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IDEAL Study Published-Pegasys v PegIntron

My trial doctor told me about this study today when I told him my concerns about my dose reduction of pegintron after significant neutropenia. There is a lot of interesting information here.



IDEAL Study Published-Pegasys v PegIntron

Head-to-Head Trial Finds HCV Regimens Equal

MedPage Today
July 22, 2009

SAN FRANCISCO, July 22 -- Treatment with one recognized hepatitis C virus (HCV) regimen appears to be as effective as the other common regimen, according to findings of the largest comparative trial to date.

Sustained virologic response rates and tolerability were similar with peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (Pegintron) both in combination with ribavirin, John G. McHutchison, MD, of Duke University, and colleagues found.

Surprisingly, low-dose peginterferon alfa-2b was just as effective as the standard dose, they reported online, ahead of print, in the Aug. 6 New England Journal of Medicine.

While the choice between regimens has been hotly debated, physicians can have confidence whatever they choose, said coauthor Andrew J. Muir, MD, also of Duke.

Action Points

* Explain to interested patients that HCV infection is notoriously difficult: less than half of patients have viral suppression after treatment.

* Note that the study was not fully blinded and may not generalize to other genotypes of HCV.

Dr. Muir said he was also reassured to find that a clinical dose reduction to manage side effects may not jeopardize the chance of success.

Still, this finding should not be taken as a recommendation of the initial lower dose approach for everyone, Dr. McHutchison cautioned.

Current guidelines recommend either of the two available standard-dose regimens for the treatment of chronic hepatitis C, but they're based on noncomparative trials.

To provide comparative evidence, Dr. McHutchison's group conducted the Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study.

It included 3,070 patients with treatment-na•ve HCV genotype 1 -- the most common variant in the United States and Europe. They were randomized to 48 weeks of treatment with one of three regimens:

* Peginterferon alfa-2b at a standard dose (1.5 µg/kg body weight per week) plus ribavirin at a dose of 800 to 1400 mg per day.
* Low-dose peginterferon alfa-2b (1.0 µg/kg per week) plus ribavirin at 800 to 1400 mg per day.
* Peginterferon alfa-2a (180 µg per week) plus ribavirin at a dose of 1000 to 1200 mg per day.

For the two primary endpoints, neither peginterferon alfa-2b dose nor type of peginterferon used significantly impacted rates of sustained virologic response. Rates were similar between the three groups:

* 39.8% with standard-dose peginterferon alfa-2b plus ribavirin (95% confidence interval 36.8% to 42.8%).
* 38.0% with low-dose peginterferon alfa-2b plus ribavirin (95% CI 35.0% to 41.0%, P=0.20 versus standard dose).
* 40.9% with peginterferon alfa-2a plus ribavirin (95% CI 37.9% to 43.9%, P=0.57 versus standard-dose peginterferon alfa-2b).

Although peginterferon alfa-2a had the highest response rate among the regimens, it also had the highest relapse rate and was an independent risk factor for relapse, the researchers said.

"Patients treated with peginterferon alfa-2a were more likely to have a response while receiving therapy, followed by relapse after the completion of therapy," they noted, "whereas patients treated with peginterferon alfa-2b were more likely to discontinue therapy at treatment week 12 or 24 because of an insufficient virologic response."

The reason for this pattern of relapse remains unclear, Dr. McHutchison said.

Subgroup analysis suggested that women may have responded better to standard-dose than low-dose peginterferon alfa-2b (P=0.01 for interaction between treatment group and gender).

Also, black patients were more likely to achieve sustained virologic response with the standard dose of peginterferon alfa-2b, although no significant interaction was seen with race and treatment type.

Among the non-prespecified covariates, impaired fasting glucose also predicted a lower likelihood of sustained virologic response. That led the researchers to suggested further study to determine whether correcting glucose intolerance can improve treatment response.

The groups experienced similar adverse event types and frequencies.

Neutropenia severe enough to require peginterferon-dose reduction occurred in 21.1% of patients on peginterferon alfa-2a, 19.4% on standard-dose peginterferon alfa-2b, and 12.5% on low-dose peginterferon alfa-2b.

Hemoglobin levels low enough to require ribavirin-dose reduction were also least common with low-dose peginterferon alfa-2b (23.2% versus 28.2% standard dose and 25.8% with peginterferon alfa-2a).

However, discontinuation rates for either reason were low (2.1% to 5.9% for neutropenia and 2.1% to 3.8% for low hemoglobin).

The investigators noted that the study was limited by how the medications are formulated -- patients and doctors were not blinded to the type of peginterferon they were getting.

Also, the study compared regimens rather than directly comparing the two types of peginterferon because of the differences in ribavirin dosing.

Even so, in the 51% of patients across treatment arms who got the same dose of ribavirin, sustained virologic response rates were similar between peginterferon alfa-2a and -2b groups, Dr. McHutchison's group said.

Generalizability across HCV genotypes and to regions outside the United States may be limited, they added.

The study was supported by grants from Schering-Plough.

Dr. McHutchison reported conflicts of interest with Schering-Plough, Roche, and Vertex Pharmaceuticals.

Dr. Muir reported conflicts of interest with Schering-Plough and Vertex Pharmaceuticals.

Coauthors reported conflicts of interest with those companies, along with Pharmassett, Johnson & Johnson, Tibotec, ZymoGenetics, Biolex, Idenix, Conatus Pharmaceuticals, GlobeImmune, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Coley Pharmaceuticals, Pfizer, Wyeth, Valeant, Romark Laboratories, Human Genome Sciences, Lilly, Novartis, Westat, Beckman, Bayer, FibroScan, Kendle Phynova, LabCorp, Merck, Orasure Technologies, Ortho Diagnostics, Scripps Clinic Liver Research Consortium, Siemens, Debio Pharmaceuticals, Intarcia, Intercept, Genentech, Isis Pharmaceuticals, Three Rivers Pharmaceuticals, and Peregrine Pharmaceuticals.

Several authors were employees of Schering-Plough and stockholders in the company.

Primary source: New England Journal of Medicine
Source reference:
McHutchison JG, et al "Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection" N Engl J Med 2009; 361: 580-93.

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