EASL2015: Interesting treatment for inactive carrier

[StephenCastlecrag]

P0656
ADD ON PEGINTERFERON TO ADEFOVIR ENHANCES HBsAg LOSS
IN INACTIVE HBV CARRIERS
M. Martinot Peignoux1, F. Mouri2, N. Boyer3, C. Castelnau4,
M. Pouteau5, N. Giuly4, T. Asselah4, P. Marcellin4. 1CRI Paris
Montmartre UMR1149 inserm, Hˆopital Beaujon AP-HP, 2Service
d’h´epatologie, CRI paris Montmartre UMR1149 inserm, 3Service
d’h´epatologie, Hˆopital Beaujon, 4Service d’h´epatologie, 5Service
H´epatologie, Hˆopital Beaujon AP-HP, Clichy, France
E-mail: michelle.***@****
Background and Aims: HBsAg loss, considered to be the ideal
outcome of HBV infection, occurs spontaneously at low rate in
inactive HBV carriers not candidates for therapy. We investigated
the ability of treatment to achieve accelerate incidence of HBsAg
loss in inactive carriers
Methods: 91 inactive carriers from a well phenotyped cohort
(Journal of Clinical Virology 2013; 58: 401) were followed
for a 2 years period. At that time point 69 remained
untreated, 22 underwent 4 years adefovir therapy. At 4 years
16 patients received 48 weeks peginterferon, 6 continued adefovir
monotherapy. All the patients ended therapy at 5 years, and were
followed for at least 2 years after treatment cessation.
Results: At baseline; ALT were 24±7 and 23±7 (ns), HBV genotypes
A, B–C, D, E observed in 33%, 15%, 33%, 19% in untreated
and 37%, 20%, 37%, 6% in treated patients (ns). HBsAg levels
3.24±1.0 and 3.34±0.92 log IU/ml (ns), HBVDNA levels 2.57±0.97
and 2.90±0.84 log IU/ml (ns), in untreated and treated patients,
respectively. At the end of follow up, HBVDNA was undetectable
in 12/69 (17%) of untreated and 9/22 (41%) of treated patients
(p 3.3 log IU/ml shows a negative predictive value (NPV) of 92% for
HBs loss. Among the treated patients a HBs loss was observed
in 0/6 (0%) receiving adefovir and 7/16 (44%) receiving add-on
peginterferon (p = 0.04). Baseline HBsAg levels were 3.50±0.99
and 2.88±1.16 log IU/ml in adefovir and add-on peginterferon
therapy patients, respectively (ns). In the 16 patients receiving addon
peginterferon therapy, baseline HBsAg levels were 1.97±0.83
and 3.59±0.74 log IU/ml in patients with or without HBsAg loss,
respectively (p 3.3 log IU/ml shows a
NPV 100% for HBsAg loss. No patient relapsed.
Conclusions: In inactive HBV carriers treated with adefovir add-on
peginterferon dramatically accelerates the HBsAg decline and rate
of HBsAg loss (44%), in comparison to untreated patients (17%).

[stef2011]

it maybe available only to some of their patients for now

[studyforhope]

thhe micro rna test is interesting, but what about its availability?

[stef2011]

i guess we can predict hbsag loss using pegintf add on by this test

[stef2011]

what about the micro rna test discovered by dr.brunetto in pisa?they said it shows immune activation before we see hbsag decline
i guess we can predict hbsag loss by pegintf add on on this study

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211710/

[studyforhope]

Regarding gs4774, it seems just to continue the long line of failed trials using therapeutic vaccines.
A notable exception was the Cuban core surface particle combo vaccine, that was applied sc and intranasal. It's relative success might be explained by the core particles extreme immunogenicity,  it also triggers a strong th1 helper response, a critical element in antiviral immunity.

This yeast fusion protein was obviously designed to contain all the tcell epitopes of surface, core and x protein, but I have doubts that it is a match to the superantigen features of true hbv core particles, that BTW also impart it's stimulatory features to the other antigen in the vaccine mix, the hbsag.

We can be hopeful that the abivax trial will be able to repeat this success.
Nevertheless,  it will be a helpful push in the right direction,  but far from a cure. It's true usefulness could be seen as an adduct to replicors therapy to enhance the robustness of the achieved short term svr or seroconversion.

The most fundamental Problem with all tcell vaccines is the fact that they elicit at best a response to the vaccine epitopes, while the patients hbv has already developed many epitope escape mutations, against which the newly recruited tells are ineffective.

[StephenCastlecrag]

Thanks, so the patients were not treated because they developed HBeAg negative chronic Hepatitis B. What a bold move. However the time to HbsAg loss for those with HbsAg around 100 iu/ml still seems to take a long time:
2 year initial follow-up, 4 years ADV, I year ADV + PegIFN,  2 year follow-up: 7- 9 years?

[studyforhope]

This was a trial with patients that might not have been treated according to the guidelines.  
They wanted to test the hypothesis that an existing  fairly strong immune control can be further enhanced to the point of hbsag seroconversion by interferon combined with antivirals.
And that is exactly what they were able to show, in particular that the remaining infected cell population and/or cytokine control, expressed as hbsag Quant has to be quite small, so that the modest enhancement to the pre-existing T cell control by interferon is actually able to push it over into hbsag loss.

To sorte:
The t cell control cannot be assessed directly in vivo, but can simply be estimated by the hbsag quantity.

[sorte]

"A preexisting strong T cell response" - how you can measure if it exists in some level ?

[StephenCastlecrag]

Thank you for your comments. I read the poster several times and I am very puzzled by the term "baseline". Does baseline refer to the start of the study when all the 91 patients were inactive? Some how this does not make sense because of the 7/16 that lost HBsAg, their baseline HbsAg centred around 100 iu/ml as ypu pointed out, yet they went on treatment (ADV, followed by ADv + PegIFN), presumably because they developed HBeAg negative chronic Hepatitis B? Your comments please.

Also, can you have a look at the just announced clinical results for GS4774. I understand it to be a therapeutic vaccine, consisting of heat-inactivated yeast genetically modified to express HBsAg, HBcAg, and HBx (I could be wrong here). After 6 injections of the vaccine (every 4 weeks for 24 weeks) in patients virally suppressed using oral NUCs, only 3 patients reported some decline in HBsAg and it is statistically not significant (ns?). For what its worth, the shares dropped 50% . Any comments from you will be appreciated.

[studyforhope]

Note that only the subgroup with hbsag around 100 IU had hbsag loss, the non responders centered around 1000 IU.
This indicates what one would expect. A preexisting strong T cell response is the key aspect that made possible a further strengthening by interferon.
The other small add on trials that we have seen point in exactly the dame direction.