When to start treatment of hepatitis b
Hepatitis B - Treatment and Consequences | Steven-Huy Han, MD | UCLA Digestive Diseases
our first speaker is doctors stephen and
steve is a professor of medicine and
surgery and one of our bright
hepatologists at UCLA and his topic is
going to be hepatitis b treatment and
consequences Steve thank you I like to
thank the course organizers for inviting
me it comes to be I'm going to in the
next 20 minutes bring you up to date on
hepatitis B which is really seen a huge
revolution in treatment and diagnosis
over the last decade so as you can see
here hepatitis B is a huge worldwide
problem it causes a lot of morbidity and
mortality but most importantly you can
see that most hepatitis B carriers are
Asian three quarters of all hepatitis B
in the world is are in Asian patients so
if you look at the worldwide
distribution it looks like this the
countries in red are high prevalence the
u.s. overall is still considered low
prevalence for hepatitis B except for
areas like this where we have a high
population of Asian patients so how is
it that Asian patients were afflicted
with this problem it all goes back to
how the virus was acquired and you can
see here that in the West hepatitis B is
usually acquired parenterally or from
sexual contact
whereas in Asia hepatitis B is acquired
vertically from mother to baby usually
perinatal E so the big difference is the
age at which the hepatitis was acquired
in the West it was acquired as young
adults in the East it's acquired as
infants and you can see in infants where
the immune response is weak the
chronicity if they should acquire
hepatitis B is quite high compared to
young adults so that's why hepatitis B
has been perpetuated in Asian patients
is passed on vertically and the
chronicity rate is very high so those
are the at-risk patients the young
infants and that's why now the standard
of care for hepatitis B prevention is a
routine vaccination of all infants at
birth and we should be very vigilant
about vaccinating all at-risk
populations including young children and
actually all of us being medical
caregivers should all have been
vaccinated also so now a little bit
about the virality of hepatitis B it's a
small virus it replicates very
efficiently but it is error-prone and
what that translates into clinically are
mutants
so hepatitis B is plagued with a problem
with mutants and one of the most common
mutants is the so called e antigen
negative Precor basal core promotor
mutant and the most important thing to
remember is that this e and negative
mutant is usually seen in older patients
and it is more aggressive than the
wild-type we see more fibrosis with this
mutant and is also more difficult to
treat so the issue with hepatitis B is
we have this condition that most
patients acquire at birth they've had
the virus for 30 to 50 years of
infection and somewhere along the way
this various can cause disease it can
cause cirrhosis it can cause liver
cancer now the interesting and probably
the most difficult thing about hepatitis
B is it's not a stagnant virus it's very
dynamic
the virus goes through various phases
from an immune tolerant phase to chronic
active hepatitis to inactive carrier and
it's fluid a patient can go through
these phases many times in their
lifetime the end result is that the
patient can at some point develop
cirrhosis likewise a patient at some
point can develop cancer in the problem
with hepatitis B which is unique
is that a patient with hepatitis B can
develop cancer even in the absence of
cirrhosis so in the hepatology world our
mission was to try to figure out how can
we predict which patients are going to
go from inactive infection to disease
what blood tests should we be looking
for now the issue is we didn't know for
many many years but recently in 2006
this study came out and is called the
reveal study and it was a huge study
that was done in Taiwan they followed a
number of patients for 15 years
untreated and at the end of 15 years
they knew who developed cirrhosis they
knew who developed cancer and when they
went back to look at all the predictive
variables everything fell out except for
one thing and that was the baseline
viral load so you can see here that if
the viral load is less than 10 to the
fourth copies per ml the chance of
developing cancer over time is much
lower but if the viral load is higher
than 10 to the fourth copies per ml the
the the risk of cancer increases and
when they looked at cirrhosis the curves
were almost the same 10 to the fourth
copies is the so-called threshold value
that knot translates to 2,000
international units per ml so this study
was the first big study that came out
telling us the importance of the viral
load in hepatitis B with that revelation
came the revolution hepatitis B
treatment took off after that and quite
frankly we saw a huge increase in the
number of drugs that became available
for hepatitis B so you can see now we
have seven fda-approved drugs for
hepatitis B five are oral on top to on
the bottom of the interferons and if you
look at the date that these drugs were
approved you can see that most of the
good drugs were approved subsequently
after that
study came out so 2005 and Beyond was
when most of our new drugs came out so
the knowledge and the treatment that we
have for hepatitis B has really improved
dramatically but this has been a very
recent development so clearly because
the viral load is important in disease
progression treatment is aimed at
suppressing the viral load and if you
can do that then you can hopefully
suppress the cirrhosis and the liver
cancer so who are the patients that are
going to need hepatitis B treatment in
order to decide you first have to decide
are the e antigen positive EE antigen
negative
do they have cirrhosis once you stratify
them into one of those groups then the
two blood tests that you look at to
decide treatment are the viral load and
the alt level now all the different
societies have had all their
recommendations they're summarized here
but in general you can see you have to
decide are you dealing with a antigen
positive wild type e antigen negative
mutant once you decide that you're
looking at the viral load and the alt
level to decide treatment and for the
most part you can see that for antigen
positive patients they're using twenty
thousand international units as the
cutoff and for e antigen negative
patients they're using two thousand so
the two thousand international units is
what translates to the ten thousand
copies per ml that the reveal study had
pointed out to us so this is kind of a
little bit difficult to to to look at
and living in Los Angeles you know we're
all used to driving we're all used to
stoplights and so I always like to to
point it out this way in an e antigen
positive patient who should you treat
well if the viral load is less than
20,000 that's considered a red light
if the alt is normal that's considered
another red light to red lights this is
a patient that you can monitor without
treatment but if the patient has a viral
load above 20,000 that's a green light
and if the alt is elevated that's
another green light two green lights and
that's the patient usually consider for
treatment now the problem is we always
see patients who have a high viral load
which is a green light but a normal alt
which is a red light I call that my
yellow light patients they're typically
called the immune tolerant patients and
what the societal guidelines say to do
in these patients is do a biopsy as a
tiebreaker but who wants to do a biopsy
patients don't want biopsies they're
invasive it's difficult to convince them
to have it so doctor Tong came up with
what we call a risk stratification score
and based on some non-invasive easily
obtainable criteria you can assign
points to this patient and if the end
these these criteria are listed here and
if the patient has three or more points
then that's probably a patient you
should treat if they have less than
three points
that's a patient you can continue to
monitor so that's the algorithm for
deciding which antigen positive patients
to treat the antigen negative exactly
the same except that the cutoff where
the viral load is lower mm so low viral
load red light normal alt red light to
red lights watch high viral load green
light high alt two green lights two
green lights this is a patient you
should consider for treating if they
have a high viral load but a normal alt
that's your yellow light patient and
then you can apply dr. tongs point
stratification system if they have three
points or more consider for treatment if
they have less than three points
consider just monitoring these patients
if you have a cirrhotic patient the
algorithm is a little bit different with
a cirrhotic patient if the alt is
elevated that's an indication for
treatment according to the societal
guidelines
if the alt is normal then you look at
the viral load if the viral load is
elevated you go ahead and treat but if
the alt is normal and the viral load is
low that's a patient you can just
monitor so you now have your patient the
antigen positive you've decided they met
the two greenlight criteria for
treatment you started them on treatment
what are the endpoints on treatment the
first thing that goes down is the viral
load followed by the alt now in antigen
positive patients we treat until the
so-called e seroconversion and that can
be variable it can take years it can
take months for this to happen is its
variable in each individual patient
but once they e antigen zero convert you
treat them for six to twelve months of
additional therapy we call that
consolidation and then you can stop and
if you do that up to ninety one percent
of the patients that you treat this way
will have a durable response and the
virus will stay down you can see looking
at a comparison of all the medications
the drugs to the right which are the
newer drugs are much more effective at
dropping the viral load you can see that
en agent zero conversion is variable but
tends to increase with longer treatment
duration and you can see that if you do
this if you follow this algorithm you're
durability maintaining viral suppression
is pretty good across the board for the
different medications what about your
antigen negative patient that you
decided to treat same thing there on
drug the viral load drops the alt
normalizes now the problem with antigen
negative hepatitis B is the relapse rate
is very high almost a hundred percent of
the patients the viral load comes right
back when we stop medication so now the
recommendation is for e antigen negative
that they need indefinite treatment or
until they are lucky enough to mate
whose surface antigen but this is a very
uncommon event if they lose surface
antigen you can potentially stop but
otherwise he antigen negative patients
are going to need indefinite therapy and
again comparing the different drugs you
can see the newer drugs to the right are
much more effective in dropping that
viral load now the big problem with the
oral medications for hepatitis B is this
problem of resistance some drugs have
very good resistance some drugs have
very poor resistance in general the
newer drugs to Natha vir and in tech
aveer have the lowest resistance and so
now the societal guidelines say that
these two drugs are the preferred
medications for hepatitis B treatment if
you compare the drugs you can see on the
top the new drugs and TECA veer into
Nava vir probably less than one and a
half one percent resistance over five
years but the older drugs on the bottom
terrible resistance with each additional
year of treatment resistance can be as
high as 80% with lamivudine so now if we
decide to treat hepatitis B it should
really be only with the preferred drugs
in tech aveer or to nevere so in
conclusion hepatitis B is a chronic
worldwide problem three-quarters of the
patients are Asian the importance of the
viral load cannot be stressed any
stronger
ever since that reveal studies so if you
have hepatitis B patients we should be
monitoring that viral load and then
remember the indications for treatment
rely on the viral load and the alt so
you're looking for two green lights
versus two red lights and we hope that
with long-term suppression of the virus
we can prevent further disease
progression perhaps in the future will
be better at treating patients and
actually getting rid of surface antigen
which is considered the holy grail of
treatment but we're not quite there yet
thank you very much
you
