It
is well recognized that chronic hepatitis C patients with certain characteristics
are more difficult to treat successfully compared with those who do not have the
same profile. The former group includes patients with HCV
genotype 1 (G1), high HCV
viral load (HVL) and above average body weight.
The
sustained virologic response rates
(SVR) of these individuals is <50%. There is a pressing need to create
treatment strategies that will improve SVR among these individuals using the currently
available standard of care, peginterferon plus ribavirin.
In
the current study, presented as a poster at the 57th Annual Meeting of the American
Association for the Study of Liver Diseases (57th AASLD) in Boston, MA (October
27-31, 2006), researchers at multiple medical centers in the US and Puerto Rico*
sought to determine whether treatment intensification of these difficult-to-treat
patients could increase their SVR rates without causing undue risk from adverse
effects (AEs).
Treatment
intensification in this prospective, controlled pilot study consisted of higher
fixed doses of peginterferon
alfa-2a (Pegasys) and ribavirin (Copegus). The study enrolled 187 HCV treatment-naïve
adults with G1, HCV RNA (viral load) >800,000 IU/mL and bodyweight >85 kg.
These patients were randomized to 48 wks of either Pegasys 180 or 270 µg/wk
plus either 1200 or 1600 mg/d RBV, as follows:
Pegasys 180 g/week plus ribavirin 1200mg/day (Group A)
Pegasys 180 g/week plus ribavirin 1600mg/day (Group B)
PEgasys 270 g/week plus ribavirin 1200mg/day (Group C)
Pegasys 270 g/week plus ribavirin 1600mg/day (Group D)
SVR
in this study was defined as undetectable HCV RNA (<50 IU/mL) at 24 weeks following
cessation of therapy.
Results
187 patients were randomized and treated.
Approx 18% of pts in each arm had bridging fibrosis/cirrhosis.
Similar end-of-treatment
response rates were seen in the 3 test arms;
The highest SVR rate (47% vs 28%) occurred in Group D, the arm with the most intensive
regimen: Pegasys 270 µg/wk plus RBV 1600 mg/d, compared to standard dosing.
Improved
SVR was driven by a lower relapse rate (40% vs 19%), according to the study authors.
This regimen
was associated with an increased incidence of some hematological laboratory abnormalities
compared to standard dosing, and led to modifications for labs and adverse events
(AEs) and premature withdrawals for AEs.
Table
PegIFNα-2a
(40KD) 180 µg/wk +
PegIFNα-2a
(40KD) 270 µg/wk +
RBV
1200 mg/d (n=46)
RBV
1600 mg/d (n=47)
RBV
1200 mg/d (n=47)
RBV
1600 mg/d (n=47)
Mean
age, yrs Mean HCV RNA, x106 IU/mL
Mean weight, kg
Dose
modifications for adverse events or lab abnormalities (%) Peginterferon
alfa-2a (40KD) Ribavirin
20
24
26
45
17
45
28
60
Withdrawals
due to safety reasons (%)
13
6
17
23
Based
on these results, the authors conclude, "In pts with treatment-resistant
characteristics (G1, HVL and bodyweight >85 kg), higher fixed doses of both
peginterferon alfa-2a [Pegasys] 270 µg/wk and RBV 1600 mg/d led to a substantial
increase in SVR rate (19% more than standard dosing) but with some negative safety
trends."
"The
benefit of an increased SVR rate with higher fixed doses of peginterferon alfa-2a
and RBV should outweigh the increased potential for adverse events/lab abnormalities."
"These
results provide the rationale for future studies attempting to optimize treatment
response using higher doses of peginterferon alfa-2a and RBV and suggest opportunities
to further improve benefit/risk in patients with unfavorable treatment characteristics.
Commenting
on the implications of the study, lead investigator Dr. Michael Fried, Division
of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill,
said "If strategies using intensified treatment with peginterferon alfa-2a
and ribavirin are validated in larger studies, these findings suggest that even
more patients living with chronic hepatitis C can have treatment success." *University
of North Carolina, Chapel Hill, NC; University of Chicago, Chicago, IL; Fundacion
de Investigacion De Diego Santurce, Santurce, Puerto Rico; Kaiser Permanente Medical
Center, San Diego, CA; St. Louis University Gastroenterology, St. Louis, MT; Veterans
Administration Medical Center, Long Beach, CA; Scripps Clinic, La Jolla, CA; Roche,
Nutley, NJ; University of Florida , Gainesville, FL.
10/30/06
Reference M
Fried, D Jensen, M Rodriguez-Torres, and others. Improved sustained virological
response (SVR) rates with higher, fixed doses of peginterferon alfa-2a (40KD)
(PEGASYS®) plus ribavirin (RBV)(COPEGUS®) in patients with "difficult-to-cure"
characteristics. 57th AASLD. October 27-31, 2006. Boston, MA. Abstract 335.
Pegasys 180 g/week plus ribavirin 1200mg/day (Group A)
