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


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


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


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


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


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