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Etravirine (Intelence, TMC 125)
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Class
Background
Manufacturer for U.S. Market
Approval
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Potential Adverse Effects
Interactions with Other Drugs
Resistance
Implications of etravirine resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for etravirine treatment
References
Related Resources
DHHS Guidelines
Characteristics of NNRTIs
Drug Interactions with NNRTIs
Interactions between NNRTIs, Maraviroc, Raltegravir, and PIs
Drugs That Should Not Be Used with PIs, NNRTIs, or CCR5 Antagonists
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Etravirine (Intelence)
Class

Nonnucleoside reverse transcriptase inhibitor

Background
Manufacturer for U.S. Market

Janssen Therapeutics

Approval

Etravirine was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in January 2008 for adults with HIV infection. In 2012, it was granted approval for use in treatment-experienced pediatric patients 6 years of age and older. It is intended for use in combination with other antiretroviral agents in treatment-experienced adults and children whose HIV is resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and other antiretroviral medications.

Initial approval was based on 24-week results from 2 randomized, placebo-controlled Phase III studies in treatment-experienced patients with resistance to NNRTI and protease inhibitor medications. Patients received either etravirine or placebo, plus a background regimen that contained ritonavir-boosted darunavir and nucleoside analogues with or without enfuvirtide. At 24 weeks, the etravirine groups had significantly higher rates of HIV RNA suppression to <50 copies/mL (60% vs 40% in combined analysis), and had greater increases in CD4 cell counts.(1,2,3)

Etravirine shows activity against HIV strains that are resistant to previously approved NNRTIs.

Formulation and Dosing

Etravirine is available in tablet formulation.

Dosing of Etravirine
Adult*200 mg BID
Pediatric**Age <6 yearsNot FDA approved
Age 6 to <18 yrs and weight:
<16 kgNot FDA approved
16 to <20 kg100 mg BID
20 to <25 kg125 mg BID
25 to <30 kg150 mg BID
≥30 kg200 mg BID

Key to abbreviations: BID = twice daily

Etravirine should be taken after a meal; it should not be taken on an empty stomach. For patients unable to swallow pills, the tablet may be dispersed in water; see product labeling.
Etravirine interacts with a number of antiretroviral medications; see Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for the interaction of etravirine with other antiretrovirals.
No dosage adjustment is necessary in renal insufficiency.
No dosage adjustment is necessary in Child-Pugh Class A or B liver disease. No recommendation has been made for dosage adjustment in Child-Pugh Class C hepatic impairment; use with caution.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category B.

Clinical Use
Use in Initial vs Subsequent Therapy

Treatment guidelines of the U.S. Department of Health and Human Services classify etravirine as "not recommended" for initial treatment of HIV infection because there is insufficient data in treatment-naive individuals.

The FDA has approved etravirine only for use in patients whose HIV is resistant to NNRTI and other antiretroviral medications and who have incomplete virologic suppression while on antiretroviral therapy.

Data on the use of etravirine in treatment-naive patients are limited. One small randomized study compared etravirine (400 mg once daily) with efavirenz, each in combination with 2 nucleoside analogues. At week 48, by intention-to-treat TLOVR analysis, 76% of etravirine recipients and 74% of efavirenz recipients had HIV RNA levels of <50 copies/mL.(4)

In treatment-experienced patients, 2 randomized, controlled Phase III studies (described above in Approval) have compared etravirine with placebo in patients who had advanced HIV disease, at least 1 mutation associated with resistance to NNRTIs, ≥3 primary protease inhibitor mutations, and ongoing viral replication. All patients were given darunavir/ritonavir plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), with or without enfuvirtide. At 24 weeks, by intention-to-treat analysis, higher rates of virologic suppression were seen in the etravirine arms (in pooled analysis, HIV RNA levels of <50 copies/mL in 60% vs 40%); this difference was statistically significant (p < .0001).(1,2,3) At 48 weeks, the proportions of patients maintaining HIV RNA levels of <50 copies/mL were essentially unchanged: 61% of the etravirine group and 40% of the placebo group, in pooled analysis (p < .0001).(5) Virologic suppression was closely correlated with the number of active antiretroviral agents in the background regimen, and with the number of NNRTI mutations present at baseline (see Resistance, below), indicating the importance of including at least 2 agents with potent activity in the antiretroviral regimen. However, etravirine was associated with better virologic response in all subgroups with baseline characteristics that put them at higher risk of treatment failure, including those with higher HIV viral loads, more NNRTI mutations, and higher degrees of resistance to darunavir, and in those who did not use enfuvirtide.(1,2,3,5)

In the etravirine treatment groups, the mean increase in CD4 cell count was higher than in the placebo group at 24 and 48 weeks (in pooled analysis, 81 cells/µL vs 64 cells/µL at 24 weeks, 98 cells/µL vs 73 cells/µL at 48 weeks; p = .0006 at 48 weeks).(1,2,3,5)

In a randomized, controlled study of patients with NNRTI resistance after failure of an initial NNRTI-based regimen, treatment with etravirine plus 2 NRTIs resulted in high rates of virologic failure by 12 weeks. By contrast, treatment with a protease inhibitor plus 2 NRTIs showed expected rates of virologic decline. The likelihood of virologic failure in the etravirine group was correlated with the number of NNRTI and NRTI mutations.(6) These data demonstrate that, in order to avoid rapid virologic failure resulting from NNRTI resistance, etravirine should be used only in combinations that are expected to be fully suppressive.

Potential Adverse Effects

The most common symptomatic side effects of etravirine are rash, nausea, and diarrhea. In clinical studies to date, rash typically was not serious and usually resolved after 1-2 weeks without discontinuation of therapy. In rare cases, etravirine-associated rash has been severe and life threatening. The risk of rash does not appear to be higher in persons with a history of rash resulting from other NNRTI medications.

Laboratory abnormalities include elevation in serum cholesterol, triglyceride, glucose, and hepatic transaminase levels. Transaminase elevations are more common in patients with hepatitis B or hepatitis C coinfection.

It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with etravirine is initiated.

Etravirine has not been studied in pregnant women; it is classified as an FDA Pregnancy Category B drug.

Interactions with Other Drugs

Etravirine is a substrate of the cytochrome (CYP) P450 enzyme system (CYP3A4, CYP2C9, and CYP2C19) as well as an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19; it has therapeutically significant interactions with many medications, including a number of antiretroviral agents. Etravirine decreases serum concentrations of atazanavir, maraviroc, and raltegravir and increases concentrations of fosamprenavir. Tipranavir, full-dose ritonavir, efavirenz, and nevirapine substantially decrease etravirine levels, whereas darunavir, saquinavir, and tenofovir, decrease etravirine levels moderately. Lopinavir/ritonavir and delavirdine increase etravirine levels. Based on current information, etravirine should not be given with other NNRTIs, unboosted protease inhibitors, atazanavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir. The use of etravirine with interacting antiretrovirals may require dosage adjustment or close monitoring.(3,7)

The hepatic metabolism of nonantiretroviral medications may affect or be affected by etravirine. For example, etravirine decreases the serum levels of clarithromycin and certain HMG-coenzyme A reductase inhibitors (statins), and increases the serum levels many antiarrhythmics, diazepam, warfarin, fluvastatin, and others; this may lead to inadequate therapy in the former case and serious adverse events in the latter. Rifampin, rifapentine, St. John's wort, and the anticonvulsants carbamazepine, phenobarbital, and phenytoin substantially decrease etravirine levels; they should not be given concomitantly. Rifabutin and dexamethasone decrease etravirine levels by a moderate degree and may require dosage adjustment or modification of therapy. Etravirine also has 2-way interactions with some medications; for example, antifungal agents increase etravirine concentrations, whereas etravirine may decrease itraconazole and ketoconazole concentrations and increase voriconazole concentrations.(3,8)

Some of the interactions between etravirine and other antiretroviral or nonantiretroviral medications are complex and may have effects that are difficult to predict. In many cases, extensive pharmacokinetic data and clinical correlates are not yet available, particularly in regard to multidrug interactions. Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

For additional information, see Dosage Adjustments for ARV-ARV Drug Interactions and the Database of Antiretroviral Drug Interactions.

Resistance

Because HIV strains resistant to other NNRTIs (efavirenz, nevirapine, rilpivirine, and delavirdine) are selected rapidly during failure of an NNRTI-containing regimen, NNRTI use has largely been confined to first-line therapy. Etravirine may be effective against strains of HIV that have developed resistance to other NNRTIs. However, etravirine's activity against resistant strains is strongly affected by the number of NNRTI mutations present, as well as by the specific mutations. With patients who have developed resistance to an NNRTI, it is important to discontinue the NNRTI as early as possible in order to prevent the selection of additional resistance mutations that would diminish the efficacy of etravirine.

Resistance to etravirine is associated with the selection of 1 or more of several resistance mutations. Clinical data in NNRTI-naive patients are needed to characterize de novo etravirine resistance. In patients with preexisting NNRTI resistance mutations and virologic failure on etravirine, a number of NNRTI mutations emerged, most commonly L100I, E138G, V179F V179I, Y181C Y181I, and H221Y; these were associated with decreased susceptibility to etravirine.(3)

Implications of etravirine resistance for treatment with other antiretrovirals

Resistance mutations selected by etravirine usually are associated with resistance to efavirenz, nevirapine, rilpivirine, and delavirdine.

Implications of resistance to other antiretrovirals for etravirine treatment

Resistance mutations selected by other NNRTIs can contribute to etravirine resistance. A number of NNRTI mutations decrease susceptibility to etravirine, including V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S. In Phase II and Phase III studies, the presence of specific mutations and of ≥3 mutations sharply diminished response to etravirine-containing regimens. K103N by itself did not affect efficacy of etravirine.(1,2,3,9,10) In other studies, viral strains with resistance to rilpivirine generally had phenotypic cross-resistance to etravirine.(11) A weighted score of mutations has been developed to evaluate the effect of mutations on the activity of etravirine.(9)

References
1.   Madruga JV, Cahn P, Grinsztejn B, et al; DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):29-38.
2.   Lazzarin A, Campbell T, Clotet B, et al; DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007 Jul 7;370(9581):39-48.
3.  Intelence [www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm]. Prescribing information. Titusville, NJ: Janssen Therapeutics; January 19, 2008.
4.   Gazzard B, Duvivier C, Zagler C, et al. Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48-week results. AIDS. 2011 Nov 28;25(18):2249-58.
5.   Katlama C, Haubrich R, Lalezari J, et al; DUET-1, DUET-2 study groups. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS. 2009 Nov 13;23(17):2289-300.
6.   Ruxrungtham K, Pedro RJ, Latiff GH, et al; TMC125-C227 Study Group. Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naive, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227. HIV Med. 2008 Nov;9(10):883-96.
7.   Kakuda T, Schöller-Gyüre M, Hoetelmans RM. Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Antivir Ther. 2010;15(6):817-29.
8.   Kakuda T, Schöller-Gyüre M, Hoetelmans RM. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011 Jan;50(1):25-39.
9.   Vingerhoets J, Tambuyzer L, Azijn H, et al. Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies. AIDS. 2010 Feb 20;24(4):503-14.
10.   TMC125-C223 Writing Group, Nadler JP, Berger DS, Blick G, et al. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS. 2007 Mar 30;21(6):F1-10.
11.   Rimsky L, Vingerhoets J, Van Eygen V, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis. J Acquir Immune Defic Syndr. 2012 Jan 1;59(1):39-46.