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: May 22, 2018; Last Reviewed: May 22, 2018
|Efavirenz (EFV, Sustiva)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
|Capsules: 50 mg, 200 mg
Tablets: 600 mg
Fixed-Dose Combination Tablets:
|Dosing Recommendations||Selected Adverse Events|
Adolescent (Weighing ≥40 kg) and Adult Dose:
Pediatric (Weighing ≥35 kg) and Adult Dose:
- Metabolism: Co-administration of efavirenz with drugs primarily metabolized by cytochrome P (CYP) 2C9, CYP2C19, CYP2B6, or CYP3A isozymes may result in altered plasma concentrations of the co-administered 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 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 primarily been reported 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: For discussion, see Pediatric Use section below; see also Efavirenz in the Perinatal Guidelines.
Efavirenz is Food and Drug Administration (FDA)-approved for use as part of antiretroviral therapy in children aged ≥3 months and weighing ≥3.5 kg. Although the FDA has approved the use of Symfi Lo, the fixed-dose combination of efavirenz 400 mg plus lamivudine 300 mg plus tenofovir disoproxil fumarate (TDF) 300 mg, in children weighing ≥35 kg, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) has not yet discussed pediatric use of this new formulation and the implications of using a fixed-dose combination that contains a lower dose of efavirenz in children.
Efficacy in Clinical Trials
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.
- 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
- 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.12-18
- 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.19
Genetic polymorphisms in genes coding 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 (which has an allele frequency of 20% in African Americans) have reduced metabolism, resulting in higher efavirenz levels in these patients than in those with the G/G or G/T genotype.20-24 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 G/G or G/T genotype but excessive exposure in those with T/T genotype.25 Optimal dosing may require pretreatment CYP2B6 genotyping in children aged <3 years (see discussion below).24,25 Additional variant CYP2B6 alleles and variant CYP2A6 alleles have been found to influence efavirenz concentrations in adults and children.24,26-30 The CYP2B6 T983C mutation has also been associated with reduced efavirenz clearance in African children.24
Pharmacokinetics and Dosing: Infants and Children Aged <3 Years
The Panel does not recommend 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.22,31 These data show age-related differences in absorption and impact of formulation on efavirenz PKs.23 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.23 This maturation of oral clearance is postulated to result from an increase in the expression of CYP2B6 with age.23 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 genotype.20 In children with 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.20 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 efavirenz dosed by weight band based on CYP2B6 GG/GT versus T/T genotype (see Tables A1 and A2 below). When used without regard to genotype, doses higher than the FDA-approved doses 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 those with T/T genotypes.25 Therefore, dosing tables have been modified so that infants and young children with T/T genotype will receive a reduced dose. Additional analyses are needed to confirm that this dose is appropriate for this subset of patients. The modified doses listed in Tables A1 and A2 are under investigation.
Investigational Dosing for Children Aged 3 Months to <3 Years Based on CYP2B6 Genotype
|5 kg to <7 kg||300 mg|
|7 kg to <14 kg||400 mg|
|14 kg to <17 kg||500 mg|
|≥17 kg||600 mg|
|5 kg to <7 kg||50 mg|
|7 kg to <14 kg||100 mg|
|14 kg to <17 kg||150 mg|
|≥17 kg||150 mg|
|a Investigational doses are based on IMPAACT study P1070.25 Evaluation of CYP2B6 genotype is required. Therapeutic drug level monitoring is recommended with a trough measured 2 weeks after initiation of efavirenz 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 older subjects in PACTG 1021 and PACTG 382, and also from data collected during AI266-922, which is a study assessing the PK, safety, and efficacy of capsule sprinkles in children aged 3 months to 6 years (see Table B).
|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 CYP2B6 extensive metabolizer (EM) doses and higher than the CYP2B6 slow metabolizer (SM) 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 underdosing in CYP2B6 EMs. Estimates of efavirenz area under the curve (AUC) for FDA dosing using P1070 data were calculated using the following equation:
A high initial dose of efavirenz in the first version of the P1070 protocol was used to produce a target AUC of 35 to 180 mcg*h/mL, a systemic exposure similar to that shown to be safe and effective in older children and adults.25 The P1070 dosing for children aged 3 to 36 months leads to higher levels than seen with FDA recommendations for adults receiving 600 mg daily. However, the higher doses reduced the frequency of low AUCs (<35 mcg*h/mL) with P1070 EM dosing (11% P1070 EM dosing vs. an estimated 32% with FDA dosing). The lower P1070 dose for SM genotype is predicted to reduce the frequency of high AUCs from 56% to 11% compared to the FDA genotypic agnostic dose (a dose given without consideration of genotype) in this population.
The Panel does not recommend use of efavirenz in children aged 3 months to <3 years. If the clinical situation demands use of efavirenz, the Panel recommends determining CYP2B6 genotype prior to use. (See a list of laboratories performing this testing.) Patients should be classified as extensive CYP2B6-516-G/G and -G/T genotype metabolizers (EMs) or slow CYP2B6-516-T/T genotype metabolizers (SMs) to guide dosing as indicated by the investigational doses from IMPAACT study P1070 (see Tables A1 and A2). Whether the doses used are investigational or FDA-approved, measuring efavirenz plasma concentrations should be considered 2 weeks after initiation (see Therapeutic Drug Monitoring 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.32 Consultation with an expert 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 making the transition to the new dose.
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.20,33-37 Therefore, some experts recommend therapeutic drug monitoring (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 to 23 mg/kg (69–559 mg/m2).38 A PK study in 20 children aged 10 to 16 years treated with LPV/r 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 values were lower than PK targets. The authors therefore recommended that higher doses of efavirenz might be needed when these drugs are used together.39
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.40 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.41 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 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.19,42
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.43,44 This association, however, was not found in analyses of two large observational cohorts45,46 and no cases of suicide were reported in a systematic review of randomized trials.41 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.47-51 In patients with pre-existing psychiatric conditions, efavirenz should be used cautiously. Adverse CNS events occurred in 14% of children receiving efavirenz in clinical studies52 and in 30% of children with efavirenz concentrations >4 mcg/mL.21 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.47,48 Homozygous carriers of the CYP2B6*6 allele (CYP2B6*6/*6) may be at increased risk for efavirenz-induced rate QTc prolongation. The CYP2B6*6 allele codes for the CYP2B6-516-G>T complementary DNA nucleotide change;53 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 enriched for CYP2B6 polymorphisms. 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.54 Consider using an alternative to efavirenz in patients 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
Toxicity: Potential Risk of Teratogenicity
In prior versions of the Perinatal Guidelines, efavirenz use was not recommended before 8 weeks’ gestational age because of concerns regarding potential teratogenicity. Although this caution is still included in the package insert, and efavirenz use has been associated with significant teratogenic effects in nonhuman primates, results of a large meta-analysis have been reassuring that risks of neural tube defects after first-trimester efavirenz exposure are not greater than those seen in the general population.2,55 As a result, the current Perinatal Guidelines do not include the restriction of use before 8 weeks’ gestation, consistent with both the British HIV Association and World Health Organization guidelines for use of antiretroviral drugs during pregnancy (both of which note that efavirenz can be used throughout pregnancy).56,57 Importantly, women who become pregnant on suppressive efavirenz-containing regimens should continue their current regimens.
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.59,60 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. An efavirenz concentration, measured 2 weeks after initiation, and consultation with an expert should be considered to inform dose adjustment. In addition, some experts would measure efavirenz concentrations at age 3 years after making the transition to the new dose if dosing was initiated at age <3 years using investigational dose recommendations. The currently accepted minimum effective concentration of efavirenz is a mid-dose concentration (C12) >1 mg/L in adults, and concentrations >4.0 mg/L are associated with CNS side effects.48 A recent study in children showed that a higher proportion of children with a C12 <1 mg/L showed evidence of viral replication than those with a C12 >1 mg/L.61 However, the validity using a single target has been called into question.62 In addition, a lower limit C12 >0.7mg/L was most predictive of virologic outcome in a study of 180 adults.63 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.32
- 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. Available at http://www.ncbi.nlm.nih.gov/pubmed/26262777.
- 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.
- Group ES, 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.
- 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.
- 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. Montréal, 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.
- Ren Y, Nuttall JJ, Egbers C, et al. High prevalence of subtherapeutic plasma concentrations of efavirenz in children. J Acquir Immune Defic Syndr. 2007;45(2):133-136. Available at http://www.ncbi.nlm.nih.gov/pubmed/17417100.
- 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. 2009;53(10):4407-4413. Available at http://www.ncbi.nlm.nih.gov/pubmed/19635964.
- 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. 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. 2011;58(4):392-398. Available at http://www.ncbi.nlm.nih.gov/pubmed/21926634.
- 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. 2013;62(1):e27-29. Available at http://www.ncbi.nlm.nih.gov/pubmed/23262981.
- 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. 2008;83(2):300-306. Available at http://www.ncbi.nlm.nih.gov/pubmed/17609682.
- 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. 2009;28(2):159-161. Available at http://www.ncbi.nlm.nih.gov/pubmed/19106779.
- Larru B, Eby J, Lowenthal ED. Antiretroviral treatment in HIV-1 infected pediatric patients: focus on efavirenz. Pediatric Health Med Ther. 2014;5:29-42. Available at https://www.ncbi.nlm.nih.gov/pubmed/25937791.
- Ford N, Shubber Z, Pozniak A, et al. Comparative safety and neuropsychiatric adverse events associated with efavirenz use in first-line antiretroviral therapy: a systematic review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr. 2015;69(4):422-429. Available at http://www.ncbi.nlm.nih.gov/pubmed/25850607.
- Group ES, Puls R, Amin J, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014;383(9927):1474-1482. Available at http://www.ncbi.nlm.nih.gov/pubmed/24522178.
- Mollan KR, Smurzynski M, Eron JJ, et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med. 2014;161(1):1-10. Available at http://www.ncbi.nlm.nih.gov/pubmed/24979445.
- Arenas-Pinto A, Grund B, Sharma S, et al. Increased risk of suicidal behaviour with use of efavirenz: results from the START trial. Presented at: 21st International AIDS Conference. 2016. Durban, South Africa.
- Smith C, Ryom L, Monforte A, et al. Lack of association between use of efavirenz and death from suicide: evidence from the D:A:D study. J Int AIDS Soc. 2014;17(4 Suppl 3):19512. Available at http://www.ncbi.nlm.nih.gov/pubmed/25394021.
- Napoli AA, Wood JJ, Coumbis JJ, Soitkar AM, Seekins DW, Tilson HH. No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database. J Int AIDS Soc. 2014;17:19214. Available at http://www.ncbi.nlm.nih.gov/pubmed/25192857.
- 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. 2005;41(11):1648-1653. Available at http://www.ncbi.nlm.nih.gov/pubmed/16267739.
- 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. 2001;15(1):71-75. Available at http://www.ncbi.nlm.nih.gov/pubmed/11192870.
- Zugar A. Studies disagree on frequency of late cns side effects from efavirenz. AIDS Clin Care. 2006;4(1).
- Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral agents. AIDS. 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. 2008;61(6):1336-1339. Available at http://www.ncbi.nlm.nih.gov/pubmed/18343800.
- Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS. 2013;27(9):1403-1412. Available at http://www.ncbi.nlm.nih.gov/pubmed/23343913.
- Karolinska Institutet. Human cytochrome P450 (CYP) allele nomenclature database. 2016. Available at http://www.cypalleles.ki.se.
- Food and Drug Administration. Guidance for Industry. E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic Drugs. 2005. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073153.pdf.
- Ford N, Mofenson L, Shubber Z, et al. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2014;28 Suppl 2:S123-131. Available at http://www.ncbi.nlm.nih.gov/pubmed/24849471.
- de Ruiter A, Taylor GP, Clayden P, et al. British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review). HIV Med. 2014;15 Suppl 4:1-77. Available at https://www.ncbi.nlm.nih.gov/pubmed/25604045.
- World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection—recommendations for a public health approach; second edition 201. 2016. Available at http://www.who.int/hiv/pub/arv/arv-2016/en/.
- Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. 2016. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
- 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. 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. 2002;18(12):825-834. Available at http://www.ncbi.nlm.nih.gov/pubmed/12201904.
- Homkham N, Cressey TR, Bouazza N, et al. Efavirenz concentrations and probability of HIV replication in children. Pediatr Infect Dis J. 2015;34(11):1214-1217. Available at http://www.ncbi.nlm.nih.gov/pubmed/26226442.
- Dickinson L, Amin J, Else L, et al. Comprehensive pharmacokinetic, pharmacodynamic and pharmacogenetic evaluation of once-daily efavirenz 400 and 600 mg in treatment-naive HIV-infected patients at 96 Weeks: results of the ENCORE1 study. Clinical Pharmacokinetics. 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26715213.
- Orrell C, Bienczak A, Cohen K, et al. Recommended efavirenz concentration for therapeutic drug monitoring is too high. Presented at: Conference on Retroviruses and Opportunistic Infections. 2016. Boston, MA.