Side-effects

Since etravirine was approved, two types of severe reaction to it have been reported: toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS). Reported cases developed between three and six weeks after treatment initiation.

In most cases, symptoms 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 eosinophils in the blood.

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 had occurred in around 1.3% of patients in phase 3 studies of the drug and 2% of patients had to stop taking the drug due to serious rash, usually occurring in the first six weeks of treatment. It is expected that a similar warning will be added to European package inserts by the European Medicines Agency.

This action was followed up in October 2009 with a 'Dear Healthcare Professional' letter from the manufacturer, warning of rare, but potentially fatal, allergic reactions to etravirine. Issuance of the letter came after a fatal case of severe rash was reported. This letter was issued in agreement with the European Medicines Agency (EMEA). 

Patients who develop a severe rash while taking etravirine are advised to seek immediate medical advice. If a hypersensitivity reaction to the drug is diagnosed, treatment with it should be stopped immediately. Patients who have stopped treatment due to hypersensitivity reactions should not re-start therapy.

In the DUET I and II pooled 48-week results, maculopapular rash occurred in significantly more patients receiving etravirine than in those receiving placebo (19 vs 11%). Most rashes occurred within the first 14 days of therapy, were mild-to-moderate, lasted about 15 days, and rarely caused discontinuation of drug (in 13 patients with grade 3 rash, two stopped using the drug). However, just over 1% of reactions were grade 3 or worse. At least in the first year, etravirine did not seem to have the hepatotoxicity that is seen with nevirapine and efavirenz.1

Overall, 30% of women in the study reported rash vs 18% of men. CD4 cell count, lab abnormalities, or past rash on ARV treatment were not predictive of rash on etravirine in this study.2 Following rash, the most frequently reported adverse events (>10%) of any intensity were diarrhoea (15%) and nausea (14% vs 11% placebo).3

Results from the TMC125-C203 study group also showed that etravirine at 48 weeks was generally safe and well tolerated in treatment-experienced, HIV-1-infected patients with a safety profile comparable to that of placebo.4

References

  1. Lalezari J et al. Hepatic Safety and Tolerability of Etravirine (ETR, TMC125) in HIV-1-Infected Treatment-Experienced Patients: Pooled Analysis of the DUET-1 and DUET-2 Trials. 59th Annual Meeting of the American Association for the Study of Liver Disease, San Francisco, abstract 347, 2008
  2. Mills A et al. The incidence of rash observed with the NNRTI etravirine (TMC125, ETR) in the phase III DUET trials using pooled 48-week data. 17th International AIDS Conference, Mexico City, abstract TUPE0059, 2008
  3. Tibotec Therapeutics New 48-Week efficacy and safety data presented for INTELENCE(TM) (etravirine) as part of HIV combination therapy. Tibotec Press Release, 2008
  4. Montaner J et al. Safety, tolerability, and preliminary efficacy of 48 weeks of etravirine therapy in phase IIb dose-ranging study involving treatment-experienced patients with HIV-I infection. Clin Infect Dis 47: 969-978, 2008
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