Fetal Risk Summary
Nelfinavir is an inhibitor of human immunodeficiency virus (HIV) protease (PI). In in vitro tests, the agent was found to be active against both type 1 and type 2 (HIV-1 and HIV-2) (1). Other drugs in this class are amprenavir, indinavir, ritonavir, and saquinavir. Protease is an enzyme that is required for the cleavage of viral polyprotein precursors into active functional proteins found in infectious HIV. Nelfinavir, usually in combination with other antiretroviral agents, is indicated for the treatment of HIV infections.
Reproduction studies with nelfinavir have been conducted in rats and rabbits (1). No effects on fertility, mating, embryo survival, or fetal development were observed in rats given doses that produced plasma concentrations comparable to those measured in humans with therapeutic doses. Exposure of pregnant rats from mid-gestation through lactation had no effect on survival, growth, development to weaning, or subsequent fertility of the offspring (1). In rabbits, doses up to a maternal toxic dose (decreased maternal body weight) had no effect on fetal development. However, even at the highest dose, the systemic exposure in rabbits was significantly less than that observed in humans (1).
It is not known if nelfinavir crosses the human placenta to the fetus. The molecular weight of the free base (about 568) is low enough that transfer to the fetus should be expected.
The Antiretroviral Pregnancy Registry reported, for the period January 1, 1989 through July 31, 2000, prospective data (reported to the Registry before the outcomes were known) involving 526 live births that had been exposed to one or more antiretroviral agents during the 1st trimester (2). Nine of the newborns had congenital defects (1.7%, 95% confidence interval [CI] 0.83.3). There were 25 infants with birth defects among 1,256 live births with exposure anytime during pregnancy (2.0%, 95% CI 1.33.0). The prevalence rates for the two periods did not differ significantly, nor did they differ from the rates expected in a nonexposed population (2).
There were 270 outcomes that were exposed to nelfinavir, either alone (N=3) or in combination (N=267) with other agents. In 122 outcomes (including the 3 cases in which the agent was used alone), the earliest exposure occurred in the 1st trimester, whereas in 148 cases the earliest exposure was in the 2nd and/or 3rd trimesters. There were three birth defects (none with nelfinavir alone) in those exposed during the 1st trimester and two in those exposed in the 2nd and/or 3rd trimesters. The specific birth defects and treatments 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 (2). (See Lamivudine for required statement).
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 (3). Many of the women were substance abusers. Protease inhibitors (nelfinavir N=7, indinavir N=6, 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.
A public health advisory has been issued by the Food and Drug Administration (FDA) on the association between protease inhibitors and diabetes mellitus (4). 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 (30 with nelfinavir) compared to 41 controls that evaluated the association with diabetes (5). No association between protease inhibitors and an increased incidence of gestational diabetes was found.
A 1999 abstract reported the effect of protease inhibitors (nelfinavir, indinavir, ritonavir, or saquinavir) in combination with two or more other antiretroviral agents in 39 pregnant women (6). Nelfinavir was the most commonly used protease inhibitor. The mean gestational age at the start of protease inhibitor therapy was 31 weeks (range 839 weeks). All of the newborns tested HIV-negative. Based on these outcomes, and the lack of congenital anomalies and serious neonatal complications, and the mother’s response to therapy, the authors concluded that protease inhibitor therapy during pregnancy was effective for maternal HIV disease and contributed to the very low rate of perinatal HIV transmission (6).
A multicenter, retrospective survey of pregnancies exposed to protease inhibitors was published in 2000 (7). 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, and during the 1st, 2nd, or 3rd trimesters in 12, 44, and 14, respectively, and not reported in 1. Other antiretrovirals used with the protease inhibitors included four nucleoside reverse transcriptase inhibitors (NRTIs) (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 (7). 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%) (7).
In summary, the lack of animal toxicity and the human pregnancy data suggest that nelfinavir is not a major teratogen. 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). 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 (4). If indicated, therefore, protease inhibitors, including nelfinavir, 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 known risk to the fetus. Pregnant women taking protease inhibitors should be monitored for hyperglycemia. The efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn, however, are unknown, and zidovudine remains the only antiretroviral agent recommended for this purpose (8,9).
Breast Feeding Summary
No reports describing the use of nelfinavir during human lactation have been located. The molecular weight of the free base (about 568) is low enough that excretion into breast milk should be expected. The agent is excreted in the milk of lactating rats (1).
Reports on the use of nelfinavir during human lactation are unlikely because the antiviral agent is used in the treatment of human immunodeficiency virus (HIV) infections. HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (8,9,10,11 and 12). In developing countries, breast feeding 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 in spite of breast feeding when compared to controls (see Zidovudine).
- Product information. Agouron Pharmaceuticals, 2001.
- 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-HGV), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). 1 January 1989 through 31 July 2000. Interim Report. 2000(December);11(No.2):155.
- McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:6416.
- 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.
- 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.
- Stek A, Kramer F, Fassett M, Khoury M. The safety and efficacy of protease inhibitor therapy for HIV infection during pregnancy (abstract). Am J Obstet Gynecol 1999;180:S7.
- 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;25:30611.
- 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;14654.
- Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:47889.
- Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:27689.
- 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;6:9917.
- Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:4837.