trial: hbsag clearance after 4ys hbvdna und and stopping tdf

[stef2011]

http://clinicaltrials.gov/ct2/show/NCT01320943

it is possible that stable nucs therapy with potent tdf or etv rescue immune response after many years or that the alt flare due to tdf stop makes cccdna unstable and clears hbv, very interesting trial

one thing is certain normal ast/alt make cccdna very stable and abnormal alt are needed to lower hbsag and cccdna fast

[4est]

you are correct the guy has a lot of imagination :)

[4est]

the alcohol proposal is a ingenious one but also a  foolish one and abuse of alcohol can be dangerous (abuse in case of a HVB means totally different levels compared to a healthy men )

[StephenCastlecrag]

A lot of Chinese like to drink, especially at a banquet. So they are forever looking for an excuse not to drink without telling others that they cannot drink because of HepB. Others want to find an excuse to drink even when they have HepB - like this guy about using alcohol to  get rid of cccDNA. You must give him credit for creative thinking. LOL.

[4est]

i think that all AgHBe negative (seroconverted without drugs) can expect at least one muttation.

[stef2011]

i do agree nucs are a waste of time if liver is not severely damaged and if used very long term, since sides on long term use are unknown it makes sense to use nucs for limited time and then add on peg to try to clear.

life long use of drugs is never a good thing is there  is a way out option

[stef2011]

But what happens if you have a mutant infection like I do?

actually most hbv infections worldwide have that mutant now and wildtype is becoming less common.
you are at increased risk of liver cancer and cirrhosis so it would be better to monitor liver damage closely by fibroscan every 6 months.hbvdna is better undetactable with these mutants

if possible i d use tenofovir instead entecavir because etv is less potent, also hbsag decreases more on tdf and also combo tdf+intf looks more potent

i am personally pro tdf because i also used etv 2 years and some residual hbvdna remained even though less than 20iu/ml and hbsag tended to increase instead of lowering.in case you want to change from etv to tdf you have to combo both for 3-6 months and then stay with tdf mono

[veteranB]

Guys,

But what happens if you have a mutant infection like I do?

HBV Genotype A
Basal Core Promoter Nucleotide - T1762/A1764 Mutant
PreCore Codon 28 - Wild type

I have stopped baraclude after 5 years. My Hepatologist was was waiting for that flare. VL went up to 100,000 copies and my AST and ALT stayed normal. I decided not to take a chance and went back on baraclude.

I also want to do PEG because these nucs are just a waste of time.

[stef2011]

alcool is definitely out of the question the damage needs to come from our immune system and not toxic substances, alcool destroys immune cells too.i dont mean to offend the chinese forum guy but using alcool is a little bit foolish

[4est]

LOL - they are many way to destroy liver cells.

Indeed is you find why / how the HbsAg decline we can have a better answer to our quest. (in patient 4318 the HbsAg kinetics look to be  independently by TNf, or by ALT or  HVB DNA or other visible marker)

[StephenCastlecrag]

with Patient 4318, I think (my guess) he/she just stopped taking TNF. It was not planned. All the patients who lost HbsAg, all have continuous decline of HbsAg levels - why?

You are right about using drinking to kill liver cells. How can you control how many cells to kill and which ones with drinking? A reader replied that you can also achieve the damage by taking out your liver, cook it a bit, and put it back (LOL)

[4est]

Patient 4318 is realy interesting and the protocol for this patient was designed with a off drug period, so I wandering what was the theoretical reason for the dr. to try such a approach. (I was under the impression that stooping a antiviral include the risk of mutation - so do to this reason no one will design a schem using a off drug period). Another observation was that the AgHBs of this patient was decreasing also during the falare, so I suppose that some other relation can exist.

Regarding the suggestion from the Chine forum member (regarding the alcohol consumption) the ideea have a point, but is hard to target the cells that have ccDNA (or all the cells have ccDNA? ). Anyway until I found out that i have HVB infection I was a social drinker and use to drink weekly and my test results were relay - but this not means that we should have start to drink even if some dr. mentioned that in case of a inactive carier limited social drinking is ok.

interferon on a flare can be dangerous, but if is made by a good doctor and the dose is adjust properly this can be a option.
.

[StephenCastlecrag]

This is what the clinical trial said. You may or may not get a flare (ALT or  hbv dna), if you do have a flare, it may be damaging or self-limiting. Lots of possibilities, sure hope we can get some answers.

"Withdrawal of antiviral therapy can result in hepatic or alanine aminotransferase (ALT) flares as Hepatitis B Virus (HBV) replication resumes; however, in some patients, a flare exacerbates chronic hepatitis temporarily but can also result in viral clearance. Hepatic flares are common after stopping anti-HBV therapy.

Only patients who already are on treatment with tenofovir disoproxil fumarate (TDF) for at least 4 years and who achieved and maintained virologic suppression (< 400 copies/mL) for 3.5 or more years will be included in this study. One treatment arm will stop the TDF therapy while the other treatment arm will continue the TDF therapy.

Patients who stop TDF (Arm A) will be monitored very closely with special focus on biochemical flares (especially ALT increases) and virological relapses (Hepatitis B viral load increases). If any subject in the stop therapy arm exceeds one or more predefined limits for such flares or relapses, TDF will be reinstituted.

The study will assess Hepatitis B surface antigen (HBsAg) loss (i.e. specific Hepatitis B virus components are no longer detectable) and seroconversion (occurrence of Hepatitis B surface antibody, a specific antibody which usually occurs after HBsAg loss) rates during study duration. The percentage of patients who need to restart TDF therapy in the stop arm will also be evaluated."

[4est]

what puzzle me is the posibility to develop some mutation during the flare.
Start a antiviral, make HVB DNA und, stop the antiviral and wait for the flare ... - is not risky to develop some mutation ? are this mutation rescu by starting the antivirals again ?

[StephenCastlecrag]

You are absolutely right - having a flare is not for everyone and must be carefully monitered by experienced doctors.

I forgot to mention, in the case of the 20 years, who was combined with Interferon after Lam, his ALT flare was very big (, around 600,more than the usual with Interferon), but the doctors decided to persist with his Interferon because his other liver functions were within normal range and his hbv dna remained undetectable.

[stef2011]

the no flare hbsag clearance is very slow taking years usualy while the flare is very fast clearance

[stef2011]

by the way the flare will happen anyway even on tdf+interferon with hbvdna und when hbsag is cleared

the acute hbv, which shows a normal immune system  working, has this pattern:
hbvdna und and only after hbvdna und or very low the alt flare
hbsag starts to lower during the flare
hbsab develops when hbsag very low or und

[stef2011]

Is there a danger in ALT flares though? Can it kill you?

no it cannot kill you if you have a normal liver (not cirrotic), if you are perfectly monitor by a expert doctor, if you go back immediately to etv+tdf if liver function deteriorates

[stef2011]

i mean let the alt flare but monitor all liver function and be fibroscan 4kpa or f0-f1 on biopsy.alt can be 2000-4000 but liver function must be ok, at 19yo i had alt 1500 for about 6 months, perfect liver and no damage....unfortunately the flare did not clear hbsg at that time.....a researcher/doctor who monitored me said probably a superinfection by another virus because with that alt flare for so long hbv should have cleared

[stef2011]

2. Stop antiviral and wait for a flare in ALT or a flare in hbvdna or both(?), then hit the patient with Interferon.

no that s too dangerous, during alt flare you have immune system activated already no need to add interferon

to me th ebst safe way is: tdf  and then intf add on when hbsag starts to go down while hbvdna well suppresed

for those with perfect liver the stopping rule may be tried but be sure to be monitored perfectly by very expert doctors, the alt flare although very rare may also get in to liver failure

[Cjb3695]

Is there a danger in ALT flares though? Can it kill you?

[StephenCastlecrag]

You may be right. Previously, we assume Dr Gish may put you in a trial using GS9620 (TLR7 agonist). Maybe you can ask him about the trial - we all love to hear inside information :-)

[StephenCastlecrag]

This is really interesting: take Tenofovir (or any antivirals) until hbv dna is undetectable, then stop and wait for a flare?

1. A Chinese forum member jokingly made the same observation after reading about Patient 4318 who stopped tnf, had a hbvdna and ALT flare, resumed TNF and then cleared HBsAg.
2. Another Chinese forum member suggested patients with undetectable hbv dna should drink alcohol in order to kill off some liver cells with cccDNA.
3. stef2011 posted a case of a young man who took Lam when he was 20 and achieved undetectable hbvdna. Because he did not want to take LAM forever, his doctor put him on Interferon at the same time. Sure enough, he had a big ALT flare, BUT his hbv dna remained low! And he cleared the HBsAg later on.

So what does all this tell us? After achieving undetectable hbvdna using antivirals: stop and wait for a ALT flare or start Interferon?

So to have a bet each way, may I suggest a third way:
1. Achieve undetectable hbv dna using a potent antiviral
2. Stop antiviral and wait for a flare in ALT or a flare in hbvdna or both(?), then hit the patient with Interferon.

LOL. I wish we have an explanation for these HBsAg clearance cases.

[djxpress]

I have not read the study yet, but my hepatologist (Dr. Robert Gish) mentioned a study to me that Gilead was going to do that was supposed to get people off nucs all together.  He said I may be able to get into the trial.  

Maybe this is part of that study?

[stef2011]

yes i strongly agree with you and i also think the alt flare is what is needed to clear cccdna while during tnf alt are too low

i remember the old study of interferon+adefovir and that researchers noticed that those with some hbvdna not suppressed and abnormal alt had lower hbsag/cccdna than those on complete hbvdna suppression.their guess was some liver damage is needed to get cccdna unstable and reduce it faster