Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial

Kristin Baltrusaitis, Bonus Makanani, Camlin Tierney, Mary Glenn Fowler, Dhayendre Moodley, Gerhard Theron, Lynette H Nyakudya, Musunga Tomu, Lee Fairlie, Kathleen George, Barbara Heckman, Kevin Knowles, Renee Browning, George K Siberry, Taha E Taha, Lynda Stranix-Chibanda, PROMISE P1084s Study Team, Lynda Stranix-Chibanda, Judith Currier, Katherine Luzuriaga, Adriana Weinberg, James McIntyre, Tsungai Chipato, Karin Klingman, Renee Browning, Mireille Mpoudi-Ngole, Jennifer S Read, George Siberry, Heather Watts, Lynette Purdue, Terrence Fenton, Linda Barlow-Mosha, Mary Pat Toye, Mark Mirochnick, William B Kabat, Benjamin Chi, Marc Lallemant, Karin Nielsen, Kevin Butler, Konstantia Angelidou, David Shapiro, Sean Brummel, Anne Coletti, Veronica Toone, Megan Valentine, Kathleen George, Amanda Zadzilka, Michael Basar, Amy Jennings, Adam Manzella, Sandesh Patil, Ramesh Bhosale, Neetal Nevreka, Salome Kunje, Alex Siyasiya, Mervis Maulidi, Francis Martinson, Ezylia Makina, Beteniko Milala, Nozibusiso Rejoice Skosana, Sajeeda Mawlana, Jeanne Louw, Magdel Rossouw, Lindie Rossouw, Masebole Masenya, Janet Grab, Nasreen Abrahams, Mandisa Nyati, Sylvia Dittmer, Dhayendre Moodley, Vani Chetty, Alicia Catherine Desmond, Boniface Njau, Cynthia Asiyo, Pendo Mlay, Maxensia Owor, Moreen Kamateeka, Dorothy Sebikari, Tichaona Vhembo, Nyasha Mufukari, Lynda Stranix-Chibanda, Teacler Nematadzira, Gift Chareka, Jean Dimairo, Tsungai Chipato, Bangani Kusakara, Mercy Mutambanengwe, Emmie Marote, Kristin Baltrusaitis, Bonus Makanani, Camlin Tierney, Mary Glenn Fowler, Dhayendre Moodley, Gerhard Theron, Lynette H Nyakudya, Musunga Tomu, Lee Fairlie, Kathleen George, Barbara Heckman, Kevin Knowles, Renee Browning, George K Siberry, Taha E Taha, Lynda Stranix-Chibanda, PROMISE P1084s Study Team, Lynda Stranix-Chibanda, Judith Currier, Katherine Luzuriaga, Adriana Weinberg, James McIntyre, Tsungai Chipato, Karin Klingman, Renee Browning, Mireille Mpoudi-Ngole, Jennifer S Read, George Siberry, Heather Watts, Lynette Purdue, Terrence Fenton, Linda Barlow-Mosha, Mary Pat Toye, Mark Mirochnick, William B Kabat, Benjamin Chi, Marc Lallemant, Karin Nielsen, Kevin Butler, Konstantia Angelidou, David Shapiro, Sean Brummel, Anne Coletti, Veronica Toone, Megan Valentine, Kathleen George, Amanda Zadzilka, Michael Basar, Amy Jennings, Adam Manzella, Sandesh Patil, Ramesh Bhosale, Neetal Nevreka, Salome Kunje, Alex Siyasiya, Mervis Maulidi, Francis Martinson, Ezylia Makina, Beteniko Milala, Nozibusiso Rejoice Skosana, Sajeeda Mawlana, Jeanne Louw, Magdel Rossouw, Lindie Rossouw, Masebole Masenya, Janet Grab, Nasreen Abrahams, Mandisa Nyati, Sylvia Dittmer, Dhayendre Moodley, Vani Chetty, Alicia Catherine Desmond, Boniface Njau, Cynthia Asiyo, Pendo Mlay, Maxensia Owor, Moreen Kamateeka, Dorothy Sebikari, Tichaona Vhembo, Nyasha Mufukari, Lynda Stranix-Chibanda, Teacler Nematadzira, Gift Chareka, Jean Dimairo, Tsungai Chipato, Bangani Kusakara, Mercy Mutambanengwe, Emmie Marote

Abstract

Background: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited.

Trial design: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants.

Methods: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth.

Results: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0).

Conclusions: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function.

Trial registration: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Keywords: Antiretroviral therapy; HIV/AIDS; Pregnancy; Prevention of perinatal HIV transmission; Renal function.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Enrollment and Analysis Inclusion by Antepartum Period, Hepatitis B Surface Antigen Status, and Randomization Arm. HBsAg Hepatitis B Surface Antigen, ZDV zidovudine, TDF tenofovir disoproxil fumarate, ART antiretroviral therapy
Fig. 2
Fig. 2
Distribution of Calculated CrCl across GA Categories, Delivery, and PP Study Visits*. *Among women eligible for TDF randomization; CrCl Creatinine Clearance, ZDV zidovudine, TDF tenofovir disoproxil fumarate, GA gestational age,.Diamonds represent mean calculated CrCl; CrCl (mL/min) was calculated using the Cockroft-Gault equation, adjusted for female sex [32]

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