Transcript Margarett Davis

What Is Pharmacovigilance
and Why Is It Important?
Margarett Davis, MD, MPH
Centers for Disease Control and Prevention
Atlanta, Georgia
ART in Pregnancy, Breastfeeding, and Beyond
Johannesburg, Republic of South Africa
18-20 June, 2012
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
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
–
–
–
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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
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•
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•
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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 Exposure
Ford N et al. AIDS 2011;25:2301-4
# 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
-
1544
-
1437
39/1437 =
2.7%
1/1437 =
0.07% (0.002-0.39%)
Study
TOTAL
*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 ?
•
•
•
•
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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 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
[email protected]