Etravirine (Intelence) is an anti-HIV drug that reduces the amount of virus in the body and belongs to the class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). The enzyme reverse transcriptase converts single-stranded viral RNA into DNA. Drugs in the NNRTI class stop HIV from replicating within cells by binding near reverse transcriptase’s active site and inhibiting polymerase activity.
Formerly known as TMC-125, etravirine was developed by Tibotec Pharmaceuticals, Ltd. and is a diarylpyrimidine (DAPY), a different type of NNRTI specifically designed to be less susceptible than other NNRTIs to resistance mutations. As a flexible molecule, it can fit into different shaped binding pockets in the reverse transcriptase enzyme and this is why it remains active against HIV that is resistant to other NNRTIs. (Das)
Etravirine is indicated for treatment-experienced adults who have evidence of viral replication and HIV strains resistant to an NNRTI and other antiretrovirals. It should not be combined with licensed nucleoside analogues alone, due to the risk of virologic failure.
Etravirine is not recommended for use with an unboosted protease inhibitor, ritonavir-boosted atazanavir, fosamprenavir, or tipranavir. In addition, the manufacturer recommends resistance testing before initiating therapy with this drug.
Etravirine was approved in the US and European Union in 2008. Etravirine is marketed by Janssen, a subsidiary of Johnson & Johnson.
Studies that led to the approval of etravirine showed that when combined with darunavir/ritonavir plus at least two nucleoside analogues selected by resistance testing, etravirine was significantly more effective than placebo in suppressing viral load in treatment-experienced people with at least one NNRTI resistance mutation and three or more primary protease inhibitor mutations. (Katlama) A subsequent study showed that etravirine was more effective in treatment-experienced people with fewer than three NNRTI mutations. (TMC125-C223 Writing Group)
Despite its impressive activity against NNRTI-resistant HIV, those findings showed that the more NNRTI resistance mutations a person has, the lower the viral load reduction. Individuals with no NNRTI resistance mutations at baseline had a median viral load reduction of nearly 3 logs after 34 weeks of etravirine treatment combined with an optimised background regimen. Those with three or more NNRTI mutations had a viral load reduction of less than a log.
The recommended oral dose of etravirine tablets is 200mg (two 100mg tablets) twice daily following a meal. Taking the drug on an empty stomach is not advised. For those who have difficulty swallowing, etravirine can be dissolved in water.
In 2008, the US manufacturer of etravirine stated that it should not be co-administered with atazanavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir. (Tibotec Therapeutics)
Although generally well tolerated in clinical trials, since the approval of etravirine, two types of severe reaction to the drug have been reported: toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS).
Reported cases of these reactions developed between three and six weeks after treatment with the drug was started. In most cases, they disappeared when treatment with etravirine was stopped and therapy with corticosteroids was provided. Symptoms include rash, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and high concentrations of a type of blood cell calls eosinophils.
In August 2009, the US Food and Drug Administration inserted a new warning to the package insert for etravirine (Intelence). It stated that severe cases of rash occurred in around 1.3% of people in phase 3 studies of the drug and 2% of people had to stop taking the drug due to serious rash, usually occurring in the first six weeks of treatment. In the most serious cases, people taking etravirine developed Stevens-Johnson syndrome or other severe skin reactions in which regions of the skin blister and peel away. It is expected that a similar warning will be added to European package inserts by the European Medicines Agency.
People who develop a severe rash while taking etravirine were advised to seek immediate medical advice. If a hypersensitivity reaction to the drug is diagnosed, treatment with it should be stopped immediately. People who have stopped treatment due to hypersensitivity reactions should not restart therapy.
In contrast to other NNRTIs, more than one resistance mutation needs to develop, in order to bring about resistance to etravirine. (Brillant) (Vingerhoets) The presence of the most common NNRTI mutation, K103N, did not affect the treatment response in individuals on etravirine in the DUET studies; however, the presence at baseline of V179D, V179F, V179T, Y181V, or G190S was associated with a decreased virologic response to etravirine. (Madruga) (Lazzarin)
Tibotec, manufacturer of etravirine, has noted that cross-resistance to efavirenz and/or nevirapine is to be expected after virologic failure while on an etravirine-containing regimen.
Interactions with protease inhibitors complicate regimens containing etravirine. This is an especially important issue for a second-line NNRTI that may be used in third-line regimens with protease inhibitors.
Etravirine cannot be co-administered with boosted tipranavir/ritonavir (Aptivus), boosted fosamprenavir (Lexiva), full-dose ritonavir (Norvir 600mg), boosted atazanavir (Reyataz), unboosted protease inhibitors, and other NNRTIs.
Etravirine blood levels increase by 17% when prescribed with lopinavir (Kaletra). This combination may be used, but should be administered with caution.
Because etravirine is such a potent inducer of the cytochrome p450 CYP3A4 pathway, it greatly speeds up the metabolism of the CCR5 antagonist maraviroc (Celsentri, Selzentry). Co-administration can reduce total maraviroc concentrations over a 12-hour period by 53% (AUC12) and peak levels of maraviroc (Cmax) by 60%.
Therefore, if an individual isn't also taking a potent CYP3A4 inhibitor such as a protease inhibitor, the recommended clinical dose for maraviroc alongside etravirine is 600mg twice daily. However, if maraviroc is being dosed alongside etravirine and darunavir together, a dose reduction to 150mg twice daily is necessary. Data showed no effect of maraviroc on etravirine pharmacokinetics, so no dose adjustment of etravirine is necessary.
Etravirine cannot be given with carbamazepine, phenobarbital, phenytoin, rifabutin (if part of a protease inhibitor/ritonavir containing-regimen), rifampin, rifapentine, or St John's wort (Hypericum perforatum). It does not appear to affect blood levels of methadone. Etravirine may reduce levels of clopidogrel.
Etravirine should be used with caution alongside fluconazole or voriconazole, because these drugs have the potential to raise etravirine levels.
The efficacy of etravirine and/or its side-effect profile can change when given with inhibitors, inducers, or substrates of CYP3A4, CYP2C9, and CYP2C19. Further information on drug interactions is available at www.intelence-info.com.
Etravirine is safe and effective in treatment-experienced children and adolescents. When combined with an optimised background regimen and dosed either by weight (5.2mg/kg) or 200mg twice a day etravirine suppressed viral load below 50 copies/ml in 56% of 101 children and adolescents. (Tudor-Williams)
Etravirine has received only minimal study in pregnant women.
Laboratory studies in animals suggest that the drug is safe during pregnancy, and a case study has been presented of five pregnant women who received the drug through compassionate access due to limited options. (Izurieta) Three of the women took therapy for their entire pregnancy, the other two during the third trimester only.
Monitoring of peak, trough and steady-state concentrations of etravirine showed that these were comparable to those seen in non-pregnant adults, suggested that no dose modification is necessary during pregnancy. None of their infants were infected with HIV. One infant was born with a minor abnormality to the right ear, but was healthy in all other respects. No birth abnormalities were observed in the other five babies.
Das K et al. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. Journal of Medicinal Chemistry, 47: 2550-2560, 2004.
Katlama C et al. Efficacy and Safety of Etravirine in Treatment-Experienced, HIV-1 Patients: Pooled 48 Week Analysis of Two Randomized, Controlled Trials. AIDS 23: 2289-300, 2009.
TMC125-C223 Writing Group Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS 21: F1-F10, 2007.
Tibotec Therapeutics Etravirine [package insert]. Bridgewater NJ, 2008.
Brillant JE et al. In vitro resistance development for a second-generation NNRTI: TMC125. 13th International HIV Drug Resistance Workshop, Costa Adeje, abstract 16, 2004.
Vingerhoets J et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. Journal of Virology, 79: 12773-12782, 2005.
Madruga JV et al. 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. The Lancet, 370: 29-38, 2007.
Lazzarin A et al. 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. The Lancet, 370: 39-48, 2007.
Tudor-Williams G 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 Medicine 15: 513-24, 2014.
Izurieta P et al. Safety and pharmacokinetics of etravirine in pregnant HIV-infected women. 12th European AIDS Conference, Cologne, abstract PE 4.1/6, 2009.