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Hepatitis B Virus Drugs in Pregnancy:
Findings from the Antiretroviral
Pregnancy Registry
RS Brown, Jr1, M Buti2, D Goodwin3,
S Zhang3, E Fagan3
1Columbia
University College of Physicians and Surgeons,
New York, NY, USA
2Hospital Vall d’Hebron, Barcelona, Spain
3Gilead Sciences, Inc., Foster City, CA, USA
44th Annual Meeting of the European Association for the Study of the Liver
April 22 – 26, 2009
Copenhagen, Denmark
Oral #
Introduction
• Without post-exposure prophylaxis, HBV vertical
transmission rates range from 70-90% in HBsAg
positive, HBeAg positive mothers1
• Combination passive-active immunoprophylaxis with
HBIg plus HBV vaccine has a protective efficacy rate
of 85-95%2,3
• Infants acquiring HBV by vertical transmission are at
high risk for chronic HBV
• High maternal HBV DNA at the time of delivery is a
risk factor for vertical transmission
1Okada,
et al. N Engl J Med 1976;284:746-749
for Disease Control and Prevention, MMWR 2005;54(RR16):1-23
3Wiseman, et al. 59th AASLD 2008; Abstract 827.
2Centers
Introduction
• Lamivudine (LAM) and tenofovir disoproxil fumarate
(TDF) are both licensed for the treatment of chronic
HIV-1 and HBV infection
– FDA Pregnancy Categories
• LAM: category C, TDF: category B
• LAM- and TDF-containing regimens are well tolerated
in pregnancy and reduce vertical transmission of
HIV-1 in animal models and in humans1-4
• Use of LAM and TDF to reduce vertical transmission
of HBV is of interest, but safety and efficacy data are
limited5,6
1European
Collaborative Study. Clin Infect Dis. 2005; 40(3):458-65; 2European Collaborative Study.
J Acquir Immune Defic Syndr. 2003; 32(4):380-387; 3Mandelbrot, et al. JAMA 2001;285:2083-2093;
4Van Rompay, et al. Antimicrob Agents Chemother 2008;52:3144-3160; 5van Zonneveld, et al. J Viral Hepat
2003;10:294-287; 6Xu, et al. J Viral Hepat 2009;16:94-103.
Antiretroviral Pregnancy Registry (APR)
• APR is an international prospective exposure-registration cohort study
established in January 1989 to monitor major teratogenic effects of
antiretroviral (ARV) drugs and anti-HBV drugs following exposure
during pregnancy
– Data collection on exposure in HBV mono-infection began in
January 2003
• Reporting is voluntary; data are not verified
• Majority of cases (>80%) are reported from the US
– Approximately 1300 new cases from the US and 200 new cases
from other countries are added annually
• Interim primary analysis reports are issued biannually
Antiretroviral Pregnancy Registry (APR)
• Inclusion criteria (primary analysis)
– Pregnancy must be prospectively registered with the APR
– Pregnancy outcome must be known and reported to the APR
• An independent advisory committee of members from CDC, FDA, and
NIH provides oversight of APR scientific conduct and analysis
• Current APR interim report includes 11,950 prospective cases
(includes data from January 1,1989 through July 31, 2008)
• APR began collecting data on exposure to tenofovir disoproxil fumarate
(TDF) in 2001
Study Objectives
• To identify birth defect rates for infants with in utero
exposure to ARV and anti-HBV medications, by class
and by individual drugs, using APR data
• Compare birth defect rates:
– 1st trimester NRTI regimen (including LAM) and NtRTI
regimen (tenofovir DF, adefovir dipivoxil) exposure vs. other
ARV classes
– 1st or 2nd/3rd trimester exposure LAM and TDF regimen
exposure vs. all ARV regimens
– All LAM and TDF regimen exposure vs population-based
controls
Primary Registry Analysis
Population for Analysis –
Prospective Registry Cases
(Enrolled January 1, 1989 Through July 31, 2008)
Pregnancies Enrolled
Pending Casesa
Cases Lost to Follow-Upb
Reports Used in Analysis
aCases
11950
494 (4.1%)
985 (8.2%)
10471 (87.6%)
where the outcome of pregnancy is not yet known
where the outcome of pregnancy has never been received, despite requests, or in which the reporter
did not know whether there was a birth defect
bCases
APR Primary Analysis Cases:
Maternal Demographics at Registration
Pregnancies Enrolled
10471
Median Age (interquartile range)
28.0 (9.0) yrs
≥ 500 cells/µL
3204 (30.6%)
200-499 cells/µL
4811 (45.9%)
<200 cells/µL
1902 (18.2%)
A. Asymptomatic, acute (primary) HIV or
PGLa
7591 (72.5%)
CD4+ T-Cell
Count at Start of
Pregnancy
B. Symptomatic, not (A) or (C)
HIV Infected
C.
b
AIDS-indicator conditions
963 (9.2%)
1341 (12.8%)
HIV/HBV co-infected
107 (1%)
HIV post-exposure prophylaxis
28 (0.3%)
Hepatitis B mono-infected
71 (0.7%)
HIV Uninfected
aPersistent
bAPR
generalized lymphadenopathy
started systematically collecting data on HBV in January 2003
Birth Defect Rates in APR and in Large Prospective
Cohort Studies of HIV-Infected Pregnant Women with
Exposure to ARV Medications
Earliest
Exposure to
ARVs
1st Trimester
2nd/3rd
Trimester
Any Trimester
aReporting
bAs
APR
UK and Ireland
Surveillanceb
European
Collaborative
Studyb
Number of Defects/
Live Births
126/4329
45/1236
18/880
Prevalence
(95% CI)
2.9%
(2.4 - 3.5)
3.6%
(2.7 - 4.9)
2.0%
(1.2 - 3.2)
Number of Defects/
Live Births
145/5618
114/4162
21/1765
Prevalence
(95% CI)
2.6%
(2.2 - 3.0)
2.7%
(2.3 - 3.3)
1.2%
(0.7 - 1.8)
Number of Defects/
Live Births
272/9948
159/5398
39/2645
Prevalence
(95% CI)
2.7%
(2.4 - 3.1)
2.9%
(2.5 - 3.4)
1.5%
(1.1 - 2.0)
a
period of January 1, 1989-July 31, 2008
reported in the APR interim report; data were collected December 1984-March 2007
Comparison to a Population-Based
Birth Defect Rate
• Comparison to CDC’s population-based birth defects
surveillance system, the Metropolitan Atlanta
Congenital Defects Program (MACDP)
– MACDP actively searches for birth defects among all births
in five counties of metropolitan Atlanta area (approximately
50,000 annual births)
– MACDP reported total prevalence of birth defects of 2.72%
of live births (1989-2003)
APR Advisory Consensus Statementa
For the overall population exposed to antiretroviral
drugs in this Registry, no increases in risk of
overall birth defects or specific defects have been
detected to date when compared with observed
rates for “early diagnoses” in population-based
birth defects surveillance systems or with rates
among those with earliest exposure in the second
or third trimester
aData
collected January 1, 1989 – July 31, 2008; APR interim report issued December 2008
Birth Defect Rates for First-Trimester Exposure,
By Antiretroviral Therapy Class Regimena
Birth Defects Rate (%)
5
4
65/2156
124/4200
3
3.01%
30/1110
2.95%
2.7%
2
14/636
2.2%
1
0/14
0/3
0
Any PI
Any NRTI
Any NNRTI
b
Any NtRTI
Any E I
c
Any InSTI
Antiretroviral Therapy Class
aAs
any individual ARV may have been used in combination with other ARVs, the count represents the
number of outcomes with at least one exposure in that class; data collection January 1, 1989 through
July 31, 2008; APR interim report issued December 2008
bNtRTI includes TDF (n=606), ADV (n=30)
cEI=entry inhibitor
dInSTI=integrase strand transfer inhibitor
d
Birth Defect Rates By Trimester of Earliest Exposure to TDF
Regimens and All ARV Regimens in APRa
Earliest
Exposure to
ARVs
LAM
Regimens
TDF
Regimens
All ARV
Regimens
Number of Defects/
Live Births
91/3089
14/606
126/4329
Prevalence
(95% CI)
2.9%
(2.4-3.6%)
2.3%
(1.3-3.9%)
2.9%
(2.4 - 3.5)
Number of Defects/
Live Births
121/4631
5/336
145/5618
Prevalence
(95% CI)
2.6%
(2.2-3.1%)
1.5
(0.5-3.4%)
2.6%
(2.2 - 3.0)
1st Trimester
nd
rd
2 /3
Trimester
aData
collected January 1, 1989 – July 31, 2008; APR interim report issued December 2008
CDC MACDP Birth Defect Rate = 2.72%
Birth Defect Prevalences for First Trimester Exposure to ARVs
with ≥ 200 Reported Exposuresa
Regimen
Defects/Live Births
Prevalence, % (95%CI)
Didanosine
16/362
4.4 (2.5, 7.1)
Nelfinavir
37/1066
3.5 (2.5, 4.8)
Efavirenz
13/407
3.2 (1.7, 5.4)
Emtricitabine
8/252
3.2 (1.4, 6.2)
Zidovudine
94/3068
3.1 (2.5, 3.7)
Abacavir
18/578
3.1 (1.9, 4.9)
Lamivudine
91/3089
2.9 (2.4, 3.6)
Stavudine
19/696
2.7 (1.7, 4.2)
Nevirapine
18/785
2.3 (1.4, 3.6)
Ritonavir
18/783
2.3 (1.4, 3.6)
Tenofovir DF
14/606
2.3 (1.3, 3.9)
Indinavir
6/275
2.2 (0.8, 4.7)
Atazanavir
5/246
2.0 (0.7, 4.7)
Lopinavir
8/420
1.9 (0.8, 3.7)
aData
collected January 1, 1989 – July 31, 2008; APR interim report issued December 2008
Birth Defect Prevalences for First Trimester Exposure to
Anti-HBV Drugsa
Regimen
Defects/Live Births
Prevalence, % (95%CI)
Lamivudine
91/3089
2.9 (2.4, 3.6)
Tenofovir DF
14/606
2.3 (1.3, 3.9)
Adefovir
0/30
0
Entecavir
0/2
0
Telbivudine
0/1
0
a. Data collected January 1, 1989 – July 31, 2008; APR interim report issued December 2008
APR Advisory Committee Consensus
Primary Registry Analysis (Prospective Reports)a
• In analyzing individual drugs with sufficient data to warrant a
separate analysis, no increases in risk have been detected,
with the exception of didanosine during previous years. No
pattern of birth defects has been detected with didanosine,
and no new reports of defects with didanosine exposure
have been received in recent reporting periods.
• For abacavir, atazanavir, efavirenz, emtricitabine, indinavir,
lopinavir, nelfinavir, nevirapine, ritonavir, stavudine, and
tenofovir, sufficient numbers of first trimester exposures have
been monitored to detect at least a two-fold increase in risk
of overall birth defects. No such increases have been
detected to date.
a. Data collected January 1, 1989 – July 31, 2008; APR interim report issued December 2008
APR Advisory Committee Consensus
Primary Registry Analysis (Prospective Reports)a
• For lamivudine and zidovudine, sufficient numbers of first
trimester exposures have been monitored to detect at least
a 1.5-fold increase in risk of overall birth defects and a 2fold increase in risk of birth defects in the more common
classes, cardiovascular and genitourinary systems. No
such increases have been detected to date, with the
exception of hypospadias following first trimester exposure
to zidovudine from the addition of the Women and Infants
Transmission Study (WITS) data. With additional accrual of
first trimester exposures, this finding has not persisted.
a. Data collected January 1, 1989 – July 31, 2008; APR interim report issued December 2008
Other Anti-HBV Drugs
• There are insufficient numbers of pregnancy
exposures to adefovir dipivoxil, entecavir and
telbivudine to draw conclusions on exposure risk
Limitations of APR Data
• Limitations of the APR include, but are not limited to:
– Underreporting (i.e., not every report of an exposure is
obtained)
– Differential reporting (e.g., there may be reasons why one
report would be provided to the Registry and another would
not)
– Under-ascertainment of birth defects (e.g., not every birth
defect is identified, reporter may not see the defect at birth)
– Differential ascertainment of birth defects (e.g., variable use of
diagnostic tests)
– Loss to follow up (e.g., no outcome information is obtained)
– Small number of cases of HBV mono-infection or co-infection
Conclusions
• APR overall birth defect prevalence (2.7%) is comparable to other
large prospective cohort studies of newborns with prenatal
exposure to ARVs (2.9% and 1.5%) and to CDC population-based
surveillance data (2.72%)
• Prevalence of birth defects with 1st-trimester exposure to ARVs
(2.9 per 100 live births) is similar to prevalence of defects with the
first exposure during the 2nd/3rd trimesters (2.6 per 100 live births)
• No specific patterns of birth defects were observed
• The APR contains a larger number of LAM and TDF cases,
compared to other HBV drugs
• Birth defect prevalence with 1st-trimester exposure to NRTI class
(including LAM) and NtRTI class (TDF or adefovir regimens) is
similar to other ARV classes
Conclusions
• Birth defect prevalence with exposure to LAM and
TDF regimens is similar to all ARV regimens
– Earliest exposure in the 1st trimester (LAM 2.9%, TDF 2.3%,
all ARV regimens 2.9%)
– Earliest exposure in the 2nd/3rd trimester (LAM, 2.6%, TDF
1.5%, all ARV regimens 2.6%)
• Monitoring of birth defects among infants born to
women with exposure to ARVs and anti-HBV drugs
during pregnancy is important
– Health care providers are encouraged to report pregnancy
exposures to ARVs and anti-HBV drugs to the APR
APR Contact Information
APR Website: www.APRegistry.com
Phone/Fax Contacts:
US, Canada:
(800) 258-4263 (Phone)
(800) 800-1052 (Fax)
International:
+1-910-256-0238 (Phone)
+1-910-256-0637 (Fax)
UK, Germany, France:
(00800) 5913-1359 (Phone)
(00800) 5812-1658 (Fax)
Europe:
+32-2-714-5028 (Phone)
+32-2-714-5024 (Fax)
Brazil:
(888) 259-5618 (Fax)
Back-Up Slides
Definitions of Pregnancy Category
•
Pregnancy Category A – Controlled studies show no risk: Adequate, wellcontrolled studies in pregnant women failed to demonstrate risk to the fetus
•
Pregnancy Category B – No evidence of risk in humans: either animal findings
show risk, but human findings do not; or, if no adequate human studies have
been done, animal findings are negative
•
Pregnancy Category C – Risk cannot be ruled out: human studies are lacking,
and animal studies are either positive for fetal risk, or lacking as well; however,
potential benefits may justify the potential risk
•
Pregnancy Category D – Positive evidence of risk: investigational or
postmarketing data show risk to the fetu; nevertheless, potential benefits may
outweigh the potential risk
•
Pregnancy Category X – Contraindicated in pregnancy: studies in animals or
humans, or investigational or postmarketing reports, have shown fetal risk which
clearly outweighs any possible benefit to the patient
Number of Birth Defects in Non-Live Birthsa with
First Trimester Exposure to NtRTI Regimens
and to All ARV Regimensb
NtRTI
(Total Outcomesc = 775)
All ARVs
(Total Outcomes = 4,958)
Birth Defects
(N)
Non-Live
Births (N)d
Birth Defects
(N)
Non-Live
Births (N)e
Spontaneous
Losses
0
56
0
221
Stillbirths
0
21
3 (4.2%)f
72
Induced
Abortions
0
69
4 (1.2%)f
336
a. Defined as a stillborn infant, or a spontaneous or induced abortion ≥ 20 weeks gestation
b. Data collected January 1, 1989 - July 31, 2008; APR interim report issued December 2008
c. Total outcomes include live births and non-live births
d. Number of non-live births = 146
e. Number of non-live births = 629
f. Percentage of non-live births