Updated
Dec. 29, 2020
Reviewed
Dec. 29, 2020

Integrase Inhibitors

Dolutegravir (Tivicay, DTG)

Animal Studies

Carcinogenicity
Dolutegravir (DTG) has not been shown to be genotoxic or mutagenic in vitro. No carcinogenicity was detected in 2-year, long-term studies in mice at DTG 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 DTG 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
DTG did not affect fertility in male and female rats and rabbits at doses that produced exposures (based on area under the curve [AUC]) that were approximately 27-fold higher than that achieved in humans who received the recommended dose.1

Teratogenicity/Adverse Pregnancy Outcomes
Studies of DTG 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 DTG crosses the placenta and is excreted into breast milk.1

Human Studies in Pregnancy

Pharmacokinetics
DTG 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, DTG plasma concentrations were lower during pregnancy than postpartum, with DTG AUC reduced by 21% during pregnancy. Although trough concentrations were reduced by 34% during the third trimester compared to postpartum, trough concentrations during pregnancy were well above 0.064  μg/mL, the 90% effective concentration for DTG. DTG 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.6 Similar reductions in DTG exposure were seen in a study of 15 European pregnant women, with DTG AUC reduced by 14% and minimum concentration (Cmin) by 26% during pregnancy compared to postpartum. DTG was well tolerated, and all participants had viral load below 50 copies/mL during the third trimester.8

In contrast, PK sampling during pregnancy and the early postpartum period of 17 African women who were receiving DTG showed a small reduction in DTG maximum concentration (Cmax) and no differences in the 24-hour concentration (C24h) and AUC from 0 to 24 hours (AUC0-24h) when geometric mean ratios in pregnancy were compared to the postpartum period. However, postpartum sampling was performed at a median of 10 days postpartum, when maternal physiology had likely not yet returned to the nonpregnant state.7 In the case reports, DTG was used safely and effectively in individual pregnant women and plasma exposures were adequate.2–5

Placental and Breast Milk Passage
Placental transfer of DTG in an ex vivo perfusion model was high, with a mean fetal-to-maternal concentration ratio of 0.6.9 In two in vivo PK studies, the median DTG cord blood-to-maternal-plasma concentration ratios were 1.21 and 1.25.6,7 High placental transfer of DTG has also been reported in several of the case reports.2,4,5 In 17 breastfeeding mothers, the median ratio of DTG in breast milk to maternal plasma was 0.03. Their infants had a median maximum DTG concentration of 66.7 ng/mL (range 21–654 ng/mL) and a median minimum concentration of 60.9 ng/mL (range 16.3–479 ng/mL) at a median age of 10 days (range 7–18 days). The geometric mean ratio of infant plasma to maternal plasma DTG concentrations in these 17 mother-infant pairs was 0.03.7 

Teratogenicity/Adverse Pregnancy Outcomes
The Antiretroviral Pregnancy Registry has monitored sufficient numbers of first-trimester exposures to DTG to detect at least a twofold increase in the risk of overall birth defects. No such increase in the risk of birth defects has been observed with DTG. Among the cases of first-trimester DTG exposure that have been reported to the Antiretroviral Pregnancy Registry as of January 31, 2020, the prevalence of birth defects was 3.5% (16 of 455 live births; 95% confidence interval, 2.0–5.7).10 Supplemental data from the Antiretroviral Pregnancy Registry on central nervous system (CNS) birth defect outcomes in 740 live births to women who were exposed to DTG during periconception or pregnancy reported 4 infants with central nervous system birth defects: 2 of 382 infants with periconception exposure, 1 of 73 infants with exposure in the later first trimester, and 1 of 285 infants with second- or third-trimester exposure. One of the CNS defects was a neural tube defect (NTD) in an infant with periconception exposure; no encephalocele defects were reported.10 

In the U.S. PK study in pregnant women discussed above, birth abnormalities were reported in 7 of 29 infants: 3 with normal variants; 1 with total anomalous pulmonary venous return (DTG was initiated at 16 weeks gestation); 1 with a polycystic right kidney (DTG was initiated at 11 weeks gestation); 1 with an isolated left renal cyst (DTG was initiated at 12 weeks gestation); and 1 with jitteriness and chin tremors (DTG was initiated at 28 weeks gestation).6 DTG was initiated at 28 weeks gestation or later in the PK study in African women discussed above, and no congenital anomalies were observed among 28 live births.7 In two reviews of clinical experience with pregnant women who received DTG, birth defects were noted in 4 infants born to 81 European women, in 2 infants born to 66 women from the United States, and in no infants born to 116 women from Botswana who received DTG during the first trimester.11–13

In July 2019, a report from a National Institutes of Health–funded surveillance study of birth outcomes among pregnant women in Botswana who were receiving antiretroviral therapy found that DTG exposure at the time of conception was associated with a slightly higher rate of NTDs than other types of antiretroviral drug exposure (0.3% vs. 0.1%).14 Expanded and ongoing surveillance of birth outcomes in Botswana among pregnant women receiving antiretrovirals between April 1, 2019, and April 30, 2020, revealed a rate of NTDs with DTG use of 0.19% and a decrease in the NTD prevalence difference between women receiving DTG and those receiving other antiretrovirals from 0.20% in the earlier report to 0.09%, a difference that is not statistically significant.15 Unlike in the United States, there is no folate fortification of food in Botswana, and it is unknown how folate levels may affect the possible association between periconceptual DTG exposure and NTDs. Decisions about DTG use should be made after discussing the risks and benefits of using DTG with the patient. This discussion should include the potential risk of NTDs, as well as the benefits of the DTG-containing regimen and the risks and benefits of alternative regimens (see Appendix D: Dolutegravir Counseling Guide for Health Care Providers). For additional information, please contact the National Perinatal HIV Hotline (1-888-448-8765) and see Updated Guidance About the Use of Dolutegravir in Pregnancy in Recommendations for Use of Antiretroviral Drugs During Pregnancy and Teratogenicity.

Excerpt from Table 10

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

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

Dolutegravir
(DTG)
Tivicay
Tivicay PD

(DTG/3TC)
Dovato

(DTG/RPV)
Juluca

(DTG/ABC/3TC)
Triumeq

DTG (Tivicay):
  • DTG 10 mg, 25 mg, and 50 mg film coated tablets
DTG (Tivicay PD):
  • DTG 5 mg dispersible tablet for oral suspension
DTG film-coated tablets and DTG dispersible tablets are not bioequivalent and are not interchangeable. DTG/3TC (Dovato):
  • DTG 50 mg/3TC 300 mg tablet
DTG/RPV (Juluca):
  • DTG 50 mg/RPV 25 mg tablet
DTG/ABC/3TC (Triumeq):
  • DTG 50 mg/ABC 600 mg/3TC 300 mg tablet
Standard Adult Doses
In ARV-Naive or ARV-Experienced (but INSTI-Naive) Patients
DTG (Tivicay):
  • One 50 mg tablet once daily, without regard to food
DTG (Tivicay PD):
  • Six 5 mg tablets (30 mg) dissolved in water once daily, without regard to food
DTG/3TC (Dovato):
  • One tablet once daily, without regard to food
DTG/RPV (Juluca):
  • One tablet once daily with food
DTG/ABC/3TC (Triumeq):
  • One tablet once daily, without regard to food
In ARV-Naive or ARV-Experienced (but INSTI-Naive) Patients Who Are Also Receiving EFV, FPV/r, TPV/r, or Rifampin
DTG (Tivicay):
  • One 50 mg tablet twice daily, without regard to food
DTG (Tivicay PD):
  • Six 5 mg tablets (30 mg) dissolved in water twice daily, without regard to food
In INSTI-Experienced Patients
DTG (Tivicay):
  • One tablet twice daily, without regard to food
Pregnancy
PKs in Pregnancy:
  • AUC may be decreased during the third trimester compared with postpartum, but exposures during pregnancy are well above those needed to inhibit viral replication.
Dosing in Pregnancy:
  • No change in dose indicated.

For guidance about the 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 rats or rabbits. In pregnancy surveillance data from Botswana, there was a slightly increased risk of NTDs in infants born to women who initiated DTG prior to pregnancy and who were receiving it at the time of conception.

DTG may be used as part of a Preferred regimen in all pregnant women at all gestational ages and as part of an Alternative regimen in women who are trying to conceive. Clinicians should discuss the risks and benefits of DTG use with the patient. For more information, see Updated 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 ingesting any preparation that contains such minerals 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 Antiretroviral Guidelines, Appendix B, Table 10).

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: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; AUC = area under the curve; DTG = dolutegravir; EFV = efavirenz; FDC = fixed-dose combination; FPV/r = fosamprenavir/ritonavir; INSTI = integrase strand transfer inhibitor; NTD = neural tube defect; PK = pharmacokinetic; RPV = rilpivirine; TPV/r = tipranavir/ritonavir

References

  1. Dolutegravir (Tivicay and Tivicay PD) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204790s024lbl.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. 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.
  7. Waitt C, Orrell C, Walimbwa S, et al. Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study). PLoS Med. 2019;16(9):e1002895. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31539371.
  8. Bollen P, Freriksen J, Konopnicki D, et al. The effect of pregnancy on the pharmacokinetics of total and unbound dolutegravir and its main metabolite in women living with human ummunodeficiency virus. Clin Infect Dis. 2020;ciaa006. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32103260.
  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. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2020. Wilmington, NC: Registry Coordinating Center. 2020. Available at: www.APRegistry.com.
  11. 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.
  12. 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.
  13. 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.
  14. Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med. 2019;381(9):827-840. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31329379.
  15. Zash R, Holmes L, Diseko M, et al. Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana. Presented at: International AIDS Conference. 2020. Virtual Conference.

Integrase Inhibitors

Dolutegravir (Tivicay, DTG)

Excerpt from Table 10

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

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

Dolutegravir
(DTG)
Tivicay
Tivicay PD

(DTG/3TC)
Dovato

(DTG/RPV)
Juluca

(DTG/ABC/3TC)
Triumeq

DTG (Tivicay):
  • DTG 10 mg, 25 mg, and 50 mg film coated tablets
DTG (Tivicay PD):
  • DTG 5 mg dispersible tablet for oral suspension
DTG film-coated tablets and DTG dispersible tablets are not bioequivalent and are not interchangeable. DTG/3TC (Dovato):
  • DTG 50 mg/3TC 300 mg tablet
DTG/RPV (Juluca):
  • DTG 50 mg/RPV 25 mg tablet
DTG/ABC/3TC (Triumeq):
  • DTG 50 mg/ABC 600 mg/3TC 300 mg tablet
Standard Adult Doses
In ARV-Naive or ARV-Experienced (but INSTI-Naive) Patients
DTG (Tivicay):
  • One 50 mg tablet once daily, without regard to food
DTG (Tivicay PD):
  • Six 5 mg tablets (30 mg) dissolved in water once daily, without regard to food
DTG/3TC (Dovato):
  • One tablet once daily, without regard to food
DTG/RPV (Juluca):
  • One tablet once daily with food
DTG/ABC/3TC (Triumeq):
  • One tablet once daily, without regard to food
In ARV-Naive or ARV-Experienced (but INSTI-Naive) Patients Who Are Also Receiving EFV, FPV/r, TPV/r, or Rifampin
DTG (Tivicay):
  • One 50 mg tablet twice daily, without regard to food
DTG (Tivicay PD):
  • Six 5 mg tablets (30 mg) dissolved in water twice daily, without regard to food
In INSTI-Experienced Patients
DTG (Tivicay):
  • One tablet twice daily, without regard to food
Pregnancy
PKs in Pregnancy:
  • AUC may be decreased during the third trimester compared with postpartum, but exposures during pregnancy are well above those needed to inhibit viral replication.
Dosing in Pregnancy:
  • No change in dose indicated.

For guidance about the 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 rats or rabbits. In pregnancy surveillance data from Botswana, there was a slightly increased risk of NTDs in infants born to women who initiated DTG prior to pregnancy and who were receiving it at the time of conception.

DTG may be used as part of a Preferred regimen in all pregnant women at all gestational ages and as part of an Alternative regimen in women who are trying to conceive. Clinicians should discuss the risks and benefits of DTG use with the patient. For more information, see Updated 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 ingesting any preparation that contains such minerals 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 Antiretroviral Guidelines, Appendix B, Table 10).

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: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; AUC = area under the curve; DTG = dolutegravir; EFV = efavirenz; FDC = fixed-dose combination; FPV/r = fosamprenavir/ritonavir; INSTI = integrase strand transfer inhibitor; NTD = neural tube defect; PK = pharmacokinetic; RPV = rilpivirine; TPV/r = tipranavir/ritonavir

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