Hepatitis B Therapy at AASLD

[Guest guest]

NATAP - www.natap.org

----------------------

Hepatitis B Therapy at AASLD

Nov 9-13

Written for NATAP by T. Dieterich, MD

Cabrini Hospital and NYU Medical Center, NYC

See ongoing reporting from AASLD at NATAP website

The therapy of hepatitis B is becoming almost as

complicated as the

disease

itself. It is suffering from the success of all the

new therapies

coming as

well as some information on the older therapies. I

will attempt to keep

this

as uncomplicated as possible and have been debating

how to organize

this,

alphabetical order or order of likely approval and I

think it would be

better

to put this in historical perspective to build on the

base and educate

those

still confused by the field.

The first treatment approved by the FDA for HBV was

alfa interferon 2b

at a

disabling dose of 10 MIU thrice weekly or 5 MIU daily

for 4 months.

This

resulted in about a 25% HbeAg to HbeAb seroconversion

rate and a

histological

benefit on liver biopsy. In late 1998 3TC or

lamivudine was approved at

a

dose of 100 mg per day, considerably less than the HIV

dose of 300 mg

per

day. One years’ treatment resulted in a

seroconversion rate of about

25%,

like interferon and a histological benefit on biopsy

similar to

interferon’s.

The difference in this therapy was that HBV resistance

developed in

nearly as

many patients who seroconverted per year. The good

news was that the

resistant virus was seen as more benign than the wild

type virus and

even

though the virus was still replicating, the

seroconversion rate was

significantly higher if the patients continued taking

3TC. News from

this

meeting however suggested that the early biopsy

benefit is lost after 4

years

on 3TC and the biopsies start to worsen again. This is

beginning to

sound

like the HIV story where sequential nucleoside

analogue therapy

resulted in

sequential nucleoside resistance and I believe that is

clearly the

case.

Why not combine the two therapies? Well there were

several combination

trials

presented here in Dallas. They, unlike the first study

performed a few

years

ago, showed that combination 3TC and interferon is

better than either

alone

and that interferon prevents the development of 3TC

resistance

mutations.

There was even a combination trial of famciclovir and

interferon, which

showed some benefit. Famciclovir is approved for the

treatment of

herpes

virus infections but not for hepatitis B. It does

however have some

activity

against hepatitis B albeit slightly less than 3TC.

Famciclovir and 3TC

share

some resistance mutations as well, but not all and

there is one paper

from

2000 at least that demonstrates synergy between the

two. In my

practice, for

patients not on clinical trials, I always use the

combination of

famciclovir

and 3TC.

The advances in interferon technology to pegylate it

and lengthen the

half

life so that it can be administered weekly, have

spread to hepatitis B

treatment as well. One study showed that pegylated

interferon alfa 2 a

is

clearly superior to plain alfa 2a interferon thrice

weekly in the

treatment

of hepatitis B. Clearly the next step is to combine

pegylated

interferon and

3TC in a trial. That trial is now in progress, but has

no results to

date.

The next drug likely to be approved in the US for HBV

is adefovir. It

is a

nuceotide analogue similar to tenofovir which just

arrived on pharmacy

shelves in early November for the treatment of HIV.

Adefovir was

studied in

HIV patients and had little activity and quite a bit

of kidney toxicity

at

120 mg and 60 mg per day. The HBV dose is fortunately

only 10 mg and so

far

has demonstrated very little toxicity and a great deal

of efficacy.

Long-term

data were presented up to 136 weeks for adefovir,

which showed a

seroconversion rate of 21% and only 3/39 patients

discontinued drug for

toxicity. Also encouraging was the loss of e Ag in 39%

and the HBV DNA

< 400

copies of 61% at week 48 and 70% at week 100

demonstrating a 3.75 log

drop in

HBV DNA. One of the biggest advantages of adefovir

was that over 2

years no

resistance developed! There were some mutations found

in the HBV

genome, but

they did not confer resistance to adefovir. That is

very promising and

encouraging. HIV HBV infection is becoming a bigger

problem each year

because after 4 years of 3TC treatment over 90% of HIV

HBV infected

patients

demonstrate 3TC resistant HBV. An abstract from Paris

clearly showed in

35

HIV HBV co-infected patients with 3TC resistant HBV

that adefovir

reduced

HBV DNA by 4.74 logs. This was accompanied by 3/33

patients

seroconverting

from e Ag to e Ab. This demonstrates the efficacy of

adefovir in 3TC

resistant virus even in HIV patients. There was no

change in HIV RNA or

CD4

count in these patients. Combinations of adefovir and

3TC were studied

for

drug-drug interactions and there appear to be none,

paving the way for

a

combination adefovir 3TC trial, which is ongoing now.

There is every

reason

to believe that this drug will be licensed in the US

by this time next

year

for the treatment of hepatitis B and 3TC resistant

hepatitis B

Next in the arena is FTC, a close cousin of 3TC.

There was originally

no

real reason to suspect that this would be any better

than 3TC. However

in a

large multiple dose trial presented here the highest

dose 200 mg

resulted in

61% of patients with <4700 copies of HBV DNA, but

even more

impressive was

the e Ag loss of 50% and the eAb seroconversion rate

of 23%. Only 2

patients

developed the classic 550 and 526 mutations, which are

the same as the

3TC

resistant ones. There were no serious side effects

noted in this trial.

From

the same company, Triangle, another drug clevudine or

L-FMAU was

studied

first in an animal toxicology study and shown to be

safe in animals.

Then it

was studied in a 28 day trial in man . The results

were somewhat

surprisingly good. All three doses showed as much as a

3 log drop in

HBV DNA

in the 28 days, but what was surprising was that HBV

DNA stayed down by

as

much as 2 logs even 5 months after stopping

clevudine!. The highest

dose

resulted in some ALT elevations, but that just may

mean that it is

working

well. The obvious next step is to combine these two

agents and the

results of

that trial will be really interesting.

editorial note: Entecavir is a new hepatitis B drug. A

study was

presented on

entecavir vs 3TC resistance-

New Hepatitis B Drugs at AASLD (LDT, adefovir,

entecavir)

<A HREF= " http://www.natap.org/2001/aasld2/day13.htm " >

http://www.natap.org/2001/aasld2/day13.htm</A>

One study of entecavir in transplant patients clearly

showed activity

of

about a 1.5 log drop in HBV DNA in heavily pre treated

patients

suggesting

that entecavir may indeed be active in 3TC resistant

patients.

LDT is another nucleoside made by Novirio which has

good activity

against HBV

and HIV and the phase I dose escalation results were

presented here

which

showed linear pharmacokinetics, a good thing to have.

A large

combination

trial with 3TC is due to get started in the US any day

now and it

should be

exciting. The trial design is very intriguing and

adventurous and

should look

immediately for synergies between the two drugs.

D4C is the Achillion addition to the hepatitis B

nucleoside pool. A

phase I

trial in healthy volunteers was presented which

revealed good

absorption and

good half-life. In vitro this drug shows activity

against both wild

type and

3TC resistant hepatitis B. This is also a promising

new agent for which

trials are presently underway.

There is much progress in the world of hepatitis B now

and much of it

is

proceeding in the direction of combination therapy

based on the

building

blocks of 3 TC and perhaps pegylated interferon.

Nucleoside only

combinations, of course have fewer side effects and

appear to be the

wave of

the future.

__________________________________________________

[Guest guest]

NATAP - www.natap.org

----------------------

Hepatitis B Therapy at AASLD

Nov 9-13

Written for NATAP by T. Dieterich, MD

Cabrini Hospital and NYU Medical Center, NYC

See ongoing reporting from AASLD at NATAP website

The therapy of hepatitis B is becoming almost as

complicated as the

disease

itself. It is suffering from the success of all the

new therapies

coming as

well as some information on the older therapies. I

will attempt to keep

this

as uncomplicated as possible and have been debating

how to organize

this,

alphabetical order or order of likely approval and I

think it would be

better

to put this in historical perspective to build on the

base and educate

those

still confused by the field.

The first treatment approved by the FDA for HBV was

alfa interferon 2b

at a

disabling dose of 10 MIU thrice weekly or 5 MIU daily

for 4 months.

This

resulted in about a 25% HbeAg to HbeAb seroconversion

rate and a

histological

benefit on liver biopsy. In late 1998 3TC or

lamivudine was approved at

a

dose of 100 mg per day, considerably less than the HIV

dose of 300 mg

per

day. One years’ treatment resulted in a

seroconversion rate of about

25%,

like interferon and a histological benefit on biopsy

similar to

interferon’s.

The difference in this therapy was that HBV resistance

developed in

nearly as

many patients who seroconverted per year. The good

news was that the

resistant virus was seen as more benign than the wild

type virus and

even

though the virus was still replicating, the

seroconversion rate was

significantly higher if the patients continued taking

3TC. News from

this

meeting however suggested that the early biopsy

benefit is lost after 4

years

on 3TC and the biopsies start to worsen again. This is

beginning to

sound

like the HIV story where sequential nucleoside

analogue therapy

resulted in

sequential nucleoside resistance and I believe that is

clearly the

case.

Why not combine the two therapies? Well there were

several combination

trials

presented here in Dallas. They, unlike the first study

performed a few

years

ago, showed that combination 3TC and interferon is

better than either

alone

and that interferon prevents the development of 3TC

resistance

mutations.

There was even a combination trial of famciclovir and

interferon, which

showed some benefit. Famciclovir is approved for the

treatment of

herpes

virus infections but not for hepatitis B. It does

however have some

activity

against hepatitis B albeit slightly less than 3TC.

Famciclovir and 3TC

share

some resistance mutations as well, but not all and

there is one paper

from

2000 at least that demonstrates synergy between the

two. In my

practice, for

patients not on clinical trials, I always use the

combination of

famciclovir

and 3TC.

The advances in interferon technology to pegylate it

and lengthen the

half

life so that it can be administered weekly, have

spread to hepatitis B

treatment as well. One study showed that pegylated

interferon alfa 2 a

is

clearly superior to plain alfa 2a interferon thrice

weekly in the

treatment

of hepatitis B. Clearly the next step is to combine

pegylated

interferon and

3TC in a trial. That trial is now in progress, but has

no results to

date.

The next drug likely to be approved in the US for HBV

is adefovir. It

is a

nuceotide analogue similar to tenofovir which just

arrived on pharmacy

shelves in early November for the treatment of HIV.

Adefovir was

studied in

HIV patients and had little activity and quite a bit

of kidney toxicity

at

120 mg and 60 mg per day. The HBV dose is fortunately

only 10 mg and so

far

has demonstrated very little toxicity and a great deal

of efficacy.

Long-term

data were presented up to 136 weeks for adefovir,

which showed a

seroconversion rate of 21% and only 3/39 patients

discontinued drug for

toxicity. Also encouraging was the loss of e Ag in 39%

and the HBV DNA

< 400

copies of 61% at week 48 and 70% at week 100

demonstrating a 3.75 log

drop in

HBV DNA. One of the biggest advantages of adefovir

was that over 2

years no

resistance developed! There were some mutations found

in the HBV

genome, but

they did not confer resistance to adefovir. That is

very promising and

encouraging. HIV HBV infection is becoming a bigger

problem each year

because after 4 years of 3TC treatment over 90% of HIV

HBV infected

patients

demonstrate 3TC resistant HBV. An abstract from Paris

clearly showed in

35

HIV HBV co-infected patients with 3TC resistant HBV

that adefovir

reduced

HBV DNA by 4.74 logs. This was accompanied by 3/33

patients

seroconverting

from e Ag to e Ab. This demonstrates the efficacy of

adefovir in 3TC

resistant virus even in HIV patients. There was no

change in HIV RNA or

CD4

count in these patients. Combinations of adefovir and

3TC were studied

for

drug-drug interactions and there appear to be none,

paving the way for

a

combination adefovir 3TC trial, which is ongoing now.

There is every

reason

to believe that this drug will be licensed in the US

by this time next

year

for the treatment of hepatitis B and 3TC resistant

hepatitis B

Next in the arena is FTC, a close cousin of 3TC.

There was originally

no

real reason to suspect that this would be any better

than 3TC. However

in a

large multiple dose trial presented here the highest

dose 200 mg

resulted in

61% of patients with <4700 copies of HBV DNA, but

even more

impressive was

the e Ag loss of 50% and the eAb seroconversion rate

of 23%. Only 2

patients

developed the classic 550 and 526 mutations, which are

the same as the

3TC

resistant ones. There were no serious side effects

noted in this trial.

From

the same company, Triangle, another drug clevudine or

L-FMAU was

studied

first in an animal toxicology study and shown to be

safe in animals.

Then it

was studied in a 28 day trial in man . The results

were somewhat

surprisingly good. All three doses showed as much as a

3 log drop in

HBV DNA

in the 28 days, but what was surprising was that HBV

DNA stayed down by

as

much as 2 logs even 5 months after stopping

clevudine!. The highest

dose

resulted in some ALT elevations, but that just may

mean that it is

working

well. The obvious next step is to combine these two

agents and the

results of

that trial will be really interesting.

editorial note: Entecavir is a new hepatitis B drug. A

study was

presented on

entecavir vs 3TC resistance-

New Hepatitis B Drugs at AASLD (LDT, adefovir,

entecavir)

<A HREF= " http://www.natap.org/2001/aasld2/day13.htm " >

http://www.natap.org/2001/aasld2/day13.htm</A>

One study of entecavir in transplant patients clearly

showed activity

of

about a 1.5 log drop in HBV DNA in heavily pre treated

patients

suggesting

that entecavir may indeed be active in 3TC resistant

patients.

LDT is another nucleoside made by Novirio which has

good activity

against HBV

and HIV and the phase I dose escalation results were

presented here

which

showed linear pharmacokinetics, a good thing to have.

A large

combination

trial with 3TC is due to get started in the US any day

now and it

should be

exciting. The trial design is very intriguing and

adventurous and

should look

immediately for synergies between the two drugs.

D4C is the Achillion addition to the hepatitis B

nucleoside pool. A

phase I

trial in healthy volunteers was presented which

revealed good

absorption and

good half-life. In vitro this drug shows activity

against both wild

type and

3TC resistant hepatitis B. This is also a promising

new agent for which

trials are presently underway.

There is much progress in the world of hepatitis B now

and much of it

is

proceeding in the direction of combination therapy

based on the

building

blocks of 3 TC and perhaps pegylated interferon.

Nucleoside only

combinations, of course have fewer side effects and

appear to be the

wave of

the future.

__________________________________________________