 65% of whom are women • The recommended first line treatment regimen is now TDF+3TC+EFV • Women become pregnant while on EFV-based ART and women initiate EFV-based ART when they are pregnant in PMTCT Option B+ programs • Is this a problem? We do not know the answer • Limited animal data suggest possibility of increased risk for birth defects, especially neural tube defects • We must monitor pregnancy outcomes for possible birth defects

5. Multiple Advantages of EFV over NVP • Low pill burden and once daily regimen: EFV one pill fixed dose combination (FDC) daily vs. NVP twice daily. • Lower risk of hypersensitivity and liver toxicity than NVP. • If given with TDF/3TC or FTC, effective against HBV co-infection. • Can be safely given with rifampin, resulting in better viral efficacy when given to patients with TB than NVP.

6. Concerns about Safety of EFV • Current concerns are the result of animal studies with unclear predictive value for humans • However, human data to date have not shown any increased risk for birth defects with EFV use in 1st trimester • Human data now >1,000 1st trimester exposures with 1 neural tube defect reported (Ford N et al. AIDS 2012). • ARV safety data forEFV in pregnancy is limited - need to ensure high quality evidence to respond to concerns raised by animal studies

7. What data do we have and what do these data tell us about EFV and birth defects? • Data • Case reports, case series, pregnancy registries • APR= Antiretroviral Pregnancy Registry • Other registries • Special studies: animal and human studies • These data sources are important; they provide signals indicating possible problems resulting from exposures, like an ARV.

8. What data do we have and what do these data tell us about EFV and birth defects? However, they do not provide adequate information to give us the prevalence estimates and risk estimates we want • Unclear denominator • Passive voluntary reporting • Not population-based • No baseline prevalence for comparison

9. 20 pregnant cynomolgus monkeys dosed during pregnancy (postcoital day 20-150) with EFV 60 mg/kg/day and 20 pregnant control monkeys received no drug. • This dose results in plasma concentrations in monkey similar to humans given 600 mg/day EFV; EFV crosses placenta and results in fetal drug levels similar to maternal levels. • 3/20 EFV-exposed monkeys had neural tube like defects vs. 0/20 monkeys with no EFV exposure: • Anencephaly, microphthalmia, and unilateral anophthalmia • Cleft palate • Rats: increased fetal resorptions at doses resulting in plasma and AUC levels similar to humans. • Rabbits: no toxicity with doses producing plasma concentrations similar to and AUC value half those in humans. Efavirenz Preclinical Animal Studies

10. Antiretroviral Pregnancy Registry • International registry jointly sponsored by manufacturers of all ARV drugs. • Voluntary registration of prenatal exposures by treating providers (international). • Purpose: to estimate risk of major birth defects and compare to that of general population (CDC’s population-based birth defects surveillance system). • Contact information: • Telephone: (800) 258-4263 • Fax: (800) 800-1052 • Available at http://www.apregistry.com

11. 19 Studies with Birth Defect Data with 1st Trimester EFV ExposureFord N et al. AIDS 2011;25:2301-4 *1 additional CNS defect (but not neural tube): anophthalmia, facial clefts, arm amniotic band

12. Should women in their first trimester be on drugs whose safety has been questioned but not proven? • Pre-conceptional planning in developing countries with high fertility usually not feasible. • Evidence should be substantial to change a treatment regimen when the alternative could be harmful • We do not have human data that are concerning, but the best answer will come from high quality BD surveillance, not from case series or voluntary exposure registries • Must monitor with excellent data quality while EFV is in use to either elevate concern or to gain reassurance of safety

13. Pharmacovigilance: What do we need? • Excellent data documenting both exposures of interest (e.g. EFV) and adverse pregnancy outcomes (e.g. NTDs) • How do we conduct birth defects surveillance for this purpose ? • Systematically determine an accurate denominator • Document all birth outcomes (normal and abnormal) • Document timing of exposures of interest • Link to infant outcomes. • This requires active case ascertainment, rather than passive reporting of cases.

14. Any long-term adverse consequence for a child would need to be severe, common, and early to outweigh benefit of prevention of transmission of fatal or chronic HIV infection. • At the present time, known risks do not outweigh the known benefits of ARVs. However, continued surveillance is required. Safety of In Utero ARV Exposure for Infant

15. Many thanks! Contact details: Margarett Davis Chief, MCH Branch TWG Co-chair: PMTCT and Peds Care & Tx Division of Global HIV/AIDS Center for Global Health Centers for Disease Control and Prevention mdavis@cdc.gov