Fetal Risk Summary
Saquinavir, a synthetic peptide-like substrate analogue, inhibits the activity of human immunodeficiency virus (HIV) protease, thus preventing the cleavage of viral polyproteins and the maturation of infectious virus. The mechanism of action is similar to four other protease inhibitors: amprenavir, indinavir, nelfinavir, and ritonavir.
In reproduction studies in rats and rabbits, embryotoxicity and teratogenicity were not observed at plasma concentrations up to approximately 50% and 40%, respectively, of the human exposure based on area under the plasma concentration versus time curves (AUC) achieved from the recommended clinical dose (1). There was also no evidence that at this dose the drug affected fertility or reproductive performance in rats. A similar lack of toxicity, as measured by survival, growth, and development of offspring to weaning, was found in rats treated during late pregnancy through lactation with doses producing the same plasma concentrations as those above (1).
It is not known if saquinavir crosses the human placenta. The molecular weight of the free base is low enough (about 671) that some degree of transfer should be anticipated. In rats and rabbits, placental transfer of saquinavir is low (less than 5% of maternal plasma concentrations) (1).
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 (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 61 outcomes exposed to saquinavir (49 in the 1st trimester and 12 in the 2nd and/or 3rd trimesters) in combination with other antiretroviral agents (2). There was one birth defect in an infant exposed in the 2nd and/or 3rd trimesters, 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 (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 (3).
The experience of one perinatal center with the treatment of HIV-infected pregnant women was summarized in a 1999 abstract (4). Of 55 women receiving 3 antiviral drugs, 39 were treated with a protease inhibitor (11 with saquinavir). 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, had major congenital anomalies, or complications (4).
A public health advisory has been issued by the Food and Drug Administration (FDA) on the association between protease inhibitors and diabetes mellitus (5). 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 (7 with saquinavir) compared to 41 controls that evaluated the association with diabetes (6). No relationship between protease inhibitors and an increased incidence of gestational diabetes was found.
A case of combined transient mitochondrial and peroxisomal b-oxidation dysfunction after exposure to nucleoside analog reverse transcriptase inhibitors (NRTIs) (lamivudine and zidovudine) combined with protease inhibitors (ritonavir and saquinavir) throughout gestation was reported in 2000 (7). A male infant was delivered at 38 weeks’ gestation. He received postnatal prophylaxis with lamivudine and zidovudine for 4 weeks until the agents were discontinued because of anemia. Other adverse effects that were observed in the infant (age at onset) were hypocalcemia (shortly after birth), group B streptococcal sepsis, ventricular extrasystoles, prolonged metabolic acidosis and lactic acidemia (8 weeks), a mild elevation of long chain fatty acids (9 weeks), and neutropenia (3 months). The metabolic acidosis required treatment until 7 months of age, whereas the elevated plasma lactate resolved over 4 weeks. Cerebrospinal fluid lactate was not determined nor was a muscle biopsy conducted. Both the neutropenia and the cardiac dysfunction had resolved by 1 year of age. The elevated plasma fatty acid level was confirmed in cultured fibroblasts, but other peroxisomal functions (plasmalogen biosynthesis and catalase staining) were normal. Although mitochondrial dysfunction has been linked to NRTI agents, the authors were unable to identify the cause of the combined abnormalities in this case (7). The child was reported to be healthy and developing normally at 26 months of age.
A multicenter, retrospective survey of pregnancies exposed to protease inhibitors was published in 2000 (8). 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 one. Other antiretrovirals used with the protease inhibitors included four 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 (8). One mother developed postpartum cardiomyopathy and died 2 months after birth of twins, but the cause of 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%) (8).
In summary, although the limited human data do not allow an assessment of the safety of saquinavir during pregnancy, the animal data suggests that the risk may be low for the developing fetus. 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 was inadequate therapy (9,10). 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 (5). If indicated, therefore, protease inhibitors, including saquinavir, 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 risk to the fetus. Pregnant women taking protease inhibitors should be monitored for hyperglycemia. Possibly because of the poor bioavailability of saquinavir, one review suggested that during pregnancy ritonavir (see Ritonavir) was the drug of choice among the protease inhibitors (10). 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 (9,10).
Breast Feeding Summary
No reports describing the use of saquinavir during lactation have been located. The molecular weight of the free base (about 671) is low enough that excretion into breast milk should be expected.
Reports on the use of saquinavir during lactation are unlikely because the drug is indicated in the treatment of patients with HIV. HIV type 1 (HIV-1) is transmitted in milk, and in developed countries, breast feeding is not recommended (9,10,11,12 and 13). 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 antiviral 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. Invirase. Roche Laboratories, 2000.
- 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):155.
- McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:6416.
- 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.
- 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. RR2.
- 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.
- Stojanov S, Wintergerst U, Belohradsky BH, Rolinski B. Mitochondrial and peroxisomal dysfunction following perinatal exposure to antiretroviral drugs. AIDS 2000;14:1669.
- 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.