Table 7-7: Antiretroviral Drug Use in Pregnant HIV-Infected Women:
Pharmacokinetic and Toxicity Data in Human Pregnancy
and Recommendations for Use in Pregnancy
| Antiretroviral Drug |
Pharmacokinetics in Pregnancy |
Concerns in Pregnancy |
Rationale for Recommended Use in Pregnancy |
| NRTI/NtRTIs |
|
See text for discussion of potential maternal and infant mitochondrial toxicity. |
NRTIs are recommended for use as part of combination regimens, usually including two NRTIs with either an NNRTI or one or more PIs. Use of single or dual NRTIs alone is not recommended for treatment of HIV infection (AZT alone may be considered for prophylaxis of perinatal transmission in pregnant women with HIV RNA <1,000 copies/mL) |
| Recommended agents (NRTI/NtRTIs) |
| Zidovudine* |
Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated |
No evidence of human teratogenicity. Well-tolerated, short-term safety demonstrated for mother and infant |
Preferred NRTI for use in combination antiretroviral regimens in pregnancy based on efficacy studies and extensive experience; should be included in regimen unless significant toxicity or stavudine use. |
| Lamivudine* |
Pharmacokinetics not significantly altered in pregnancy; no change in dose indicatedC |
No evidence of human teratogenicity. Well-tolerated, short-term safety demonstrated for mother and infant |
Because of extensive experience with lamivudine in pregnancy in combination with zidovudine, lamivudine plus zidovudine is the recommended dual NRTI backbone for pregnant women. |
| Alternate agents (NRTI/NtRTIs) |
| Didanosine |
Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated |
Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving didanosine and stavudine together |
Alternate NRTI for dual nucleoside backbone of combination regimens. Didanosine should be used with stavudine only if no other alternatives are available. |
| Emtricitabine |
No studies in human pregnancy |
No studies in human pregnancy |
Alternate NRTI for dual nucleoside backbone of combination regimens. |
| Stavudine |
Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated |
No evidence of human teratogenicity. Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving didanosine and stavudine together |
Alternate NRTI for dual nucleoside backbone of combination regimens. Stavudine should be used with didanosine only if no other alternatives are available. Do not use with zidovudine due to potential for antagonism. |
| Abacavir* |
Phase I/II study in progress. |
Hypersensitivity reactions occur in ~ 5–8% of nonpregnant persons, a much smaller percentage are fatal and usually associated with rechallenge; rate in pregnancy unknown. Patient should be educated regarding symptoms of hypersensitivity reaction |
Alternate NRTI for dual nucleoside backbone of combination regimens. See footnote regarding use in triple NRTI regimen.# |
| Insufficient data to recommend use (NRTI/NtRTIs) |
| Tenofovir |
No studies in human pregnancy. Phase I study in late pregnancy in progress. |
Studies in monkeys show decreased fetal growth and reduction in fetal bone porosity within two months of starting maternal therapy. Clinical studies in humans (particularly children) show bone demineralization with chronic use; clinical significance unknown. |
Because of lack of data on use in human pregnancy and concern regarding potential fetal bone effects, tenofovir should be used as a component of a maternal combination regimen only after careful consideration of alternatives. |
| Zalcitabine |
No studies in human pregnancy |
Rodent studies indicate potential for teratogenicity and developmental toxicity |
Given lack of data and concerns regarding teratogenicity in animals, not recommended for use in human pregnancy unless alternatives not available |
| NNRTIs |
| Recommended agents (NNRTIs) |
| Nevirapine |
Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated |
No evidence human teratogenicity. Increased risk of symptomatic, often rash-associated and potentially fatal, liver toxicity among women with CD4+ lymphocyte counts > 250/mm3 when first initiating therapy, unclear if pregnancy increases risk. |
Nevirapine should be initiated in pregnant women with CD4+ lymphocyte counts > 250/mm3 only if benefit outweighs risk; if used, monitor closely for liver toxicity in first 18 weeks of therapy. Women who enter pregnancy on nevirapine regimens and are tolerating well may continue therapy, regardless of CD4+ lymphocyte count. |
| Not recommended (NNRTIs) |
| Efavirenz |
No studies in human pregnancy |
Significant malformations (anencephaly, anophthalmia, cleft palate) were observed in 3 (15%) of 20 infants born to cynomologus monkeys receiving efavirenz during the first trimester at a dose giving plasma levels comparable to systemic human therapeutic exposure; there are three case reports of neural tube defects in humans after first trimester exposure; relative risk unclear. |
Use of efavirenz should be avoided in the first trimester, and women of childbearing potential must be counseled regarding risks and avoidance of pregnancy. Alternative effective regimens should be considered, if available. Use after the second trimester of pregnancy can be considered if other alternatives not available and if adequate contraception can be assured postpartum. |
| Delavirdine |
No studies in human pregnancy |
Rodent studies indicated potential for carcinogenicity and teratogenicity |
Given lack of data and concerns regarding teratogenicity in animals, not recommended for use in human pregnancy unless alternatives not available |
| Protease Inhibitors |
Hyperglycemia, new onset or exacerbation of diabetes mellitus, and diabetic ketoacidosis reported with PI use; unclear if pregnancy increases risk. Conflicting data regarding preterm delivery in women receiving PIs |
|
| Recommended agents (Protease Inhibitors) |
| Nelfinavir |
Adequate drug levels are achieved in pregnant women with nelfinavir, 1250 mg, given twice daily |
No evidence of human teratogenicity. Well-tolerated, short-term safety demonstrated for mother and infant. Nelfinavir dosing at 750 mg three times daily produced variable and generally low levels in pregnant women |
Given pharmacokinetics data and extensive experience with use in pregnancy compared to other PIs, preferred PI for combination regimens in pregnant women, particularly if HAART is being given solely for perinatal prophylaxis. In clinical trials of initial therapy in non-pregnant adults, nelfinavir-based regimens had a lower rate of viral response compared to lopinavir/ritonavir or efavirenz-based regimens, but similar viral response compared with atazanavir or nevirapine-based regimens. |
| Saquinavir-soft gel capsule [SGC] (Fortavase)/ritonavir |
Adequate drug levels are achieved in pregnant women with saquinavir-SGC 800 mg boosted with ritonavir 100 mg given twice daily.
Recommended adult dosing of saquinavir-SGC 1000 mg plus ritonavir 100 mg may be used.
No pharmacokinetic data on saquinavir-hard gel capsule [HGC]/ritonavir in pregnancy, but better GI tolerance in non-pregnant adults. |
Well-tolerated, short-term safety demonstrated for mother and infant. Inadequate drug levels observed in pregnant women when saquinavir-SGC given alone at 1200 mg three times daily. |
Given pharmacokinetics data and extensive experience with use in pregnancy, ritonavir-boosted saquinavir-SGC can be considered a preferred PI for combination regimens in pregnant women. |
| Alternative agents (Protease Inhibitors) |
| Indinavir |
Study underway to evaluate pharmacokinetics of indinavir 800 mg with ritonavir 100 mg, given twice daily |
Theoretical concern re: increased indirect bilirubin levels, which may exacerbate physiologic hyperbilirubinemia in the neonate, but minimal placental passage. Two studies including six women receiving indinavir 800 mg three times daily showed marked lower levels during pregnancy compared to postpartum, although suppression of HIV RNA was seen |
Alternate PI to consider if unable to use nelfinavir or saquinavir-SGC/ritonavir. Use of unboosted indinavir during pregnancy is not recommended. Optimal dosing for the combination of ritonavir/indinavir in pregnancy unknown. |
| Lopinavir/ritonavir |
Phase I/II safety and pharmacokinetic study in progress using twice daily lopinavir 400 mg and ritonavir 100 mg |
Limited experience in human pregnancy |
Preliminary studies suggest increased dose may be required during pregnancy, though specific dosing recommendations not established. If used during pregnancy, monitor response to therapy closely. If expected virologic result not observed, consider increasing dose in consultation with a specialist with expertise in HIV in pregnancy. |
| Ritonavir |
Phase I/II study in pregnancy showed lower levels during pregnancy compared to postpartum |
Minimal experience in human pregnancy |
Given low levels in pregnant women when used alone, recommended for use in combination with second PI as low dose ritonavir “boost” to increase levels of second PI |
| Insufficient data to recommend use (Protease Inhibitors) |
| Amprenavir |
No studies in human pregnancy |
Oral solution contraindicated in pregnant women because of high levels of propylene glycol, which may not be adequately metabolized during pregnancy. |
Data are insufficient regarding safety and pharmacokinetics in pregnancy to recommend use of capsules during pregnancy. Oral solution contraindicated |
| Fos-amprenavir |
No studies in human pregnancy |
No experience in human pregnancy |
Data are insufficient regarding safety and pharmacokinetics in pregnancy to recommend use during pregnancy. |
| Atazanavir |
No studies in human pregnancy |
Theoretical concern re: increased indirect bilirubin levels, which may exacerbate physiologic hperbilirubinemia in the neonate, although transplacental passage of other PIs has been low |
Data are insufficient regarding safety and pharmacokinetics in pregnancy to recommend use during pregnancy. |
| Fusion Inhibitors |
| Insufficient data to recommend use (Fusion Inhibitors) |
| Enfuvirtide |
No studies in human pregnancy |
No experience in human pregnancy |
Data are insufficient regarding safety and pharmacokinetics in pregnancy to recommend use during pregnancy. |