Isentress Offers Long-Term Benefits for Drug-Resistant Patients

September 18, 2007

By Tim Horn

New follow-up data from a Phase II clinical trial evaluating Merck's integrase inhibitor Isentress (raltegravir) suggests that the drug may offer long-term benefits to HIV-positive people with extensive treatment experience and drug resistance. The study also suggests that drug combinations containing Isentress are relatively well-tolerated.

The results were reported today at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago. Forty-eight weeks of follow-up data were reported by Jose Gatell, MD, PhD, of the Evandro Chagas Clinical Research Institute in Rio De Janeiro, Brazil.

The clinical trial compared Isentress plus an optimized background regimen (OBR) to placebo plus OBR, looking at changes in viral load and CD4 cell counts, along with safety and tolerability. Enrolled study volunteers received one of three doses of Istentress (200mg, 400mg, or 600mg) or placebo—both taken twice daily—plus OBR consisting of available HIV drugs that were selected using drug-resistance testing.

When the 400mg twice-daily Isentress dose was selected for use in the Phase III BENCHMRK studies, the Phase II study was amended so that everyone was offered open-label Isentress after they had been followed in their original double-blind treatment group for at least 24 weeks.

After 178 patients completed the double-blind part of the study, 100 volunteers—including six patients originally assigned to the placebo group—made the switch to open-label Isentress plus OBR.

On average, enrolled patients had been on some form of HIV therapy for nine years—averaging four previous drug regimens—and had viral loads between 40,000 and 70,000 upon entering the trial. Their CD4 cell counts, prior to beginning either Isentress or placebo, ranged from 220 to 274.

According to Dr. Gatell, reductions in viral load observed at week 24 were sustained over 48 weeks. After almost a year of therapy, 64 to 71 percent of those taking Isentress plus OBR had viral loads below 400; 46 to 64 percent had viral loads below 50. What’s more, among patients followed for up to 72 weeks, viral loads remained below 400 in approximately 70 percent.

CD4 counts increased, on average, by 64 to 110 cells among patients treated with Isentress plus OBR over 48 weeks.

Of the 38 patients who saw their viral loads rebound while on treatment, 35 had evidence of drug resistance to Isentress, documented using genotypic testing.

The risk of Isentress failing was highest among patients who were highly resistant to all of the drugs used in their OBRs, underscoring the importance of constructing treatment regimens that contain at least two effective antiretrovirals.  Dr. Gatell reported that, among the 38 patients no longer responding the their regimen, 68 percent used an OBR that didn't contain any active agents.

Istentress, at all doses studied, plus OBR was reported to be generally well-tolerated and comparable to placebo plus OBR. The most common side effects in the double-blind component of the study were diarrhea, nausea, fatigue, headache and itching. Five patients discontinued treatment due these (or other) adverse effects.

Earlier this month, an FDA advisory committee recommended that Isentress be approved for the treatment of drug-resistant HIV. An official decision from the agency is expected by mid-October.

Source:

Grinsztejn B, Nguyen B, Katlama C, et al. 48 week efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus [Abstract H-713]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 2007.

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