Integrase Inhibitors

Elvitegravir (EVG)

Animal studies 

Carcinogenicity
In long-term studies, no carcinogenicity was detected at exposures that were 14-fold higher (in mice and rats) and 27-fold higher (in rats) than those achieved in humans during systemic exposure to the recommended dose.¹

Reproduction/Fertility
Elvitegravir (EVG) did not affect fertility in male and female rats at approximately 16-fold and 30-fold higher exposures than those seen in humans who received standard doses. Fertility was normal in the offspring of these rats.¹

Teratogenicity/Adverse Pregnancy Outcomes
Studies have shown no evidence of teratogenicity and no effect on reproductive function in rats and rabbits receiving EVG.¹

Placental and Breast Milk Passage
No data are available on the placental transfer of EVG in nonhuman primates. Studies in rats have demonstrated that EVG is secreted in breast milk.¹

Human Studies in Pregnancy

Pharmacokinetics
Pharmacokinetic (PK) and safety data from 30 pregnant women with HIV who received a fixed-dose combination (FDC) of EVG, cobicistat (COBI), emtricitabine, and tenofovir disoproxil fumarate (TDF) have been published. EVG exposure (based on area under the curve [AUC]) was 24% lower during the second trimester and 44% lower during the third trimester than during the postpartum period. EVG trough concentration (C_24h) was 81% lower during the second trimester and 89% lower during the third trimester than during the postpartum period. COBI AUC was 54% to 57% lower and C_24h was 72% to 76% lower during the second and third trimesters than during the postpartum period. EVG AUC failed to reach the exposure target of 23 mcg·hr/mL (the 10th percentile for nonpregnant adults) in 50% of women during the second trimester and 55% of women during the third trimester; 12% of women reached the exposure target during the postpartum period. Plasma HIV RNA at delivery was <50 copies/mL in 19 of 25 women (76%) for whom data were available.² In a smaller study that evaluated the PK of EVG administered with COBI in seven pregnant women, EVG AUC was reduced by 33% and C_trough was reduced by 65% during the third trimester compared with postpartum. One of the seven women had detectable plasma HIV RNA at delivery.³

Two case reports of EVG and COBI PKs, safety, and efficacy in individual pregnant women found similar reductions in EVG and COBI exposure during pregnancy, although viral loads in both women remained undetectable throughout pregnancy.^4,5 One case report described unbound EVG concentrations and found that the unbound fraction was 0.3% during pregnancy and 0.5% at 6 months postpartum. Reductions in both total EVG concentration and unbound EVG concentration increase the risk of suboptimal exposure.⁵

Because studies have reported reduced EVG exposure when pregnant women receive FDC tablets that contain EVG and COBI, the prescribing information for these products has been changed to say that these formulations are not recommended for use in pregnancy and should not be initiated in pregnancy; an alternative regimen is recommended for individuals who become pregnant while receiving these formulations.^1,6 If these formulations are used in pregnancy, in order to maximize absorption, they should be administered with a meal and should not be administered within 2 hours of intake of preparations containing minerals such as iron or calcium, including prenatal vitamins.⁶

Placental and Breast Milk Passage
Placental passage of EVG has been evaluated in three studies. The largest study of EVG PKs and safety observed that EVG crossed the placenta well, with a median cord-to-maternal-plasma ratio of 0.91. Median EVG elimination half-life in neonates was 7.6 hours, similar to that in nonpregnant adults. COBI concentrations were low in cord blood and were not detected in the plasma of any neonates.² Similar results were seen in the two smaller studies of women from the United States and Europe and in several case reports.^4,5 No data are available on the human breast milk transfer of EVG.

Teratogenicity/Adverse Pregnancy Outcomes
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to EVG in humans have been monitored to be able to detect a two-fold increased risk of overall birth defects. No such increase in the risk of birth defects has been observed in infants who were exposed to EVG.⁷ Among cases of first-trimester EVG exposure, the prevalence of birth defects was 2.50% (six of 240 births; 95% confidence interval, 0.92% to 5.36%), compared with a 2.72% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.⁷ In the largest PK and safety study of EVG in pregnancy, which included data on 26 live-born infants, congenital anomalies were reported in two infants: one infant with amniotic band syndrome, microcephaly, and intrauterine growth restriction and one infant with ulnar postaxial polydactyly (supernumerary digit).² In a retrospective report of 137 infants in the United States who were born to mothers who received EVG during pregnancy, there were two birth defects noted: one case of hydronephrosis and one case of encephalocele. There were also two cases of intrauterine fetal demise among the 134 pregnancies included in this report.⁸

Excerpt from Table 8

Note: When using FDCs, refer to other sections in Appendix B and Table 8 for information about the dosing and safety of individual drug components of the FDC during pregnancy.

References

1. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203100s034lbl.pdf.
2. Momper J, Best BM, Wang J, et al. Elvitegravir/cobicistat pharmacokinetics in pregnant and postpartum women with HIV. AIDS. 2018;32(17):2507-2516. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30134297.
3. Colbers A, Schalkwijk S, Konopnicki D, Rockstroh J, Burger D. Elvitegravir pharmacokinetics during pregnancy and postpartum. Abstract 17. Presented at:19th International Workshop on Clinical Pharmacology of Antiviral Therapy. 2018. Baltimore, MD. Available at: http://www.natap.org/2018/Pharm/Pharm_11.htm.
4. Schalkwijk S, Colbers A, Konopnicki D, et al. First reported use of elvitegravir and cobicistat during pregnancy. AIDS. 2016;30(5):807-808. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26913711.
5. Marzolini C, Decosterd L, Winterfeld U, et al. Free and total plasma concentrations of elvitegravir/cobicistat during pregnancy and postpartum: a case report. Br J Clin Pharmacol. 2017;83(12):2835-2838. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28512794.
6. Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207561s023lbl.pdf.
7. 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.
8. Badell ML, Sheth AN, Momplaisir F, et al. A multicenter analysis of elvitegravir use during pregnancy on HIV viral suppression and perinatal outcomes. Open Forum Infect Dis. 2019;6(4):ofz129. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31037241.