Aa
SVR persons:Persistence of HCV After Successful Treatment of Chronic Hepatitis C: Is HCV Infection for Life?
Persistence of HCV After Successful Treatment of Chronic Hepatitis C: Is HCV Infection for Life?
It is presumed that resolution of hepatitis C reflects virus eradication, as evidenced by normalization of liver function tests and disappearance of hepatitis C virus (HCV) RNA from serum, as determined by conventional laboratory assays.
In this study, researchers in Poland examined the expression of the HCV genome in the sera, peripheral blood mononuclear cells (PBMC), and, on some occasions, monocyte-derived dendritic cells (DC) long after resolution of hepatitis C by using a highly sensitive reverse transcription (RT)-polymerase chain reaction-nucleic acid hybridization (RT-PCR-NAH) assay.
The samples obtained from 16 randomly selected patients (5 with spontaneous resolution and 11 with treatment-induced resolution), monitored for up to 5 years, were studied by qualitative and semi-quantitative RT-PCR-NAH and by real-time RT-PCR to detect the HCV RNA positive strand.
The replicative HCV RNA negative strand was examined in PBMC after culture with a T cell proliferation stimulating mitogen.
Results
The findings show that HCV RNA was carried in the convalescent-phase sera and/or PBMC in all 16 individuals investigated.
Also, DC from six of seven patients were reactive for the HCV genome. 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.
Sequencing of the HCV 5' untranslated region fragment revealed genotype 1b in four of nine individuals examined and genotypes 1a and 2a in three and two patients, respectively.
In conclusion, these results imply that HCV RNA can persist at very low levels in the serum and peripheral lymphoid cells and that an intermediate replicative form of the HCV genome can persist in PBMC for many years after apparently complete spontaneous or antiviral therapy-induced resolution of chronic hepatitis C.
Warsaw Medical Academy, Poland.
It is presumed that resolution of hepatitis C reflects virus eradication, as evidenced by normalization of liver function tests and disappearance of hepatitis C virus (HCV) RNA from serum, as determined by conventional laboratory assays.
In this study, researchers in Poland examined the expression of the HCV genome in the sera, peripheral blood mononuclear cells (PBMC), and, on some occasions, monocyte-derived dendritic cells (DC) long after resolution of hepatitis C by using a highly sensitive reverse transcription (RT)-polymerase chain reaction-nucleic acid hybridization (RT-PCR-NAH) assay.
The samples obtained from 16 randomly selected patients (5 with spontaneous resolution and 11 with treatment-induced resolution), monitored for up to 5 years, were studied by qualitative and semi-quantitative RT-PCR-NAH and by real-time RT-PCR to detect the HCV RNA positive strand.
The replicative HCV RNA negative strand was examined in PBMC after culture with a T cell proliferation stimulating mitogen.
Results
The findings show that HCV RNA was carried in the convalescent-phase sera and/or PBMC in all 16 individuals investigated.
Also, DC from six of seven patients were reactive for the HCV genome. 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.
Sequencing of the HCV 5' untranslated region fragment revealed genotype 1b in four of nine individuals examined and genotypes 1a and 2a in three and two patients, respectively.
In conclusion, these results imply that HCV RNA can persist at very low levels in the serum and peripheral lymphoid cells and that an intermediate replicative form of the HCV genome can persist in PBMC for many years after apparently complete spontaneous or antiviral therapy-induced resolution of chronic hepatitis C.
Warsaw Medical Academy, Poland.
I did get the article and I thank you so much for sending it to me. I will study it carefully and, if you have no objection, I will forward it to my surgeon, although it is quite possible he's already seen it. If I or he has any additional insight I will post it here and email it to you but it may take me a while to digest it. Again Willing, thank you very much. It is rather curious that a thread that started like this one evolved to this level. It has me in a state of wonderment. Mike
Mike - I emailed you the pdf, let me know if it doesn't show up. I wouldn't say there was anything worrisome about this find and I'm also curious to hear any thoughts others have on the topic. It just seems like another insight into the strange and amazingly flexible survival stragegies of this virus. The authors speculate that the function of the missing proteins is rescued by a low background level of full-length virus detected in cells but not in serum:
"The long-term stable detection of HCV subgenomes in
plasma reported here may therefore reflect the occasional
generation of intracellular replicons whose deleted structural
functions, including envelope glycoproteins, can be provided
by trans-complementation in cells co-infected with wild-type
helper HCV. Resulting subgenome RNA containing particles
released into the bloodstream from co-infected cells would be
competent for cell entry and further RNA replication into new
target cells thereby amplifying truncated genomes and sustaining
the high and chronic plasma levels seen here."
what I don't get is that if (1) only the truncated sub-genome particles are circulating in plasma, (2) these are capable of cell entry but (3) need to enter a cell co-infected with full-length, wild-type, to make up the functionality of the "missing" proteins necessary for replication (glycoprotein coat etc.) then
*how are the full-length wild-type virions getting from cell to cell?*
the observation seems to (indirectly) confirm plasma UND replication of the wild-type virus, though the authors don't actually say this. The other interesting item about the article, which was news to me, is that such sub-genomic virions have been previously reported among quite a few other viral species (west-nile, dengue, etc.)
"The long-term stable detection of HCV subgenomes in
plasma reported here may therefore reflect the occasional
generation of intracellular replicons whose deleted structural
functions, including envelope glycoproteins, can be provided
by trans-complementation in cells co-infected with wild-type
helper HCV. Resulting subgenome RNA containing particles
released into the bloodstream from co-infected cells would be
competent for cell entry and further RNA replication into new
target cells thereby amplifying truncated genomes and sustaining
the high and chronic plasma levels seen here."
what I don't get is that if (1) only the truncated sub-genome particles are circulating in plasma, (2) these are capable of cell entry but (3) need to enter a cell co-infected with full-length, wild-type, to make up the functionality of the "missing" proteins necessary for replication (glycoprotein coat etc.) then
*how are the full-length wild-type virions getting from cell to cell?*
the observation seems to (indirectly) confirm plasma UND replication of the wild-type virus, though the authors don't actually say this. The other interesting item about the article, which was news to me, is that such sub-genomic virions have been previously reported among quite a few other viral species (west-nile, dengue, etc.)
Thanks for the links. My credit card has been compromised despite the fact that I always use virtual numbers online and cash everywhere else so I can not buy the article right now. I am interested very much in reading the rest of it and seeing if anything there applies to me. I assume that if it's bad it will apply but that may be due to my heavily jaundiced viewpoint. Do you have any further ideas about this persistence? I would love to hear anything you are thinking. Mike
whoa, Mike, you're on a roll today! Those following the ongoing saga of persistent, post-SVR, HCV infection might also be interested in a recent sudy
http://tinyurl.com/24u4r7
by Bernandin et al. They tracked individuals who had no hcv antibodies but chronic and high HCV serum levels, sequenced the HCV RNA and found that though the 5' end of the genome, which includes the short, highly conserved, stretch used for commercial HCV RNA VL tests was largely identical to that of "standard" HCV genomes , there were *large* chunks (~2000 bases) missing, from the 3' region.
The implication here is such fragmented HCV virions are functional enough to happily reproduce in the body, but somehow escape detection by the immune system (or at least antibody production). Since damage to the liver is not caused by the virus but by the body's attempt to elimninate it, these guys were also quite healthy with normal ALTs. As far as I know this is the first evidence for persistence of not fully functional hcv genomes. It's been speculated that the HCV RNA detected by Pham, Radkowski, Castillo, etc. in the cell tissue of serum UND individuals etc. could be associated with replicating but non-viable virus. Hopefully someone will get around to sequencing this persistent HCV RNA in the near future...
PS
another recent study showing that serum VL, though predictive of SVR, doesn't seem to be strongly correlated with anything else..
http://tinyurl.com/2ma4fl
http://tinyurl.com/24u4r7
by Bernandin et al. They tracked individuals who had no hcv antibodies but chronic and high HCV serum levels, sequenced the HCV RNA and found that though the 5' end of the genome, which includes the short, highly conserved, stretch used for commercial HCV RNA VL tests was largely identical to that of "standard" HCV genomes , there were *large* chunks (~2000 bases) missing, from the 3' region.
The implication here is such fragmented HCV virions are functional enough to happily reproduce in the body, but somehow escape detection by the immune system (or at least antibody production). Since damage to the liver is not caused by the virus but by the body's attempt to elimninate it, these guys were also quite healthy with normal ALTs. As far as I know this is the first evidence for persistence of not fully functional hcv genomes. It's been speculated that the HCV RNA detected by Pham, Radkowski, Castillo, etc. in the cell tissue of serum UND individuals etc. could be associated with replicating but non-viable virus. Hopefully someone will get around to sequencing this persistent HCV RNA in the near future...
PS
another recent study showing that serum VL, though predictive of SVR, doesn't seem to be strongly correlated with anything else..
http://tinyurl.com/2ma4fl
YOU GO GUY!!!!!!!!!!!!!!!!!!!!!!!!!!!! Woooooooo WHOOOOOOOO!!!!!!
When they realise that they are dummer than most of us here, maybe they will shut up.
Keep it up, I am still laughing.
Cajun
When they realise that they are dummer than most of us here, maybe they will shut up.
Keep it up, I am still laughing.
Cajun
Final ID: 393
A Prospective, Double-Blinded Neuropsychiatric Comparison of Pegylated Interferons Alfa-2a and Alfa-2b
D. Sylvestre; 1, 2; A. Smith; 2; L. Barrett; 2; D. Greene; 2;
1. University of CA, San Francisco, Oakland, CA, USA.
2. OASIS, Oakland, CA, USA.
Abstract Body: Background: Inter-study evidence using interferon alfa as a standard suggests that pegylated interferons alfa-2a (PI2a) and alfa-2b (PI2b) may have different neuropsychiatric toxicity profiles. Because of its potential importance to the many HCV-infected patients with comorbid mental illness, we conducted a prospective, double-blinded pilot study of PI2a vs. PI2b in patients undergoing treatment for HCV. Endpoints included psychiatric discontinuations; initiation and adjustment of psychiatric medications; monthly Beck Depression Inventory (BDI) and SF-36 Quality of Life scores, and self-reported depression (D), anxiety (A), and irritability (I).
Methods: 40 patients were randomized to treatment with ribavirin and either PI2a or PI2b at standard dosing. Selfreported D, A, and I scored on a 0-10 scale were recorded weekly. The BDI and SF-36 were administered every 4 weeks.
Results: 39 subjects initiated treatment and 1 was discontinued due to inadvertent unblinding. The average age was 48, 23 (57%) were male, and 27 (67%) had genotype 1. None of these measures differed between the cohorts. 15 in
each cohort (75%) reported a pre-existing psychiatric diagnosis. 26 were taking a psychiatric medication at treatment initiation, 12 (67%) in the PI2a cohort and 14 (70%) in the PI2b cohort (p=0.55).27 (71%) completed treatment and there were 11 (29%) discontinuations. 4 patients had psychiatric discontinuations,
1 taking PI2a and 3 taking PI2b (p=0.32). New psychiatric medications were initiated in 9 (50%) taking PI2a and 14(70%) taking PI2b (p=0.18), and they were adjusted in 12 (67%) taking PI2a and 15 (75%) taking PI2b (p=0.41). BDI, SF-36, and self-reported depression, anxiety, and irritability scores were not statistically different at baseline, nor were there significant differences when analyzed on a monthly basis. However, the PI2b cohort had a significantly higher cumulative BDI score, 16.3 vs 13.1 (p=0.01), and a lower SF-36 score, 40.8 vs 48.5 (p=0.004). Additionally, those taking PI2b reported significantly higher overall depression, 2.4 vs 2.1 (p=0.04), and anxiety, 2.8 vs 2.2 (p <0.001), but
not irritability, 2.9 vs 2.7 (p=0.32).
Conclusion: This small but rigorous study provides the first direct evidence that PI2a and PI2b may elicit small but measurable differences in depression, anxiety, and quality of life during HCV treatment. It is unclear, however,
whether these will translate to meaningful differences in major neuropsychiatric outcomes. A larger study is needed to assess the magnitude of the differences in the psychiatric toxicity profiles of these medications and to assess any impact on HCV outcomes.
A Prospective, Double-Blinded Neuropsychiatric Comparison of Pegylated Interferons Alfa-2a and Alfa-2b
D. Sylvestre; 1, 2; A. Smith; 2; L. Barrett; 2; D. Greene; 2;
1. University of CA, San Francisco, Oakland, CA, USA.
2. OASIS, Oakland, CA, USA.
Abstract Body: Background: Inter-study evidence using interferon alfa as a standard suggests that pegylated interferons alfa-2a (PI2a) and alfa-2b (PI2b) may have different neuropsychiatric toxicity profiles. Because of its potential importance to the many HCV-infected patients with comorbid mental illness, we conducted a prospective, double-blinded pilot study of PI2a vs. PI2b in patients undergoing treatment for HCV. Endpoints included psychiatric discontinuations; initiation and adjustment of psychiatric medications; monthly Beck Depression Inventory (BDI) and SF-36 Quality of Life scores, and self-reported depression (D), anxiety (A), and irritability (I).
Methods: 40 patients were randomized to treatment with ribavirin and either PI2a or PI2b at standard dosing. Selfreported D, A, and I scored on a 0-10 scale were recorded weekly. The BDI and SF-36 were administered every 4 weeks.
Results: 39 subjects initiated treatment and 1 was discontinued due to inadvertent unblinding. The average age was 48, 23 (57%) were male, and 27 (67%) had genotype 1. None of these measures differed between the cohorts. 15 in
each cohort (75%) reported a pre-existing psychiatric diagnosis. 26 were taking a psychiatric medication at treatment initiation, 12 (67%) in the PI2a cohort and 14 (70%) in the PI2b cohort (p=0.55).27 (71%) completed treatment and there were 11 (29%) discontinuations. 4 patients had psychiatric discontinuations,
1 taking PI2a and 3 taking PI2b (p=0.32). New psychiatric medications were initiated in 9 (50%) taking PI2a and 14(70%) taking PI2b (p=0.18), and they were adjusted in 12 (67%) taking PI2a and 15 (75%) taking PI2b (p=0.41). BDI, SF-36, and self-reported depression, anxiety, and irritability scores were not statistically different at baseline, nor were there significant differences when analyzed on a monthly basis. However, the PI2b cohort had a significantly higher cumulative BDI score, 16.3 vs 13.1 (p=0.01), and a lower SF-36 score, 40.8 vs 48.5 (p=0.004). Additionally, those taking PI2b reported significantly higher overall depression, 2.4 vs 2.1 (p=0.04), and anxiety, 2.8 vs 2.2 (p <0.001), but
not irritability, 2.9 vs 2.7 (p=0.32).
Conclusion: This small but rigorous study provides the first direct evidence that PI2a and PI2b may elicit small but measurable differences in depression, anxiety, and quality of life during HCV treatment. It is unclear, however,
whether these will translate to meaningful differences in major neuropsychiatric outcomes. A larger study is needed to assess the magnitude of the differences in the psychiatric toxicity profiles of these medications and to assess any impact on HCV outcomes.
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