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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Integrase Inhibitors

Dolutegravir (Tivicay, DTG)

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

The Antiretroviral Pregnancy Registry does not contain enough reports regarding exposure to dolutegravir during pregnancy to develop a drug-associated risk determination for birth defects and miscarriage. A preliminary report from observational surveillance of birth outcomes among pregnant women on antiretroviral therapy (ART) in Botswana found an increased number of neural tube defects (NTDs) among infants born to women who were on a dolutegravir-based regimen initiated prior to pregnancy that they were receiving at time of conception. There was no significant increase in the risk of NTDs among infants born to women who initiated dolutegravir during pregnancy.

Animal Studies

Carcinogenicity
Dolutegravir was not genotoxic or mutagenic in vitro. No carcinogenicity was detected in 2-year, long-term studies in mice at dolutegravir exposures that were up to 14-fold higher than the exposures achieved in humans with systemic exposure to the recommended dose. In addition, no carcinogenicity was detected in rats at dolutegravir exposures up to 10-fold higher in males and 15-fold higher in females than the exposures seen in humans who received the recommended dose.1

Reproduction/Fertility
Dolutegravir did not affect fertility in male and female rats and rabbits at doses that produced systemic area under the curve (AUC) approximately 27-fold higher than that achieved in humans who received the recommended dose.1

Teratogenicity/Adverse Pregnancy Outcomes
Studies of dolutegravir in rats and rabbits have shown no evidence of developmental toxicity, teratogenicity, or effects on reproductive function.1

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

Human Studies in Pregnancy

Pharmacokinetics
Dolutegravir pharmacokinetics (PK) in human pregnancy have been reported in three studies and a series of case reports.2-8 In a safety and PK study of 29 pregnant women in the United States, dolutegravir plasma concentrations were lower during pregnancy than postpartum, with dolutegravir AUC reduced by 21% during pregnancy. Although trough concentrations were reduced by 34% during the third trimester compared to postpartum, trough concentrations in pregnancy were well above 0.064 μg/mL, the 90% effective concentration for dolutegravir. Dolutegravir was well tolerated by these pregnant women. During the third trimester, HIV-1 RNA was below 50 copies/mL in 27 of 29 participants, and no infants acquired HIV.7 In two smaller studies of five European and seven African pregnant women, dolutegravir was well tolerated and the reduction in plasma exposures during pregnancy was similar to the one observed in the study described above.6,8 In the case reports, dolutegravir was used safely and effectively in individual pregnant women and plasma exposures were adequate.2-5

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%.9 In the largest in vivo PK study, median cord blood-to-maternal ratio for dolutegravir concentration was 1.25 and high placental transfer of dolutegravir has been reported in several of the case reports.2,4,5,7 In one breastfeeding mother who was receiving dolutegravir, the dolutegravir breast milk-to-maternal-plasma-concentration ratio was 0.2 and the dolutegravir concentration in breast milk and in infant plasma was 0.10 mg/L, equal to the dolutegravir target trough plasma concentration in treatment-naive patients.10

Teratogenicity/Adverse Pregnancy Outcomes
Among live births reported to the Antiretroviral Pregnancy Registry as of January 31, 2018, the overall birth defect rate for infants with first-trimester exposure to dolutegravir was 3.1% (five infants out of 161 live births).11 In the largest PK study in pregnant women discussed above, birth abnormalities were reported in seven of 29 infants: three with normal variants; one with total anomalous pulmonary venous return (dolutegravir was initiated at 16 weeks’ gestation); one with a polycystic right kidney (dolutegravir was initiated at 11 weeks’ gestation); one with an isolated left renal cyst (dolutegravir was initiated at 12 weeks’ gestation); and one with jitteriness and chin tremors (dolutegravir was initiated at 28 weeks’ gestation).7 In two reviews of clinical experience with pregnant women who received dolutegravir, birth defects were noted in four infants born to 81 European women, in two infants born to 66 women from the United States, and in no infants born to 116 women from Botswana who received dolutegravir during the first trimester.12-14

A preliminary report from a National Institutes of Health-funded observational surveillance study of birth outcomes among pregnant women on ART in Botswana indicated a potential increase in the incidence of NTDs among infants born to women who initiated a dolutegravir-based regimen prior to pregnancy that they were receiving at the time of conception.13,15 The Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission conservatively recommends that dolutegravir not be initiated during the first trimester of pregnancy (<14 weeks [up to 13 6/7 weeks] gestational age by last menstrual period) or in women who are trying to conceive (see Interim Recommendations about the Use of Dolutegravir in Pregnancy in Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Teratogenicity).

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
Dolutegravir
(DTG)
Tivicay

(DTG/RPV)
Juluca

(DTG/ABC/3TC)
Triumeq
DTG (Tivicay)
Tablet:
  • DTG 50 mg tablet
DTG/RPV (Juluca):
  • DTG 50 mg plus RPV 25 mg tablet
DTG/ABC/3TC (Triumeq):
  • DTG 50 mg plus ABC 600 mg plus 3TC 300 mg tablet
Standard Adult Dose
In ARV-Naive or ARV-Experienced (but Integrase Inhibitor-Naive) Patients
DTG (Tivicay):
  • 1 tablet once daily, without regard to food
DTG/RPV (Juluca):
  • 1 tablet once daily with 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 observed in third-trimester recipients.
Dosing in Pregnancy:
  • No change in dose indicated.
  • For guidance about use of combination products in pregnancy, please see the specific sections on other components (i.e., ABC, 3TC, RPV)
High placental transfer to fetus.b

No evidence of teratogenicity in mice, rats, or rabbits. Preliminary data suggest a possible increased risk of NTDs in infants born to women who initiated DTG prior to pregnancy and were receiving it at the time of conception.

Dolutegravir should not be initiated during the first trimester of pregnancy (less than 14 weeks [up to 13 6/7 weeks] gestational age by LMP.) For more information see Interim Guidance about the Use of Dolutegravir in Pregnancy in Recommendations for Use of Antiretroviral Drugs During Pregnancy.

To maximize DTG absorption, doses should not be administered within 2 hours of ingestion of any preparation containing minerals such as iron or calcium, including prenatal vitamins.

a Individual ARV drug doses 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 are determined by mean or median cord blood/maternal delivery plasma drug ratio:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; AUC = area under the curve; DTG = dolutegravir; EFV = efavirenz; FDC = fixed-dose combination; FPV/r = fosamprenavir/ritonavir; LMP = last menstrual period; NTD = neural tube defect; PK = pharmacokinetic; RPV = rilpivirine; TPV/r = tipranavir/ritonavir

References

  1. Dolutegravir [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204790s016s018lbl.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. 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.
  5. 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.
  6. 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.
  7. Mulligan N, Best BM, Wang J, et al. Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV. AIDS. 2018;32(6):729-737. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29369162.
  8. Waitt C, Walimbwa S, Orrell C, et al. DolPHIN-1: dolutegravir vs efavirenz when initiating treatment in late pregnancy. Presented at: Conference on Retroviruses and Opportunistic Infections. 2018. Boston, MA. Available at: http://www.croiconference.org/sessions/dolphin-1-dolutegravir-vs-efavirenz-when-initiating-treatment-late-pregnancy.
  9. 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.
  10. 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.
  11. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989–31 July 2018. Wilmington, NC: Registry Coordinating Center. 2018. Available at: http://www.apregistry.com/.
  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, Jacobson DL, Diseko M, et al. Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study. Lancet Glob Health. 2018;6(7):e804-e810. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29880310.
  14. Grayhack C, Sheth A, Kirby O, et al. Evaluating outcomes of mother-infant pairs using dolutegravir for HIV treatment during pregnancy. AIDS. 2018;32(14):2017-2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29944472.
  15. Zash R, Makhema J, Shapiro RL. Neural-tube defects with dolutegravir treatment from the time of conception. N Engl J Med. 2018. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30037297.

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