Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)
(Last updated:11/1/2012; last reviewed:11/1/2012)
Efavirenz (EFV, Sustiva)
|Efavirenz (EFV, Sustiva)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Capsules: 50 mg, 200 mg
Tablets: 600 mg
- With emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF):
FTC 200 mg + TDF 300 mg + EFV 600 mg (Atripla)
- EFV is not approved for use in neonates/infants.
- Children aged <3 years:
No data are currently available on the appropriate EFV dosage for children aged <3 years.
- Children aged ≥3 years and body weight ≥10 kg:
Administer EFV once daily:
* The dose in mg can be dispensed in any combination of capsule strengths.
||EFV dose (mg)*†
10 to <15
15 to <20
20 to <25
25 to <32.5
32.5 to <40
† Some experts recommend a dose of 367 mg/m2 of body surface area (maximum dose 600 mg) because of concern for underdosing, especially at the upper end of each weight band (see Pediatric Use for details).
Adolescent (body weight ≥40 kg)/adult dose:
Selected Adverse Events
- Atripla should not be used in pediatric patients <40 kg where the EFV dose would be excessive.
- Adult dose: One tablet once daily.
- Central nervous system (CNS) symptoms such as dizziness, somnolence, insomnia, abnormal dreams, impaired concentration, psychosis, seizures
- Increased transaminases
- False-positive with some cannabinoid and benzodiazepine tests
- Potentially teratogenic
- Lipohypertrophy, although a causal relationship has not been established and this adverse event may be less likely than with the boosted protease inhibitors.
- Administer EFV on an empty stomach, preferably at bedtime. Avoid administration with a high-fat meal because of potential for increased absorption.
- Administer Atripla on an empty stomach.
- Bedtime dosing is recommended, particularly during the first 2 to 4 weeks of therapy, to improve tolerability of CNS side effects.
- EFV should be used with caution in female adolescents and adults with reproductive potential because of the potential risk of teratogenicity.
- Cytochrome P450 3A4 (CYP3A4) inducer/inhibitor (more inducer than inhibitor).
- CYP3A4 and CYP2B6 substrate.
- Dosing of EFV in patients with hepatic impairment: No recommendation is currently available; use with caution in patients with hepatic impairment.
- Adult dose of Atripla in patients with renal impairment: Because Atripla is a fixed-dose combination product, it should not be used in patients with creatinine clearance (CrCl) of <50 mL/minute or in patients on dialysis.
- Interpatient variability in EFV exposure can be explained in part by polymorphisms in CYP450 with slower metabolizers having higher risk of toxicity. (See text for information about therapeutic drug monitoring [TDM] for management of mild or moderate toxicity.)
Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents):
- Metabolism: Mixed inducer/inhibitor of CYP3A4 enzymes; concentrations of concomitant drugs can be increased or decreased depending on the specific enzyme pathway involved. There are multiple drug interactions. Importantly, dosage adjustment or the addition of ritonavir may be necessary when efavirenz is used in combination with atazanavir, fosamprenavir, indinavir, lopinavir/ritonavir, or maraviroc.
- Before efavirenz is administered, a patient’s medication profile should be carefully reviewed for potential drug interactions with efavirenz.
- More common: Skin rash, increased transaminase levels. Central nervous system (CNS) abnormalities, such as dizziness, somnolence, insomnia, abnormal dreams, confusion, abnormal thinking, impaired concentration, amnesia, agitation, depersonalization, hallucinations, euphoria, seizures, primarily reported in adults.
- Rare: Prenatal efavirenz exposure has been associated with CNS congenital abnormalities in the offspring of cynomolgus monkeys. Based on these data and retrospective reports in humans of an unusual pattern of severe CNS defects in five infants after first-trimester exposure to efavirenz-containing regimens (three meningomyelocoeles and two Dandy-Walker malformations), efavirenz has been classified as Food and Drug Administration (FDA) Pregnancy Class D, which means that there is positive evidence of human fetal risk based on studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Because of the potential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester (the primary period of fetal organogenesis) whenever possible. Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz and should be counseled about the potential risk to the fetus and desirability of avoiding pregnancy. Alternate antiretroviral (ARV) regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception (if such alternative regimens are acceptable to provider and patient and will not compromise the woman’s health).
Resistance: The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/EFV.html).
Pediatric Use: Efavirenz is FDA-approved for use as part of antiretroviral therapy in children aged 3 years or older who weigh at least 10 kg. Limited pharmacokinetic (PK) data in children younger than age 3 or who weigh less than 13 kg have shown that it is difficult to achieve target trough concentrations in this age group, even with very high (>30 mg/kg) doses of an investigational liquid formulation.1 Thus, efavirenz is not recommended for use in children younger than age 3 years at this time, and no liquid formulation is commercially available. Additional studies are required to determine the appropriate dose of efavirenz in infants and young children. P1070 is an ongoing study collecting data on efavirenz dosing in HIV-infected and HIV/tuberculosis-co-infected children younger than age 3 years. In addition, efavirenz should be used with caution in adolescent women of childbearing age because of the potential risk of teratogenicity.
Efavirenz metabolism is controlled by enzymes that are polymorphically expressed and result in large interpatient variability in drug exposure. CYP2B6 is the primary enyzme for efavirenz metabolism, and pediatric patients with the 516 T/T or G/T genotype have reduced metabolism and higher efavirenz levels compared with those with the G/G genotype.2,3 Additional variant CYP2B6 alleles and variant CYP2A6 alleles have been found to influence efavirenz concentrations in adults.4,5
Long-term HIV RNA suppression has been associated with maintenance of trough efavirenz concentrations greater than 1 mcg/mL in adults.6 Early HIV RNA suppression in children has also been seen with higher drug concentrations. Higher efavirenz troughs of 1.9 mcg/mL were seen in subjects with HIV RNA levels less than or equal to 400 copies/mL versus efavirenz troughs of 1.3 mcg/mL in subjects with detectible virus (>400 copies/mL).7 In a West African pediatric study, ANRS 12103, early reduction in viral load (by 12 weeks) was greater in children with efavirenz minimum plasma concentration (Cmin) levels greater than 1.1 mcg/mL or area under the curve (AUC) greater than 51 mcg*h/mL.8 Even with the use of FDA-approved pediatric dosing, efavirenz concentrations can be suboptimal.2,8-11 Therefore, some experts recommend therapeutic drug monitoring with efavirenz and possibly use of higher doses in young children, especially in select clinical situations such as virologic rebound or lack of response in an adherent patient. In one study in which the efavirenz dose was adjusted in response to measurement of the AUC, the median administered efavirenz dose was 13 mg/kg (367 mg/m2) and the range was from 3 to 23 mg/kg (69–559 mg/m2).7 A PK study in 20 children aged 10 to 16 years treated with the combination of lopinavir/ritonavir 300 mg/m2 twice daily plus efavirenz 350 mg/m2 once daily showed adequacy of the lopinavir trough values but suggested that the efavirenz trough was lower than PK targets. The authors therefore recommended that higher doses of efavirenz might be needed when these drugs are used together.12 Therapeutic drug monitoring can be considered when using efavirenz in combinations with potentially complex drug interactions.
The toxicity profile for efavirenz differs for adults and children. A side effect commonly seen in children is rash, which was reported in up to 40% of children compared with 27% of adults. The rash is usually maculopapular, pruritic, and mild to moderate in severity and rarely requires drug discontinuation. Onset is typically during the first 2 weeks of treatment.13 Although severe rash and Stevens-Johnson syndrome (SJS) have been reported, they are rare. In adults, CNS symptoms have been reported in more than 50% of patients.14 These symptoms usually occur early in treatment and rarely require drug discontinuation, but they can sometimes occur or persist for months. Bedtime efavirenz dosing appears to decrease the occurrence and severity of these neuropsychiatric side effects. Ensuring that efavirenz is taken on an empty stomach also reduces the occurrence of neuropsychiatric adverse effects. In several studies, the incidence of such adverse effects was correlated with efavirenz plasma concentrations and the symptoms occurred more frequently in patients receiving higher concentrations.6,15-18 In patients with pre-existing psychiatric conditions, efavirenz should be used cautiously for initial therapy. Adverse CNS effects occurred in 14% of children receiving efavirenz in clinical studies13 and in 30% of children with efavirenz concentrations greater than 4 mcg/mL.3 CNS adverse effects may be harder to detect in children because of the difficulty in assessing neurologic symptoms such as impaired concentration, sleep disturbances, or behavior disorders in these patients.
Therapeutic drug monitoring (TDM) can be considered for children with mild or moderate toxicity possibly attributable to a particular ARV agent (see Role of Therapeutic Drug Monitoring in Management of Treatment Failure). In that situation, it is reasonable for a clinician to use therapeutic drug monitoring to determine whether the toxicity is due to an efavirenz concentration in excess of the normal therapeutic range.19,20 This is the only setting in which dose reduction would be considered appropriate management of drug toxicity and, even then, it should be used with caution.
Efavirenz should not be used by women who desire to become pregnant or who do not use effective, consistent contraception. Efavirenz should not be used throughout the first trimester of pregnancy because of the potential risk of teratogenicity21 (see 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 22). Alternative ARV regimens that do not include efavirenz should be strongly considered for use in sexually active adolescent females because of the potential for inconsistent use of contraception and the high risk of unintended pregnancy.
- Capparelli E, Rochon-Duck M, Robbins B, et al. Age-related pharmacokinetics of efavirenz solution. 16th Conference on Retroviruses and Opportunistic Infections (CROI); February 8-11, 2009; Montréal, Canada.
- Saitoh A, Fletcher CV, Brundage R, et al. Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. J Acquir Immune Defic Syndr. Jul 1 2007;45(3):280-285. Available at http://www.ncbi.nlm.nih.gov/pubmed/17356468.
- Puthanakit T, Tanpaiboon P, Aurpibul L, Cressey TR, Sirisanthana V. Plasma efavirenz concentrations and the association with CYP2B6-516G >T polymorphism in HIV-infected Thai children. Antivir Ther. 2009;14(3):315-320. Available at http://www.ncbi.nlm.nih.gov/pubmed/19474465.
- di Iulio J, Fayet A, Arab-Alameddine M, et al. In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenet Genomics. Apr 2009;19(4):300-309. Available at http://www.ncbi.nlm.nih.gov/pubmed/19238117.
- Arab-Alameddine M, Di Iulio J, Buclin T, et al. Pharmacogenetics-based population pharmacokinetic analysis of efavirenz in HIV-1-infected individuals. Clin Pharmacol Ther. May 2009;85(5):485-494. Available at http://www.ncbi.nlm.nih.gov/pubmed/19225447.
- Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. Jan 5 2001;15(1):71-75. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11192870.
- Fletcher CV, Brundage RC, Fenton T, et al. Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial. Clin Pharmacol Ther. Feb 2008;83(2):300-306. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17609682.
- Hirt D, Urien S, Olivier M, et al. Is the recommended dose of efavirenz optimal in young West African human immunodeficiency virus-infected children? Antimicrob Agents Chemother. Oct 2009;53(10):4407-4413. Available at http://www.ncbi.nlm.nih.gov/pubmed/19635964.
- Ren Y, Nuttall JJ, Egbers C, et al. High prevalence of subtherapeutic plasma concentrations of efavirenz in children. J Acquir Immune Defic Syndr. Jun 1 2007;45(2):133-136. Available at http://www.ncbi.nlm.nih.gov/pubmed/17417100.
- Viljoen M, Gous H, Kruger HS, Riddick A, Meyers TM, Rheeders M. Efavirenz plasma concentrations at 1, 3, and 6 months post-antiretroviral therapy initiation in HIV type 1-infected South African children. AIDS Res Hum Retroviruses. Jun 2010;26(6):613-619. Available at http://www.ncbi.nlm.nih.gov/pubmed/20507205.
- Fillekes Q, Natukunda E, Balungi J, et al. Pediatric underdosing of efavirenz: A pharmacokinetic study in Uganda. J Acquir Immune Defic Syndr. Dec 1 2011;58(4):392-398. Available at http://www.ncbi.nlm.nih.gov/pubmed/21926634.
- King JR, Acosta EP, Yogev R, et al. Steady-state pharmacokinetics of lopinavir/ritonavir in combination with efavirenz in human immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J. Feb 2009;28(2):159-161. Available at http://www.ncbi.nlm.nih.gov/pubmed/19106779.
- Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team. N Engl J Med. Dec 16 1999;341(25):1874-1881. Available at http://www.ncbi.nlm.nih.gov/pubmed/10601506.
- Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med. Dec 16 1999;341(25):1865-1873. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10601505.
- Gutierrez F, Navarro A, Padilla S, et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis. Dec 1 2005;41(11):1648-1653. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16267739.
- Zugar A. Studies disagree on frequency of late cns side effects from efavirenz. AIDS Clin Care. 2006;4(1). Available at
- Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral agents. AIDS. Jun 14 2002;16(9):1201-1215. Available at http://www.ncbi.nlm.nih.gov/pubmed/12045485.
- Wintergerst U, Hoffmann F, Jansson A, et al. Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children. J Antimicrob Chemother. Jun 2008;61(6):1336-1339. Available at http://www.ncbi.nlm.nih.gov/pubmed/18343800.
- van Luin M, Gras L, Richter C, et al. Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations. J Acquir Immune Defic Syndr. Oct 1 2009;52(2):240-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/19593159.
- Acosta EP, Gerber JG, Adult Pharmacology Committee of the ACTG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses. Aug 10 2002;18(12):825-834. Available at http://www.ncbi.nlm.nih.gov/pubmed/12201904.
- Saitoh A, Hull AD, Franklin P, Spector SA. Myelomeningocele in an infant with intrauterine exposure to efavirenz. J Perinatol. Aug 2005;25(8):555-556. Available at http://www.ncbi.nlm.nih.gov/pubmed/16047034.
- 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. Available at /contentfiles/lvguidelines/PerinatalGL.pdf. Accessed on August 17, 2012.