Neil Osterweil

November 12, 2014

BOSTON — An interferon-free combination drug regimen produces a high rate of sustained virologic response with good safety in liver transplant recipients with recurrent hepatitis C viral infection, according to the open-label CORAL-1 study.

Sustained virologic response 12 weeks after treatment was 97.1%, reported Parvez Mantry, MD, from the Liver Institute at the Methodist Dallas Medical Center.

To coincide with the presentation here at The Liver Meeting 2014, the study was published online November 11 in the New England Journal of Medicine.

"The regimen definitely works, and we get extraordinarily high efficacy rates," Paul Kwo, MD, from Indiana University in Indianapolis, who was one of the study researchers, told Medscape Medical News.

Hepatitis C infections and the liver damage they cause are the leading indications for liver transplantation worldwide, but reinfection after transplantation is nearly universal.

Liver transplant recipients on chronic immunosuppression fare poorly with interferon-based regimens. Although such regimens have been the mainstay of hepatitis C therapy, they are rapidly being supplanted by new targeted antiviral therapies.

CORAL-1 involved noncirrhotic adults with recurrent chronic hepatitis C genotype 1 infection and no or only mild fibrosis who had undergone liver transplantation. They were treated with an oral direct-acting antiviral regimen for 24 weeks.

The patients received the once-daily combination of the NS5A inhibitor ombitasvir 25 mg and the protease inhibitor ABT-450 150 mg boosted with ritonavir 100 mg. In addition, they received and the nucleoside polymerase inhibitor dasabuvir 250 mg twice daily, with or without ribavirin, which was administered at the discretion of investigators.

Sustained Virologic Response

This regimen has been studied in more than 2700 patients with hepatitis C genotype 1 primary infection, and has produced rates of sustained virologic response 12 weeks after treatment that are in the low- to mid-90% range in treatment-naïve and treatment-experienced patients with and without compensated cirrhosis, Dr Mantry explained.

Because the regimen has been shown to have drug–drug interactions that can significantly increase the serum half-life of calcineurin inhibitors (such as tacrolimus and cyclosporine), the team recommended dose adjustments for the immunosuppressants, but left the management of the drugs to the discretion of the individual investigators.

For the 34 adults enrolled in the study, mean time from transplantation was 39.5 months.

In an intention-to-treat analysis, 33 of the 34 patients met the primary end point of sustained virologic response at 12 weeks. For the secondary end points of sustained response at 4 and 24 weeks, results were identical to 12-week responses. All patients had a rapid viral response, and all had an end-of-treatment response as well.

No patients experienced virologic breakthrough, but in one patient, a virologic relapse was detected 3 days after the end of treatment. At the time of relapse, this patient had viral variants associated with resistance that were not present at baseline.

The regimen was generally well tolerated, although one patient discontinued the study on day 144 because of a moderate rash, memory impairment, and anxiety. However, this patient had achieved sustained responses at 12 and 24 weeks.

There were two serious adverse events. One patient had hypotension and tachycardia associated with the use of tamsulosin (Flomax) after elective surgery, and one with a history of diabetes and edema had moderate peripheral edema and extremity pain.

Two patients had a grade 3/4 laboratory abnormality — an elevation of bilirubin more than 3 times the upper limit of normal. This finding is consistent with the known inhibitory effect of ABT-450 on bilirubin transporters, and on the dose-dependent hemolytic anemia associated with ribavirin. All patients who required a reduction in ribavirin dose went on to achieve a sustained response at 24 weeks, Dr Mantry reported.

Five patients required treatment for anemia with erythropoietin.

On the basis of these positive results, the study cohort is being expanded to include patients with stage 3 fibrosis and those with cirrhosis, Dr Kwo told Medscape Medical News. The researchers will also explore 12-week and ribavirin-free regimens.

"This is remarkable, with a nearly 100% response rate," said session comoderator Ray Kim, MD, from the Stanford University Medical Center in California.

"Whether this regimen is the answer, or whether some of the sofosbuvir-containing regimens will be as good or better remains to be seen, but this certainly looks very attractive," Dr Kim told Medscape Medical News.

This study was supported by AbbVie. Dr Mantry and Dr Kwo report serving as consultants to the company or to Abbott, its affiliate. Dr Kim has disclosed no relevant financial relationships.

The Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract 198 Presented November 11, 2014

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