Table 14-3: Antiretrovirals
| Drug Name |
Dosing |
Adverse Effects |
FDA
Class |
Animal Data |
Human Experience in Pregnancy |
| Nucleoside Reverse Transcriptase Inhibitors (NRTIs) |
Abacavir
(Ziagen®,
ABC) |
300 mg bid or 600 mg qd
Available as 300 mg tablets; 10 mg/ml oral solution; Trizivir: ZDV 300 mg/ 3TC 150 mg/ ABC 300 mg
Epzicom: 3TC 300 mg ABC 600 mg |
Hypersensitivity reaction—fever, rash, fatigue, malaise, GI symptoms, and arthralgias (noted in 2–3% of patients). Mandatory and permanent discontinuation with hypersensitivity reaction. Deaths reported upon rechallenge; rare cases of lactic acidosis and severe hepatomegaly with steatosis. |
C |
Rodent studies demonstrated placental passage, anasarca, skeletal malformation at 1000 mg/kg dose (35 times human therapeutic levels) during organogenesis. However rabbits receiving 8.5 times human therapeutic levels did not have fetal malformation. |
Based on ex vivo data, placental transfer was 32–66% (Bawdon, 1998). |
No data on use for prevention of perinatal transmission. |
| Zidovudine (Retrovir®, AZT, ZDV) |
300 mg po bid, PACTG protocol dosing: Prenatal: 100 mg 5x per day (alternatively 300 mg bid) beginning at weeks 14–34; Intrapartum 2 mg/kg IV for first hour then 1 mg/kg IV until birth. Infant received 2 mg/kg po q 6 h for the first 6 wk of life beginning 8–12 hr after birth
Available as 100 mg capsules; 300 mg tablets; 10 mg/ml IV solutions; 10 mg/mL oral solution; 300 mg Combivir (ZDV 300 mg/3TC 150 mg), Trizivir (ZDV 300 mg/3TC 150 mg/ABC 200 mg) |
GI intolerance, malaise; headache (in 5–10%); bone marrow suppression (anemia and neutropenia seen more commonly with late stage AIDS); myalgia; myopathy; transaminase elevation; fingernail discoloration; rare cases of lactic acidosis and severe hepatomegaly with steatosis. |
C |
Prolonged high dose ZDV exposure associated with nonmetastasizing vaginal squamous tumors in 13% of adult rodents, possibly due to concentration of unmetabolized ZDV in rodent urine (but not in humans). Transplacental carcinogenicity studies in mice with differing results: (1) doses 25-50 times human dose given in late gestation resulted in increase in lung, liver, female reproductive tract tumors in offspring exposed to highest dose level; (2) doses approximately 3 times human therapeutic exposure in pregnancy associated with no increase in tumor incidence in offspring. No evidence of fetal malformations or developmental toxicity with doses up to 500-600 mg/kg/day in pregnant rats, mice, rabbits |
Human studies demonstrated 85% placental passage. No excess maternal toxicities or fetal defects noted with AZT during pregnancy. Long-term toxicity data (up to 6 yrs.) for infants exposed to AZT in utero and postpartum did not show an increased risk of tumors or abnormal developmental parameters. |
The nucleoside analogue with the most extensive clinical data on safety and efficacy during pregnancy. When feasible all antiretroviral regimens for the prevention of perinatal transmission should include AZT. |
| Stavudine (Zerit®, d4T) |
Wt >60 kg dose: 40 mg po bid. Wt <60 kg dose: 30 mg po bid
XR: wt >60kg 100 mg po qd. Wt <60 kg 75 mg po qd.
Available as 15, 20, 30, 40 mg capsules; 1mg/mL for oral solution. New 100 mg extended release capsule (Zerit XR) Released early 2003. |
Peripheral neuropathy
(in 5–15% of patients); transaminase elevation (in 8% of patients); rare cases of lactic acidosis and severe hepatomegaly with steatosis, lipodystrophy; pancreatitis; rare cases of rapidly progressive ascending neuromuscular weakness |
C |
Studies in rhesus monkeys demonstrated 76% placental passage. Not teratogenic in rodents, but decreased sternal bone calcium. Carcinogenic studies not completed. |
Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving combination of d4T and ddI as component of ARV therapy.
No increase in birth defects noted in Antiretroviral Pregnancy Registry |
Combination of d4T and ddI should be prescribed in pregnancy with caution, generally only when other NRTI drug combinations have failed or caused unacceptable toxicity/side effects. Due to the antagonism between AZT and d4T, they should never be used together as a part of a HAART regimen. |
| Didanosine (Videx®, ddI) |
Wt >60 kg dose: 200 mg po bid or 400 mg po qd (tabs); 400 mg po qd (EC); 250 mg po bid or 500 mg po qd (powder).
Wt <60 kg dose: 125 mg po bid or 250 mg po qd (tabs); 250 mg po qd (EC); or 167 mg po bid or 334 mg po qd (powder).
Available as 25, 50, 100, 150 200 mg chewable buffered tablets; 100, 167, 250 mg buffered powder for oral solution; 125, 200, 250, or 400 mg enteric coated capsules
Take 1/2 hr. before or 2 hr. after meals. |
GI intolerance (diarrhea, mouth sores), peripheral neuropathy in (5–12% of patients); pancreatitis (in 1–9% of patients with 6% of cases fatal); transaminase elevation; rare cases of lactic acidosis and severe hepatomegaly with steatosis. |
B |
Not teratogenic or carcinogenic in rodent studies. |
Placental passage approximately 50% PACTG 249 Phase I study showed that ddI was well tolerated by mother and fetus when started at weeks 26–36. (Wang, 1999). |
GI side effects may limit use. The pediatric powder and EC tablet formulations are better tolerated (for every 4 g of ddI, mix with 200 cc of Maalox®). |
| Lamivudine, (Epivir®, 3TC) |
150 mg po bid or 300 mg po qd
Available as 150 mg, 300 mg tablets; 10 mg/mL oral solution; Combovir (ZDV 300 mg/3TC 150 mg); Trizivir (ZDV 300 mg/3TC 150 mg/ABC 300 mg); Epzicom: 3TC 300 mg/ABC 600 mg |
Generally very well tolerated; occasional headache; nausea; diarrhea; abdominal pain; and insomnia; rare cases of lactic acidosis and severe hepatomegaly with steatosis. |
C |
Not teratogenic or carcinogenic in rodent studies. |
Human studies demonstrated 100% placental passage. No increase in birth defects noted in Antiretroviral Pregnancy Registry. |
Associated with reduction in perinatal transmission when combined with ZDV (PETRA clinical trial) in later pregnancy or labor plus 1 wk post partum to mother and newborn (see chapter VII Reproduction). |
| Emtricitabine (Emtriva®, FTC) |
200 mg po qd
Available as 200 mg capsules
Truvada: FTC 200 mg/ TDF 300 mg |
Occasional headache, diarrhea, nausea, rash, generally of mild to moderate severity; rare cases of lactic acidosis and severe hepatomegaly with steatosis. |
B |
No increase in fetal malformations in mice and rabbits. Unknown if placental passage. |
No data
Placental passage unkown |
Similar to 3TC, FTC is active against hepatitis B. Resistance profile is identical to 3TC. Little experience in pregnancy.
Not indicated for treatment of chronic HBV infection and safety and efficacy not established in patients with HBV/HIV coinfection. |
| Zalcitabine, (Hivid®, Dideoxy-cytidine, ddC) |
0.75 mg po tid
Available as 0.375, 0.75 mg tablets. |
High incidence of peripheral neuropathy (17–31% of patients); stomatitis, aphthous ulcers; hepatitis; rare cases of pancreatitis reported; rare cases of lactic acidosis and severe hepatomegaly with steatosis. |
C |
Studies in rhesus monkey demonstrated 30–50% placental passage. Carcinogenic in rodent studies resulting in thymic lymphoma. Teratogenic in rodent studies resulting in hydrocephalus at high dose (see Table 14-6 Drug-Drug Interactions). |
Insufficient information to provide reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses. |
ddC is not a component in currently recommended ARV regimens; should not be used with ddI or d4T due to additive peripheral neuropathy and other toxicity. |
| Nucleotide Reverse Transcriptase Inhibitors (N+RTIs) |
| Tenofovir DF (Viread®, TDF) |
300 mg po qd
Available as 300 mg capsules.
Tuvada: TDF 300 mg/FTC 200 mg |
Generally well tolerated. Most common side effects: Headache, diarrhea, nausea and vomiting. Asymptomatic elevation of CPK and transaminase levels in 10%. Neutropenia in 7% and increased amylase in 6%. Rare reports of renal insufficiency. Rare lactic acidosis with hepatic steatosis |
B |
Gravid Rhesus monkeys study showed no fetal malformations, however reduction in body weight, insulin-like growth factor, and fetal bone porosiity was observed (25 times AUC with human therapeutic dosing) (Tarantal, 2004).
Placental passage demonstrated in rats and monkeys. |
No data
Placental passage unknown |
Should be taken with food. Data from monkeys support the use of tenofovir DF for post-exposure prophylaxis. |
| Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) |
| Efavirenz (Sustiva®, EFV) |
600 mg po q hs
Available as 50, 100, 200 mg capsules or 600 mg tablets
Take on empty stomach. |
Morbilliform rash in 15–27% of patients with 1–2% requiring discontinuation; one case of Stevens-Johnson syndrome reported; CNS effects (confusion, depersonalization, abnormal dreams) usually seen in up to 52% of patients and resolve in 2–4 wk; transaminase elevation in 2–3% of patients, hyperlipidemia. |
D |
Placental passage of 100% seen in cynomolgus monkeys, rats, and rabbits. Teratogenicity demonstrated in cynomolgus monkeys resulting in anencephaly, anophthalmia, microphthalmia. Increase in hepatocellular adenomas and carcinomas and pulmonary alveolar bronchiolar adenomas in female mice at exposures 1.7 times human therapeutic doses. |
4 cases of central nervous system defects with 1st trimester exposure; birth defects observed in 3 of 88 live births with 1st trimester exposure and 0 of 11 births with exposure later in pregnancy (Antiretroviral Pregnancy Registry) |
Efavirenz should be avoided during pregnancy (particularly early pregnancy) and in women trying to conceive or not using effective contraception. |
| Nevirapine (Viramune®, NVP) |
200 mg po qd for 14 days then 200 mg po bid
Available as 200 mg tablets or 50 mg/5mL oral suspension. |
Rash in 17% of patients (7% discontinued due to rash, many patients require hospitalization) Stevens-Johnson syndrome reported; transaminase elevation; severe hepatitis; fever; nausea; headache.
Women may be at increased risk of rash and liver toxicity, especially with CD4 >250 cells/mm3 (Mazhude, 2002; Bersoff-Matdra, 2001; Stern, 2002) |
C |
Not teratogenic in rodent studies. No data on carcinogenicity. |
Nevirapine-associated skin rash and hepatotoxicity (including hepatic failure) reported in pregnancy (Knudtson, 2003; Lyons, 2003; Langlet, 2000). These toxicities have not been reported in women or infants receiving HIVNET 012 two-dose regimen for prevention of perinatal transmission. |
In HIVNET 012 administration of single-dose nevirapine given to mother during labor and to infants within 72 hr of delivery was compared with administration of AZT during labor and AZT for 7 days to infants. The 18 mo data showed that 26% of infants in the AZT and 16% of infants in the nevirapine arm were infected, a 41% reduction with nevirapine (Jackson, 2003). Monitor LFTs q 2wk x 1st 4 wk, then q mo x 4 mo; then q 1-3 mo. Use with caution as part of combination regimen in pregnant women for purpose of prevention of perinatal transmission. Contraindicated in women with CD4 counts > 250/mm3. |
| Delavirdine (Rescriptor®, DLV) |
400 mg po tid
Available as 100 mg or 200 mg tablets |
Rash in 18% of patients (4.3% discontinued due to rash, usually does not require discontinuation unless mucous membrane involvement); rare erythema multiforme or Stevens Johnson syndrome; headache; increased transaminase levels (see Table 14-6 Drug-Drug Interactions) |
C |
Placental passage of 4–15% in late-term rodent studies. Teratogenic in rodent studies resulting in ventricular septal defects. Maternal toxicity, embryotoxicity and decreased pup survival seen with doses five times the human dose. No data on carcinogenicity. |
Insufficient information to provide reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses. |
Due to the availability of more potent NNRTIs (e.g., nevirapine) use of delavirdine is generally not recommended. |
| Protease Inhibitors (PIs) |
Lopinavir/
Ritonavir
(LPV/r)
(Kaletra®) |
Lopinavir 400 mg/ritonavir 100 mg (3 capsules or 5 mL) twice daily with food
Available as 133.33 mg lopinavir/33.3 mg ritonavir capsules; 80 mg lopinavir/20 mg ritonavir per mL oral solution. |
Diarrhea in 13.8–23.8% of patients; nausea, vomiting, abdominal pain, asthenia, headache and rash reported. Class adverse events such as hyperlipidemia, fat redistribution and hyperglycemia are possible. |
C |
No treatment-related malformations in animal studies. No embryonic or fetal development toxicities seen in rabbits. Delayed skeletal ossification and increase in skeletal variations in rats at maternally toxic doses. |
No human data available.
Preliminary data indicate minimal placental passage of ritonavir; unknown for lopinavir |
|
Ritonavir (Norvir®,
RTV) |
600 mg po bid (when used as sole PI), but
Ritonavir now used at lower doses with other PIs as pharmacologic enhancer or booster. (See Table 14-6)
Available as 100 mg capsules; 600 mg/7.5 mL oral solution. Take with food, if possible (may improve tolerability) |
Severe GI intolerance (nausea, vomiting, diarrhea; abdominal pain, common with 600 mg bid dosing); taste perversion; asthenia; circumoral and peripheral paresthesias; pancreatitis; lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation (increased incidence seen with hepatitis B and C coinfection); elevated CPK and uric acid. |
B |
Not teratogenic but slight increase in cryptorchidism reported in rodent studies. Increase in liver adenomas and carcinomas in male mice (4 times human therapeutic dose). No carcinogenic effects in rats. |
Minimal transplacental passage. |
Use may be limited by GI intolerance at full dose. Better tolerated when used as booster with another PI (RTV 100 mg bid and 2nd PI). |
| Saquinavir, SQV (Invirase®, INV, hard gel capsules; Fortovase®, FTV soft gel capsules) |
INV or FTV 400 mg po bid with ritonavir 400 mg po bid. Invirase not recommended as sole PI; Fortovase 1200 mg po tid when used alone (see Table 14-6)
Available as: Invirase 200 mg capsules; Invirase 500 mg tablets; Fortovase 200 mg capsules; take Fortovase with large meal. |
GI intolerance (nausea, diarrhea, abdominal pain); lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation. |
B |
Placental passage in rat and rabbit is minimal. No teratogenicity reported in rodent studies. No data on carcinogenicity. |
Insufficient information to provide reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses.
Minimal transplacental passage. |
Invirase 1,000 mg RTV/ 100 mg bid is the preferred dosing regimen due to better pharmacokinetics and tolerance. |
| Indinavir, IDV (Crixivan®) |
800 mg po tid
(see Table 14-6) 400/400 mg or 800/100 mg or 800/200 mg IDV/RTV bid + EFV 600 mg
Available as 200, 333, 400 mg capsules. Take 1 hr before or 2 hr after meals; may take with low fat meals |
Nephrolithiasis +/- hematuria in 5–15% of patients (48 oz of fluid recommended to decrease incidence); indirect hyperbilirubinemia (≥ 2.5 mg/dL in 10–15% of patients); lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation. |
C |
Placental passage is significant in rats, but low in rabbits. Not teratogenic in rodent studies (but extra ribs have been reported). Incidence of hyperbilirubinemia in neonatal Rhesus monkeys increased with neonatal but not in utero exposure. No data on carcinogenicity. |
Insufficient information to provide reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses. Minimal transplacental passage. |
Due to theoretical concerns of hyperbilirubinemia and nephrolithiasis in newborns, indinavir should be avoided during late pregnancy. |
| Nelfinavir, NFV (Viracept®) |
750 mg po tid or 1250 mg po bid
Available as 250 mg tablets; 625 mg tablets; FDA-approved 50 mg/g oral powder. Take with increased fat meal |
Diarrhea (treatable with Imodium or pancrealipase); lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation. |
B |
Not teratogenic in rodent studies. No data on carcinogenicity. |
No increase in birth defects noted in Antiretroviral Pregnancy Registry. Minimal transplacental passage. |
The combination of AZT, 3TC, and nelfinavir is widely used and has been well tolerated during pregnancy. |
| Fosamprenavir, fos APV (Lexiva®) (prodrug of amprenavir) |
1400 mg po bid with RTV: 1400 mg Lexiva/200 mg RTV po qd (not recommended for PI-experienced patients) or 700 mg Lexiva/100 mg RTV po bid
Available as 700 mg tablets |
GI intolerance most common (nausea, vomiting, diarrhea); headache; rash (in 19% of patients), usually mild-moderate but Stevens Johnson syndrome reported; lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation. |
C |
Increased abortions in rabbits, reduction in pup survival and body weight in rats. Placental passage unknown |
No data |
Use with caution in patient with sulfa allergy |
| Amprenavir, APV (Agenerase®) |
1400 mg bid (oral solution); <50 kg: APV 20 mg/kg bid (max 2800 mg/day oral solution). APV and RTV oral solutions should not be co-administered due to competition of metabolic pathway of the two vehicles. Available as 15 mg/mL oral solution; also as 50 mg capsules, but capsules and solution NOT interchangeable on mg-per-mg basis. Capsules rarely used because of high pill burden—APV largely replaced by fAPV. |
GI intolerance most common (nausea, vomiting, diarrhea); rash (in 20–27% of patients), Stevens Johnson syndrome (in approximately 1%); paresthesias; headache; lipodystrophy syndrome; hyperlipidemia; transaminase elevation |
C |
Increased incidence benign and malignant liver tumors in male rodents at exposures
2- to 4-fold higher than human dosing. Increased abortions in rabbits and increased incidence of deficient bone ossification in rabbits and rats at exposures lower than recommended human dosing. Reduced body weight in rodent offspring at exposures
2-fold higher than human dosing. |
Placental passage unknown. No data in use of APV in pregnant women |
Use of oral solution contraindicated in pregnant women, patients with renal or hepatic failure, or those treated with disulfiram or metronidazole because of inability to adequately metabolize propylene glycol base. Use with caution in patients with sulfa allergy. |
| Atazanavir, ATV (Reyataz®) |
400 mg qd with food.
With RTV: 300 mg qd/RTV 100 mg qd
Available as 100 mg, 150 mg, 200 mg capsules. |
Common: Reversible benign hyperbilirubinemia (grade 3-4 occurring in 35–47% of patients), jaundice, and scleral icterus.
Occ: nausea, vomiting, abdominal pain, lipodystrophy, rash, headache, and mild transaminase elevation minimal impact on serum lipids. |
B |
No teratogenic effects in rats or rabbits |
No data
Placental passage unknown |
Avoid near term due to the potential exacerbation of physiologic hyperbilirubinemia in the neonate. |
Enfuvirtide (Fuzeon®,
T-20) |
90 mg (1ml) SQ q12h into upper arm, anterior thigh or abdomen with each injection given at a site different from the preceding injection site
Each single-use vial contains 108 mg of enfuvirtide to be reconstituted with 1.1 mL of sterile water for injection with delivery of approx. 90 mg/1mL |
Common ADR: local site reaction (grade 3 or 4) including pain (9%), erythema (32%), pruritus (4%), induration (57%), and nodules or cysts (26%) (with 3% requiring d/c).
Occ: Bacterial pneumonia (reported in 4.68 events vs. 0.61 events per 100 pts-years.
Hypersensitivity reaction (<1%): symptoms may include rash, fever, nausea, vomiting, chills, hypotension, elevated transaminases – may recur on rechallenge. |
B |
Not teratogenic in animal studies |
No data
Placental passage unknown |
A clear advantage of enfuvirtide is the lack of cross-resistance with currently available antiretrovirals, however, as with other antiretrovirals and as seen in clinical trials, salvage therapy with enfuvirtide is only as good as the background regimen with which it is combined. |