What Is Pharmacovigilance and Why Is It Important?
Margarett Davis, MD, MPHCenters for Disease Control and Prevention
Atlanta, Georgia
ART in Pregnancy, Breastfeeding, and BeyondJohannesburg, Republic of South Africa
18-20 June, 2012
• 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
Who we are and what we will cover
Pharmacovigilance
• 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
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
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.
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 for EFV in pregnancy is limited - need to ensure high quality evidence to respond to concerns raised by animal studies
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.
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
Efavirenz Preclinical Animal Studies
• 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.
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
19 Studies with Birth Defect Data with 1st Trimester EFV ExposureFord N et al. AIDS 2011;25:2301-4
Study# EFV 1st trimester
Mean duration
# Live births # Birth Defects (live births)
# Neural Tube Defect
Westreich 60 NS 60 0 -
APR 623 NS 623 17 1 (meningomyelocoele) *
Bera 195 39 wks 184 5 0
Townsend 205 NS 204 5 0
Oliveria 17 NS 17 0 -
Machado 19 NS 18 1 0
Gonzales-Tome 31 2 mos 31 7 0
Rossouw 37 NS 31 0 -
Bussman 38 43 days 22 1 0
Floridia 39 NS 32 2 0
Joao 23 15 wks 21 0 -
Jeantils 12 8 wks 7 1 0
Patel 19 40 days 19 0 -
Batallan 5 23.7 wks 5 0 -
Phanuphak 7 NS 6 0 -
Ekouevi 203 59 days 147 0 -
Cressey 4 NS 4 0 -
Blood 2 NS 1 0 -
Areechokchai 5 NS 5 0 -
TOTAL 1544 - 1437 39/1437 =2.7%
1/1437 =0.07% (0.002-0.39%)
*1 additional CNS defect (but not neural tube): anophthalmia, facial clefts, arm amniotic band
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
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.
Safety of In Utero ARV Exposure for Infant
• 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.
Many thanks!
Contact details:
Margarett DavisChief, MCH BranchTWG Co-chair: PMTCT and Peds Care & TxDivision of Global HIV/AIDSCenter for Global HealthCenters for Disease Control and [email protected]
