Safety and Tolerability of Antiretrovirals during Pregnancy

Weinberg, Adriana; Forster-Harwood, Jeri; Davies, Jill; McFarland, Elizabeth J.; Pappas, Jennifer; Kinzie, Kay; Barr, Emily; Paul, Suzanne; Salbenblatt, Carol; Soda, Elizabeth; Vazquez, Anna; Levin, Myron J.

doi:10.1155/2011/867674

Cited by 15 publications

(11 citation statements)

References 47 publications

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“…Pregnant women received a clinician-prescribed antenatal ARV regimen that consisted of cART (≥3 ARV from ≥2 ARV classes) in most cases; modifications during the pregnancy were based on viral genotype, virologic response, safety, and tolerability, as previously described [ 33 – 35 ]. PI serum levels were routinely monitored and doses adjusted to achieve a trough above the 25th percentile for nonpregnant adults.…”

Section: Methodsmentioning

confidence: 99%

Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir

Smith

Weinberg

Forster

et al. 2016

Infectious Diseases in Obstetrics and Gynecology

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Combination antiretroviral therapy (cART) is successfully used for prevention of perinatal HIV transmission. To investigate safety, we compared adverse events (AE) among infants exposed to different maternal cART regimens. We reviewed 158 HIV-uninfected infants born between 1997 and 2009, using logistic regression to model grade ≥1 AE and grade ≥3 AE as a function of maternal cART and confounding variables (preterm, C-section, illicit drug use, race, ethnicity, infant antiretrovirals, and maternal viremia). Frequently used cART regimens included zidovudine (63%), lamivudine (80%), ritonavir-boosted lopinavir (37%), nelfinavir (26%), and atazanavir (10%). At birth, anemia occurred in 13/140 infants (9%), neutropenia in 27/107 (25%), thrombocytopenia in 5/133 (4%), and liver enzyme elevation in 21/130 (16%). Corresponding rates of AE at 4 weeks were 59/141 (42%), 54/130 (42%), 3/137 (2%), and 3/104 (3%), respectively. Serious AE (grade ≥ 3) exceeded 2% only for neutropenia (13% at birth; 9% at 4 weeks). Compared with infants exposed to maternal lopinavir/ritonavir, infants exposed to nelfinavir and atazanavir had a 5-fold and 4-fold higher incidence of AE at birth, respectively. In conclusion, hematologic and hepatic AE were frequent, but rarely serious. In this predominantly protease inhibitor-treated population, lopinavir/ritonavir was associated with the lowest rate of infant AE.

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Section: Methodsmentioning

confidence: 99%

Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir

Smith

Weinberg

Forster

et al. 2016

Infectious Diseases in Obstetrics and Gynecology

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“…Further functional studies in brush border membrane preparations for substrates of these transporters, such as metformin (Terada et al, 2006) and antiretroviral drugs (Schuetz et al, 1999;Huisman et al, 2002), should be performed to determine the relevance of the observed protein changes. These chemicals are renally eliminated and have been under-investigation for prescribing during pregnancy (Unadkat et al, 2007;Weinberg et al, 2011;Silva et al, 2012). Likewise, circulating bile acids are increased during pregnancy, and their renal secretion may be reduced during pregnancy because of decreased Mrp4 expression (Rius et al, 2006).…”

Section: Tablementioning

confidence: 99%

Down-Regulation of Brush Border Efflux Transporter Expression in the Kidneys of Pregnant Mice

2012

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Pregnancy increases the urinary excretion of chemicals in women and rodents. It is unknown whether the enhanced clearance of drugs during pregnancy involves changes in the expression of transporters that mediate chemical secretion and reabsorption. The purpose of this study was to quantify the mRNA and protein expression of efflux transporters in kidneys from virgin and pregnant mice on gestational days 7, 11, 14, and 17 and postnatal days 1, 15, and 30 with use of quantitative polymerase chain reaction, Western blot, and immunofluorescence. Multidrug resistance protein (Mdr) 1b mRNA, multidrug resistance-associated protein (Mrp) 4 mRNA, and protein levels decreased significantly by 25-75% throughout pregnancy and lactation. Similarly, Mrp2 and multidrug and toxin extrusion transporter (Mate) 1 mRNA expression were down-regulated 20-40% during mid to late gestation but returned to control levels by postnatal day 15. In contrast, Mrp3 mRNA and protein increased 225% and 31%, respectively, at gestational day 14. Coordinated down-regulation of brush border transporters Mate1, Mrp2, and Mrp4 and up-regulation of the basolateral Mrp3 transporter would reduce chemical secretion into urine. IntroductionPregnancy-induced hormonal and hemodynamic changes significantly alter renal function. In humans and rodents, increases in cardiac output and renal vasodilation enlarge the size of the kidneys, elevate renal plasma flow by 50-85%, and increase the rate of glomerular filtration by 40-65% (Chapman et al., 1998;Conrad, 2004;Maynard and Thadhani, 2009;Cornelis et al., 2011). Clinically, pregnant women exhibit proteinuria, glucosuria, and aminoaciduria, which have been attributed to alterations in renal function (Davison and Dunlop, 1980;Cornelis et al., 2011). Together, hyperfiltration and increased blood flow to the kidneys alter maternal pharmacokinetics by elevating the renal clearance of chemicals during pregnancy.Renal transporters are membrane-spanning proteins that play a critical role in facilitating the movement of toxins and drugs into the urine via secretion and into the blood via reabsorption. To enable these processes, transporters are prominently localized on both the apical (brush border) and basolateral membranes of proximal tubule epithelial cells. Transporters expressed within the kidneys are members of one of the two superfamilies: the solute carrier (SLC) and ATP-binding cassette (ABC) families. Efflux transporters that extrude chemicals from cells are members of both the ABC and the SLC families and include the multidrug resistance-associated proteins (Mrps), multidrug resistance proteins (Mdrs), breast cancer resistance protein (Bcrp), and multidrug and toxin extrusion proteins (Mates) (reviewed in Klaassen and Aleksunes, 2010).Recent studies have begun to explore transporter regulation in the kidneys during pregnancy and the subsequent postpartum period. In one study, expression of renal Mdr1b mRNA in mice decreased between mid and late gestation, with little to no change at the protein level (...

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“…Nevertheless, possible short-and long-term adverse effects of these medications in both the mother and the fetus should be considered [18,19]. The use of protease inhibitors during pregnancy has been associated with an increase in premature deliveries and low birth weight [20,21].…”

Section: Discussionmentioning

confidence: 99%

Analysis of endoplasmic reticulum stress in placentas of HIV-infected women treated with protease inhibitors

Brüning

Kimmich

Brem

et al. 2014

Reproductive Toxicology

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Safety and Tolerability of Antiretrovirals during Pregnancy

Cited by 15 publications

References 47 publications

Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir

Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir

Down-Regulation of Brush Border Efflux Transporter Expression in the Kidneys of Pregnant Mice

Analysis of endoplasmic reticulum stress in placentas of HIV-infected women treated with protease inhibitors

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