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Tenofovir Disoproxil Fumarate-Containing Regimens in Pregnancy:
Report From the Antiretroviral Pregnancy Registry
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Reported by Jules Levin
AASLD Nov 3 2009 Boston
Robert Brown, Jr.1, Diane Goodwin2, Ken Peschell2, Sherry Zhang2, Elizabeth Fagan2
1Columbia University College of Physicians and Surgeons, New York, NY, USA,
2Gilead Sciences, Inc., Foster City, CA, USA
APR Advisory Consensus Statementa
"In reviewing all reported defects from the prospective registry, informed by clinical studies and retrospective reports of antiretroviral drugs exposure, the Registry finds that the defects reported show no apparent increases in frequency and no pattern to suggest a common cause. While the Registry population exposed and monitored to date is not sufficient to detect an increase in the risk of relatively rare defects, these findings should provide some assurance when counseling patients. However, potential limitations of registries such as this one should be recognized. The Registry is ongoing. Health care providers are encouraged to report eligible patients to the Registry at
www.APRegistry.com."
a. Data collected January 1, 1989 - January 31, 2009; APR interim report issued June 2009
INTRODUCTION
Tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor (NtRTI), is licensed for the treatment of chronic HIV-1 infection and chronic hepatitis B infection in adults
TDF is classified as a Food and Drug Administration (FDA) Pregnancy Category B drug
- No evidence of risk to fetus in animal studies
- No adequate and well-controlled studies in humans
TDF-containing regimens are well tolerated in pregnancy and reduce mother-to-child transmission (MTCT) of HIV-1 in animal models and in humans1-4
1. European Collaborative Study. Clin Infect Dis. 2005; 40(3):458-65;
2. European Collaborative Study. J Acquir Immune Defi c Syndr. 2003; 32(4):380-387;
3. Cooper ER, et al. JAIDS. 2002; 29:484-494;
4. Centers for Disease Control and Prevention. MMWR. June 2, 2006; 55(21):592-597.
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
· Reporting is voluntary; data are not verified
· Majority of cases (87.5%) are reported from the US
- Approximately 1,300 new cases from the US and 200 new cases from other countries are added annually
Interim primary analysis reports are issued semiannually
- Current APR interim report includes 12,451 prospective cases (includes data from January 1,1989 through January 31, 2009)
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 Centers for Disease Control and Prevention (CDC), FDA, and National Institute of Health (NIH) provides oversight of APR scientific conduct and analysis
APR began collecting data on exposure to tenofovir disoproxil fumarate (TDF) in 2001
a. Cases where the outcome of pregnancy is not yet known
b. Cases 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
a. Includes 111 patients co-infected with HIV and hepatitis B
b. Persistent generalized lymphadenopathy
c. Where ARV drugs have been used for therapy
Note: APR started systematically collecting data on HBV in January 2003
a. Includes 111 patients co-infected with HIV and hepatitis B
b. Persistent generalized lymphadenopathy
c. Where ARV drugs have been used for therapy
Note: APR started systematically collecting data on HBV in January 2003
a. Defects meeting the CDC criteria only. Excludes reported defects in pregnancy losses <20 weeks
b. Reporting period of January 1, 1989 - January 31, 2009
c. As 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 fi ve 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)
Figure 1. Birth Defect Rates for First-Trimester Exposure, By Antiretroviral Therapy Class Regimena
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.
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.
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 2-fold increase in risk of birth defects in the more common classes, cardiovascular and genitourinary systems. No
such increases have been detected to date.
a. Data collected January 1, 1989 - January 31, 2009; APR interim report issued June 2009
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)
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