24 Weeks vs 48 Weeks of Treatment in HCV Genotype 1

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24 Weeks vs 48 Weeks of Treatment in HCV Genotype 1

Discussion

Evidence from trials of conventional interferon á and ribavirin

suggests that patients with HCV genotype 1 require 48 weeks treatment

length, while patients with HCV genotype 2 or 3 may be treated for a

shorter duration.[11-13] More recently, Hadziyannis et al.[14] showed

that this remains true for patients treated with the combination of

peginterferon á-2a (40 kDa) and ribavirin. They showed that the best

response in genotype 1 patients (SVR of 52%) was achieved with both

48 weeks of treatment and full standard dose of ribavirin (1000-1200

mg/day). The results of our study confirm the efficacy and safety of

peginterferon á-2a (40 kDa) and ribavirin combination therapy in

patients with CHC. Treatment for 48 weeks with peginterferon á-2a (40

kDa) in combination with a low dose of ribavirin (800 mg/day)

produced SVR in 48% of patients (group . These results compare very

well with the results showed by Hadziyannis et al.[14] in the group

treated with the same regimen (48 weeks of treatment and ribavirin

800 mg/day - SVR 47%). However, decreasing treatment duration to 24

weeks in genotype 1 patients (group A) also decreases the likelihood

of SVR (19%; P = 0.01 compared with group . In contrast, genotype

non-1 patients treated for 24 weeks in group C achieved 75% of SVR (P

< 0.0001 compared with group A). It is important to notice that the

higher male proportion in this group could have negatively impacted

the results. These results confirm the important role of genotype as

a prognostic factor in the treatment of HCV infection. As the correct

dose of ribavirin for genotype 1 patients was not defined by the time

this protocol was designed, one may consider that if genotype 1

patients treated for 48 weeks had received a full standard dose of

ribavirin (1000—1200 mg/day) then the SVR would have been higher. The

analysis of EVR as a positive predictive factor for genotype 1

patients treated for 48 weeks showed the same pattern as showed by

Fried et al.[15] Furthermore, among the nine patients in group B who

had a negative HCV-RNA (qualitative polymerase chain reaction) at

week 4 and remained negative at weeks 12, 24 and 48, 89% (8/9) had

SVR. This shows that the faster the viral declines and/or the longer

it remains suppressed the higher the chance of SVR.[15,16]

The analysis of EVR as a negative predictive factor for genotype 1

patients treated for 48 weeks showed that among patients (n = 5) who

did not have an EVR no one achieved SVR (i.e. negative predictive

value of 100%). This compares closely to Fried et al.[15] overall

results that showed a negative predictive value of 97%. Among

genotype 1 patients there was a trend of better responses in favour

of low baseline viral load patients (not statistically significant -

probably type II error).

Overall, the safety profile was similar to what has been reported

with the 'influenza-like' syndrome symptoms (headache, pyrexia

and 'influenza-like' syndrome not otherwise specified) being the most

prevalent ( Table 6 ). There were eight discontinuations. Among these

patients, four withdrew because of adverse events that improved after

discontinuations ( Table 7 ). Dose modification because of

neutropoenia occurred in 29% of patients being treated for 48 weeks,

which compares with what was observed by Fried et al.[15] (20%). It

is expected that patients being treated for less than 48 weeks show

less laboratory abnormalities as we observed in our trial.

Currently, there are two forms of pegylated interferons.

Peginterferon á-2b (12 kDa) was not evaluated in a randomized trial

looking at different treatment lengths for genotype 1 patients making

historical comparisons difficult. As branched peginterferon á-2a (40

kDa) differs from linear peginterferon á-2b (12 kDa) in terms of

pharmacokinetics parameters,[17] we think that an extrapolation of

virological results from our trial seems not appropriate.

Our data corroborates that optimal duration of HCV treatment is

primarily driven by genotype. Genotype 1 patients should be treated

for 48 weeks to achieve the best chance for SVR. The rate of SVR

achieved in the 48-week treatment group is close to what was observed

by Hadziyannis et al.[14] in a group that received 1-1.2 g/day of

ribavirin (52%). We believe that should we have had used a higher

dose of ribavirin we could have achieved better SVR. The

predictability model in our trial confirms the opportunity to refine

therapy. This certainly will help to support and encourage patients

who have good on-treatment responses and allow for the discussion of

treatment goals and the utility of continuing therapy in those

patients without reasonable chances sustained virological clearance.