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What Do You Think About This Scary Study?
Study: Patients With Resolved Hepatitis C Likely Still Contagious
Patients with chronic hepatitis C that has been resolved through therapy or immune response may still be able to infect others with the virus. That finding is from a new study in the May issue of Hepatology, a journal published by John Wiley & Sons on behalf of the American Association for the Study of Liver Diseases (AASLD). The article is also available online at Wiley Interscience (www.interscience.wiley.com).
About 170 million people worldwide are infected with hepatitis C virus, which can progress to chronic hepatitis, cirrhosis and even liver cancer. In some individuals, the infection seems to resolve, either spontaneously from the efforts of the immune system, or after treatment with interferon and ribavirin.
Patients who achieve a sustained viral response show no clinical or biochemical evidence of liver disease and standard tests can no longer detect the virus in their blood. However, more sensitive research tests are finding that such patients often still have miniscule amounts of the virus in their bodies. No one knows if these trace remainders are infectious.
Researchers led by Tomasz I. Michalak of Memorial University of Newfoundland, Canada examined this question using a system that allows for propagation of HCV in human T cells in vitro.
They began with nine patients with HCV who had achieved a sustained viral response that persisted for at least two years after treatment. HCV RNA was detectable in their blood only with the more sensitive tests.
The researchers set up twelve cultures of lymphoid cells from healthy donors, and exposed them to plasma or to supernatants of cultured circulating lymphoid cells from the HCV patients. Eleven of the cell cultures became HCV RNA positive. Furthermore, HCV from three of the nine patients was able to establish active HCV replication in the cultures.
“These findings provide in vitro evidence that trace quantities of HCV persisting in the circulation for a long time after therapeutically induced resolution of CHC can remain infectious,” the authors report.
Interestingly, HCV replication in the T cells was prevented after neutralization of the virus, and by treatment with interferon.
This study is the first to investigate the infectivity of HCV traces that remain when the infection is occult. It agrees with previous animal studies of the same question.
“Our present findings reveal that HCV circulating in some individuals with resolved hepatitis C is capable of inducing productive infection in vitro at doses of 20 to 50 copies,” the authors conclude. “This can be interpreted as a strong indication of potential virus infectivity in vivo.”
Article: “Hepatitis C Virus Persisting at Low Levels after Clinically Apparent Sustained Virological Reponse to Antiviral Therapy Retains Its Infectivity in Vitro.” MacParland, Sonya A.; Pham, Tram N.Q.; Guy, Clifford S.; Michalak, Tomasz I. Hepatology; May 2009.
Patients with chronic hepatitis C that has been resolved through therapy or immune response may still be able to infect others with the virus. That finding is from a new study in the May issue of Hepatology, a journal published by John Wiley & Sons on behalf of the American Association for the Study of Liver Diseases (AASLD). The article is also available online at Wiley Interscience (www.interscience.wiley.com).
About 170 million people worldwide are infected with hepatitis C virus, which can progress to chronic hepatitis, cirrhosis and even liver cancer. In some individuals, the infection seems to resolve, either spontaneously from the efforts of the immune system, or after treatment with interferon and ribavirin.
Patients who achieve a sustained viral response show no clinical or biochemical evidence of liver disease and standard tests can no longer detect the virus in their blood. However, more sensitive research tests are finding that such patients often still have miniscule amounts of the virus in their bodies. No one knows if these trace remainders are infectious.
Researchers led by Tomasz I. Michalak of Memorial University of Newfoundland, Canada examined this question using a system that allows for propagation of HCV in human T cells in vitro.
They began with nine patients with HCV who had achieved a sustained viral response that persisted for at least two years after treatment. HCV RNA was detectable in their blood only with the more sensitive tests.
The researchers set up twelve cultures of lymphoid cells from healthy donors, and exposed them to plasma or to supernatants of cultured circulating lymphoid cells from the HCV patients. Eleven of the cell cultures became HCV RNA positive. Furthermore, HCV from three of the nine patients was able to establish active HCV replication in the cultures.
“These findings provide in vitro evidence that trace quantities of HCV persisting in the circulation for a long time after therapeutically induced resolution of CHC can remain infectious,” the authors report.
Interestingly, HCV replication in the T cells was prevented after neutralization of the virus, and by treatment with interferon.
This study is the first to investigate the infectivity of HCV traces that remain when the infection is occult. It agrees with previous animal studies of the same question.
“Our present findings reveal that HCV circulating in some individuals with resolved hepatitis C is capable of inducing productive infection in vitro at doses of 20 to 50 copies,” the authors conclude. “This can be interpreted as a strong indication of potential virus infectivity in vivo.”
Article: “Hepatitis C Virus Persisting at Low Levels after Clinically Apparent Sustained Virological Reponse to Antiviral Therapy Retains Its Infectivity in Vitro.” MacParland, Sonya A.; Pham, Tram N.Q.; Guy, Clifford S.; Michalak, Tomasz I. Hepatology; May 2009.
DD: I know you haven't received much support here on this topic, but I think in some ways you've been ahead of your time. Hepatology's accepted articles/early view section includes yet another published letter exchange on this topic ( the 3rd in a year). This one is a response by Carreno et al to the review by Welker/Zeuzem listed above along with Zeuzem's reply. Carreno references a forthcoming paper with the title (" Hepatitis C Virus Infection in the Family Setting of Patients with Occult Hepatitis C. ", J Med Virol. In press. Castillo et al '09) and states
"family members of patients with occult HCV infection show serological markers of HCV infection even more frequently than those of patients with chronic hepatitis C"
Zeuzem, of course, is skeptical
"These data may be interpreted in detail after full publication, but prima facie it seems difficult to understand why immune responses to HCV in family members of subjects with undetectable HCV-RNA in serum was more frequently than in family members of patients with detectable HCV-RNA."
we'll have to wait and see...
Jim: I'm not sure any published paper has ever argued that occult is "a whole, virulent virus". It may in fact be, though I agree that seems unlikely. The simple truth is that we know very little about whatever it is :
- it shares enough sequence similarity with wild-type that PCRs using standard 5'utr primers detect it
- its proteins (at least ns5 and e2) shares affinity for antibodies to standard viral proteins
- it is capable of infecting other cells in an artificial in-vitro setting
- it can trigger elevated cytokine levels in the host
However it seems more honest and consistent to acknowledge this ignorance than to disregard available data and/or claim we already know the remnants to be benign. Acknowledging we don't yet understand why SVR remains durable in the presence of residual virus seems a good 1st step...
"family members of patients with occult HCV infection show serological markers of HCV infection even more frequently than those of patients with chronic hepatitis C"
Zeuzem, of course, is skeptical
"These data may be interpreted in detail after full publication, but prima facie it seems difficult to understand why immune responses to HCV in family members of subjects with undetectable HCV-RNA in serum was more frequently than in family members of patients with detectable HCV-RNA."
we'll have to wait and see...
Jim: I'm not sure any published paper has ever argued that occult is "a whole, virulent virus". It may in fact be, though I agree that seems unlikely. The simple truth is that we know very little about whatever it is :
- it shares enough sequence similarity with wild-type that PCRs using standard 5'utr primers detect it
- its proteins (at least ns5 and e2) shares affinity for antibodies to standard viral proteins
- it is capable of infecting other cells in an artificial in-vitro setting
- it can trigger elevated cytokine levels in the host
However it seems more honest and consistent to acknowledge this ignorance than to disregard available data and/or claim we already know the remnants to be benign. Acknowledging we don't yet understand why SVR remains durable in the presence of residual virus seems a good 1st step...
Willing said:
" Overall, I've never understood why SVR durability is an argument against low-level viral persistence; the data seems to strongly support both. Every relapser who remains UND by the most sensitive tests for 36 weeks or more knows this... "
My comment: I agree with this statement. I have always felt that SVR is very highly durable, but, that there is still documented persistent HCV virus left in SVR's, that we don't fully understand. The research pretty much confirms this in study after study.
What we do not know is just how dangerous this residual virus might be. It does indeed appear, from several cited examples, that a few individuals have relapsed years after confirmed SVR's, after heavy immuno-suppressive therapy. Yes Jim, I understand that not everyone who receives immuno-suppressive tx relapses, but the fact that some have relapsed, tells me that the exception might just be the rule...but only in extreme circumstance.
What if we really ARE in a somewhat permanent state of viral remission, rather than complete eradication? Are you absolutely certain that this is not the case Jim? Because I do not believe that even the best researchers in the world are sure what is going on. My point is just this: I think we have some open questions and not clearly understood behaviors with this virus, and many researchers continue to try to hone in, and figure out what it all means.
Of course we could all just ASSUME that the virus is completely gone, in spite of research findings, and we could just ASSUME that any possible residual infection, or remission behavior of this virus, is totally benign, and will not cause any future problems....but I personally do not believe that this is a scientifically sound choice to make. I want to have clearer answers, and I really want to know whether a possible 'persistent infection', under the radar so to speak, might have consequences for our immune systems, out long term health, and even our level of infectivity, if there is any infectivity to be concerned about.
I prefer to believe that the real truth will become fully understood as time goes on, and further research is done. I do not want to jump to conclusions on any aspect of this issue. But I still do believe that a few documented cases of legitimate relapse more or less disprove the 'rule' that SVR equals eradication, no matter how rare, AND that these cases beckon us to further study this viral behavion, and the HCV persistence observations, so that we can all be better prepared to deal with the realities, or potential consequences.
Hopefully its all just smoke, and is totally benign, as you often claim....but I will feel much more comfortable after we get a much deeper understanding of what it all means. I won't rehash past observations regarding immunosuppressed relapsers, and fluctuating positive PCR's after SVR, only to disappear again, etc. other than to state that much of what we read about, and see in these cases fit a model of 'remission' much better than eradication.
The virus might behave more like Herpes Zoster, and could possibly go away, only to cause different sorts of damage way down the road. Maybe even just immune system disruption, cytokine storms, etc. We just don't have all the answers yet, in spite of your certainty on the subject. That is something I feel really comfortable betting on! I respect your views nonetheless.
DoubleDose
" Overall, I've never understood why SVR durability is an argument against low-level viral persistence; the data seems to strongly support both. Every relapser who remains UND by the most sensitive tests for 36 weeks or more knows this... "
My comment: I agree with this statement. I have always felt that SVR is very highly durable, but, that there is still documented persistent HCV virus left in SVR's, that we don't fully understand. The research pretty much confirms this in study after study.
What we do not know is just how dangerous this residual virus might be. It does indeed appear, from several cited examples, that a few individuals have relapsed years after confirmed SVR's, after heavy immuno-suppressive therapy. Yes Jim, I understand that not everyone who receives immuno-suppressive tx relapses, but the fact that some have relapsed, tells me that the exception might just be the rule...but only in extreme circumstance.
What if we really ARE in a somewhat permanent state of viral remission, rather than complete eradication? Are you absolutely certain that this is not the case Jim? Because I do not believe that even the best researchers in the world are sure what is going on. My point is just this: I think we have some open questions and not clearly understood behaviors with this virus, and many researchers continue to try to hone in, and figure out what it all means.
Of course we could all just ASSUME that the virus is completely gone, in spite of research findings, and we could just ASSUME that any possible residual infection, or remission behavior of this virus, is totally benign, and will not cause any future problems....but I personally do not believe that this is a scientifically sound choice to make. I want to have clearer answers, and I really want to know whether a possible 'persistent infection', under the radar so to speak, might have consequences for our immune systems, out long term health, and even our level of infectivity, if there is any infectivity to be concerned about.
I prefer to believe that the real truth will become fully understood as time goes on, and further research is done. I do not want to jump to conclusions on any aspect of this issue. But I still do believe that a few documented cases of legitimate relapse more or less disprove the 'rule' that SVR equals eradication, no matter how rare, AND that these cases beckon us to further study this viral behavion, and the HCV persistence observations, so that we can all be better prepared to deal with the realities, or potential consequences.
Hopefully its all just smoke, and is totally benign, as you often claim....but I will feel much more comfortable after we get a much deeper understanding of what it all means. I won't rehash past observations regarding immunosuppressed relapsers, and fluctuating positive PCR's after SVR, only to disappear again, etc. other than to state that much of what we read about, and see in these cases fit a model of 'remission' much better than eradication.
The virus might behave more like Herpes Zoster, and could possibly go away, only to cause different sorts of damage way down the road. Maybe even just immune system disruption, cytokine storms, etc. We just don't have all the answers yet, in spite of your certainty on the subject. That is something I feel really comfortable betting on! I respect your views nonetheless.
DoubleDose
Overall, I've never understood why SVR durability is an argument against low-level viral persistence;
----------------
because, if the low-level virus is found in the occult studies was truly a whole, virulent virus, then why wouldn't it keep replicating to the point where one would have a full-blown relapse. If the argument is that it's the immune system preventing this, then why doesn't this happen more often in immune compromised individuals? it seems to me at least that it's because what they're seeing is not the same kind of virus that gave us HCV in the 1st place. perhaps just some sort of lesser remnant.
----------------
because, if the low-level virus is found in the occult studies was truly a whole, virulent virus, then why wouldn't it keep replicating to the point where one would have a full-blown relapse. If the argument is that it's the immune system preventing this, then why doesn't this happen more often in immune compromised individuals? it seems to me at least that it's because what they're seeing is not the same kind of virus that gave us HCV in the 1st place. perhaps just some sort of lesser remnant.
It's a bit hard to understand why a 36 month late relapse (after the 24w check period) is more significant than a 15 month late relapse, particularly when the additional note
" the reappearance of HCV RNA occurred 3 months after two treatments with steroid bolus therapy for severe rejection"
clearly suggests virus was present but maintained UND by a functioning immune system. Nevertheless, here's another:
"SUSTAINED VIROLOGIC RESPONSE AFTER PEGINTERFERON ALFA-2B AND RIBAVIRIN TREATMENT PREDICTS LONG-TERM CLEARANCE OF HCV AT 5-YEAR FOLLOW-UP"
abstract 804 by Manns et al from the 08 EASLD (available at J. of Hepatology site)
Of 366 SVRs from PEG/RBV tx followed for 5 years:
" Four SRs relapsed during the 5-year follow-up period (2 at year 1, 1 at year 2, and 1 at year 5)"
This is ref 150 in the Zeuzem survey cited above. Their table 2 gives a comprehensive list of data in the area. The criticisms of Pradat are legitimate but I believe are intrinsic to follow ups in the general population where it is essentially impossible to distinguish late relapse from re-infection, check for false positives, etc. Data that indicates causality between immuno-suppression and late relapse, as in the case above or a similar one:
http://www.ncbi.nlm.nih.gov/pubmed/18626242
argues pretty convincingly to my mind that SVR, notwithstanding undisputed durability, does not always equate to eradication.
Thanks for the link to the Hafon letter exchange - when I get a bit of time I want to go through the duelling PCR details - the discrepancies are frustrating! A similar exchange is a Pham Michalak letter in response to the Bernandin study finding no HCV in PBMCs.
http://www.ncbi.nlm.nih.gov/pubmed/18537176
among other things they criticised the Bernandin authors for omission of mitogen stimulation:
"a brief culture of PBMCs with mitogens and cytokines that activated immune cells facilitated HCV RNA detection in as much as 75% of initially HCV-negative cases.[7] Further, in up to 20% of cases, the HCV genome can be found in stimulated PBMCs but not in parallel serum. The simultaneous detection of an HCV RNA replicative strand, HCV protein, and unique HCV variants served to authenticate active virus replication in PBMCs, irrespective of serum HCV RNA status, as our recent study reassured.[6] The above approach to HCV RNA identification was not employed by Bernardin and colleagues.[1] Thus, as they alluded, it remains a distinct possibility that ex vivo stimulation of PBMCs might have augmented HCV detection in their study."
tellingly, the authors in their response, don't dispute the point:
"We clearly acknowledged[1] that in chronically viremic subjects, PBMCs could be a site of HCV replication and that in vitro mitogen plus cytokine treatment might increase PBMC-associated HCV levels.[8-10]"
also the lymphocytes in the MacParland paper were paper were T cells, not macrophages. Mitogen stimulation is basically an augmentation technique which after all is what a PCR is; it may not reflect in-vivo conditions but enables detection of trace levels.
Overall, I've never understood why SVR durability is an argument against low-level viral persistence; the data seems to strongly support both. Every relapser who remains UND by the most sensitive tests for 36 weeks or more knows this...
" the reappearance of HCV RNA occurred 3 months after two treatments with steroid bolus therapy for severe rejection"
clearly suggests virus was present but maintained UND by a functioning immune system. Nevertheless, here's another:
"SUSTAINED VIROLOGIC RESPONSE AFTER PEGINTERFERON ALFA-2B AND RIBAVIRIN TREATMENT PREDICTS LONG-TERM CLEARANCE OF HCV AT 5-YEAR FOLLOW-UP"
abstract 804 by Manns et al from the 08 EASLD (available at J. of Hepatology site)
Of 366 SVRs from PEG/RBV tx followed for 5 years:
" Four SRs relapsed during the 5-year follow-up period (2 at year 1, 1 at year 2, and 1 at year 5)"
This is ref 150 in the Zeuzem survey cited above. Their table 2 gives a comprehensive list of data in the area. The criticisms of Pradat are legitimate but I believe are intrinsic to follow ups in the general population where it is essentially impossible to distinguish late relapse from re-infection, check for false positives, etc. Data that indicates causality between immuno-suppression and late relapse, as in the case above or a similar one:
http://www.ncbi.nlm.nih.gov/pubmed/18626242
argues pretty convincingly to my mind that SVR, notwithstanding undisputed durability, does not always equate to eradication.
Thanks for the link to the Hafon letter exchange - when I get a bit of time I want to go through the duelling PCR details - the discrepancies are frustrating! A similar exchange is a Pham Michalak letter in response to the Bernandin study finding no HCV in PBMCs.
http://www.ncbi.nlm.nih.gov/pubmed/18537176
among other things they criticised the Bernandin authors for omission of mitogen stimulation:
"a brief culture of PBMCs with mitogens and cytokines that activated immune cells facilitated HCV RNA detection in as much as 75% of initially HCV-negative cases.[7] Further, in up to 20% of cases, the HCV genome can be found in stimulated PBMCs but not in parallel serum. The simultaneous detection of an HCV RNA replicative strand, HCV protein, and unique HCV variants served to authenticate active virus replication in PBMCs, irrespective of serum HCV RNA status, as our recent study reassured.[6] The above approach to HCV RNA identification was not employed by Bernardin and colleagues.[1] Thus, as they alluded, it remains a distinct possibility that ex vivo stimulation of PBMCs might have augmented HCV detection in their study."
tellingly, the authors in their response, don't dispute the point:
"We clearly acknowledged[1] that in chronically viremic subjects, PBMCs could be a site of HCV replication and that in vitro mitogen plus cytokine treatment might increase PBMC-associated HCV levels.[8-10]"
also the lymphocytes in the MacParland paper were paper were T cells, not macrophages. Mitogen stimulation is basically an augmentation technique which after all is what a PCR is; it may not reflect in-vivo conditions but enables detection of trace levels.
Overall, I've never understood why SVR durability is an argument against low-level viral persistence; the data seems to strongly support both. Every relapser who remains UND by the most sensitive tests for 36 weeks or more knows this...
the quote attributed above to ML, above, should have been abbreviated as such:
" We just don't see the results we would expect to see if so many people who have treated successfully (SVR) worldwide were actually still infected." Fortunately, we live in the real world and not in a Petri dish.
" We just don't see the results we would expect to see if so many people who have treated successfully (SVR) worldwide were actually still infected." Fortunately, we live in the real world and not in a Petri dish.
That's an important point about test tube results versus real world relevance.
As technology advances, motivated scientists will be able to find and discover things unseen before.
Who knows what remnants the human body harbors when you get beyond the cellular level and keep looking and looking. It may turn out that everybody has some remnant of HCV (or most every other disease) if you magnify and extrapolate enough. But again, what is the clinical relevance?
What we do know is what you just said " We just don't see the results we would expect to see if so many people who have treated successfully (SVR) worldwide were actually still infected. Fortunately, we live in the real world and not in a Petri dish." This is not to diminish the importance of these studies, just a comment on their relevancy in terms of the real world concerns many have expressed in this thread.
Hope all is good in your part of the world as well.
- Jim
As technology advances, motivated scientists will be able to find and discover things unseen before.
Who knows what remnants the human body harbors when you get beyond the cellular level and keep looking and looking. It may turn out that everybody has some remnant of HCV (or most every other disease) if you magnify and extrapolate enough. But again, what is the clinical relevance?
What we do know is what you just said " We just don't see the results we would expect to see if so many people who have treated successfully (SVR) worldwide were actually still infected. Fortunately, we live in the real world and not in a Petri dish." This is not to diminish the importance of these studies, just a comment on their relevancy in terms of the real world concerns many have expressed in this thread.
Hope all is good in your part of the world as well.
- Jim
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