Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial
Authors: Baltrusaitis Kristin , Makanani Bonus , Tierney Camlin , Fowler Mary Glenn , Moodley Dhayendre , Theron Gerhard , Nyakudya Lynette H. , Tomu Musunga , Fairlie Lee , George Kathleen , Heckman Barbara , Knowles Kevin , Browning Renee , Siberry George K. , Taha Taha E. , Stranix-Chibanda Lynda ,   for the PROMISE P1084s Study Team, Stranix-Chibanda Lynda , Currier Judith , Luzuriaga Katherine , Weinberg Adriana , McIntyre James , Chipato Tsungai , Klingman Karin , Browning Renee , Mpoudi-Ngole Mireille , Read Jennifer S. , Siberry George , Watts Heather , Purdue Lynette , Fenton Terrence , Barlow-Mosha Linda , Toye Mary Pat , Mirochnick Mark , Kabat William B. , Chi Benjamin , Lallemant Marc , Nielsen Karin , Butler Kevin , Angelidou Konstantia , Shapiro David , Brummel Sean , Coletti Anne , Toone Veronica , Valentine Megan , George Kathleen , Zadzilka Amanda , Basar Michael , Jennings Amy , Manzella Adam , Patil Sandesh , Bhosale Ramesh , Nevreka Neetal , Kunje Salome , Siyasiya Alex , Maulidi Mervis , Martinson Francis , Makina Ezylia , Milala Beteniko , Skosana Nozibusiso Rejoice , Mawlana Sajeeda , Louw Jeanne , Rossouw Magdel , Rossouw Lindie , Masenya Masebole , Grab Janet , Abrahams Nasreen , Nyati Mandisa , Dittmer Sylvia , Moodley Dhayendre , Chetty Vani , Desmond Alicia Catherine , Njau Boniface , Asiyo Cynthia , Mlay Pendo , Owor Maxensia , Kamateeka Moreen , Sebikari Dorothy , Vhembo Tichaona , Mufukari Nyasha , Stranix-Chibanda Lynda , Nematadzira Teacler , Chareka Gift , Dimairo Jean , Chipato Tsungai , Kusakara Bangani , Mutambanengwe Mercy , Marote Emmie 
Published: July 2022

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.