HCV
genotypes 2 and 3 are easier to treat than genotypes
1 or 4. The standard course of therapy for genotype 2 or
3 is pegylated interferon
plus ribavirin for 24 weeks, increasing to 48 weeks for
hard-to-treat genotype 1. Genotypes 2 and 3 also have a higher
response rate of 70%-80% in most studies, compared with only
about 50% for genotype 1.
Because
chronic hepatitis C patients with genotypes 2 and 3 often respond
rapidly to therapy -- and because interferon is expensive and
can cause difficult side effects -- researchers have explored
whether treatment for 12, 14, or 16 weeks might work as well
as 24 weeks.
During
hepatitis C treatment efficacy is assessed by measuring HCV
viral load after 4 weeks (rapid virological response, or RVR),
12 weeks (early virological response, or EVR), 24 weeks (end-of-treatment
response, or ETR), and 24 weeks after completion of therapy
(sustained virological response, or SVR). Patients who experience
RVR at week 4 are significantly more likely to go on to achieve
SVR. People who still have undetectable viral load 24 weeks
after finishing treatment are considered cured.
12-16
Weeks Meta-analysis
As
reported in the September
2010 Journal of Clinical Gastroenterology, Ashwani
Singal from the University of Texas Medical Branch in Galveston
and colleagues performed a meta-analysis of prior studies of
abbreviated treatment.
The study authors searched medical literature databases for
studies that compared short-term (12 to 16 weeks) vs standard
24 week treatment using pegylated interferon plus 800 mg/day
fixed-dose ribavirin for genotype 2 or 3 patients who had achieved
RVR. They identified 6 relevant studies -- including a total
of 2434 participants -- that reported data on ETR, SVR, and
relapse rates.
After achieving RVR, patients treated for a total of 24 weeks
were significantly more likely to achieve SVR than those treated
for 16 weeks (79% vs 70%; P = 0.008). Conversely, 24 week patients
had a significantly lower relapse rate (9% vs 23%, respectively;
P < 0.00001). Results did not change when people with genotype
2 vs 3, or those with high vs low baseline viral load, were
analyzed separately.
The pooled odds ratio for SVR using shorter treatment was 0.54,
or about half as likely, while the pooled odds ratio for experiencing
viral relapse was 3.12, or about 3 times more likely (P = 0.008
and < 0.00001, respectively).
However, people treated for 24 weeks were significantly more
likely to discontinue therapy ahead of schedule than those receiving
shorter-duration treatment (12% vs 5%; P < 0.0001). The researchers
found that it would be cost-effective to reduce treatment duration
to 12-16 weeks, and then re-treat patients who experience relapse
with a second 24 week course of therapy.
"Advantages of short-term treatment include better patient
compliance, lower rate of adverse effects, and cost," the
authors concluded. "Short-term treatment may be an option
for patients unable to tolerate treatment."
Scandinavian Trials
In
the second study, published in the May
2010 European Journal Gastroenterology and Hepatology,
Olav Dalgard from Rikshospitalet in Oslo and colleagues compared
14 vs 24 week treatment in chronic genotype 2 or 3 patients
with RVR, defined as HCV RNA < 50 IU/mL after 4 weeks of
therapy.
The
analysis included participants in 2 Scandinavian studies, one
a non-randomized pilot trial with 122 patients, the other a
randomized controlled trial with 428 patients. In both trials,
treatment-naive participants were treated with 1.5 mcg/kg/week
pegylated interferon alpha-2b
(PegIntron) plus 800-1400 mg/day weight-adjusted ribavirin
(genotype 2 or 3 patients typically receive a fixed dose of
800 mg regardless of weight).
In
the pilot trial, all patients with RVR were treated for 14 weeks,
while in the larger trial participants with RVR were randomized
to receive therapy for either 14 or 24 weeks.
In
an analysis of all RVR patients treated per protocol, 91% of
those who received 14 weeks of therapy achieved SVR, compared
with 95% of those treated for 24 weeks. The difference of 4%
fell well within the pre-determined 10% margin needed to show
inferiority, allowing the researchers to conclude that 14 week
treatment was non-inferior to 24 weeks.
The
relapse rate was highest among participants older than 40 years,
those with genotype 3, and those with a high baseline viral
load. However, prolonging treatment from 14 to 24 weeks did
not reduce the relapse rate substantially for any of these groups.
International
Study
Finally, in the third study, described in the June
2010 issue of Hepatology, Moises Diago from Hospital
General de Valencia in Spain and an international team of colleagues
compared SVR and relapse rates among patients with RVR (again
< 50 IU/mL) who were randomly assigned to receive treatment
for 16 or 24 weeks in the ACCELERATE trial.
This study included 863 genotype 2 or 3 participants with RVR
(66% of the initial 1309 eligible patients in the study). All
were treated with 180 mcg/week pegylated interferon alfa-2a
(Pegasys) plus 800 mg/day ribavirin. The analysis included only
those participants who took their assigned treatment for at
least 80% of the planned duration.
The overall SVR rate was significantly higher among genotype
2 patients treated for 24 weeks rather than 16 weeks (91% vs
82%, respectively; P = 0.0006). The difference for participants
with genotype 3, however, did not reach statistical significance
(90% vs 84%, respectively; P = 0.1308). Among patients with
low baseline viral load (HCV RNA <400.000 IU/mL),
SVR rates with 24 or 16 weeks of treatment were also statistical
equivalent (95% vs 91%, respectively; P = 0.2012).
Relapse rates were significantly lower among people randomized
to 24 weeks of therapy vs 16 weeks, both overall (6% vs 15%;
P < 0.0001) and when participants with genotype 2 (5% vs
17%; P = 0.0001) and those with genotype 3 (7% vs 14%; P = 0.0489)
were analyzed separately.
Significant pre-treatment predictors of SVR included assigned
treatment duration of 24 weeks (P = 0.0006), absence of advanced
liver fibrosis or cirrhosis according to biopsy (P = 0.0032),
lower HCV viral load (P = 0.0017), and lower body weight (P
< 0.0001).
"The standard 24-week regimen of [Pegasys] plus ribavirin
is significantly more effective than an abbreviated 16-week
regimen in genotype 2/3 patients who achieve an RVR," the
study authors concluded. "Abbreviated regimens may be considered
in patients with a low baseline viral load who achieve an RVR."
Overview
In an editorial accompanying Singal's meta-analysis, Donald
Jensen from the University of Chicago Medical Center attempted
to make sense of the conflicting findings from studies to date
of shorter treatment durations for genotype 2 or 3 patients.
Even previous meta-analyses, which are intended to resolve such
questions, have produced contradictory results.
Along with baseline viral load and genotype 2 vs 3, ribavirin
dose may be an important factor, he suggested, since it reduces
the chances of relapse after completion of treatment.
"In summary, finding convincing evidence to support RVR-guided
duration shortening in all genotypes 2 and 3 subjects is still
not available," Jensen wrote. "The difference in SVR
rates, however, remains small (< 10%) and narrower still
for those patients with low baseline viral load."
"As the authors point out, it may not be unreasonable in
selected cases -- perhaps those with an RVR yet poorly tolerant
of side effects -- to strongly consider shortening therapy and
if relapse occurs, retreat for a longer duration," he concluded.
Investigator affiliations:
Singal study: Department of Gastroenterology and Hepatology,
University of Texas Medical Branch, Galveston, TX; Department
of Gastroenterology and Hepatology, Michael DeBakey VA Medical
Center, Baylor College of Medicine, Houston, TX.
Dalgard study: Medical Department, Rikshospitalet, Oslo, Norway.
Diago study: Hepatology Section, Hospital General de Valencia,
Valencia, Spain; Hepatology Section, Virginia Commonwealth University
Medical Center, Richmond, VA; Department of Hepatology and Gastroenterology,
INSERM U724, CHU de Nancy, Vandoeuvre-les-Nancy, France; J.W.
Goethe University Hospital, Frankfurt, Germany; Fundacion de
Investigacion de Diego, Santurce, Puerto Rico; St Luke's Center
for Liver Disease, Houston, TX; Roche, Basel, Switzerland; University
of Florida, Gainsville, FL.
10/26/10
References
AK
Singal and BS Anand. Tailoring Treatment Duration to 12 to 16
Weeks in Hepatitis C Genotype 2 or 3 With Rapid Virologic Response:
Systematic Review and Meta-analysis of Randomized Controlled
Trials. Journal of Clinical Gastroenterology 44(8): 583-587
(Abstract).
September 2010.
O
Dalgard, K Bjoro, H Ring-Larsen, and H Verbaan. In patients
with HCV genotype 2 or 3 infection and RVR 14 weeks treatment
is noninferior to 24 weeks. Pooled analysis of two Scandinavian
trials. European Journal Gastroenterology and Hepatology
22(5): 552-556 (Abstract).
May 2010.
M Diago, ML Shiffman, JP Bronowicki, and others. Identifying
hepatitis C virus genotype 2/3 patients who can receive a 16-week
abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin.
Hepatology 51(6): 1897-1903 (Abstract).
June 2010.
DM Jensen. Treatment duration for genotypes 2 and 3: still confusing
after all these years (Editorial). Journal of Clinical Gastroenterology
44(8): 527-528 (Free
full text). September 2010.
