do not forget!interferon+telbivudine (sebvivo) hbsag clearance

[stef2011]

http://www.kenes.com/easl2010/orals/118.htm

Session Title: Parallel Session: HEPATITIS B: THERAPEUTIC ADVANCES
Presentation Date: Apr 15, 2010

TELBIVUDINE (LDT) PLUS PEG-INTERFERON (PEGIFN) IN HBEAG-POSITIVE CHRONIC HEPATITIS B - VERY POTENT ANTIVIRAL EFFICACY BUT RISK OF PERIPHERAL NEUROPATHY (PN)

P. Marcellin1, C. Avila2, K. Wursthorn3, W.-L. Chuang4, G.K. Lau5, C.-Y. Peng6, E.J. Gane7, H. Fainboim8, M.P. Manns3, N.V. Naoumov2
1Service d'Hépatologie, INSERM, Hôpital Beaujon, Clichy, France, 2Novartis Pharma AG, Basel, Switzerland, 3Hannover Medical School, Hannover, Germany, 4Kaohsiung Medical University, Kaohsiung, Taiwan R.O.C., 5Clinical Trial Center, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China, 6China Medical University Hospital, Taichung, Taiwan R.O.C., 7Middlemore Hospital, Auckland, New Zealand, 8Hospital de Enfermedades Infecciosas, Buenos Aires, Argentina. *patrick.***@****-hop-paris.fr


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).

[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.

  

[stef2011]

http://www.intmedpress.com/serveFile.cfm?sUID=c0f29db5-b3ac-4ddd-b45d-2b5cd41ef3cc

this study helps to have an idea of the hbsag levels that have the highest chances of hbsag loss on interferon mono

this study can show how stupid the researchers of the study "lack of hbsag and cccdna on nucs", those researchers made the study to make confusion because they cannot be so stupid to think that nuc therapy has an effect on immune system and hbsag that can lower both hbsag and cccdna.
on nucs there is only hbvdna decrease all other parameters have no correlation because nucs are extremely weak on both cccdna, hbsag and immune system.

we are not researchers but we can very easily understand how the nucs are useless on hbv infection except those with liver damage or liver cancer risk

correlation of hbsag and cccdna must be studied only on immune modulating therapies that clear hbsag, it is also good to remember that cccdna is not detectable when hbsag gets negative

[stef2011]

there is plently of time before PN onset since it requires 4.5months so staggered therapy is a very good possibility
http://en.cnki.com.cn/Article_en/CJFDTOTAL-YWBL200905017.htm

i think the big problem is that we know nothing about PN and we have nothing to cure it so they should check for ways to prevent it, in any case 12 weeks staggered therapy should be a very good option since there is more than 0,5log reduction already at 12 weeks and interferon mono might keep this declining kinetics combo with alinia or etv or tnf

Full-Text Search：
《Adverse Drug Reactions Journal》 2009-05Add to Favorite Get Latest Update
Peripheral neuropathy due to combination therapy with telbivudine and interferon:clinical features,prevention,and treatment

Cai Haodong ( Outpatient of Beijing Ditan Hospital,Beijing 100115,China)  
Peripheral neuropathy is defined as a damage of the peripheral motor nerve ,sensory nerve,and autonomic nervous system. Recently,peripheral neuropathy caused by combination therapy with telbivudine and interferon has been sometimes reported,and the incidence is 16.7%. The time to onset of peripheral neuropathy during combination with telbivudine and interferon is 4.5 months. Telbivudine plus interferon-induced peripheral neuropathy manifests as mononeuropathy or polyneuropathy,and it mainly is sensory nerve damage. Diagnosis of peripheral neuropathy is based on clinical manifestation,the results of electromyography and nerve conduction velocity tests. Peripheral neuropathy must be distinguished from myopathies which could be produced by telbivudine. Telbivudine combined with interferon should be avoided in clinical practice as much as possible. If peripheral neuropathy caused by telbivudine plus interferon is confirmed,both drugs should be stopped.

[stef2011]

in any case once 1log decline of hbsag is achieved even inf monotherapy can lead to seroconversion even if very slow, the chances of success with such low hbsag on inf mono are very very high

[stef2011]

a researcher said that this deserves furthur trials despite PN, i wonder if there are tests to monitor closely PN and prevent development......

the staggered inf+sebvivo might prevent PN and even get better results because the staggered inf+nucs has usually more potent results, i bet that also stagering with alinia might get better results

[stef2011]

i dont refer exactly to the study but to overall hbv carriers, the most (dont know about asians), have hbsag 3logs and even more between 2000-5000iu/ml (especially hbeag neg) so after you lose 1log you get to 200-500iu/ml

those who lose hbsag with interferon get 1 log decline of hbsag, also consdier that interferon has a maximum response of 1log decline (it rarely achieves more).if you add that this was achieved by 24weeks only on 63% patients you get the picture of what you can do......

i bet they stopped everything because this combo is too potent and might cure too fast, that's why i posted this because there are ways to prevent PN and there is interferon lambda which has no effects ouside the liver

the problem of interferon+sebvivo is that also interferon carries sides as PN.....i have just seen that intravenous glutathione 3000mg has immidiate effects on parkinson disease for example so it might be a good thing to study if this can have any protective effect on PN, also high dose dha and epa from fish oil has an effect on nerves and maybe another good thing to study on PN

[StephenCastlecrag]

Telbivudine has a better safety profile than this. I wonder whether the combination with Peg Interferon increases the side effect? I also wonder about the makeup of patients in the sample.

63% PegIFN+LDT got more than 0.5log hbsag decline by week 12 and about 1.3log decline at week 24

"THIS MEANS THEY HAD HBSAG LESS THAN 1000 AND GOING TO CLEAR HBSAG" - How did you draw this conclusion?

0.5 log is 10**0.5 - very small? 1.log10 is 10?

[stef2011]

these are the sides of telbivudine (sebvivo), FDA approved...so i dont understand why they stopped combo since the use of the drug monotherapy has already this side effect without curing anything

peripheral neuropathy (numbness,
tingling and/or burning sensations
in the arms and/or legs

anyway let's remember about this because when interferon lambda will be approved this is a very good combo to try.i also think that liposomal glutathione and other substances might be tried to lower PN

i think that also staggered interferon+telbivudine is a very good option to try, for example 1 year:
12 weeks interferon+telbivudine
12 weeks interferon+alinia or entecavir

i dont think 2 years are necessary because 1log decline at 24 weeks is already close to clearance if hbsag <300iu/ml even on interferon mono

[stef2011]

the report is written so bad.....
63% PegIFN+LDT got more than 0.5log hbsag decline by week 12 and about 1.3log decline at week 24

THIS MEANS THEY HAD HBSAG LESS THAN 1000 AND GOING TO CLEAR HBSAG

several researchers said that this therapy should be used under continuous control over PN because results were too good...what did they do nothing!

[stef2011]

[Figure 2]
HBsAg decline (>0.5log10IU/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.