An oral, interferon-free drug regimen produced a 97% rate of sustained virologic response in liver transplant recipients who had recurrent hepatitis C viral infection – “an historically difficult-to-treat population” at high risk of death who have extremely limited treatment options, according to a study reported at the annual meeting of the American Association for the Study of Liver Diseases.
In an industry-sponsored, open-label phase II trial involving 34 adults with recurrent HCV infection following liver transplantation, 24 weeks of daily ombitasvir plus the ritonavir-boosted protease inhibitor ABT-450 (ABT-50/r), added to dasabuvir and ribavirin, eradicated every patient’s HCV RNA levels within 4 months. Only one patient had a relapse during a further 24 weeks of follow-up, said Dr. Parvez Mantry of the Liver Institute at Methodist Dallas, who presented the data at the meeting.*
Results of the study, which was conducted at 10 transplant centers in the United States and Spain, were presented at the meeting and simultaneously published online Nov. 11 in the New England Journal of Medicine (N. Engl. J. Med. 2014 Nov. 11 [doi: 10.1056/NEJMoa1408921]).
The standard of care for treating recurrent HCV infection after liver transplantation has been 48 weeks of peginterferon with ribavirin, but response rates are relatively low (13%-43%) because of interferon’s toxic effects. Moreover, the agent is known to induce graft injury, reducing both graft and patient survival.
The investigators assessed the safety and efficacy of a tablet formulation combining ombitasvir, a potent NS5A inhibitor, with ABT-50/r, a protease inhibitor that increases peak, trough, and overall drug exposure and allows once-daily dosing. To this was added standard dasabuvir and ribavirin, with ribavirin dosing adjusted according to the treating physician’s discretion to avert adverse hematologic effects in these immunosuppressed transplant recipients. Modified doses of standard calcineurin inhibitors (cyclosporine or tacrolimus) also were recommended for all patients, and low-dose glucocorticoids were permitted as needed.
The study participants were 18-70 years of age (mean age, 59.6 years) and had received liver transplants because of chronic HCV infection a minimum of 1 year previously. They had no or only mild liver fibrosis, were receiving stable cyclosporine- or tacrolimus-based immunosuppression, and were not coinfected with HIV or hepatitis B.
The primary efficacy endpoint was a sustained virologic response (SVR) 12 weeks after treatment was completed. All the study participants achieved an SVR by week 4 of treatment, which persisted in all of them until treatment was completed. At that time, 1 patient relapsed, so the overall SVR rate was 97%. This same SVR rate was sustained through final follow-up at post-treatment week 24.
In the patient who relapsed, HCV DNA showed resistance-associated genetic variants that had not been present at baseline. This patient also had been unresponsive to previous peginterferon-ribavirin therapy.
Adverse events were common, although the majority were mild or moderate in severity. Fatigue, headache, and cough were the most frequent adverse events. Grade 2 elevations in total bilirubin developed in two patients (6%), with no jaundice or scleral icterus. Nine patients showed grade 2 decreases in hemoglobin; none required a blood transfusion, and five required erythropoietin. There were no deaths and no cases of graft rejection.
One patient discontinued the study drug at week 18 after developing moderate rash, memory impairment, and anxiety deemed to be possibly drug related. However, that patient had already achieved an SVR before discontinuing treatment, and that SVR persisted at final follow-up 12 weeks later.
However, this study was not large enough to allow adequate assessment of adverse event rates or comparison of them with rates for other treatments, the investigators noted.
The researchers also noted that these study participants were easier to treat than the general population of liver transplant recipients with recurrent HCV, because they did not have advanced fibrosis or comorbid infections. In addition, patients with early, aggressive forms of recurrent HCV, such as fibrosing cholestatic hepatitis, were excluded from this study, as were patients maintained on immunosuppressive agents other than cyclosporine or tacrolimus.
This trial was sponsored by AbbVie, whose employees also designed the study, gathered and analyzed the data, and wrote the report. Study investigator Dr. Paul Y. Kwo reported receiving personal fees and grants from, and serving on advisory boards for, AbbVie, Bristol-Myers Squibb, and other companies. His associates reported ties to numerous industry sources.
*Clarification, 11/11/14: A previous version of this story did not state that the data were presented by Dr. Mantry