Add -on interferon to a stable nucleoside, hbsag loss 40% full poster

https://docs.google.com/open?id=0B_yFgxI8KNcROTI2YzFkYTctMjZjMy00MjBjLWE0ZDEtNWY3NmI0MDQ3MzNl

this is very important because we can make the following comments:

adefovir had the higest results but since tenofovir is similar with less toxicity, more potency and no resistance we maight have same or higher results

another observation is etv mono for only 3 years and huge hbsag decrease from 7900iu/ml.while all others had already very low levels of hbsag this patient had response on the hbsag range where interferon mono has little decrease on hbsag.the decrease looks also a sudden decrease and not slow and homogeneous

too bad we dont have etv+tdf combo among these patients i guess it may have stronger effect

[stef2011]

the non response is the last patient in the list:
lam+adv 8years
baseline hbsag 1754iu/ml

to me entecavir and tenofovir are sure the best combos to prepare for an interferon add-on

[Bob0620]

Great news. 40 % lost HBsag.

Stef, HCV now can cure with many new drugs. Do you think HCV drugs can be used for HBV ?

[Bob0620]

Maybe in 2 years time, Inteferon Lamda + new tenofvir for HBV ?

[stef2011]

no different viruses hcv is not integreated in human dna, very easy to clear compard to hbv
there is one drug active on trl7 which can be sued on hbv, dont rememeber the name

from this latest compete data i'd not wait for lambda, interferon alpha looks more than good after hbvdna und for years under potent combos like etv+tdf or mono etv or mono tdf

i'd never wait for lambda if hbsag<1500iu/ml already

[StephenCastlecrag]

Just adding to Stef2011's response. HCV  is a RNA virus, whilst HBV is a DNA virus. The latest drugs to treat HCV are protease inhibitors. Apparently, when HCV virus replicates, it produces long chain of proteins and requires an enzyme, protease, to cleave the chain into smaller pieces. These drugs inhibit this enzyme, and therefore HCV cannot replicate successfully.
Unfortunately, these protease inhibitors are not relevant to HBV.

Hope I got it right.

[4est]

40% is a realy good number, but notice that they chose patients with low values on HBsAg (I don't know why) and I think that if they follow up they will report that more then 40% loss HBsAg.

[stef2011]

the good and unexpected, at least by me is the patient on entecavir:

only 3 years on entecavir vs other patients 6-8 years
hbsag was about 7800iu/ml on entecavir patient

he had a big decrease of hbsag all of a sudden and also had the best off therapy response keeping low hbsag, i think this patient will seroconvert in a couple of years or just by another interferon course, not to menthion the possibility to add alinia to improve svr

[4est]

indeed, ent patient was a good surprise ... hope that they will continue this kind of studys and they will came up with a new tx guide base on more info and particularization for the patient and nuc/interferon ....

[stef2011]

40% is such a good number that waiting on lambda might be less important:

we dont know if lambda will reach these numbers yet (although hcv had already better svr)

we dont know approval date and healthcare coverage on combos

[4est]

I agree that wiating for INF lambda is a long time and we don't know how will be the results.

If a patient manage to go around 1500 UI HbsAg then a serious discussion with the doctor have to be initiated and adding INF have to be considered, if the patient is not under tx, then a discusion with the doctro to see if is necessary to start a NUC tx and add INF after that, or just INF or start NUC+INF on the same time .... also multiple sesion of INF can be considered in case that HBsAg decrese but not to 0 ....

we have a lot of possibilities and I hope that more research will be done on this area and new guidelines to be issued (guideline that consider hbv dna, qhbsag, hbeag, naive or not, combo on NUC, combo on NUC+ INF, entry inhibitors ...)

btw do you see Myracludex and REP 9AC presentation on webcast link ?

[stef2011]

no, there are so many missing and most are among the most interesting

also tnf+etv poster is missing, i dont like the way it has been presented it was not serious with just claims and little/no data or data with poor sensibility is not used anymore (at least in europe), you can use old tests and sensibility which is poorer than normal tests done on patient in clinical practice.i think we can expect some driven trials to hide or  postpone no resistance mutation combos and hbsag lowering.drug makers are using all old uless tests with hbvdna still at 30-60iu/ml and normal alt 40, this is rediculous

endpoint of combo is hbsag/cccdna decrease and total resistance prevention by ultra deep sequence but none of these have been performed and without these tests all trial is useless.they do have all the money to do this....

on the contrary we are very lucky because european and asian researchers are making serious trials like the nuc+inf combos

[4est]

i don't see the reason why they try to hide tnf result, gilead should push on this and prove that no mutation and good results ... this will determine a increase of selling.

[stef2011]

patent is close to expire they have increadilbly kept pushing entecavir which is far enough from patent expire and still pushing adv and lam.
we just have to consider this when reading posters so in case it happens we can easily detect it while if it doesnt happen that's good anyway

all studies should be pointed on tenofovir, most potent and no resistance, but this is not the case it looks the less studied in detail (ultra deep sequence, cccdna, hbsag)
the only study on hbsag nad tdf is not from drug makers, is not on hbv patients, it is from a university and done on hiv+hbv

[stef2011]

let's keep contact with the researchers because that 40% will go to 90% in the following years

all had hbsag less than 100-300iu/ml and in this range after an interferon course hbsag is cleared almost 100%

another very good point is that such low levels of hbsag dont require therapies because the virus doesn t reactivate so even this end point is very very good
in the rare case hbsag is not cleared interferon is restarted and clearance when hbsag is 100-300iu/ml is almost certain

[stef2011]

and to all members

i was looking how to contact the doctors of this poster because 40% clearance is by 48weeks already while the other patients are still on therapy until 96weeks.the other patients have hbsag between 30-300iu/ml by 72 weeks and till decreasing
so it is very important to contact them for the following:
final hbsag clearance after 96 weeks of combo
final hbsag clearance off therapy or off interferon after 96 weeks and sustained response

i am sure the final result will be close to 90% clearance and of course all these patients are already in the range where hbv can t reactivate off therapy.

so please look for contact by email for:
Denis Ouzan (1), Guillaume Pénaranda (2),
Hélène Joly (1), Hacène Khiri (2),
Philippe Halfon (2).
(1) Liver unit, Institut Arnault-Tzanck, Saint-Laurent du Var;
(2) Alphabio Laboratory, Marseille, FRANCE

[stef2011]

for those who could not read the poster:

patient:A2F2    adefovir(6years) then adv+interferon:
hbsag baseline 50iu/ml  hbsag 48weeks 0iu/ml stopped all therapies

patient:A2F3    lamivudine(8years) then lam+interferon:
hbsag baseline 123iu/ml  hbsag 48weeks 0iu/ml stopped all therapies

patient:A3F3    adefovir(7years) then adv+interferon:
hbsag baseline 248iu/ml  hbsag 48weeks 0iu/ml stopped all therapies

patient:A1F1   adefovir(6years) then adv+interferon:
hbsag baseline 789iu/ml  hbsag 48weeks 0iu/ml stopped all therapies

[stef2011]

patient:A3F3    adefovir+entecavir (8years) then  adefovir+entecavir +interferon:
hbsag baseline 110iu/ml  hbsag 48weeks 87iu/ml  hbsag 72weeks 30iu/ml

patient:A2F4 (cirrhosis)  entecavir+adefovir (6years) then entecavir+adefovir+interferon:
hbsag baseline 530iu/ml  hbsag 48weeks 380iu/ml  hbsag 72weeks 200iu/ml

patient:A1F1 lamivudine+tenofovir (3years) then  lamivudine+tenofovir+interferon:
hbsag baseline 1320iu/ml  hbsag 48weeks 345iu/ml  hbsag 72weeks 300iu/ml

patient:A1F1   adefovir+entecavir (7years) then  adefovir+entecavir +interferon:
hbsag baseline 974iu/ml  hbsag 48weeks 40iu/ml  hbsag 72weeks 140iu/ml

[stef2011]

most interesting patient because very very high hbsag baseline and only 3 years of etv

patient:A2F3  entecavir (3years) then  entecavir +interferon:
hbsag baseline 7900iu/ml  hbsag 48weeks 120iu/ml  hbsag 72weeks 30iu/ml

only patient with non response so interferon was stopped at 24weeks, it would be interesting to know hbvdna and resistance mutants tests of this patient:
patient:A2F4 (cirrhosis) lamivudine+adefovir (8years) then  lamivudine+adefovir+interferon 24weeks:
hbsag baseline 1754iu/ml  hbsag 48weeks 1380iu/ml  hbsag 72weeks 1720iu/ml

[ronny12]

Stefano, what do you think is the probability of seroconversion based on hbsag value? because if someone is to go for interferon + tnf he/she must know the chances of seroconversion as it is an expensive treatment and not everybody spends such amount of money if he hasn't some good chances of getting cured i think. What do you think stefano?The ones mentioned at this post had very low baseline hbsag(1500? Are we expecting these % of hbsag loss.
Very interesting and important poster for us hbv-ers.

[ronny12]

What if qHbsag >1500. What are the chances of seroconversion. Are we expecting these %( i.e 40 % at 48 weeks) or no.What do you think.

[stef2011]

these studies are mainly made i europe were all treatments re free of charge (at least france, italy and germany) and some from china.
if you have to pay for it it is really really expensive and only india or asia may be a place to spend very little where both interferon and antivirals are available generic.
having to pay full i d stay on tdf until hbsag lowers to 1500iu/ml for genotype A-D and then add-on interferon, the minimum you can expect is to lower hbsag to less than 1000iu/ml and virus doesn t reactivate at these low hbsag even if you stop everything, so this is a point where money is well spent anyway

if you want to be even more sure of clearance you can wait for hbsag to reach 500iu/ml too, virus is totally inactive at this level (geno A-D) and you may clear even with no interferon very very slowly in 5-10 years

[stef2011]

with higher hbsag we have too many little patients to know, but it is very interesting that those under entecavir and tenofovir had response even if antivirals were taken for little time about 3 years

i also see the big decrease of etv mono patient, he had hbsag 8000iu/ml at this level interferon monotherapy have very little chances of response, more patients are needed to confirm that etv and tdf withinterferon can lower hbsag so much on many patients

[ronny12]

I live in a country near Italy Stefano.Can you tell me how can i manage to start an interferon course(if qHbsag<1500 and hbvdna und) in Italy? Is there any possibility to find a hospital there where i can have a discount on interferon course? If yes can you tell me where? Thanks in advance.

[stef2011]

my suggestion is to check carefully hbvdna with sensitivity very high like less then 10iu/ml and stay with hbv undetactable for years like patients in this study and of course check hbsag at least yealy to see if it goes down

the study says all patients were less than 20iu/ml hbvdna for 3 years, this maybe a very good point to start for us

and like my experience, if hbsag goes up and down but doesnt lower in 2-3 years and hbvdna also become detactable even at low level like 1-10iu/ml better combo with a second nuc
from other posters the best combo looks tenofovir+entecavir or tenofofvir+telbivudine with no previous resistance, these combos registered homogeneous hbvdna 0iu/ml with high sensitivity tests while other monotherapies with antivirals had low viremia detactable, i guess this can low down hbsag decrease although no study checked this fact yet

low viremia under nucs.down load to see very clear.
https://docs.google.com/present/edit?id=0AfyFgxI8KNcRZGQ2NXhtaDZfNTE5cGtoa3NzaGc&hl=en_US

[stef2011]

i ve uploaded native pdf, download here because with google docs conversion there is loss of data and it is less clear

low viremia under nucs
https://docs.google.com/open?id=0B_yFgxI8KNcRMWU5MmY5MTgtNzNiOC00YWQ1LWFjZGEtNjA0MTU4ZWJiN2Rj

my guess is maximum suppression plus active immune system will clear much of cccdna faster

[stef2011]

the file is native ppt file, i ve uploaded as openoffice file to be displayed correctly.i dont know if work can display ppt or openoffice files

https://docs.google.com/open?id=0B_yFgxI8KNcRMDExNmMzYzUtOWE1Ny00NWY5LWE5OTctZGU0YzBhYWNhYjk0

[stef2011]

i dont know if word can display ppt or openoffice files, open office is the best to display all formats

[4est]

"i was looking how to contact the doctors of this poster because 40% clearance is by 48weeks already while the other patients are still on therapy until 96weeks.the other patients have hbsag between 30-300iu/ml by 72 weeks and till decreasing" - for sure I will follow-up this presentation. I hope that they will came with an update on the flowing sessions, but until then I will try to find as many information as possible by contacting the doctors.

[4est]

http://clinicaltrials.gov/ct2/show/NCT00973219?term=hepatitis+b&recr=Open&cntry1=EU%3ANL&rank=3 - this is another study that we have to keep an eye on him and also to try to contact the researchers.
this is one of few study that have INF+TNF and also claim a result that I was not able to found in previous study " ... Recently the investigators have shown that HBeAg negative patients with high HBV-DNA load and low baseline HBsAg levels had a significantly higher HBsAg clearance (positive predictive value of 85%) after combination therapy with peginterferon alfa2a (Peg-IFN) and adefovir" - notice that this affirmation is from 2009.

[stef2011]

that's a very good study made by a university.the most important thing is to find studies not funded by drug makers because they dont supply data, on the contrary they made combo study from a long time and never published data

i used to go to interferon drug maker website because they used to say data will be published by.......they never did and we know why now

[raja1972]

denis ouzan -  denis.***@****

Guillaume Pénaranda -- g.***@****
Guillaume Pénaranda - g.penaranda@ alphabio.fr


Marc Bourličre - [e-mail];


Hacène Khiri -  h.khiri@alphabio. fr

Philippe Halfon - philippe.***@****

[raja1972]

Hi steff,
Pls refer to the link for the email addresses.

http://www.springerlink.com/content/bl027j04p7488704/fulltext.pdf

[raja1972]

what is the tenofovir and entecavir  dosage  (is the tenofovir the same used for HIV patients?)

[raja1972]

can we use INTALFA (Recombinant Interferon Alfa-2b) available in india?

reference site is:
http://www.intasbiopharma.co.in/Interferon.html

[4est]

yes, tenofovir has the same dosage for HBV and for HIV

[4est]

"can we use INTALFA (Recombinant Interferon Alfa-2b) available in india?" - treatment have to be done under the doctor surveillance and authority, so beter look for a good doctor.

as for INTALFA, better check with the doctors from India (they know the market) and also with the drug producer (for me it sound like a interferon and not peg interferon (and in this case the dosage is different ))

[4est]

http://www.medhelp.org/posts/Hepatitis-B/news-from-researchers-interferontdf-or-etv-clears-hbv-in-almost-all-patients-96weeks/show/1643024

to have tractability for all related topics

[stef2011]

thank you very much for finding the emails but i have just returned from pisa and they know already that hbv is cleared by combo int+tdf or int+etv, just a matter of time to clear almost all of hbsag.

so now we just need to make these combos and see how hbsag goes down and personalize interferon+nucs durability according to it:

for example interferon+tdf or etv doesn t lower hbsag by 24 weeks, stop interferon and continue the antiviral only.interferon can be retried later on

if hbsag keeps lowering the combo must be kept as long as hbsag detactable, even 2-3 or more years

[4est]

http://www.medhelp.org/posts/Hepatitis-B/wow-found-post-of-a-guy-who-cleared-after-48weeks-combo-interferontelbivudine-in-italy/show/1643426

just to keep all information in the same place :)

[stef2011]

http://www.kenes.com/easl2010/orals/118.htm
this was peg+telbivudine (ltd) 24-48weeks with hbsag 0.5log decline on 63%

Background and aims: HBeAg seroconversion is a key milestone for HBeAg-positive chronic hepatitis B (CHB) patients allowing for treatment discontinuation. Compared with other treatments, higher rates of HBeAg seroconversion (e-seroconversion) are reported with PegIFN or LDT. We aimed to investigate whether PegIFN+LDT combination could further improve antiviral efficacy and e-seroconversion compared to their monotherapy.
Methods: 159 HBeAg-positive CHB patients were randomized (55 LDT, 54 PegIFN, 50 PegIFN+LDT). 110 patients (49 LDT, 43 PegIFN, 18 PegIFN+LDT) reached treatment week 24 (W24), but the study was terminated early due to PN events with PegIFN+LDT. Key efficacy (HBV DNA, ALT, HBsAg/HBeAg quantitation by Abbott Architect) and safety is reported.
Results: Mean baseline HBV DNA levels (log10copies/mL) were 9.8 (LDT), 9.6 (PegIFN), 10.1 (PegIFN+LDT). At W24, LDT containing regimens achieved significantly greater viral load decline than PegIFN (figure 1).
HBV DNA became undetectable in 35%, 7% and 71% of patients (LDT, PegIFN and PegIFN+LDT, respectively), p0.5log10IU/mL) occurred in 41% LDT, 31% PegIFN and 63% PegIFN+LDT treated patients (p=0.03); ALT normalization: 54% LDT, 32% PegIFN, 12% PegIFN+LDT. For the few LDT and PegIFN patients who achieved W48, 7/19 and 3/12 respectively had e-seroconversion.
ITT discontinuations due to SAE/AE occurred in 7.3%, (LDT), 5.6% (PegIFN) and 18%, (PegIFN+LDT). PN cases with PegIFN+LDT were more severe and shorter median time (months) to symptom (4.5, range 2-6) vs LDT (14, range 4-25). 9 SAE PN cases were drug related, 8 were on PegIFN+LDT, 1 was on LDT and at last follow up, 6 were improving, 2 ongoing and 1 unknown.
Conclusions: The combination of PegIFN+LDT provided very potent antiviral efficacy with rapid and profound reduction in HBV DNA and HBsAg/HBeAg levels, but combination therapy with PegIFN+LDT carried an increased risk of PN. The underlying mechanism needs further investigation. Despite increased efficacy, concomitant use of PegIFN+LDT should be avoided at present.

[4est]

A new trial for tnf + inf  is in recruitment phase:

http://clinicaltrials.gov/ct2/show/study/NCT01277601?term=hepatitis+b&recr=Open&cntry1=EU%3ARO&rank=1&show_locs=Y#locn

this is a trial that we have to look for the results.

[4est]

and another clinical trial that have to keep an eye on it:

http://clinicaltrials.gov/ct2/show/NCT00877760?cond=Hepatitis+B&cntry1=EU%3ARO&rank=3

[stef2011]

i think that will be my trial

[4est]

good luck!

and keep us updated  ;)