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发表于 2002-4-11 02:58
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.
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