Marieke Bierhoff1,2, Elise J Smolders3,4, Joel Tarning5,6, David M Burger3, Rene Spijker2, Marcus J Rijken7,8, Chaisiri Angkurawaranon9, Rose McGready1,6, Nicholas J White6, Francois Nosten1,6, Michèle van Vugt2. 1. Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand. 2. Department of Internal Medicine and Tropical Diseases, Amsterdam University Medical Center, location Academic Medical Center Amsterdam, Amsterdam, the Netherlands. 3. Department of Pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands. 4. Department of Pharmacy, Isala Hospital, Zwolle, the Netherlands. 5. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. 6. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 7. Utrecht University Medical Centre, Utrecht, the Netherlands. 8. Julius Centre Global Health, Utrecht, the Netherlands. 9. Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Abstract
BACKGROUND: Tenofovir disoproxil fumarate (TDF), the oral prodrug of tenofovir (TFV), is advocated in pregnancy for prevention of mother-to-child transmission (PMCT) with failure of hepatitis B immunoglobulin and vaccination. The pharmacokinetics of TDF monotherapy for PMCT-HBV is important if deployment is to emulate the success of multiple antiretrovirals (ARVs) for PMCT-HIV in resource-constrained settings. METHODS: This systematic review followed a protocol and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) guidelines. We included studies that enrolled pregnant women who received oral TDF therapy as monotherapy or in combination with other ARVs: irrespective of the reason for receiving the drug (for example, HIV, HBV or pre-exposure prophylaxis); and reported pharmacokinetics. RESULTS: The area under the concentration-time curve (AUC), maximum plasma concentrations (Cmax) and last measurable plasma concentration (Clast) of TFV were decreased in the second and third trimester compared with first trimester or post-partum. In none of the manuscripts was the non-pregnant HBV threshold of Cmax of 300 ng/ml reached, but the 50% effective concentration (EC50) of TFV is lower for treatment of HBV compared with HIV. The TFV concentration in breastfed infants was 0.03% of the recommended infant dose. CONCLUSIONS: Most knowledge of pharmacokinetics of TFV in pregnancy results from studies on HIV involving multiple ARVs. Increased TFV clearance occurred in the second and third trimester when optimal TFV concentrations are required to maximize suppression of HBV in the window before birth. Dose or duration adjustments will be better conceptualized with concurrent analysis of the pharmacokinetics of TFV monotherapy and hepatitis B pharmacodynamics in pregnancy.
BACKGROUND:Tenofovir disoproxil fumarate (TDF), the oral prodrug of tenofovir (TFV), is advocated in pregnancy for prevention of mother-to-child transmission (PMCT) with failure of hepatitis B immunoglobulin and vaccination. The pharmacokinetics of TDF monotherapy for PMCT-HBV is important if deployment is to emulate the success of multiple antiretrovirals (ARVs) for PMCT-HIV in resource-constrained settings. METHODS: This systematic review followed a protocol and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) guidelines. We included studies that enrolled pregnant women who received oral TDF therapy as monotherapy or in combination with other ARVs: irrespective of the reason for receiving the drug (for example, HIV, HBV or pre-exposure prophylaxis); and reported pharmacokinetics. RESULTS: The area under the concentration-time curve (AUC), maximum plasma concentrations (Cmax) and last measurable plasma concentration (Clast) of TFV were decreased in the second and third trimester compared with first trimester or post-partum. In none of the manuscripts was the non-pregnant HBV threshold of Cmax of 300 ng/ml reached, but the 50% effective concentration (EC50) of TFV is lower for treatment of HBV compared with HIV. The TFV concentration in breastfed infants was 0.03% of the recommended infant dose. CONCLUSIONS: Most knowledge of pharmacokinetics of TFV in pregnancy results from studies on HIV involving multiple ARVs. Increased TFV clearance occurred in the second and third trimester when optimal TFV concentrations are required to maximize suppression of HBV in the window before birth. Dose or duration adjustments will be better conceptualized with concurrent analysis of the pharmacokinetics of TFV monotherapy and hepatitis B pharmacodynamics in pregnancy.
Authors: Lynda Stranix-Chibanda; Peter L Anderson; Deborah Kacanek; Sybil Hosek; Sharon Huang; Teacler G Nematadzira; Frank Taulo; Violet Korutaro; Clemensia Nakabiito; Maysebole Masenya; Kathryn Lypen; Emily Brown; Mustafa E Ibrahim; Jenna Yager; Lubbe Wiesner; Benjamin Johnston; K Rivet Amico; James F Rooney; Nahida Chakhtoura; Hans M L Spiegel; Benjamin H Chi Journal: Clin Infect Dis Date: 2021-10-05 Impact factor: 20.999