Transplacental passage of etravirine and maraviroc in a multidrug-experienced HIV-infected woman failing on darunavir-based HAART in late pregnancy

Calcagno, Andrea; Trentini, Laura; Marinaro, Letizia; Montrucchio, Chiara; D’Avolio, Antonio; Ghisetti, Valeria; Perri, Giovanni Di; Bonora, Stefano

doi:10.1093/jac/dkt095

Cited by 12 publications

(15 citation statements)

References 9 publications

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“…This finding is consistent with that of the only case reported to date, where the cord blood/maternal blood ratio at delivery in a single patient was 0.74 (5). Similar cord blood/maternal blood ratios have been reported for other NNRTIs, including 0.67 for nevirapine (16) and 0.51 for etravirine (17). There are considerable differences in placental transfer rates among the various antiretroviral drugs, which are partly but not entirely related to the class, defined as the site at which they inhibit viral replication.…”

Section: Rilpivirine (4-[[4-[[4-[(e)-2-cyanoethenyl]-26-dimethylphensupporting

confidence: 90%

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Mandelbrot

Duro

Belissa

et al. 2015

Antimicrob Agents Chemother

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e Placental transfers of the HIV nonnucleoside reverse transcriptase inhibitor rilpivirine were investigated in 8 term human cotyledons perfused with rilpivirine (400 ng/ml) in the maternal-to-fetal direction. The mean fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 15 to 90 min) was 26% ؎ 8% (mean ؎ standard deviation), and the clearance index (rilpivirine FTR/antipyrine FTR) was 61% ؎ 20%. This shows that rilpivirine crosses the placenta at a relatively high rate, suggesting that the fetus is exposed to the compound during treatment of the mother.A ntiretroviral drugs are remarkably effective for preventing vertical transmission of HIV-1, resulting in a decline in the rate of transmission, which is now less than 0.5% in France (1, 2). Current guidelines recommend antiretroviral therapy for all HIVinfected pregnant women for their own health and to prevent transmission (3, 4)., a diarylpyrimidine analog, is a nonnucleoside reverse transcriptase inhibitor (NNRTI) which is increasingly used to treat HIV infection and in recent guidelines is considered a first-line treatment. It is available in a single-tablet formulation in combination with tenofovir and emtricitabine (Complera-Eviplera). Rilpivirine is classified as a pregnancy category B drug by the Food and Drug Administration (4), which means that animal studies have failed to demonstrate a risk to the fetus, but there have been no adequate and well-controlled studies in HIV-1-infected pregnant women. To date, only one report has been published on two cases of rilpivirine use in pregnant women (5), in which the plasma concentrations of rilpivirine were lower than would be expected in nonpregnant women. Placental transfer was studied in one of these two cases. Currently, there are no data on the safety of rilpivirine use during pregnancy.Determining fetal exposure is important for all new medications in order to estimate the potential for preexposure prophylaxis and the risk for toxicities to the fetus. A number of adverse events have been reported following perinatal exposure to antiretroviral medications, including mitochondrial diseases (6). Since data from animal studies are difficult to extrapolate to humans due to differences in placental physiology, other preclinical approaches are required.The ex vivo human cotyledon is an accepted model used to study and interpret placental transfer (7,8). The purpose of this study was to investigate the placental transfer of rilpivirine in an ex vivo perfused human cotyledon.Placentas were collected after uncomplicated pregnancy with full-term delivery (Ն37 weeks gestational age) in mothers who were seronegative for HIV and hepatitis B and C viruses and had taken no medication, except for vitamin supplements and perimedullar analgesia. They were collected in a single center, the maternity ward of the Hôpitaux Universitaires Paris-Nord Val de Seine (Colombes, France), and were rapidly perfused on site. Written informed consent was obtained from each of the women who donated a placenta, acc...

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Section: Rilpivirine (4-[[4-[[4-[(e)-2-cyanoethenyl]-26-dimethylphensupporting

confidence: 90%

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Mandelbrot

Duro

Belissa

et al. 2015

Antimicrob Agents Chemother

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“…For the other emtricitabine study (n = 10), the median cord to maternal ratio was 1.6 but the median time between dosing and delivery was 8.5 hours [14]. For an emtricitabine case report (n = 1) the ratio was 1.7 at 13 hours after dosing [15]. …”

Section: Resultsmentioning

confidence: 99%

“…Two studies and a case report all included patients at steady-state, yet the median cord to maternal plasma concentration ratio varied from 0.82 (range 0.64-1.1, n=14) [14] in one study to 6.0 (range 3.5-7.2, n =3) [10] for the other; the case report (n = 1) was in between with a ratio of 1.1 [15]. Data for differences in time elapsed post-dose were not available for comparison.…”

Section: Resultsmentioning

confidence: 99%

“…In one (n=23), the average cord to maternal ratio was 0.5 [28]; the other (n=56) used neonatal plasma with an estimated median ratio of 0.1 [29]. Three case reports of etravirine [30, 31] have been published, two (n=1 each) with cord to maternal plasma ratios of 0.3 [30] and 0.5 [15]; the other report did not include maternal plasma sampling [31] (see Table 1 for cord values). Nevirapine is the NNRTI that has been most studied in pregnancy, both throughout pregnancy and in patients presenting in labor.…”

Section: Resultsmentioning

confidence: 99%

“…Limited data for darunavir [31, 67-70], fosamprenavir [71], and tipranavir [72] reveal potential for moderate placental transfer (see Table 1 for details). In particular, darunavir has been studied in 5 case reports and 1 small (n = 9) study with cord to maternal plasma concentration ratios ranging from 0.11 to 0.32 [15, 31, 67, 68, 69, 70]…”

Section: Resultsmentioning

confidence: 99%

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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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Antiretroviral Pharmacokinetics in Pregnant Women

et al. 2015

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For women infected with the human immunodeficiency virus (HIV) who become pregnant, the use of combination antiretroviral therapy (ART) significantly reduces transmission of HIV from mother to child. Selection of an appropriate ART regimen for use among pregnant women requires consideration of numerous factors including maternal and fetal safety, antiretroviral pharmacokinetics, and regimen efficacy. Optimization of antiretroviral pharmacokinetics during pregnancy requires special consideration because pregnancy-associated changes in drug absorption, distribution, metabolism, and excretion are known to occur throughout pregnancy and postpartum. Understanding antiretroviral placental transfer may offer additional insight into each drug's potential role in preventing HIV transmission in utero and may also have implications regarding viral resistance in cases where transmission does occur. In this review, we summarize key published data describing antiretroviral pharmacokinetics in pregnant women, providing suggestions for clinical application of these data where appropriate.

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Transplacental passage of etravirine and maraviroc in a multidrug-experienced HIV-infected woman failing on darunavir-based HAART in late pregnancy

Cited by 12 publications

References 9 publications

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

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

Antiretroviral Pharmacokinetics in Pregnant Women

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