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  53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO
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Raltegravir Safe for Pregnant Women and Their Newborns in 31-Case Study
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Download the PDF here
53rd ICAAC, September 10-13, 2013, Denver
Mark Mascolini
Raltegravir proved virologically effective in 31 pregnant women and caused no adverse events in women or their newborns in an ongoing study of mother-infant pairs at Jean Verdier Hospital in Bondy, France [1].
All HIV-positive pregnant women at the hospital are managed by a team including infectious disease specialists, obstetricians, and pediatricians. All receive regular obstetrical exams, routine laboratory and HIV-related tests, and ultrasonography to assess fetal growth. Women receive intravenous zidovudine during labor to prevent vertical transmission of HIV.
This analysis, which began in 2008, involved 31 women with a median age of 31 years (range 18 to 44). Twenty-five women (81%) were black. Sixteen women (52%) were antiretroviral-naive when they became pregnant. Women with antiretroviral experience had been treated for a median of 76 months (range 10 to 233) before becoming pregnant.
Five women (16%) started raltegravir before pregnancy, 3 (10%) started in the second trimester, and 23 (74%) started in the third trimester. Nineteen women began raltegravir because of poor adherence to other antiretrovirals, 5 because of side effects of other agents, and 2 because of late HIV diagnosis. Previous research established rapid suppression of plasma viremia with raltegravir in pregnant women [2-4]. Besides raltegravir, 19 women (61%) took a protease inhibitor, 3 took a nonnucleoside, and 12 took tenofovir/emtricitabine.
Raltegravir began in these women at a median CD4 count of 442 (range 155 to 786) and a median viral load of 17,765 copies (range 61 to 114,638). Median raltegravir duration among this women stood at 71 days (range 3 to 287). Plasma viral load fell an averaged 1.12 log10 copies per week when women started raltegravir in the second or third trimester. Median last viral load before delivery was 41 copies (range 0 to 641). Among 6 women (19%) with a detectable viral load at delivery, those loads were 45, 47, 56, 161, 253, and 641.
Median gestation at delivery measured 36 weeks. Fifteen women delivered vaginally and the rest by elective or emergency cesarean section. The investigators observed no biological abnormalities in mothers or 32 liveborn neonates. (A published case report recorded increased transaminase levels in a woman who started raltegravir with a high viral load at 35 weeks gestation [5].)
Median infant weight was 3100 g (range 2120 to 4030), median height 48 cm (range 44.5 to 52), and median head circumference 34 cm (range 32 to 36.1). Median Apgar score, which measures the physical condition of newborns, was 9.6 (10 is the best score).
Twenty-three infants received postnatal zidovudine prophylaxis alone, 4 received two-drug prophylaxis, and 5 received 3-drug prophylaxis. Twenty-nine infants (91%) had undetectable HIV DNA at 6 months. No infants had apparent adverse reactions to treatment.
The researchers determined raltegravir cord blood and maternal plasma concentrations in 16 cases. Maternal concentration ranged from 10 to 270 ng/mL, while median cord blood concentration ranged from 5 to 198 ng/mL. Median cord/maternal ratio was 3.48 (range 1 to 7.6). Published studies from the United Kingdom recorded effective transplacental transfer and delayed plasma clearance of raltegravir in preterm neonates [6] and high neonatal raltegravir concentrations via transplacental transfer [7].
The French team cautioned that the small size of this ongoing study prevents firm conclusions. But they proposed that "the safety of a raltegravir-containing regimen, together with a rapid antiretroviral activity, the absence of embryonic or foetal toxicity in animal studies, [and] a high placental transfer, offers a promising new strategy."
1. Jeantils V, Messaouden H, Carbillon L. Pregnancy and a regimen containing raltegravir: a pilot study on the materno foetal safety. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-1463.
2. De Hoffer L, Di Biagio A, Bruzzone B, et al. Use of raltegravir in a late presenter HIV-1 woman in advanced gestational age: case report and literature review. J Chemother. 2013;25:181-183.
3. Nobrega I, Travassos AG, Haguihara T, Amorim F, Brites C. Use of raltegravir in late-presenting, HIV-infected pregnant women. AIDS Res Hum Retroviruses. 2013 Jun 3. Epub ahead of print.
4. Hegazi A, Hay P. HIV seroconversion in the third trimester of pregnancy: using raltegravir to prevent mother-to-child transmission. Int J STD AIDS. 2013 Feb 25. Epub ahead of print.
5. Renet S, Closon A, Brochet MS, Bussieres JF, Boucher M. Increase in transaminase levels following the use of raltegravir in a woman with a high HIV viral load at 35 weeks of pregnancy. J Obstet Gynaecol Can. 2013;35:68-72.
6. Hegazi A, McKeown D, Doerholt K, Donaghy S, Sadiq ST, Hay P. Raltegravir in the prevention of mother-to-child transmission of HIV-1: effective transplacental transfer and delayed plasma clearance observed in preterm neonates. AIDS. 2012;26:2421-2423.
7. McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women. AIDS. 2010;24:2416-2418.
High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women
AIDS: 24 September 2010
Mckeown, Denise Aa; Rosenvinge, Melanieb; Donaghy, Sheilac; Sharland, Mikec; Holt, David Wa; Cormack, Iand; Hay, Phillipb,e; Sadiq, S Tariqb,e aAnalytical Unit, St George's, University of London, UKbDepartment of GUM, UKcDepartment of Child Health, St George's Healthcare NHS Trust, UKdMayDay Healthcare NHS Trust, London, UKeCentre for Infection, St George's, University of London, London, UK.
Raltegravir, an integrase inhibitor, used in the treatment of triple class resistant HIV-1, causes rapid reduction in HIV-1 viral load and is usually well tolerated. Principally metabolized by UGT1A1-mediated glucuronidation, it neither inhibits cytochrome P450 (CYP450) enzymes nor induces CYP3A4, giving it a favourable drug interaction profile [1-3]. These features make raltegravir a useful option for pregnant women who present late or have drug-resistant HIV-1. Little is known about human transplacental transfer of raltegravir, neonatal pharmacokinetics and safety.
We report three cases in which raltegravir was used late in pregnancy to rapidly reduce maternal HIV-1 viral load (Roche Taqman 2.0 assay), in women with multidrug resistant virus. Blood samples were taken from mother and baby as close to delivery as possible and maternal viral load was monitored up to delivery. Neonates were assessed by HIV-1 DNA PCR at 0, 6, and 12 weeks. Raltegravir plasma concentrations were quantified by liquid chromatography-tandem mass spectrometry. Written consent was obtained for all cases.
Results are summarized in Table 1. Patient 1 was a 39-year-old Ugandan multiparous woman with highly resistant virus. Because of poor virological control at 28 weeks of gestation, the lopinavir/ritonavir component of her antiretroviral regimen was replaced by raltegravir and etravirine. Patient 2 was a 26-year-old Ghanaian nulliparous woman presenting to antenatal clinic with dual/mixed CCR5-tropic virus and transmitted resistance. Defaulting follow-up until 35 weeks of gestation, she then started darunavir/ritonavir, tenofovir/emtricitabine and etravirine. After finding no viral load reduction and undetectable darunavir concentrations, she was admitted for supervised therapy and raltegravir was added at 38 weeks. At 39 weeks, she developed nausea and an elevated serum aspartate transaminase, which improved after etravirine was stopped. Patient 3 was a 31-year-old Zimbabwean nulliparous woman with a history of nevirapine allergy, intolerance of protease inhibitors and poor adherence. At 29 weeks of gestation, because viral load was 3210 copies/ml, her prescription was changed from tenofovir/emtricitabine and lopinavir/ritonavir to efavirenz. At 39 weeks, viral load was still detectable and raltegravir was added.
Raltegravir concentrations, within 3 h after delivery, in the neonates of patients 1 and 2, were approximately 7 and 9.5 times higher than in the mothers' paired samples, respectively. Paired samples were not collected for patient 3. However, neonatal concentrations were still high 2.5 h after delivery. All infants were HIV-1 DNA PCR negative at 12 weeks. To date, no adverse reactions in mother or child have been reported.
In all three cases, addition of raltegravir to the mother's regimen was associated with rapid reduction in maternal viral load. The much higher raltegravir concentrations in neonates compared with their mothers suggests effective placental transfer, perhaps reflecting poor neonatal and foetal maturity of the UGT-dependent pathways [4]. It is possible that increased activity of UGT1A1 observed in pregnant women contributed to the disparity [5]. Reduced activity of UGT1A1 in neonates, probably resulting from low transcription levels rather than variation in UGT1A1 genotypes [4], is potentially more critical after placental separation because of the effects of placental dialysis. If, as in these cases, there are limited neonatal adverse effects associated with high raltegravir concentrations, it suggests potential favourable pharmacokinetics for preloading raltegravir in newborns. This could be important in the case of preterm neonates who absorb oral agents poorly. However, increases in UGT1A1 activity after birth may be related to birth-related events and not gestational age [4]. Neonatal raltegravir concentrations in patient 3 had fallen to subtherapeutic (<15 ng/ml) within 72 h of birth. Excretion of unchanged raltegravir in the urine and faeces may have been important here [2].
Placental transfer is also influenced by plasma protein binding and placental transporters [6]. Raltegravir is approximately 83% bound to plasma proteins [3], concentrations of which alter in pregnancy [6]. Protease inhibitors are more protein bound than raltegravir and transfer poorly across the placenta [6]. Raltegravir is a substrate of P-glycoprotein (PGP) [2], which is highly expressed in placental tissue and which appears to protect the foetus from maternal concentrations of drugs and metabolites [7]. Decreased PGP expression may increase foetal drug exposure. Potent drug-induced inhibition of placental PGP has been shown to increase transfer of the protease inhibitor, indinavir, but this effect was not achieved by ritonavir, which is also a PGP inhibitor [8]. Exploring the use of PGP inhibitors in pregnancy to increase foetal drug exposure may widen options for preventing mother-to-child transmission of HIV. In conclusion, raltegravir was effectively transferred across the placenta of three pregnant women and persisted in neonates for up to 3 days, without adverse effects.
Raltegravir in the prevention of mother-to-child transmission of HIV-1: effective transplacental transfer and delayed plasma clearance observed in preterm neonates
28 November 2012
Hegazi, Aseela; Mc Keown, Deniseb; Doerholt, Katjac; Donaghy, Sheilac; Sadiq, Syed T.a,d; Hay, Phillipa,d aDepartment of Genitourinary Medicine, St George's Healthcare NHS TrustbAnalytical Unit, St George's, University of LondoncDepartment of Paediatric Infectious Diseases, St George's Healthcare NHS TrustdCentre for Infection and Immunity, St George's University of London, London, UK. Correspondence to Dr Phillip Hay, Reader and Honorary Consultant in Genitourinary Medicine, Centre for Infection and Immunity, St George's University of London, Cranmer Terrace, London SW17 0RE, UK. Tel: +44 0 208 7253355; e-mail: phay@sgul.ac.uk
HIV infection may be associated with an increased risk of preterm labour [1], and preterm neonates are at an increased risk of acquiring HIV congenitally [2]. Absorption of orally administered drugs in preterm neonates is unpredictable due to gastrointestinal tract immaturity, and parenteral antiretroviral options are also limited [3]. The HIV-1 integrase inhibitor, raltegravir (RGV), has rapid antiretroviral activity with shorter times to achieving virological suppression when used in combination treatments compared with conventional combination antiretroviral therapy (ART) [4,5]. RGV has a favourable pharmacokinetic profile with a terminal elimination half-life of between 7 and 12 h and a time to steady state of approximately 2 days [6]. It is eliminated by glucuronidation in the liver by human UGT1A1 [6] and much of the RGV glucuronide metabolite is eventually excreted in bile (approximately 50%) or in urine (31%) [6].
Although unlicensed in pregnancy, RGV has been used in patients who present late in pregnancy with high HIV-1 viral loads when it is critical to reduce the viral load to undetectable levels before delivery [7]. We have previously demonstrated effective RGV transplacental transfer and persistence of therapeutic drug concentrations in neonates for several days after delivery in mothers with HIV-1 resistant to protease, nucleoside/nucleotide and nonnucleoside inhibitors [8].
We describe three cases of preterm delivery in which RGV was used in the prevention of mother-to-child transmission (PMTCT) of HIV-1. Paired blood samples were taken from the mother and baby as close to delivery as possible and subsequently postpartum. RGV plasma concentrations (RPC) were measured using liquid chromatography with tandem mass spectrometric detection. Maternal HIV-1 viral load was monitored regularly until delivery and neonates were assessed for HIV-1 infection by HIV-1 DNA PCR at 0, 6 and 12 weeks (Roche Taqman 2.0 assay). Cases are summarized in Table 1. The mother in case 1 was a 24-year-old Rwandan lady who had been diagnosed with HIV-1 infection 10 years previously. She had a long history of poor adherence to ART and was known to have had K103N and M184V resistance mutations previously detected, as well as intolerance to ritonavir at pharmacoenhancing doses. This was her sixth unplanned pregnancy, and all her previous pregnancies had been obstetrically complicated. The mother in case 2 was 32 years old, from Ghana, and in her first pregnancy. She was newly diagnosed with HIV-1, having tested positive through routine antenatal screening, and was having difficulty accepting the diagnosis. She was poorly adherent to ART and her viral load never became undetectable. Her viral load was unknown when she presented at the time of delivery. The mother in case 3 was 32 years old, from Uganda and also in her first pregnancy. She had been diagnosed with HIV-1 3 years previously but had never previously received ART. She was started on combination ART in the second trimester of pregnancy and was fully adherent with a suppressed HIV viral load. All babies received 4 weeks of ART postpartum and have tested HIV negative by DNA PCR to date with no apparent adverse reactions.
Therapeutic RPC (≥15 ng/ml) were achieved in all mothers and in all babies at both sampling times, despite RGV being initiated 22.5 and 14 h prior to delivery in two cases. RPC can remain at therapeutic levels for up to 5 days in preterm neonates, longer than babies born at term [8], probably reflecting immature UGT1A1-mediated glucuronidation.
The use of RGV preloading in pregnancy for HIV PMTCT in preterm neonates may thus have added benefits above rapidly reducing maternal viral load by having a similar role to nevirapine [9] or double-dose tenofovir [10] for preloading preterm neonates who cannot take or absorb oral drugs poorly and for whom parenteral options are limited. In this small series, RGV levels in the mothers and neonates who commenced RGV with the aim of preloading the baby were much lower than in the mother who was on established treatment and had presumably reached steady state. The use of a dose of 800 mg should be explored for rapidly preloading premature infants. Larger studies are needed to further characterize the pharmacokinetics of RGV in pregnant women and neonates.