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Immune Tolerant Phase - Few Queries
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Immune Tolerant Phase - Few Queries

Hi All. I am a 27 years old Indian male. I live in Glasgow, U.K. and like most of us present in this community, I am praying and hoping for a cure for Chronic Hep B in near future.

I am new to this community. So please bear with my naivety.
I was diagnosed with Chronic Hep-B 3 years ago. Following are few details from the subsequent tests done 3 years ago:

Chronic HBV Infection genotype D
Hep B Surface antigen - Positive
Hep B e Antigen - Positive
Hep B e Antibody - Negative
Hep B Core IgM Antibody - Negative
Hep B core Antibody - Equivocal
Hep B core Antibody - Positive
Chronic Liver Screen - Negative

HBV DNA: 3179743794 copies/ml; HBV log(ref): 9.5
Fibroscan: 5.6kpa (Doctor's comment - No evidence of fibrosis)
Abdominal Ultrasound: Normal.

At that time, the liver specialist informed me that I am in immune tolerant phase and treatment is not required. However, as advised, I have been carrying out LFTs pretty much every 3-4 months. The ALT/AST levels have been normal except for two borderline flares in last 3 years. The most recent flare (2 months ago) was ALT: 65 with normal AST level. As I have recently moved to a new place, my new G.P. has referred me to a Liver Specialist. I have an appointment with Liver specialist in a month's time.

After reading few posts on this community, I understand that it's normal to have such a high HBV DNA in immune tolerant phase with normal LFTs. As you would expect, stress and anxiety have overwhelmed me for last couple of years. I often wonder about future prognosis of my condition and it's affect on my young family.

I also understand that treatment is not recommended in immune tolerant phase under current medical guidelines for various reasons. Please advise about the questions I should be asking during my visit to the liver specialist. Any comments or few words of support and encouragement are welcome. Many thanks.

S.
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Avatar_m_tn
You asked several questions regarding Immune Tolerance. I will give you my personal opinions.

Immune Tolerance may last several decades for those infected at birth. Most will seroconvert to HbeAg negative before the age of 40. However, this is not an absolute, some will do in their teens, others in their 50s. Also the  age of seroconversion may depend on genotype.

Generally, treatment is not recommended for those in the Immune Tolerance phase. In my opinion, this will change. No treatment is recommended because no current treatments are optimal for those in this phase. Here are some of the reasons:
1. Interferon does not work for everyone.
2. First generation antivirals too easily become drug resistant.
3. Whilst in Immune Tolerance, most patients suffer minimal liver damage and very little disease progression. So why treat.
4. Third generation antivirals such as Entecavir and Tenofovir have very high genetic barrier to drug resistance, and they have been approved for use for adolescents. So some doctors will be tempted to treat with them. The cons are they don't know the long term effects of these antivirals (they have not been around for too long). The pros are by treating earlier, the risk of HCC may be significantly reduced, but nobody knows for sure.

Another major reason is that, during the Immune Clearance phase, when treatment is considered, the patients may seroconvert naturally and then enter the Immune Control (inactive) phase. So some doctors will advocate a period of observation when ALT is elevated and not rush to treatment.

UK's NICE has recently issued new guidelines regarding management of Hepatitis B. You should go to its website to have a read. For HbeAg positive patients (Immune Clearance phase), when certain criteria are met, the recommended treatment is Pegyplated Interferon, followed by Tenofovir if PegIFN treatment were not successful.

Finally, what questions should you ask - I would ask your specialist to give your another Fibroscan as a peace of mind.  
15 Comments Post a Comment
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Avatar_m_tn
treatment is not recommended because it doesn t work and it can only make damage to you now, you are perfectly healthy so dont worry until immune tollerance is broken

the only thing you can do now is:
eat organic and fresh only
increase your vitamin d levels to 80-100ng/ml

high vitamin d level allows immune cells to produce more antimicrobials active on all bacteria, viruses.we dont know if this can have any effect on hbv yet but having max normal range of vit d will make no harm
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Avatar_m_tn
Good day Stef2011,
Thanks for your prompt reply. I was wondering if you advise me about the questions i should be asking my liver specialist during the appointment in a month's time.

Also, Do you happen to know about how long does it take for immune tolerance phase to change into Immune Clearance phase? Any particular age-group? I believe I may have been infected during my childhood.

I have made contact with a liver specialist in India (as advised by my parents) and he advised to start on antivirals when the immune clearance phase starts. He advised against using interferons. What's your take on this?
Once again, many thanks in advance.

Regards
S
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Avatar_m_tn
strictly, you dont need any right now. even then if you want try no treatment except interferon.
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Avatar_m_tn
specially strictly no antiviral for now,,,,,,,,plz..immunize your wife and children and take care, no worry.
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Avatar_m_tn
My wife during her pregnancy had an acute phase of Hep B from which she recovered. She is now immune to HBV. My daughter was passively and actively immunised. She, too is immune to HBV. Thanks for your reply. Could you elaborate on what do you mean when you say No antivirals only interferons?
I am not seeking treatment now if it's not required in immune tolerant phase. At least, that's what the general advice is around here.
Again, many thanks for your reply.
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Avatar_m_tn
You asked several questions regarding Immune Tolerance. I will give you my personal opinions.

Immune Tolerance may last several decades for those infected at birth. Most will seroconvert to HbeAg negative before the age of 40. However, this is not an absolute, some will do in their teens, others in their 50s. Also the  age of seroconversion may depend on genotype.

Generally, treatment is not recommended for those in the Immune Tolerance phase. In my opinion, this will change. No treatment is recommended because no current treatments are optimal for those in this phase. Here are some of the reasons:
1. Interferon does not work for everyone.
2. First generation antivirals too easily become drug resistant.
3. Whilst in Immune Tolerance, most patients suffer minimal liver damage and very little disease progression. So why treat.
4. Third generation antivirals such as Entecavir and Tenofovir have very high genetic barrier to drug resistance, and they have been approved for use for adolescents. So some doctors will be tempted to treat with them. The cons are they don't know the long term effects of these antivirals (they have not been around for too long). The pros are by treating earlier, the risk of HCC may be significantly reduced, but nobody knows for sure.

Another major reason is that, during the Immune Clearance phase, when treatment is considered, the patients may seroconvert naturally and then enter the Immune Control (inactive) phase. So some doctors will advocate a period of observation when ALT is elevated and not rush to treatment.

UK's NICE has recently issued new guidelines regarding management of Hepatitis B. You should go to its website to have a read. For HbeAg positive patients (Immune Clearance phase), when certain criteria are met, the recommended treatment is Pegyplated Interferon, followed by Tenofovir if PegIFN treatment were not successful.

Finally, what questions should you ask - I would ask your specialist to give your another Fibroscan as a peace of mind.  
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Avatar_m_tn
Could you elaborate on what do you mean when you say No antivirals only interferons?

i mean if you are forced for treatment go for interferon, not for antiviral. this is valid for u atleast for next 5 years.
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Avatar_m_tn
Good day Stephen

Many thanks for your reply. What's your opinion about managing/reducing the high viral load, HBV DNA of 5 x 10^8 IU/ml in my Immune Tolerant phase. I understand that high HBV DNA is directly associated with HCC. Does this mean that I am higher risk of HCC even during immune tolerant phase? Should  I be put on 3rd gen antivirals at this stage to bring these levels down?
Again, many thanks.
Regards
S.
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Avatar_m_tn
I am in no position to give even an opinion - I simply have no clue. I will show an extract from an article by Liz Highleyman
http://www.hivandhepatitis.com/hepatitis-b/hepatitis-b-topics/hbv-treatment/4073-easl-2013-truvada-works-best-for-immune-tolerant-hepatitis-b-patients-but-do-they-need-treatment.

Prof Ed Gane from NZ conducted the study of treating Immune Tolerant patients using Truvada. The drug worked in reducing hbvdna but once stopped, all patients' hbvdna level returned to their pre-treatment level.

"Session chair Mark Thursz asked whether these findings suggest that treatment guidelines should be revised to recommend treatment for immune-tolerant patients.

Gane replied that while the study shows that we certainly can treat such individuals, the question is who will benefit. "We need to show that long-term viral suppression in patients with normal ALT will prevent progression and HCC," he said.

He noted that many patients in this situation are young women of childbearing potential, who are advised not to take tenofovir during early pregnancy due to its association with birth defects. An audience member further noted that young patients have a very low risk of liver cancer even without treatment.

"We'd like to know if there's a subset of patients with high risk of progression -- such as family history of liver cancer -- who may benefit from early treatment," Gane concluded."

I quite agree with the views of Prof. Gane.
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Avatar_m_tn
Hey Tandana,

Just looking at your diagnosis, I guess good healthy diet is the way to go plus at least 5000iu daily Vit D supplements with selenium.

Since you had a flare 2 months ago, your next ALT test could be in the 70's or 80's in which case treatment options might be presented to you by your Doctor.

Good luck.
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Avatar_m_tn
Guys. With his viral load numbers he should be on treatment. immune tolerance means only that it does not attack the virus. Maybe the the quality of immune system is low. But he does not have any control over the virus. That inters the nucleus and causes the liver cell to function  the wrong way. I can almost bet that he feels very tired  every day with this VL.

I think he should take nucs in this case and get the viral count down. Because doing interferon with such high DNA can cause a massive flare that can lead to liver failure when immune system wakes up.
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Avatar_m_tn
any viral load over 2000 copies/ ml for several months requires treatment. That us the liver council recommendations.

More virus in the blood more infected liver cells. Thus they dont work like they should. Liver enzymes only measure inflammation in the liver. And yours are slightly elevated. Not normal for your age.

Just because your immune system does not attack the virus does not mean the virus does not do damage - by acting as a mutagen.

So please start treatment and find yourself a better doctor who is more aware of hbv.  
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Avatar_m_tn
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653363/
http://m.ccjm.org/content/76/Suppl_3/S14.full
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Avatar_m_tn
Thanks for all the replies.
I have had one appointment with my liver specialist. She advised me to keep monitoring my ALT levels. I have had an ultrasound which was normal. Latest ALT was 51 which was classified as 'normal' by my G.P. and liver specialist. When asked about treatment options, I was briefed that treatment is not required at this stage. She confirmed that I am in immune-tolerant stage.

Now, I have read the recent NICE Chronic Hep B guidelines and as per them, antiviral treatment should be offered to adults (2000 iu/ml and ALT levels above 30iu/ml. This figure of 30 iu/ml makes most of my previous ALT levels 'abnormal'.

I have asked for another LFT in a week's time. Guys, what's your take on this? Should i be requesting treatment from my liver specialist?
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Avatar_m_tn
When to treat in  the Immune Tolerance phase is always problematic. In the draft NICE (I am assuming it is the same as the final version):

1.5.2 Offer antiviral treatment to adults aged 30 years and older who  have HBV DNA >2000 IU/ml and abnormal ALT (≥30 in males and  ≥19 in females) on 2 consecutive tests conducted 3 months apart.
1.5.3 Offer antiviral treatment to adults younger than 30 years who have  HBV DNA >2000 IU/ml and abnormal ALT (≥30 in males and ≥19 in females) on 2 consecutive tests conducted 3 months apart if there  is evidence of necroinflammation or fibrosis on liver biopsy or a  transient elastography score >6 kPa.
1.5.4 Offer antiviral treatment to adults who have HBV DNA >20,000 IU/ml and abnormal ALT (≥30 in males and ≥19 in females) on 2 consecutive tests conducted 3 months apart regardless of age or  the extent of liver disease.
1.5.5 Offer antiviral treatment to adults with cirrhosis regardless of  HBeAg status, HBV DNA and ALT levels.
1.5.6 Consider antiviral treatment in adults with HBV DNA >2000 IU/ml  and evidence of necroinflammation or fibrosis on liver biopsy.

Being in the Immune Tolerant Phase, your HBV DNA is most likely to be > 20,000 IU/ml, so treatment is considered if ALT is elevated on 2 consecutive tests. This is a very stringent guideline, but considering that the first line treatment recommended is PegINF, it may be an optimial option. I would suggest a Fibroscan and then decide.

Just my opinion.
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