Immune tolerant or break immune tolerant phase?

Hi everyone
  I am a chronic hepatitis b carrier, probably type B or C, since born. I am 25 years old right now.  My recent check shows  HBsAG and HBeAg are positive with high HBV DNA count. My ALT is normal as defined by my family doctor (i didnt check the exact number). Not sure of AST.  My doctor said I am still in immune tolerant state.  I am wondering of following questions
1. its is possible to stay in immune tolerant state for lifetime? (from research paper i read, most of ppl enter immune  clearing phase in 30 to 40s, so my guess is not?? i need confirmations)
2. Is it better to stay in immune tolerant phase or to break immune tolerant state? ( for this question, i cant rationalize a good answer. Since in immune tolerant phase, there is minimal liver damage, but high viral replication and high viral load (high HBV DNA). Minimal liver damage is always a good thing I guess. IN THE OTHER HAND,  breaking of immune tolerant state means high degree of liver inflammation for a period of time with HBeAg seroconversion and low HBV DNA. After immune tolerant most of people enters inactive (HBeAg negative) carrier stage (low HBV DNA, normal ALT)  and maintains that way. So low HBV DNA is also a good sign. Then which one is favoured???)
3. If breaking immune tolerant state is favourable,
    a) how to break it (increase in immune system? taking drug?)
    b) how to mimic liver damage during immune clearing phase (that is my major concern here)
4. Does entering immune clearing phase define as a Hepatitis B patient instead of carrier then? ( or the term carrier does not really mean anything)

Hopefully someone can give me advises to those question while i look deeper into individual research paper.
Thank you in advance.

[stef2011]

1 i guess not, if so there is no need to treat hbv

2 stay immune tollerant since you dont know if you can clear hbv.as immune tollerant you are perfectly healthy, in the other phases you are not.
the best strategy is monitor and attack with immune modulators and tenofovir when immune clearance starts

3 no it is not favorable at all, you become unhealthy, better wait for hbv cures to be available

4 it means from healthy to mostly unhealthy unless you reach very low hbsag and become inactive carrier

[StephenCastlecrag]

I want to commend you for reading up on Hep B. I will give you my opinions. Please remember we are all patients here and not doctors, so we lack clinical experiences and expert knowledge. Also, everyday scientists are finding more about this complicated disease, so what we understand today may be incorrect to-morrow.

Immune Tolerance(IT) - It is my opinion that we cannot "break" our tolerance, it just happens as a result of interaction between our immune system maturing or changing with age/environment and the evolving virus. The exact causes for "breaking" are still not clear. Most people will exit the IT  phase before age 40. I would doubt someone can be IT for ever. Bear in mind, we are all different and a lot of people are not even aware that they have HepB.

Most researchers believe the HBV virus is not cytotoxic, that is it does not harm the liver cells that it infects. It is our own immune system when recognising that a liver cell has been infected, starts attacking and clearing infected cells that cause inflammation, cell death, fibrosis, cirrhosis, and HCC. Therefore a large viral load is not by itself harmful. This is evidenced from patients in the IT phase with their very high viral load, but normal ALT and minimal liver damage.But high viral load is dangerous when we are no longer IT, recognise the virus, and start attacking when we have replicative viruses, the higher the viral load, the more intense the attack and hence more damage.

As you say, after exiting the IT phase, patients enter the Immune Clearance phase (IC). During this phase, the immune system recognises the virus and infected cells and will attempt to clear the infection. If the immune response is adequate, the virus will be brought under immune control, but not completely eradicated, and patients enter the Immune Inactive phase (IA). During the IC phase as battles are being fought, viral loads will go up and down, so will the ALT, and the liver is being damaged. Scientists believe the severity of the battles and how long and how often will determine how much the liver is damaged.

So we come to your Q3:
3. If breaking immune tolerant state is favourable,
    a) how to break it (increase in immune system? taking drug?)
    b) how to mimic liver damage during immune clearing phase (that is my major concern here)

3a. You cannot break IT as it happens without your control. Is it favourable? It depends on the how long, how many battles, and how hard are the battles. Treatment is not recommended during the IT phase for 2 main reasons:
1. Treatment is usually not effective during the IT phase;
2. Why treat when there is minimal damage.

3b. How to minimize the damage to the liver? I wish I know the answer. Let me explain. The obvious answer is to start treatment, either with Interferon or oral antivirals. Interferon is a finite course of treatment, antivirals will take at least several years. So at the end of treatment, you may achieve drug induced seroconversion of your e-antigen, and enter into a  low replicative phase (low viral loads) and also normal ALT (indicating minimal ongoing liver damage). So this is good, but the downside is that this induced state is not necessary durable and you may have to stay on treatment longer.
On the other hand, you can forgo treatment to see whether your  immune system can win the battle for you on its own. If successful, this victory of immune control (seroconversion of the the e-antigen and entering the IA phase) is usually durable. The downside of course is you may not win in a short period of time and your liver is being damaged in the meantime.

So whether to treat or not during the IC phase is a fine art and best be decided by an experienced Hepatitis B specialist. In my opinion, don't rush to treatment on the first sign of high ALT, consider all your options, have a plan (what happens if the particular treatment fails), and be realistic. There are many optimal treatment strategies with varying degrees of success/failure, that is why you need an experienced doctor.

Finally, there is another phase, the HBeAg negative chronic hepatitis. People in this phase are usually over 40 with fluctuating viral loads and elevated ALT. Treatments should definitely be considered as long-time-on-drug is no longer an issue and it should be treated just like chronic high blood pressure and diabetes. Oh, I believe some people will never enter this phase as they are IA phase.

If all these is giving you a headache, I can understand. So don't worry too much, you may be run over by a bus to-morrow or there may be a cure!

Hope I got it right.

[4est]

look for "To Treat or Not to Treat Immune-Tolerant Hepatitis B?" in http://www.hbvadvocate.org/news/HBJ9.3.htm maybe it will help you

[kinetix1208]

Currently I have a very high HBVDNA, > 110M iu/ml,
elevated ALT around 800+
HBeAg - reactive

Am i considered in immune clearance phase? Also, i have been feeling a little discomfort in the upper right abdomen, probably in the liver part. My last normal ALT level was on Sep - Oct 2011.

My visit with the doctor will be this first week of May.

I have a few questions:

1. What actions should i take right now to minimize the damage to my liver?
2. Also, the results indicated icteric sample, what are risks of having this?

[StephenCastlecrag]

Being eAg positive, high hbvdna level and elevated ALT level, you are most likely to be in the Immune Clearance phase, especially when your ALT level was normal previously.

Most of us have this discomfort (pain) in the upper-right abdomen, even though some doctors dismiss the pain as "being in our head" as the liver has no pain receptors connected to the nervous system. However, some people pointed out that the sac containing the liver has nerve receptors and these may be activated during hepatitis (inflammation).

Your questions:
1. I don't know whether there is actually any medication to minimize the damage. What we can do is not to add any extra burden to the liver, such as: no drinking, no smoking, and a healthy diet. Also we should have adequate rest, exercise, and may be make sure we have the right level of vitamin D?
2. If you do develop jaundice, this will be one of the factors your doctor will consider  when deciding whether to treat or monitor.

I am not a doctor so I hope other readers will add their comments.  

[kinetix1208]

Thanks a lot, ever since i have known that i have hepatitis b, i never drink alcohol for a year now, i never smoke. I started taking vitamin c, e and d3 a year ago. Is this also a factor why i'm in immune clearance phase? my immune system started to recognize the virus?

With regards on jaundice, i've been comparing myself to other peoples' skin at the time my results came out with icteric sample, probably i'm so worried about it. But i guess its all normal. How long will the jaundice appears if not treated?

[StephenCastlecrag]

The exact reasons why our immune system suddenly begins to recognise and attempt to clear the virus are unknown - they have a few theories. Most likely it has to do with accumulated genetic changes in the virus over a period of time.

It is difficult to compare skin color - look at the white in your eyes - if they turn yellow then most likely you have jaundice. Jaundice only appears when your liver is not functioning properly. Most hbvers will not have jaundice.

[kinetix1208]

yes i also read about that, bilirubin started to elevate in a decompensated liver and jaundice occurs. is that correct? But why cases of the acute hbv has jaundice? does it mean the liver did not function properly for some period and started the function again during clearance of hbsag?

[StephenCastlecrag]

From Wikipedia:
Jaundice (also known as icterus;[1] attributive adjective: icteric) is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae (whites of the eyes), and other mucous membranes caused by hyperbilirubinemia (increased levels of bilirubin in the blood). This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid. Concentration of bilirubin in blood plasma does not normally exceed 1 mg/dL (>17µmol/L). A concentration higher than 1.8 mg/dL (>30µmol/L) leads to jaundice.[2] The term jaundice comes from the French word jaune, meaning yellow.

Jaundice is often seen in liver disease such as hepatitis or liver cancer. It may also indicate obstruction of the biliary tract, for example by gallstones or pancreatic cancer, or less commonly be congenital in origin.

Yellow discoloration of the skin, especially on the palms and the soles, but not of the sclera and mucous membranes (i.e. oral cavity) is due to carotenemia - a harmless condition[3] important to differentiate from jaundice.

[stef2011]

if your alt are 800 you have now an immune response to virus (although weak because also hbvdna is so much), this is the best time to try to attack the virus before it mutates to escape your immune response nd before hbeag becomes negtive

the best therapy is the same as grm is doing tenofovir and when hbvdna very low/und peginterferon add on, making vit d25oh>50ng/ml will increase svr and response to interferon

[kinetix1208]

I'll try to ask the doctor if she can prescribe me with tenofovir even it is not available here. In the Philippines, baraclude is often prescribed by most of the doctors. But aside from high cost of baraclude (entecavir), i'am also hesistant to take it since as you have said it may fail due to very high hbvdna, that's why i'm really aiming in taking tenofovir because it has no resistance, but it is not available here in the Philippines. This is really the sad part. what if the doctor don't prescribe it to me. That's why i'm really trying hard to find a generic tenofovir online without prescription of the doctor.

I'am also calling out doctors in the Philippines who would prescribe me with tenofovir, please pm me. I'll visit your clinic/hospital.

[stef2011]

you ll find it everywhere out of philippines, it is the first hiv antiviral approved in 2000 it is almost out of patent.in sia you will be able to order it from almost all pharmacies

this proves the corruption in the philippines, they approved banned useless drugs like clevudine which has stopped even development worldwide and dont approve the cheapest and most potent hbv drug available since decades

[kinetix1208]

agree, the corruption in our country is rampant, that's why many dies from illnesses. i'm disappointed in our system.

[stef2011]

i guess the best way is get a big pharmacy in the philippines to get it for you after you find a doc to prescribe and monitor or directly move to a close country for monitoring since you even miss all the tests to monitor response in the philippines

i remember vietnam goverment pharmacies started generic cheap peginterferon too and they have all tests like hbsag quant, hbvdna and fibroscan to monitor

[kinetix1208]

I'll try to talk to the doctor about this, she is a new doctor to me because i keep on changing doctors everytime i notice that they don't know anything. Hopefully it would be a good discussion, i'll ask her about tenofovir and her thoughts about it.

There is a fibroscan in the hospital but i will also confirm it. Hoping also that they have test for hbsag quant in iu/ml as well.

Thanks a lot.

[stef2011]

you can also add that hbv clearance on hbeag positive is irrelevant on entecavir and 16% on tenofovir at 3years, so entecavir is a total failure also in clearance rates in your case

the highest clearance was on tenofovir+peginterferon like gmr treatment, it reached 24% hbv clearance in ashort time, dont remember if 6 or 12 months, this 24% could rise much more in  personalized hbsag tdf+pegintf long term treatment like tdf+pegintf for 2 years or more

[judas13]

   it sad to say that some of our doctors here in the philippines are not so good to handle HBV patients and it happened to me personally that makes me doubtful and cautious about thier profession. this case is very rampant now in our country and our government do nothing about this. very FRUSTRATING.!
  im very thankful i came up this forum ,it gave me a lots of informations and educates me as well that i cannot find to some ignorant doctors.!
pls let me know if you find a good doctor.
  

[kinetix1208]

just got my result from fibroscan, it's 11.9kpa, very high, and according to
the result:

For Hepatitis B with elevated ALT:
Minimal or No Fibrosis  = 7.5 - 12.0
Advanced Fibrosis >12.0 - 13.4
Cirrhosis > 13.4

so i'm in the gray zone, but close to advanced fribrosis. now i'm scared.
what should i do the normalize my liver?

the doctor told me to take entecavir, i talked about tenofovir but hesistant in prescribing it to me since this is not approved yet in the Philippines, this is sad.

is it ok to take entecavir? does it lessen the chance of getting into cirrhosis?

I hope i was still in immune tolerant phase. :(

[stef2011]

if your alt is 800 fibroscan is not reliable now because most of the reading can be inflammation, you have to retest in 6months when alt is less than 200 and inflammtion is less, better start treatment anyway

is it ok to take entecavir? does it lessen the chance of getting into cirrhosis?

it is ok if you can make resistance test, is it available in the philippines?this because if you have    the resistance to entecavir is more than 50% while tenofovir doesn t require this test because it has no resistance

around 10% hbvers carries lam mutants
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1803124/

[stef2011]

how is it possible you have no hiv drugs in the philippines?my opinion is they dont work on hiv but i dont see why they are not sold in the philippines

[StephenCastlecrag]

Stef2011 will give you better  comment. Because your ALT is elevated, Fibroscan is not than accurate, as you can see only 1.4 (13.3 - 12.0) kpa between minimal fibrosis to Cirrhosis. Because of your ALT (800), you are most likely in the Immune Clearance phase - the question is: can you achieve the e Antigen seroconversion naturally?

[4est]

how about your ALT and HBV DNA (do you have any new result on this)?

[4est]

as stef2011 and  StephenCastlecrag already notice high ALT can cause that  Fibroscan result to be not than accurate, also this is specify on your list result "For Hepatitis B with elevated ALT".

[stef2011]

e natural seroconversion is not ok because most of these seroconversions are bcp or precore mutant while on treatment it is possible to avoid this, i think the best is gmr treatment, tenofovir first and then interferon add on

do not use etv because hbv clearance is about 5% vs 16% of tenofovir and with intf add on it gets to 24%, i have no idea about the cost of the flights in asia but in europe there are many low costs flights less expensive than a bus ticket, take a flight to vietnam or any close country to see a doctor and get tdf prescription

[kinetix1208]

Currently my hbvdna is > 110,000,000 IU/ml and sgpt is 852.18 U/L

[kinetix1208]

it is also indicated in the comment:
-----------
A liver stiffness value of 11.9kPa falls within the gray zone. While this may be indicative of intermediate fibrosis (Metavir F2-F3), liver fibrosis assessment is less realiable within the gray zone. Correlation with other clinical parameters including a liver biopsy should be considered.
-----------
so is this normal with high ALT?

[StephenCastlecrag]

Mmm, I disagree. It is true that transition from Immune Tolerance to Immune Clearance phase is most likely to be caused by accumulated genetic changes related to the e-antigen. Some research indicates a rise in the percentage of precore mutants before seroconversion. This was a troubling thought as it implies all natural seroconversions will lead inevitably to chronic HBeAg negative hepatitis. However, I read a latest research by Timonthy Block of HBF that the percentage of precore mutants decreases after seroconversion. All these are based on my own understanding, so it can be totally wrong. I think we still need more research.

However, there are numerous papers that indicate natural seroconversion is more durable and many patients do remain in the Inactive phase for a long long time.

As for Tenofovir  first and then Interferon, this treatment will take at least several years - at least few years of Tenofovir to reduce viral load to undetectable then at least 48 weeks of Interferon. I know your local researchers are very confident about this treatment, I would still like to see the results from a large group of patients, their baseline characteristics, especially genotypes, to be sure.

[kinetix1208]

But if there is really no choice, can i take the etv?  just to lower down my ALT and HBVDNA? Probably my concern right now is to minimize the liver damage and getting into cirrhosis.

And after a while, if i can get a prescription on tdf, i'll just switch from etv to tdf? Is this just ok?

[StephenCastlecrag]

With high ALT, your liver is inflamed, Fibroscan cannot give you a reliable indication of your fibrosis stage. An experienced liver doctor may be able to, but as the report clearly said - it is a grey area. So you have to wait until your ALT is normal to do another Fibroscan, or you do a biopsy.

[kinetix1208]

Probably we don't have the resistance test but i will ask.

HBsAg quantification is i guess available here, the doctor mentioned about it and told me to do it, it is available here in one laboratory. but i'll confirm it if it is abbott architect.

[stef2011]

not only researchers this is routine in italy since nucs mono is useless most doctors are making combo just like for hcv.
we are probably very different because all hbv drugs are free of charge so less problems as regards costs/health insurance which doesn t pratically exsist in italy

[kinetix1208]

Being in immune clearance phase is really something, and i guess hard to manage.

Aside from biopsy, is ultrasound ok for me to be tested? Or will be just the same result with the fibroscan? since liver is inflammed. I never had an ultrasound before.

[stef2011]

you have probably no damage to the liver, on hbeag pos hbvdna and alt levels are not correlated with liver damage, you are also young, you shoould go to treatment just as a precaution and to clear hbv

most doctors initaly probably would monitor or put you on pegintf+tdf like gmr, tdf to lower hbvdna and when very low add on pegitf.this is about 6 months tdf and then tdf+pegintf
another choise can be tdf+etv to make hbvdna und in  a very short time since yours is too high and then tdf+pegintf, it all depends on updated and experience docs being available

making just etv can be very wrong because you are too young and taking nucs for most of your life is not good, i d treat to try to clear hbv not for the liver

[kinetix1208]

you're right, it's good to clear hbv rather for the liver.
but it's really a dilemma for me, i don't want to take etv either. If only i have access to all those things, tdf+pegintf, i would really like to do it.
but in our case, most Filipinos will just die from liver diseases, i'm lucky enough to have enough income and somehow manage to monitor my condition.

That's why many alternative medicines here are marketed just to give hope to other hbvers who can't afford medicine.

Anyway, i really wanted to take tdf but no access to it. I'm thinking of what you have said in getting off to other countries and have prescription on tdf. I don't know if how many months i will get a prescription.

From experience, how many months will it take in my condition to be in advanced fibrosis stage?

[stef2011]

maybe u ll never reach any fibrosis, ast/alt and hbvdna are not correlated with fibrosis on hbeag pos

check the cost of flights, laws in ur country about taking your drugs and prescriptions in india or vietnam which have genrics

i think the main problem of philippines is corruption since you have no healthcare you should use indian generics only otherwise it is obvious you dye of liver diseases if you cannot afford US drugs you must take the generics not dye

[kinetix1208]

Thanks a lot for all the inputs, i'll weigh things up considering all of this.
cost of flights, chances of having a doctor in other countries, availability of drugs, etc.

Maybe in a few years, tenofovir will be available here because of high rates of hiv cases seen every month.

[stef2011]

http://www.medhelp.org/posts/Hepatitis-B/HbsAg-quantity-in-Phnom-penh--Cambodia-or-Ho-Chi-Minh-City---Vietname/show/1430388

as regards vietnam a member had a very good experience with a very good doctor better than what is available in US as regards tests and drugs