Elsevier

Journal of Hepatology

Volume 57, Issue 5, November 2012, Pages 953-959
Journal of Hepatology

Research Article
Hepatitis B virus and human immunodeficiency virus drugs in pregnancy: Findings from the Antiretroviral Pregnancy Registry

https://doi.org/10.1016/j.jhep.2012.06.031Get rights and content

Background & Aims

Fetal safety of antiviral therapies is important given the long-term treatment of women with chronic hepatitis B (CHB) infection who may become pregnant. We analyzed neonatal safety data from the Antiretroviral Pregnancy Registry (APR), the largest safety database in pregnancy for antivirals used for HIV and CHB.

Methods

Data were extracted from APR cases prospectively enrolled between 1989 and 2011. Primary outcomes were major birth defects rates with exposure to all antivirals, individual classes, and drugs compared to population-based controls. Relevant to CHB, only lamivudine (LAM) and tenofovir disoproxil fumarate (TDF) had sufficient individual data for review (⩾200 cases).

Results

Of 13,711 cases analyzed, the overall birth defect prevalence (2.8%, 95% CI 2.6–3.1%) was comparable to Centers for Disease Control population-based data (2.72%, 2.68–2.76%, p = 0.87) and two prospective antiretroviral exposed newborn cohorts (2.8%, 2.5–3.2%, p = 0.90 and 1.5%, 1.1–2.0%, p <0.001). The birth defects prevalence between first and second/third trimesters exposure was similar (3.0% vs. 2.7%). No increased risk of major birth defects with LAM or TDF exposure compared to population-based controls was observed. No specific pattern of major birth defects was observed for individual antivirals or overall.

Conclusions

No increased risk of major birth defects including in non-live births was observed for pregnant women exposed to antivirals relevant to CHB treatment overall or to LAM or TDF compared to population-based controls. Continued safety and efficacy reporting on antivirals in pregnancy are essential to inform patients on their risks and benefits during pregnancy.

Introduction

Chronic hepatitis B (CHB) remains an important global health problem. Up to one million of the approximately 350 million carriers worldwide die annually due to CHB-related disease [1]. Mother-to-child transmission (MTCT) is the most common form of transmission in high prevalence areas [2], [3] and may occur in up to 90% of mothers who are hepatitis B surface antigen (HBsAg) positive without prophylaxis [4]. This high rate of transmission may be partially due to the high proportion of patients with active replication, hepatitis B e antigen (HBeAg) positivity [5], [6], [7], [8], and high maternal viral load during reproductive years [9], [10], [11], [12].

Although no anti-CHB therapies are currently approved for use in pregnancy, women in their child-bearing years with CHB liver disease may need antiviral therapy, including during pregnancy, or be actively taking antivirals when they become pregnant. Moreover, pregnant women in the immune tolerant phase of CHB with high HBV DNA levels (>108 copies/ml; 2 × 107 IU/ml) may want to be considered for antiviral therapy to reduce the viremia and the risk of MTCT that can occur despite neonatal immunoprophylaxis [9], [13]. The use of antiviral therapies in pregnancy is controversial and knowledge of their risks is not widely disseminated among hepatologists. Accordingly, data on the safety of antivirals in pregnancy, and especially their impact on potential teratogenic risk, are of paramount importance when counseling pregnant patients with CHB on risks and benefits to their offspring.

Antiviral therapies for CHB and human immunodeficiency virus (HIV) infections have advanced markedly in the last decade and the benefits of treatment are clear. CHB patients experience low (<1%/year) rates of viral resistance and breakthrough with up to 5 years of antiviral monotherapy with entecavir or tenofovir [14], [15], and long-term virus suppression is associated with slowing of liver disease progression and reversal of fibrosis and cirrhosis [16], [17], [18]. For HIV, the use of combination antiretroviral therapy with a backbone of two nucleos(t)ide analogues plus at least one drug from another class, also reliably produces durable suppression of HIV viremia [19], [20], restores immune function [21], reduces HIV- [22], [23] and non-HIV- [24], [25], [26] related mortality and morbidity, and prevents transmission [27], [28]. In HIV infection, the use of antivirals to suppress HIV RNA levels, particularly during late pregnancy, has also dramatically reduced the rate of MTCT [29], [30].

The Antiretroviral Pregnancy Registry (APR) is an international, voluntary registry that monitors prenatal exposures to antiviral drugs to detect a possible increased risk of major birth defects in a prospective exposure-registration cohort [31]. Although the primary focus of the Registry has been on women with HIV infection, data collection on CHB monoinfected patients began in 2003, and data on birth outcome are now also available for these women.

The aim of this study is to review the APR safety data for antivirals approved for the treatment of CHB, where sufficient numbers of reported exposures during pregnancy permit conclusions to be drawn concerning risk of major birth defects, i.e., lamivudine (LAM) and tenofovir disoproxil fumarate (TDF). The objective is to compare major birth defect rates to population-based controls for all antivirals and then for these two antiviral agents and classes of antivirals. In addition, we compared major birth defect rates and other birth outcomes (e.g., spontaneous, and induced, abortions and stillbirths) following antiviral exposure commencing in the first versus (vs.) remaining trimesters of pregnancy. Though these data exist in summary formats elsewhere, this is the first attempt to quantify and tabulate these risks as they pertain to HBV drugs in a manner useful to practicing hepatologists.

Section snippets

The APR

The APR is an international, voluntary prospective exposure-registration cohort study established in January 1989 that monitors major birth defects and adverse fetal outcomes (e.g., spontaneous abortions, induced abortions, stillbirths) in pregnancies exposed to antiviral medications to treat maternal HIV and/or CHB infections. Data collection on exposure in CHB monoinfected mothers commenced in January 2003. Maternal safety and efficacy data are not addressed in this cohort. More details about

Results

This APR interim report analysis examined 13,711 cases, prospectively enrolled between January 1, 1989 and January 31, 2011. Patients excluded from this analysis included 1364 (8.7%) cases lost to follow-up and 535 (3.4%) cases pending outcome (Table 1). Patients with HIV infection comprised 93.9% (including 147 or 1% of patients with HIV–HBV co-infection), HBV monoinfection 1.2%, HIV post-exposure prophylaxis 0.3%, unknown 1.3% and missing 3.2%. Since the vast majority of the cohort was

Discussion

This is the first report using Antiretroviral Pregnancy Registry (APR) data to describe the rates of major birth defects in newborns of women with in utero exposure to antiviral medications approved for use in CHB. Our analysis evaluates CHB and HIV antivirals overall, and then specifically LAM and TDF and their associated drug classes (NRTI and NtRTI, respectively). LAM and TDF are the only two drugs in the APR approved for CHB treatment with sufficient data available to draw reasonable

Financial support

Financial support was provided by Gilead Sciences.

Author contributions

Robert S. Brown, Jr. contributed fully to the concepts, design and writing of the manuscript.

Elizabeth C. Verna contributed fully to the concepts, design and writing of the manuscript.

Marcus R. Pereira contributed fully to the concepts, design and writing of the manuscript.

Hugh H. Tilson served as a liaison to the APR where he is involved in collection, analysis, and reporting of the APRs data, and also served as writer, reviewer and commentator.

Christopher Aguilar, serves as Gilead’s sponsor

Conflict of interest

Robert S. Brown, Jr. receives support from Gilead Sciences Inc. for consulting and research. Christopher Aguilar is an employee of Gilead Sciences Inc. and holds stock. Elizabeth A. Fagan is/was an employee of Gilead Sciences Inc. and holds stock.

The other authors have nothing to disclose.

Advisory committee consensus statement

In reviewing all reported defects from the prospective registry, informed by clinical studies and retrospective reports of antiretroviral exposure, the Registry finds no apparent increases in frequency of specific defects with first trimester exposures and no pattern to suggest a common cause. The Registry notes modest but statistically significant elevations of overall defect rates with didanosine and nelfinavir compared with its population-based comparator, the MACDP. While the Registry

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