CHICAGO – The addition of telaprevir to standard hepatitis C treatment substantially improved sustained virologic response rates across all IL28B genotypes in an unplanned post hoc analysis of the phase III ADVANCE trial.
The sustained virologic response (SVR) rate doubled and even tripled in patients with the CT or TT allele, and those with the CC allele also experienced an increase in SVR when telaprevir (Incivek) was included in the regimen, lead investigator Dr. Ira M. Jacobson reported in a late-breaking abstract session at the annual Digestive Disease Week.
Dr. Ira Jacobson
Single nucleotide polymorphisms in the region of the IL28B gene have been strongly associated with response to standard treatment with pegylated interferon and ribavirin in patients infected with genotype 1 hepatitis C virus (HCV).
The current findings will change the physician dialogue with patients disheartened by early IL28B findings indicating that patients with the CC allele achieved much better responses than those with the CT or TT alleles, session cochair Dr. Andrew J. Muir said in an interview.
"From a clinical standpoint, some of my patients who did not know if they were CC or TT were very concerned," he said. "This changes that discussion a lot. All those patients can see they all get a benefit from this treatment. The CC [patients] still do better, but the fact that the TT and CT do very well is what the important message is for those patients."
The other benefit is that a shorter course of hepatitis C treatment might be possible for patients with the CC allele, said Dr. Muir, clinical director of hepatology at Duke University, Durham, N.C.
At press time, U.S. Food and Drug Administration approval of the protease inhibitors telaprevir and boceprevir was considered imminent, after the two drugs garnered unanimous support in late April from an FDA advisory committee. Pivotal data from the ADVANCE trial in patients with untreated HCV infection showed SVR rates of 75% for patients on a 12-week regimen of telaprevir plus standard treatment with pegylated interferon and ribavirin (PR) followed by 12 or 36 weeks of PR alone; 69% for those on 8 weeks of telaprevir plus PR followed by 4 weeks of placebo plus PR, followed by 12 or 36 weeks of PR alone; and just 44% for those on PR for 48 weeks (with placebo for telaprevir during the first 12 weeks).
The dosages used were: telaprevir, 750 mg every 8 hours; peginterferon alfa-2a, 180 mcg/week; and ribavirin, 1,000 or 1,200 mg/day.
The researchers conducted the genotype analysis during evaluation of an exploratory diagnostic assay that characterizes genetic polymorphisms near the IL28B gene. Using leftover, deidentified samples, test results were available for 454 (42%) of the 1,088 HCV genotype 1 patients at ADVANCE sites in the United States. Only white patients were genotyped for IL28B because of the small number of patients of other races.
The allele distribution was consistent with previous reports about treatment-naive patients, with 49% of patients having the CT allele, 33% the CC allele, and 18% the TT allele, said Dr. Jacobson, chief of the division of gastroenterology and hepatology at New York-Presbyterian Hospital/Weill Cornell Medical Center in New York.
SVR rates among patients with the CC allele were 90% with 12-week telaprevir plus PR, 84% with 8-week telaprevir plus PR, and 64% with PR alone.
The largest improvements in response, however, were observed in patients with the CT and TT alleles – the addition of telaprevir doubled and even tripled SVR rates, Dr. Jacobson said. SVR rates in the CT group reached 71% with 12-week telaprevir plus PR, 57% with 8-week telaprevir plus PR, and 25% with PR alone. SVR rates in the TT group were 73%, 59% and 23%, respectively.
"The impact of 12- and 8-week telaprevir appear to be greater in patients with a T allele than with a CC allele," he said.
Rapid virologic response (RVR) rate, defined as undetectable HCV RNA at week 4, and eRVR, defined as undetectable HCV RNA at weeks 4 and 12, were improved with the telaprevir-based regimens across all IL-28B genotypes, compared to PR alone.
The RVR rates in patients with the CC allele were 84% with the 12-week telaprevir regimen plus PR vs. 71% with 8-week telaprevir plus PR and 16% for PR alone. Corresponding data for the CT allele were 60%, 62%, and 2%, and for the TT allele were 59%, 50%, and 0%.
Most eRVR patients achieved SVR to telaprevir with PR in all allele groups: CC at 95%, CT at 92%, and TT at 80%, Dr. Jacobson said. Patients with the CT and TT alleles who did not achieve eRVR had lower SVR rates than CC patients.