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Serum cccDNA (attn; studyforhope & stef2011)
On their FaceBook page, HBF posted a link to a very interesting paper:
Effects of Entecavir on Hepatitis B Virus Covalently Closed Circular DNA in Hepatitis B e Antigen-Positive Patients with Hepatitis B
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117741
In this study, researchers in China devised a method to measure the quantity of serum cccDNA. This is in addition to serum hbvdna. This raises the question of where these serum cccDNA come from and what can their quantity inform us?
According to the authors, the serum cccDNA must likely come from dead cells of infected liver cells. It is my understanding that infected liver cells die by either natural or induced cell death by apoptosis or lysis by immune cells. Apoptosis is supposed to be an orderly process with the whole dead cell eaten cleanly by macrophages. Some literature suggested when infected liver cells divide (by mitosis), some cccDNA may be lost , into the cytoplasm or outside the cells? Finally, can serum cccDNA quantity tells us the rate infected liver cells are being killed and therefore be a surrogate marker of whether our cytopathic immune system is active, with or without treatment?
Effects of Entecavir on Hepatitis B Virus Covalently Closed Circular DNA in Hepatitis B e Antigen-Positive Patients with Hepatitis B
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117741
In this study, researchers in China devised a method to measure the quantity of serum cccDNA. This is in addition to serum hbvdna. This raises the question of where these serum cccDNA come from and what can their quantity inform us?
According to the authors, the serum cccDNA must likely come from dead cells of infected liver cells. It is my understanding that infected liver cells die by either natural or induced cell death by apoptosis or lysis by immune cells. Apoptosis is supposed to be an orderly process with the whole dead cell eaten cleanly by macrophages. Some literature suggested when infected liver cells divide (by mitosis), some cccDNA may be lost , into the cytoplasm or outside the cells? Finally, can serum cccDNA quantity tells us the rate infected liver cells are being killed and therefore be a surrogate marker of whether our cytopathic immune system is active, with or without treatment?
I had FibroScan October 1, 2013 and was 11,4kpa.en started immediately Baraclude 0.5 mg.en this week had FibroScan and I'm 12 pounds lighter and my FibroScan was 7.7 kPa.
and will it decrease less fibrosis
and will it decrease less fibrosis
Thank you very much for your expert comments, as per usual. I totally agree the research analysis is not thorough, it is something that I hope will improve in time.
Personally, I would like the seum cccDNA measured for patients in different phases, with or without treatments. With HBeAg positive patients, I always believe the clearance phase will significantly remove a lot of the infect liver cellss, so a parallel reduction in both serum hbvdna and cccDNA is consistent with that idea. Of course, the mechanism is not obvious to me.
Thanks, once again.
Personally, I would like the seum cccDNA measured for patients in different phases, with or without treatments. With HBeAg positive patients, I always believe the clearance phase will significantly remove a lot of the infect liver cellss, so a parallel reduction in both serum hbvdna and cccDNA is consistent with that idea. Of course, the mechanism is not obvious to me.
Thanks, once again.
it would indeed be very useful to have a measurable indicator of infected cell lysis. It would allow to gain insights in the actual mechanisms at work to reduce cccDNA in a given treatment attempt.
Apoptosis and the subsequent removal of cell remnants by macrophages is not such a perfectly clean mechanism as the textbooks want you to believe.
thus it is conceivable that quant serum cccdna measurements reflect current intensity of hepatocyte lysis, even if only a small percentage spills into the general circulation.
the authors did not do a good job in describing and interpreting their own data. They want for example to use this for a determination of cccdna in the liver, which it apparantly is not.
Their calculation and interpretation of the median reduction seems incorrect and misleading.
eg carefully analyze this section of the paper:
Serum total HBV and cccDNA reduction after treatment
Among the 120 patients receiving entecavir treatment, 79 (65.8%) and 86 (71.2%) had undetectable total HBV DNA and cccDNA, respectively, in serum. There was a significant reduction in total HBV DNA levels from a median level of 6.8×107 copies/mL (range, 1.5×107 to 3.2×108 copies/mL) at baseline to a median level of 2.5×103 copies/mL (range, undetectable to 2.2×106 copies/mL) at week 48. The cccDNA levels were also decreased from a median level of 5.1×106 copies/mL (range, 3.1×105 to 2.6×107 copies/mL) at baseline to a median level of 2.4×103 copies/mL (range, undetectable to 6.7×104 copies/mL) at week 48. Because most patients demonstrated undetectable serum HBV DNA and cccDNA at week 48, only patients with detectable results were included for calculation of the median. The magnitudes of total HBV DNA and cccDNA reduction were well correlated (r2 = 0.79, P0.05].
so 71% had undetectable serum cccdna after treatment, but since these were simply ignored in median calculation, the reduction was not statistically significant? Quite misleading.
After entecavir treatment, we do expect a strong reduction in immune attack on the liver cells, this is nicely reflected in the und of the serum cccdna. We also know, that a substantial amount of intrahepatic cccdna remains, hence the meager reduction in hbsag. This is obviously not shown in the serum cccdna, as expected.
Apoptosis and the subsequent removal of cell remnants by macrophages is not such a perfectly clean mechanism as the textbooks want you to believe.
thus it is conceivable that quant serum cccdna measurements reflect current intensity of hepatocyte lysis, even if only a small percentage spills into the general circulation.
the authors did not do a good job in describing and interpreting their own data. They want for example to use this for a determination of cccdna in the liver, which it apparantly is not.
Their calculation and interpretation of the median reduction seems incorrect and misleading.
eg carefully analyze this section of the paper:
Serum total HBV and cccDNA reduction after treatment
Among the 120 patients receiving entecavir treatment, 79 (65.8%) and 86 (71.2%) had undetectable total HBV DNA and cccDNA, respectively, in serum. There was a significant reduction in total HBV DNA levels from a median level of 6.8×107 copies/mL (range, 1.5×107 to 3.2×108 copies/mL) at baseline to a median level of 2.5×103 copies/mL (range, undetectable to 2.2×106 copies/mL) at week 48. The cccDNA levels were also decreased from a median level of 5.1×106 copies/mL (range, 3.1×105 to 2.6×107 copies/mL) at baseline to a median level of 2.4×103 copies/mL (range, undetectable to 6.7×104 copies/mL) at week 48. Because most patients demonstrated undetectable serum HBV DNA and cccDNA at week 48, only patients with detectable results were included for calculation of the median. The magnitudes of total HBV DNA and cccDNA reduction were well correlated (r2 = 0.79, P0.05].
so 71% had undetectable serum cccdna after treatment, but since these were simply ignored in median calculation, the reduction was not statistically significant? Quite misleading.
After entecavir treatment, we do expect a strong reduction in immune attack on the liver cells, this is nicely reflected in the und of the serum cccdna. We also know, that a substantial amount of intrahepatic cccdna remains, hence the meager reduction in hbsag. This is obviously not shown in the serum cccdna, as expected.
i dont think it is important to know why, the only thing that matters is immune activation for continuous lowering and you get it from hbsag quant and Serum MicroRNA Signature.
i dont think serum cccdna can tell exactly anything useful for hbsag loss or treatments like peg add on.i m not so expert on this, just saw 1 study only on serum cccdna so studyforhope can tell much better
i dont think serum cccdna can tell exactly anything useful for hbsag loss or treatments like peg add on.i m not so expert on this, just saw 1 study only on serum cccdna so studyforhope can tell much better
This is a moot point. HBsAg quantity reflects the overall amount of transcriptionally active cccDNA in the liver. IF there is a decline in HBsAg quantity, it does not tell you exactly why: T-Cell lysis, liver cells turnover, or non-cytopathic degradation of cccDNA?
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