PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
The very limited human pregnancy experience during the 1st trimester does not allow a prediction as to the risk of tipranavir during gestation. The animal data suggest low risk, but the obtainable systemic exposures were very low. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Tipranavir is a nonpeptide inhibitor of HIV type 1 (HIV-1) protease. Tipranavir is indicated, in combination with ritonavir 200 mg, for combination antiretroviral treatment of adults infected with HIV-1 with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. Tipranavir and ritonavir are combined because tipranavir is primarily metabolized by CYP3A and ritonavir inhibits CYP3A, thereby markedly increasing the plasma concentrations of tipranavir (darunavir and lopinavir also are combined with ritonavir for the same reason). Metabolism in the presence of ritonavir is minimal. Tipranavir is extensively bound to plasma proteins (>99.9%), both albumin and α1-acid-glycoprotein. In HIV-infected adults, the mean terminal elimination half-life is about 6 hours when combined with ritonavir (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, no effect on early embryonic development was observed at tipranavir exposures about equal to the human exposure from the recommended dose of 500/200 mg tipranavir/ritonavir given twice daily. No teratogenicity was observed in rats or rabbits with tipranavir doses up to 1.1 and 0.1 times, respectively, the human exposure (AUC) of tipranavir at the recommended dose (HE). At about 0.8 times the HE or higher in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed. In rats and rabbits, fetal toxicity was not observed at exposures (AUC) that were about 0.2 and 0.1 times, respectively, the HE. In pre- and postdevelopment studies in rats, dose levels about 0.8 times the HE caused growth inhibition in pups and maternal toxicity. The no-adverse-effect level was about 0.2 times the HE (1).
Long-term carcinogenicity studies have not been completed with tipranavir and tipranavir/ritonavir. No evidence of mutagenicity or clastogenicity was observed in a variety of assays. There also was no evidence of impaired fertility in rats at tipranavir exposures about equal to the human exposure from the recommended dose of 500/200 mg tipranavir/ritonavir given twice daily (1).
It is not known if tipranavir crosses the human placenta. The molecular weight (about 603), minimal metabolism, and elimination half-life suggest that the drug will cross, but the high plasma protein binding will be limiting factor.
A 33-year-old woman with drug-resistant HIV presented to a treatment center at 27 weeks’ gestation (2). The woman’s current therapy was stavudine, tenofovir, and lopinavir/ritonavir, but the response to this combination had been poor, as had been her compliance. Her therapy was changed to zidovudine, lamivudine, abacavir, tenofovir, enfuvirtide, and tipranavir/ritonavir. The patient was hospitalized. High-dose zidovudine was given at 34 weeks’ gestation and a cesarean section delivered a healthy infant (sex not specified). No evidence of HIV was found in the infant on the day of birth and at 6 and 26 weeks of age (2).
In 1998, a public health advisory was issued by the FDA on the association between protease inhibitors and diabetes mellitus (3). 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 (4). No association between protease inhibitors and an increased incidence of gestational diabetes was found.
The Antiretroviral Pregnancy Registry reported, for the period 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 (prevalence 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 (prevalence 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 five outcomes exposed to tipranavir (four in the 1st trimester and one in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There were no birth defects. 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).
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 (6,7). 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 (8). In 2009, the updated U.S. Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1-infected patients continued the recommendation that the therapy, with the exception of efavirenz, should be continued during pregnancy (9). If indicated, therefore, protease inhibitors, including tipranavir, 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 (10). 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 (10).
No reports describing the use of tipranavir during lactation have been located. The molecular weight (about 603), minimal metabolism, an elimination half-life (6 hours) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown.
Reports on the use of tipranavir during human lactation are unlikely because the antiviral agent is used in the treatment of HIV infection. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (6,7,9,11–13). In developing countries, breastfeeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Until 1999, no studies had been published that examined the effect of any antiretroviral therapy on HIV-1 transmission in milk. In that year, a study involving zidovudine was published that measured a 38% reduction in vertical transmission of HIV-1 infection despite breastfeeding when compared with controls (see Zidovudine).
1.Product information. Aptivus. Boehringer Ingelheim Pharmaceuticals, 2007.
2.Wensing AMJ, Boucher CAB, van Kasteren M, van Dijken PJ, Geelen SP, Juttmann JR. Prevention of mother-to-child transmission of multi-drug-resistant HIV-1 using maternal therapy with both enfuvirtide and tipranavir. AIDS 2006;20:1465–7.
3.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.
4.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.
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.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.
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8.Minkoff H. Human immunodeficiency virus infection in pregnancy. Obstet Gynecol 2003;101:797–810.
9.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.
10.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).
11.Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
12.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.
13.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breastfeeding dilemma. Am J Obstet Gynecol 1995;173:483–7.