A three-drug combination of direct-acting antivirals developed by AbbVie cured hepatitis C genotype 1 infection in 96% of transplant recipients with recurrent hepatitis C in a small phase II study reported earlier this month at the 49th annual meeting of the European Association for the Study of the Liver (EASL) in London.
The findings were presented by Dr Paul Kwo, Professor of Medicine at Indiana University, Indianapolis.
Hepatitis C recurs in almost all people who receive a liver transplant as a result of hepatitis C-related end-stage liver disease and it progresses rapidly in many patients. It has been estimated that around 25 to 30% of transplant patients with hepatitis C will develop cirrhosis again within five years of transplantation. In addition, liver transplant patients with hepatitis C are at high risk of organ rejection, requiring them to undergo liver transplantation again.
Effective treatment for hepatitis C recurrence in liver transplant patients is a high priority. The M12-999 study was designed to evaluate the safety and efficacy of a regimen of three direct-acting antivirals developed by AbbVie. The investigational therapy consisted of the protease inhibitor ABT450 with ritonavir booster (150mg/100mg once daily), the NS5A inhibitor ombitasvir (ABT-267) (250mg once daily) and the non-nucleoside NS5B polymerase inhibitor dasabuvir (ABT-333) (250mg twice daily), and ribavirin.
The study recruited patients under the age of 70 who had undergone liver transplantation at least one year prior to study entry and who had experienced recurrence of hepatitis C genotype 1 infection. The study excluded people with more aggressive liver disease (fibrosis score > F2) or those who had already undergone post-transplant treatment for hepatitis C. All participants were receiving a stable immunosuppressant regimen (tacrolimus or cyclosporine) and prednisone use (<5mg/day) was permitted.
The study recruited 34 people with an average age of 59 years, 79% male. The average time since liver transplantation was four years and 47% of participants already had F2 stage fibrosis. The study population was predominantly infected with genotype 1a virus (85.3%) and had a very high viral load (6.6log10IU/ml). 85.3% of participants were receiving tacrolimus, and 14.7% cyclosporine. The mean creatinine clearance was just below the normal range (90.5 ml/min).
The primary outcome of the study was virological response 12 weeks after completion of treatment (SVR12). Thirty-four patients had completed treatment by the time the results of the study were analysed; all of these patients had an undetectable viral load (end of treatment response). Thirty-three had completed four weeks of post-treatment follow up and one patient experienced viral relapse during this period. Twenty-six patients had completed 12 weeks of post-treatment follow up; of these, 25 had achieved SVR12, considered a cure.
No patients experienced organ rejection during the study. One patient discontinued treatment at week 18 due to moderate rash, memory impairment and anxiety but achieved SVR12. Two serious adverse events were reported but were not considered to be associated with study medication (one case of tachycardia after initiation of tamsulosin prior to surgery, and one case of peripheral oedema and pain in a diabetic patient with a history of this condition).
The most common adverse events were headache, fatigue, cough and insomnia, each reported by more than 25% of patients.
Two cases of bilirubin elevation were reported and one patient experienced a haemoglobin decline below 8g/dL. Thirty-five per cent of patients had haemoglobin levels below 10g/dL during the study and dose modifications were necessary in approximately 20% of patients.
Ritonavir, used to boost blood levels of ABT-450, has the potential to greatly elevate blood levels of tacrolimus. Tacrolimus levels were monitored in all patients. There was no significant increase in average tacrolimus levels across the whole study population, but four patients did experience increases above 15 ng/ml. In each case the increase was a consequence of errors in tacrolimus dosing. In the five patients taking cyclosporine no significant increase in drug levels was observed.
References
Kwo P et al. Results of the Phase 2 study M12-999: interferon-free regimen of ABT-450/r/ABT-267+ABT-333+ribavirin in liver transplant recipients with recurrent HCV genotype 1 infection. 49th Meeting of the European Association for the Study of the Liver (EASL), London, abstract O144, 2014.