Pooled 24-week Data from DUET-1 and DUET-2 Show Etravirine (TMC 125) Is Active Against NNRTI-Resistant HIV

By Liz Highleyman

At the recent 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago, researchers presented further data showing that the investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (TMC 125) demonstrates antiviral activity against HIV that has developed resistance to other drugs in this class.

Researchers previously presented separate data from DUET-1 and DUET-2 at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention this past summer, and in the July 7, 2007 issue of The Lancet. * The presentation at ICAAC looked at pooled data from the 2 trials together.

DUET-1 and DUET-2 are identically designed, ongoing Phase III, double-blind, randomized trials of etravirine vs placebo, both in combination with an optimized background regimen containing the new protease inhibitor darunavir/ritonavir (Prezista), with or without enfuvirtide (Fuzeon; T-20).

The combined intent-to-treat population included 1203 patients. Most (89%) were men, 70% were Caucasian, 58% had CDC stage C HIV disease, the median HIV RNA level was 4.8 log10 copies/mL, and the median CD4 count was 105 cells/mm3.

At baseline, participants had documented NNRTI resistance-associated mutations (RAMs) and at least 3 primary protease inhibitor resistance mutations. About 25% started enfuvirtide for the first time, but about 17% had no fully active background drugs in addition to etravirine.

Results

• Etravirine was consistently superior to placebo with respect to:

- confirmed viral load < 50 copies/mL (59% vs 41%; P < 0.0001);
- viral load < 400 copies/mL (74% vs 53%; P < 0.0001);
- mean reduction in viral load (2.38 vs 1.69 log10 copies/mL; P < 0.0001);
- mean CD4 cell increase (86 vs 67 cells/mm3; P < 0.0001).

• 45% of patients with no other fully active drugs in their regimen achieved a viral load below 50 copies/ml.

• The response rate increased with more active background drugs.

• There was a trend toward reduced numbers of AIDS-defining illnesses and deaths in the etravirine arm.

• 13 baseline reverse transcriptase mutations (etravirine RAMs), usually present with additional NNRTI RAMs, were associated with decreased response to etravirine.

• A larger numbers of etravirine RAMs was associated with reduced responses to etravirine, with the largest impact among the 15% of patients with 3 or more etravirine RAMs.

• 75% of the patients with no etravirine RAMS achieved a viral load below 50 copies/ml.

• The K103N mutation, which confers resistance to nevirapine (Viramune) and efavirenz (Sustiva), was not associated with resistance to etravirine.

• Adverse events and laboratory data, including blood lipids and liver enzymes, were generally similar in the etravirine and placebo arms.

• Most adverse events were mild to moderate (Grade 1 or 2) and seldom led to treatment discontinuation (6% with etravirine vs 5% with placebo).

• The most common adverse events were skin rash (17% vs 9%), diarrhea (15% vs 20%), and nausea (14% vs 11%).

• Rashes in the etravirine arm were:

- usually self-limited and Grade 1 or 2 (only 1.3% with Grade 3, none with Grade 4);
- occurred during the first 1-2 weeks after starting the drug;
- were more common in women;
- had no apparent association with CD4 cell count;
- usually resolved if treatment continued;
- 2.2% discontinued for this reason.

• The nature, severity, and incidences of nervous system adverse events (15% vs 19%) and psychiatric adverse events (13% vs 15%) were similar in the etravirine and placebo arms.

Conclusion

Based on these findings the investigators concluded, "At week 24, in treatment experienced patients with documented NNRTI resistance, [etravirine] showed statistically superior virologic and immunologic responses vs placebo, and both groups showed a similar tolerability profile."

As previously reported, the U.S. Food and Drug Administration accepted etravirine for priority review in September , and is expected to issue a decision on approval by mid-January 2008.

Fundacion Huesped, Buenos Aires, Argentina; Univ. of California, San Diego, CA; Jacobi & N. Central Bronx Hosp., New York, NY; Hosp. Tenon, Paris, France; Univ. of Toronto, Canada; Tibotec, Mechelen, Belgium.

10/02/07

References

P Cahn, R Haubrich, J Leider, and others. Pooled 24-Week Results of DUET-1 and -2: TMC125 (Etravirine; ETR) vs Placebo in 1203 Treatment-Experienced HIV-1-Infected Patients. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL. September 17-20, 2007. Abstract H-717.

* J V Madruga, P Cahn, B Grinsztejn, and others (on behalf of the 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. The Lancet 370(9581): 29-38. July 7, 2007.

* A Lazzarin, T Campbell, B Clotet, and others (on behalf of the 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. The Lancet 370(9581): 39-48. July 7, 2007.