Aa
PMBC - Shown not to be viral reservoirs
http://natap.org/2008/HCV/030508_01.htm
I'm not seing in the article where the PBMCs that were tested were obtained. Were they extracted from blood, from the lymph system, or from some other compartmentalized system?
Thanks for the link to this study. If these results are the real thing, as supported by using more sensitive testing, as they claimed to have used, then we should be very happy with these findings. This is a study that goes against the recent trend of claiming to find reservoirs of active low level HCV in aviremic groups (SVR's and spontaneous clearers).
It looks like they were very rigorous, and double-tested the individuals, using highly sensitive TMA tests. I will be the first to applaud if this becomes the accepted status for post-tx, persistent virus theory. That is, that the virus is just NOT there. BUT, I think we need to also be cautious. This is one study, that contradicts numerous recent studies that claimed to have FOUND active HCV in the PBMC's.
I am willing to take the 'leap of faith' on this article, and would LOVE for this to be the real thing....but I now want to see more validation of these results, through follow up, larger scale testing. Also, they surmise some things about LIVER related clearance, and try to connect the dots...but I also think there needs to be definitive studies on biopsied samples from the livers of SVR's ,and long term spontaneous clearers, using these sensitive tests, and even newer, amplified testing. I would really like to find out what remains in the liver, years after serum clearance. I really hope the answer is, NO virus replicating.
Here is one quote from the study that raised my eyebrows. Note, this is reproduced from the study:
"Sixty of 67 initially aviremic seropositive donors therefore remained aviremic over an average of 2.5 years, and of the 7 donors that became viremic, only 1 donor had a viral load > 100 RNA copies/mL. These 7 seropositive subjects may reflect low-level plasma viral load fluctuations near the limit of detection or, in the case of the high viral load follow-up sample, possible reinfection with another HCV strain.[31]"
How can we interpret the fact that the 'aviremic' group that they chose, that is those who have ZERO HCV on the PCR testing in serum, had seven individuals who went back and forth from aviremic to viremic during the study????? Or from non-detectable to detectable, in other words. Only ONE was deemed a reinfection. He had a higher viremic load. The other six swung back and forth from undetected, to low level detected!!! Doesn't this, in and of itself , seem to contradict the whole definition of SVR or Cleared, in our population??? I don't get it, that they threw this little carpet bomb in there, and made so little of it, in the discussion. What the heck do we make of THAT sort of viral behavior, on lab testing?
Overall, a very uplifting study, very heartening, but with further reinforcement needed, and some clarification of what these low level 'viremic/ aviremic' cases are all about. These are the little exceptions that raise the red flags for me, and cast question on our accepted notions of SVR! Don't you agree?
DoubleDose
It looks like they were very rigorous, and double-tested the individuals, using highly sensitive TMA tests. I will be the first to applaud if this becomes the accepted status for post-tx, persistent virus theory. That is, that the virus is just NOT there. BUT, I think we need to also be cautious. This is one study, that contradicts numerous recent studies that claimed to have FOUND active HCV in the PBMC's.
I am willing to take the 'leap of faith' on this article, and would LOVE for this to be the real thing....but I now want to see more validation of these results, through follow up, larger scale testing. Also, they surmise some things about LIVER related clearance, and try to connect the dots...but I also think there needs to be definitive studies on biopsied samples from the livers of SVR's ,and long term spontaneous clearers, using these sensitive tests, and even newer, amplified testing. I would really like to find out what remains in the liver, years after serum clearance. I really hope the answer is, NO virus replicating.
Here is one quote from the study that raised my eyebrows. Note, this is reproduced from the study:
"Sixty of 67 initially aviremic seropositive donors therefore remained aviremic over an average of 2.5 years, and of the 7 donors that became viremic, only 1 donor had a viral load > 100 RNA copies/mL. These 7 seropositive subjects may reflect low-level plasma viral load fluctuations near the limit of detection or, in the case of the high viral load follow-up sample, possible reinfection with another HCV strain.[31]"
How can we interpret the fact that the 'aviremic' group that they chose, that is those who have ZERO HCV on the PCR testing in serum, had seven individuals who went back and forth from aviremic to viremic during the study????? Or from non-detectable to detectable, in other words. Only ONE was deemed a reinfection. He had a higher viremic load. The other six swung back and forth from undetected, to low level detected!!! Doesn't this, in and of itself , seem to contradict the whole definition of SVR or Cleared, in our population??? I don't get it, that they threw this little carpet bomb in there, and made so little of it, in the discussion. What the heck do we make of THAT sort of viral behavior, on lab testing?
Overall, a very uplifting study, very heartening, but with further reinforcement needed, and some clarification of what these low level 'viremic/ aviremic' cases are all about. These are the little exceptions that raise the red flags for me, and cast question on our accepted notions of SVR! Don't you agree?
DoubleDose
i think what they want to say is, well, there is something like low-level viremia, and yes, if viremia is present in plasma, then it is also present in PBMCs, BUT the PBMCs themselves are not "responsible" for the low level viremia that some people still maintain. And, if somebody gets rid of (high and low level) plasma viremia, then they will stay so almost certainly.
nevertheless, i think studies like this need independent evaluation, simply to rule out clergical error. I also find it strange that they talk about re-infection without telling if that would be consistent with patients history or not. So, they "chicken out" a bit here, which can surely not be appreciated.
`´´´Our results indicate that PBMC are unlikely to serve as a long-lived reservoir of HCV in aviremic subjects´´´´
so, to me the key words in their conclusion are "indicate" and "unlikely", but nevertheless, its encouraging work, that will in the long run, for sure, cement the notion of HCV being curable.
nevertheless, i think studies like this need independent evaluation, simply to rule out clergical error. I also find it strange that they talk about re-infection without telling if that would be consistent with patients history or not. So, they "chicken out" a bit here, which can surely not be appreciated.
`´´´Our results indicate that PBMC are unlikely to serve as a long-lived reservoir of HCV in aviremic subjects´´´´
so, to me the key words in their conclusion are "indicate" and "unlikely", but nevertheless, its encouraging work, that will in the long run, for sure, cement the notion of HCV being curable.
Studies like this -- and I believe there have been similar in the past -- are why many liver specialists don't buy into the "occult/persistent" theory, at least not in the sense of clinically viable virus that threatens our health, or the health in others, in any way.
On the other hand, didn't the studies that found HCV in PBMC's use less conventional more sentive (and more controversial) centrifugal-type tests then appear to being used here which are more conventional TMAs? If so, this could account for the reason why one study finds something and another doesn't?
The other reason given by the authors is that they used sensitive TMA screening to determine who was "cleared" and who wasn't. The implication being that previous studies may have found virus in PBMC's because of less sensitive screening, i.e. they were finding virus in PBMC's of some who were actually had not cleared the virus in plasma had a more sensitive test been use. Not sure if the authors were simply speculating here or if they knew the sensitivity of the screening tests used by previous studies.
On the other hand, didn't the studies that found HCV in PBMC's use less conventional more sentive (and more controversial) centrifugal-type tests then appear to being used here which are more conventional TMAs? If so, this could account for the reason why one study finds something and another doesn't?
The other reason given by the authors is that they used sensitive TMA screening to determine who was "cleared" and who wasn't. The implication being that previous studies may have found virus in PBMC's because of less sensitive screening, i.e. they were finding virus in PBMC's of some who were actually had not cleared the virus in plasma had a more sensitive test been use. Not sure if the authors were simply speculating here or if they knew the sensitivity of the screening tests used by previous studies.
it's an interesting addition to the topic, but for the reasons below, I don't think it does much to tip the prevailing view that hcv persists in most patients post-SVR. First, I think their results (which by the way were published in Hepatology last December) report a result contrary to one found (in repeated publications) by Pham, Radkowski, and Carreno among others. This doesn't invalidate them of course, but makes them the outlier and thus more questionable. For example, the following German study, also from last year, dected virus in SVR sera using a standard commercial test:
http://www.ncbi.nlm.nih.gov/pubmed/17625963
"An HCV-RNA of less than 12 IU/ml was found in nine of the 50 SVR patients"
(Jim, I believe the ultracentrifugation technique you are referring to is
http://www.ncbi.nlm.nih.gov/pubmed/17475654
but note that they were going after "occult" ie HCV antibody negative patients, presumably ones with a much lower anount of virus than ordinary SVRs since the amount of virus was insufficient to even trigger antibody production)
The second reason is the study only considered PBMCs. This focus may be reasonable given that the authors work for a blood lab, howver the Carreno, Pham, Radkowski findings suggest liver cells are the most likely source of post-SVR replication as they were before tx.
The third reason is a technical one. The Pham/Michalak lab has made it clear that mitogen stimulation is an important part of the protocol of low-level VL detection :
"In previous studies, it is reported that ex vivo treatment of lymphocytes from persons who achieved SVR with nonspecific mitogens led to an upregulation of viral replication, allowing detection of the virus in the cells which were apparently nonreactive [5,6]. It became evident that such an approach facilitates a more accurate detection of HCV than by testing sera or naive PBMC. This finding also reaffirmed the notion that lymphotropism is an intrinsic property of HCV."
from http://www.ncbi.nlm.nih.gov/pubmed/17650287
However, the Bernardin study made no use of this, which I think places their result in the category of now-you-see-it-now-you-don't data based on a dated protocol.
The fact that many clinicians are dismissive of post-SVR viremia doesn't contradict any of the results in this area, it merely emphasizes that the health consequences, as far as we know, are mild to none. At this point, post-SVR virus seems a well-established result:
"In the current study, by employing the assays of superior sensitivity [5,6], it was found that more than 80% of the individuals who had been deemed free of HCV by standard detection methods in fact carried small amounts of viral RNA in sera (≤102 vge/mL) and 50% of them were also positive for HCV RNA in naive lymphoid cells at the levels ranging between estimated 5 × 100 to 7 × 103 vge/μg total RNA. Importantly, HCV RNA replicative intermediate was identified in approximately 65% of the lymphoid cell samples positive for the HCV negative strand. Heterogeneity in viral sequences detected in serum and PBMC samples, collected at the same or at two different occasions from the same individuals, provided additional evidence for persistently progressing viral replication in lymphoid cells."
from the same Pham'07 paper.
However, I continue to think these results are much more relevant to relapsers (why was the residual virus able to rebound?) than to SVRs in whom the minimal residual virus seems to do little damage (and, on the plus side, some SVRs do seem to eventually lose their HCV antibodies..)
http://www.ncbi.nlm.nih.gov/pubmed/17625963
"An HCV-RNA of less than 12 IU/ml was found in nine of the 50 SVR patients"
(Jim, I believe the ultracentrifugation technique you are referring to is
http://www.ncbi.nlm.nih.gov/pubmed/17475654
but note that they were going after "occult" ie HCV antibody negative patients, presumably ones with a much lower anount of virus than ordinary SVRs since the amount of virus was insufficient to even trigger antibody production)
The second reason is the study only considered PBMCs. This focus may be reasonable given that the authors work for a blood lab, howver the Carreno, Pham, Radkowski findings suggest liver cells are the most likely source of post-SVR replication as they were before tx.
The third reason is a technical one. The Pham/Michalak lab has made it clear that mitogen stimulation is an important part of the protocol of low-level VL detection :
"In previous studies, it is reported that ex vivo treatment of lymphocytes from persons who achieved SVR with nonspecific mitogens led to an upregulation of viral replication, allowing detection of the virus in the cells which were apparently nonreactive [5,6]. It became evident that such an approach facilitates a more accurate detection of HCV than by testing sera or naive PBMC. This finding also reaffirmed the notion that lymphotropism is an intrinsic property of HCV."
from http://www.ncbi.nlm.nih.gov/pubmed/17650287
However, the Bernardin study made no use of this, which I think places their result in the category of now-you-see-it-now-you-don't data based on a dated protocol.
The fact that many clinicians are dismissive of post-SVR viremia doesn't contradict any of the results in this area, it merely emphasizes that the health consequences, as far as we know, are mild to none. At this point, post-SVR virus seems a well-established result:
"In the current study, by employing the assays of superior sensitivity [5,6], it was found that more than 80% of the individuals who had been deemed free of HCV by standard detection methods in fact carried small amounts of viral RNA in sera (≤102 vge/mL) and 50% of them were also positive for HCV RNA in naive lymphoid cells at the levels ranging between estimated 5 × 100 to 7 × 103 vge/μg total RNA. Importantly, HCV RNA replicative intermediate was identified in approximately 65% of the lymphoid cell samples positive for the HCV negative strand. Heterogeneity in viral sequences detected in serum and PBMC samples, collected at the same or at two different occasions from the same individuals, provided additional evidence for persistently progressing viral replication in lymphoid cells."
from the same Pham'07 paper.
However, I continue to think these results are much more relevant to relapsers (why was the residual virus able to rebound?) than to SVRs in whom the minimal residual virus seems to do little damage (and, on the plus side, some SVRs do seem to eventually lose their HCV antibodies..)
" prevailing view that hcv persists in most patients post-SVR"
This is hardly the prevailing view. In fact, it is the view of just a few that have not so far, been able to scientifically support their claims.
This is hardly the prevailing view. In fact, it is the view of just a few that have not so far, been able to scientifically support their claims.
Judging by your comments on Willing's post, you apparently did not read the studies he listed, nor the findings on active HCV in the great majority of recent research papers investigating 'persistent HCV' after SVR. Just because the mainstream doctors are not yet running around saying that HCV persists after SVR does NOT mean: A. that this is not the prevailing view, B. That the overwhelming research evidence does not support this view. and C. That the mainstream medical community is not 'quietly' aware of these findings, and just not publicizing or acknowledging this information.
You can 'say' that the concept of 'persistent HCV after clearance' is not scientifically supported, but I think that is very hollow, in and of itself. The research that Willing provided above, alone, is enough scientific proof to support the concept....not to speak of the many other recent research studies finding similar viral behaviors.
I think you are issuing statements with little or no visible support, scientifically. The lone research article highlighted, finding no HCV in PBMC's is just one nice example. There are more than ten that produced hard evidence to the contrary. How do you discount all of those studies, to then only believe the results of the study that you like?
Let's search for TRUTH here, not try to trump up a case to support what you want to believe, and shout down everybody who points out contrary evidence. Just how scientific do you want us to be? Thirty studies to your one? And, will you adhere to the same demands?
I sure don't have the answers yet, but I'll bet for darn sure, that you don't either!
DoubleDose
You can 'say' that the concept of 'persistent HCV after clearance' is not scientifically supported, but I think that is very hollow, in and of itself. The research that Willing provided above, alone, is enough scientific proof to support the concept....not to speak of the many other recent research studies finding similar viral behaviors.
I think you are issuing statements with little or no visible support, scientifically. The lone research article highlighted, finding no HCV in PBMC's is just one nice example. There are more than ten that produced hard evidence to the contrary. How do you discount all of those studies, to then only believe the results of the study that you like?
Let's search for TRUTH here, not try to trump up a case to support what you want to believe, and shout down everybody who points out contrary evidence. Just how scientific do you want us to be? Thirty studies to your one? And, will you adhere to the same demands?
I sure don't have the answers yet, but I'll bet for darn sure, that you don't either!
DoubleDose
DoubleDose: Let's search for TRUTH here, not try to trump up a case to support what you want to believe, and shout down everybody who points out contrary evidence.
----------------------------------------------------------------------------------------------------------------------------------
Cough.
----------------------------------------------------------------------------------------------------------------------------------
Cough.
My guess is that what "Mr. Liver" meant by "prevailing view" is the view expressed by many leading hepatologists (including those I've consulted) who have no doubt looked at the same data you and Willing have presented, but came to different conclusions. That doesn't mean that they are right and you are wrong, but "Willing's" original statement potentially left the impression that the majority of the professional Hep C community agreed, and this is far from the case as Mr. Liver stated. If you want to question their judgment, that's another issue, but again, the point debated was "prevailing" view.
-- Jim
-- Jim
I understand what you are saying, but the question does, as you say, boil down to 'prevailing view', and more specifically, who's prevailing view/ That of doctors who are not generally doing intensive, laboratory research on the virus and its behaviors in the body, and often times even if they do review the research, may not have the background or tools to validate or dispute what they have just read...or, is 'prevailing view' the findings presented by the overall research community? I guess it ends up being what definition you choose to use, in defining what 'prevailing view' really means.
Trish.... If I am 'trumping up a case' myself (cough), please call me on it! I am trying to merely point out the position that most, or at least MANY researchers have taken in the past five years or so, regarding the existence of HCV after SVR in certain cells, or organs. If I am mis-stating, please do criticize my statements, point out whatever is fallacious, and I will be happy to correct my comments or position.
I am really not trying to be heavy-handed, but I just get the feeling that some of our members ofter jump on any information that supports 'total eradication', even when contradictory studies are clearly in the majority. I would personally LOVE for their ideas to be true. But I have a hard time dismissing a basket full of thorough research studies that seem to document, scientifically, the existence of low level viremia, after SVR. I get the feeling that some of us just do not want that to be a possibility, and hence, go into total denial over studies that support 'persistent virus'. Those studies are always 'wrong', or not supported by hepatologists..(why not????), or are just plain 'questionable, when there is no other reason to dispute them...etc.
I will believe either side, just show me the money! Where are an equal number of highly precise and thorough studies that find NO evidence of this 'persistent virus' after SVR? If they are available, I would really LOVE to know that. Because I am worrying about this issue all for nothing, in that case. I just can't seem to find all of THAT research.
Hey, I know that I can sometimes beat the drum hard, and go overboard on a theme, but I see a similar, knee-jerk reactionary behavior in others on the forum whenever uncomfortable issues come up. Usually these controversial issues are dismissed quickly without much evidence, and with statements like..nobody really believes that , or its not generally accepted. DUH!!! I realize that! That's why much of this is still controversial. Few people are studying it, and fewer still want to believe it! For VARIOUS reasons.
I respect all of your opinions. But let's also look closely and critically at ALL of the research...please.
DoubleDose
Trish.... If I am 'trumping up a case' myself (cough), please call me on it! I am trying to merely point out the position that most, or at least MANY researchers have taken in the past five years or so, regarding the existence of HCV after SVR in certain cells, or organs. If I am mis-stating, please do criticize my statements, point out whatever is fallacious, and I will be happy to correct my comments or position.
I am really not trying to be heavy-handed, but I just get the feeling that some of our members ofter jump on any information that supports 'total eradication', even when contradictory studies are clearly in the majority. I would personally LOVE for their ideas to be true. But I have a hard time dismissing a basket full of thorough research studies that seem to document, scientifically, the existence of low level viremia, after SVR. I get the feeling that some of us just do not want that to be a possibility, and hence, go into total denial over studies that support 'persistent virus'. Those studies are always 'wrong', or not supported by hepatologists..(why not????), or are just plain 'questionable, when there is no other reason to dispute them...etc.
I will believe either side, just show me the money! Where are an equal number of highly precise and thorough studies that find NO evidence of this 'persistent virus' after SVR? If they are available, I would really LOVE to know that. Because I am worrying about this issue all for nothing, in that case. I just can't seem to find all of THAT research.
Hey, I know that I can sometimes beat the drum hard, and go overboard on a theme, but I see a similar, knee-jerk reactionary behavior in others on the forum whenever uncomfortable issues come up. Usually these controversial issues are dismissed quickly without much evidence, and with statements like..nobody really believes that , or its not generally accepted. DUH!!! I realize that! That's why much of this is still controversial. Few people are studying it, and fewer still want to believe it! For VARIOUS reasons.
I respect all of your opinions. But let's also look closely and critically at ALL of the research...please.
DoubleDose
"Few people are studying it, and fewer still want to believe it!"
Is this your definition of a prevailing view ?
making claims about any "prevailing view" is indeed highly questioniable; it depends on who you ask, what you ask them, etc. etc. However the statement that researchers reporting post-SVR virus have not been able to "scientifically support their claims" is patently false.
Here's a sampling of excerpts from recent peer-reviewed publications:
1) "In conclusion, our results suggest that in patients with SVR after therapy, small quantities of HCV RNA may persist in liver or macrophages and lymphocytes for up to 9 years. This continuous viral presence could result in persistence of humoral and cellular immunity for many years after therapy and could present a potential risk for infection reactivation."
Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C.
Hepatology. 2005 Jan;41(1):106-14.
PMID: 15619235
2) "In conclusion, occult HCV infection must now be accepted as much an entity as occult HBV infection, and we should no longer loosely refer to prolonged SVR as a cure (Hepatology 2005;41:23–25), especially because this term is still being used today (Ann Intern Med 2005;142:105–114, Hepatology 2005;41:275–279). As clinicians, we may need to revise our clinical attitude to the outcome of SVR following successful treatment of HCV with more careful follow up, and we must be aware of the possibility of occult HCV infection in patients with liver disease of unknown cause."
Occult viral hepatitis: What is the significance?
Gastroenterology
Volume 128, Issue 7, June 2005, Pages 2168-2170
3) "The samples obtained from 16 randomly selected patients (5 with spontaneous and 11 with treatment-induced resolution), monitored for up to 5 years,...importantly, traces of the HCV RNA negative strand, suggesting progressing virus replication, were detected in the majority of mitogen-stimulated PBMC, including four samples collected 5 years after recovery."
(note again the use of mitogen stimulation of PBMCs)
Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C.
J Virol. 2004 Jun;78(11):5867-74.
PMID: 15140984
4) "Genomic HCV RNA was detected in liver biopsy specimens obtained from 10 (83%) of 12 patients, and the antigenomic strand was detected in 10 (100%) of 10 liver biopsy specimens in which genomic HCV RNA was detected....CONCLUSION: HCV may persist and replicate in the liver and PBMCs of healthy, anti-HCV antibody-positive, serum HCV RNA-negative patients who have persistently normal ALT levels. These patients should be followed up, because they have an ongoing viral infection."
Detection of hepatitis C virus (HCV) RNA in the liver of healthy, anti-HCV antibody-positive, serum HCV RNA-negative patients with normal alanine aminotransferase levels.
J Infect Dis. 2006 Jul 1;194(1):53-60. Epub 2006 May 16.
PMID: 16741882
5) "We conclude that the absence of HCV in the serum of patients with chronic hepatitis C by the end of treatment does not mean that there is no circulating virus. HCV in mononuclear cells may be an indicator of the persisting infection."
Detection of HCV by PCR in serum and PBMC of patients with hepatitis C after treatment.
Braz J Infect Dis. 2007 Oct;11(5):471-4.
PMID: 17962872
6) "An HCV-RNA of less than 12 IU/ml was found in nine of the 50 SVR patients. Two patients had a viral load of 34 IU/ml and 84 IU/ml, respectively, one of those showed persistently elevated ALT levels over a period of 5 years after the end of antiviral treatment."
Frequency of very low HCV viremia detected by a highly sensitive HCV-RNA assay.
J Clin Virol. 2007 Aug;39(4):308-11. Epub 2007 Jul 12.
PMID: 17625963
7) "The results showed that treatment of peripheral lymphoid cells with mitogens stimulating T- and B-cell proliferation and with cytokines supporting their growth significantly increased HCV RNA detection in patients with both CHC and SVR."
Mitogen-induced upregulation of hepatitis C virus expression in human lymphoid cells.
J Gen Virol. 2005 Mar;86(Pt 3):657-66.
PMID: 15722526
8) "We studied the presence of both positive- and negative-strand HCV RNA in the livers of 20 sustained responders with chronic hepatitis C whose response persisted for a mean (+/- standard deviation [SD]) of 47.4+/-32.8 months after treatment....CONCLUSIONS: HCV persisted and replicated in the livers and peripheral blood mononuclear cells of most sustained responders. Thus, these patients did not experience HCV infection clearance, despite apparent clinical disease resolution."
Hepatitis C virus replicates in the liver of patients who have a sustained response to antiviral treatment.
Clin Infect Dis. 2006 Nov 15;43(10):1277-83. Epub 2006 Oct 5.
PMID: 17051492
that's not an exhaustive list, but I'm getting exhausted. I've been following this topic fairly closely since the original reports in '04 and as best I can tell, absence of supporting data is a charge that can be fairly leveled at those arguing for post-SVR virus eradication. All of the studies above, except (2) which is an editorial, base their findings on original data.
If anyone can find an equivalent list in support of "complete eradication", and I mean PUBMED-cited, peer-reviewed, publications, not editorial opinion-pieces or "my dr told me X" anectodes, please post it!
It's interesting that that recent JAMA HCV overview by Scott and Gretch,
http://jama.ama-assn.org/cgi/content/full/297/7/724?ck=nck
in their discussion of occult/persistent HCV only came up with 1 reference, and that one dating back to '97, in support of the "eradication" view.
Finally, note that even the Bernardin study that started this thread, acknowledges they hadn't quite done all their homework :
"Increased levels of cell-associated HCV RNA have also been reported following nonspecific in vitro stimulation and culture of PBMC.[20][21][36] The PBMC tested here were purified directly from blood without external stimulation. It therefore remains formally possible that nonspecific PBMC stimulation could have increased residual PBMC-associated HCV RNA to detectable levels."
so, if this is "formally possible", why didn't they check?
Here's a sampling of excerpts from recent peer-reviewed publications:
1) "In conclusion, our results suggest that in patients with SVR after therapy, small quantities of HCV RNA may persist in liver or macrophages and lymphocytes for up to 9 years. This continuous viral presence could result in persistence of humoral and cellular immunity for many years after therapy and could present a potential risk for infection reactivation."
Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C.
Hepatology. 2005 Jan;41(1):106-14.
PMID: 15619235
2) "In conclusion, occult HCV infection must now be accepted as much an entity as occult HBV infection, and we should no longer loosely refer to prolonged SVR as a cure (Hepatology 2005;41:23–25), especially because this term is still being used today (Ann Intern Med 2005;142:105–114, Hepatology 2005;41:275–279). As clinicians, we may need to revise our clinical attitude to the outcome of SVR following successful treatment of HCV with more careful follow up, and we must be aware of the possibility of occult HCV infection in patients with liver disease of unknown cause."
Occult viral hepatitis: What is the significance?
Gastroenterology
Volume 128, Issue 7, June 2005, Pages 2168-2170
3) "The samples obtained from 16 randomly selected patients (5 with spontaneous and 11 with treatment-induced resolution), monitored for up to 5 years,...importantly, traces of the HCV RNA negative strand, suggesting progressing virus replication, were detected in the majority of mitogen-stimulated PBMC, including four samples collected 5 years after recovery."
(note again the use of mitogen stimulation of PBMCs)
Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C.
J Virol. 2004 Jun;78(11):5867-74.
PMID: 15140984
4) "Genomic HCV RNA was detected in liver biopsy specimens obtained from 10 (83%) of 12 patients, and the antigenomic strand was detected in 10 (100%) of 10 liver biopsy specimens in which genomic HCV RNA was detected....CONCLUSION: HCV may persist and replicate in the liver and PBMCs of healthy, anti-HCV antibody-positive, serum HCV RNA-negative patients who have persistently normal ALT levels. These patients should be followed up, because they have an ongoing viral infection."
Detection of hepatitis C virus (HCV) RNA in the liver of healthy, anti-HCV antibody-positive, serum HCV RNA-negative patients with normal alanine aminotransferase levels.
J Infect Dis. 2006 Jul 1;194(1):53-60. Epub 2006 May 16.
PMID: 16741882
5) "We conclude that the absence of HCV in the serum of patients with chronic hepatitis C by the end of treatment does not mean that there is no circulating virus. HCV in mononuclear cells may be an indicator of the persisting infection."
Detection of HCV by PCR in serum and PBMC of patients with hepatitis C after treatment.
Braz J Infect Dis. 2007 Oct;11(5):471-4.
PMID: 17962872
6) "An HCV-RNA of less than 12 IU/ml was found in nine of the 50 SVR patients. Two patients had a viral load of 34 IU/ml and 84 IU/ml, respectively, one of those showed persistently elevated ALT levels over a period of 5 years after the end of antiviral treatment."
Frequency of very low HCV viremia detected by a highly sensitive HCV-RNA assay.
J Clin Virol. 2007 Aug;39(4):308-11. Epub 2007 Jul 12.
PMID: 17625963
7) "The results showed that treatment of peripheral lymphoid cells with mitogens stimulating T- and B-cell proliferation and with cytokines supporting their growth significantly increased HCV RNA detection in patients with both CHC and SVR."
Mitogen-induced upregulation of hepatitis C virus expression in human lymphoid cells.
J Gen Virol. 2005 Mar;86(Pt 3):657-66.
PMID: 15722526
8) "We studied the presence of both positive- and negative-strand HCV RNA in the livers of 20 sustained responders with chronic hepatitis C whose response persisted for a mean (+/- standard deviation [SD]) of 47.4+/-32.8 months after treatment....CONCLUSIONS: HCV persisted and replicated in the livers and peripheral blood mononuclear cells of most sustained responders. Thus, these patients did not experience HCV infection clearance, despite apparent clinical disease resolution."
Hepatitis C virus replicates in the liver of patients who have a sustained response to antiviral treatment.
Clin Infect Dis. 2006 Nov 15;43(10):1277-83. Epub 2006 Oct 5.
PMID: 17051492
that's not an exhaustive list, but I'm getting exhausted. I've been following this topic fairly closely since the original reports in '04 and as best I can tell, absence of supporting data is a charge that can be fairly leveled at those arguing for post-SVR virus eradication. All of the studies above, except (2) which is an editorial, base their findings on original data.
If anyone can find an equivalent list in support of "complete eradication", and I mean PUBMED-cited, peer-reviewed, publications, not editorial opinion-pieces or "my dr told me X" anectodes, please post it!
It's interesting that that recent JAMA HCV overview by Scott and Gretch,
http://jama.ama-assn.org/cgi/content/full/297/7/724?ck=nck
in their discussion of occult/persistent HCV only came up with 1 reference, and that one dating back to '97, in support of the "eradication" view.
Finally, note that even the Bernardin study that started this thread, acknowledges they hadn't quite done all their homework :
"Increased levels of cell-associated HCV RNA have also been reported following nonspecific in vitro stimulation and culture of PBMC.[20][21][36] The PBMC tested here were purified directly from blood without external stimulation. It therefore remains formally possible that nonspecific PBMC stimulation could have increased residual PBMC-associated HCV RNA to detectable levels."
so, if this is "formally possible", why didn't they check?
Thanks for your, as always, precise and detailed response. You brought into sharp focus what I was trying to say in my last post above.
DoubleDose
DoubleDose
Arguments not withstanding, I think what you're saying is that this *should* be the prevailing view, not that it is the prevailing view. And that's all Mr. Liver was bringing to your attention, as I read it. Say what you want about "my doctor told me so", but if the majority of top docs are telling people that it's not like that, then it's not the prevailing view as I see it. Maybe it should be or will be in your opinion, but it's not. And not sure how much more we can slice and dice that point.
I find your comments very interesting. Its like looking at the statistics for the economy, and having the technical experts determine that we are in the early stages of recession, and then turning on CNBC and hearing the moderators and hosts scream that "We are NOT IN RECESSION, the Chicken Littles are screaming that the sky is falling!!!" etc, etc. Jim Cramer and the Mad Money crowd are waving the flag!!!
Now I guess we could accept the CNBC point of view, that they don't THINK we really are in recession, and the heck with what all those gloomy numbers say, and on and on...so just keep buying those stocks, and keep a smile on your face...etc. And I guess, if you buy into that way of reasoning then the CNBC guys ARE the prevailing view.
Who cares what the analysts say, who cares what the statistics say, who really cares what the truth is??? The CNBC crew said it, so we must go with their point of view.
So if that is analogous to how you want to determine 'prevailing view' then you are right on the money, and I can't argue with you. I prefer to listen to the subject matter experts, and look at the hard facts. But yes, you are probably right, prevailing view has not caught up with the facts yet, and for the media world, cure still has a capital "C"!
DoubleDose
Now I guess we could accept the CNBC point of view, that they don't THINK we really are in recession, and the heck with what all those gloomy numbers say, and on and on...so just keep buying those stocks, and keep a smile on your face...etc. And I guess, if you buy into that way of reasoning then the CNBC guys ARE the prevailing view.
Who cares what the analysts say, who cares what the statistics say, who really cares what the truth is??? The CNBC crew said it, so we must go with their point of view.
So if that is analogous to how you want to determine 'prevailing view' then you are right on the money, and I can't argue with you. I prefer to listen to the subject matter experts, and look at the hard facts. But yes, you are probably right, prevailing view has not caught up with the facts yet, and for the media world, cure still has a capital "C"!
DoubleDose
I wish you had told me this before I bought some stocks earlier. So Jim Cramer is not the prevailing point of view then :)
-- Jim
-- Jim
It's like this, to me, in simplistic terms. At one time, the prevailing view is that the world was flat. They were dead wrong, however, they were absolutely convinced. Then.. as more evidence came into being, irrefutable evidence, that prevailing view changed.
At one time, what SOC was considered to be .. whatever it was...certainly not what it is now...was the prevailing view. That has changed.
Your viewpoint, DD, may indeed be correct. I'm open to that, interested and want to read up more and you DO spur me to do research on things. However. I would say, at this point in time, that it is not the PREVAILING view. No matter how much you think it should be, want it to be and believe it to be. It simply isn't. It may get to that .. but it isn't.
The first thing I thought when I read Willing's comments were... "prevailing view? I don't think so...." and then Mr. Liver posted the same thought I was having.
So...perhaps we agree to disagree. You think it's the prevailing view. Some of us don't. Does it really matter? What happens here is that an opinion is stated, people agree or disagree with that opinion...and life goes on. I have no idea why it upset you so much to have Mr. Liver make such a very simple statement indicating he doesn't think this is the prevailing view. It certainly evoked a very strong reaction from you. (I know how that happens.. I backed off posting for awhile because I was getting alarmed at the timbre of my posts...)
What REALLY matters... as you've said yourself... is what the truth of the matter is. So ... let's keep posting articles and debating the finer points of them and allow all of us to have differing points of view and debate them back and forth but not take it personally when we all want the same thing, hopefully. The truth.
And...expect me to challenge you when you call something truth and I don't see it that way and I'll explain why. I don't think you'd want it any other way .. would you? :)
Trish
At one time, what SOC was considered to be .. whatever it was...certainly not what it is now...was the prevailing view. That has changed.
Your viewpoint, DD, may indeed be correct. I'm open to that, interested and want to read up more and you DO spur me to do research on things. However. I would say, at this point in time, that it is not the PREVAILING view. No matter how much you think it should be, want it to be and believe it to be. It simply isn't. It may get to that .. but it isn't.
The first thing I thought when I read Willing's comments were... "prevailing view? I don't think so...." and then Mr. Liver posted the same thought I was having.
So...perhaps we agree to disagree. You think it's the prevailing view. Some of us don't. Does it really matter? What happens here is that an opinion is stated, people agree or disagree with that opinion...and life goes on. I have no idea why it upset you so much to have Mr. Liver make such a very simple statement indicating he doesn't think this is the prevailing view. It certainly evoked a very strong reaction from you. (I know how that happens.. I backed off posting for awhile because I was getting alarmed at the timbre of my posts...)
What REALLY matters... as you've said yourself... is what the truth of the matter is. So ... let's keep posting articles and debating the finer points of them and allow all of us to have differing points of view and debate them back and forth but not take it personally when we all want the same thing, hopefully. The truth.
And...expect me to challenge you when you call something truth and I don't see it that way and I'll explain why. I don't think you'd want it any other way .. would you? :)
Trish
Interesting thread.
My brain is to tired to engage, most of you know where I stand on this. Because I know it to be true.
Deb
My brain is to tired to engage, most of you know where I stand on this. Because I know it to be true.
Deb
I couldn't agree with you more. Let's find the truth, and everything else will just follow along. That is what I am trying to aim for, and I want to stimulate conversation on new findings that may often contradict 'accepted' views. If we just stay with what's comfortable or accepted, we will never learn anything new.
I think Willing's list of rigorous research papers are indeed a great starting point for conversation, and to generate more research (to either finally confirm all these findings, or to refute them with even more rigorous testing , which the initial study in the thread did NOT do) and to gain a better understanding of what MIGHT be going on with this virus beyond current medical practice knowledge.
I just want to stimulate people to think, question, and have the courage to look for real, honest, answers...not just comforting, shallow maxims. I am sure that some of my more far-reaching conjectures, and theories probably tick some people off, or really threaten some others, but you know what? If I don't pose some of these 'possibilities' someone else will. And if there is some truth to any of my theories, then eventually that will come to the surface anyway...no matter whether people like the news or not.
Science will eventually find the answers, for sure.
But, I will say, I do not often 'call something the truth', but usually try to preface my comments and conjectures with 'my opinion, my thoughts, my speculation, etc."
As you have probably seen, theorizing with one's opinion on the forum, or asking scary questions, often provokes a furious response here. I have no real problems with that, and I have a pretty thick skin. I don't recklessly make comments, but put forward my theories based on something rational, or concrete that I see or have noticed. Doesn't mean that I am right, but I will absolutely continue to ask painful questions, and look for explanations that go deeper than today's understandings.
But again, I agree with you, let's do keep debating the finer points, and searching for the truth. That should be the main goal of all of us on the forum. And 'debating' is a good watchword. NOT just saying 'no one believes that, my doctors don't buy that stuff, its not what everyone else thinks, etc. This is not debate, but just following the lemmings.
Let's look for facts, research, and data. We need lots more than we have.
DoubleDose
I think Willing's list of rigorous research papers are indeed a great starting point for conversation, and to generate more research (to either finally confirm all these findings, or to refute them with even more rigorous testing , which the initial study in the thread did NOT do) and to gain a better understanding of what MIGHT be going on with this virus beyond current medical practice knowledge.
I just want to stimulate people to think, question, and have the courage to look for real, honest, answers...not just comforting, shallow maxims. I am sure that some of my more far-reaching conjectures, and theories probably tick some people off, or really threaten some others, but you know what? If I don't pose some of these 'possibilities' someone else will. And if there is some truth to any of my theories, then eventually that will come to the surface anyway...no matter whether people like the news or not.
Science will eventually find the answers, for sure.
But, I will say, I do not often 'call something the truth', but usually try to preface my comments and conjectures with 'my opinion, my thoughts, my speculation, etc."
As you have probably seen, theorizing with one's opinion on the forum, or asking scary questions, often provokes a furious response here. I have no real problems with that, and I have a pretty thick skin. I don't recklessly make comments, but put forward my theories based on something rational, or concrete that I see or have noticed. Doesn't mean that I am right, but I will absolutely continue to ask painful questions, and look for explanations that go deeper than today's understandings.
But again, I agree with you, let's do keep debating the finer points, and searching for the truth. That should be the main goal of all of us on the forum. And 'debating' is a good watchword. NOT just saying 'no one believes that, my doctors don't buy that stuff, its not what everyone else thinks, etc. This is not debate, but just following the lemmings.
Let's look for facts, research, and data. We need lots more than we have.
DoubleDose
Have an Answer?
You are reading content posted in the Hepatitis C Community
Learn about this treatable virus.
Getting tested for this viral infection.
3 key steps to getting on treatment.
4 steps to getting on therapy.
What you need to know about Hep C drugs.
How the drugs might affect you.
These tips may up your chances of a cure.
A list of national and international resources and hotlines to help connect you to needed health and medical services.
Herpes sores blister, then burst, scab and heal.
Herpes spreads by oral, vaginal and anal sex.
STIs are the most common cause of genital sores.
Condoms are the most effective way to prevent HIV and STDs.
PrEP is used by people with high risk to prevent HIV infection.
