Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)
Last Updated: April 16, 2019; Last Reviewed: April 16, 2019
|Efavirenz (EFV, Sustiva)
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
|Capsules: 50 mg, 200 mg
Tablet: 600 mg
|Dosing Recommendations||Selected Adverse Events|
Once-Daily Doses of Efavirenz by Weight
Child and Adolescent (Weighing ≥40 kg) and Adult Dose:
Child and Adolescent (Weighing ≥40 kg) and Adult Dose:
Child and Adolescent (Weighing ≥40 kg) and Adult Dose:
Child and Adolescent (Weighing ≥35 kg) and Adult Dose:
- Metabolism: Coadministration of efavirenz with drugs primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, CYP2B6, or CYP3A isozymes may result in altered plasma concentrations of the coadministered drugs. Drugs that induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz, resulting in lower plasma concentrations. There is potential for multiple drug interactions with efavirenz. Importantly, dose adjustment or the addition of ritonavir may be necessary when efavirenz is used in combination with atazanavir, fosamprenavir, lopinavir/ritonavir (LPV/r), or maraviroc.
- Before efavirenz is administered, a patient’s medication profile should be carefully reviewed for potential drug interactions with efavirenz.
- Corrected QT (QTc) prolongation has been observed with the use of efavirenz.1,2 Consider using an alternative to efavirenz in patients who are receiving a drug that has a known risk of Torsades de Pointes or in patients who are at higher risk of Torsades de Pointes.
- 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, and seizures have been reported, primarily in adults.
- Rare: QTc prolongation has been observed with the use of efavirenz.1,2 A case report associated efavirenz use with marked QT prolongation and Torsades de Pointes.3 An association between efavirenz and suicidal ideation, suicide, and attempted suicide (especially among those with a history of mental illness or substance abuse) was found in one retrospective analysis of four comparative trials in adults. This association, however, was not found in analyses of two large observational cohorts.
- Potential risk of teratogenicity: See Efavirenz in the Perinatal Guidelines.
Efavirenz has been approved by the Food and Drug Administration (FDA) for use as part of antiretroviral (ARV) therapy in children aged ≥3 months and weighing ≥3.5 kg. The FDA has also approved the use of Symfi Lo, the fixed-dose combination of efavirenz 400 mg/lamivudine 300 mg/tenofovir disoproxil fumarate (TDF) 300 mg, in children weighing ≥35 kg.
Efficacy in Clinical Trials
Efavirenz-based regimens have proven virologically superior or noninferior to a variety of regimens in adults, including those containing LPV/r, nevirapine, rilpivirine, atazanavir, elvitegravir, raltegravir, and maraviroc.4-10 Efavirenz proved inferior to dolutegravir in the SINGLE trial in adults, which compared the virologic response of dolutegravir plus abacavir/lamivudine to the virologic response of efavirenz/TDF/emtricitabine at Weeks 48 and 144. The differences were most likely due to more drug discontinuations in the efavirenz group.11
In clinical trials in adults and children with HIV, efavirenz used in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) has been associated with excellent virologic response. FDA approval of Symfi (efavirenz 600 mg/lamivudine/TDF) was based on the results from a clinical trial that compared the use of TDF to the use of stavudine when each drug was administered with lamivudine and efavirenz.12 This trial showed that these regimens were similarly effective. The 96-week results of the Encore1 trial, a randomized trial in adults, showed that efavirenz 400 mg used in combination with TDF and emtricitabine was noninferior to efavirenz 600 mg used in combination with TDF and emtricitabine.13 Efavirenz used in combination with two NRTIs or with an NRTI and a protease inhibitor has been studied in children and has shown virologic potency and safety that is comparable to what has been seen in adults.14-20
FDA approval of Symfi Lo (efavirenz 400 mg/lamivudine 300 mg/TDF 300 mg) was based on a comparison between efavirenz 400 mg and efavirenz 600 mg, both taken with emtricitabine 200 mg plus TDF 300 mg in 630 ARV-naive adult participants with a mean age of 36 years (range 18–69 years). Sixty-eight percent of participants were male, 37% were of African heritage, 33% were of Asian ethnicity, 17% were Hispanic, and 13% were Caucasian. This study showed similar rates of viral load suppression and toxicities among participants in each group.13 Since efavirenz clearance is related to age and to CYP2B6 polymorphisms, and since allele frequency varies by ethnicity, some members of the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) recommend caution when using the lower-dose efavirenz formulation in pediatric patients weighing ≥40 kg and suggest the use of therapeutic drug monitoring (TDM) in these patients.
Genetic polymorphisms in the genes that code for enzymes involved in the metabolism of efavirenz may alter enzyme activity, which causes a high degree of interpatient variability in drug exposure. CYP2B6 is the primary enzyme for efavirenz metabolism, and pediatric patients with the CYP2B6-516-T/T genotype have reduced metabolism, resulting in higher efavirenz levels in these patients than in those with the G/G or G/T genotypes.21-25 The CYP2B6-516-T/T allele frequency varies by ethnicity. In a study of adults from the United States and Italy, this allele had a frequency of 24.4% among white study participants, a frequency of 31.3% among black study participants, and a frequency of 34.9% among Hispanic study participants.26 A retrospective study confirmed the inter-individual variability of efavirenz plasma concentration among pediatric patients in a multi-ethnic, high-income setting, and the differences could be explained in large part by polymorphisms in drug metabolizing genes as well as by age at treatment initiation and time from treatment initiation.27 IMPAACT P1070 has shown that aggressive dosing with approximately 40 mg/kg of efavirenz using opened capsules resulted in therapeutic efavirenz concentrations in 58% of children aged <3 years with the G/G or G/T genotypes, but excessive exposure occurred in those with the T/T genotype.28 Optimal dosing may require pretreatment CYP2B6 genotyping in children aged <3 years (see discussion below).25,28 Additional variant CYP2B6 alleles and variant CYP2A6 alleles have been found to influence efavirenz concentrations in adults and children.25,29-33 The CYP2B6 T983C mutation has also been associated with reduced efavirenz clearance in African children.25
Pharmacokinetics and Dosing: Infants and Children Aged <3 Years
The Panel does not recommend the use of efavirenz in children aged 3 months to <3 years. Limited pharmacokinetic (PK) data in children aged <3 years or weighing <13 kg have shown that it is difficult to achieve target trough concentrations in this age group.23,34 These data show age-related differences in absorption and impact of formulation on efavirenz PKs.24 Also, hepatic enzyme activity is known to change with age. Using a pharmacometric model, the increase in oral clearance of efavirenz as a function of age is predicted to reach 90% of mature value by age 9 months.24 This maturation of oral clearance is postulated to result from an increase in the expression of CYP2B6 with age.24 The CYP2B6-516-G/G genotype is associated with the greatest expression of hepatic CYP2B6 when compared with the CYP2B6-516-G/T or -T/T genotypes.21 In children with the CYP2B6-516-G/G genotype, the oral clearance rate of efavirenz has been shown to be higher in children aged <5 years than in older children.21 Efficacy data for opened capsules with contents used as a sprinkle preparation suggest acceptable palatability and bioavailability for infants and children aged <3 years; however, the difficulty associated with sprinkling the contents of opened capsules contributes to the variability of PK measures in this age group.
IMPAACT P1070 studied children aged <3 years with HIV and HIV/tuberculosis coinfection, using doses of efavirenz that were determined by weight band based on CYP2B6-516-G/G and -G/T genotypes (children with G/G and G/T genotypes were considered extensive metabolizers [EMs]; children with T/T genotypes were considered slow metabolizers [SMs]. See Table A below). When doses were used without regard to genotype, a dose of approximately 40 mg/kg per day resulted in therapeutic efavirenz concentrations in an increased proportion of study participants with G/G or G/T genotypes but excessive exposure in a high proportion of participants with T/T genotypes. This dose is higher than the FDA-approved dose of efavirenz.28 Therefore, doses were modified so that infants and young children with the T/T genotype received a reduced dose. The doses listed for P1070 in Table A are investigational.
Investigational Dosing for Children Aged 3 Months to <3 Years By CYP2B6 Genotype
|Weight||Protocol P1070 Dosing for Patients with CYP2B6-516-G/G and -G/T Genotypes (Extensive Metabolizers)a||Protocol P1070 Dosing for Patients with CYP2B6-516-T/T Genotype (Slow Metabolizers)a||FDA-Approved Dosing for Children Aged 3 Months to <3 Years (Without Regard to CYP2B6 Genotype)|
|5 kg to <7 kg||300 mg||50 mg||150 mg|
|7 kg to 7.5 kg||400 mg||100 mg||150 mg|
|7.5 kg to <10 kg||400 mg||100 mg||200 mg|
|10 kg to <14 kg||400 mg||100 mg||200 mg|
|14 kg to <15 kg||500 mg||150 mg||200 mg|
|15 kg to ≤17 kg||500 mg||150 mg||250 mg|
a Investigational doses are based on IMPAACT study P1070.28 Evaluation of CYP2B6 genotype is required. Therapeutic drug level monitoring is recommended, with a trough measured 2 weeks after initiation of efavirenz and again at age 3 years for a possible dose adjustment.
The FDA-approved doses of efavirenz for use in infants and children aged 3 months to <3 years were derived from a population PK model that was based on data from older subjects in PACTG 1021 and PACTG 382, and also from data collected during AI266-922, a study that assessed the PKs, safety, and efficacy of capsule sprinkles in children aged 3 months to 6 years (see Table A).
The FDA-approved doses are lower than the CYP2B6 EM doses and higher than the CYP2B6 SM doses from the P1070 study. There is concern that FDA-approved doses may result in frequent underdosing in CYP2B6 EMs. PK modeling, based on P1070 PK data, was used to generate estimates of the percentage of participants who were likely to reach therapeutic efavirenz target concentrations on FDA-indicated dosages, according to the participants’ genotypes.28 The frequency of area under the curve (AUC) in the target range of 35 to 180 mcg*h/mL and C24h in the target range of 1 mg/L to 4 mg/L, a systemic exposure similar to that shown to be safe and effective in older children and adults, was calculated.28 The P1070 genotype-based dosing resulted in approximately 80% of EM participants and 90% of SM participants achieving the targeted AUC, whereas the FDA-approved dosing would result in an estimated 63% of EM participants and 44% of SM participants achieving the target AUC. In addition, using FDA-approved dosing would result in an estimated one-third of EM children with subtherapeutic efavirenz exposures and more than half of SM children with AUCs above the target range.
The Panel does not recommend use of efavirenz in children aged 3 months to <3 years. If the clinical situation demands the use of efavirenz, the Panel recommends determining CYP2B6 genotype prior to use (see a list of laboratories that perform this test). Patients should be classified as extensive CYP2B6-516-G/G and -G/T genotype metabolizers or slow CYP2B6-516-T/T genotype metabolizers to guide dosing as indicated by the investigational doses from IMPAACT study P1070 (see Table A). Whether the doses used are investigational or approved by the FDA, measuring efavirenz plasma concentrations should be considered 2 weeks after initiation (see the Therapeutic Drug Monitoring section below). The mid-dose efavirenz plasma concentration target of 1.0 to 4.0 mg/L derived from adult clinical monitoring data is typically also applied to trough concentrations. A study of 128 African children (aged 1.7–13.5 years) suggests that the C24h threshold for increased risk of unsuppressed viral load is C24h 0.65 mg/L.35 Consultation with an expert in pediatric HIV infection is recommended before adjusting dose. In addition, when following the P1070 investigational dose recommendations, some experts would measure efavirenz concentrations at age 3 years before transitioning the child to the recommended dose for children aged ≥3 years.
Pharmacokinetics: Children Aged ≥3 Years and Adolescents
Even with the use of FDA-approved pediatric dosing in children aged ≥3 years, efavirenz concentrations can be suboptimal.21,36-40 Therefore, some experts recommend TDM with efavirenz and possible 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 dose was efavirenz 13 mg/kg (367 mg/m2) and the range was from 3 mg/kg to 23 mg/kg (69 mg/m2–559 mg/m2).41 A PK study in 20 children aged 10 to 16 years who were treated with LPV/r 300 mg/m2 and 75 mg/m2 twice daily plus efavirenz 350 mg/m2 once daily showed that lopinavir trough values were adequate but suggested that the efavirenz trough values were lower than PK targets. The authors therefore concluded that higher doses of efavirenz might be needed when these drugs are used together.42
Toxicity: Children versus Adults
The toxicity profile for efavirenz differs for adults and children. One adverse effect (AE) commonly seen in children is rash, which was reported in up to 40% of children and 27% of adults.43 The rash is usually maculopapular, pruritic, mild to moderate in severity, and rarely requires drug discontinuation. Onset is typically during the first 2 weeks of treatment. Although severe rash and Stevens-Johnson syndrome have been reported, they are rare. In adults, CNS symptoms are commonly reported, affecting 29.6% of patients in one meta-analysis of randomized trials.44 These symptoms usually occur early in treatment and rarely require drug discontinuation, but they can sometimes 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 AEs. The ENCORE1 study in adults demonstrated that a dose of efavirenz 400 mg is associated with fewer AEs and a noninferior virologic response when compared with the recommended 600-mg dose of efavirenz in adults.13,45
An association between efavirenz and suicidal ideation, suicide, and attempted suicide (especially among those with a history of mental illness or substance abuse) was found in a retrospective analysis of four comparative trials in adults and in the START Trial, a prospective analysis of adults.46,47 This association, however, was not found in analyses of two large observational cohorts,48,49 and no cases of suicide were reported in a systematic review of randomized trials.44 In several studies, the incidence of neuropsychiatric AEs was correlated with efavirenz plasma concentrations, and the symptoms occurred more frequently in patients with higher concentrations.50-54 In patients with pre-existing psychiatric conditions, efavirenz should be used cautiously. Adverse CNS events occurred in 14% of children who received efavirenz in clinical studies55 and in 30% of children with efavirenz concentrations >4 mg/L.22 CNS AEs may be harder to detect in children because it is difficult to assess neurologic symptoms such as impaired concentration, sleep disturbances, or behavior disorders in these patients.
Toxicity: QTc Prolongation
CYP2B6 genetic variants are known to slow efavirenz clearance. The CYP2B6*6 allele is associated with reduced clearance and increased efavirenz-induced CNS toxicity, hepatic injury, and treatment discontinuation.50,51 Homozygous carriers of the CYP2B6*6 allele (CYP2B6*6/*6) may be at increased risk for efavirenz-induced QTc prolongation. The CYP2B6*6 allele codes for the CYP2B6-516-G>T complementary DNA nucleotide change;56 therefore, CYP2B6*6/*6 carriers can be categorized as SMs. The effect of efavirenz on the QTc interval was evaluated in a study of 58 healthy adult subjects that collectively represented a variety of 58 healthy adult subjects, with a mix of CYP2B6 polymorphisms represented within the group. A positive relationship between efavirenz concentration and QTc prolongation was observed. The mean QTc prolongation and its upper-bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of efavirenz 600 mg daily for 14 days.1 Drugs that prolong the mean QTc interval by more than 20 ms have a substantially increased likelihood of being pro-arrhythmic. While the data on drugs that prolong the mean QTc interval by more than 5 ms but less than 20 ms are inconclusive, some of these drugs have been associated with pro-arrhythmic risk.57 Consider using an alternative to efavirenz in patients who are receiving a drug that has a known risk of Torsades de Pointes (e.g., quinidine, clarithromycin) or in patients who are at higher risk of Torsades de Pointes.2
Therapeutic Drug Monitoring
In the setting of potential toxicity, it is reasonable for a clinician to use TDM to determine whether the toxicity is due to an efavirenz concentration in excess of the normal therapeutic range.58,59 Dose reduction would be considered appropriate management of drug toxicity; however, dose reduction should be used with caution. Also, TDM should be considered when dosing efavirenz in children aged 3 months to <3 years due to increased oral clearance and variable PK properties in this young age group. TDM should also be considered when using a lower dose of efavirenz, such as the dose found in Symfi Lo, in children weighing ≥40 kg. Two weeks after the initiation of efavirenz in patients aged <3 years, clinicians should measure the plasma concentration of efavirenz. In cases where a dose adjustment may be necessary, clinicians should consult an expert in pediatric HIV infection prior to adjusting dosage. If a child initiated efavirenz at an investigational dose while <3 years of age, some experts would also measure plasma concentration at age 3 years after the child transitions to the recommended dose for children aged ≥3 years.
The currently accepted minimum effective concentration of efavirenz is a mid-dose concentration (C12h) >1 mg/L in adults, and concentrations of >4.0 mg/L are associated with CNS side effects.51 A recent study in children showed that a higher proportion of children with a C12h <1 mg/L showed evidence of viral replication than those with a C12h >1 mg/L.60 However, the validity using a single target has been called into question.61 In addition, a lower limit of C12h > 0.7mg/L was most predictive of virologic outcome in a study of 180 adults.62 Findings from a study of 128 African children (aged 1.7–13.5 years) suggest that the C24h threshold for increased risk of unsuppressed viral load is C24h 0.65 mg/L.35
- Abdelhady AM, Shugg T, Thong N, et al. Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers. J Cardiovasc Electrophysiol. 2016;27(10):1206-1213. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27333947.
- Efavirenz [package insert]. Food and Drug Administration. 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020972s053,021360s041lbl.pdf.
- Castillo R, Pedalino RP, El-Sherif N, Turitto G. Efavirenz-associated QT prolongation and torsade de pointes arrhythmia. Ann Pharmacother. 2002;36(6):1006-1008. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12022902.
- Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr. 2004;36(5):1011-1019. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15247553.
- Torti C, Maggiolo F, Patroni A, et al. Exploratory analysis for the evaluation of lopinavir/ritonavir-versus efavirenz-based HAART regimens in antiretroviral-naive HIV-positive patients: results from the Italian MASTER cohort. J Antimicrob Chemother. 2005;56(1):190-195. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15917286.
- Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358(20):2095-2106. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18480202.
- Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19647866.
- Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010;201(6):803-813. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20151839.
- Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr. 2012;60(1):33-42. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22343174.
- Nunez M, Soriano V, Martin-Carbonero L, et al. SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals. HIV Clin Trials. 2002;3(3):186-194. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12032877.
- Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015;70(5):515-9 Available at: http://www.ncbi.nlm.nih.gov/pubmed/26262777.
- Margot NA, Lu B, Cheng A, Miller MD, Study 903 Team. Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903. HIV Med. 2006;7(7):442-450. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16925730.
- ENCORE1 Study Group, Carey D, Puls R, et al. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015;15(7):793-802. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25877963.
- Fraaij PL, Bergshoeff AS, van Rossum AM, Hartwig NG, Burger DM, de Groot R. Changes in indinavir exposure over time: a case study in six HIV-1-infected children. J Antimicrob Chemother. 2003;52(4):727-730. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12917234.
- Funk MB, Notheis G, Schuster T, et al. Effect of first line therapy including efavirenz and two nucleoside reverse transcriptase inhibitors in HIV-infected children. Eur J Med Res. 2005;10(12):503-508. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16356864.
- McKinney RE, Jr., Rodman J, Hu C, et al. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS clinical trials group protocol P1021. Pediatrics. 2007;120(2):e416-423. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17646352.
- Spector SA, Hsia K, Yong FH, et al. Patterns of plasma human immunodeficiency virus type 1 RNA response to highly active antiretroviral therapy in infected children. J Infect Dis. 2000;182(6):1769-1773. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11069252.
- 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. 1999;341(25):1874-1881. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10601506.
- Starr SE, Fletcher CV, Spector SA, et al. Efavirenz liquid formulation in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 2002;21(7):659-663. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12237599.
- Teglas JP, Quartier P, Treluyer JM, Burgard M, Gregoire V, Blanche S. Tolerance of efavirenz in children. AIDS. 2001;15(2):241-243. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11216933.
- 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. 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.
- Bolton C, Samson P, Capparelli E, Bwakura-Dangarembizi M, Jean-Philippe P, et al. Strong influence of CYP2B6 genotypic polymorphisms on EFV pharmacokinetics in HIV+ children <3 years of age and implications for dosing. Presented at: Conference on Retroviruses and Opportunistic Infections. 2013. Atlanta, GA.
- Salem AH, Fletcher CV, Brundage RC. Pharmacometric characterization of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. Antimicrob Agents Chemother. 2014;58(1):136-143. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24145522.
- Bienczak A, Cook A, Wiesner L, et al. The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children. Br J Clin Pharmacol. 2016;82(1):185-198. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26991336.
- Haas DW, Smeaton LM, Shafer RW, et al. Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and/or nelfinavir: an Adult AIDS Clinical Trials Group Study. J Infect Dis. 2005;192(11):1931-1942. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16267764.
- Soeria-Atmadja S, Osterberg E, Gustafsson LL, et al. Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin. PLoS One. 2017;12(9):e0181316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28886044.
- Bolton Moore C, Capparelli EV, Samson P, et al. CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3-36 months with HIV infection. AIDS. 2017;31(8):1129-1136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28323755.
- di Iulio J, Fayet A, Arab-Alameddine M, et al. In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenet Genomics. 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. 2009;85(5):485-494. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19225447.
- 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. 2012;60(4):400-404. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22481606.
- 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. 2012;206(9):1453-1461. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22927450.
- Holzinger ER, Grady B, Ritchie MD, et al. Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS clinical trials group protocols implicates several CYP2B6 variants. Pharmacogenet Genomics. 2012;22(12):858-867. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23080225.
- Capparelli E, Rochon-Duck M, Robbins B, et al. Age-related pharmacokinetics of efavirenz solution. Presented at: 16th Conference on Retroviruses and Opportunistic Infections. 2009. Montreal, Canada.
- Bienczak A, Denti P, Cook A, et al. Plasma efavirenz exposure, sex, and age predict virological response in HIV-infected African children. J Acquir Immune Defic Syndr. 2016. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27116047.
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