Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.


Intelence (Janssen-Cilag)
100 mg tablets
Approved indication: HIV
Australian Medicines Handbook section 5.4

Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It binds to reverse transcriptase and blocks the RNA- and DNA-dependent activities of DNA polymerase. Etravirine is indicated for treatment-experienced adults with HIV who have evidence of viral replication and drug resistance to other antiretroviral drugs including NNRTIs.

The approval of etravirine is based on two identically designed randomised placebo-controlled trials (DUET-1 and DUET-2) in patients with advanced disease. These patients were resistant to currently available NNRTIs and had at least three primary mutations to protease inhibitors. All patients received darunavir (a protease inhibitor) boosted with ritonavir, as well as at least two other antiviral drugs. At the beginning of the studies the average viral load in enrolled patients was 70 000 copies/mL blood. The main measure of effectiveness for etravirine was the number of patients with less than 50 viral copies/mL blood. After 24 weeks of treatment, 59% (353/599) of patients who added etravirine (200 mg twice daily) had less than 50 viral copies/mL compared to 41% (248/604) of patients who had added placebo. The mean increase in CD4 cells was 84 cells/microlitre blood in the etravirine groups and 65 cells/microlitre of blood in the placebo groups. Using other active antiretroviral drugs with etravirine increases the likelihood of treatment response.1,2

The trials are ongoing and preliminary results presented at a conference reported that response rates to etravirine were maintained after 48 weeks of treatment (www.retroconference.org/2008/PDFs/790.pdf and www.retroconference.org/2008/PDFs/791.pdf). The total duration of the trials is expected to be 96 weeks.

Resistance to NNRTIs can develop easily. A single mutation in the reverse transcriptase gene of the virus can lead to reductions in susceptibility, often to all currently available inhibitors in the class. This broad cross-resistance limits the sequential use of other NNRTIs after treatment failure. In the DUET trials, decreased susceptibility to etravirine emerged and was associated with a number of different viral mutations. Cross-resistance with etravirine and other NNRTIs was also observed. The majority of viral strains containing 2 or 3 mutations conferring NNRTI resistance also had decreased susceptibility to etravirine.

The most common adverse events with etravirine are rash (17%), diarrhoea (15%) and nausea (14%). Rash was the most common adverse event for which patients discontinued treatment in the DUET trials (2% for etravirine, 0% for placebo). Severe and potentially life-threatening skin reactions, including Stevens-Johnson syndrome, hypersensitivity reactions and erythema multiforme, have occurred in patients taking etravirine. Treatment should be stopped if this occurs. Other common adverse effects of etravirine include abdominal pain, tiredness and high blood pressure. Neuropsychiatric events occurred in 25% of patients taking etravirine. Similar numbers of events were seen in the placebo group.

Patients who also had hepatitis B and/or hepatitis C were included in the DUET trials, providing they were clinically stable. The incidence of hepatic events (such as hepatobiliary disorders) tended to be higher in patients taking etravirine compared to those taking placebo (11% vs 6%).

This drug should be taken after a meal to increase its bioavailability. Following oral administration, maximum plasma concentration of etravirine is reached by 4 hours. Although etravirine is primarily metabolised by the liver, no dose adjustment is needed for patients with mild to moderate liver impairment. Etravirine has not been studied in patients with severe liver disease.

As etravirine induces CPY34A and inhibits CYP2C9 and CYP2C19, co-administration of drugs that are metabolised by these enzymes may affect the therapeutic or adverse effects of etravirine. Many drugs may interact with etravirine, including combinations of other antivirals. Etravirine should not be co-administered with other NNRTIs and there are specific recommendations about giving etravirine with protease inhibitors. Other drugs which potentially interact with etravirine include antiarrhythmics, anticoagulants, anticonvulsants, antifungals, antibiotics, benzodiazepines, corticosteroids, statins, immunosuppressants, phosphodiesterase type 5 inhibitors and St John's wort. It is therefore important to obtain a full record of the patient's medications before prescribing etravirine.

Etravirine represents another option for patients infected with multi-resistant HIV strains, although decreased susceptibility to this drug has been observed. Long-term data are needed to assess how durable the observed responses are. The patient's treatment history and antiviral resistance testing should guide the use of this drug.

manufacturer declined to supply data

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).

References

  1. Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, 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. Lancet 2007;370:29-38.
  2. Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll 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. Lancet 2007;370:39-48.