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

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Integrase Inhibitors

Dolutegravir (Tivicay, DTG)

Last Updated: November 14, 2017; Last Reviewed: November 14, 2017

Preliminary human data suggest that use of dolutegravir during pregnancy is not associated with an increased risk of birth defects and miscarriage.

Animal Carcinogenicity Studies

Dolutegravir was not genotoxic or mutagenic in vitro. No carcinogenicity was detected in 2-year long-term studies in mice at exposures up to 14-fold higher than that achieved with human systemic exposure at the recommended dose, or in rats at exposures up to 10-fold higher in males and 15-fold higher in females than human exposure at the recommended dose.1

Reproduction/Fertility
Dolutegravir did not affect fertility in male and female rats and rabbits at exposures approximately 27-fold higher than human clinical exposure, based on area under the curve, at the recommended dose.1

Animal Teratogenicity/Developmental Toxicity
Studies in rats and rabbits have shown no evidence of developmental toxicity, teratogenicity or effect on reproductive function with dolutegravir.1

Placental and Breast Milk Passage
Studies in rats have demonstrated that dolutegravir crosses the placenta in animal studies and is excreted into breast milk in rats.1

Human Studies in Pregnancy

Pharmacokinetics
Reports of dolutegravir pharmacokinetics (PK) in human pregnancy are limited to two studies and a series of case reports.2-7 In a safety and PK study of 21 pregnant women, dolutegravir plasma concentrations were lower during pregnancy than postpartum, but HIV-1 RNA in the third trimester was below 50 copies/mL in all 15 women for whom third-trimester data were available. Dolutegravir was well tolerated by these pregnant women.4 In a study of five European pregnant women, dolutegravir was well tolerated and plasma exposures during pregnancy were similar to that postpartum.7 In the case reports, dolutegravir was used safely and effectively in pregnancy and plasma exposures were adequate.2,3,5,6

Placental and Breast Milk Passage
Placental transfer of dolutegravir in an ex vivo perfusion model was high, with a fetal-to-maternal ratio of 60%.8 High placental transfer of dolutegravir has been confirmed in several of the case reports.2,5,6 In a report from one breast feeding mother receiving dolutegravir and her infant, the dolutegravir breast milk-to-maternal-plasma-concentration ratio was 0.02 and the plasma dolutegravir concentration in the infant was 0.10 mg/L, equal to the dolutegravir target trough plasma concentration in treatment-naive patients.9

Teratogenicity Data
As of January 31, 2017, the overall birth defect rate was 3.0% (4 infants) in 133 live births from 142 pregnancies with exposure to dolutegravir reported to the Antiretroviral Pregnancy Registry.10 In the larger PK study in pregnant women, discussed above, birth abnormalities were reported in 4 of 18 infants: total anomalous pulmonary venous return; cystic fibrosis and polycystic right kidney; congenital chin tremor; sacral dimple with filum terminale fibrolipoma.11 In 2 reviews of clinical experience with pregnant women receiving dolutegravir, birth defects were noted in 3 infants born to 42 European women and in no infants born to 116 women from Botswana receiving dolutegravir during the first trimester.12,13

Excerpt from Table 9a
Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy
Dolutegravir
(DTG)
Tivicay

(DTG/ABC/3TC)
Triumeq
Tablets:
  • 50 mg
Triumeq:
  • ABC 600 mg plus DTG 50 mg plus 3TC 300-mg tablet
Standard Adult Dose
ARV-Naive or ARV-Experienced (but Integrase Inhibitor-Naive Patients)
DTG (Tivicay):
  • 1 tablet once daily, without regard to food.
DTG/ABC/3TC (Triumeq):
  • 1 tablet once daily, without regard to food
ARV-Naive or ARV-Experienced (but Integrase Inhibitor-Naive) if Given with EFV, FPV/r, TPV/r, or Rifampin; or Integrase Inhibitor-Experienced
DTG (Tivicay):
  • 1 tablet twice daily, without regard to food.

PK in Pregnancy:
  • AUC may be decreased during the third trimester compared with postpartum, but good viral suppression in third trimester recipients.
Dosing in Pregnancy:
  • No change in dose indicated.
High placental transfer to fetus.

No evidence of teratogenicity in mice, rats, or rabbits. Preliminary data suggest no increased risk of teratogenicity in humans.
a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see the Adult and Adolescent Guidelines Appendix B, Table 7).
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
c See Teratogenicity section for discussion of EFV and risks in pregnancy.
d Only indicated for use in chronic hepatitis B virus infection in adults
e Generic formulation available

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; AUC = area under the curve; DTG = dolutegravir; EFV = efavirenz; FPV/r = fosamprenavir/ritonavir; PK = pharmacokinetic; TPV/r = tipranavir/ritonavir

References

  1. Dolutegravir (Tivicay) [package insert]. Food and Drug Administration. 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204790s013lbl.pdf.
  2. Pain JB, Le MP, Caseris M, et al. Pharmacokinetics of dolutegravir in a premature neonate after HIV treatment intensification during pregnancy. Antimicrob Agents Chemother. 2015;59(6):3660-3662. Available at http://www.ncbi.nlm.nih.gov/pubmed/25845873.
  3. Pinnetti C, Tintoni M, Ammassari A, et al. Successful prevention of HIV mother-to-child transmission with dolutegravir-based combination antiretroviral therapy in a vertically infected pregnant woman with multiclass highly drug-resistant HIV-1. AIDS. 2015;29(18):2534-2537. Available at http://www.ncbi.nlm.nih.gov/pubmed/26372490.
  4. Mulligan N, Best B, Capparelli E, et al. Dolutegravir pharmacokinetics in HIV-infected pregnant and postparum women. Presented at: Conference on Retroviruses and Opportunistic Infections. 2016. Boston, MA.
  5. Lewis JM, Railton E, Riordan A, Khoo S, Chaponda M. Early experience of dolutegravir pharmacokinetics in pregnancy: high maternal levels and significant foetal exposure with twice-daily dosing. AIDS. 2016;30(8):1313-1315. Available at https://www.ncbi.nlm.nih.gov/pubmed/27128333.
  6. Schalkwijk S, Feiterna-Sperling C, Weizsacker K, et al. Substantially lowered dolutegravir exposure in a treatment-experienced perinatally HIV-1-infected pregnant woman. AIDS. 2016;30(12):1999-2001. Available at https://www.ncbi.nlm.nih.gov/pubmed/27428578.
  7. Bollen P, Colbers A, Schalkwijk S, et al. A Comparison of the pharmacokinetics of dolutegravir during pregnancy and postpartum. Presented at: 18th International Workshop on Clinical Pharmacology of Antiviral Therapy. 2017 Chicago, IL.
  8. Schalkwijk S, Greupink R, Colbers AP, et al. Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human cotyledon perfusion model. J Antimicrob Chemother. 2016;71(2):480-483. Available at https://www.ncbi.nlm.nih.gov/pubmed/26538508.
  9. Kobbe R, Schalkwijk S, Dunay G, et al. Dolutegravir in breast milk and maternal and infant plasma during breastfeeding. AIDS. 2016;30(17):2731-2733. Available at https://www.ncbi.nlm.nih.gov/pubmed/27782968.
  10. Vannappagari V, Albano J, Ragone A, et al. Dolutegravir use during pregnancy and birth outcomes: data from the Antiretroviral Pregnancy Registry (APR). Presented at: 9th International AIDS Society Conference. 2017. Paris, France.
  11. Mulligan N, Schalkwijk S, Best BM, et al. Etravirine pharmacokinetics in HIV-infected pregnant women. Front Pharmacol. 2016;7:239. Available at https://www.ncbi.nlm.nih.gov/pubmed/27540363.
  12. Thorne C, Favarato G, Peters H, et al. Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir. Presented at: International AIDS Society Conference. 2017. Paris, France.
  13. Zash R, Jacobsen DM, Mayondi G, et al. Dolutegravir/tenofovir/emtricitabine (DTG/TDF/FTC) started in pregnancy is as safe as efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in Botswana. Presented at: 9th International AIDS Society Conference. 2017. Paris, France.

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