Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The limited human data do not suggest a major embryo–fetal risk, but the animal data involving birth defects are 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 The authors of that study also observed anophthalmia in a rat experiment with ritonavir (1 of 113 offspring, unpublished data), another protease inhibitor (1). An editorial, accompanying this study, reviewed how the changes in the treatment of HIV disease (e.g., multiple combinations of drugs and use of agents throughout gestation) were altering the risk:benefit ratio of antiretroviral therapy during pregnancy (2). However, if indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
The antiretroviral agent, indinavir, is an inhibitor of the HIV protease, an enzyme that is required for the cleavage of viral polyprotein precursors into active functional proteins found in infectious HIV.
Indinavir was not teratogenic in rats and rabbits at doses comparable to or slightly higher than those used in humans (3). 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 (3).
A study of the developmental toxicity of indinavir in rats was reported in 2000 (1). 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 systemic 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. Unilateral anophthalmia was observed in 7 pups (3%) from 2 of the 19 litters. 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) (1).
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 monkeys (3). In monkeys, fetal plasma drug levels were 1%–2% of maternal plasma levels about 1 hour after a dose given in the 3rd trimester (3).
The pharmacokinetics of indinavir during pregnancy has been reported in two women (800 mg every 8 hours) (4). 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.
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 trimester, 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 436 outcomes exposed to indinavir (276 in the 1st trimester and 160 in the 2nd/3rd trimester) in combination with other antiretroviral agents. There were nine birth defects (six in the 1st trimester and three in the 2nd/3rd trimester). 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 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) (6). 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. Four weeks after the start of therapy, the indinavir dose was reduced to 1800 mg/day because of the development of renal calculi. The 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 (6).
The experience of one perinatal center with the treatment of HIV-infected pregnant women was summarized in a 1999 abstract (7). Of 55 women receiving ≥3 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 indinavir because of ureteral obstruction and another woman (drug therapy not specified) developed gestational diabetes. None of the newborns tested positive for HIV or had major congenital anomalies or complications (7).
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 (8). 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 in which these were not used, except that the birth weights were lower (8).
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 (3). No such effects have been observed in monkey neonates exposed in utero to indinavir during the 3rd trimester.
A public health advisory was issued by the FDA on the association between protease inhibitors and diabetes mellitus (9). 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 with 41 controls that evaluated the association with diabetes (10). 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 (11). There were 92 liveborn 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 trimester in 12, 44, and 14, respectively, and not reported in one. 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. 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%) (11).
Two reviews, one in 1996 and the other in 1997, concluded that all women 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). 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 (14). 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 therapy, with the exception of efavirenz, should be continued during pregnancy (15). If indicated, therefore, protease inhibitors, including indinavir, 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 (16). 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 (16).
BREASTFEEDING SUMMARY
No reports describing the use of indinavir during lactation have been located. 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 patients with HIV. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (12,13,15,17–19). In developing countries, breastfeeding 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 despite breastfeeding when compared with controls (see Zidovudine).
References
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16.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).
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