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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz

(Last updated:2/12/2014; last reviewed:2/12/2014)

Efavirenz (EFV, Sustiva)
Efavirenz (EFV, Sustiva)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Capsules: 50 mg, 200 mg
Tablets: 600 mg
Combination Tablets:
With Emtricitabine and Tenofovir Disoproxil Fumarate (Tenofovir):
  • Emtricitabine 200 mg + Tenofovir 300 mg + Efavirenz 600 mg (Atripla)
Dosing Recommendations
Neonatal Dose:
  • Efavirenz is not approved for use in neonates.
Pediatric Dose:
Infants and Children Aged 3 Months to <3 Years and Weight ≥3 kg:
  • The Panel recommends that efavirenz generally not be used in children aged 3 months to <3 years. If use of efavirenz is unavoidable due to the clinical situation, the Panel suggests the use of investigational doses of efavirenz in this age group. See text for investigational dosing tables; evaluation of CYP 2B6 genotype is required prior to use. Therapeutic drug monitoring is recommended with an efavirenz concentration measured 2 weeks after initiation and at age 3 years for possible dose adjustment. For dose adjustment based on efavirenz concentrations, consultation with an expert is recommended.
Children Aged ≥3 years and  Weight ≥10 kg:
Weight (kg) Efavirenz dose (mg)a,b
10 kg to <15 kg 200 mg
15 kg to <20 kg 250 mg
20 kg to <25 kg 300 mg
25 kg to <32.5 kg 350 mg
32.5 kg to <40 kg 400 mg
≥40 kg 600 mg
a The dose in mg can be dispensed in any combination of capsule strengths.
Some experts recommend a dose of 367 mg/m2 body surface area (maximum dose 600 mg) because of concern for under-dosing, especially at the upper end of each weight band (see Pediatric Use for details).

Adolescent (Body Weight ≥40 kg)/Adult Dose:
  • 600 mg once daily
Atripla
  • Atripla should not be used in pediatric patients <40 kg where the efavirenz dose would be excessive.
Adult Dose
  • One tablet once daily
Selected Adverse Events
  • Rash
  • 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 
Special Instructions
  • Efavirenz can be swallowed as a whole capsule or tablet or administered by sprinkling the contents of an opened capsule on food as described below.
  • Administer whole capsule or tablet of Atripla on an empty stomach. Avoid administration with a high-fat meal because of potential for increased absorption.
  • Bedtime dosing is recommended, particularly during the first 2 to 4 weeks of therapy, to improve tolerability of CNS side effects.
  • Efavirenz should be used with caution in female adolescents and adults with reproductive potential because of the potential risk of teratogenicity.
Instructions for Use of Capsule as a Sprinkle Preparation with Food or Formula:
  • Hold capsule horizontally over a small container and carefully twist to open to avoid spillage.
  • Gently mix capsule contents with 1–2 teaspoons of an age-appropriate soft food (e.g., applesauce, grape jelly, yogurt), or reconstituted infant formula at room temperature.
  • Administer infant formula mixture using a 10-mL syringe.
  • After administration, an additional 2 teaspoons of food or infant formula must be added to the container, stirred, and dispensed to the patient.
  • Administer within 30 minutes of mixing and do not consume additional food or formula for 2 hours after administration.
Metabolism
  • Cytochrome P450 3A4 (CYP3A4) inducer/inhibitor (more inducer than inhibitor)
  • CYP2B6, CYP3A4, and CYP2A6 substrate
  • Dosing of efavirenz 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 and tenofovir and emtricitabine require dose adjustment based on renal function, Atripla should not be used in patients with creatinine clearance (CrCl) <50 mL/minute or in patients on dialysis.
  • Interpatient variability in efavirenz exposure can be explained in part by polymorphisms in CYP450 with slower metabolizers at higher risk of toxicity (see text for information about therapeutic drug monitoring 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.

Major Toxicities:

  • 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: Potential risk of teratogenicity. 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 (see Pediatric Use section below; see also the Perinatal Guidelines.1

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

Approval
Efavirenz is FDA-approved for use as part of combination antiretroviral therapy in children aged 3 months or older who weigh at least 3.5 kg. 

Pharmacokinetics (PK): Pharmacogenomics
Efavirenz metabolism is controlled by enzymes that are polymorphically expressed and result in large interpatient variability in drug exposure. CYP2B6 is the primary enzyme for efavirenz metabolism, and pediatric patients with the CYP 2B6 516 T/T genotype (which has an allele frequency of 20% in African Americans), have reduced metabolism resulting in higher efavirenz levels compared with those with the G/G or G/T genotype.2-4 IMPAACT P1070 has shown that aggressive dosing with approximately 40 mg/kg using opened capsules resulted in therapeutic efavirenz concentrations in 68% of children aged <3 years with G/G or G/T genotype but excessive exposure in those with T/T genotype.4 Optimal dosing may require pretreatment CYP2B6 genotyping in children aged <3 years.4 Additional variant CYP2B6 alleles and variant CYP2A6 alleles have been found to influence efavirenz concentrations in adults and children.5-8

PK and Dosing: Infants and Children Aged <3 Years
Limited PK data in children aged <3 years or who weigh <13 kg have shown that it is difficult to achieve target trough concentrations in this age group.4,9 Hepatic enzyme activity is known to change with age. CYP 2B6-516-G/G genotype is associated with the greatest expression of hepatic CYP 2B6 when compared with the CYP 2B6-516-G/T or -T/T genotype.2 In children with CYP 2B6-516-G/G genotype, oral clearance rate has been shown to be higher in children younger than aged 5 years than in older children.2 Efficacy data in infants and young children are mostly limited to studies of liquid efavirenz formulations, such as in PACTG 382 and PACTG 1021, and showed poor virologic response due to variable PK properties and tolerability of the liquid formulations in this young age group. Liquid formulations are not approved for use or available in the United States. Efficacy data for opened capsules with contents used as sprinkles suggest better palatability and bioavailability for infants and children aged <3 years. IMPAACT study P1070, an ongoing study of HIV-infected and HIV/tuberculosis-coinfected children aged <3 years, using efavirenz dosed by weight band based on CYP2B6 GG/GT versus TT genotype (see Tables 1a and 1b below), showed HIV RNA <400 copies/mL in 61% by intent to treat analysis at 24 weeks.4 When used without regard to genotype, doses higher than the FDA-recommended ones resulted in therapeutic efavirenz concentrations in an increased proportion of study participants with GG/GT genotypes but excessive exposure in a high proportion of those with TT genotypes.4 Therefore, dosing tables have been modified so that infants and young children with TT genotype will receive a reduced dose. Additional subjects will be studied to confirm that this dose is appropriate for this subset of patients. The modified doses listed in Tables 1a and 1b are under investigation.

Tables 1a and 1b
Investigational Dosing for Children Aged 3 Months to < 3 Years Based on CYP 2B6 Genotype


Table 1a. For Patients with CYP 2B6 516 GG and GT Genotypes (Extensive Metabolizers)*
Weight (kg) Efavirenz Dose (mg)
3 kg–4.99 kg 200 mg
5 kg–6.99 kg 300 mg
7 kg–13.99 kg 400 mg
14 kg–16.99 kg 500 mg
≥17 kg 600 mg

Table 1b. For patients with CYP 2B6 516 TT genotype (slow metabolizers)*
Weight (kg)
Efavirenz Dose (mg)
3 kg–6.99 kg
50 mg
7 kg–13.99 kg
100 mg
14 kg–16.99 kg
150 mg
≥17 kg
150 mg
* Investigational doses are based on IMPAACT study P1070.4 Evaluation of CYP 2B6 genotype is required. Therapeutic drug level monitoring is recommended with a trough measured 2 weeks after initiation and at age 3 years for possible dose adjustment. 

The FDA has approved efavirenz for use in infants and children aged 3 months to <3 years at doses derived from a population PK model based on data from adult subjects in PACTG 1021 and PACTG 382, and AI266-922, which is an ongoing study assessing the PK, safety, and efficacy of capsule sprinkles in children aged 3 months to 6 years (see Table 2). 

Table 2. FDA-approved Dosing for Children Aged 3 Months to <3 years (Without Regard to CYP 2B6 Genotype)

 

 

 

Weight (kg)
Efavirenz Dose (mg)
3.5 kg to <5 kg
100 mg
5 kg to <7.5 kg
150 mg
7.5 kg to <15 kg
200 mg
15 kg to <20 kg
250 mg

The FDA-approved doses are lower than the CYP 2B6 extensive metabolizer doses and higher than the CYP 2B6 slow metabolizer doses currently under study in P1070. Further studies are needed to determine if the FDA dosing can achieve therapeutic levels for the group aged 3 months to 3 years. There is concern that FDA-approved doses may result in frequent under-dosing in CYP 2B6 extensive metabolizers. The Panel recommends that efavirenz generally not be used in children aged 3 months to <3 years. If the clinical situation demands use of efavirenz, Panel members recommend determining CYP2B6 genotype (search for laboratory performing this testing at http://www.ncbi.nlm.nih.gov/gtr/labs). Patients should be classified as extensive CYP 2B6 516 GG and GT genotypes versus slow CYP 2B6 516 TT genotype metabolizers to guide dosing as indicated by the investigational doses from IMPAACT study P1070 (see Tables 1a and 1b). Whether the doses used are investigational or FDA-approved, efavirenz plasma concentrations should be measured 2 weeks post-initiation (see Role of Therapeutic Drug Monitoring). For dose adjustment, consultation with an expert is recommended. In addition, when dosing following the P1070 investigational dose recommendations, efavirenz concentrations should be measured at age 3 years to guide potential dose adjustments.

PK: Children Aged ≥3 Years and Adolescents
Long-term HIV RNA suppression has been associated with maintenance of trough efavirenz concentrations >1 mcg/mL in adults.10 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 ≤400 copies/mL versus efavirenz troughs of 1.3 mcg/mL in subjects with detectible virus (>400 copies/mL).11 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 >1.1 mcg/mL or area under the curve (AUC) >51 mcg h/mL.12 

Even with the use of FDA-approved pediatric dosing in children aged ≥3 years, efavirenz concentrations can be suboptimal.2,12-16 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).11 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.17 Therapeutic drug monitoring can be considered when using efavirenz in combinations with potentially complex drug interactions.

Dosing: Special Considerations
For patients at least 3 months old who cannot swallow capsules or tablets, the efavirenz capsule contents can be administered with a small amount (1 to 2 teaspoons) of food. Use of 2 teaspoons of infant formula can be considered for infants who cannot reliably consume solid foods. The capsule should be held horizontally over a small container and carefully twisted open to avoid spillage and dispersion of capsule contents into the air. The capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, or reconstituted infant formula at room temperature, in a small container. The infant formula mixture should be administered using a 10-mL syringe. After administration, an additional 2 teaspoons of food or infant formula must be added to the container, stirred and dispensed to the patient. The efavirenz mixture should be administered within 30 minutes of mixing and no additional food or formula should be consumed for 2 hours after administration.

Toxicity: Children versus Adults
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.18 Although severe rash and Stevens-Johnson syndrome have been reported, they are rare. In adults, CNS symptoms have been reported in more than 50% of patients.19 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. For patients who can swallow capsules or tablets, 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.10,20-23 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 studies18 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.

Toxicity: Potential Risk of Teratogenicity
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 reports of meningomyeloceles and two of Dandy-Walker malformations), efavirenz has been classified as 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.24 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 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 a woman’s health). See the Perinatal Guidelines.1 

Therapeutic Drug Monitoring
Note: See Role of Therapeutic Drug Monitoring

In the setting of potential toxicity, it is reasonable for a clinician to use therapeutic drug monitoring (TDM) to determine whether the toxicity is due to an efavirenz concentration in excess of the normal therapeutic range.25,26 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. Also, the Panel recommends TDM when dosing efavirenz in children aged 3 months to <3 years due to variable PK properties in this young age group. An efavirenz concentration, preferably a trough, measured 2 weeks after initiation, and consultation with an expert, is recommended for dose adjustment. Long-term HIV RNA suppression has been associated with maintenance of trough efavirenz concentrations greater than 1000 ng/mL in adults.10 In addition, efavirenz concentrations should be measured at age 3 years for potential dose adjustment if dosing was initiated at age <3 years using investigational dose recommendations.

References

  1. 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 http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed on August 17, 2012.
  2. 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.
  3. 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.
  4. Bolton C, Samson P, Capparelli E, al. e. Strong influence of CYP2B6 genotypic polymorphisms on EFV pharmacokinetics in HIV+ children <3 years of age and implications for dosing. CROI Paper #981. Conference on Retrovirueses and Opportunistic Infections; 2012; Seattle, Washington.
  5. 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.
  6. 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.
  7. Mutwa PR, Fillekes Q, Malgaz M, et al. Mid-dosing interval efavirenz plasma concentrations in HIV-1-infected children in Rwanda: treatment efficacy, tolerability, adherence, and the influence of CYP2B6 polymorphisms. J Acquir Immune Defic Syndr. Aug 1 2012;60(4):400-404. Available at http://www.ncbi.nlm.nih.gov/pubmed/22481606.
  8. Gandhi M, Greenblatt RM, Bacchetti P, et al. A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. J Infect Dis. Nov 2012;206(9):1453-1461. Available at http://www.ncbi.nlm.nih.gov/pubmed/22927450.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Cressey TR, Aurpibul L, Narkbunnam T, et al. Pharmacological assessment of efavirenz weight-band dosing recommendations in HIV-infected Thai children. J Acquir Immune Defic Syndr. Jan 1 2013;62(1):e27-29. Available at http://www.ncbi.nlm.nih.gov/pubmed/23262981.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. Zugar A. Studies disagree on frequency of late cns side effects from efavirenz. AIDS Clin Care. 2006;4(1). Available at 
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.