Genotype
Genotype is the strongest
predictor of response to treatment.
Genotypes 1 and 4 do not respond to treatment as well as
genotypes 2 and 3, regardless of the type of interferon used
(Berg 2003; Fried 2002a; S. Lee 2002; McHutchison 1998; Poynard
1998). In their meta-analysis of data from three trials of
pegylated interferon alfa-2a, Lee and colleagues found a non-1
genotype to be the strongest independent predictor of SVR (OR,
4.11; 95% CI, 2.90-5.86; P=0.0001) (S. Lee 2002). A 24-week
course of treatment for individuals with genotypes 2 and 3
appears to be sufficient; a 48-week course of treatment is
recommended for individuals with genotypes 1 and 4 (Di Bisceglie
2002; Hadziyannis 2004).
Genotype 3 does not appear to be as sensitive to treatment as
genotype 2 (Mangia 2004: Zeuzem 2003). Zeuzem and colleagues
treated 224 individuals with HCV-2 or HCV-3 with 1.5 µg/kg of
pegylated interferon alfa-2b plus weight-based rivavirin (800 to
14,000 mg/day) for 24 weeks. Overall, 81% achieved sustained
virological response, but SVR rates were lower in those with
genotype 3 (79% [143/182]) than in genotype 2 (93% [39/42]).
Relapse rates were higher in genotype 3 (14% vs. 7% in genotype
2). The difference in response rates may be attributed in part
to steatosis and high baseline viral load. Steatosis was
significantly more prevalent in genotype 3 (P=0.003), and it was
associated with a high baseline viral load (P=0.001). Steatosis
of <5% was significantly associated with SVR (P=0.015) (Zeuzem
2003).
Genotype 4 may be more responsive to treatment than genotype
1. Sustained virological response rates from two studies that
used 48 weeks of pegylated interferon plus ribavirin have ranged
from 40% to 61% (Esmat 2003; Hassan 2003).
The viral kinetics of hepatitis C during early treatment
differ depending on the genotype of HCV (A. U. Neumann 2000;
Pawlotsky 2002; Zeuzem 2001). Frequent blood sampling from 12
individuals with HCV genotypes 1a, 1b, 2a, and 2b over the first
14 days of high-dose interferon revealed significant
differences. Individuals with genotypes 2a and 2b had larger and
more rapid decreases in HCV RNA after 48 hours than those with
genotypes 1a and 1b (2.95 log copies/mL vs. 1.65 log copies/mL;
t1/2 = 2.0 ± 0.5 hours vs. t1/2 = 3.0 ± 1.0 hours). At the end
of 14 days, a significantly larger proportion of individuals
with genotypes 2a and 2b had undetectable HCV RNA (P=0.03) (A.
U. Neumann 2000). An examination of first and second-phase viral
kinetics by genotype and mode of treatment (standard or
pegylated interferon monotherapy) revealed more rapid
first-phase and second-phase viral decay slopes for non-1
genotypes treated with pegylated interferon (Zeuzem 2001).
Pawlotsky and colleagues observed less marked decreases in
second-phase viral decay in genotypes 1 and 4 vs. genotype 3. At
four weeks of treatment, individuals with genotypes 1 and 4 were
less likely to be classified as rapid responders (individuals
with decreases ≥0.3 log per week) (Pawlotsky 2002).
http://www.aidsinfonyc.org/tag/coinf/hcv2004/chap5.html |
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24 weeks of peginterferon alfa-2a plus
ribavirin as effective as 48 weeks with higher-dose ribavirin for
HCV genotype 2 and 3 |
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By Jillian L. Lokere, MS
November 3, 2004 —
The current recommendation that patients infected with hepatitis C virus
(HCV) genotype 2 or 3 receive 24 weeks of peginterferon plus low-dose
ribavirin is appropriate, regardless of baseline viral load, and the
duration need not be extended to 48 weeks. These results were presented
by Mario Rizzetto, Universita di Torino, Torino, Italy, and colleagues
at the 55th Annual Meeting of the American Association for the Study of
Liver Diseases.
The standard of care for patients with HCV genotype 2 or 3 infection
is 24 weeks of therapy with peginterferon plus ribavirin 800 mg/d.
Although this regimen provides high rates of sustained virologic
response, some have thought that longer treatment or a higher dose of
ribavirin might increase SVR rates.
Rizzetto and colleagues analyzed combined data from 2 large,
international phase 3 trials by Fried and colleagues and Hadziyannis and
colleagues. They compared SVR rates in patients infected with genotypes
2 and 3 and the efficacy of different durations and doses of ribavirin.
They also investigated the effects of baseline HCV RNA level on SVR.
A total of 258 patients infected with genotype 2 and 374 patients
infected with genotype 3 were included in the study. Eligible patients
were treatment naive and had detectable serum HCV RNA greater than 2000
copies/mL, elevated alanine aminotransferase (ALT) levels, and
compensated liver disease. The study population was predominantly white
and male.
Patients were randomized to receive peginterferon alfa-2a 180 µg
weekly plus ribavirin at a low dose (800 mg/d) or a high dose (1000 or
1200 mg/d) for either 24 or 48 weeks. Thus, the 4 study arms were low
dose for 24 weeks, high dose for 24 weeks, low dose for 48 weeks, and
high dose for 48 weeks.
There was a nonsignificant trend toward higher SVR rates in patients
infected with genotype 2 compared to 3. The overall SVR rate was 82% for
patients infected with genotype 2 vs 77% for patients infected with
genotype 3. No consistent trend in SVR was noted high (greater than
800,000 IU/mL) and low baseline viral load groups were compared.
Prolonging treatment or increasing the daily dose of ribavirin also did
not increase SVR rates, which were similar among the 4 treatment arms.
The investigators concluded that the current recommendation of 24
weeks of treatment for patients infected with HCV genotype 2 or 3
appears to be appropriate, regardless of baseline HCV RNA level. These
data contrast with a recent study of peginterferon alfa-2b and ribavirin,
which indicated that patients infected with genotype 3 who have a high
viral load should receive 48 weeks of treatment.
Reference
Rizzetto M, Hadziyannis S, Ackrill AM. Sustained virological response
to peginterferon alfa-2a plus ribavirin: comparison of outcomes in
patients infected with HCV genotype 2 and 3. Program and abstracts of
the 55th Annual Meeting of the American Association for the Study of
Liver Diseases; October 29 - November 2, 2004; Boston, Massachusetts.
Abstract 198.
Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus
ribavirin for chronic hepatitis C virus infection. N Engl J Med.
2002;347:975-982.
Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a
and ribavirin combination therapy in chronic hepatitis C: a randomized
study of treatment duration and ribavirin dose. Ann Intern Med.
2004;140:346-355.
http://clinicaloptions.com/hep/news/news_AASLD2004_198.asp
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