Raltegravir in the prevention of mother-to-child transmission of HIV-1

Hegazi, Aseel; Keown, Denise Mc; Doerholt, Katja; Donaghy, Sheila; Sadiq, S Tariq; Hay, Phillip

doi:10.1097/qad.0b013e32835a9aeb

Cited by 19 publications

(8 citation statements)

References 10 publications

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“…The third set of cases focused on pre-term deliveries. One patient was at steady state prior to delivery at 33 + 2/7 weeks and had a neonatal plasma concentration of 3.8 mg/L with a neonatal to maternal ratio of 1.63 [76]. The other two patients in this report were not at steady-state, having started raltegravir only 14 to 23 hours prior to delivery.…”

Section: Resultsmentioning

confidence: 96%

Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals

McCormack

Best

2014

Clin Pharmacokinet

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Background Maternal-fetal transfer of antiretroviral drugs contributes to prevention of vertical transmission of HIV. Objective This systematic review discusses published studies containing data pertaining to the pharmacokinetics of placental transfer in humans, including paired cord and maternal plasma samples collected at the time of delivery as well as ex vivo placental perfusion models. Methods Articles pertaining to placental transfer of antiretrovirals were identified from PubMed, from references of included articles, and from U.S. Department of Health and Human Services Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission guidelines. Articles from non-human animal models or that had no original maternal-fetal transfer data were excluded. PRISMA guidelines were followed. Results A total of 103 published studies were identified. Data across studies appeared relatively consistent for the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleotide reverse transcriptase inhibitors (NNRTIs), with cord to maternal ratios approaching 1 for many of these agents. The protease inhibitors atazanavir and lopinavir exhibited consistent maternal-to-fetal transfer across studies, although the transfer may be influenced by variations in drug-binding proteins. The protease inhibitors indinavir, nelfinavir, and saquinavir exhibited unreliable placental transport, with cord blood concentrations that were frequently undetectable. Limited data, primarily from case reports, indicate that darunavir and raltegravir provide detectable placental transfer. Conclusion These findings appear consistent with current guidelines of using two NRTIs plus an NNRTI, atazanavir/ritonavir, or lopinavir/ritonavir to maximize placental transfer as well as to optimally suppress maternal viral load. Darunavir/ritonavir and raltegravir may reasonably serve as second-line agents.

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Section: Resultsmentioning

confidence: 96%

Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals

McCormack

Best

2014

Clin Pharmacokinet

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“…[9–11] While these reports suggest that raltegravir readily crosses the placenta, they provide limited data describing the postnatal elimination of transplacentally-acquired raltegravir in the infant. One preterm infant has been described who had raltegravir concentrations present one month after delivery, suggesting very prolonged elimination.…”

Section: Discussionmentioning

confidence: 99%

Raltegravir Pharmacokinetics in Neonates Following Maternal Dosing

Clarke

Acosta

Rizk

et al. 2014

JAIDS Journal of Acquired Immune Deficiency Syndromes

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IMPAACT P1097 was a multicenter trial to determine washout pharmacokinetics and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-infected pregnant women receiving raltegravir-based antiretroviral therapy. Twenty-two mother-infant pairs were enrolled; evaluable pharmacokinetic data was available from 19 mother-infant pairs. Raltegravir readily crossed the placenta, with median cord blood/maternal delivery plasma raltegravir concentration ratio 1.48 (range, 0.32–4.33). Raltegravir elimination was highly variable and extremely prolonged in some infants; [median t½ 26.6 hours (range 9.3–184 hours)]. Prolonged raltegravir elimination likely reflects low neonatal UGT1A1 enzyme activity and enterohepatic recirculation. Excessive raltegravir concentrations must be avoided in the neonate, since raltegravir at high plasma concentrations may increase the risk of bilirubin neurotoxicity. Sub-therapeutic concentrations, which could lead to inadequate viral suppression and development of raltegravir resistance, must be avoided as well. Two ongoing IMPAACT studies are investigating further the pharmacology of raltegravir in neonates.

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“…tions detected in maternal and cord blood plasma from mothers receiving RTG-based therapy during pregnancy (7,(11)(12)(13). Dolutegravir has also been shown to readily cross the blood-placenta barrier (8).…”

mentioning

confidence: 99%

Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy

Rimawi

Johnson

Rajakumar

et al. 2017

Antimicrob Agents Chemother

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The integrase inhibitors elvitegravir (EVG) and dolutegravir (DTG) rapidly decrease the plasma HIV-1 viral load, a key factor in the prevention of maternal-tofetal transmission of HIV-1. No data have been reported on the concentrations of these drugs in cord blood, maternal peripheral blood mononuclear cells (PBMCs), or placental tissue in pregnant women. We present in vivo pharmacokinetic data on antiretrovirals (ARV) within maternal and cord blood and within placentae from HIV-1-infected pregnant women. Maternal blood and cord blood were obtained from women receiving EVG, cobicistat, tenofovir disoproxil fumarate, and emtricitabine as a single fixed-dose combination formulation or DTG as part of a combination regimen. Plasma and PBMCs from maternal and cord blood were obtained along with villous placental samples. Drug concentrations were simultaneously determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Utilizing medians and ranges to interpret our data, we compared the drug concentration ratios between different matrices (maternal and cord blood plasma, PBMCs, and placenta). All five agents transferred from maternal into fetal circulation via the placenta. Concentration ratios for EVG, cobicistat, tenofovir, and emtricitabine (n ϭ 10) and DTG (n ϭ 3) were determined between cord plasma and placenta, cord and maternal plasma, and cord PBMCs and maternal PBMCs. TFV moves from maternal plasma through the placenta to the cord blood and then into cord PBMCs, where it is phosphorylated into its active forms (TFV diphosphate). These five ARVs were detected in each of the compartments, highlighting transfer of these agents from the maternal into the fetal circulation.

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Raltegravir in the prevention of mother-to-child transmission of HIV-1

Cited by 19 publications

References 10 publications

Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals

Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals

Raltegravir Pharmacokinetics in Neonates Following Maternal Dosing

Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy

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