Interesting strategy

[StephenCastlecrag]

http://www.virologyj.com/content/10/1/21/abstract
Efficacy of pegylated interferon alpha2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy

Xu-Qing Zhang, Hui-Yan Zhang, Jian-Ping You and Qing Mao


Virology Journal 2013, 10:21 doi:10.1186/1743-422X-10-21
Published: 15 January 2013
Abstract (provisional)
Background

Improving the HBe seroconversion rate of patients without HBeAg loss after long-term lamivudine therapy has become an urgent clinical problem that we have to face. Unfortunately, there is no consensus on the mananement of these patients. The aim of this study was to evaluate the efficacy of pegylated interferon (PEG-IFN) alpha2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy.
Methods

Fifty patients with chronic hepatitis B without the loss of HBeAg after >=96 weeks of lamivudine treatment were enrolled to withdraw from treatment to induce a biochemical breakthrough. Patients who achieved a biochemical breakthrough within 24 weeks received 48-weeks of PEG-IFN alpha2a therapy, and were then assessed during a subsequent 24-week follow-up period.
Results

Forty-three (86.0%) patients achieved a biochemical breakthrough within 24 weeks of lamivudine withdrawal. The rates of combined response (both undetectable HBV DNA and HBeAg loss) and HBsAg loss were alone 51.2% and 20.9%, respectively after 48 weeks of PEG-IFN alpha2a therapy, and 44.2% and 18.6%, respectively, at 24 weeks after treatment cessation. The end-of-treatment combined response rate was 65.4% among patients with a baseline HBsAg =20,000 IU/mL (P=0.031). For patients with HBsAg levels=1,500 IU/mL (33.3% and 14.3%; P=0.048 and 0.001). The end-of-treatment combined response rate was significantly higher among patients with HBV DNA=105 copies/mL (27.3%) after 24 weeks of therapy (P=0.004).
Conclusion

Retreatment with PEG-IFN alpha2a was effective and safe for patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. HBsAg levels at the baseline, 12 and 24 weeks of therapy, and HBV DNA levels at 24 weeks of therapy, can predict the effect of PEG-IFN alpha2a after 48 weeks of therapy.
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

[imdrew]

Can any of you explain a little more about staggered therapy? I've read the article a few times and still can't get an idea of how this staggered therapy is done.

[stef2011]

dr brunetto in pisa had studies on hbcab igm quantitative to know when there is immune activation and start intf

mine were virus mutations, increase in hbvdna but always in the range of thousands, flare to 700-1000, decrease of hbvdna.

keep in mind that there are so many scenarios due to immune system status and control of quasispieces:
hbeag negative wildtype bcp precore with both hbvdna und and normal ast alt or abnormal

hbeag neg bcp precore with both hbvdna und and normal ast alt or abnormal

its mainly imune response to drive disease activaty, not only the mutants.you find all this in brunetto studies, she discovered hbeag neg chrnic hbv.in the end it all goes back to hbsag quantity, it tells you immune control or no immune control whatever bcp/precore

[StephenCastlecrag]

I am interested to hear that you had frequent significant ALT flares without virus clearance. As you know there are two types of ALT flares: host-induced  and virus-induced. It is easy to identify a host-induced flare if hbvdna level drops after the flare. Flare that occurs when hbvdna level is thought to be very low is likely to be virus-induced(after a rise in hbvdna). But it can be host-induced if there is no prior rise in hbvdna or there is a fall in HBsAg level after the flare?

So, I wonder whether all your flares are host-induced?

On another matter, I agree with you that all HBeAg negative hbvers have some precore/bcp mutants, but there must a difference between inactive HBeAg-ve and chronic(active) HBeAg-ve. With the advent of deep sequencing and the concept of quasispecies, my understanding is that there is no longer such thing as pure wildtype and mutant. So can the difference be due to the percentage of precore/bcp mutants in HBeAg-ve hbvers?

[StephenCastlecrag]

Thanks for your comments. What is interesting is the idea of starting Interferon during a "withdrawal-induced ALT flare". This is slightly different to just starting Interferon after several years of undetectable viral load. BTW, in the paper, it said the response to this treatment is best when HBsAg level is lower at the start of treatment.
"For HBeAg-positive patients with PEG-IFNα, higher rates of HBeAg loss or seroconversion are associated with higher pre-treatment serum alanine aminotransferase (ALT) levels. Additionally, post-treatment ALT flares with viral proliferation often occur following the withdrawal of lamivudine. Thus, a new retreatment strategy that involves switching from lamivudine during a withdrawal-induced ALT flare to PEG-IFN α2a therapy is a reasonable protocol for patients without HBeAg loss after long-term lamivudine
treatment. "

[stef2011]

already part of clinical case reports

i mean case reports in the hospitals or small conferences, not in letterature that i know of but again this is the staggered intf combo therapy

[stef2011]

i have been thinking about this strategy many times since i have had flares like acute hbv around 1000 many many times in my life (they said immune system trying to clear) and the flares were with low hbvdna (no hbsag at that time...)

i never accepted this strategy because of the fear for my cirrhotic liver but having no damage it is a very good strategy

the other danger can be mutations in hbsag during interferon monotherapy, especially at my age and with all the mutations my hbv strain has.

trying this at young age, possibly with hbeag positive is very very safe both against mutations and liver damage (wildtype virus, very very few danger of hbsag mutations)

[stef2011]

Can the results be repeated?
yes, already part of clinical case reports

Can it be applied other antivirals?
yes already part of clinical case reports

More importantly, can it be applied to those with HBeAg seroconversion?
hbeag neg have precore and bcp so intf response is weaker but who knows, a big trial needed to answer to this

in pisa they do this staggered intf/antiviral therapy, they just applied this to many single patients, i dont know if they build data on this for their internal use, i guess so

as to hbeag neg with precore and bcp, myself, i was proposed something like this at the begining even if i was cirrhotic at that time (alt flares are ok if lower than 1000 but i guess only for such research center)

[StephenCastlecrag]

Can the results be repeated? Can it be applied other antivirals?
More importantly, can it be applied to those with HBeAg seroconversion?