Intelence (etravirine, TMC-125)

October 2007     View PDF     En español
Reprinted from www.aidsmeds.com, US

What is the most important information I should know about etravirine?
Etravirine is an experimental non-nucleoside reverse transcriptase inhibitor (NNRTI) being developed by Tibotec, a subsidiary of Johnson & Johnson. The U.S. Food and Drug Administration (FDA) is now reviewing the safety and effectiveness of etravirine (the FDA has granted the drug priority review status and is expected to decide on approval by January 2008).

Tibotec has announced that it has initiated an expanded access program (EAP) for etravirine. The program provides the drug, free of charge, to HIV-positive people with limited treatment options. This is defined as people who: 1) have limited or no treatment options due to virologic failure or intolerance to multiple HIV regimens, 2) are unable to use currently approved NNRTIs due to resistance and or intolerance, 3) have been treated in the past with medications in the three major classes of oral HIV drugs, and 4) have no prior or current participation in the phase III clinical trials. For more information on the EAP, call 1-866-889-2074, send an e-mail to TMC125EAP@i3research.com, or visit the EAP description on clinicaltrials.gov.

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What is etravirine?
Etravirine is in a category of HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Etravirine prevents HIV from entering the nucleus of healthy T-cells. This prevents the cells from producing new virus and decreases the amount of virus in the body.

Etravirine will need to be used in combination with other drugs. Clinical trials will evaluate its effect in combination with other drugs, including protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs).

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What is already known about etravirine?
The etravirine dose being studied in phase III clinical trials is two 100mg tablets taken by mouth, with food, twice a day.

Like other NNRTIs, etravirine might interact with other medications, including those used to treat HIV. It is important that your personal physician and/or the research nurse or study investigator be aware of all drugs you are taking, including those you buy without a prescription.

It is expected that etravirine, when combined with two nucleoside analogues, will have strong activity against HIV in people who have never taken an NNRTI in the past.

In clinical trials, the 800mg twice-daily dose was considered to be the safest and most effective. However, a new formulation of etravirine is being tested. Instead of 800mg twice-daily, the new formulation will allow for a much lower dose: 200mg twice-daily.

It is not clear how effective etravirine is against strains of HIV that are already resistant to currently available NNRTIs. All of the currently marketed NNRTIs are highly cross-resistant to each other. Test tube data suggest that etravirine might be effective against strains of HIV that are at least partly resistant to any of the approved NNRTIs. But this cannot be determined until information from clinical trials is made available.

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What has been learned from clinical trials?
Etravirine is being studied in clinical trials involving HIV-positive people who are new to anti-HIV treatment and HIV-positive people who have tried and failed other NNRTIs in the past. The results of two clinical trials have been reported.

In one phase IIa clinical trial conducted in Russia (TMC125-C208), HIV-positive people who had not taken any other drugs in the past saw their HIV viral load decrease anywhere from 1.1 log (approximately 99%) to more than 3.4 log (more than 99.9%) after seven days of therapy. Eight of the 12 patients in this study saw their viral loads decrease to undetectable levels (less than 400 copies/mL) after one week of treatment, which did not involve the use of any other drugs other than etravirine.

In another phase IIa clinical trial conducted in England (TMC125-207), 16 HIV-positive who were failing either Sustiva (efavirenz) or Viramune (nevirapine) were switched to etravirine (in combination with the nucleoside analogues they were taking previously). Twelve of these 16 patients had mutations in their virus known to cause high-level resistance to both Sustiva and Viramune. Eight days after switching to etravirine, viral load decreased, on average, by 0.86 log and seven patients saw their viral load decrease by more than 1 log. More encouraging data from studies evaluating etravirine are expected soon.

A phase IIb clinical trial (TMC125-C203) enrolled 240 HIV-positive people, all of whom had tried at least one protease inhibitor (PI), NNRTI, and nucleoside reverse transcriptase inhibitor (NRTI) in the past and were failing their current regimen. The primary goal of this study was to evaluate the safety and tolerability of three etravirine doses (400mg, 800mg, or 1200mg twice daily) in combination with approved anti-HIV medications (optimized background regimen; OBR), compared to a group of patients in an “active control” group (patients receiving a complete regimen consisting of currently available anti-HIV drugs). After 24 weeks, approximately 92% of all patients taking etravirine experienced at least one side effect, compared to 91% of all patients in the active control group. The most common side effects were diarrhea, nausea, rash, and psychiatric problems. However, statistical analysis of these results concluded that there were no significant differences between the etravirine groups and the active control group in terms of side effects.

Preliminary results from another phase II clinical trial (TMC125-C227) comparing etravirine to a PI in patients with HIV resistant to current NNRTIs (but sensitive to current PIs) have been reported. The study enrolled HIV-positive patients who had failed a regimen containing an approved NNRTI, but had not taken a PI in the past, and randomized them to another regimen containing either etravirine or a PI. After 12 weeks, the patients in the PI group were more likely to have undetectable viral loads than the patients in the etravirine group. Based on these early results, the study was prematurely discontinued.

Results from another phase II clinical trial (TMC125-C223) comparing etravirine-based drug combinations to currently approved drug combinations have also been reported. Unlike TMC125-C227, this study enrolled 199 HIV-positive patients who had failed both NNRTIs and PIs in the past. The study volunteers were randomized to one of two etravirine doses (400mg or 800mg twice-daily) plus OBR, or an “active control” group. By week 48, approximately 39 of the 40 (98%) patients in the active control group had discontinued their selected treatment, mostly due to rebounding viral loads. In both etravirine groups, rebounds in viral load were only seen in 9% of the patients. Patients in the active control group remained on their selected treatment regimen for an average of 18 weeks, compared to an average of time on therapy of 48 weeks in the etravirine groups. Approximately 23% of patients in the 400mg etravirine group and 22% of patients in the 800mg etravirine group had viral loads below 50 after 48 weeks of treatment, compared to no patients in the active control group. As for CD4 counts (T cell counts), there was a 61 cell increase in the 800mg etravirine group and a 58 cell increase in the 400mg group. In the active control group, there was only a 13 cell increase.

Etravirine is also being studied in combination with Tibotec’s protease inhibitor, Prezista (darunavir). Data from a preliminary study involving ten patients—all of whom had significant HIV resistance to currently available PIs and NNRTIs—have been reported. The ten patients were treated with etravirine, Norvir-boosted darunavir, and at least two NRTIs for 12 weeks. Eight out of the ten patients had undetectable viral loads (<40) by week twelve and all patients saw a viral load reduction of at least 2 log.

Preliminary results from two Phase III clinical trials of etravirine have been reported. DUET 1 and DUET 2 are comparing etravirine (200 mg) to placebo, both combined with a background regimen in treatment-experienced patients with documented resistance to NNRTIs and PIs. For all patients, the background regimen includes twice-daily Prezista plus Norvir, along with a choice of NRTIs. Patients were also given the option of using the approved entry inhibitor Fuzeon (enfuvirtide). A total of 1,203 patients have been randomized and treated in the DUET studies—599 in the two etravirine groups and 604 in the two placebo groups. After 24 weeks, significantly more patients (59%) in the etravirine groups had viral loads below 50 copies, compared with those in the placebo groups (41%).

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What is known about side effects?
Headache, diarrhea, nausea, and rash appear to be the most common side effects of etravirine.

Additional information about the possible side effects of etravirine will come from phase II trials still being conducted and the new phase III studies.

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Who should not take etravirine?
It is not known whether etravirine will harm an unborn baby. It is very important to treat HIV/AIDS during pregnancy to reduce the risk of infecting your baby. Talk to your doctor about your treatment options.

It is not known whether etravirine passes into breast milk and what effect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed.

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Where can I learn more about clinical trials of etravirine?
If you would like to find out if you are eligible for any clinical trials that include etravirine, there is an interactive web site run by ACRIA, the AIDS Community Research Initiative of America.

For more information on the etravirine EAP, call 1-866-889-2074, send an e-mail to TMC125EAP@i3research.com, or visit the EAP description on clinicaltrials.gov

Another useful service for finding clinical trials is AIDSinfo.nih.gov, a site run by the U.S. National Institutes of Health. They have "health information specialists" you can talk to at their toll-free number at 1-800-HIV-0440 (1-800-448-0440).

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