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AIDS:
doi: 10.1097/QAD.0b013e32833d8a50
Correspondence

High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women

Mckeown, Denise Aa; Rosenvinge, Melanieb; Donaghy, Sheilac; Sharland, Mikec; Holt, David Wa; Cormack, Iand; Hay, Phillipb,e; Sadiq, S Tariqb,e

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aAnalytical Unit, St George's, University of London, UK

bDepartment of GUM, UK

cDepartment of Child Health, St George's Healthcare NHS Trust, UK

dMayDay Healthcare NHS Trust, London, UK

eCentre for Infection, St George's, University of London, London, UK.

Received 18 June, 2010

Accepted 22 June, 2010

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.

Table 1
Table 1
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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.

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Acknowledgements

D.A.M. developed the analytical methodology and analysed the raltegravir concentrations for the samples collected from patients 1 and 3 and jointly drafted the manuscript. M.R. was a specialist registrar (attending physician), for patients 1 and 3 and jointly drafted the manuscript. S.D. is a paediatric clinical nurse specialist for patients 1 and 3. M.S. is a paediatric HIV consultant specialist for patients 1 and 3. D.W.H. is the Director of the Analytical Unit, where the analytical work was performed, and contributed to the manuscript. I.C. is a HIV consultant specialist for patient 2. P.H. jointly instigated the study and contributed to the content of the manuscript. He is the supervising HIV consultant specialist in charge for patients 1 and 3. S.T.S. jointly instigated the study, enabled local analysis of raltegravir concentrations and significantly contributed to the content of the manuscript.

Raltegravir and 13C6-raltegravir utilized in the development of the LC-MS/MS method were a kind gift from MERCK (Rahway, New Jersey, USA).

Data for patient 2 were presented as an oral at the Second Joint Conference of the British HIV Association (BHIVA) with the British Association for Sexual Health and HIV (BASHH), 20–23 April 2010, Manchester, UK. BHIVA/BASHH Workshop 4on ‘Raltegravir: a niche in late pregnancy’ and the slides published on the BHIVA Web site, http://www.bhiva.org.

Data for all three patients have been accepted as a poster presentation at the XVIII International AIDS Conference on ‘Raltegravir in the prevention of mother-to-child transmission of HIV: high concentrations demonstrated in newborns’, Vienna, Austria, 18–23 July 2010. The abstract will be published on CD-ROM and online.

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References

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2. Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, et al. Metabolism and disposition in humans of raltegravir (MK-0518): an anti-aids drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos 2007; 35:1657–1663.

3. Dickinson L, Khoo S, Back D. Pharmacokinetics and drug–drug interactions of antiretrovirals: an update. Antiviral Res 2010; 85:176–189.

4. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans. Pharmacogenetic and developmental aspects. Clin Pharmacokinet 1999; 36:439–452.

5. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet 2005; 44:989–1008.

6. Gulatia A, Gerk PM. Role of placental ATP-binding cassette (ABC) transporters in antiretroviral therapy during pregnancy. J Pharm Sci 2009; 98:2317–2335.

7. St-Pierre MV, Serrano MA, Macias RI, Dubs U, Hoechli M, Lauper U, et al. Expression of members of the multidrug resistance protein family in human term placenta. Am J Physiol Regul Integr Comp Physiol 2000; 279:1495–1503.

8. Sudhakaran S, Rayner CR, Li J, Kong DC, Gude NM, Nation RL. Inhibition of placental P-glycoprotein: impact on indinavir transfer to the fetus. Br J Clin Pharmacol 2007; 65:667–673.

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