14 Weeks vs 24 Weeks Peg/RBV for Genotypes 2/3

[Guest guest]

14 Weeks vs 24 Weeks Peg/RBV for Genotypes 2/3

Reported by Jules Levin

EASL, April 15, 2007

Barcelona, Spain

This was the very last oral presentation at the conference so by this

time many attendees had left to go home but I attended this

interesting session where there was a presentation on a new therapy

celgosivir, which I reported on, and this study. I returned home the

next morning but if you recall there was a noreaster storm so many of

us returning on the same flight to Newark were concerned about being

able to land. Howver, we landed on time as apparently the rain and

storm had stopped already in NYC.

“Peginterferon Alfa-2b and Ribavirin for 14 or 24 Weeks in Patients

with HCV Genotype 2 or 3 and Rapid Virological Response (RVR): the

North-C Trialâ€

Olav Dalgard et al, Infectious Disease Dept, Ulleval University

Hospital, Oslo, Norway

The aim of the study is to compare the virological response of 14 and

24 weeks of treatment to patients with genotype 2 or 3 infection and

rapid virological response (RVR). This is a randomized, multicenter

study: 49 hospitals in Sweden, Denmark, and Norway. It is a non-

inferiority trial. Patients were required to have elevated ALT, no

biopsy required, and were treatment-naïve. Patients received

pegylated interferon alfa-2b s.c. 1.5 ug/kg/weekly, and ribavirin 800-

1400 mg/daily weight-based dose. Rapid viral response was defined as

HCV RNA <50 IU/mL at week 4. Sustained viral response (EVR) was HCV

RNA <50 IU/mL 24 weeks after end of treatment. If patients were HCV

RNA negative after 4 weeks they were randomized to an additional 10

or 20 weeks treatment. Patients who were HCV RNA positive received

24 weeks treatment. Dalgard had previously published results of a

pilot study of 94 patients (Dalgard, Hepatology 2004) where the SVR

rate was 91% and relapse rate was 9% with 14 weeks treatment.

The author concluded that “90% with genotype 2/3 and RVR obtain SVR

after 14 weeks treatment; reduced side effects, saved costs, and good

response to retreatment, make shorter treatment a rational approach

for these patients, in our opinion; even though longer treatment may

provide better responseâ€. 95% receiving 24 weeks therapy achieved

SVR. These results were apparently “per protocolâ€, that is with

>80/80/80 adherence.

This was a non-inferiority trial but due to patient dropouts they did

not have enough patients remaining for the final analysis to draw a

conclusion that 14 weeks was as good as 24 weeks. In the final per

protocol analysis 90% of patients in the 14 week group had SVR (10%

relapse rate) and 95% in the 24 week group had SVR (5% relapse rate).

Based on an intent-to-treat analysis 81% in the 14 week group had SVR

and 91% in the 24 week group had SVR, with a 19% relapse rate in the

14 week group and 9% relapse rate in the 24 week group, but the

author said “the majority of the relapsers are lost to followupâ€.

They identified a few subgroups of patients that had a lower SVR

rate. Genotype 3 patients had 85% SVR rate with 14 weeks compared to

92% with 24 weeks. They were concerned about patients with high viral

loads but surprisingly patients with low viral load (<400,000 IU/mL)

had a lower response rate with 14 weeks than patients with low viral

load receiving 24 weeks (86% vs 100%), “there is a big difference

although the numbers of patients were smallâ€: 42 in the low viral

load group/14 weeks and 55 in the low viral load/24 weeks group. The

author said “it seems that patients when they start treatment with

low viral load they more often relapse with short treatment duration,

and this seems logical, we can speculate on why that happens.

Patients with genotype 3 and low viral load <400,000 IU/ml) “more

often had relapseâ€, SVR rate of 81% after shorter duration

treatment of 14 weeks (n=36) compared to 100% SVR rate for patients

with genotype 3/low viral load who received 24 weeks treatment. The

author also said age was “an important determinant for responseâ€

with younger patients achieving high rates of SVR and the SVR rates

declining as age increases. In Scandanavia “we often see young

patients who seek treatmentâ€. Patients younger than 30 years had

97% SVR rate with 14 weeks and 100% SVR rate with 24 weeks (n=65),

while patients >50 years had 81% SVR rate with 14 weeks and 83% SVR

rate with 24 weeks treatment. There were only 39 patients in the

subgroup who were older than 50 years so the author said “is it

safe to offer short duration of therapy to older patients? It would

seem so from this trial although we have only 39 patients in this

groupâ€. Of note the age groups of 30-39 yrs (84% vs 96%, n=103) and

40-49 (83% vs 90%, n=78) yrs also had lower SVR rates with 14 weeks

therapy compared to 24 weeks therapy. The author added however age

could be a surrogate marker for stage of disease and they did not do

biopsies.

There were a number of patients lost to follow-up in the study

because they were “former drug usersâ€. As well, some patients had

less than 80/80/80 adherence; in the long treatment arm, 24 weeks,

patients tended to stop treatment early, 48 patients (author said

“1 in 3 patients stopped early). Because they had previously

conducted a pilot trial with similar results and clinicians and

patients knew the results and because of side effects these patients

apparently decided to stop treatment earlier. While in the 14 week

treatment arm only 11 patients stopped treatment early out of 148

patients between weeks 4 and 40. After the database was locked they

discovered another problem, “these were former drug users' and I

think he said young patients, as there were 9 patients lost to follow-

up in the 14 week arm and 4 in the 24 week arm. But since the SVR was

so high it's a big problem to call them treatment failures. So they

decided to base their conclusions on the per protocol population:

patients who received more than 80% of both drugs and with follow-up

data.

COSTS

Mangia et al published in the NEJM 2004: 9/10 relapsers following 12

weeks treatment obtained SVR after 24 weeks retreatment. Retreatment

is a “very good option†although 24 weeks may provide better

response. The authors calculated that even after retreatment of 1 in

10 patients 14 weeks treatment will reduce costs by 30-35%

(approximately Euro 3,500, per patient).

SAMPLE SIZE

Non-inferiority margin; 10%

Significance level: 2.5%

Power: 80%

Sample size: 435 (300 randomized)

PATIENT FLOW

428 patients were enrolled.

HCV RNA <50 IU/mL at week 4 (n=302) (71%).

Group A: 14 weeks treatment, ITT population, n=148

<80/80/80, n=11

Lost to follow-up, n=9

PER PROTOCOL POPULATION, n=128 (>80% of both drugs and followup data)

Group B: 24 weeks treatment, ITT population, n=150

<80/80/80 n=48

Lost to follow-up, n=4

PER PROTOCOL POPULATION: n=98 (>80% drugs and followup data)

BASELINE CHARACTERISTICS

Group A Group B

14 wks 24 wks

n=148 n=150

women 36% 35%

men 64% 65%

age (median) 38 38

genotype 2 20% 20%

genotype 3 80% 80%

Viral load

(median) 1.1 mill IE/ml 0.9 mill IE/ml

SVR PER PROTOCOL

Group A: 90% SVR, 10% relapse (n=128)

Group B: 95% SVR, 5% relapse (n=98)

5.1% difference (95% CI: -2.4, +12.4)

Non-inferiority margin: 10%

Author said: “the 95% confidence interval overlaps 10% probably

because we lost power as we only have 98 patients in the control

group. Therefore, we cannot conclude non-inferiorityâ€.

SUB-GROUP ANALYSIS

SVR and Genotype

Genotype 2: 93% SVR 14 weeks (n=29), 97% SVR 24 weeks (n=31)

Genotype 3: 85% SVR 14 weeks (n=110), 92% 24 weeks (n=1150

Viral Load

<400,000 IU/mL: 86% SVR 14 weeks (n=42), 100% 24 weeks (n=55)

>400,000 IU/mL: 88% 14 weeks (n=88), 88% 24 weeks (n=85)

Genotype & Viral Load

Genotype 3 and low viral load (<400,000 IU/mL): 81% SVR 14 weeks

(n=36), 100% 24 weeks (n=44)

Genotype 3 and high viral load (>400,000 IU/mL): 86% 14 weeks (n=66),

86% 24 weeks (n=66)

ADHERENCE

>80/80/80: 90% SVR 14 weeks (n=128), 95% SVR 24 weeks (n=98)

<80/80/80: 57% SVR weeks (n=11), 90% 24 weeks (n=44)