Maternal toxicity and pregnancy complications in human immunodeficiency virus–infected women receiving antiretroviral therapy: PACTG 316

Watts, D. Heather; Balasubramanian, Rajalakshmi; Maupin, Robert; Delke, Isaac; Dorenbaum, Alejandro; Fiore, S.; Newell, Marie‐Louise; Delfraissy, Jean‐François; Gelber, Richard D.; Mofenson, Lynne; Culnane, Mary; Cunningham, Coleen K.

doi:10.1016/j.ajog.2003.07.018

Cited by 93 publications

(61 citation statements)

References 22 publications

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“…Reports of drug disposition being sensitive to disease have appeared in the literature for nearly 40 years (reviewed in Morgan et al, 2008); however, only in the last decade have the effects of disease during pregnancy, including gestational diabetes mellitus (GDM), been investigated (Wang et al, 2005;Petrovic et al, 2008;Anger and Piquette-Miller, 2010). Studies indicate that the prevalence of GDM in HIV-positive pregnant women far exceeds that of HIV-negative pregnant women (Watts et al, 2004;Kourtis et al, 2006;Martí et al, 2007;González-Tomé et al, 2008), but to the best of our knowledge, it is unknown if this has an effect on the disposition of highly active antiretroviral therapy drugs. In rats with streptozotocin (STZ)-induced GDM, we have observed recently that the plasma protein binding of the protease inhibitor saquinavir decreases because of displacement by elevated lipids, whereas the expression of hepatic Mdr1 and a variety of cytochrome P450 and UDP-glucuronosyltransferase enzymes increases (Anger and Piquette-Miller, 2010).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metabolism and Disposition

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ABSTRACT:Lopinavir (LPV) is the preferred HIV protease inhibitor in pregnancy, but it is unknown if gestational diabetes mellitus (GDM) affects its disposition. Hepatic protein expression and plasma protein binding are altered in rodent models of GDM. Because LPV is influenced by hepatic transporters and metabolic enzymes and is highly protein bound, it was hypothesized that streptozotocininduced GDM would alter its disposition. Maternal and fetal tissues were collected from GDM rats and controls 45 min after LPV injection. In another cohort, fetuses were serially extracted 5 to 60 min after injection. LPV was quantified using liquid chromatography tandem mass spectrometry. Expression of relevant transporters, such as Multidrug resistance protein 1 (Mdr1), and cytochrome P450 3a2 (Cyp3a2), which metabolizes LPV in rodents, was measured in maternal liver via quantitative reverse transcriptase polymerase chain reaction and Western blot analysis. Expression of relevant transporters also was measured in placenta via quantitative reverse transcriptase polymerase chain reaction. Protein binding was determined by ultrafiltration. Relative to controls, we observed dramatically reduced maternal and fetal LPV exposure in GDM. Compared with controls, maternal hepatic Mdr1 and Cyp3a2 were up-regulated, and protein binding was reduced in the GDM group. Increased Mdr1-and Cyp3a2-mediated hepatobiliary clearance, coupled with a larger unbound LPV fraction, is likely to have facilitated hepatic elimination, thereby decreasing maternal and fetal exposure. Not surprisingly, up-regulation of Mdr1 and Cyp3a2's transcriptional regulator, pregnane X receptor, was demonstrated in maternal liver via Western blot analysis. Up-regulation of Mdr1 in placentas isolated from the GDM group likely also contributed to decreased fetal exposure to LPV. This study provides preclinical support for an as yet unreported drug-disease (LPV-GDM) interaction.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Anger

Piquette-Miller²

2011

Drug Metabolism and Disposition

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“…Until recently, most guidelines recommended either nevirapine or nelfinavir in combination with two nucleoside reverse transcriptase inhibitors (NRTIs), usually zidovudine (AZT)+lamivudine (3TC) in HIV-infected pregnant women who do not have evidence of drugresistant virus. However, the use of both nevirapine and nelfinavir has been questioned because of either an increased risk for toxicity or subtherapeutic plasma levels, respectively [1,2] .…”

Section: Introductionmentioning

confidence: 99%

Low-Birth Weight and Pre-Term Delivery in Relation to Lopinavir/Ritonavir Use in Pregnancy

Senise¹,

Cruz²,

Palácios³

et al. 2008

American J. of Infectious Diseases

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Abstract:The toxic potential of nevirapine in pregnant women with CD4 count over 250 cells mmand the unsatisfactory efficacy of nelfinavir in patients with baseline Viral Load (VL) over 100,000 copies mL −1 has prompted the use of Lopinavir/ritonavir (LPV/r) in selected situations. This study aims to assess safety of LPV/r in pregnancy. Medical records from pregnant women receiving LPV/r were retrospectively reviewed. Charts corresponding to twin pregnancy, hypertension and having a lack of data supporting a reliable estimate of Gestational Age (GA) at delivery were excluded. Low Birth Weight (LBW) was defined as less than 2500 g. Pre-Term Delivery (PD), defined as GA at delivery less than 259 days, was estimated using date of Last Menstruation Period (LMP) and obstetrical ultrasound. A total of 64 women were analyzed. LPV/r was used in 46.9% due to virologic failure with other Protease Inhibitors (PIs). LPV/r was used for a mean of 108.8 days. Baseline median CD4+ cell count and HIV-1 RNA were 287 mm −3 and 31,100 copies mL, respectively and 345 mmand less than 400 copies mL −1 at delivery. HIV-1 was not transmitted to any newborn. LBW was observed in 13 (20.3%) and PD in 16 (25%) newborns. Time on LPV/r during pregnancy, maternal age, baseline CD4+ cell count and HIV-1 RNA, GA at initiation of LPV/r, reason for prescribing LPV/r and type of delivery were not associated with PD. Frequencies of LBW and PD were, respectively, 20.3 and 25%. Neither the magnitude nor the timing in pregnancy of LPV/r use was associated with PD.

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“…Data are emerging on diabetes mellitus during pregnancy. In the Pediatric AIDS Clinical Trials Group, gestational diabetes was found to occur more frequently in PI recipients [30]. By contrast, another study reported gestational glucose intolerance was not associated with PI use [31].…”

Section: Glucose Disorders In Treated Hiv Infection and Potential Suscementioning

confidence: 97%

How Sweet It Is? Susceptibility to Diabetes Mellitus in HIV-1 Treatment

Samaras

2009

HIV Ther.

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Treatment of HIV-1 infection with combined antiretroviral therapy substantially improves survival and quality of life, but is associated with metabolic disturbances such as insulin resistance, dyslipidemia and body fat partitioning disorders. These metabolic complications in the setting of suppression of viral replication are associated with increased observed risk for Type 2 diabetes mellitus. Disorders of glucose metabolism present additional challenges in the management of HIV infection, including the long-term complications of hyperglycemia, such as nephropathy, neuropathy and retinopathy, and magnified cardiovascular risk. This article considers how HIV infection and its treatment increases susceptibility to disorders of glucose metabolism. Diagnostic criteria, historical and clinical antecedents that assist the clinician in detection of diabetes susceptibility and treatment objectives are discussed.

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Maternal toxicity and pregnancy complications in human immunodeficiency virus–infected women receiving antiretroviral therapy: PACTG 316

Cited by 93 publications

References 22 publications

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Mechanisms of Reduced Maternal and Fetal Lopinavir Exposure in a Rat Model of Gestational Diabetes

Low-Birth Weight and Pre-Term Delivery in Relation to Lopinavir/Ritonavir Use in Pregnancy

How Sweet It Is? Susceptibility to Diabetes Mellitus in HIV-1 Treatment

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