INDINAVIR

Fetal Risk Summary

The antiretroviral agent, indinavir, is an inhibitor of the human immunodeficiency virus (HIV) protease, an enzyme that is required for the cleavage of viral polyprotein precursors into active functional proteins found in infectious HIV. Other drugs in this class are amprenavir, nelfinavir, ritonavir, and saquinavir.

Indinavir was not teratogenic in rats and rabbits at doses comparable to or slightly higher than those used in humans (1). In rats, however, an increase in the incidence of supernumerary ribs (at exposures at or less than those in humans) and cervical ribs (at exposures at or slightly greater than those in humans) were observed. These changes were not observed in rabbits and no effects were noted on embryonic and/or fetal survival or on fetal weight in either rats or rabbits. A study in dogs (because fetal exposure was about 2% of maternal levels in rabbits) observed no indinavir-related effects on embryo or fetal survival, fetal weight, or teratogenicity. At the highest dose tested in dogs, 80 mg/kg/day, fetal drug levels were about 50% of the maternal levels (1).

A study of the developmental toxicity of indinavir in rats was reported in 2000 (2). Pregnant rats were given an oral dose of 500 mg/kg once daily during day 6 to 15 of gestation or twice daily from day 9 to 11 of gestation (a dose of 640 mg/kg/day produces systemtic exposure in the rat that is comparable to or slightly greater than human exposure). In both groups, an increased incidence of supernumerary ribs and variations of the vertebral ossification centers occurred, but no effects on litter sizes, fetal weight, or viability were observed (2). Unilateral anophthalmia was observed in 7 pups (3%) from 2 of the 19 litters (2). On examination, the ocular bulbs were noted to be absent and the bulbar cavity was filled with an enlarged lacrimal gland. No such cases were noted in controls. Other postnatal abnormalities included delayed fur development, eye opening, and slightly earlier descent of the testis. In addition, some liver changes were noted in dams (hepatocellular inclusions of lipids and myelin figure-like structures) and in offspring (infiltration with granulocytes) (2).

It is not known if indinavir crosses the human placenta. The molecular weight (about 712 for the sulfate salt) is low enough that transfer to the fetus should be expected. The drug has been found in fetal plasma of rats, rabbits, dogs, and Rhesus monkeys (1). In Rhesus monkeys, fetal plasma drug levels were 1% to 2% of maternal plasma levels about 1 hour after a dose given in the 3rd trimester (1).

The pharmacokinetics of indinavir during pregnancy have been reported in two women (800 mg every 8 hours) (3). A marked decrease in maternal drug concentrations occurred around 33–34 weeks' gestation, suggesting that women may be exposed to subtherapeutic levels late in pregnancy (3).

The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2000, prospective data (reported to the Registry before the outcomes were known) involving 526 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (4). Nine of the newborns had congenital defects (1.7%, 95% confidence interval [CI] 0.8–3.3). There were 25 infants with birth defects among 1,256 live births with exposure anytime during pregnancy (2.0%, 95% CI 1.3–3.0). The prevalence rates for the two periods did not differ significantly nor did they differ from the rates expected in a nonexposed population (4).

There were 165 outcomes exposed to indinavir (135 in the 1st trimester and 30 in the 2nd and/or 3rd trimesters) either alone (20 in the 1st trimester and 1 in the 2nd trimester) or in combination with other antiretroviral agents (4). There was one birth defect in an infant exposed during the 1st trimester, but the specific defect and treatment were not identified. In comparing the outcomes of prospectively registered cases to the birth defects among retrospective cases (pregnancies reported after the outcomes were known), the Registry concluded that there was no pattern of anomalies to suggest a common cause (4). (See Lamivudine for required statement.) In an unusual case, a woman was exposed to HIV through self-insemination with fresh semen obtained from a man with a high HIV ribonucleic acid viral load (>750,000 copies/mL plasma) (5). Ten days later, she was started on a prophylactic regimen of indinavir (2400 mg/day), zidovudine (600 mg/day), and lamivudine (300 mg/day). Pregnancy was confirmed 14 days after insemination. The indinavir dose was reduced to 1800 mg/day, 4 weeks after the start of therapy because of the development of renal calculi. All antiretroviral therapy was stopped after 9 weeks because of negative tests for HIV. She gave birth at 40 weeks' gestation to a healthy 3490-g male infant, without evidence of HIV disease, who was developing normally at 2 years of age (5).

The experience of one perinatal center with the treatment of HIV infected pregnant women was summarized in a 1999 abstract (6). Of 55 women receiving (³3 antiviral drugs, 39 were treated with a protease inhibitor (5 with indinavir). The outcomes included 2 spontaneous abortions, 5 elective abortions, 27 newborns, and 5 ongoing pregnancies. One woman was taken off of indinavir because of ureteral obstruction and another (drug therapy not specified) developed gestational diabetes. None of the newborns tested positive for HIV or had major congenital anomalies or complications (6).

A study published in 1999 evaluated the safety, efficacy, and perinatal transmission rates of HIV in 30 pregnant women receiving various combinations of antiretroviral agents (7). Many of the women were substance abusers. Protease inhibitors (indinavir N=6, nelfinavir N=7, and saquinavir N=1 in combination with nelfinavir) were used in 13 of the women. Antiretroviral therapy was initiated at a median of 14 weeks' gestation (range preconception to 32 weeks). In spite of previous histories of extensive antiretroviral experience and of vertical transmission of HIV, combination therapy was effective in treating maternal disease and in preventing transmission to the current newborns. The outcomes of the pregnancies treated with protease inhibitors appeared to be similar to the 17 cases that did not receive these agents, except that the birth weights were lower (7).

Indinavir has frequently produced hyperbilirubinemia in adults, but it is not known whether treatment of the mother prior to delivery will exacerbate physiologic hyperbilirubinemia in the neonate (1). No such effects have been observed in Rhesus monkey neonates exposed in utero to indinavir during the 3rd trimester (1).

A public health advisory has been issued by the Food and Drug Administration (FDA) on the association between protease inhibitors and diabetes mellitus (8). Because pregnancy is a risk factor for hyperglycemia, there was concern that these antiviral agents would exacerbate this risk. An abstract published in 2000 described the results of a study involving 34 pregnant women treated with protease inhibitors (4 with indinavir) compared to 41 controls that evaluated the association with diabetes (9). No relationship between protease inhibitors and an increased incidence of gestational diabetes was found.

A multicenter, retrospective survey of pregnancies exposed to protease inhibitors was published in 2000 (10). There were 92 live born infants delivered from 89 women (3 sets of twins) at six health care centers. One nonviable infant, born at 22 weeks' gestation, died. The surviving 91 infants were evaluated in terms of adverse effects, prematurity rate, and frequency of HIV-1 transmission. Most of the infants were exposed in utero to a single protease inhibitor, but a few were exposed to more than one because of sequential or double combined therapy. The number of newborns exposed to each protease inhibitor was indinavir (N=23), nelfinavir (N=39), ritonavir (N=5), and saquinavir (N=34). Protease inhibitors were started before conception in 18, during the 1st, 2nd, or 3rd trimesters in 12, 44, and 14, respectively, and not reported in one. Other antiretrovirals used with the protease inhibitors included four nucleoside reverse transcriptase inhibitors (NRTI) (didanosine, lamivudine, stavudine, and zidovudine). The most common NRTI regimen was a combination of zidovudine and lamivudine (65% of women). In addition, seven women were enrolled in the AIDS Clinical Trials Group Protocol 316 and, at the start of labor, received either a single dose of the nonnucleoside reverse transcriptase inhibitor, nevirapine, or placebo. Maternal conditions, thought possibly or likely to be related to therapy, were mild anemia in eight, severe anemia in one (probably secondary to zidovudine), and thrombocytopenia in one. Gestational diabetes mellitus was observed in three women (3.3%), a rate similar to the expected prevalence of 2.6% in a nonexposed population (10). One mother developed postpartum cardiomyopathy and died 2 months after birth of twins, but the cause death was not known. For the surviving newborns, there was no increase in adverse effects over that observed in previous clinical trials of HIV-positive women, including the prevalence of anemia (12%), hyperbilirubinemia (6%; none exposed to indinavir), and low birth weight (20.6%). Premature delivery occurred in 19.1% of the pregnancies (close to the expected rate). The percentage of infants infected with HIV was 0 (95% CI 0%–3%) (10).

In summary, although the limited human data do not allow an assessment of the fetal risks of indinavir, the animal data involving birth defects is a concern. The finding of anophthalmia in rat pups at a systemic exposure approximately equivalent to human exposure needs further investigation. The authors of that study also observed anophthalmia in a rat experiment with ritonavir (1 of 113 offspring, unpublished data), another protease inhibitor (2). An editorial, accompanying this study, reviewed how the changes in the treatment of HIV disease (e.g., multiple combinations of drugs; use of agents throughout gestation) were altering the risk:benefit ratio of antiretroviral therapy during pregnancy (11).

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 (12,13). In 1998, the Centers for Disease Control and Prevention (CDC) made a similar recommendation that antiretroviral therapy should be continued during pregnancy, but discontinuation of all therapy during the 1st trimester was a consideration (8). If indicated, therefore, protease inhibitors, including indinavir, should not be withheld in pregnancy (with the possible exception of the 1st trimester) because the expected benefit to the HIV-positive mother probably outweighs the unknown risks to the fetus. For indinavir, these theoretical risks include birth defects, hyperbilirubinemia, complications of maternal diabetes, and renal stones. Pregnant women taking protease inhibitors should be monitored for hyperglycemia. Because of the potential for hyperbilirubinemia with indinavir, one review suggested that ritonavir (see Ritonavir) may be a more appropriate first-choice drug (13). Moreover, indinavir has been associated with the development of renal stones in adults and, if significant human placental transfer occurs, maternal usage near delivery may, theoretically, cause development of renal toxicity in the newborn. The combination of immature neonatal renal function and the potential for suboptimal hydration may allow for high or prolonged concentrations of the drug leading to crystallization and renal stones. Finally, the efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn are unknown, and zidovudine remains the only antiretroviral agent currently recommended for this purpose (12,13).

Breast Feeding Summary

No reports describing the use of indinavir during lactation have been located. The antiviral agent is excreted into the milk of lactating rats (1). The molecular weight (about 712 for the sulfate salt) is low enough that excretion into breast milk should be expected.

Reports on the use of indinavir during lactation are unlikely because of the potential toxicity in the nursing infant, especially hyperbilirubinemia, and because the drug is indicated in the treatment of patient's with HIV. HIV type 1 (HIV-1) is transmitted in milk, and in developed countries, breast feeding is not recommended (12,13,14,15 and 16). In developing countries, breast feeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Until 1999, no studies have 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 in spite of breast feeding when compared to controls (see Zidovudine).

References

1. Product information. Crixivan. Merck, 2001.
2. Riecke K, Schultz TG, Shakibaei M, Krause B, Chahoud I, Stahlmann R. Developmental toxicity of the HIV-protease inhibitor indinavir in rats. Teratology 2000;62:291–300.
3. Hayashi S, Beckerman K, Homma M, Kosel BW, Aweeka FT. Pharmacokinetics of indinavir in HIV-positive pregnant women. AIDS 2000;14:1061–2.
4. The Antiretroviral Pregnancy Registry for abacavir (Ziagen), amprenavir (Agenerase, APV), delavirdine mesylate (Rescriptor), didanosine (Videx, ddl), efavirenz (Sustiva, Stocrin), indinavir (Crixivan, IDV), lamivudine (Epivir, 3TC), lamivudine/zidovudine (Combivir), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), saquinavir (Fortovase, SQV-SGC), saquinavir mesylate (Invirase, SQV-HGC), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). Interim Report. 1 January 1989 through 31 July 2000. 2000(December);11(No. 2):1–55.
5. Bloch M, Carr A, Vasak E, Cunningham P, Smith D. The use of human immunodeficiency virus postexposure prophylaxis after successful artificial insemination. Am J Obstet Gynecol 1999;181:760–1.
6. Stek A, Kramer F, Fassen M, Khoury M. The safety and efficacy of protease inhibitor therapy for HIV infection during pregnancy (abstract). Am J Obstet Gynecol 1999;180:S7.
7. McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:641–6.
8. Centers for Disease Control and Prevention. 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.
9. 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.
10. Morris AB, Cu-Uvin S, Harwell JI, Garb J, Zorrilla C, Vajaranant M, Dobles AR, Jones TB, Carlan S, Allen DY. Multicenter review of protease inhibitors in 89 pregnancies. J Acquir Immune Defic Syndr 2000;25:306–11.
11. Miller RK. Anti-HIV therapy during pregnancy: risk-benefit ratio. Teratology 2000;62:288–90.
12. 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.
13. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
14. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
15. 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.
16. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.