Michael Curry of Beth Israel
Center in Boston presented findings from a study of
sofosbuvir and ribavirin to prevent HCV recurrence following liver
transplantation. Sofosbuvir (formerly GS-7977) is a once-daily oral nucleotide
polymerase inhibitor with a high barrier to resistance.
phase 2 study enrolled 61 people at 16 sites, mostly in the US.
Most participants (80%) were men, 90% were white and the median age was 59
years. A majority (73%) had HCV genotype 1 (including 39% with harder-to-treat
subtype 1a), 13% had genotype 2, 12% had genotype 3 and one had genotype 4.
Three-quarters had previously been treated for hepatitis C and 22% had the
favourable IL28B CC gene variant associated with interferon responsiveness.
had well-compensated liver disease and were listed for transplantation due to hepatocellular carcinoma, a type of liver
cancer. The median MELD score was 8
and most had Child-Pugh scores of 5 (43%), 6 (30%) or 7 (23%). People with
hepatitis B or HIV co-infection, decompensated cirrhosis or kidney impairment
Participants received 400mg once-daily sofosbuvir plus 1000-1200mg/day
weight-based ribavirin while awaiting transplants. The original protocol called
for treatment lasting 24 weeks but this was later extended to 48 weeks. The
last dose was taken on the day of transplantation. They received standard
immunosuppressive therapy (tacrolimus, mycophenolate mofetil or prednisone) to prevent rejection of the new
The primary study endpoint was post-transplant
virological response, or continued undetectable HCV RNA among people who
received sofosbuvir/ribavirin for more than 12 weeks and had undetectable viral
load at the time of transplantation.
A total of 41 of participants underwent
transplantation with undetectable HCV RNA while three people did so while viral
load was still detectable. Ten discontinued treatment, four finished treatment
but were still awaiting transplants and one was still on therapy while waiting.
HCV viral load declined rapidly after starting
sofosbuvir/ribavirin. Most patients who received treatment for any duration
(93%) or for at least 12 weeks (91%) had HCV RNA below the lower limit of
quantitation (LLOQ) at the time of transplantation. Among those with
undetectable HCV at transplantation, 64% maintained viral suppression at 12
People who did not experience HCV recurrence had
undetectable viral load for a median of 95 days before transplantation compared
with just 5.5 days for those who did have a recurrence. Only 1 patient had a
recurrence after having undetectable HCV for 30 days or more.
In a multivariate analysis, longer duration of
undetectable HCV RNA prior to transplantation was the only factor that significantly
predicted HCV non-recurrence. HCV genotype 1b and IL28B CC status were of
borderline significance in a univariate analysis but not the multivariate
Sofosbuvir/ribavirin was generally safe and well
tolerated in this difficult-to-treat population. There were 11 serious adverse
events – none of which were considered related to sofosbuvir – and two
discontinuations due to adverse events (3%), as well as seven cases of grade 4
laboratory abnormalities. Three people died before transplantation and five
afterwards. The most common side-effects were fatigue (38%), anaemia (23%) and
"Sofosbuvir + ribavirin treatment prior to
transplantation prevented HCV recurrence in the majority (64%) of patients who
were HCV RNA <LLOQ at transplant," the researchers concluded. "The
number of consecutive days with HCV RNA [undetectable] prior to transplant
appears to be the strongest predictor of post-transplant virological
These results, Curry said, are a "vast improvement" over current
treatment. But it is not yet possible to answer an audience question about
whether it might be advisable to delay transplantation in order to take
sofosbuvir for longer prior to transplantation.