Preliminary results from the M12-999 study show that treatment with ABT-450/ritonavir/ombitasvir plus dasabuvir and ribavirin is well tolerated and associated with high rates of sustained virologic response in adult liver transplant recipients with recurrent HCV genotype 1 infection.
Liver disease secondary to hepatitis c virus (HCV) is one of the most common indications for liver transplantation worldwide and is a primary cause of graft loss. HCV infection of the graft following transplant is common, with up to 30% of graft recipients developing graft cirrhosis within 5 years. Current interferon (IFN)-based HCV therapies have treatment-limiting toxicities and low efficacy, underscoring the need for the development of more effective therapy options with a less severe side effect profile.
During a general session Saturday at the 2014 EASL International Liver Conference in London, UK, Paul Y. Kwo, MD, professor of medicine in the Division of Gastroenterology/Hepatology at Indiana University School of Medicine, presented preliminary results from the M12-999 study, which is a phase II study that examined the safety and efficacy of combination ABT-450/ritonavir/ombitasvir plus dasabuvir and ribavirin in adult liver transplant recipients with recurrent HCV genotype 1 (HCV-G1) infection.
ABT-450 is an HCV NS3/4A protease inhibitor. Ombitasvir (formerly ABT-267) is a potent NS5A inhibitor and dasabuvir (formerly ABT-333) is an NS5B RNA polymerase inhibitor.
M12-999 is an ongoing open-label phase 2 study of 34 HCV-G1, non-cirrhotic liver transplant recipients with recurrent HCV-G1 infection. All patients received a 24-week treatment regimen of the co-formulated oral tablet of ABT-450/ritonavir/ombitasvir (150 mg/100 mg/25 mg QD) plus dasabuvir (250 mg BID) and ribavirin (1000-1200 mg divided BID).
The primary end point of the study was sustained virologic response at week 12 (SVR12) and at week 4 (SVR4). Other end points of interest were rapid viral response (RVR) and end-of-treatment-response (EOTR). Safety was also an important end point.
All patients included in the M12-999 study were between age 18 and 70 (median age was 59), with the majority of patients being male (over 80%), white (85%), and with a BMI of approximately 30. Study participants had all received a liver transplant 12 months or more before entering the study, with an average post-transplantation time of 48 months. All patients had been treatment-naïve since transplantation with no evidence of steroid-resistant rejection of the transplant. All patients had a screening biopsy-confirmed Metavir score less than or equal to F2, confirmed by liver biopsy.
A pre-M12-999 drug interaction study showed drug-drug interactions between cyclosporine and tacrolimus (both used in immunosuppression of transplant patients). Cyclosporine and tacrolimus doses were therefore adjusted during the M12-999 study at the discretion of the investigator; cyclosporin doses were adjusted to 1/5 of the pre-M12-999 study dose.
Presenting the preliminary efficacy results for these first 34 patients, Kwo said, “this IFN-free 24-week regimen of ABT-450/ritonavir/ombitasvir plus dasabuvir and ribavirin achieved high response rates in immunosuppressed post-liver transplant recipients with recurrent HCV-G1 infection.”
Kwo noted that in this ongoing study, “100% of these individuals achieved RVR and 100% achieved EOTR. 97% of patients to date have achieved SVR4 and 96.2% thus far have achieved SVR12.”
There was only 1 relapse that occurred on the third day of treatment that was associated with resistance-associated variants that were not present at baseline.
Kwo said the treatment regimen was well-tolerated in general, with generally mild adverse events. There were 2 serious adverse events during the study: one patient with a history of diabetes and peripheral edema developed moderate peripheral edema; another patient developed hypotension and tachycardia following an elective surgery.
Laboratory abnormalities were generally mild. There were no Grade 2 or 3 AST/ALT elevations; 2 patients had raised bilirubin 3 times the upper limit of normal, but this was transient and thought to be due to ribavirin. Three patients had reduction in haemoglobin and 5 patients received erythropoietin at the investigators’ discretion. Again these abnormalities were associated with ribavirin. No patients required transfusion and there were no discontinuations due to anaemia. There were no episodes of acute or chronic rejection. No patients died during this study.
According to Kwo, “with this preliminary data, we may be able to remove liver transplant recipients from the group of special populations, as we appear to have been able to do with patients with HIV infection in the era of protecting antiviral agents.”
Further study results will be released after follow-up.