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
Protease Inhibitors
Indinavir (Crixivan, IDV)
(Last updated:9/14/2011)
Indinavir (Crixivan, IDV) is classified as FDA pregnancy category C.
Animal carcinogenicity studies
Indinavir is neither mutagenic nor clastogenic in both in vitro and in vivoassays. No increased incidence of any tumor types occurred in long-term studies in mice. At the highest dose studied in rats (640 mg/kg/day or 1.3-fold higher than systemic exposure at human therapeutic doses), thyroid adenomas were seen in male rats.
Reproduction/fertility
No effect of indinavir has been seen on reproductive performance, fertility, or embryo survival in rats.
Teratogenicity/developmental toxicity
There has been no evidence of teratogenicity or treatment-related effects on embryonic/fetal survival or fetal weights of indinavir in rats, rabbits, or dogs at exposures comparable to or slightly greater than therapeutic human exposure. In rats, developmental toxicity manifested by an increase in supernumerary and cervical ribs was observed at doses comparable to those administered to humans. No treatment-related external or visceral changes were observed in rats. No treatment-related external, visceral, or skeletal changes were seen in rabbits (fetal exposure limited, approximately 3% of maternal levels) or dogs (fetal exposure approximately 50% of maternal levels). Indinavir was administered to pregnant Rhesus monkeys during the third trimester (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, indinavir exacerbated the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately 4-fold greater than controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester. In Rhesus monkeys, fetal plasma drug levels were approximately 1%–2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily.
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposure to indinavir in humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with indinavir. Among cases of first-trimester indinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.1% (6 of 285 births, 95% CI, 0.8%–4.5%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance [1].
Placental and breast milk passage
Significant placental passage of indinavir occurs in rats and dogs, but only limited placental transfer occurs in rabbits. In a Phase I study in pregnant women and their infants (PACTG 358, see below), transplacental passage of indinavir was minimal [2]. In addition, in a study of cord blood samples from 21 women treated with indinavir during pregnancy, the cord blood concentration of indinavir was less than the assay limit of detection in samples from all women [3]. Indinavir is excreted in the milk of lactating rats at concentrations slightly greater than maternal levels (milk-to-plasma ratio 1.26 to 1.45); it is not known if indinavir is excreted in human milk.
Human studies in pregnancy
The optimal dosing regimen for use of indinavir in pregnant patients has not been established. A Phase I/II safety and PK study (PACTG 358) was conducted of indinavir (800 mg three times a day) in combination with zidovudine and lamivudine in pregnant HIV-infected women and their infants [2]. The mean indinavir plasma AUC0-8hr at 30–32 weeks’ gestation (n =11) was 74% (95% CI, 50%–86%) lower than that observed 6 weeks postpartum. The PKs of indinavir in these 11 patients at 6 weeks postpartum were generally similar to those observed in nonpregnant patients in another study. In another study, two pregnant HIV-infected women receiving combination therapy including indinavir (800 mg three times a day) had significantly reduced AUC indinavir exposures in the third trimester compared with postpartum evaluations (52% and 86%, respectively) [4]. Therefore, given the substantially lower antepartum exposures observed in these studies and the generally limited data in this patient population, use of indinavir as a sole PI is not recommended in HIV-infected pregnant patients.
Two studies have evaluated twice-daily dosing with indinavir combined with low-dose ritonavir. The first evaluated 2 women whose regimen included indinavir 800 mg and ritonavir 200 mg, both twice daily. Both patients achieved third-trimester AUC indinavir levels greater than those for historical nonpregnant controls [4]. A more recent study evaluated use of twice-daily combination therapy including indinavir (400 mg) and ritonavir (100 mg). Data are available for 28 women, 23 (82%) of whom had Ctrough values greater than the targeted cutoff of 120 ng/mL. Of the 5 women with low Ctrough values, 3 had undetectable HIV RNA viral loads at delivery [5]. Based on these data, indinavir may be used in pregnancy with ritonavir boosting. Given the limited data on appropriate dosing, HIV RNA levels and, potentially, trough drug levels should be monitored during indinavir use in pregnancy.
References
1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2011. Wilmington, NC: Registry Coordinating Center; 2010. Available from URL: http://www.APRegistry.com. 2011.
2. Unadkat JD, Wara DW, Hughes MD, et al. Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother. 2007 Feb;51(2):783-786.
3. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in utero exposure. Pediatr Infect Dis J. 2002 Sep;21(9):835-838.
4. Kosel BW, Beckerman KP, Hayashi S, Homma M, Aweeka FT. Pharmacokinetics of nelfinavir and indinavir in HIV-1-infected pregnant women. AIDS. 2003 May 23;17(8):1195-1199.
5. Ghosn J, De Montgolfier I, Cornelie C, et al. Antiretroviral therapy with a twice-daily regimen containing 400 milligrams of indinavir and 100 milligrams of ritonavir in human immunodeficiency virus type 1-infected women during pregnancy. Antimicrob Agents Chemother. 2008 Apr;52(4):1542-1544.