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
|Etravirine (ETR, Intelence, TMC 125)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
|Tablets: 25 mg, 100 mg, and 200 mg|
|Dosing Recommendations||Selected Adverse Events|
Adult Dose (Antiretroviral-Experienced Patients):
- Etravirine is associated with multiple drug interactions. Before administration, the patient’s medication profile should be carefully reviewed for potential drug interactions with etravirine.
- Etravirine should not be co-administered with the following antiretroviral (ARV) drugs: tipranavir/ritonavir, fosamprenavir/ritonavir, and unboosted protease inhibitors (PIs). It should not be administered with other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (i.e., nevirapine, efavirenz, rilpivirine). Limited data in adults suggest that etravirine may reduce the trough concentration of raltegravir,1 but no dose adjustment is currently recommended when etravirine and raltegravir are used together. Etravirine significantly reduces plasma concentrations of dolutegravir and elvitegravir/cobicistat (EVG/c). Dolutegravir should only be used with etravirine when co-administered with atazanavir/ritonavir, darunavir/ritonavir (DRV/r), or lopinavir/ritonavir. Etravirine should not be co-administered with EVG/c.
- More common: Nausea, diarrhea, and mild rash. Rash occurs most commonly during the first 6 weeks of therapy. Rash generally resolves after 1 to 2 weeks on continued therapy. A history of NNRTI-related rash does not appear to increase the risk of developing rash with etravirine. However, patients who have a history of severe rash with prior NNRTI use should not receive etravirine.
- Less common (more severe): Peripheral neuropathy, severe rash, hypersensitivity reactions (HSRs), and erythema multiforme have all been reported. Instances of severe rash have included Stevens Johnson syndrome, and HSRs have included constitutional findings and organ dysfunction, including hepatic failure. Discontinue etravirine immediately if signs or symptoms of severe skin reactions or HSRs develop (including severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, and eosinophilia). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping etravirine treatment after the onset of severe rash may result in a life-threatening reaction. It is recommended that patients who have a prior history of severe rash with nevirapine or efavirenz not receive etravirine.
The International AIDS Society-USA (IAS-USA) maintains a list of updated resistance mutations and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.
Etravirine is Food and Drug Administration-approved for use in ARV-experienced children and adolescents aged 6 years to 18 years.
Efficacy in Clinical Trials
In the PIANO study,2 ARV-experienced children aged 6 years to <18 years received etravirine with a ritonavir-boosted PI as part of an optimized background regimen. At Week 24, 67% of these participants had plasma HIV RNA concentrations <400 copies/mL and 52% had <50 copies/mL. At Week 48, 56% of the participants had <50 copies/mL and a mean increase in their CD4 T lymphocyte cell counts of 156 cells/mm3 from baseline. A greater fraction of children aged 6 years to <12 years had plasma HIV-1 RNA <50 copies/mL than adolescents aged 12 years to <18 years (68% vs. 48%).
In a retrospective study of 23 adolescents and young adults, 78% of participants achieved an HIV-1 RNA <50 copies/mL at a median of 48.4 weeks of follow-up.3
In a Phase 1 dose-finding study involving children aged 6 year to 17 years, 17 children were given etravirine 4 mg/kg twice daily. Two pharmacokinetic (PK) parameters—area under the curve for 12 hours post-dose (AUC0-12h) and minimum plasma concentration (Cmin)—were below preset statistical targets based on prior studies involving adults.4 On the basis of acceptable PK parameters, the higher dose (etravirine 5.2 mg/kg twice daily; maximum 200 mg per dose) was chosen for evaluation in the Phase 2 PIANO study. Exposures (mean AUC0-12h) remained lower in older adolescents than in adults and younger children, and exposures were lower in Asian participants than in either white or black participants. In the PIANO study children and adolescents with etravirine concentrations in the lowest quartile (<2,704 ng*h/mL or C0h <145 ng/mL) were less likely to achieve sustained virologic responses (plasma viral load <50 copies/mL) after 48 weeks of treatment than those with etravirine concentrations in the upper three quartiles.5
|Mean AUC0-12h (ng*h/mL)||Mean C0h (ng/mL)|
|Children Aged 6–11 Years (N = 41)||5,684||377|
|Adolescents Aged 12–17 Years (N = 60)||4,895||325|
|Key to Acronyms: AUC0-12h = Area under the curve for 12 hours post-dose; C0h = pre-dose concentration during chronic administration|
Etravirine is often combined with DRV/r for treatment of adults with HIV with prior virologic failure. Cressey et al. examined PK data from 36 adolescents and young adults receiving etravirine 200 mg twice daily in combination with DRV/r 600 mg/100 mg twice daily. The PK exposures of both agents were similar to those seen in adults, although with high interindividual variability.6 The PKs of both drugs were also studied in adolescents and young adults receiving DRV/r 800 mg/100 mg once daily with either etravirine 200 mg twice daily or etravirine 400 mg once daily.7 Darunavir concentrations were higher when co-administered with etravirine, particularly when the latter was given in doses of 200 mg twice daily. Etravirine exposures were lower when given with DRV/r, particularly when etravirine was given twice daily, although the authors commented on the limited sample size involved in these studies. While the combination of etravirine and DRV/r has been effective in a small cohort of adolescents with HIV8 and in 51% of participants in the PIANO study,2,5 these data suggest a need for additional study of PK interactions involving etravirine and other ARV agents in pediatric patients, including regimens that do not include ritonavir-boosted PIs. Until such data become available, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV recommends using etravirine as part of a regimen that includes a ritonavir-boosted PI.
In the PIANO study, rash and diarrhea were the most common adverse drug reactions deemed possibly related to etravirine. Rash (Grade 2 or higher) occurred in 13% of pediatric subjects and emerged at a median of 10 days, lasting a median of 7 days. Rash was observed more frequently in females (17 of 64; 26.6%) than in males (6 of 37; 16.2%). Etravirine was discontinued due to rash in four individuals (4% of all participants), all of whom were female. Diarrhea occurred in three individuals (3% of participants) and was only reported in adolescents.
- Do VT, Higginson RT, Fulco PP. Raltegravir dosage adjustment in HIV-infected patients receiving etravirine. Am J Health Syst Pharm. 2011;68(21):2049-2054. Available at http://www.ncbi.nlm.nih.gov/pubmed/22011983.
- Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Etravirine in treatment-experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and resistance analysis of the phase II PIANO study. HIV Med. 2014. Available at http://www.ncbi.nlm.nih.gov/pubmed/24589294.
- Briz V, Palladino C, Navarro M, et al. Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients. HIV Med. 2011;12(7):442-446. Available at http://www.ncbi.nlm.nih.gov/pubmed/21395964.
- Konigs C, Feiterna-Sperling C, Esposito S, et al. Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents. AIDS. 2012;26(4):447-455. Available at http://www.ncbi.nlm.nih.gov/pubmed/22156961.
- Kakuda TN, Brochot A, Green B, et al. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of etravirine in HIV-1-infected, treatment-experienced children and adolescents in PIANO. J Clin Pharmacol. 2016;56(11):1395-1405. Available at https://www.ncbi.nlm.nih.gov/pubmed/27060341.
- Cressey TR, Yogev R, Wiznia A, et al. Pharmacokinetics of darunavir/ritonavir with etravirine both twice daily in human immunodeficiency virus-infected adolescents and young adults. J Pediatric Infect Dis Soc. 2016. Available at http://www.ncbi.nlm.nih.gov/pubmed/27103489.
- Larson KB, Cressey TR, Yogev R, et al. Pharmacokinetics of once-daily darunavir/ritonavir with and without etravirine in human immunodeficiency virus-infected children, adolescents, and young adults. J Pediatric Infect Dis Soc. 2016;5(2):131-137. Available at http://www.ncbi.nlm.nih.gov/pubmed/27199469.
- Thuret I, Chaix ML, Tamalet C, et al. Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS. 2009;23(17):2364-2366. Available at http://www.ncbi.nlm.nih.gov/pubmed/19823069.