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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Integrase Inhibitors

Raltegravir (Isentress)

(Last updated: March 28, 2014; last reviewed: March 28, 2014)

Raltegravir is classified as Food and Drug Administration Pregnancy Category C.

Animal Carcinogenicity Studies
Raltegravir was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Long-term carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential at systemic exposures 1.8-fold (females) or 1.2-fold (males) greater than human exposure at the recommended dose. Treatment-related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir (exposure 3-fold higher than in humans at the recommended adult dose) for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats receiving doses resulting in systemic exposures that were 1.7-fold (males) to 1.4-fold (females) greater than the human exposure at the recommended dose. 

Reproduction/Fertility Animal Studies
Raltegravir produced no adverse effects on fertility of male or female rats at doses up to 600 mg/kg/day (providing exposures 3-fold higher than the exposure at the recommended adult human dose).

Teratogenicity/Developmental Toxicity Animal Studies
Studies in rats and rabbits revealed no evidence of treatment-related effects on embryonic/fetal survival or fetal weights from raltegravir administered in doses producing systemic exposures approximately 3- to 4-fold higher than the exposure at the recommended adult human daily dose. In rabbits, no treatment-related external, visceral, or skeletal changes were observed. However, treatment-related increases in the incidence of supernumerary ribs were seen in rats given raltegravir at 600 mg/kg/day (providing exposures 3-fold higher than the exposure at the recommended human daily dose).

Placental and Breast Milk Passage
Placental transfer of raltegravir was demonstrated in both rats and rabbits. In rats given a maternal dose of 600 mg/kg/day, mean fetal blood concentrations were approximately 1.5- to 2.5-fold higher than in maternal plasma at 1 and 24 hours post-dose, respectively. However, in rabbits, the mean drug concentrations in fetal plasma were approximately 2% of the mean maternal plasma concentration at both 1 and 24 hours following a maternal dose of 1000 mg/kg/day. 

In humans, raltegravir appears to readily cross the placenta. In P1026s, maternal and cord blood from six deliveries of mothers receiving raltegravir-based therapy during pregnancy were evaluated; the ratio of cord blood to maternal plasma was 0.98 (95% confidence interval, 0.09–2.26).1 Other case reports have shown similarly high cord blood/maternal blood drug level ratios of 1.00 to 1.06.2,3 In a report of three pregnant women with multiresistant HIV-1 who were given raltegravir in late pregnancy to rapidly reduce maternal viral load, raltegravir concentrations within 3 hours of delivery in the neonates of two patients were approximately 7 and 9.5 times higher than in the mother’s paired sample; in the third infant, maternal plasma was not available but neonatal concentration was still high 2.5 hours after delivery.4 However, no adverse reactions were observed in mothers or infants. In a series of three cases with preterm deliveries at 29 to 33 weeks’ gestation (in 2 cases raltegravir was added to the maternal antiretroviral regimen shortly before anticipated preterm delivery), cord blood-to-maternal-plasma ratios ranged from 0.44 to 1.88.5 

Raltegravir is secreted in the milk of lactating rats, with mean drug concentrations in milk about 3-fold higher than in maternal plasma at a maternal dose of 600 mg/kg/day. No effects in rat offspring were attributable to raltegravir exposure through breast milk. Whether raltegravir is secreted in human breast milk is unknown.

Human Studies in Pregnancy
Only limited data exist on the use of raltegravir in pregnancy. Raltegravir pharmacokinetics (PK) were evaluated in 10 women in the IMPAACT P1026s study. Raltegravir PKs showed extensive variability but did not appear to be consistently altered during the third trimester compared with postpartum and historical data in non-pregnant individuals; thus the standard dose appears appropriate in pregnancy.1 In multiple case reports and case series of 4, 5, and 14 pregnant women treated with raltegravir in combination with 2 or 3 other antiretroviral drugs because of persistent viremia or late presentation, the drug was well tolerated and led to rapid reduction in HIV RNA levels.6-10 However, in one case of similar use, 10- to 23-fold increases in liver transaminases were reported after initiation of raltegravir with resolution when raltegravir was discontinued.11 Drug levels were not measured in any of those studies.

Because raltegravir is highly protein bound to albumin, there is concern about displacement of bilirubin from albumin in the neonate potentially increasing the risk of neonatal hyperbilirubinemia. In an in vitro study of the effect of raltegravir on bilirubin-albumin binding, raltegravir had minimal effect on bilirubin-albumin binding at concentrations of 5 µM and 10 µM, caused a small but statistically significant increase in unbound bilirubin at 100 µM, and caused potentially harmful increases at 500 and 1000 µM.12 These data suggest that the effect of raltegravir on neonatal bilirubin binding is unlikely to be clinically significant at typical peak concentrations reached in adults with usual dosing (adult concentrations with standard raltegravir doses were geometric mean Cmax of 4.5 µM, median Cmax of 6.5 µM and maximum observed Cmax of 10.2 µM).12 Raltegravir should not be used in neonates until PK and toxicity studies have been completed.

Chewable tablets contain phenylalanine.

References

  1. Best BM, Capparelli EV, Stek A, et al. Raltegravir Pharmacokinetics during Pregnancy. Paper presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; 2010; Boston, MA.
  2. Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy. J Antimicrob Chemother. 2010;65(9):2050-2052. Available at http://www.ncbi.nlm.nih.gov/pubmed/20630894.
  3. Croci L, Trezzi M, Allegri MP, et al. Pharmacokinetic and safety of raltegravir in pregnancy. Eur J Clin Pharmacol. 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22382989.
  4. 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(15):2416-2418. Available at http://www.ncbi.nlm.nih.gov/pubmed/20827058.
  5. Hegazi A, Mc Keown 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(18):2421-2423. Available at http://www.ncbi.nlm.nih.gov/pubmed/23151500.
  6. Taylor N, Touzeau V, Geit M, et al. Raltegravir in pregnancy: a case series presentation. Int J STD AIDS. 2011;22(6):358-360. Available at http://www.ncbi.nlm.nih.gov/pubmed/21680678.
  7. Cha A, Shaikh R, Williams S, Berkowitz LL. Rapid reduction in HIV viral load in late pregnancy with raltegravir: a case report. J Int Assoc Provid AIDS Care. 2013;12(5):312-314. Available at http://www.ncbi.nlm.nih.gov/pubmed/23695227.
  8. 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(3):181-183. Available at http://www.ncbi.nlm.nih.gov/pubmed/23783144.
  9. Westling K, Pettersson K, Kaldma A, Naver L. Rapid decline in HIV viral load when introducing raltegravir-containing antiretroviral treatment late in pregnancy. AIDS Patient Care STDS. 2012;26(12):714-717. Available at http://www.ncbi.nlm.nih.gov/pubmed/23101466.
  10. Nobrega I, Travassos AG, Haguihara T, Amorim F, Brites C. Short communication: Use of raltegravir in late-presenting HIV-infected pregnant women. AIDS Res Hum Retroviruses. 2013;29(11):1451-1454. Available at http://www.ncbi.nlm.nih.gov/pubmed/23731224.
  11. 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(1):68-72. Available at http://www.ncbi.nlm.nih.gov/pubmed/23343800.
  12. Clarke DF, Wong RJ, Wenning L, Stephenson DK, Mirochnick M. Raltegravir In Vitro Effect on Bilirubin Binding. Pediatr Infect Dis J. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23470680.

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