Adding the approved HCV protease inhibitor
telaprevir (Incivo or Incivek) to pegylated interferon and
ribavirin can increase sustained viral response rates even for difficult-to-treat
liver transplant recipients, but adverse events are common, researchers reported
at the 48th International Liver Congress (EASL 2013) last month in
While many hepatitis C patients await interferon-free
direct-acting antiviral regimens, others have advanced liver disease and need
treatment now. This group includes liver transplant recipients, as HCV almost
always recurs and infects the new liver in the absence of treatment.
Elizabeth Verna from Columbia University and fellow
investigators with the CRUSH-C study evaluated triple therapy in a cohort of
liver transplant recipients at six US centres.
The analysis included 112 patients with HCV genotype 1 (55%
with harder-to-treat subtype 1a). Nearly 80% were men, a majority were white,
the median age was 58 years and 26% had the favourable IL28B CC gene variant.
Half had previously been treated with interferon-based therapy post-transplant,
with 25% being relapsers, 27% being partial responders and 48% being null
responders. Most had moderate-to-severe fibrosis. Participants used various
immunosuppressive regimens to prevent organ rejection including cyclosporine,
mycophenolate mofetil, tacrolimus and steroids.
Participants were treated with pegylated interferon,
ribavirin and one of the first-generation HCV protease inhibitors, telaprevir or
boceprevir (Victrelis). The median
time since liver transplantation at the start of therapy was 3.7 years.
Most patients (88%) used telaprevir, almost all with a
pegylated interferon/ribavirin lead-in. (This occurred as a consequence of
adding telaprevir to an existing course of therapy.) The median duration of
treatment after starting the HCV protease inhibitor was about 36 weeks. Standard
telaprevir triple therapy lasts 12 weeks, with pegylated interferon/ribavirin
alone continued through week 24 or 48, depending on early response. People who
received an extended lead-in of 90 days or longer were included in the safety
but not the efficacy analysis.
Looking at early virological response among participants who
had reached a given treatment duration, 66% of patients had undetectable HCV
RNA at week 4 of treatment, rising to 84% at week 12. Taken together, 64% had
extended rapid virological response (eRVR) – a good predictor of treatment
success in pivotal trials of easier-to-treat patients.
Of the 43 patients who completed therapy and
had at least 4 weeks of post-treatment follow-up, 65% achieved SVR4. Among
those with eRVR, however, the SVR4 rate rose to 93%. Extent of post-transplant liver
disease played a role, with 44% of patients with advanced disease
(cirrhosis or fibrosing cholestatic hepatitis) achieving SVR4
compared with 71% of those without advanced disease.
Adverse events were common in this cohort and 11%
discontinued treatment for this reason (23% with advanced disease and 6%
without). A majority of patients used growth factors, reduced their doses of
interferon or ribavirin, or required transfusions to manage blood cell
deficiencies. About one-third had creatinine increases indicative of impaired
kidney function. One in five experienced serious adverse events that required
hospitalisation, 4% experienced liver graft rejection and 6% died during
follow-up (4% due to liver-related causes).
"High rates of eRVR are achievable with triple therapy
exceeding previous rates with [pegylated interferon/ribavirin] alone despite a
difficult to treat population," the researchers concluded. "SVR4
rates may be lower in patients with advanced disease."
"These results must be balanced with high rates of
[adverse events], including hospitalization, kidney dysfunction and death,"
they continued. "Improving tolerability and identifying predictors of SVR
are critical to optimizing the risks-benefits of post-liver transplant triple