Friday, November 16, 2012

AASLD-Investigational HCV Regimens Ditch the Interferon

Infectious Diseases

Investigational HCV Regimens Ditch the Interferon

By: NEIL OSTERWEIL, Family Practice News Digital Network

BOSTON – Poor interferon: It was once the favored (and virtually only) effective therapy for hepatitis C viral infections, and now clinicians can’t wait to get rid of it.

Several investigational interferon-free oral regimens were the focus of studies presented at the annual meeting of the American Association for the Study of Liver Diseases.

The regimens combine various flavors of direct-acting antivirals (DAAs), with or without interferon’s faithful sidekick ribavirin, in dizzying combinations with varying degrees of efficacy.

Triple Therapy With Only New Agents

A triple DAA regimen that has been under study consists of daclatasvir, an investigational viral NS5Areplication complex inhibitor; asunaprevir, an investigational NS3 protease inhibitor; and BMS-791325, a nonnucleoside NS5B polymerase inhibitor (all three were from Bristol-Myers Squibb). This cocktail yielded high sustained virologic response (SVR) rates after both 12 and 24 weeks of treatment in previously untreated noncirrhotic patients with hepatitis C virus (HCV) genotype 1 chronic infections.

"SVR4 [SVR at 4 weeks post therapy] was achieved in all treatment-naïve genotype patients with post-treatment data available, including harder-to-treat patients with genotype 1a infection, high viral load, non-cirrhotic IL28b genotype," said Dr. Gregory T. Everson, professor of medicine and director of the section of hepatology at the University of Colorado in Denver.

In pilot studies, a dual regimen of daclatasvir and asunaprevir for 24 weeks was effective in prior null responders with genotype 1b but not 1a infections, prompting the investigators to see whether a triple whammy could improve efficacy in genotype 1a infections, remain tolerable, and ideally, be effective when given for only 12 weeks.

The ongoing open-label study compares daclatasvir 60 mg daily, asunaprevir 200 mg twice daily, and BMS-791325 75 mg twice daily for 12 or 24 weeks; a second part of the study looking at the combination with a 150-mg-higher dose of the latter agent does not have mature data as yet.

In a modified intention-to-treat analysis at 4 weeks of treatment, all 16 patients in a 24-week treatment cohort had HCV RNA levels below the lower limit of quantification (LLOQ). A the primary end point of 12 weeks, 15 (94%) had maintained viral suppression. At week 4 post treatment, 15 of the 16 patients still had viral RNA below the quantifiable level, for an SVR4 rate of 94%. One patient in this cohort withdrew from the trial at week 9 and is therefore considered a treatment failure.

In a second cohort of 16 patients treated for 12 weeks, rates of below-target or undetectable HCV RNA were 100% at treatment week 4, and 88% at week 12. Two patients who had withdrawn from the trial before the protocol-defined last treatment and therefore were not included in the 12-week analysis also had RNA levels below the LLOQ on subsequent visits, Dr. Everson said. The SVR4 and SVR12 rates were each 94% in this cohort.

The regimen was generally tolerated. No patients dropped out of the study due to adverse drug-related events, and no cases of viral breakthrough or post-treatment relapse have been reported to date, Dr. Everson said.

Ribavirin Optional

In another study, Dr. Mark S. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore, and his colleagues reported on a combination of daclatasvir and Gilead’s HCV polymerase inhibitor sofosbuvir with or without ribavirin, in patients with HCV genotypes 1, 2, and 3.

They looked at the combination of the two DAAs with or without ribavirin for 24 weeks of treatment in treatment-naïve patients with genotypes 1a or 1b, 2, and 3, and in two separate arms for 12 weeks in patients infected with genotypes 1a or 1b.

In the open-label trial, patients were randomly assigned to one of eight treatment groups. A total of 44 patients infected with genotypes 2 or 3 were assigned to receive daclatasvir 60 mg and sofosbuvir 400 mg daily, with one group also receiving ribavirin. In addition, 44 patients with genotypes 1a or 1b were assigned to daclatasvir and sofosbuvir at the same doses, with or without ribavirin, and in a separate randomization, 82 patients with genotype 1a or 1b were assigned to receive 12 weeks of the two DAAs with or without ribavirin.

The authors found that the combinations achieved SVRs in more than 93% of the entire patient sample. Among 44 patients with genotypes 2 or 3, 93% had an SVR24 rate of 93%, with 1 patient having a confirmed relapse.

Among 126 patients with genotype 1, 96% of those who had reached 12 weeks post treatment had an SVR12, including 3 who did not have an SVR4. The SVR24 rate in this group was 98%. One patient in this group was reinfected with a new HCV strain.

"Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin," Dr. Sulkowski said.

He noted that the combination was generally well tolerated, with low hemoglobin – often a concern with DAAs – occurring only among those patients who received ribavirin.

Sofosbuvir Stands Alone (Almost)

Another relatively simple regimen that was well tolerated and achieved sustained virologic response in some patients was a combination of sofosbuvir and weight-based or low-dose ribavirin. This combination was associated with a significant number of relapses, however.

Dr. Anu Osinusi, a clinical investigator at the National Institute of Allergy and Infectious Diseases, sought to determine whether a less complex and more tolerable regimen could be effective in an urban population with untreated HCV infection.

They enrolled 60 patients with HCV genotype 1. The majority of the patients were African Americans. In part 1 of the trial, the patients had stage 0 to 2 fibrosis. Part 2 of the trial included patients with all stages, including those with Child-Pugh Class A disease. Patients in part 1 received sofosbuvir 400 mg plus ribavirin 1,000-1,200 mg (10 patients). In part 2, 25 patients each were randomized either to the regimen above or to the same dose of sofosbuvir with low-dose ribavirin (600 mg).

In an interim intention-to-treat analysis, there was one dropout in part 1, and the remaining nine patients all had HCV RNA less than the LLOQ at weeks 4 and 12, at end of treatment, and maintained them out to SVR12.

In the second, randomized phase, 1 patient dropped out at week 3 of treatment in the full-dose ribavirin group; the remaining 24 patients all had RNA undetectable or below target at weeks 4, 12, and end of treatment, but by post-treatment week 4, 6 patients had relapse, yielding an SVR4 of 72%.

In the low-dose ribavirin arm, 3 patients dropped out by week 8. The remaining 22 patients, while on treatment, all had viral suppression at week 4, but 4 weeks after the end of therapy, 8 patients had relapsed, leaving an SVR4 of 56% (64% in a modified intention-to-treat analysis). "Ongoing analysis is currently focused on identifying the biologic correlates of HCV clearance, as well as identifying the mechanisms of relapse," Dr. Osinusi said.

The relapses were independent of baseline factors such as HCV RNA level, IL28B genotype, weight, race, degree of fibrosis, and ribavirin dose.

Both regimens were well tolerated, and both produced significant improvement of inflammation with treatment.

Dr. Everson’s study was supported by Bristol-Myers Squibb. He has received research support from the company. Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Osinusi’s study was funded by the National Institutes of Health. She reported having no relevant financial disclosures.

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