Aa
10.5years NUCS reductions of 71% hbsag,99.85%Ihbvdna and 99.89% of cccdna
1855
Profound Reduction of HBV Covalently Closed Circular DNA with Long-term Nucleoside / tide Analogue Therapy
1
Medicine, TheUniversity of Hong Kong, Hong Kong SAR, Hong Kong;
2
State Key
Laboratory for Liver Research, The University of Hong Kong, Hong
Kong SAR, Hong Kong;
3
Pathology, The University of Hong Kong,
Hong Kong SAR, Hong Kong;
4
Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD;
5
Medicine, Columbia College
of Physicians and Surgeons, New York City, NY
Background:. Long-term nucleoside / tide analogue (NA) treatment suppresses serum HBV DNA to undetectable levels in a majority of patients We aimed to investigate the effect of long-term NA on the suppression of covalently closed circular DNA (cccDNA) and intrahepatic HBV DNA (ihHBV-DNA).
Methods:
We recruited 40 patients (median age 44.2 years, range 24.3-63.2) who had been on continuous long-term (5 - 10 years) NA All patients had 3 liver biopsies:. At baseline, after 1 year of treatment and at the last follow-up. Serum HBV DNA
and HBsAg were measured by the COBAS TaqMan HBV Test and the Elecsys HBsAg II Assay, respectively (both Roche Diagnostics). ihHBV-DNA and cccDNA were assayed by real-time PCR, with lower limits of detection of 0.001 and 0.005 copies / cell, respectively.
Results: The median duration of treatment was 10.5 years. (Range: 6.0 - 11.9 years) At baseline, 13 patients had 100mg lamivudine, 11 had 600mg telbivudine,
9 had 0.5mg entecavir, 4 had 30mg clevudine, and 3 had 10mg adefovir. At the last follow up, these patients were on 0.5-1.0mg entecavir (n = 23), 600mg telbivudine (n = 9), 10mg adefovir (n = 4), 300mg tenofovir (n = 2), or combination therapy of lamivudine plus adefovir / tenofovir (n = 2). Histology of the third biopsy showed complete resolution of interface hepatitis in 60% of patients with the remainder showing mild-to -moderate activity. Persistent immunoreactivity for HBsAg was found in 80%, the mean number of hepatocytes positive for HBsAg
being 10.4% (range 1-80%). All but 1 (2.5%) was immunoreactive for HBcAg. At baseline, the median serum HBV DNA, HBsAg, ihHBV-DNA and cccDNA levels were 6.84 logIU / mL, 3.38 logIU / mL , 286 copies / cell, and 7.3 copies / cell,
respectively At the time of the last biopsies, 36 (90%) patients had undetectable serum HBV DNA (<20 IU / mL), all but one patient still had detectable HBsAg. (median: 2.74 logIU / mL), all had detectable ihHBV -DNA. (median: 0.4 copies / cell), but 18 (45%) patients had undetectable cccDNA There was a trend of reduction of HBsAg, ihHBV-DNA and cccDNA levels from baseline to 1 year to last follow-up (all p <0.0001). The median log drop of HBsAg at last biopsy was 0.55 logIU / mL.
The median percentage reductions of HBsAg, ihHBV-DNA and cccDNA at last biopsies were 71.46%, 99.85% and 99.89%, respectively.
Conclusions:
Long-term NA treatment significantly reduced cccDNA and ihDNA. 45% of patients had undetectable cccDNA, although small amount of ihHBV-DNA were still
detectable in all patients. Integrated HBV DNA may be a possible source of detectable ihHBV-DNA and HBsAg. Continuous long-term NA therapy can reduce cccDNA to undetectable levels, suggesting a possible end-point of treatment.
Profound Reduction of HBV Covalently Closed Circular DNA with Long-term Nucleoside / tide Analogue Therapy
1
Medicine, TheUniversity of Hong Kong, Hong Kong SAR, Hong Kong;
2
State Key
Laboratory for Liver Research, The University of Hong Kong, Hong
Kong SAR, Hong Kong;
3
Pathology, The University of Hong Kong,
Hong Kong SAR, Hong Kong;
4
Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD;
5
Medicine, Columbia College
of Physicians and Surgeons, New York City, NY
Background:. Long-term nucleoside / tide analogue (NA) treatment suppresses serum HBV DNA to undetectable levels in a majority of patients We aimed to investigate the effect of long-term NA on the suppression of covalently closed circular DNA (cccDNA) and intrahepatic HBV DNA (ihHBV-DNA).
Methods:
We recruited 40 patients (median age 44.2 years, range 24.3-63.2) who had been on continuous long-term (5 - 10 years) NA All patients had 3 liver biopsies:. At baseline, after 1 year of treatment and at the last follow-up. Serum HBV DNA
and HBsAg were measured by the COBAS TaqMan HBV Test and the Elecsys HBsAg II Assay, respectively (both Roche Diagnostics). ihHBV-DNA and cccDNA were assayed by real-time PCR, with lower limits of detection of 0.001 and 0.005 copies / cell, respectively.
Results: The median duration of treatment was 10.5 years. (Range: 6.0 - 11.9 years) At baseline, 13 patients had 100mg lamivudine, 11 had 600mg telbivudine,
9 had 0.5mg entecavir, 4 had 30mg clevudine, and 3 had 10mg adefovir. At the last follow up, these patients were on 0.5-1.0mg entecavir (n = 23), 600mg telbivudine (n = 9), 10mg adefovir (n = 4), 300mg tenofovir (n = 2), or combination therapy of lamivudine plus adefovir / tenofovir (n = 2). Histology of the third biopsy showed complete resolution of interface hepatitis in 60% of patients with the remainder showing mild-to -moderate activity. Persistent immunoreactivity for HBsAg was found in 80%, the mean number of hepatocytes positive for HBsAg
being 10.4% (range 1-80%). All but 1 (2.5%) was immunoreactive for HBcAg. At baseline, the median serum HBV DNA, HBsAg, ihHBV-DNA and cccDNA levels were 6.84 logIU / mL, 3.38 logIU / mL , 286 copies / cell, and 7.3 copies / cell,
respectively At the time of the last biopsies, 36 (90%) patients had undetectable serum HBV DNA (<20 IU / mL), all but one patient still had detectable HBsAg. (median: 2.74 logIU / mL), all had detectable ihHBV -DNA. (median: 0.4 copies / cell), but 18 (45%) patients had undetectable cccDNA There was a trend of reduction of HBsAg, ihHBV-DNA and cccDNA levels from baseline to 1 year to last follow-up (all p <0.0001). The median log drop of HBsAg at last biopsy was 0.55 logIU / mL.
The median percentage reductions of HBsAg, ihHBV-DNA and cccDNA at last biopsies were 71.46%, 99.85% and 99.89%, respectively.
Conclusions:
Long-term NA treatment significantly reduced cccDNA and ihDNA. 45% of patients had undetectable cccDNA, although small amount of ihHBV-DNA were still
detectable in all patients. Integrated HBV DNA may be a possible source of detectable ihHBV-DNA and HBsAg. Continuous long-term NA therapy can reduce cccDNA to undetectable levels, suggesting a possible end-point of treatment.
you are right. its beter to be realistic than naive. i share this thought with you. we are looking forward to see new data from replicor, maybe at this conference . thanks for your help. we are very greatful that there are people on this forum that still cares for others.
hope comes from being realistic, not from naive speculations or interpretations. replicors results hold real hope, btw and are so overwhelmingly better than anything else currently reported or pursued, that many hepatologists and researchers simply shake their head in disbelief and plainly distrust the data.
do a little math:
if the starting situation was that 10% of liver cells were infected, then you have 1/10th of 10 trillion cells infected - one trillion..... now you reduce this by 99.9% a factor of 1000.....now you have only ONE BILLION infected cells.
Does this sound like clearing the virus?
if the starting situation was that 10% of liver cells were infected, then you have 1/10th of 10 trillion cells infected - one trillion..... now you reduce this by 99.9% a factor of 1000.....now you have only ONE BILLION infected cells.
Does this sound like clearing the virus?
it is likely, as explained, that the cccDNA results are overestimated, due to lack of assay accuracy.
The virus has obviously not cleared. read the abstract "all but one patient still had detectable serum hbsag".
Peg ifn for one year at this stage will probably clear a good percentage of these patients.
if just antivirals would be stopped, a significant % would only return to moderate levels of dna and hbsag, but longer term follow up would be needed to confirm the subsequent stability of this phase.
The virus has obviously not cleared. read the abstract "all but one patient still had detectable serum hbsag".
Peg ifn for one year at this stage will probably clear a good percentage of these patients.
if just antivirals would be stopped, a significant % would only return to moderate levels of dna and hbsag, but longer term follow up would be needed to confirm the subsequent stability of this phase.
What are you saying, are this wrong results, or overestimated ? Do you belive that this long (10.5-12 years) therapy can be succesufull in clearing the virus? The resultsnthey showed were pretty astonishing .thanks
i am suspicious about a reduction in cccDNA that exceeds the reduction of surface antigen that much and also the intrahepatic hbv DNA.
CCCDNA is the template for the production of hbsag and they should roughly move parallel. That is the reason we value the quant hbsag, it basically reflects the cccdna left in the liver, except for the integrated dna.
the pcr method to quantitate cccdna in the liver is technically very demanding and prone to underestimate the true quantity. i suspect that this group had exactly that problem.
dealing with a smaller amount of infected cells with a preexisting immune mechanism will provide a better starting platform for the period of enhanced immune activation at several levels that peg ifn will provide.
thus the rate of successfully starting the permanent control mechanism of sustained hbsag seroconversion should be higher after many years of high quality antiviral treatment.
CCCDNA is the template for the production of hbsag and they should roughly move parallel. That is the reason we value the quant hbsag, it basically reflects the cccdna left in the liver, except for the integrated dna.
the pcr method to quantitate cccdna in the liver is technically very demanding and prone to underestimate the true quantity. i suspect that this group had exactly that problem.
dealing with a smaller amount of infected cells with a preexisting immune mechanism will provide a better starting platform for the period of enhanced immune activation at several levels that peg ifn will provide.
thus the rate of successfully starting the permanent control mechanism of sustained hbsag seroconversion should be higher after many years of high quality antiviral treatment.
and, can we say that even if it takes 10 years, we can have a cure by tenofovir and/or some vaccin or peginterfern ?
What do you think of this huge reduction in cccdna, will it make any better to immune therapies like peginterferon/zadaxin to clear hbsag and make stable hbsab?
it is poster 1855 at aasld conference of this year, no link it will be at the conference
it is published at liver meeting aasld 2014
it is published at liver meeting aasld 2014
i want to show my doctor this results, can you please attach the link from this study ?
no these are reductions and since there is almost no cccdna it is thought hbsag is from integrated hbvdna in our own dna without producing virions anymore
the good of this study is that at these low levels of virions in the liver and cccdna in the cells it is extremely easy to clear hbv by peginterferon add on, by stopping antivirals or by waiting few more years so that cccdna loss reaches from 99.89% to 100%
the good of this study is that at these low levels of virions in the liver and cccdna in the cells it is extremely easy to clear hbv by peginterferon add on, by stopping antivirals or by waiting few more years so that cccdna loss reaches from 99.89% to 100%
Stef, the conclusion was that :"The median percentage reductions of HBsAg, ihHBV-DNA and cccDNA at last biopsies were 71.46%, 99.85% and 99.89%, respectively."
i wanted to ask just to be sure i understand right, were they referring that , for HBsAg , the median percentage of HbsAg quant loss was 71.46% ? for all 40 pacients ? or that it work on 71.46% , thanks..
i wanted to ask just to be sure i understand right, were they referring that , for HBsAg , the median percentage of HbsAg quant loss was 71.46% ? for all 40 pacients ? or that it work on 71.46% , thanks..
high dose TAF may shorten these times i guess
the most important data according to me is the cccdna 99.89% loss
i think one patient lost hbsag and the others are very low hbsag
the most important data according to me is the cccdna 99.89% loss
i think one patient lost hbsag and the others are very low hbsag
if you go high dose vit d and vit k i am sure all bone effects are null, and as hbv carriers we must go with vit d supplementation anyway
some studies observed that it was the low vit d and no tdf to cause bone mineral loss....all these studies are badly designed they should have vit d tested and also an arm with high dose vit d
some studies observed that it was the low vit d and no tdf to cause bone mineral loss....all these studies are badly designed they should have vit d tested and also an arm with high dose vit d
"At the time of the last biopsies, 36 (90%) patients had undetectable serum HBV DNA (<20 IU / mL), all but one patient still had detectable HBsAg. " all 90% lost hbsAG in 10 years ? and also cccdna is the most important here ?i see that almost 100% lost it if you lose cccdna you go for seroconversion ? great knews anyway, thanks for sharing
I can't wait to wake up everyday, reading our forum, and listening only good news. Now what makes me worried is only long term of tdf will cause bone demineralized(my fear) .I would prefer combo and shorter time. Anyway i feel wonderful knowing that either way we will be cured.
this was posted in chinese forum about AASLD conference and clearly shows how simple antivirals can cure hbv
use of tdf and pegintf add on will shorten time to reach hbsag und but even if we dont use peg the infection will get to an end probably at 15 years of use.in the meantime liver is perfectly safe, hbsag levels are low and this poses no risks from hbv
use of tdf and pegintf add on will shorten time to reach hbsag und but even if we dont use peg the infection will get to an end probably at 15 years of use.in the meantime liver is perfectly safe, hbsag levels are low and this poses no risks from hbv
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