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AbbVie Combination Safe and Highly Effective in Patients with Post-Transplant HCV Recurrence


A 3-drug combination of direct-acting antivirals developed by AbbVie cured hepatitis C genotype 1 infection in 96% of transplant recipients with recurrent hepatitis C virus (HCV) in a small Phase 2 study reported last week at the 49th EASL International Liver Congress (EASL 2014) in London.


[Produced in collaboration with Aidsmap and infohep]

HCV recurs in almost all people who receive a liver transplant as a result of hepatitis C-related end-stage liver disease, and liver damage progresses rapidly in many patients after HCV recurrence. It has been estimated that around 25%-30% of transplant patients with hepatitis C will develop cirrhosis again within 5 years of transplantation. In addition, liver transplant patients with hepatitis C are at high risk of organ rejection, which may 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, presented by Paul Kwo of Indiana University, was designed to evaluate the safety and efficacy of a regimen of 3 direct-acting antivirals developed by AbbVie.

The investigational therapy consisted of the protease inhibitor ABT450 boosted with ritonavir (150/100 mg once-daily), the NS5A inhibitor ombitasvir (ABT-267)(250 mg once-daily), and the non-nucleoside NS5B polymerase inhibitor dasabuvir (ABT-333)(250 mg twice-daily), and ribavirin. All participants were treated for 24 weeks.

The study recruited patients under the age of 70 who had undergone liver transplantation at least 1 year prior to study entry and who had experienced recurrence of HCV genotype 1 infection. The study excluded patients with more aggressive liver disease (advanced fibrosis or cirrhosis, 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 (<5 mg/day) was permitted.

The study enrolled 34 patients with an average age of 59 years, 79% of them men. The average time since liver transplantation was 4 years and 47% of participants already had F2 stage fibrosis. The study population was predominantly infected with HCV genotype 1a (85%) and had very high viral load (6.6 log IU/mL). 85% were receiving tacrolimus and 15% 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). At the time the study results were analyzed, 34 patients had completed treatment. All of these patients had an undetectable viral load (end-of-treatment response). Among 33 participants who had completed 4 weeks of post-treatment follow-up, 1 patient experienced viral relapse during this period. Of 26 patients who had competed 12 weeks of post-treatment follow up, 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 still achieved SVR12. There were 2 serious adverse events reported but they were not considered to be associated with study medication (1 case of tachycardia after initiation of tamsulosin prior to surgery, and 1 case of peripheral edema 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. There were 2 cases of bilirubin elevation reported and 1 patient experienced anemia with a hemoglobin decline below 8 g/dL. 35% of patients had hemoglobin levels below 10 g/dL during the study and dose modifications were necessary in approximately 20%.

Ritonavir, used to boost blood levels of ABT-450, has the potential to greatly elevate blood levels of tacrolimus, so tacrolimus levels were monitored in all patients. There was no significant increase in average tacrolimus levels across the whole study population, but 4 patients did experience increases above 15 ng/mL. In each case the increase was a consequence of errors in tacrolimus dosing. Among the 5 patients taking cyclosporine, no significant increase in drug levels was observed.



P Kwo, P Mantry, E Coakley, 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 European Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O114.