Safety of Tenofovir Disoproxil Fumarate for Pregnant Women Facing the Coronavirus Disease 2019 Pandemic

Sonia Hernández-Díaz; Brian T. Bateman; Loreen Straub; Yanmin Zhu; Helen Mogun; Michael Fischer; Krista F. Huybrechts

Disclosures

Am J Epidemiol. 2021;190(11):2339-2349. 

In This Article

Abstract and Introduction

Abstract

We assessed the teratogenicity of tenofovir, a human immunodeficiency virus (HIV) drug similar to remdesivir that is currently being evaluated for the treatment of coronavirus disease 2019 (COVID-19). Using US Medicaid Analytic eXtract (MAX) claims data (2000–2014), we identified a population-based pregnancy cohort of women with HIV who filled at least 1 prescription for antiretroviral therapies (ART) during the first trimester. Women on tenofovir disoproxil fumarate (TDF) were compared with women receiving ART without TDF. Major malformations were identified by International Classification of Diseases, Ninth Revision, codes using validated algorithms. Relative risks and 95% confidence intervals were estimated using propensity score stratification to control for potential confounders. We incorporated the results into prior knowledge by conducting a systematic literature review and a meta-analysis. Major congenital malformations were diagnosed in 37 out of 866 (4.27%) infants exposed to TDF and 38 out of 1,020 (3.73%) infants exposed to ART other than TDF; the adjusted relative risk was 1.21 (95% confidence interval: 0.77, 1.90). Estimates for specific malformations were imprecise. The pooled relative risk from the meta-analysis with 6 prior studies was 0.88 (95% confidence interval: 0.75, 1.03). Based on evidence accumulated in patients with HIV, first-trimester TDF use does not increase the risk of major congenital malformations overall in the newborn compared with other ART.

Introduction

Worldwide, as of the end of 2020, over 100,000,000 women had been pregnant since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1] Pregnant women are susceptible to SARS-CoV-2 infection and, if infected, might have a higher risk of developing severe COVID-19 than nonpregnant women of the same age.[2–5] Cases of maternal death in pregnant women with COVID-19 have been reported.[6] Moreover, severe COVID-19 might increase the risk of prematurity and other adverse obstetric or neonatal outcomes,[2,4,7,8] and vertical transmission cannot be completely ruled out.[2–4,9–11] Therefore, many pregnant women and their physicians confront the decision of whether to use treatments for COVID-19.

By September 2020, tenofovir had emerged as a promising therapy for SARS-CoV-2 infection. Molecular docking and extension reaction studies suggest that remdesivir, tenofovir, and other nucleoside reverse transcriptase inhibitors might be effective against SARS-CoV-2 by inhibiting its RNA polymerase, as long as they attain high intracellular concentration at target tissues.[12–14] Ferret infection models have shown that tenofovir-emtricitabine reduces SARS-CoV-2 titers in nasal washes.[15] In observational studies, human immunodeficiency virus (HIV)-positive patients receiving tenofovir disoproxil fumarate (TDF)-emtricitabine had an up to 50% lower risk for COVID-19 diagnosis and related hospitalization.[16–18] Tenofovir is currently being evaluated in controlled randomized clinical trials for both treatment and prophylaxis of COVID-19.[19] Given the positive clinical trials results for remdesivir,[20,21] tenofovir is expected to be effective because the 2 drugs are in the same family of medications. A key difference between these drugs is that tenofovir can be administered orally, whereas remdesivir requires daily intravenous infusion.

While there is no evidence regarding the safety profile in pregnancy for many of the treatments currently being evaluated for COVID-19, including remdesivir, some data exist for tenofovir based on its use for the treatment of HIV infection and, to lesser extent, for hepatitis B virus infection. It is therefore important to obtain and communicate reliable information about the safety of tenofovir, including teratogenicity, before pregnant populations are exposed on a broad scale. We reviewed the literature and evaluated the risk for major congenital malformations associated with early in pregnancy exposure to tenofovir as HIV treatment using a large health-care utilization database.

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