Abstract
Dear Editor:
Current treatment guidelines for HIV-1 infection in women of the childbearing age group recommend use of standard, potent combinations of highly active antiretrovirals (ARV). 1 –5 In pregnant women, treatment has two objectives: to improve the health of the mother and to prevent mother-to-child transmission of HIV. Optimal use of ARVs during pregnancy should aim to control infection and ensure complete plasma HIV RNA suppression by the third trimester and at the time of delivery. 1,2,6 The indications for initiation of ARV and the goals for treatment are the same for HIV-1–infected women as for other adults or adolescents, however, the choice of ARV regimen for women of childbearing potential must take into account what is known about the use of specific drugs in pregnancy, and the possible increase in risk of teratogenicity. The Antiretroviral Pregnancy Registry (APR) collects data on birth defects after pregnancy exposures to ARV therapy. 7
We used APR data to assess birth defect risk after pregnancy exposure to atazanavir. Once 200 first trimester exposures have accrued, the registry has sufficient power to perform comparative analysis of individual drugs in the registry and to make assertions about the use of atazanavir during pregnancy, which reached this threshold in June 2008. As we have seen the use of atazanavir in this population increase, we feel it is important to report data on the safety of this drug in pregnant women.
Atazanavir is a guideline-recommended protease inhibitor (PI) indicated for use with other ARVs for the treatment of HIV-1 infection. 1,3,4,8,9 Atazanavir boosted with ritonavir is recommended as a preferred PI for treatment of HIV infection in pregnant women by the European AIDS Clinical Society. 1 Similarly, atazanavir/ritonavir is listed as an alternative agent in the treatment of pregnant HIV-infected women by the US Department of Health and Human Services pregnancy and perinatal guidelines. 2 All drugs approved by regulatory authorities such as the US Food and Drug Administration (FDA) must undergo animal teratology testing, yet such studies are not necessarily predictive of human teratogenic potential. Atazanavir is assigned FDA Pregnancy Category B status, meaning that, in animal reproduction studies, there was no evidence of adverse fetal effects or teratogenicity and/or there are no adequate and well-controlled studies of atazanavir use during pregnancy.
Our analysis used a subset of the data from the APR designed to monitor prenatal exposures to ARV therapy and to detect any increase in the risk of major birth defects compared with a general population-based background birth defect rate from the CDC Metropolitan Atlanta Congenital Defects Program (MACDP). 7 The analysis population includes all pregnant women enrolled in the APR during the period from January 1, 1989 through January 31, 2010, as reported in the APR Interim Report issued in June 2010. 7 The APR includes cases in both HIV-infected and non-HIV–infected women. We report on the subset of HIV-infected women exposed to atazanavir and include those enrolled since 2003 when atazanavir received FDA approval. A small number of cases (<10) were reported prior to FDA approval from pregnancies that occurred in clinical trials. Overall, the exposures to atazanavir that are tracked by the APR include exposure to both unboosted atazanavir and boosted atazanavir (atazanavir/ritonavir).
We write to call your attention to the fact that the drug has reached an important threshold for analysis, the agreed 200 first trimester exposures—the number above which comparative data analyses of individual drugs in the registry are undertaken. 7,10,11
Detailed methodology of the APR is published elsewhere. 7 The APR conforms with FDA guidelines for pregnancy exposure registries. 12 Registration is voluntary. Health care providers are encouraged to enroll patients as early in the pregnancy as possible, preferably before prenatal testing. The APR has Institutional Review Board (IRB) approval from Western IRB (WIRB®), including a waiver from obtaining patient informed consent and HIPAA authorization exemption.
Through January 2010, 698 women with atazanavir-exposed pregnancies were enrolled in the APR. Patient demographics are detailed in Table 1 according to earliest trimester of exposure. There were 63 women lost to follow-up and 47 women who were not documented to be HIV-infected or had unknown infection status. A total of 588 atazanavir-exposed pregnancies among HIV-infected women comprised the subset for analysis in this study. The mean age of the women in the atazanavir subset was 29 years; 12.9% white, 63.9% black, and 16.7% Hispanic; and 87.9% from the United States. The majority (82.5%) had a baseline CD4 cell count of greater than >200 cells/mm3.
A few exposures were reported to the APR from pregnancies that occurred in clinical trials prior to FDA approval of atazanavir in 2003.
Not all APR cases were women infected with HIV.
APR, Antiretroviral Pregnancy Registry; PGL, persistent generalized lymphadenopathy; SE, standard error.
Of the 588 atazanavir-exposed pregnancies in HIV-infected women, 18 were multiple gestations. There were 604 outcomes, including 567 live births. Pregnancy outcomes are summarized in Table 2. There were 12 live births with defects, and 1 defect in an induced abortion that occurred ≥20 weeks gestation for a total of 13 outcomes with defects; 8 with first trimester exposures and 5 with second/third trimester exposures to atazanavir. There were also 2 cases of induced abortions with defects that occurred prior to 20 weeks gestation that are not counted within the analysis.
An outcome is defined as a live or stillborn infant, or a spontaneous or induced abortion.
Includes 18 multiple births.
Two defects were reported in induced abortions that occurred prior to 20 weeks gestation and are not included in the birth defect prevalence calculation.
All outcomes of induced abortions occurred prior to 20 weeks gestation.
Data are not included for birth defect cases with an unknown trimester of exposure.
Timing of exposure based on first trimester exposure to ATV; PI includes ATV exposures and some cases may have had other PI exposures in addition to ATV.
Antiretroviral Pregnancy Registry (APR) definitions/grouping: PI, protease inhibitor, includes amprenavir, atazanavir (ATV), fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, and tipranavir; NRTI, nucleoside reverse transcriptase inhibitor, includes abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, and zidovudine; NNRTI, non-nucleoside reverse transcriptase inhibitor includes delavirdine, mesylate, efavirenz, and nevirapine; NtRTI, nucleotide reverse transcriptase inhibitor includes adefovir dipivoxil, and tenofovir disoproxil fumarate.
Among all registry cases reported in the interim report issued in June 2010 (including both HIV-infected and non-HIV–infected pregnant women), there were 393 first trimester exposures to atazanavir; 9 had birth defects in the first trimester, giving a prevalence of 2.3% (9/393; 95% confidence interval [CI], 1.0–4.3). 7 In HIV-infected women (the subset for analysis in this study), there were 368 first trimester exposures to atazanavir and, of these, 8 had birth defects in the first trimester, giving a prevalence of 2.2% (8/368; 95% CI, 0.9–4.2). The birth defect prevalence for second/third trimester exposures to atazanavir was 2.5% (5/199; 95% CI, 0.8–5.8). The risk of defects from first trimester exposures relative to second/third trimester exposures to atazanavir was 0.87 (95% CI, 0.29–2.61). The overall prevalence of birth defects among atazanavir-exposed, HIV-infected women was 2.3% (13/567) (95% CI, 1.2–3.9). These proportions are similar to the overall prevalence of birth defects among HIV-infected women with exposure to any ARV during pregnancy of 2.7% (285/10747; 95% CI, 2.3–3.0) and to the general population rate for birth defects reported in the CDC MACDP of 2.72% (95% CI, 2.68–2.76). The prevalence of birth defects among HIV-infected women with first trimester exposure to atazanavir was not different from the prevalence of birth defects among all APR cases with first trimester exposure to any PI-containing regimens or other ARV classes (data not shown).
All birth defects reported prospectively among infants exposed to atazanavir during pregnancy (including those with defects that occurred prior to 20 weeks gestation) and their possible temporal relation to drug treatment are summarized as follows. Of the 15 infants exposed prenatally to atazanavir with birth defects, 10 had first trimester exposure and 7 had multiple defects. Among the defects reported by organ system, there were 5 infants with heart-other defects, 3 with chromosome anomalies, 3 with other musculoskeletal defects, 2 with cleft lip and/or palate, 2 with central nervous system defects, and 2 with renal and urinary system defects. No pattern of birth defects suggestive of a common etiology was observed.
The data from the APR Steering Committee report (issued in June 2010) suggest that atazanavir exposure during pregnancy is not associated with rates of birth defects significantly different from those noted for other ARVs, or from the rates of birth defects recorded in the APR reference CDC MACDP population. Internal data comparisons further demonstrate that the rates of birth defects associated with exposure to atazanavir do not differ by trimester of exposure and are not higher for first trimester exposures than for second and third trimester exposures. These findings suggest that atazanavir, in keeping with current clinical guidelines, 1,2 can be continued as part of a combination ARV regimen in women who become pregnant and are already receiving this agent within their treatment regimen, and may be suitable for use among women of childbearing potential, who are or who may become pregnant.
The APR data are limited by the voluntary nature of both the patient enrollment and outcome reporting by health care providers. Potential limitations of any form of registry data collection include underreporting (i.e., not every report of an exposure is obtained), differential reporting (i.e., one report is provided and others not), underascertainment of birth defects, differential ascertainment of birth defects, and loss to follow-up. The APR is designed to detect specifically teratogenic effects of ARV medications, and the occurrence of other developmental or functional defects is not systematically collected, although the Advisory Committee reviews each pregnancy outcome received. In this specific analysis, an additional limitation is the lack of detailed information in some cases about whether the exposure to atazanavir may or may not include ritonavir boosting. Strengths of APR data are that the Registry provides information to supplement animal toxicology studies and clinical trial data. Registry data can be considered robust since exposed pregnancies are enrolled prospectively before the outcome is known and the continued accrual of registry data and patient experiences provides progressively more precise estimates regarding risks of ARV therapy.
The APR is an ongoing endeavor. Exposures to all antiretroviral therapies during pregnancy may be reported by calling (800) 258-4263 in the United States and Canada, +1 910 256 0238 internationally, or by visiting the Registry at:
Footnotes
Acknowledgments
Editorial support was provided by J. Turner and W. McFadzean of PAREXEL, and Emily Cullinan from Bristol-Myers Squibb and was funded by Bristol-Myers Squibb. This work was supported, in part, by a grant from Bristol-Myers Squibb to Kendle International Inc to develop, organize, and prepare information related to this publication.
The authors thank Cathy Ryan and Conway Gee of INC Research, LLC for data collection and analysis, and Kathryn Krantz for her participation in the collection of these data.
Part of this research was presented as a poster at the 10th International Congress on Drug Therapy in HIV Infection, November 7–11, 2010, Glasgow, UK.
Author Disclosure Statement
S. Esker, J. Uy, D. Arikan, M.J. Jimenez-Exposito, and D. Seekins are employees of Bristol-Myers Squibb. J. Albano is an employee of INC Research (formerly Kendle International), the coordinating center for the registry. H. Tilson is a retained consultant to the APR, and consults with many of the individual sponsors of the registry, including Bristol-Myers Squibb on other drug safety matters.