Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo/Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The human pregnancy experience with lopinavir, always in combination with ritonavir and other antiretroviral agents, suggests that the embryo–fetal risk is low. The animal data are suggestive of moderate risk because the exposure for lopinavir was less than the human therapeutic exposure. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Lopinavir, an inhibitor of HIV protease, prevents cleavage of the Gag-Pol polyproteins, resulting in the production of immature, noninfectious viral particles. The agent is only available in a fixed combination (200 mg lopinavir/50 mg ritonavir per capsule; 80 mg lopinavir/20 mg ritonavir per mL oral solution). Ritonavir is a potent inhibitor of CYP3A isozyme from the hepatic cytochrome P450 system that is responsible for the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. The plasma levels of ritonavir are very low; therefore, the antiviral activity of the combination is due to lopinavir. Plasma protein binding of lopinavir is high (98%–99%), primarily by α1-acid glycoprotein, but some is bound to albumin. The average half-life of lopinavir over a 12-hour dosing interval is 5–6 hours (1).
Reproduction studies have been conducted in rats and rabbits. In rats, doses producing systemic exposures that were approximately 0.7 (lopinavir)/1.8 (ritonavir) times the human exposure obtained with the recommended dose of 400/100 mg twice daily based on AUC (HE) resulted in embryonic and fetal toxicity (early resorption, decreased fetal viability and body weight, increased incidences of skeletal variations and skeletal ossification delays). This dose was maternal toxic. Developmental toxicity (decreased pup survival) also was observed in a perinatal and postnatal rat study at doses producing exposures equal to or greater than about 0.3 (lopinavir)/0.7 (ritonavir) times the HE. In rabbits, maternal toxic doses (0.6 [lopinavir]/1.0 [ritonavir]) did not result in embryonic or fetal development toxicity (1).
Consistent with the molecular weight (about 629) and lipid solubility, lopinavir crosses the human placenta. A 2006 study using the ex vivo human cotyledon perfusion model found that placental transfer of lopinavir (combined with ritonavir) was compatible with passive diffusion, even in the presence of physiologic concentrations of human albumin (2). The amount entering the fetal compartment was well above the 50% inhibitory concentration (2). In an earlier study, the cord:maternal blood ratio 12.25 hours after lopinavir (533 mg twice daily in combination with lamivudine and abacavir) in a woman delivering at term (38 weeks) was <0.1 (<250 ng/mL/3105 ng/mL) (3,4).
The Antiretroviral Pregnancy Registry reported, for January 1989 through July 2009, prospective data (reported before the outcomes were known) involving 4702 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (5). Congenital defects were noted in 134, a prevalence of 2.8% (95% confidence interval [CI] 2.4–3.4). In the 6100 live births with earliest exposure in the 2nd/3rd trimesters, there were 153 infants with defects (2.5%, 95% CI 2.1–2.9). The prevalence rates for the two periods did not differ significantly. There were 288 infants with birth defects among 10,803 live births with exposure anytime during pregnancy (2.7%, 95% CI 2.4–3.0). The prevalence rate did not differ significantly from the rate expected in a nonexposed population. There were 1794 outcomes exposed to lopinavir (526 in the 1st trimester and 1268 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There were 39 birth defects (9 in the 1st trimester and 30 in the 2nd/3rd trimesters). In reviewing the birth defects of prospective and retrospective (pregnancies reported after the outcomes were known) registered cases, the Registry concluded that, except for isolated cases of neural tube defects with efavirenz exposure in retrospective reports, there was no other pattern of anomalies (isolated or syndromic) (5). (See Lamivudine for required statement.)
In 1998, a public health advisory was issued by the FDA on the association between protease inhibitors and diabetes mellitus (6). Because pregnancy is a risk factor for hyperglycemia, there was concern that these antiretroviral agents would exacerbate this risk. The manufacturer’s product information also notes the potential risk for new-onset diabetes, exacerbation of preexisting diabetes, and hyperglycemia in HIV-infected patients receiving protease inhibitor therapy (1). An abstract published in 2000 described the results of a study involving 34 pregnant women treated with protease inhibitors compared with 41 controls that evaluated the association with diabetes (7). No association between protease inhibitors and an increased incidence of gestational diabetes was found.
Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (8,9). The same conclusion was reached in a 2003 review with the added admonishment that therapy must be continuous to prevent emergence of resistant viral strains (10). In 2009, the updated U.S. Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV type 1 (HIV-1)-infected patients continued the recommendation that therapy, with the exception of efavirenz, should be continued during pregnancy (11). If indicated, therefore, protease inhibitors, including lopinavir, should not be withheld in pregnancy because the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. Pregnant women taking protease inhibitors should be monitored for hyperglycemia. Updated guidelines for the use of antiretroviral drugs to reduce perinatal HIV-1 transmission also were released in 2010 (12). Women receiving antiretroviral therapy during pregnancy should continue the therapy but, regardless of the regimen, zidovudine administration is recommended during the intrapartum period to prevent vertical transmission of HIV to the newborn (12).
BREASTFEEDING SUMMARY
No reports have been located that describe the use of the combination product, lopinavir/ritonavir, during human lactation. The molecular weights of lopinavir (about 629) and ritonavir (about 721), combined with their lipid solubility, suggest that the drugs will be excreted into human breast milk, although the extensive plasma protein binding (98%–99%) should limit this excretion. The effects of this exposure on a nursing infant are unknown.
However, reports on the use of lopinavir/ritonavir during lactation are unlikely because the combination is indicated in the treatment of patients with HIV. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (8,9,11,13–16). In developing countries, breastfeeding is undertaken, despite the risk, because there are no affordable milk substitutes available.
References
1.Product information. Kaletra. Abbott Laboratories, 2004.
2.Gavard L, Gil S, Peytavin G, Ceccaldi PF, Ferreira C, Farinotti R, Mandelbrot L. Placental transfer of lopinavir/ritonavir in the ex vivo human cotyledon perfusion model. Am J Obstet Gynecol 2006;195:296–301.
3.Marzolini C, Rudin C, Decosterd LA, Telenti A, Schreyer A, Biollaz J, Buclin T, and the Swiss Mother + Child HIV Cohort Study. Transplacental passage of protease inhibitors at delivery. AIDS 2002;16:889–93.
4.Marzolini C, Beguin A, Telenti A, Schreyer A, Buclin T, Biollaz J, Decosterd LA. Determination of lopinavir and nevirapine by high-performance liquid chromatography after solid-phase extraction: application for the assessment of their transplacental passage at delivery. J Chromatogr B Analyt Technol Biomed Life Sci 2002;774:127–40.
5.Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2009. Wilmington, NC: Registry Coordinating Center; 2009. Available at www.apregistry.com. Accessed May 29, 2010.
6.CDC. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47:No. RR-2.
7.Fassett M, Kramer F, Stek A. Treatment with protease inhibitors in pregnancy is not associated with an increased incidence of gestational diabetes (abstract). Am J Obstet Gynecol 2000;182:S97.
8.Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276:146–54.
9.Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
10.Minkoff H. Human immunodeficiency virus infection in pregnancy. Obstet Gynecol 2003;101:797–810.
11.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents. Department of Health and Human Services. December 1, 2009:1–161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed September 17, 2010:60, 96–8.
12.Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. 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. May 24, 2010:1–117. Available at http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. Accessed September 17, 2010:30 (Table 5).
13.Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
14.De Martino M, Tovo P-A, Pezzotti P, Galli L, Massironi E, Ruga E, Floreea F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:991–7.
15.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast-feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.
16.American College of Obstetricians and Gynecologists. Breastfeeding: Maternal and infant aspects. Educational Bulletin. No. 258, July 2000.