Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Archived Drugs

Nelfinavir (Viracept, NFV)

Nelfinavir is classified as Food and Drug Administration Pregnancy Category B. Nelfinavir should not be used during pregnancy.

Animal Studies

Carcinogenicity 
Nelfinavir was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. However, incidence of thyroid follicular cell adenomas and carcinomas was increased over baseline in male rats receiving nelfinavir doses of 300 mg/kg/day or higher (which produced exposures that were equal to a systemic exposure observed in humans who received therapeutic doses) and female rats receiving nelfinavir 1000 mg/kg/day (which produced a systemic exposure 3-fold higher than the exposure seen in humans who received therapeutic doses).¹

Reproduction/Fertility 
Nelfinavir has had no observable effect on reproductive performance, fertility, or embryo survival in rats at exposures comparable to human therapeutic exposure.¹ Additional studies in female rats indicated that exposure to nelfinavir from mid-pregnancy through lactation had no effect on the survival, growth, and development of the offspring to weaning. Maternal exposure to nelfinavir also did not affect subsequent reproductive performance of the offspring.

Teratogenicity/Adverse Pregnancy Outcomes 
No evidence of teratogenicity has been observed in pregnant rats at exposures that were comparable to human exposure and in rabbits with exposures that were significantly less than human exposure.¹

Human Studies in Pregnancy

Pharmacokinetics 
A Phase 1/2 safety and pharmacokinetic (PK) study (PACTG 353) of nelfinavir administered in combination with zidovudine and lamivudine was conducted in pregnant women with HIV and their infants.² In the first nine pregnant women enrolled in the study, nelfinavir administered at a dose of 750 mg three times daily produced drug exposures that were variable and generally lower than those reported in nonpregnant adults with both twice-daily and three-times-daily dosing. Therefore, the study was modified to evaluate an increased dose of nelfinavir given twice daily (1250 mg twice daily), which resulted in adequate levels of the drug in pregnancy. However, in two other small studies of women given nelfinavir 1250 mg twice daily during the second and third trimesters, drug concentrations in both those trimesters were somewhat lower than those seen in nonpregnant women.^3,4

A PK study evaluated 25 women at 30 to 36 weeks’ gestation and 12 women at 6 to 12 weeks postpartum who received the nelfinavir 625-mg tablet formulation, given as 1250 mg twice daily. Peak nelfinavir levels and area under the curve were lower during the third trimester than postpartum.⁵ Only 16% of women (4 of 25) during the third trimester and 8% of women (1 of 12) postpartum had trough values greater than the suggested minimum trough of 800 ng/mL; however, viral load was <400 copies/mL in 96% of women in the third trimester and 86% postpartum. In a follow up study, use of an increased dose of 1875 mg twice daily after 30 weeks gestation resulted in nelfinavir exposures during the third trimester that were equivalent to those seen with 1250 mg twice daily postpartum.⁶

Placental and Breast Milk Passage 
In PACTG 353, transplacental passage of nelfinavir was minimal.² In addition, in a study of cord blood samples from 38 women who were treated with nelfinavir during pregnancy, the cord blood nelfinavir concentration was less than the assay limit of detection in 24 women (63%), and the cord blood concentration was low (with a median of 0.35 µg/mL) in the remaining 14 women.⁷ Among 20 mother-infant pairs in the Netherlands, the cord blood-to-maternal-plasma ratio for nelfinavir was 0.14 compared to 0.67 for nevirapine and 0.24 for lopinavir.⁸

Nelfinavir also has low breast milk passage. In a PK study conducted in Kisumu, Kenya, concentrations of nelfinavir and its active metabolite, M8, were measured in maternal plasma and breast milk from 26 mothers who received nelfinavir as part of antiretroviral therapy and from plasma samples collected from their 27 infants at birth, 2, 6, 14, and 24 weeks.⁹ Peak nelfinavir concentrations were recorded in maternal plasma and breast milk at 2 weeks. Median breast milk-to-plasma ratio was 0.12 for nelfinavir and 0.03 for its active metabolite (i.e., M8). Nelfinavir and M8 concentrations were below the limit of detection in 20 of 28 (71%) infant plasma dried blood spots tested from nine infants over time points from delivery though 24 weeks. Overall transfer to breast milk was low and resulted in nonsignificant exposure to nelfinavir among breastfed infants through age 24 weeks.

Teratogenicity/Adverse Pregnancy Outcomes 
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to nelfinavir have been monitored to be able to detect at least a 1.5-fold increased risk of overall birth defects and a two-fold increased risk of birth defects in the cardiovascular and genitourinary systems. No such increase in birth defects has been observed with exposure to nelfinavir. Among cases of first-trimester nelfinavir exposure reported to the Antiretroviral Pregnancy Registry, prevalence of birth defects was 3.9% (47 of 1,212 births; 95% CI, 2.9% to 5.1%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.¹⁰

In the U.S. PHACS/SMARTT cohort study, after adjusting for birth cohort and other factors, maternal use of nelfinavir led to no increase in the likelihood of adverse metabolic, growth/development, cardiac, neurological, or neurodevelopmental outcomes.¹¹

References

1. Nelfinavir [package insert]. 2015.Food and Drug Administration. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020778s040,020779s061,021503s023lbl.pdf.
2. Bryson YJ, Mirochnick M, Stek A, et al. Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) protocol 353. HIV Clin Trials. 2008;9(2):115-125. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18474496.
3. Villani P, Floridia M, Pirillo MF, et al. Pharmacokinetics of nelfinavir in HIV-1-infected pregnant and nonpregnant women. Br J Clin Pharmacol. 2006;62(3):309-315. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16934047.
4. Fang A, Valluri SR, O'Sullivan MJ, et al. Safety and pharmacokinetics of nelfinavir during the second and third trimesters of pregnancy and postpartum. HIV Clin Trials. 2012;13(1):46-59. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22306587.
5. Read JS, Best BM, Stek AM, et al. Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum. HIV Med. 2008;9(10):875-882. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18795962.
6. Eke AC, McCormack SA, Best BM, et al. Pharmacokinetics of increased nelfinavir plasma concentrations in women during pregnancy and postpartum. J Clin Pharmacol. 2019;59(3):386-393. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30358179.
7. Mirochnick M, Dorenbaum A, Holland D, et al. Concentrations of protease inhibitors in cord blood after in utero exposure. Pediatr Infect Dis J. 2002;21(9):835-838. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12352805.
8. van Hoog S, Boer K, Nellen J, Scherpbier H, Godfried MH. Transplacental passage of nevirapine, nelfinavir and lopinavir. Neth J Med. 2012;70(2):102-103. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22418759.
9. Weidle PJ, Zeh C, Martin A, et al. Nelfinavir and its active metabolite, hydroxy-t-butylamidenelfinavir (M8), are transferred in small quantities to breast milk and do not reach biologically significant concentrations in breast-feeding infants whose mothers are taking nelfinavir. Antimicrob Agents Chemother. 2011;55(11):5168-5171. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21876052.
10. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989 –31 January 2019. Wilmington, NC: Registry Coordinating Center. 2019. Available at: http://www.apregistry.com/.
11. Van Dyke RB, Chadwick EG, Hazra R, Williams PL, Seage GR, 3rd. The PHACS SMARTT study: assessment of the safety of In utero exposure to antiretroviral drugs. Front Immunol. 2016;7:199. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27242802.