Duration Pegylated Interferon/ribavirin for Prior Non-responders and Relapsers|
substantial proportion of chronic hepatitis C
patients -- especially those with HCV
genotype 1 -- do not achieve a sustained
response to standard interferon-based
therapy, leading researchers to study tailored treatment utilizing higher
drug doses and/or extended duration. Two such studies were reported at the recent
59th Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD 2008) in San Francisco.
the first study, Stephan Kaiser and colleagues evaluated at 72-week re-treatment
regimen in patients who relapsed after an earlier 48-week course of therapy. Relapse
refers to individuals who achieve HCV RNA suppression during therapy, but experience
viral rebound after completing treatment, and therefore do not achieve a sustained
virological response (SVR), or continued undetectable viral load 24 weeks post-treatment.
background, the researchers noted that 20%-30% of genotype 1 patients who receive
standard therapy with pegylated interferon
plus ribavirin for 48 weeks experience relapse, with the highest rates seen
in partial or slow responders (those with HCV RNA >15 IU/mL at weeks 4 and
12, but at least a 2 log drop at week 12).
The present study included
107 chronic hepatitis C patients who experienced prior relapse after 48 weeks
of treatment with pegylated interferon
alfa-2a (Pegasys) or alfa-2b (PegIntron) plus ribavirin. Most (74%) were men,
the average weight was 81 kg (about 179 lb), 81% had HCV genotype 1, and about
20% had advanced liver fibrosis or cirrhosis.
All patients were treated
with 180 mcg/week Pegasys plus 1000-1200 mg/day weight-adjusted ribavirin for
72 weeks. Virological response was assessed at week 4 (rapid virological response
or RVR; HCV RNA < 15 IU/mL), week 12 (early virological response or EVR; HCV
RNA > 15 IU/mL at week 4 but at least a 2 log drop at week 12), week 24 (HCV
RNA < 15 IU/mL), week 72 (end of treatment response or EOT, HCV RNA < 15
IU/mL), and week 96 (SVR; HCV RNA < 15 IU/mL 24 weeks after completing treatment).
The overall SVR rate was 51%.
Overall, 27% of patients achieved RVR, of whom 97% went on to achieve SVR.
43% had HCV RNA < 15 IU/mL at week 12, of whom 93% achieved SVR.
92% had undetectable HCV RNA at week 24.
79% achieved an EOT response.
Viral breakthrough during treatment occurred in 4 patients.
The total relapse rate (during and after treatment) was 36%.
9 patients discontinued treatment prematurely, 6 of them due to adverse events
or laboratory abnormalities.
16% of patients required a dose reduction of pegylated interferon and 21% reduced
their doses of ribavirin.
on these findings, the researchers concluded, "A treatment duration of 72
weeks with peginterferon alfa-2a plus ribavirin in patients that had relapsed
to previous therapy resulted in high SVR rate, particularly in those who were
negative at weeks 4 and 12."
Therefore, they continued, "with 72
weeks of re-treatment, sustained virological response can be achieved in approximately
half of patients that previously relapsed with 48 weeks of treatment."
previously reported, the REPEAT study found that 72 weeks of treatment with
Pegasys plus ribavirin was more effective than 48 weeks in more than 900 prior
non-responders, with SVR rates of 16% and 8%, respectively.
sustained response rates remain low, and interferon-based therapy is associated
with potentially severe side effects. At AASLD, Patrick Marcellin and colleagues
reported results from an analysis of the risk-benefit ratio of treating non-responders
for 72 versus 48 weeks, comparing adverse event (AE) rates and outcomes for the
2 treatment durations.
A total of 942 REPEAT participants were randomly
assigned to receive double-dose Pegasys (360 mcg/week) for 12 weeks, followed
by 180 mcg/week for a total of either 72 weeks (Arm A) or 48 weeks (Arm B). Other
arms received only the standard dose of 180 mcg/week for either 72 weeks (Arm
C) or 48 weeks (Arm D). All received 1000-1200 mg/day weight-adjusted ribavirin.
The risk-benefit ratio of treatment was assessed by calculating AE incidence
per case of SVR, and by calculating the number of total treatment days and treatment
days with AEs per SVR.
4047 on-treatment AEs were reported among 473 patients in the 72 week arms (A&
C), compared with 3814 AEs among 469 patients in the 48-week arms (B & D).
The total number of on-treatment AEs and cumulative treatment days with any AEs
or serious AEs were slightly higher in patients randomized to receive treatment
for 72 weeks versus 48 weeks.
However, AE incidence per treatment year was lower for patients receiving 72 weeks
of treatment (8.1 vs 10.1 AEs per year).
This difference became more favorable for 72 weeks of treatment when the cumulative
treatment duration required to achieve SVR (6.7 vs 10.0 years) and AE burden per
SVR (55 vs 100 AEs) were taken into consideration.
treatment duration of 72 weeks compared with 48 weeks of [Pegasys] plus ribavirin
did not impose a large additional adverse event burden on patients who were previous
non-responders to [PegIntron] plus ribavirin undergoing retreatment with [Pegasys]
plus ribavirin in REPEAT," the investigators concluded.
the significantly higher SVR rate is considered, extended treatment has a favorable
risk: benefit ratio," they continued. "These data demonstrate that a
72-week regimen of [Pegasys] plus ribavirin is the preferred treatment duration
for non-responders to previous [PegIntron]/ribavirin therapy."
Kaiser, B Lutze, HG Hass,and others. High sustained virologic response rates in
HCV genotype 1 relapser patients retreated with peginterferon alfa-2a (40KD) plus
ribavirin for 72 weeks. 59th Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008.
P Marcellin, A Craxi, CE Brandao-Mello, and others. 1873.
A 72-week treatment duration with peginterferon alfa-2a (40KD) (PEGASYS) plus
ribavirin (COPEGUS) has a favorable risk:benefit ratio in non-responders to pegylated
interferon alfa-2b (12KD) plus ribavirin: findings of the multinational REPEAT
study. 59th Annual Meeting of the American Association for the Study of Liver
Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1873.