Pharmacokinetic and safety of raltegravir in pregnancy

Abstract

Dear Sirs:The aim of anti-HIV treatment in pregnancy is the suppres-sion of the HIV-1 RNA viral load in the plasma beforedelivery [1] to prevent mother-to-child transmission of theinfection. The achievement of this outcome may be compli-cated in pregnant women who have been treated with mul-tiple drugs by the lack of active drugs available. Althoughthere are limited data on the use of the integrase inhibitorraltegravir in pregnancy, the availability of this drug isimportant in the management of multidrug-resistant virusin pregnant women.We describe a case of a 22-year-old woman who acquiredthe infection via vertical transmission and who has beenfollowed up at our Centre since March 2009. Past antiretro-viral treatments include numerous drugs; the historical ge-notypic resistance test showed mutations in the regions ofreverse transcriptase (41L, 74V, 101Q, 103N, 103S, 108I,115F, 179I, 184V, 215D, 215N, 215S, 215Y) and protease(36I, 63P). These mutations confer resistance or poor effi-cacy to all the nucleoside/nucleotide reverse transcriptaseinhibitors and non-nucleoside reverse transcriptase inhibi-tors except etravirine.Since April 2009 the patient has received treatment withtenofovir/emtricitabine (fixeddosecombination)plusdaruna-vir/ritonavir (600/100 mg twice daily) plus raltegravir(400mgtwice daily). AtthetimeofconceptionshepresentedHIV-RNA <20 cp/mL. Despite safety and pharmacokineticsdata of raltegravir in pregnancy being insufficient to recom-mendits use duringpregnancy, itwas decided to continuethetreatment with tenofovir/emtricitabine (fixed dose combina-tion) plus raltegravir (400 mg twice daily); only darunavir/ritonavir had been discontinued since the 4th week of preg-nancy and substituted with lopinavir/ritonavir (400/100 mgtwice daily), the gold standard for protease inhibitors in preg-nant women [2].Therapeutic drugmonitoringwas performedby a validated HPLC-UV method [3] in the third trimester,which demonstrated good adherence; at that time lopinavir,ritonavirandraltegravirplasmalevelswere9.59μg/mL(min-imum target trough concentration 1 μg/mL) [3], 0.81 μg/mLand 0.21 μg/mL (median trough concentration from clinicaltrials 0.029–0.118 μg/mL) [2].At 39weeks’ gestation a 2.4-kg neonate was delivered byelective caesarean section without complications; at the timeof delivery the HIV-RNA viral load in plasma was <20cp/mL. Despite the low birth weight the infant was healthy;the Apgar scores were 9 and 10 at 1 and 5 min respectively.The mother received zidovudine intravenous prophylaxisduring labour and the newborn received 4 weeks of oralzidovudine; the HIV-RNAwas undetectable at birth and at 1and 3 months of age. At delivery the raltegravir level in cordand in maternal plasma was the same (0.19 μg/mL) with acord/maternal plasma ratio of 1. The lopinavir levels were1.3 μg/mL and 8.05 μg/mL and the ritonavir levels were0.26 μg/mL and 0.94 μg/mL, corresponding to a ratio of0.16 and 0.28 respectively.The low plasma cord concentration of lopinavir can beexplained because the drug level was measured ~15 h afterthe last drug dose as the caesarean section was delayedbecause of a complication that occurred at the previouscaesarean performed in the same surgical section. Despite