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Two-Day Results Predict Ultimate Response to Therapy in Chronic Hepatitis C
by jmjm530, Mar 21, 2009 07:09PM
Two-Day Results Predict Ultimate Response to Therapy in Chronic Hepatitis C
A new study suggests that previously noted low rates of successful hepatitis C virus (HCV) therapy in African Americans are in large part due to very early differences in the antiviral activity induced by interferon. The study is published in the April 15 issue of The Journal of Infectious Diseases, now available online.
More than 3 million Americans are infected with HCV, and in some countries more than 10 percent of the population is infected. Chronic HCV infection is the leading cause of liver failure worldwide. Response to standard therapy with peginterferon and ribavirin varies widely. Those infected with one strain of the virus—genotype 1—are the least likely to have a successful response to therapy, known as a sustained virological response (SVR). About one-half of patients infected with genotype 1 do not achieve SVR.
Studies have shown that African Americans have consistently lower rates of SVR to interferon-based therapy, compared to Caucasian Americans. A recent study of those with chronic genotype 1 HCV infection found that only 28 percent of African American patients attained SVR, compared with 52 percent in Caucasian Americans. This new study shows that the variation in therapy responsiveness between African Americans and Caucasian Americans can be partly explained by differences in viral response noted as early as one to two days after the first dose of peginterferon.
The study, conducted by a collaborative group of eight medical centers throughout the United States, monitored 341 patients with chronic HCV, genotype 1, who underwent therapy with peginterferon and ribavirin for at least 24 weeks. It focused on response rates to interferon therapy within the first 28 days of therapy, noting viral factors such as HCV RNA levels and host factors such as race, gender, and weight.
Results showed that HCV RNA levels decreased in almost all patients, and that the degree and pattern of decrease, as expected, was different between African and Caucasian Americans. Most important was the new finding that these differences were statistically significant by day 2 of treatment, and that this early viral kinetic measurement was a reliable predictor of ultimate SVR rates. After 28 days of treatment, 22 percent of Caucasian Americans, but only 12 percent of African Americans, were HCV RNA negative.
These findings are particularly important because they point toward the presence of some block or defect in the immediate antiviral response of those who do not respond to therapy. As the authors summarize, “The underlying cause of virological non-response and the reasons why it is more common among African Americans than Caucasian Americans are not clear. [But] the current analyses demonstrated that these differences are fundamentally biologic and become apparent within 24 to 48 hours of starting therapy.” As a next step, future research should focus on these host biologic factors that are induced by interferon in an attempt to improve therapy response rates.
In an accompanying editorial, Andrew W. Tai, MD, PhD, and Raymond T. Chung, MD, of Massachusetts General Hospital agree that the findings will prove vital for future research into HCV, remarking, “[this study] demonstrates that the low rates of SVR in African American patients in response to IFN-based therapy appear to result, in large part, from impaired early viral kinetics. Further studies are necessary to uncover the relevant mechanisms that underlie this defect in IFN signaling… with the hope that such mechanisms can be manipulated to restore interferon responsiveness in the otherwise nonresponsive host.”
###
Founded in 1904, The Journal of Infectious Diseases is the premier publication in the Western Hemisphere for original research on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune mechanisms. Articles in JID include research results from microbiology, immunology, epidemiology, and related disciplines. JID is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 8,600 physicians and scientists who specialize in infectious diseases. For more information, visit www.idsociety.org.
http://www.idsociety.org/Content.aspx?id=13720
A new study suggests that previously noted low rates of successful hepatitis C virus (HCV) therapy in African Americans are in large part due to very early differences in the antiviral activity induced by interferon. The study is published in the April 15 issue of The Journal of Infectious Diseases, now available online.
More than 3 million Americans are infected with HCV, and in some countries more than 10 percent of the population is infected. Chronic HCV infection is the leading cause of liver failure worldwide. Response to standard therapy with peginterferon and ribavirin varies widely. Those infected with one strain of the virus—genotype 1—are the least likely to have a successful response to therapy, known as a sustained virological response (SVR). About one-half of patients infected with genotype 1 do not achieve SVR.
Studies have shown that African Americans have consistently lower rates of SVR to interferon-based therapy, compared to Caucasian Americans. A recent study of those with chronic genotype 1 HCV infection found that only 28 percent of African American patients attained SVR, compared with 52 percent in Caucasian Americans. This new study shows that the variation in therapy responsiveness between African Americans and Caucasian Americans can be partly explained by differences in viral response noted as early as one to two days after the first dose of peginterferon.
The study, conducted by a collaborative group of eight medical centers throughout the United States, monitored 341 patients with chronic HCV, genotype 1, who underwent therapy with peginterferon and ribavirin for at least 24 weeks. It focused on response rates to interferon therapy within the first 28 days of therapy, noting viral factors such as HCV RNA levels and host factors such as race, gender, and weight.
Results showed that HCV RNA levels decreased in almost all patients, and that the degree and pattern of decrease, as expected, was different between African and Caucasian Americans. Most important was the new finding that these differences were statistically significant by day 2 of treatment, and that this early viral kinetic measurement was a reliable predictor of ultimate SVR rates. After 28 days of treatment, 22 percent of Caucasian Americans, but only 12 percent of African Americans, were HCV RNA negative.
These findings are particularly important because they point toward the presence of some block or defect in the immediate antiviral response of those who do not respond to therapy. As the authors summarize, “The underlying cause of virological non-response and the reasons why it is more common among African Americans than Caucasian Americans are not clear. [But] the current analyses demonstrated that these differences are fundamentally biologic and become apparent within 24 to 48 hours of starting therapy.” As a next step, future research should focus on these host biologic factors that are induced by interferon in an attempt to improve therapy response rates.
In an accompanying editorial, Andrew W. Tai, MD, PhD, and Raymond T. Chung, MD, of Massachusetts General Hospital agree that the findings will prove vital for future research into HCV, remarking, “[this study] demonstrates that the low rates of SVR in African American patients in response to IFN-based therapy appear to result, in large part, from impaired early viral kinetics. Further studies are necessary to uncover the relevant mechanisms that underlie this defect in IFN signaling… with the hope that such mechanisms can be manipulated to restore interferon responsiveness in the otherwise nonresponsive host.”
###
Founded in 1904, The Journal of Infectious Diseases is the premier publication in the Western Hemisphere for original research on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune mechanisms. Articles in JID include research results from microbiology, immunology, epidemiology, and related disciplines. JID is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 8,600 physicians and scientists who specialize in infectious diseases. For more information, visit www.idsociety.org.
http://www.idsociety.org/Content.aspx?id=13720
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http://www.journals.uchicago.edu/doi/pdf/10.1086/597385
how dare you keep relevant info from your members!
bandman
-----------
Maybe the phrase above is what disturbs you? I was not talking about a post being "screened out", I was talking about IR/diabetes screened out of the study. In other words did the study screen out IR/diabetes as an active factor in the study. You will note that in my next post I mention that apparently that is not the case and posted the full-text. I think you had best read a little more carefully or ask for clarification before jumping down someone's throat.
all i did was post
www.nih.gov/about/researchresultsforthepublic/Type2Diabetes.pdf
saying that this was common knowlege.
I jumped to conclusions and assumed that you had my post deleted. I apologize.
I don't have to report this to MH because apparently he already knows.... someone is taking down posts as soon as they go up. you may not even have time to read this! lol.
they already took down Cocksparrows thread.
I thought I would give this site another chance , but apparently freedom of speech is not tolerated here
sad.
bandman has left the building.
Now they'll have something more specific to focus on, this peculiar response...and research into it may prove of benefit to us all.
I hope Jim you'll keep us posted on what studies follow up this finding....it could be an important key in unlocking a better immune response.
mb
Thanks for posting this... I am quite sure that I did not RVR because of my partial African American descent. I hope that extending treatment will have done it's job. We'll see in ca 5 weeks.
Ended up extending according to formula 8 + 24 = 32
baja
-- Jim
Actually you are one of the people who has given me loads of knowledge and good advice since I joined the forum... I will always be grateful for that!
Again, we are stepping in the dark, no wonder the 'look'
Be well,
-- Jim
It might make sense anyway, as the whole population is not only based on African Americans and Caucasians... They don't mention Asians. Asians seem to have better SVR rates than Caucasians.... And then % wise, there are more Caucasians than African Americans, so it is not 50 / 50, if you guys know what I mean. I'm not very good at expressing myself these days, as tx seems to be making me more and more stupid...
JM: never thought you were being "argumentative"
RG: I was just making sure I was not coming across "argumentative"
-------------------------------
JM: Like I say, you're not, but if you want to argue the point.
JM: never thought you were being "argumentative"
RG: I was just making sure I was not coming across "argumentative"
-------------------------------
JM: Like I say, you're not, but if you want to argue the point.
RG I SAID I AM NOT BEING "ARGUMENTATIVE"
JM: never thought you were being "argumentative"
RG: I was just making sure I was not coming across "argumentative"
-------------------------------
JM: Like I say, you're not, but if you want to argue the point.
RG I SAID I AM NOT BEING "ARGUMENTATIVE"
JM: I'M AFRAID I NOW HAVE TO ARGUE THE POINT.BUT REFRESH MY MEMORY WHAT WAS THE POINT?
JM: never thought you were being "argumentative"
RG: I was just making sure I was not coming across "argumentative"
-------------------------------
JM: Like I say, you're not, but if you want to argue the point.
RG I SAID I AM NOT BEING "ARGUMENTATIVE"
JM: I'M AFRAID I NOW HAVE TO ARGUE THE POINT.BUT REFRESH MY MEMORY WHAT WAS THE POINT?
RG The point now is irrelevant. I lift the White Flag and you when the "Argument."
I have to get ready for work now. I am starting to feel guilty doing this when I can go to work and get paid for it.
I've written on this topic here before and that is indeed the reason. In fact, the participation rate of Afro-Americans in clinical trials is extremely low and as such doesn't skew numbers in any significant way.
For an explanation for low enrollee rates in clinical trials by Afro-Americans Google "Tuskegee Experiments".
ML
http://www.cancer.gov/newscenter/benchmarks-vol6-issue4/page1
Hope this finds you well.
-- Jim
Mike
For the record, I don't believe I have ever responded to a post of yours with cynicism, or even skepticism. Not that I wouldn't if I had reason to. lol ;)
It's been shown that socio-economic factors are directly correlated to HCV infection for all ethnicities. I can't remember all of the stats but those with HCV are in general poorer, less educated, more likely to abuse substances, and come from dysfunctional families significantly greater than the population-at-large.
I'm not sure how these facts would influence minorities more than caucasians when it comes to enrolling in HCV trials. It is somewhat counter-intuitive that those with the least amount of medical care and financial resources wouldn't take advantage of the free medicines and monitoring that a trial offers.
Many African-Americans that I have interacted with over the years concerning HCV have expressed horror at even the simple mention of enrolling in a trial. Some remember Tuskegee----or have been raised by those who do and the spectre of a trial (especially one funded or controlled with the help of the US gov't) has produced a lingering fear that is a quantifiable cultural phenomenon. I have known a researcher with SP for years. She helps to develop trials and has often mentioned over the years how hard it is to get minority participation especially amongst African-Americans, this despite earnest attempts to recruit this population. As a company that sells medicine they would love to have much more data on a segment of the population with high prevalence rates.
It's my belief that the lack of data pertaining to the HCV tx of African-Americans can only be overcome by allaying the fears and sense of mistrust of those who remember Tuskegee or waiting until the clouds of time obscure their collective memory.
I can't believe we did this to US citizens while at the same time we were trying to hunt down Mengele. (Gratuitous cynical remark) ;)
Jim its always nice to see you post and I too hope all is well where you are.
ML
.
ML
Other than the Tuskegee Horror, to help reconcile the "counter-intuitive" nature of minority participation, I do remember a study/survey -- something -- a year or so ago that showed that minorities were more apt to be sent home from the ER as opposed to non-minorities who might have been given a hospital bed and therefore more enhanced care. And for the same diagnosis. So I do wonder if perhaps a prejudice, subconscious or not, exists within the medical community that may give preferential trial assignments to non-minorities.
Another factor no doubt is that because Afro Americans have a significantly lower SVR rate, many trials may have excluded them on that basis because the results would be skewed differently.
-- Jim
http://www.ncbi.nlm.nih.gov/pubmed/18467494
By collecting bx tissue four hours after the 1st ifn injection and analyzing expression levels of ifn-stimulated genes in liver cells they were able to clearly distinguish rapid responders from non-RRs (See Figure 4 on the 3rd page of the paper).
Of course there's also a growing number of tests that will tell you *before* that 1st shot, but that seems like cheating.
Now think about it. You do the four-hour or 24-hour test on regimen 1. The result is not very promising, so you stop treatment. Maybe wait a month and then try ad different combo of drugs, regiment number 2. Still not promising. You wait another month and now try regiment number 3. Voila. You found the magic coctail for this particular indivdual. Of course this would mean that docs and their busy offices would actually have to think and plan as opposed to write rx and quickly hand-off patients to nurses running a mill. Still...
http://www.ncbi.nlm.nih.gov/pubmed/18467494
is that it did not base predictions on vl drop but on analysis of changes in gene expression 4 hours after the shot. There have been a lot of papers along the lines of
http://www.ncbi.nlm.nih.gov/pubmed/19291180
by Neumann, Perelson and others showing a correlation between the steepness of early vl drop and outcome, but the above is something new. The flip side of this is
http://www.ncbi.nlm.nih.gov/pubmed/19104147
which predicts tx success by looking at the changes the virus is/is-not able to make. Correlating the list of human genes predictive of outcome in Sarasin-Filipowicz with the viral genes whose changes are predictive of outcome in Aurora'09 should give some pretty good clues - sort of like getting to see all the cards in a poker tournament..