Rapid virological response at week 4 of peginterferon alfa-2a (40KD) (PEGASYS) p

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Rapid virological response at week 4 of peginterferon alfa-2a (40KD)

(PEGASYS) plus ribavirin (COPEGUS) treatment predicts sustained

virological response after 24 weeks in genotype 1 patients

Reported by Jules Levin

Presented at the 56th Annual Meeting of the American Association for

the Study of Liver Diseases: 2005 November 11-15: San Francisco, CA,

USA.

This research was funded by Roche, Basel, Switzerland.

D. Jensen,1 T.R. ,2 P. Marcellin,3 P.J. Pockros,4 K.R. Reddy,5

S.J. Hadziyannis,6 P. Ferenci,7 B. Willems8

1University of Chicago Hospitals, Chicago, IL, USA; 2VA Medical

Center, Long Beach, CA, USA; 3Hôpital Beaujon, Clichy, France; 4The

Scripps Clinic, La Jolla CA, USA; 5University of Pennsylvania,

Philadelphia, PA, USA; 6Henry Dunant Hospital, Athens, Greece;

7Department of Internal Medicine IV, Medical University of Vienna,

Austria; 8Centre Hospitalier de l'Université de Montréal, Montréal

QC, Canada

AUTHOR'S CONCLUSIONS

This retrospective analysis of a large, randomized, phase III trial

including 729 genotype 1 patients[4] shows that:

--Approximately 20% of patients with HCV genotype 1 infection

achieved undetectable HCV RNA levels by qualitative PCR (i.e. an RVR)

at week 4 of treatment with peginterferon alfa-2a (40KD) (PEGASYS)

plus ribavirin (COPEGUS).

--Overall, 89% of patients with an RVR treated for only 24 weeks

achieved an SVR. Moreover, patients with an

RVR treated for 48 weeks did not obtain a better SVR rate.

--The highest SVR rate in patients without an RVR (44%) was obtained

following treatment with peginterferon alfa-2a (40KD) plus ribavirin

at the recommended dose (1000/1200 mg/day) for the recommended

duration (48 weeks).

--A lower baseline HCV RNA level was the only significant and

independent factor associated with an RVR. (>600,000 IU/ml did not

perform as well, see table below)

--An RVR (<50 IU/ml) at week 4 of treatment is the single best

predictive factor for an SVR.

The use of RVR status to guide treatment duration in genotype 1

patients is

appealing and should ideally be confirmed by prospective studies.

INTRODUCTION

The recommended treatment for patients with hepatitis C virus (HCV)

genotype 1 infection is the combination of a pegylated interferon

plus ribavirin 1000 or 1200 mg/day for 48 weeks.[1,2] The ability to

identify genotype 1 patients that might respond to a reduced length

of treatment would limit the burden of therapy in this common but

more difficult-to-treat patient population. Recent data from an

uncontrolled study suggest that HCV genotype 1 patients with a low

baseline viral load who have undetectable HCV RNA after 4 weeks of

treatment with the combination of a pegylated interferon plus

ribavirin may require just 24 weeks of treatment to achieve a

sustained virological response (SVR).[3]

In a randomized, phase III trial by Hadziyannis et al.[4] that

examined treatment duration and ribavirin dose, 78 out of 219 (36%)

patients with HCV genotype 1 infection achieved an SVR after 24 weeks

of treatment with peginterferon alfa-2a (40KD) (PEGASYS) plus

ribavirin (COPEGUS). We analyzed data from patients with genotype 1

infection in this trial.

OBJECTIVE

The aim of this study was to retrospectively examine whether a rapid

virological response (RVR) at week 4 of treatment was predictive of

an SVR in HCV genotype 1 patients receiving peginterferon alfa-2a

(40KD) plus ribavirin for 24 weeks in a randomized, multinational,

phase III trial.[4]

The study also attempted to identify factors predictive of an RVR in

patients randomized to 24 weeks of treatment.

METHODS

Patients

Patients included in the study were treatment-naive adults aged ≥18

years with quantifiable serum HCV RNA levels, evidence of liver

disease consistent with chronic hepatitis C and elevated alanine

aminotransferase (ALT) activity in serum. Exclusion criteria included

the presence of neutropenia, thrombocytopenia, anemia or a serum

creatinine level ≥1.5 times the upper limit of normal. Patients co-

infected with hepatitis A or B virus or HIV, and those with severe

psychiatric illnesses or clinically significant coexisting medical

conditions were also excluded.

Study design

Patients were randomized to one of four groups that differed by

treatment duration and ribavirin dose. All patients received

subcutaneous peginterferon alfa-2a (40KD) 180 ug/week in combination

with:

- low-dose (LD [800 mg/day]) ribavirin for 24 (24-LD) or 48 weeks (48-

LD)

- standard-dose (SD [1000 mg/day for bodyweight <75 kg, 1200 mg/day

for bodyweight ≥75 kg]) ribavirin for 24 (24-SD) or 48 weeks (48-

SD).

The primary efficacy end-point of the trial was SVR, defined as

undetectable (<50 IU/mL) serum HCV RNA by qualitative polymerase

chain reaction (PCR) assay (COBAS AMPLICOR HCV Test, v2.0) at the end

of a 24-week untreated follow-up period. RVR was defined as

undetectable HCV RNA (<50 IU/mL) by qualitative PCR at week 4.

Statistical analysis

Stepwise multiple regression analysis was used to explore prognostic

factors for an RVR. Baseline disease and demographic factors

considered for entry included age, gender, bodyweight, body mass

index, body surface area, log10 baseline HCV RNA level, histological

diagnosis, baseline ALT activity, qualifying ALT quotient, genotype 1

subtype and ribavirin dose at baseline.

RESULTS

In total, 740 patients infected with HCV genotype 1 were randomized

to treatment and received at least one dose of study medication. Week

4 virological test results were available in 729 of these patients,

146 of whom achieved an RVR. A total of 216 patients received

treatment for 24 weeks. Of these, 51 (24%) achieved an RVR. Baseline

disease and demographic characteristics according to RVR status in

patients randomized to 24 weeks of treatment are presented in Table 1.

Table 1. Baseline disease and demographic characteristics according

to PCR status at week 4 in genotype 1 patients randomized to 24 weeks

of treatment

o In all four treatment groups, patients with an RVR achieved

higher end-of-treatment virological response rates and higher SVR

rates than patients without an RVR. SVR rates in patients with an RVR

were generally similar across all four treatment groups (Figure 1).

o In patients randomized to treatment for 24 weeks, overall SVR

rates were markedly higher in patients who did (89%) vs did not (19%)

achieve an RVR.

o Patients with an RVR had lower relapse rates between end of

treatment and followup than those without an RVR, irrespective of

treatment duration or ribavirin dose.

o In contrast, there were obvious trends towards decreased

relapse rates in patients without an RVR when treatment was given for

48 weeks and also when standard dose ribavirin was given.

- 75% and 68% of patients without an RVR relapsed following

peginterferon alfa-2a (40KD) plus ribavirin 800 and 1000/1200 mg/day

for 24 weeks

- 42% and 32% of patients without an RVR relapsed following

peginterferon alfa-2a (40KD) plus ribavirin 800 and 1000/1200 mg/day

for 48 weeks.

Multiple regression analyses

Multiple regression analysis showed that a lower baseline HCV RNA

level was predictive of an RVR in patients treated for 24 weeks.

Patients with a baseline HCV RNA level of <200 000 IU/mL (OR 9.7; 95%

CI 4.2-22.5; p<0.0001) or 200 000-600 000 IU/mL (OR 3.6; 95% CI 1.5-

9.1; p=0.0057) were significantly

more likely to achieve an RVR than patients with a baseline HCV RNA

level >600 000 IU/mL (Figure 2).

An RVR was more likely in subtype 1b vs 1a patients (OR 1.8; 95% CI

0.9-3.7; p=0.095) (Figure 3). In subtype 1a patients a baseline HCV

RNA level of <200 000 vs >200 000 IU/mL was significantly associated

with an RVR (OR 5.9; 95% CI 2.0-17.6; p=0.0015), while in genotype 1b

patients a baseline HCV RNA

of ≤600 000 vs >600 000 IU/mL was significantly associated with an

RVR (OR 10.3; 95% 3.6-29.4; p<0.0001).