18 months treatment to reduce relapse rates

[Guest guest]

from NATAP www.natap.org

by Jules Levin

The data from the Benelux study has

been

presented at AASLD 2000 and EASL 2001. And it makes a

good case to

consider

18 months pegIFN+RBV treatment.

18 Month Treatment Benelux Study

ABSTRACT:

REDUCTION OF RELAPSE IN CHRONIC HCV. A BENELUX STUDY

IN 300 PATIENTS

J.T Brouwer, S. W Schalm,

University Hospital Rotterdam,

Treatment of chronic HCV with Interferon is hampered

by incomplete

blocking

of viral replication, limiting the initial response,

and incomplete

removal

of infected hepatocytes, leading to frequent relapses.

We aimed to

improve

the initial response by adding Ribavirin and to reduce

the relapse rate

by

prolonging treatment to 18 months. Three hundred

patients with chronic

HCV

and elevated transaminases were included from 25

centers in Belgium,

the

Netherlands and Luxembourg: 69% genotype 1, 57% HCV

RNA above 2x10E6

copies/ml, 14% cirrhosis. Patients were randomized

towards 18 months

Interferon-a2b (3 MU tiw) plus Ribavirin, 18 months

Interferon plus

placebo,

or 6 months combination. All 295 patients who started

treatment were

included

in the intention-to-treat analysis; the per-protocol

analysis included

the

238 who completed therapy. After 6 months treatment,

HCVRNA was

undetectable

in 53% (p.p 59%) in combination therapy versus 29%

(p.p. 31%) in

monotherapy

(p<0.001). The relapse rate was 40% for those who

completed 6 months

combination therapy, 22% after 18 months mono therapy,

and only 7.7% in

those

who completed 18 months combination treatment

(p=0.002). A sustained

HCVRNA

response was observed in 44% (p.p. 50%) in 18 months

combination

therapy

versus 17% (p.p. 16%) in 18 months monotherapy and 34%

(p.p. 35%) in 6

months

combination (p<0.001). In conclusion, this study

confirms the enhanced

initial response due to combination of Interferon with

Ribavirin,

whereas it

shows an important reduction of relapse and thereby a

high sustained

response

rate due to prolongation of treatment to 18 months.

18 Months of Dual Therapy for Chronic Hepatitis C

Decreases Relapse

Rate and

Suggests New Treatment Approach for Hard to Treat

Patients with

Cirrhosis,

Genotype 1, and High Baseline Viral load

q 300 patients without previous treatment in

randomized, double blind,

placebo-controlled study.

q 2 arms treated with standard interferon alfa (not

pegylated) plus

ribavirin.

q For those randomized to 18 months of dual therapy,

the

end-of-treatment

response rate (ETR) was 51%, with a relapse rate of

13% (vs 38%),

leading to

a sustained-virologic-response (SVR) rate of 44%,

" ITT " analysis.

q 70% genotype 1, 14% cirrhosis and 53% high baseline

viral load.

q Patients with genotype 1, cirrhosis, and high

baseline viral load

derived

the greatest virologic benefits, in " as-treated "

analysis.

Perhaps one of the more interesting clinical

presentations at EASL 2001

that

potentially could have a major impact on treatment

outcome for patients

with

chronic hepatitis C was the Benelux Study. Benelux

Study results were

first

reported at AASLD November 2000 (see NATAP Report

http://www.natap.org/2000/nov/18_months_interferon112200.html)

Dr. J.T. Brouwer of University Hospital in Rotterdam,

The Netherlands

presented the study results. Even though the study

used the older

standard

combination (non-pegylated) interferon alfa plus

ribavirin, the low

relapse

rate of only 13% in a predominant genotype-1

population has significant

potential implications, if similar [or better] results

were to occur

after 18

months of pegylated interferon alfa plus ribavirin.

Given that end-of-treatment virologic response (ETR)

rates when

treating

chronic hepatitis C have always been higher than their

associated

sustained

virologic response (SVR) rates, the researchers in

this study were

trying to

determine whether longer treatment might increase

either ETR, SVR or

both.

A total of 300 treatment-naïve (no previous therapy)

patients with

chronic

hepatitis C (positive HCV RNA, increased liver enzyme

ALT, abnormal

liver

biopsy) were randomized to one of 3 treatment arms in

a double-blind

fashion

(treatment unknown to patient or treating physician).

They were: (1)

interferon alfa 2b (Intron A), 3 MIU (million

international units)

injected

3-times weekly plus oral ribavirin 1,000-1,200 mg

daily for 18 months*;

(2)

the same drug regimen in (1), except for only 6

months; or (3)

interferon

alfa 2b monotherapy, same dose as above, plus oral

placebo (inactive

drug)

for 18 months*. *Note that after 6 months, the

duration of the

treatment arms

only was revealed (unblinded), and all patients who

were non-responders

at

that time (detectable viral load and ALT greater than

1-times the upper

limit

of normal) stopped therapy (due to evidence that they

would not respond

[virologically] thereafter).

The 3 study arms were well randomized in terms of age

(mean 43-47

years),

gender (sex, 63% men in combination arms, although

monotherapy arm had

46%

men), ( " compensated, " stable) cirrhosis rate (liver

scarring, F4,

13-15%),

genotype 1 (most difficult to treat, 66-75%), and

baseline HCV RNA

greater

than 3 million copies/mL (50-55%) with 57% overall

having greater than

2

million copies/mL. Patients were from 25 centers in

Belgium,

Luxembourg and

the Netherlands.

The results were as follows. Stopping at 6 months due

to non-response

included 10% from arm 1 (combination 18 months) and

28% of arm 3

(interferon

18 months); all in arm 2 stopped at that time as per

protocol.

Withdrawal

from study due to any reason during the first 6 months

included 10%

each of

arms 1 and 2 and 5% of arm 3. Withdrawal due to any

reason between

months 6

and 18 included 13% of arm 1 and 20% of arm 3.

Reasons for withdrawal

were

not presented. Using a strict " intent-to-treat " (ITT)

analysis (all

patients

included), the end-of-treatment (ETR) viral

undetectability (limit 100

copies/mL) response rates were 51% (arm 1, combination

18 months), 55%

(arm

2, combination 6 months) and 27% (arm 3, monotherapy

18 months). There

was

no significant difference between arms 1 and 2, with

very little

additional

response in arm 1 after 6 months.

Treatment Outcomes in Benelux Study of 300 Patients

Arm 1: interferon alfa 2b* plus ribavirin ** \

Arm 2: interferon alfa 2b* plus ribavirin **

Arm 3: interferon alfa 2b* plus oral placebo

Arm 1

Arm 2 Arm

3

Length of therapy 18mos 6 mos

18 mos

ETR (ITT) 51% 55%

27%

Relapse Rate (ITT) 13% 38%

39%

SVR (ITT) 43% 34%

16%

Withdraw 0-6 mos 10% 10%

5%

Withdraw 6-18 mos 13% NA

20%

Duration of therapy 18 months 6 months 18 months

End of Treatment Response *** Rate, ITT # 51% 55%

27%

Relapse Rate (see text), ITT # 13% 38% 39%

Sustained Virologic Response Rate, ITT # 43% 34%

16%

Withdrawal, 0-6 months 10% 10% 5%

Withdrawal, 6-18 months 13% Not applicable 20%

* Interferon dose was 3 million international units

injected 3-times

weekly

(see row 2 for duration)

** Ribavirin dose was 1,000-1,200 mg orally each day

(see row 2 for

duration).

*** Percentage undetectable HCV RNA, limit 100 copies

per milliliter

# ITT = Intent-to-treat analysis, including all

enrolled patients

However, after 6 months of follow-up in each arm, the

relapse rate

(virus

becoming detectable after being undetectable at the

end of treatment)

was

significantly lower in arm 1 (combination 18 months)

than in arm 2

(combination 6 months). Those relapse rates were: 13%

(arm 1), 38%

(arm 2)

and 39% (arm 3), using an ITT analysis. Therefore,

this led to a SVR

(sustained virologic response) rate of 43% (arm 1),

34% (arm 2) and 16%

(arm

3).

In a separate " as-treated " analysis including patients

who completed

80% of

therapy for 80% of the intended duration or who

stopped therapy

according to

protocol, among patients in arm 1 (combination 18

months), those with

cirrhosis had a higher SVR (57%) than those without

cirrhosis (42%).

The

usual, opposite trend occurred in arm 2 (combination 6

months), with a

SVR of

29% for those with and 37% for those without cirrhosis

( " as-treated "

analysis). And the usual trend also occurred in arm 3

(monotherapy),

with a

SVR among 10% for those with and 18% for those without

cirrhosis.

(Note that

" as-treated " ETR was 56% in arm 1, 60% in arm 2 and

25% in arm 3. " As

treated " relapse rates were 7% (arm 1), 38% (arm 2)

and 32% (arm 3).

" As-treated " SVR was 52% (arm 1), 36% (arm 2) and 17%

(arm 3).

(editorial note from Jules Levin: The preliminary ETR

for

Pegasys+ribivarin

reported at EASL were 58% for monotherapy and 68% for

combination

therapy. In

this or any study, if you were to look at the response

rates for

patients who

are adherent and complete the course of treatment the

response rates

would be

expected to be considerably better. This was reflected

in the Benelux

study

as the SVR for arm 1 was 43%, while in the

" as-treated " analysis the

SVR was

57% for cirrhotics and 42% for non-cirrhotics. This

emphasizes the

importance

of adherence. Adherence support for coinfected

patients receiving

IFB+RBV

will be helpful. We will have to see if HIV-infected

can tolerate

ribivarin

for 18 months due to reduced hemoglobin and similar

adverse effects on

other

blood tests).

Interestingly, the SVR was higher only for genotype 1

patients taking

combination treatment for 18 months (arm 1, 36%) than

for those taking

it for

6 months (arm 2, 23%), since those with genotype 2 or

3 had a nearly

identical SVR whether they took combination therapy

for either 18

months (arm

1, 71% SVR) or 6 months (arm 2, 72%). However, the

genotype analysis

was

only presented " as-treated. " In a similar pattern,

the SVR was higher

for

those with a higher baseline viral load (greater than

3 million

copies/mL)

taking combination treatment for 18 months (arm 1,

42%) than for those

taking

it for 6 months (arm 2, 18%), since those with a low

baseline viral

load

(less than 3 million copies/mL) had a nearly identical

SVR whether they

took

combination therapy for either 18 months (arm 1, 47%)

or 6 months (arm

2,

49%). Again, however, the baseline viral load, SVR

analysis was

presented

only " as-treated. "

Taken together, the " as-treated " results (cirrhosis,

genotype and

baseline

viral load) suggest that a longer duration of therapy,

here 18 months,

may be

particularly beneficial for those patients who

previously have been

more

difficult to treat, i.e., with " unfavorable " baseline

characteristics.

This

suggests that " longer " might be better in terms of

being able to

eradicate

more HCV from more hepatocytes (liver cells) or by

having more time for

the

immune system to remove more HCV-infected hepatocytes.

Yet, those with

genotypes 2 or 3 or those with a low baseline viral

load did not derive

any

additional SVR benefits by treatment with combination

therapy for more

than 6

months.

Dr. Brouwer concluded that prolonged (18 months)

combination therapy

had " no

effect on response beyond 6 months [but had a] clear

effect on relapse

rate

(less than 10%) if [the] therapy is maintained. " Note

that liver

biopsy

results at the time of SVR were not reported.

However, it is likely

that

similar or possibly more (or better) improvements on

liver biopsy would

be

observed for those in arm 1 than in arm 2. However,

specific types and

rates

of adverse events and reasons for withdrawal were not

presented.

A similar study would need to be undertaken using a

" control " arm with

today’s standard of pegylated interferon alfa plus

ribavirin for 12

months

(versus 18 months) to determine whether similar

additional benefits

might be

derived, particularly for those with unfavorable

baseline

characteristics.

However, since the SVR could only be measured 24

months (2 years) after

entering into such a study (for the 18-month arm), it

is quite possible

that

a new standard-of-care would replace the current one

when such a study

were

finished. In the mean time, with the limitation that

this is only one

study

with these results and considering data not reported

(as discussed

above),

those with genotype 1, a high baseline viral load

and/or cirrhosis

might want

to have their physicians consider longer treatment for

18 months,

preferably

in a study or at least in an observational study.

(Editorial note: as

mentioned above, an 18-month study in HCV/HIV

coinfected would be

useful to

evaluate tolerability and adverse effects on

bloodwork).

__________________________________________________

[Guest guest]

from NATAP www.natap.org

by Jules Levin

The data from the Benelux study has

been

presented at AASLD 2000 and EASL 2001. And it makes a

good case to

consider

18 months pegIFN+RBV treatment.

18 Month Treatment Benelux Study

ABSTRACT:

REDUCTION OF RELAPSE IN CHRONIC HCV. A BENELUX STUDY

IN 300 PATIENTS

J.T Brouwer, S. W Schalm,

University Hospital Rotterdam,

Treatment of chronic HCV with Interferon is hampered

by incomplete

blocking

of viral replication, limiting the initial response,

and incomplete

removal

of infected hepatocytes, leading to frequent relapses.

We aimed to

improve

the initial response by adding Ribavirin and to reduce

the relapse rate

by

prolonging treatment to 18 months. Three hundred

patients with chronic

HCV

and elevated transaminases were included from 25

centers in Belgium,

the

Netherlands and Luxembourg: 69% genotype 1, 57% HCV

RNA above 2x10E6

copies/ml, 14% cirrhosis. Patients were randomized

towards 18 months

Interferon-a2b (3 MU tiw) plus Ribavirin, 18 months

Interferon plus

placebo,

or 6 months combination. All 295 patients who started

treatment were

included

in the intention-to-treat analysis; the per-protocol

analysis included

the

238 who completed therapy. After 6 months treatment,

HCVRNA was

undetectable

in 53% (p.p 59%) in combination therapy versus 29%

(p.p. 31%) in

monotherapy

(p<0.001). The relapse rate was 40% for those who

completed 6 months

combination therapy, 22% after 18 months mono therapy,

and only 7.7% in

those

who completed 18 months combination treatment

(p=0.002). A sustained

HCVRNA

response was observed in 44% (p.p. 50%) in 18 months

combination

therapy

versus 17% (p.p. 16%) in 18 months monotherapy and 34%

(p.p. 35%) in 6

months

combination (p<0.001). In conclusion, this study

confirms the enhanced

initial response due to combination of Interferon with

Ribavirin,

whereas it

shows an important reduction of relapse and thereby a

high sustained

response

rate due to prolongation of treatment to 18 months.

18 Months of Dual Therapy for Chronic Hepatitis C

Decreases Relapse

Rate and

Suggests New Treatment Approach for Hard to Treat

Patients with

Cirrhosis,

Genotype 1, and High Baseline Viral load

q 300 patients without previous treatment in

randomized, double blind,

placebo-controlled study.

q 2 arms treated with standard interferon alfa (not

pegylated) plus

ribavirin.

q For those randomized to 18 months of dual therapy,

the

end-of-treatment

response rate (ETR) was 51%, with a relapse rate of

13% (vs 38%),

leading to

a sustained-virologic-response (SVR) rate of 44%,

" ITT " analysis.

q 70% genotype 1, 14% cirrhosis and 53% high baseline

viral load.

q Patients with genotype 1, cirrhosis, and high

baseline viral load

derived

the greatest virologic benefits, in " as-treated "

analysis.

Perhaps one of the more interesting clinical

presentations at EASL 2001

that

potentially could have a major impact on treatment

outcome for patients

with

chronic hepatitis C was the Benelux Study. Benelux

Study results were

first

reported at AASLD November 2000 (see NATAP Report

http://www.natap.org/2000/nov/18_months_interferon112200.html)

Dr. J.T. Brouwer of University Hospital in Rotterdam,

The Netherlands

presented the study results. Even though the study

used the older

standard

combination (non-pegylated) interferon alfa plus

ribavirin, the low

relapse

rate of only 13% in a predominant genotype-1

population has significant

potential implications, if similar [or better] results

were to occur

after 18

months of pegylated interferon alfa plus ribavirin.

Given that end-of-treatment virologic response (ETR)

rates when

treating

chronic hepatitis C have always been higher than their

associated

sustained

virologic response (SVR) rates, the researchers in

this study were

trying to

determine whether longer treatment might increase

either ETR, SVR or

both.

A total of 300 treatment-naïve (no previous therapy)

patients with

chronic

hepatitis C (positive HCV RNA, increased liver enzyme

ALT, abnormal

liver

biopsy) were randomized to one of 3 treatment arms in

a double-blind

fashion

(treatment unknown to patient or treating physician).

They were: (1)

interferon alfa 2b (Intron A), 3 MIU (million

international units)

injected

3-times weekly plus oral ribavirin 1,000-1,200 mg

daily for 18 months*;

(2)

the same drug regimen in (1), except for only 6

months; or (3)

interferon

alfa 2b monotherapy, same dose as above, plus oral

placebo (inactive

drug)

for 18 months*. *Note that after 6 months, the

duration of the

treatment arms

only was revealed (unblinded), and all patients who

were non-responders

at

that time (detectable viral load and ALT greater than

1-times the upper

limit

of normal) stopped therapy (due to evidence that they

would not respond

[virologically] thereafter).

The 3 study arms were well randomized in terms of age

(mean 43-47

years),

gender (sex, 63% men in combination arms, although

monotherapy arm had

46%

men), ( " compensated, " stable) cirrhosis rate (liver

scarring, F4,

13-15%),

genotype 1 (most difficult to treat, 66-75%), and

baseline HCV RNA

greater

than 3 million copies/mL (50-55%) with 57% overall

having greater than

2

million copies/mL. Patients were from 25 centers in

Belgium,

Luxembourg and

the Netherlands.

The results were as follows. Stopping at 6 months due

to non-response

included 10% from arm 1 (combination 18 months) and

28% of arm 3

(interferon

18 months); all in arm 2 stopped at that time as per

protocol.

Withdrawal

from study due to any reason during the first 6 months

included 10%

each of

arms 1 and 2 and 5% of arm 3. Withdrawal due to any

reason between

months 6

and 18 included 13% of arm 1 and 20% of arm 3.

Reasons for withdrawal

were

not presented. Using a strict " intent-to-treat " (ITT)

analysis (all

patients

included), the end-of-treatment (ETR) viral

undetectability (limit 100

copies/mL) response rates were 51% (arm 1, combination

18 months), 55%

(arm

2, combination 6 months) and 27% (arm 3, monotherapy

18 months). There

was

no significant difference between arms 1 and 2, with

very little

additional

response in arm 1 after 6 months.

Treatment Outcomes in Benelux Study of 300 Patients

Arm 1: interferon alfa 2b* plus ribavirin ** \

Arm 2: interferon alfa 2b* plus ribavirin **

Arm 3: interferon alfa 2b* plus oral placebo

Arm 1

Arm 2 Arm

3

Length of therapy 18mos 6 mos

18 mos

ETR (ITT) 51% 55%

27%

Relapse Rate (ITT) 13% 38%

39%

SVR (ITT) 43% 34%

16%

Withdraw 0-6 mos 10% 10%

5%

Withdraw 6-18 mos 13% NA

20%

Duration of therapy 18 months 6 months 18 months

End of Treatment Response *** Rate, ITT # 51% 55%

27%

Relapse Rate (see text), ITT # 13% 38% 39%

Sustained Virologic Response Rate, ITT # 43% 34%

16%

Withdrawal, 0-6 months 10% 10% 5%

Withdrawal, 6-18 months 13% Not applicable 20%

* Interferon dose was 3 million international units

injected 3-times

weekly

(see row 2 for duration)

** Ribavirin dose was 1,000-1,200 mg orally each day

(see row 2 for

duration).

*** Percentage undetectable HCV RNA, limit 100 copies

per milliliter

# ITT = Intent-to-treat analysis, including all

enrolled patients

However, after 6 months of follow-up in each arm, the

relapse rate

(virus

becoming detectable after being undetectable at the

end of treatment)

was

significantly lower in arm 1 (combination 18 months)

than in arm 2

(combination 6 months). Those relapse rates were: 13%

(arm 1), 38%

(arm 2)

and 39% (arm 3), using an ITT analysis. Therefore,

this led to a SVR

(sustained virologic response) rate of 43% (arm 1),

34% (arm 2) and 16%

(arm

3).

In a separate " as-treated " analysis including patients

who completed

80% of

therapy for 80% of the intended duration or who

stopped therapy

according to

protocol, among patients in arm 1 (combination 18

months), those with

cirrhosis had a higher SVR (57%) than those without

cirrhosis (42%).

The

usual, opposite trend occurred in arm 2 (combination 6

months), with a

SVR of

29% for those with and 37% for those without cirrhosis

( " as-treated "

analysis). And the usual trend also occurred in arm 3

(monotherapy),

with a

SVR among 10% for those with and 18% for those without

cirrhosis.

(Note that

" as-treated " ETR was 56% in arm 1, 60% in arm 2 and

25% in arm 3. " As

treated " relapse rates were 7% (arm 1), 38% (arm 2)

and 32% (arm 3).

" As-treated " SVR was 52% (arm 1), 36% (arm 2) and 17%

(arm 3).

(editorial note from Jules Levin: The preliminary ETR

for

Pegasys+ribivarin

reported at EASL were 58% for monotherapy and 68% for

combination

therapy. In

this or any study, if you were to look at the response

rates for

patients who

are adherent and complete the course of treatment the

response rates

would be

expected to be considerably better. This was reflected

in the Benelux

study

as the SVR for arm 1 was 43%, while in the

" as-treated " analysis the

SVR was

57% for cirrhotics and 42% for non-cirrhotics. This

emphasizes the

importance

of adherence. Adherence support for coinfected

patients receiving

IFB+RBV

will be helpful. We will have to see if HIV-infected

can tolerate

ribivarin

for 18 months due to reduced hemoglobin and similar

adverse effects on

other

blood tests).

Interestingly, the SVR was higher only for genotype 1

patients taking

combination treatment for 18 months (arm 1, 36%) than

for those taking

it for

6 months (arm 2, 23%), since those with genotype 2 or

3 had a nearly

identical SVR whether they took combination therapy

for either 18

months (arm

1, 71% SVR) or 6 months (arm 2, 72%). However, the

genotype analysis

was

only presented " as-treated. " In a similar pattern,

the SVR was higher

for

those with a higher baseline viral load (greater than

3 million

copies/mL)

taking combination treatment for 18 months (arm 1,

42%) than for those

taking

it for 6 months (arm 2, 18%), since those with a low

baseline viral

load

(less than 3 million copies/mL) had a nearly identical

SVR whether they

took

combination therapy for either 18 months (arm 1, 47%)

or 6 months (arm

2,

49%). Again, however, the baseline viral load, SVR

analysis was

presented

only " as-treated. "

Taken together, the " as-treated " results (cirrhosis,

genotype and

baseline

viral load) suggest that a longer duration of therapy,

here 18 months,

may be

particularly beneficial for those patients who

previously have been

more

difficult to treat, i.e., with " unfavorable " baseline

characteristics.

This

suggests that " longer " might be better in terms of

being able to

eradicate

more HCV from more hepatocytes (liver cells) or by

having more time for

the

immune system to remove more HCV-infected hepatocytes.

Yet, those with

genotypes 2 or 3 or those with a low baseline viral

load did not derive

any

additional SVR benefits by treatment with combination

therapy for more

than 6

months.

Dr. Brouwer concluded that prolonged (18 months)

combination therapy

had " no

effect on response beyond 6 months [but had a] clear

effect on relapse

rate

(less than 10%) if [the] therapy is maintained. " Note

that liver

biopsy

results at the time of SVR were not reported.

However, it is likely

that

similar or possibly more (or better) improvements on

liver biopsy would

be

observed for those in arm 1 than in arm 2. However,

specific types and

rates

of adverse events and reasons for withdrawal were not

presented.

A similar study would need to be undertaken using a

" control " arm with

today’s standard of pegylated interferon alfa plus

ribavirin for 12

months

(versus 18 months) to determine whether similar

additional benefits

might be

derived, particularly for those with unfavorable

baseline

characteristics.

However, since the SVR could only be measured 24

months (2 years) after

entering into such a study (for the 18-month arm), it

is quite possible

that

a new standard-of-care would replace the current one

when such a study

were

finished. In the mean time, with the limitation that

this is only one

study

with these results and considering data not reported

(as discussed

above),

those with genotype 1, a high baseline viral load

and/or cirrhosis

might want

to have their physicians consider longer treatment for

18 months,

preferably

in a study or at least in an observational study.

(Editorial note: as

mentioned above, an 18-month study in HCV/HIV

coinfected would be

useful to

evaluate tolerability and adverse effects on

bloodwork).

__________________________________________________

[Guest guest]

from NATAP www.natap.org

by Jules Levin

The data from the Benelux study has

been

presented at AASLD 2000 and EASL 2001. And it makes a

good case to

consider

18 months pegIFN+RBV treatment.

18 Month Treatment Benelux Study

ABSTRACT:

REDUCTION OF RELAPSE IN CHRONIC HCV. A BENELUX STUDY

IN 300 PATIENTS

J.T Brouwer, S. W Schalm,

University Hospital Rotterdam,

Treatment of chronic HCV with Interferon is hampered

by incomplete

blocking

of viral replication, limiting the initial response,

and incomplete

removal

of infected hepatocytes, leading to frequent relapses.

We aimed to

improve

the initial response by adding Ribavirin and to reduce

the relapse rate

by

prolonging treatment to 18 months. Three hundred

patients with chronic

HCV

and elevated transaminases were included from 25

centers in Belgium,

the

Netherlands and Luxembourg: 69% genotype 1, 57% HCV

RNA above 2x10E6

copies/ml, 14% cirrhosis. Patients were randomized

towards 18 months

Interferon-a2b (3 MU tiw) plus Ribavirin, 18 months

Interferon plus

placebo,

or 6 months combination. All 295 patients who started

treatment were

included

in the intention-to-treat analysis; the per-protocol

analysis included

the

238 who completed therapy. After 6 months treatment,

HCVRNA was

undetectable

in 53% (p.p 59%) in combination therapy versus 29%

(p.p. 31%) in

monotherapy

(p<0.001). The relapse rate was 40% for those who

completed 6 months

combination therapy, 22% after 18 months mono therapy,

and only 7.7% in

those

who completed 18 months combination treatment

(p=0.002). A sustained

HCVRNA

response was observed in 44% (p.p. 50%) in 18 months

combination

therapy

versus 17% (p.p. 16%) in 18 months monotherapy and 34%

(p.p. 35%) in 6

months

combination (p<0.001). In conclusion, this study

confirms the enhanced

initial response due to combination of Interferon with

Ribavirin,

whereas it

shows an important reduction of relapse and thereby a

high sustained

response

rate due to prolongation of treatment to 18 months.

18 Months of Dual Therapy for Chronic Hepatitis C

Decreases Relapse

Rate and

Suggests New Treatment Approach for Hard to Treat

Patients with

Cirrhosis,

Genotype 1, and High Baseline Viral load

q 300 patients without previous treatment in

randomized, double blind,

placebo-controlled study.

q 2 arms treated with standard interferon alfa (not

pegylated) plus

ribavirin.

q For those randomized to 18 months of dual therapy,

the

end-of-treatment

response rate (ETR) was 51%, with a relapse rate of

13% (vs 38%),

leading to

a sustained-virologic-response (SVR) rate of 44%,

" ITT " analysis.

q 70% genotype 1, 14% cirrhosis and 53% high baseline

viral load.

q Patients with genotype 1, cirrhosis, and high

baseline viral load

derived

the greatest virologic benefits, in " as-treated "

analysis.

Perhaps one of the more interesting clinical

presentations at EASL 2001

that

potentially could have a major impact on treatment

outcome for patients

with

chronic hepatitis C was the Benelux Study. Benelux

Study results were

first

reported at AASLD November 2000 (see NATAP Report

http://www.natap.org/2000/nov/18_months_interferon112200.html)

Dr. J.T. Brouwer of University Hospital in Rotterdam,

The Netherlands

presented the study results. Even though the study

used the older

standard

combination (non-pegylated) interferon alfa plus

ribavirin, the low

relapse

rate of only 13% in a predominant genotype-1

population has significant

potential implications, if similar [or better] results

were to occur

after 18

months of pegylated interferon alfa plus ribavirin.

Given that end-of-treatment virologic response (ETR)

rates when

treating

chronic hepatitis C have always been higher than their

associated

sustained

virologic response (SVR) rates, the researchers in

this study were

trying to

determine whether longer treatment might increase

either ETR, SVR or

both.

A total of 300 treatment-naïve (no previous therapy)

patients with

chronic

hepatitis C (positive HCV RNA, increased liver enzyme

ALT, abnormal

liver

biopsy) were randomized to one of 3 treatment arms in

a double-blind

fashion

(treatment unknown to patient or treating physician).

They were: (1)

interferon alfa 2b (Intron A), 3 MIU (million

international units)

injected

3-times weekly plus oral ribavirin 1,000-1,200 mg

daily for 18 months*;

(2)

the same drug regimen in (1), except for only 6

months; or (3)

interferon

alfa 2b monotherapy, same dose as above, plus oral

placebo (inactive

drug)

for 18 months*. *Note that after 6 months, the

duration of the

treatment arms

only was revealed (unblinded), and all patients who

were non-responders

at

that time (detectable viral load and ALT greater than

1-times the upper

limit

of normal) stopped therapy (due to evidence that they

would not respond

[virologically] thereafter).

The 3 study arms were well randomized in terms of age

(mean 43-47

years),

gender (sex, 63% men in combination arms, although

monotherapy arm had

46%

men), ( " compensated, " stable) cirrhosis rate (liver

scarring, F4,

13-15%),

genotype 1 (most difficult to treat, 66-75%), and

baseline HCV RNA

greater

than 3 million copies/mL (50-55%) with 57% overall

having greater than

2

million copies/mL. Patients were from 25 centers in

Belgium,

Luxembourg and

the Netherlands.

The results were as follows. Stopping at 6 months due

to non-response

included 10% from arm 1 (combination 18 months) and

28% of arm 3

(interferon

18 months); all in arm 2 stopped at that time as per

protocol.

Withdrawal

from study due to any reason during the first 6 months

included 10%

each of

arms 1 and 2 and 5% of arm 3. Withdrawal due to any

reason between

months 6

and 18 included 13% of arm 1 and 20% of arm 3.

Reasons for withdrawal

were

not presented. Using a strict " intent-to-treat " (ITT)

analysis (all

patients

included), the end-of-treatment (ETR) viral

undetectability (limit 100

copies/mL) response rates were 51% (arm 1, combination

18 months), 55%

(arm

2, combination 6 months) and 27% (arm 3, monotherapy

18 months). There

was

no significant difference between arms 1 and 2, with

very little

additional

response in arm 1 after 6 months.

Treatment Outcomes in Benelux Study of 300 Patients

Arm 1: interferon alfa 2b* plus ribavirin ** \

Arm 2: interferon alfa 2b* plus ribavirin **

Arm 3: interferon alfa 2b* plus oral placebo

Arm 1

Arm 2 Arm

3

Length of therapy 18mos 6 mos

18 mos

ETR (ITT) 51% 55%

27%

Relapse Rate (ITT) 13% 38%

39%

SVR (ITT) 43% 34%

16%

Withdraw 0-6 mos 10% 10%

5%

Withdraw 6-18 mos 13% NA

20%

Duration of therapy 18 months 6 months 18 months

End of Treatment Response *** Rate, ITT # 51% 55%

27%

Relapse Rate (see text), ITT # 13% 38% 39%

Sustained Virologic Response Rate, ITT # 43% 34%

16%

Withdrawal, 0-6 months 10% 10% 5%

Withdrawal, 6-18 months 13% Not applicable 20%

* Interferon dose was 3 million international units

injected 3-times

weekly

(see row 2 for duration)

** Ribavirin dose was 1,000-1,200 mg orally each day

(see row 2 for

duration).

*** Percentage undetectable HCV RNA, limit 100 copies

per milliliter

# ITT = Intent-to-treat analysis, including all

enrolled patients

However, after 6 months of follow-up in each arm, the

relapse rate

(virus

becoming detectable after being undetectable at the

end of treatment)

was

significantly lower in arm 1 (combination 18 months)

than in arm 2

(combination 6 months). Those relapse rates were: 13%

(arm 1), 38%

(arm 2)

and 39% (arm 3), using an ITT analysis. Therefore,

this led to a SVR

(sustained virologic response) rate of 43% (arm 1),

34% (arm 2) and 16%

(arm

3).

In a separate " as-treated " analysis including patients

who completed

80% of

therapy for 80% of the intended duration or who

stopped therapy

according to

protocol, among patients in arm 1 (combination 18

months), those with

cirrhosis had a higher SVR (57%) than those without

cirrhosis (42%).

The

usual, opposite trend occurred in arm 2 (combination 6

months), with a

SVR of

29% for those with and 37% for those without cirrhosis

( " as-treated "

analysis). And the usual trend also occurred in arm 3

(monotherapy),

with a

SVR among 10% for those with and 18% for those without

cirrhosis.

(Note that

" as-treated " ETR was 56% in arm 1, 60% in arm 2 and

25% in arm 3. " As

treated " relapse rates were 7% (arm 1), 38% (arm 2)

and 32% (arm 3).

" As-treated " SVR was 52% (arm 1), 36% (arm 2) and 17%

(arm 3).

(editorial note from Jules Levin: The preliminary ETR

for

Pegasys+ribivarin

reported at EASL were 58% for monotherapy and 68% for

combination

therapy. In

this or any study, if you were to look at the response

rates for

patients who

are adherent and complete the course of treatment the

response rates

would be

expected to be considerably better. This was reflected

in the Benelux

study

as the SVR for arm 1 was 43%, while in the

" as-treated " analysis the

SVR was

57% for cirrhotics and 42% for non-cirrhotics. This

emphasizes the

importance

of adherence. Adherence support for coinfected

patients receiving

IFB+RBV

will be helpful. We will have to see if HIV-infected

can tolerate

ribivarin

for 18 months due to reduced hemoglobin and similar

adverse effects on

other

blood tests).

Interestingly, the SVR was higher only for genotype 1

patients taking

combination treatment for 18 months (arm 1, 36%) than

for those taking

it for

6 months (arm 2, 23%), since those with genotype 2 or

3 had a nearly

identical SVR whether they took combination therapy

for either 18

months (arm

1, 71% SVR) or 6 months (arm 2, 72%). However, the

genotype analysis

was

only presented " as-treated. " In a similar pattern,

the SVR was higher

for

those with a higher baseline viral load (greater than

3 million

copies/mL)

taking combination treatment for 18 months (arm 1,

42%) than for those

taking

it for 6 months (arm 2, 18%), since those with a low

baseline viral

load

(less than 3 million copies/mL) had a nearly identical

SVR whether they

took

combination therapy for either 18 months (arm 1, 47%)

or 6 months (arm

2,

49%). Again, however, the baseline viral load, SVR

analysis was

presented

only " as-treated. "

Taken together, the " as-treated " results (cirrhosis,

genotype and

baseline

viral load) suggest that a longer duration of therapy,

here 18 months,

may be

particularly beneficial for those patients who

previously have been

more

difficult to treat, i.e., with " unfavorable " baseline

characteristics.

This

suggests that " longer " might be better in terms of

being able to

eradicate

more HCV from more hepatocytes (liver cells) or by

having more time for

the

immune system to remove more HCV-infected hepatocytes.

Yet, those with

genotypes 2 or 3 or those with a low baseline viral

load did not derive

any

additional SVR benefits by treatment with combination

therapy for more

than 6

months.

Dr. Brouwer concluded that prolonged (18 months)

combination therapy

had " no

effect on response beyond 6 months [but had a] clear

effect on relapse

rate

(less than 10%) if [the] therapy is maintained. " Note

that liver

biopsy

results at the time of SVR were not reported.

However, it is likely

that

similar or possibly more (or better) improvements on

liver biopsy would

be

observed for those in arm 1 than in arm 2. However,

specific types and

rates

of adverse events and reasons for withdrawal were not

presented.

A similar study would need to be undertaken using a

" control " arm with

today’s standard of pegylated interferon alfa plus

ribavirin for 12

months

(versus 18 months) to determine whether similar

additional benefits

might be

derived, particularly for those with unfavorable

baseline

characteristics.

However, since the SVR could only be measured 24

months (2 years) after

entering into such a study (for the 18-month arm), it

is quite possible

that

a new standard-of-care would replace the current one

when such a study

were

finished. In the mean time, with the limitation that

this is only one

study

with these results and considering data not reported

(as discussed

above),

those with genotype 1, a high baseline viral load

and/or cirrhosis

might want

to have their physicians consider longer treatment for

18 months,

preferably

in a study or at least in an observational study.

(Editorial note: as

mentioned above, an 18-month study in HCV/HIV

coinfected would be

useful to

evaluate tolerability and adverse effects on

bloodwork).

__________________________________________________

[Guest guest]

from NATAP www.natap.org

by Jules Levin

The data from the Benelux study has

been

presented at AASLD 2000 and EASL 2001. And it makes a

good case to

consider

18 months pegIFN+RBV treatment.

18 Month Treatment Benelux Study

ABSTRACT:

REDUCTION OF RELAPSE IN CHRONIC HCV. A BENELUX STUDY

IN 300 PATIENTS

J.T Brouwer, S. W Schalm,

University Hospital Rotterdam,

Treatment of chronic HCV with Interferon is hampered

by incomplete

blocking

of viral replication, limiting the initial response,

and incomplete

removal

of infected hepatocytes, leading to frequent relapses.

We aimed to

improve

the initial response by adding Ribavirin and to reduce

the relapse rate

by

prolonging treatment to 18 months. Three hundred

patients with chronic

HCV

and elevated transaminases were included from 25

centers in Belgium,

the

Netherlands and Luxembourg: 69% genotype 1, 57% HCV

RNA above 2x10E6

copies/ml, 14% cirrhosis. Patients were randomized

towards 18 months

Interferon-a2b (3 MU tiw) plus Ribavirin, 18 months

Interferon plus

placebo,

or 6 months combination. All 295 patients who started

treatment were

included

in the intention-to-treat analysis; the per-protocol

analysis included

the

238 who completed therapy. After 6 months treatment,

HCVRNA was

undetectable

in 53% (p.p 59%) in combination therapy versus 29%

(p.p. 31%) in

monotherapy

(p<0.001). The relapse rate was 40% for those who

completed 6 months

combination therapy, 22% after 18 months mono therapy,

and only 7.7% in

those

who completed 18 months combination treatment

(p=0.002). A sustained

HCVRNA

response was observed in 44% (p.p. 50%) in 18 months

combination

therapy

versus 17% (p.p. 16%) in 18 months monotherapy and 34%

(p.p. 35%) in 6

months

combination (p<0.001). In conclusion, this study

confirms the enhanced

initial response due to combination of Interferon with

Ribavirin,

whereas it

shows an important reduction of relapse and thereby a

high sustained

response

rate due to prolongation of treatment to 18 months.

18 Months of Dual Therapy for Chronic Hepatitis C

Decreases Relapse

Rate and

Suggests New Treatment Approach for Hard to Treat

Patients with

Cirrhosis,

Genotype 1, and High Baseline Viral load

q 300 patients without previous treatment in

randomized, double blind,

placebo-controlled study.

q 2 arms treated with standard interferon alfa (not

pegylated) plus

ribavirin.

q For those randomized to 18 months of dual therapy,

the

end-of-treatment

response rate (ETR) was 51%, with a relapse rate of

13% (vs 38%),

leading to

a sustained-virologic-response (SVR) rate of 44%,

" ITT " analysis.

q 70% genotype 1, 14% cirrhosis and 53% high baseline

viral load.

q Patients with genotype 1, cirrhosis, and high

baseline viral load

derived

the greatest virologic benefits, in " as-treated "

analysis.

Perhaps one of the more interesting clinical

presentations at EASL 2001

that

potentially could have a major impact on treatment

outcome for patients

with

chronic hepatitis C was the Benelux Study. Benelux

Study results were

first

reported at AASLD November 2000 (see NATAP Report

http://www.natap.org/2000/nov/18_months_interferon112200.html)

Dr. J.T. Brouwer of University Hospital in Rotterdam,

The Netherlands

presented the study results. Even though the study

used the older

standard

combination (non-pegylated) interferon alfa plus

ribavirin, the low

relapse

rate of only 13% in a predominant genotype-1

population has significant

potential implications, if similar [or better] results

were to occur

after 18

months of pegylated interferon alfa plus ribavirin.

Given that end-of-treatment virologic response (ETR)

rates when

treating

chronic hepatitis C have always been higher than their

associated

sustained

virologic response (SVR) rates, the researchers in

this study were

trying to

determine whether longer treatment might increase

either ETR, SVR or

both.

A total of 300 treatment-naïve (no previous therapy)

patients with

chronic

hepatitis C (positive HCV RNA, increased liver enzyme

ALT, abnormal

liver

biopsy) were randomized to one of 3 treatment arms in

a double-blind

fashion

(treatment unknown to patient or treating physician).

They were: (1)

interferon alfa 2b (Intron A), 3 MIU (million

international units)

injected

3-times weekly plus oral ribavirin 1,000-1,200 mg

daily for 18 months*;

(2)

the same drug regimen in (1), except for only 6

months; or (3)

interferon

alfa 2b monotherapy, same dose as above, plus oral

placebo (inactive

drug)

for 18 months*. *Note that after 6 months, the

duration of the

treatment arms

only was revealed (unblinded), and all patients who

were non-responders

at

that time (detectable viral load and ALT greater than

1-times the upper

limit

of normal) stopped therapy (due to evidence that they

would not respond

[virologically] thereafter).

The 3 study arms were well randomized in terms of age

(mean 43-47

years),

gender (sex, 63% men in combination arms, although

monotherapy arm had

46%

men), ( " compensated, " stable) cirrhosis rate (liver

scarring, F4,

13-15%),

genotype 1 (most difficult to treat, 66-75%), and

baseline HCV RNA

greater

than 3 million copies/mL (50-55%) with 57% overall

having greater than

2

million copies/mL. Patients were from 25 centers in

Belgium,

Luxembourg and

the Netherlands.

The results were as follows. Stopping at 6 months due

to non-response

included 10% from arm 1 (combination 18 months) and

28% of arm 3

(interferon

18 months); all in arm 2 stopped at that time as per

protocol.

Withdrawal

from study due to any reason during the first 6 months

included 10%

each of

arms 1 and 2 and 5% of arm 3. Withdrawal due to any

reason between

months 6

and 18 included 13% of arm 1 and 20% of arm 3.

Reasons for withdrawal

were

not presented. Using a strict " intent-to-treat " (ITT)

analysis (all

patients

included), the end-of-treatment (ETR) viral

undetectability (limit 100

copies/mL) response rates were 51% (arm 1, combination

18 months), 55%

(arm

2, combination 6 months) and 27% (arm 3, monotherapy

18 months). There

was

no significant difference between arms 1 and 2, with

very little

additional

response in arm 1 after 6 months.

Treatment Outcomes in Benelux Study of 300 Patients

Arm 1: interferon alfa 2b* plus ribavirin ** \

Arm 2: interferon alfa 2b* plus ribavirin **

Arm 3: interferon alfa 2b* plus oral placebo

Arm 1

Arm 2 Arm

3

Length of therapy 18mos 6 mos

18 mos

ETR (ITT) 51% 55%

27%

Relapse Rate (ITT) 13% 38%

39%

SVR (ITT) 43% 34%

16%

Withdraw 0-6 mos 10% 10%

5%

Withdraw 6-18 mos 13% NA

20%

Duration of therapy 18 months 6 months 18 months

End of Treatment Response *** Rate, ITT # 51% 55%

27%

Relapse Rate (see text), ITT # 13% 38% 39%

Sustained Virologic Response Rate, ITT # 43% 34%

16%

Withdrawal, 0-6 months 10% 10% 5%

Withdrawal, 6-18 months 13% Not applicable 20%

* Interferon dose was 3 million international units

injected 3-times

weekly

(see row 2 for duration)

** Ribavirin dose was 1,000-1,200 mg orally each day

(see row 2 for

duration).

*** Percentage undetectable HCV RNA, limit 100 copies

per milliliter

# ITT = Intent-to-treat analysis, including all

enrolled patients

However, after 6 months of follow-up in each arm, the

relapse rate

(virus

becoming detectable after being undetectable at the

end of treatment)

was

significantly lower in arm 1 (combination 18 months)

than in arm 2

(combination 6 months). Those relapse rates were: 13%

(arm 1), 38%

(arm 2)

and 39% (arm 3), using an ITT analysis. Therefore,

this led to a SVR

(sustained virologic response) rate of 43% (arm 1),

34% (arm 2) and 16%

(arm

3).

In a separate " as-treated " analysis including patients

who completed

80% of

therapy for 80% of the intended duration or who

stopped therapy

according to

protocol, among patients in arm 1 (combination 18

months), those with

cirrhosis had a higher SVR (57%) than those without

cirrhosis (42%).

The

usual, opposite trend occurred in arm 2 (combination 6

months), with a

SVR of

29% for those with and 37% for those without cirrhosis

( " as-treated "

analysis). And the usual trend also occurred in arm 3

(monotherapy),

with a

SVR among 10% for those with and 18% for those without

cirrhosis.

(Note that

" as-treated " ETR was 56% in arm 1, 60% in arm 2 and

25% in arm 3. " As

treated " relapse rates were 7% (arm 1), 38% (arm 2)

and 32% (arm 3).

" As-treated " SVR was 52% (arm 1), 36% (arm 2) and 17%

(arm 3).

(editorial note from Jules Levin: The preliminary ETR

for

Pegasys+ribivarin

reported at EASL were 58% for monotherapy and 68% for

combination

therapy. In

this or any study, if you were to look at the response

rates for

patients who

are adherent and complete the course of treatment the

response rates

would be

expected to be considerably better. This was reflected

in the Benelux

study

as the SVR for arm 1 was 43%, while in the

" as-treated " analysis the

SVR was

57% for cirrhotics and 42% for non-cirrhotics. This

emphasizes the

importance

of adherence. Adherence support for coinfected

patients receiving

IFB+RBV

will be helpful. We will have to see if HIV-infected

can tolerate

ribivarin

for 18 months due to reduced hemoglobin and similar

adverse effects on

other

blood tests).

Interestingly, the SVR was higher only for genotype 1

patients taking

combination treatment for 18 months (arm 1, 36%) than

for those taking

it for

6 months (arm 2, 23%), since those with genotype 2 or

3 had a nearly

identical SVR whether they took combination therapy

for either 18

months (arm

1, 71% SVR) or 6 months (arm 2, 72%). However, the

genotype analysis

was

only presented " as-treated. " In a similar pattern,

the SVR was higher

for

those with a higher baseline viral load (greater than

3 million

copies/mL)

taking combination treatment for 18 months (arm 1,

42%) than for those

taking

it for 6 months (arm 2, 18%), since those with a low

baseline viral

load

(less than 3 million copies/mL) had a nearly identical

SVR whether they

took

combination therapy for either 18 months (arm 1, 47%)

or 6 months (arm

2,

49%). Again, however, the baseline viral load, SVR

analysis was

presented

only " as-treated. "

Taken together, the " as-treated " results (cirrhosis,

genotype and

baseline

viral load) suggest that a longer duration of therapy,

here 18 months,

may be

particularly beneficial for those patients who

previously have been

more

difficult to treat, i.e., with " unfavorable " baseline

characteristics.

This

suggests that " longer " might be better in terms of

being able to

eradicate

more HCV from more hepatocytes (liver cells) or by

having more time for

the

immune system to remove more HCV-infected hepatocytes.

Yet, those with

genotypes 2 or 3 or those with a low baseline viral

load did not derive

any

additional SVR benefits by treatment with combination

therapy for more

than 6

months.

Dr. Brouwer concluded that prolonged (18 months)

combination therapy

had " no

effect on response beyond 6 months [but had a] clear

effect on relapse

rate

(less than 10%) if [the] therapy is maintained. " Note

that liver

biopsy

results at the time of SVR were not reported.

However, it is likely

that

similar or possibly more (or better) improvements on

liver biopsy would

be

observed for those in arm 1 than in arm 2. However,

specific types and

rates

of adverse events and reasons for withdrawal were not

presented.

A similar study would need to be undertaken using a

" control " arm with

today’s standard of pegylated interferon alfa plus

ribavirin for 12

months

(versus 18 months) to determine whether similar

additional benefits

might be

derived, particularly for those with unfavorable

baseline

characteristics.

However, since the SVR could only be measured 24

months (2 years) after

entering into such a study (for the 18-month arm), it

is quite possible

that

a new standard-of-care would replace the current one

when such a study

were

finished. In the mean time, with the limitation that

this is only one

study

with these results and considering data not reported

(as discussed

above),

those with genotype 1, a high baseline viral load

and/or cirrhosis

might want

to have their physicians consider longer treatment for

18 months,

preferably

in a study or at least in an observational study.

(Editorial note: as

mentioned above, an 18-month study in HCV/HIV

coinfected would be

useful to

evaluate tolerability and adverse effects on

bloodwork).

__________________________________________________