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.
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
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
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