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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Protease Inhibitors

Lopinavir/Ritonavir (Kaletra, LPV/r)

(Last updated: August 6, 2015; last reviewed: August 6, 2015)

Lopinavir/ritonavir (LPV/r) is classified as Food and Drug Administration Pregnancy Category C.

Animal Studies

Carcinogenicity
Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays. The LPV/r combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increased incidence of benign hepatocellular adenomas and increased combined incidence of hepatocellular adenomas plus carcinoma in male and female mice and male rats at doses that produced approximately 1.6 to 2.2 times (mice) and 0.5 times (rats) the human exposure at the recommended therapeutic dose of 400 mg/100 mg (based on area under the curve [AUC]0–24hr measurement). Administration of LPV/r did not cause a statistically significant increase in incidence of any other benign or malignant neoplasm in mice or rats.1

Reproduction/Fertility
Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats with exposures approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose.1

Teratogenicity/Developmental Toxicity
No evidence exists of teratogenicity with administration of LPV/r to pregnant rats or rabbits. In rats treated with a maternally toxic dosage (100 mg lopinavir/50 mg ritonavir/kg/day), embryonic and fetal developmental toxicities (e.g., early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations, and skeletal ossification delays) were observed. Drug exposure in the pregnant rats was 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose. In a perinatal and postnatal study in rats, a decrease in survival of pups between birth and postnatal Day 21 occurred with exposure to 40 mg lopinavir/20 mg ritonavir/kg/day or greater. In rabbits, no embryonic or fetal developmental toxicities were observed with a maternally toxic dosage, where drug exposure was 0.6-fold for lopinavir and 1-fold for ritonavir of the exposures in humans at the recommended therapeutic dose.1 In a study of pregnant rats receiving chronic administration of zidovudine, lopinavir, and ritonavir, maternal body weight gain was significantly reduced, but no adverse fetal parameters were observed.2 In pregnant mice, ritonavir, lopinavir and atazanavir were associated with significantly lower progesterone levels, and the lower progesterone levels directly correlated with lower fetal weight.3

Placental and Breast Milk Passage
No information is available on placental transfer of lopinavir in animals. Studies in rats show secretion of lopinavir in breast milk.1

Human Studies in Pregnancy

Pharmacokinetics
The original capsule formulation of LPV/r has been replaced by a tablet formulation that is heat-stable, has improved bioavailability characteristics, and does not have to be administered with food.4,5 Pharmacokinetic (PK) studies of standard adult LPV/r doses (400 mg/100 mg twice a day) using either the capsule or tablet formulations in pregnant women have demonstrated a reduction in lopinavir plasma concentrations during pregnancy of around 30% compared with that in non-pregnant adults.6-8 Further reductions in lopinavir exposure by 33% were demonstrated in food-insecure, malnourished pregnant women in Uganda compared to well-nourished, historical pregnant controls. The authors attributed this reduction to decreased bioavailability.9 Increasing dose of LPV/r during pregnancy to 600 mg/150 mg (tablets) results in lopinavir plasma concentrations equivalent to those seen in non-pregnant adults receiving standard doses.10,11 Reports of clinical experience suggest that most, but not all, pregnant women receiving standard LPV/r tablet dosing during pregnancy will have trough lopinavir concentrations that exceed 1.0 mcg/mL, the usual trough concentration target used in therapeutic drug monitoring programs for antiretroviral-naive subjects, but not the higher trough concentrations recommended for protease inhibitor (PI)-experienced subjects.4,7 A population PK study of LPV/r in 154 pregnant women demonstrated that body weight influences lopinavir clearance and volume, with larger women (>100 kg) or women who missed a dose at higher risk for subtherapeutic trough concentrations when taking the standard dose during pregnancy.12 In one study of 29 women, lopinavir plasma protein binding was reduced during pregnancy, but the resulting increase in free (unbound) drug was insufficient to make up for the reduction in total plasma lopinavir concentration associated with pregnancy.13 In a study of 12 women, total lopinavir exposure was significantly decreased throughout pregnancy, but unbound AUC and C12 did not differ throughout pregnancy, even with an increased dose of 500/125 mg.14 Bonafe, et al. randomized 32 pregnant women to standard dose and 31 pregnant women to the 600/150 mg dose of LPV/r at gestational ages between 14 and 33 weeks. No differences in adverse events were seen between groups. In women with baseline viral loads >50 copies/mL, 45% in the standard dose group had plasma viral loads >50 copies/mL during the last 4 weeks of pregnancy, compared to 10.5% in the increased dose group (P = 0.01). In women with baseline viral loads <50 copies/mL, no difference was seen between groups in viral load measurements in the last 4 weeks of pregnancy.15

These studies have led some experts to support use of an increased dose of LPV/r in HIV-infected pregnant women during the second and third trimesters, especially in PI-experienced pregnant women and women who start treatment during pregnancy with a baseline viral load >50 copies/mL. If standard doses of LPV/r are used during pregnancy, virologic response and lopinavir drug concentrations, if available, should be monitored. An alternative strategy to increasing LPV/r dosing during pregnancy by using 3 adult 200/50 mg tablets to provide a dose of 600/150 mg is to add a pediatric LPV/r tablet (100/25 mg) to the standard dose of 2 adult 200/50 mg tablets to provide a dose of 500/125 mg.14 Once-daily dosing of LPV/r is not recommended in pregnancy because no data exist to address whether drug levels are adequate with such administration.

Placental and Breast Milk Passage
Lopinavir crosses the human placenta; in the P1026s PK study, the average ratio of lopinavir concentration in cord blood to maternal plasma at delivery was 0.20 ± 0.13. In contrast, in a study of plasma and hair drug concentration in 51 mother-infant pairs in Uganda receiving LPV/r during pregnancy and breastfeeding, infant plasma levels at delivery and hair levels at age 12 weeks suggested significant in utero transfer: 41% of infants had detectable plasma lopinavir concentrations at birth and mean infant-to-maternal-hair concentrations at 12 weeks postpartum were 0.87 for lopinavir.16 However, transfer during breastfeeding was not observed, and no infant had detectable plasma lopinavir levels at 12 weeks. Lopinavir concentrations in human breast milk are very low to undetectable and lopinavir concentrations in breastfeeding infants whose mothers received lopinavir are not clinically significant.16-20
 
Teratogenicity/Developmental Toxicity
The French Perinatal Cohort found no association between birth defects and lopinavir or ritonavir with 85% power to detect a 1.5-fold increase.21 The Pediatric HIV/AIDS Cohort Study found no association between lopinavir and congenital anomalies.22 In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to LPV/r have been monitored for detection of at least a 2-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with LPV/r. Among cases of first-trimester exposure to LPV/r reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.2% (26 of 1174; 95% CI, 1.4% to 3.2%) compared with a total prevalence of 2.7% in the U.S. population, based on Centers for Disease Control and Prevention surveillance.23
 
Safety
LPV/r oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/volume) propylene glycol. Reduced hepatic metabolic and kidney excretory function in newborns can lead to accumulation of lopinavir as well as alcohol and propylene glycol, resulting in adverse events such as serious cardiac, renal, metabolic, or respiratory problems. Preterm babies may be at increased risk because their metabolism and elimination of lopinavir, propylene glycol, and alcohol are further reduced. Post-marketing surveillance has identified 10 neonates (i.e., babies aged <4 weeks), nine of whom were born prematurely, who received LPV/r and experienced life-threatening events.24 In a separate report comparing 50 HIV-exposed newborns treated with LPV/r after birth to 108 HIV-exposed neonates treated with zidovudine alone, elevated concentrations of 17-hydoxyprogesterone and dehydroepiandrosterone-sulfate, consistent with impairment of 21α-hydroxylase activity, were seen only in the lopinavir-exposed infants. All term infants were asymptomatic but three of eight preterm infants had life-threatening symptoms, including hyponatremia, hyperkalemia, and cardiogenic shock, consistent with adrenal insufficiency.25 LPV/r oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth, plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained.

References

  1.  Lopinavir/Ritonavir (KALETRA) [package insert] AbbVie. Revised January 2015. Available at http://www.rxabbvie.com/pdf/kaletratabpi.pdf and http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021226s037lbl.pdf. Accessed May 22, 2015.
  2. F CL, Simoes RS, Araujo Junior Corresponding Author E, Oliveira Filho RM, Kulay Junior L, Nakamura MU. Highly active antiretroviral therapy during gestation: effects on a rat model of pregnancy. Ceska gynekologie/Ceska lekarska spolecnost J. Ev. Purkyne. 2014;79(2):128-133. Available at http://www.ncbi.nlm.nih.gov/pubmed/24874827.
  3. Papp E, Mohammadi H, Loutfy MR, et al. HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction. J Infect Dis. 2015;211(1):10-18. Available at http://www.ncbi.nlm.nih.gov/pubmed/25030058.
  4. Khuong-Josses MA, Azerad D, Boussairi A, Ekoukou D. Comparison of lopinavir level between the two formulations (soft-gel capsule and tablet) in HIV-infected pregnant women. HIV Clin Trials. 2007;8(4):254-255. Available at http://www.ncbi.nlm.nih.gov/pubmed/17720666.
  5. Else LJ, Douglas M, Dickinson L, Back DJ, Khoo SH, Taylor GP. Improved oral bioavailability of lopinavir in melt-extruded tablet formulation reduces impact of third trimester on lopinavir plasma concentrations. Antimicrob Agents Chemother. 2012;56(2):816-824. Available at http://www.ncbi.nlm.nih.gov/pubmed/22106215.
  6. Stek AM, Mirochnick M, Capparelli E, et al. Reduced lopinavir exposure during pregnancy. AIDS. 2006;20(15):1931-1939. Available at http://www.ncbi.nlm.nih.gov/pubmed/16988514.
  7. Bouillon-Pichault M, Jullien V, Azria E, et al. Population analysis of the pregnancy-related modifications in lopinavir pharmacokinetics and their possible consequences for dose adjustment. J Antimicrob Chemother. 2009;63(6):1223-1232. Available at http://www.ncbi.nlm.nih.gov/pubmed/19389715.
  8. Ramautarsing RA, van der Lugt J, Gorowara M, et al. Thai HIV-1-infected women do not require a dose increase of lopinavir/ritonavir during the third trimester of pregnancy. AIDS. 2011;25(10):1299-1303. Available at http://www.ncbi.nlm.nih.gov/pubmed/21516029.
  9. Bartelink IH, Savic RM, Mwesigwa J, et al. Pharmacokinetics of lopinavir/ritonavir and efavirenz in food insecure HIV-infected pregnant and breastfeeding women in Tororo, Uganda. J Clin Pharmacol. 2014;54(2):121-132. Available at http://www.ncbi.nlm.nih.gov/pubmed/24038035.
  10. Mirochnick M, Best BM, Stek AM, et al. Lopinavir exposure with an increased dose during pregnancy. J Acquir Immune Defic Syndr. 2008;49(5):485-491. Available at http://www.ncbi.nlm.nih.gov/pubmed/18989231.
  11. Best BM, Stek AM, Mirochnick M, et al. Lopinavir tablet pharmacokinetics with an increased dose during pregnancy. J Acquir Immune Defic Syndr. 2010;54(4):381-388. Available at http://www.ncbi.nlm.nih.gov/pubmed/20632458.
  12. Cressey TR, Urien S, Capparelli EV, et al. Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy. J Antimicrob Chemother. 2015;70(1):217-224. Available at http://www.ncbi.nlm.nih.gov/pubmed/25261418.
  13. Aweeka FT, Stek A, Best BM, et al. Lopinavir protein binding in HIV-1-infected pregnant women. HIV Med. 2010;11(4):232-238. Available at http://www.ncbi.nlm.nih.gov/pubmed/20002783.
  14. Patterson KB, Dumond JB, Prince HA, et al. Protein binding of lopinavir and ritonavir during 4 phases of pregnancy: implications for treatment guidelines. J Acquir Immune Defic Syndr. 2013;63(1):51-58. Available at http://www.ncbi.nlm.nih.gov/pubmed/23221983.
  15. Bonafe SM, Costa DA, Vaz MJ, et al. A randomized controlled trial to assess safety, tolerability, and antepartum viral load with increased lopinavir/ritonavir dosage in pregnancy. AIDS Patient Care STDS. 2013;27(11):589-595. Available at http://www.ncbi.nlm.nih.gov/pubmed/24138537.
  16. Gandhi M, Mwesigwa J, Aweeka F, et al. Hair and plasma data show that lopinavir, ritonavir, and efavirenz all transfer from mother to infant in utero, but only efavirenz transfers via breastfeeding. J Acquir Immune Defic Syndr. 2013;63(5):578-584. Available at http://www.ncbi.nlm.nih.gov/pubmed/24135775.
  17. Rezk NL, White N, Bridges AS, et al. Studies on antiretroviral drug concentrations in breast milk: validation of a liquid chromatography-tandem mass spectrometric method for the determination of 7 anti-human immunodeficiency virus medications. Ther Drug Monit. 2008;30(5):611-619. Available at http://www.ncbi.nlm.nih.gov/pubmed/18758393.
  18. Shapiro RL, Rossi S, Ogwu A, et al. Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk in the Mma Bana Study, Botswana. Antivir Ther. 2013;18(4):585-590. Available at http://www.ncbi.nlm.nih.gov/pubmed/23183881.
  19. Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther. 2012;17(8):1511-1519. Available at http://www.ncbi.nlm.nih.gov/pubmed/22910456.
  20. Corbett AH, Kayira D, White NR, et al. Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post-partum: results of the BAN Study. Antivir Ther. 2014;19(6):587-595. Available at http://www.ncbi.nlm.nih.gov/pubmed/24464632.
  21. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at http://www.ncbi.nlm.nih.gov/pubmed/24781315.
  22. Williams PL, Crain M, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015;169(1):45-55. Available at http://www.ncbi.nlm.nih.gov/pubmed/25383770.
  23. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989—31 July 2014. Wilmington, NC: Registry Coordinating Center. 2014. 
  24. Boxwell D, Cao K, Lewis L, Marcus K, Nikhar B. Neonatal toxicity of Kaletra oral solution: LPV, ethanol or prophylene glycol? Presented at: 18th Conference on Retroviruses and Opportunistic Infections. 2011. Boston, MA.
  25. Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA. 2011;306(1):70-78. Available at http://www.ncbi.nlm.nih.gov/pubmed/21730243.

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