Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Pharmacoenhancers

Cobicistat (Tybost, COBI)

Last Updated: December 7, 2018; Last Reviewed: December 7, 2018

Cobicistat has insufficient data on human use in pregnancy to inform a drug-associated risk determination for birth defects or miscarriage.

Animal Studies 

Carcinogenicity
At cobicistat exposures 7 times and 16 times the human systemic exposure, no increases in tumor incidence were seen in male and female mice. In rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses up to twice the typical human exposure. The follicular cell findings are considered rat-specific and not relevant to humans.1

Reproduction/Fertility
No effect has been seen on fertility in male or female rats.1

Teratogenicity/Adverse Pregnancy Outcomes
Studies in pregnant rats and rabbits have shown no evidence of teratogenicity, even with cobicistat exposures that were 1.4 times higher than the recommended human exposure in rats and 3.3 times higher than the recommended human exposure in rabbits.1

Placental and Breast Milk Passage
No information is available on placental passage of cobicistat. Studies in rats have shown that cobicistat is secreted in breast milk.2

Human Studies in Pregnancy 

Pharmacokinetics
Cobicistat pharmacokinetics (PKs) have been described in pregnant and postpartum women who were taking concomitant elvitegravir and darunavir. In a study of 30 pregnant women who were receiving elvitegravir/cobicistat, the area under the curve (AUC) for cobicistat was 44% lower in the second trimester and 59% lower in the third trimester than during the postpartum period. Trough cobicistat concentrations (24 hours post-dose) were 60% lower in the second trimester and 76% lower in the third trimester than during the postpartum period. Trough cobicistat concentrations were below the assay quantitation limit (<10 ng/mL) in 65% of women during the second trimester, 73% of women during the third trimester, and 24% of postpartum women.

The pharmaco-enhancing effect of cobicistat on elvitegravir was impacted during pregnancy; elvitegravir AUC was reduced by 44% and trough concentrations were reduced by 89% in the third trimester when compared to postpartum AUC and trough concentrations. Elvitegravir apparent oral clearance during pregnancy and postpartum was negatively associated with cobicistat AUC.3 Study results reported in two conference abstracts have described decreases of similar magnitudes in cobicistat and darunavir exposures among pregnant women.4,5 In one of these abstracts, cobicistat AUC was decreased by 63% in the second trimester and 49% in the third trimester compared to AUC postpartum. Trough cobicistat concentrations decreased by 83% in both the second and third trimesters.

The pharmaco-enhancing effect of cobicistat on darunavir was also impacted during pregnancy; AUC based on total darunavir concentrations was 56% (in the second trimester) and 50% (in the third trimester) lower than AUC postpartum, and AUC based on unbound concentrations was 45% and 40% lower, respectively. The effect on darunavir trough concentrations was more pronounced, with both total and unbound concentrations showing essentially identical decreases of 92% (in the second trimester) and 88% to 89% (in the third trimester) compared to postpartum. One of six women in this study experienced virologic failure during the third trimester, and virologic failure continued through the postpartum period.4 Because of these substantial reductions in drug exposures during pregnancy, use of elvitegravir/cobicistat or darunavir/cobicistat is not recommended during pregnancy.6,7

A study reported in a recent conference abstract evaluated tenofovir alafenamide (TAF) exposure when TAF was administered as a daily 10-mg dose with cobicistat 150 mg and found no differences between TAF exposure during pregnancy and TAF exposure in the same women postpartum. The authors concluded that no dose adjustment is needed during pregnancy for TAF when it is coadministered with cobicistat.8 However, TAF 10 mg with cobicistat is only available in fixed-dose combination products that also include either dolutegravir or elvitegravir, which are not recommended for use during pregnancy.

Placental and Breast Milk Passage
A study in 10 pregnant women receiving elvitegravir/cobicistat found a median cord blood to maternal delivery plasma cobicistat concentration ratio of 0.09. This study also found measurable concentrations of cobicistat in placental tissue and cord blood peripheral blood mononuclear cells (PBMC), with a cord/maternal PBMC ratio of 0.49.9 In another study, seven pregnant women who received elvitegravir/cobicistat had quantifiable cobicistat concentrations that were detectable in plasma at delivery. The median ratio for cord blood to maternal delivery plasma cobicistat concentration was 0.09. In 27 neonates born to mothers who were receiving elvitegravir/cobicistat, cobicistat was below the assay quantitation limit of 10 ng/mL in all washout PK samples taken between 2 hours and 9 days post-delivery.3 No data are available on breast milk passage of cobicistat in humans.

Teratogenicity/Adverse Pregnancy Outcomes
In the Antiretroviral Pregnancy Registry, five birth defects have been reported out of 204 live births to mothers with first-trimester exposure to cobicistat. The number of first-trimester exposures to cobicistat in humans is insufficient to be able to make a risk determination.2

 

Excerpt from Table 10a

Note: When using FDCs, refer to other sections in Appendix B and Table 10 for information about the dosing and safety of individual drug components of the FDC during pregnancy.

Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy

Cobicistat
(COBI)
Tybost

(ATV/COBI)
Evotaz

EVG/COBI/FTC/TAF)
Genvoya

(DRV/COBI)
Prezcobix

(EVG/COBI/FTC/TDF)
Stribild

(DRV/COBI/FTC/TAF)
Symtuza

 

COBI (Tybost)
Tablet:
  • COBI 150 mg
ATV/COBI (Evotaz):
  • ATV/COBI 300 mg/50mg tablet

EVG/COBI/FTC/TAF (Genvoya):
  • EVG 150 mg plus COBI 150 mg plus FTC 200 mg plus TAF 10 mg tablet
DRV/COBI (Prezcobix):
  • DRV/COBI 800 mg/150 mg tablet
EVG/COBI/FTC/TDF (Stribild):
  • EVG 150 mg plus COBI 150 mg plus FTC 200 mg plus TDF 300 mg tablet

DRV/COBI/FTC/TAF (Symtuza):
  • DRV 800 mg plus COBI 150 mg plus FTC 200 mg plus TAF 10 mg tablet
Standard Adult Doses
COBI (Tybost):
  • As an alternative PK booster with ATV or DRV: 1 tablet (150 mg) once daily with food.
ATV/COBI (Evotaz):
  • 1 tablet once daily with food.
EVG/COBI/FTC/TAF (Genvoya):
  • 1 tablet once daily with food.
DRV/COBI (Prezcobix):
  • 1 tablet once daily with food
DRV/COBI/FTC/TAF (Symtuza):
  • 1 tablet once daily with food
PK in Pregnancy:
  • Based on limited data COBI exposure and pharmaco-enhancing effect on DRV and EVG are markedly reduced in pregnancy.
  • No data are available on the pharmaco-enhancing effect of COBI on ATV.
  • When coadministered with COBI, TAF exposure is not significantly different between pregnancy and the postpartum period.
Dosing in Pregnancy:
  • While COBI exposure exposure is markedly reduced during pregnancy, higher than standard doses have not been studied. The Panel recommends RTV as the preferred pharmaco-enhancer for PIs and INSTIs during pregnancy until more data are available on COBI activity during pregnancy.
  • For guidance about the use of combination products in pregnancy, please see the specific sections on other components (i.e., FTC, TAF, TDF, ATV, DRV, EVG).

Low placental transfer to fetus.b

Insufficient data to assess for teratogenicity in humans. No evidence of teratogenicity in rats or rabbits.

Use of COBI-boosted ATV, DRV, or EVG is not recommended in pregnancy.

a Individual ARV drug dosages may need to be adjusted in patients with renal or hepatic insufficiency (for details, see the Adult and Adolescent Guidelines Appendix B, Table 8).
b Placental transfer categories—Mean or median cord blood/maternal delivery plasma drug ratio:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3

Key to Acronyms: ATV = atazanavir; COBI = cobicistat; DRV = darunavir; DRV/r = darunavir/ritonavir; EFV = efavirenz; EVG = elvitegravir; FDC = fixed-dose combination; FTC = emtricitabine; INSTIs = integrase strand transfer inhibitors; PIs = protease inhibitors; PK = pharmacokinetic; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

References

  1. Cobicistat [package insert]. Food and Drug Administration. 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203094s007lbl.pdf.
  2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2018. Wilmington, NC: Registry Coordinating Center. 2018. Available at: http://www.apregistry.com/.
  3. 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.
  4. Crauwels HM, Osiyemi O, Zorilla C, Bicer C, Brown K. Pharmacokinetics of total and unbound darunavir in HIV-1–infected pregnant women receiving a darunavir/cobicistat-based regimen. Presented at: 8th International Workshop on HIV & Women. 2018. Boston, Massachusetts. Available at: http://www.natap.org/2018/CROI/HIV&Women2018DRVcPKPregnancyPoster_JUV-63244_FINAL.PDF.
  5. Momper J, Best B, Wang J, et al. Pharmacokinetics of darunavir boosted with cobicistat during pregnancy and postpartum. Presented at: International AIDS Conference. 2018. Amsterdam, Netherlands.
  6. Darunavir/cobistat (Prezcobix) [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205395s009lbl.pdf.
  7. Genvoya [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207561s000lbl.pdf.
  8. Momper J, Best B, Wang J, et al. Tenofovir alafenamide pharmacokinetics with and without cobicistat in pregnancy. Presented at: 22nd International AIDS Conference. 2018.Amsterdam, Netherlands.
  9.  Rimawi BH, Johnson E, Rajakumar A, et al. Pharmacokinetics and Placental Transfer of Elvitegravir and Dolutegravir, and Other Antiretrovirals during Pregnancy. Antimicrob Agents Chemother. 2017. Available at https://www.ncbi.nlm.nih.gov/pubmed/28348149.
     

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