Add -on of peg interferon to a stable nucleoside, hbsag loss 40%

[stef2011]

Add -on of peg interferon to a stable nucleoside regimen led to loss of HBs Ag in chronic hepatitis HBe Ag negative patients
D. Ouzan1; G. Penaranda2; H. Joly1; H. Khiri2; P. Halfon2
1. Institut Arnault Tzanck, Saint-Laurent du Var, France.
2. Laboratoire ALPHABIO, Marseille, France.

Objectives: Suppression of HBV viral load by nucleoside treatment reduces disease progression but requires indefinite treatment. Hbs Ag loss is a rare event after long term treatment with analogues therapy. In HBe Ag negative patients peg interferon alpha 2a for 96 weeks improved the sustained responses rate versus 48 weeks. It is of interest to know whether the addition of peg interferon for 96 weeks to a stable nucleoside therapy will reduce quantitative HBs-Ag which may follow by HBs Ag loss.
Methods: We analyzed HBs Ag levels of 10 patients who received additional peg

[stef2011]

this remains the best strategy to clear hbv found until now and with highest rates, profund hbvdna suppression for years, tenofovir probably the best or tnf+etv, then add on of interferon

the good thing is also a good decline of hbsag in almost all patients so interferon might be prolonged or stopped and restarted later

[April9903]

So many useful information for the community! Thank you, stef.
I still have to read them all.
I have been so busy at work at the moment....

[ytdthjznyj]

stef2011, thank you for all this information.

[stef2011]

AASLD 2011 Annual Meeting
ID#1382
Location:Poster Hall
Time of Presentation:Nov 07 8:00 AM - 5:30 PM
Category:SO2. Treatment and Clinical Trials


Add -on of peg interferon to a stable nucleoside regimen led to loss of HBs Ag in chronic hepatitis HBe Ag negative patients
D. Ouzan1; G. Penaranda2; H. Joly1; H. Khiri2; P. Halfon2
1. Institut Arnault Tzanck, Saint-Laurent du Var, France.
2. Laboratoire ALPHABIO, Marseille, France.

Objectives: Suppression of HBV viral load by nucleoside treatment reduces disease progression but requires indefinite treatment. Hbs Ag loss is a rare event after long term treatment with analogues therapy. In HBe Ag negative patients peg interferon alpha 2a for 96 weeks improved the sustained responses rate versus 48 weeks. It is of interest to know whether the addition of peg interferon for 96 weeks to a stable nucleoside therapy will reduce quantitative HBs-Ag which may follow by HBs Ag loss.
Methods: We analyzed HBs Ag levels of 10 patients who received additional peg –interferon alpha2a as an individualized therapy during 96 weeks according to the evolution of HBsAg titer. All patients were male; HBe Ag negative; median age was 58 (range 41-76) years. Current treatments were lamivudine (one patient) adefovir (three patients), entecavir (two patients), lamivudine + adefovir (two patients), adefovir+entecavir (two patients). Median baseline HBsAg was 660 IU/ml range (50-1754). HBV DNA was below the limit of detection <20UI/ml in all patients for more than 3 years.
Results: During add-on therapy, in four patients, a continuous decline of quantitative HBs Ag lead to negative values <10 UI/ml between 24 and 48 weeks. All antiviral (peg interferon and nucleoside analogue) therapy was stopped at week 48 in these 4 patients and results remain the same 24 week after cessation of all therapy (AgHBs loss and HBV DNA negative). HBs serocoversion was observed in one out of these four patients. Quantitative HBsAg highly decreased in five of the remaining six patients. For one patient, HBsAg remained high; treatment was stopped in this patient at week 24. The remaining five patients received peg interferon for 72 week at the time of this analysis. Median decrease of quantitative HBs Ag was 834 IU/ml in these five patients (compared with a decrease of 34 IU/ml in the patient with low decrease).
Conclusions: In patients with sustained virological remission under long term nucleoside analogue therapy, add-on of peg interferon allows HBsAg loss in 40% of our patients. HBsAg titer decline constitutes a useful tool which predicts the loss of HBsAg and may lead to the optimal duration of IFN therapy.

[stef2011]

if you find more indepth info and data on this poster please link or post.

i think this is the most interesting poster to show how combo treatments nucs+interferon are more effective especialy after hbvdna suppression of a couple of years by nuc monotherpay

[4est]

will be interesting to found out more details about each of the patients.

What patient was the one that remains on high level of HBsAg and what was the base line for hin? (was the one that has lam  treatment, or the one that has adefovir or entecavir or ...  )

[4est]

will be the full paper available after conference ?

[stef2011]

usually these are available on scientific journals or pubmed, but not sure f this is a study or just clinical case reports

we should have a look on the france universities where they doing it and in italy but i think this is nothing new, i heard they are doing about the same in pisa but they have problems because healthcare and insurance dont want to pay for tnf and interferon together because too expensive.......the blocks on hbv combo treatments are just a matter of costs, that's why in india you can find even triple or more combos they have the cheap generics

anyway tenofovir should have little time left and interferon too, cn you check when their patents expire in europe?  

[StephenCastlecrag]

I agree, this paper is interesting. It ties in with your idea of using interferon to lower HBsAg. I remain cautious because the sample is small, only 10 persons. From an Asian perspective, I also want to know the genotypes of the hbv.

Have a read of this paper:
HBV Treatment Induced HBsAg Seroconversion to Anti-HBs in 9 Asian-American Patients: Experience in a Community Clinic
H. Lee1; K. Hu1; S. Tonthat1
1. GI/Hepatology, U.C. Irvine, Irvine, CA, United States.


Background: Although HBeAg seroconversion to anti-HBe has been a standard treatment endpoint for HBeAg+ patients, patients who achieve this endpoint have a 20-40% relapse rate over a 5 year period. HBsAg seroconversion appears to be a more durable endpoint of HBV treatment than HBeAg seroconversion, but it is difficult to achieve. Several natural history cohorts of HBV patients have shown a low incidence of spontaneous HBsAg seroconversion, approximately 0.5-1.0% per year. Registration trials of HBeAg+ patients on tenofovir DF have shown 10.8% of patients achieve HBsAg loss and 7.7% of patients seroconvert to anti-HBs over 4 years. However, HBsAg loss was not seen in Asian patients or in HBeAg-negative patients.

Aim: To assess the probability and durability of HBsAg seroconversion in Asian-American patients treated with standard of care (SOC) nucleos(t)ide analogue oral agents in a community clinic.

Methods: A retrospective chart review of patients with CHB, who received nucleos(t)ide therapy from a single Irvine, CA clinic from 2008-2010.

Results: We identified nine Asian-American patients on treatment with nucleos(t)ide analogs who achieved HBsAg seroconversion. 4/9 (44%) were male, 8/9 (89%) were HBeAg negative at baseline, and the median age was 48 y.o. 4/9 patients were started on therapy by their primary physician, and their baseline viral load and ALT were not available. For the five patients with complete data, the median starting HBV DNA level was 69,392 IU/ml, and median ALT level was 53 U/L. 6/9 patients were treated with tenofovir (one of whom had lamivudine + TDF), 2 were treated with entecavir (ETV), and 1 was treated with adefovir (ADV). All nine patients achieved a normal ALT and undetectable HBV DNA on treatment. Treatment was discontinued in one patient when he achieved a HBsAb level over 50 mIU/ml. He was treated for 27 months with entecavir before achieving this endpoint. Ten months later, this patient was found to have a viral load of 13,737 IU/ml (79,949 copies/ml). His HBsAg was detectable, and he was started on tenofovir (TDF) at the time of this abstract submission.

Conclusions: Our experience shows it is possible for HBeAg negative Asian-American patients to seroconvert to anti-HBs while on oral CHB therapy. Using a quantitative HBsAb level of >50 mIU/ml as an endpoint to discontinue therapy was difficult to achieve, and did not prevent relapse in the one patient who achieved it, despite a persistently detectable HBsAb level. Further studies are needed in larger patient populations to determine the best endpoint for stopping oral CHB therapy, to maximize durable seroconversion and viral suppression.


HBsAb of 10mIU/mL is considered to be protective!. This one patient had 50 mIU/mL and he still relapsed. Sure would like to understand why.

[4est]

this is interesting and for sure everybody want to understand why this was happening.

what about the other 8 ?  they are in the same situation?



HBsAg loos and HBsAg seroconversion is the same or HBsAg seroconversion means HBsAg loos + HBsAb ?

[4est]

cn you check when their patents expire in europe?  

I will check and if found an answer I came back with an answer.

[4est]

pattern for tenofovir look like will expire in 2017 US and 2018 Europe (http://en.wikipedia.org/wiki/Gilead_Sciences)

[StephenCastlecrag]

The paper said very little about the other 8. Wonder whether they are still on treatment?

Gilead has just entered into an agreement with Globelmmune:
"Gilead Sciences Inc. said Monday it will work with GlobeImmune Inc. to develop a new hepatitis B treatment that includes Gilead's drug Viread."

Some commenters say this is usually a ploy to extend the patent?
N.B. GlobeImmune seems to have a therapeutic DNA vaccine for HBV?

[Fevskie]

@ steff just want to ask  I am an asian  year 2004 i found out i am hbsAg+ and HbeAg+ went to doctor and I was given a lamivudine(zeffix) for treatment after taking the medication for 1 year i check my hbeAg becomes negative just want to ask is it a good thing or bad?but right now im not into medication i just take vitamins for my immune system...

[4est]

Peg Interferon patent will expire in 2015 / (or 2016) in USA (http://www.uspto.gov/patents/resources/terms/156.jsp)

[stef2011]

to StephenCastlecrag

i have seen italy  is  making ultra deep sequence around major university hospital, i hope my tests was the ultra deep
it loks like many mutants are already presnet low level or in the cccdna and the nucs monotherapy just select these mutants

in the paper above it is extemely stupid to publish without checking ultra deep sequence of hbsag mutations, it can be both hbsag mutated, there are mix wild type/mutated hbsag or the immune system is too weak to clear hbv despite hbsab
i really dont understand these researchers, are they working on guinea pigs just to say one person cleared by nucs?it is obvious interferon add-on will clear hbv and sustain clearance even in the case of mutated hbsag

the most important antibody to clear hbv is not hbsab but hbcab

[stef2011]

we, cronic carriers, have very low hbcab while to clear a very high hbcab is needed, after hbcab is very high even low hbsab can clear hbv

[stef2011]

ADD-ON OF PEG-INTERFERON TO A STABLE NUCLEOS(T)IDE REGIMEN LEADS TO LOSS OF HBS-AG IN PATIENTS WITH CHRONIC HEPATITIS B

J.M. Kittner1*, M.F. Sprinzl2, A. Grambihler1, A. Weinmann1, P.R. Galle1, M. Schuchmann1
11st Medical Dept., University Hospital Mainz, Mainz, 2Institute for Virology, Technical University of Munich, Munich, Germany. ****@****


Objective: Suppression of HBV viral load by nucleos(t)ide therapy effectively reduces disease progression but requires long-term medication. Preferably, self-contained immunological control represented by HBs-Ag seroconversion should be achieved. It is of interest to know whether the addition of peg-interferon to a stable nucleos(t)ide therapy will reduce quantitative HBs-Ag which may be followed by HBs-Ag seroconversion.
Methods: We observed HBs-Ag levels of 12 patients who received additional peg-interferon-alfa2a as an individualized therapy. 9 patients were male, mean age was 44 (range 25-60) years. 3 patients were HBe-antigen positive. Current treatment comprised lamivudine (1pt.), lamivudine plus adefovir (2pts.), entecavir (7pts.), or entecavir plus tenofovir (2pts.). Mean baseline HBs-Ag accounted for 4,695 (range 16-15,120) IU/ml. HBV viral load was below limit of detection ( 6 months.
Results: During add-on therapy, in 2 patients a continuous decline of quantitative HBsAg by -2,6log10 and -3,66 log10 was observed at week 32 and 36, respectively. The decline became detectable from week 8 and 16 on, resp. The first patient was HBe-Ag negative, genotype D, with cirrhosis grade Child-Pugh A, had a low initial HBsAg level of 16 U/l which dropped to 0.04 U/l. HBV-DNA had previously been non-detectable during therapy with entecavir for 27 months.
The second patient was HBe-positive, genotype A, F3 fibrosis (Desmet), and HBV-DNA had been non-detectable for 10 months with entecavir plus tenofovir. Despite a non-response to peg-interferon monotherapy in the past, she now experienced an HBe-antigen seroconversion at week 24. HBs-Ag dropped to 0.54 U/l, and anti-HBs became detectable in week 32.
In the remaining 10 patients quantitative HBsAg declined only by -0.01 to -0.25 log10 (mean 0.09 log10) after 8-24 (mean 16.4) weeks of combination therapy, and therefore interferon was stopped.
No unexpected side effects were observed in combination therapy.
Conclusion: HBs-Ag loss during oral antiviral therapy is rare, even more in HBe-negative patients. Here, we show that the add-on of peg-interferon induced HBsAg loss in 2 of 12 patients (one HBe-Ag negative) and even led to HBs-Ag seroconversion in one patient. This concept merits to be proven in a larger trial.

[stef2011]

i was comparing the 2 studies on antivirals plus interferon add on and i think we may do some considerations based on the difference among the 2 studies.

40% hbsag loss is achived by long term antivirals for a minimum of 3 years with potent antivirals like tenofovir and entecavir to 7-8years with less potent antivirals like lamivudine+adefovir.on these patients response was 90%

the other study used antivirals for very short time, we have indication >6months, of these 12 patients response was much lower than 40% probably due to the short time of hbvdna suppression compared to the other study.
response happened only on those who used the potent antivirals etv or tdf, too bad we dont have the time of hbvdna suppression for every patient.

my guess is the longer the treatment the higher interferon response
the more potent use of antivirals, example tdf+etv, the more the interferon response

[calmama]

A big difference between these two studies is their mean baseline HbsAg.  This one is 4,695 (range 16-15,120) IU/ml, while the previous study is 660 IU/ml range (50-1754).  About 10-fold difference there.  If the baseline HbsAg is a predicting factor of interferon treatment response (ie. HbsAg < 1500 iu/ml means more likely to respond), the results make sense.  

I just wonder how much HbsAg reduction would tenofovir or entecavir (or combo of the two) make after 3 years of antiviral treatment?  Is there such data published somewhere?

[stef2011]

these are my observation, weak antivirals like lam and adv take about 7 years to make interferon response work and 1 patient did not respond, these weak antivirals worked only with low hbsag less than 1000iu/ml

potent antivirals like entecavir and tenofovir worked even if treatment was short:
1 patient etv 3 years with very high hbsag about 8000iu/ml
1 patient tdf+etv 10 months hbsag not known
1 patient tdf 3 years, high hbsag around 1400iu/ml

so my guess is tenofovir is the most potent, etv+tdf even more potent and may shorten the time needed to get peginterferon response.etv and tdf can get peginterferon response even with high hbsag

what makes interferon response?i guess cccdna+intrahepatic hbvdna suppression because the longer you treat the lower cccdna, and also etv and tdf have little more decline on cccdna+intrahepatic hbvdna, combo etv+tdf even more cccdna+intrahepatic hbvdna suppression

we also know intrahepatic hbvdna suppress immune system, i think tests in serum are not reliable for this type of studies they should biopsy these patients to see hbsag quant, hbcag quant and cccdna hbvdna in the liver, i know it is difficult to obtain biopsy from patients but we do know serum tests dont show real status of the liver

as regards my treatment i will make tdf+etv+peg for sure, since this ******* virus doesn t respond so easily to treatment we must throw at him all we can, we do know all these combos have no sides....just expensive for insurance

[4est]

as calmama notice a big difference in terms of HbsAg can be notice in this two studys. 4,695  IU/ml (range 16-15,120) vs  660 IU/ml (range 50-1754) and iIwas wandering if the HbsAg level was a entry criteria for  the second case or if they use a different technology to measure.

somehow I think that the difference is to big

[stef2011]

i think the we can have response from entecavir or tenofovir on hbsag as high as 1700-8000iu/ml but we need more data and bigger trials on use of tenofovir and entecavir and on hbsag at those ranges

unfortuantely only gilead is funding very big trials with peginterferon add on that i know of

[4est]

http://www.ncbi.nlm.nih.gov/pubmed/22365367

- just a link for already presented case