Hepatitis B Therapy at AASLD-2001

dadadada

American Association for the Study of Liver Diseases



November 9-13, 2001, Dallas





Hepatitis B Therapy at AASLD



Written for NATAP by Douglas T. Dieterich, MD Cabrini Hospital and NYU

Medical Center, NYC



   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 notes: 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)

http://www.natap.org/2001/aasld2/day13.htm)



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.











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