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Bi-Phasic Viral Load Declines
So, I went to my week 28 study Wednesday, and my regular hepa was out on vacation, so I got another doc. Nice young guy, seemed very up on the latest in treatment etc. Anyhow, as an aside, still UND at week 28, and my AST/ALT/GGT and other parameters are the lowest they've been in my adult life... in the TEENS. WHOO HOO!
Back to the point.
Being the curious pain in the butt that I am, I kept him after the physical exam by bombarding him with some questions. In particular, I'm still very interested in how the viral load declines as one responds to treatment.
I asked him the same question I asked the other doc "Why does it take so long to get all the virus - are they just harder to kill, the tougher ones left over as time goes on?"
This doc gave me a different perspective. He said UNLESS a particular strain has developed that is resistant, ala a DAA induced type thing, no one virion is really any tougher to kill than another. What he said was that it was more a case of WHERE the virus was located in the body. The last ones to die are the "toughest" to get to, and they just kind of "trickle out" into the bloodstream where they are eliminated.
We all know that in most cases, viral load declines very, very rapidly initially, followed by a much slower decline in a typical response curve. This is called a biphasic decline.
Does the doctor's explanation sound plausible? Seems to me the IFN would be dispersed into every nook and cranny, and it's seems odd to think there is somewhere the virus can "hide" from the drugs.
Opinions?
RBW
Back to the point.
Being the curious pain in the butt that I am, I kept him after the physical exam by bombarding him with some questions. In particular, I'm still very interested in how the viral load declines as one responds to treatment.
I asked him the same question I asked the other doc "Why does it take so long to get all the virus - are they just harder to kill, the tougher ones left over as time goes on?"
This doc gave me a different perspective. He said UNLESS a particular strain has developed that is resistant, ala a DAA induced type thing, no one virion is really any tougher to kill than another. What he said was that it was more a case of WHERE the virus was located in the body. The last ones to die are the "toughest" to get to, and they just kind of "trickle out" into the bloodstream where they are eliminated.
We all know that in most cases, viral load declines very, very rapidly initially, followed by a much slower decline in a typical response curve. This is called a biphasic decline.
Does the doctor's explanation sound plausible? Seems to me the IFN would be dispersed into every nook and cranny, and it's seems odd to think there is somewhere the virus can "hide" from the drugs.
Opinions?
RBW
If I'm not mistaken, replicaion has to occur within a viable cell, and virons can't themselves remain viable indeffinitely - they have to spin off new copies in order to preserve the infection. So it's not as if they could hide in some little cranny forever - if so I don't see how we'd ever see SVR. Just kinda connecting ill-defined dots here.
Good point willing. One thing we forget is that IFN does not attack the virus, as you mentioned, but modulates immune response. Since the virus is many magnitudes of size smaller, perhaps there are places where the virus could hide where the CTL's cannot get.
Makes you wonder how anyone ever achieves SVR.
Bring out the NANOBOTS.
RBW
Makes you wonder how anyone ever achieves SVR.
Bring out the NANOBOTS.
RBW
seems there are really three separate questions here (1) why a two-phase decline? (2) are some virions more resistant than others to soc therapy? (3) are some infected cells less accessible or harder to clear of infection?
1) is the easiest : the two phase decline comes right out of the three differential equations used in modeling hcv kinetics. The original '98 paper
http://www.ncbi.nlm.nih.gov/pubmed/9756471
adapted from HIV models has been refined and extended, mostly recently for DAAs, but the basic ODEs are unchanged. You define functions for viral production, clearance, infectivity, etc., relate them by ODES, and obtain a model for VL fluctuation. In response to an inhibiting drug (soc or DAA) VL follows a two phase decline.
2) the stock answer here seems to be no but if you have the chance you might ask your Dr. about selection of virus that evades class I MHC presentation, The ifn doesn't actually do anything to the virus directly. It stimulates cellular responses that shut down replication and put the stock adaptive/innate immune response into overdrive. As fas as clearing infected cells, the stock tool in adaptive immunity are cytotoxic T cells (CTLs). However these guys can only recognize a cell as infected when it presents bit and pieces of dead virus on its surface via class I MHC molecules. If viral proteins evolve to avoid MHC binding the containing cell will never be detected as infected - stealth virus.
3) since the enforcement side of killling off infected cells depends on other, immune system, cells (such as CTLs) you have to wonder whether such cells can easily diffuse around a liver heavily compromised by scar tissue. I seem to remember HR speculating that this might well account for why cirrhosis presents an additional challenge to SVR.
It was interesting to me that Bali mentioned his Dr. is considering late-stage PI addition for avoiding relapse in a cirrhotic patient. The tiny PI molecules could easily diffuse to tissue where bulkier immune cells might not and would also not be subject to the MHC evasion issues.
1) is the easiest : the two phase decline comes right out of the three differential equations used in modeling hcv kinetics. The original '98 paper
http://www.ncbi.nlm.nih.gov/pubmed/9756471
adapted from HIV models has been refined and extended, mostly recently for DAAs, but the basic ODEs are unchanged. You define functions for viral production, clearance, infectivity, etc., relate them by ODES, and obtain a model for VL fluctuation. In response to an inhibiting drug (soc or DAA) VL follows a two phase decline.
2) the stock answer here seems to be no but if you have the chance you might ask your Dr. about selection of virus that evades class I MHC presentation, The ifn doesn't actually do anything to the virus directly. It stimulates cellular responses that shut down replication and put the stock adaptive/innate immune response into overdrive. As fas as clearing infected cells, the stock tool in adaptive immunity are cytotoxic T cells (CTLs). However these guys can only recognize a cell as infected when it presents bit and pieces of dead virus on its surface via class I MHC molecules. If viral proteins evolve to avoid MHC binding the containing cell will never be detected as infected - stealth virus.
3) since the enforcement side of killling off infected cells depends on other, immune system, cells (such as CTLs) you have to wonder whether such cells can easily diffuse around a liver heavily compromised by scar tissue. I seem to remember HR speculating that this might well account for why cirrhosis presents an additional challenge to SVR.
It was interesting to me that Bali mentioned his Dr. is considering late-stage PI addition for avoiding relapse in a cirrhotic patient. The tiny PI molecules could easily diffuse to tissue where bulkier immune cells might not and would also not be subject to the MHC evasion issues.
Robert, I'm not an engineer but I have this need to understand things and how they work also.
I found this interesting and might have some details that satisfy this one a bit for you.
http://www.clinicaloptions.com/Hepatitis/Annual%20Updates/2009%20Annual%20Update/Modules/Chung/Pages/Page%204.aspx
I found this interesting and might have some details that satisfy this one a bit for you.
http://www.clinicaloptions.com/Hepatitis/Annual%20Updates/2009%20Annual%20Update/Modules/Chung/Pages/Page%204.aspx
i know that this does not answer your original question directly, but it seems that the PIs will be very useful for the relapsers to speed the second phase decline and hopefully get folks like Joe to undetected and keep him there.
Second phase HCV RNA decline during telaprevir based therapy increases with drug effectiveness: Implications for treatment duration
Hepatology. 2011 Mar 7. doi: 10.1002/hep.24272. [Epub ahead of print]
Guedj J, Perelson AS.
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos 87545, USA.
Abstract
Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase decay to the treatment effectiveness, whereas the second phase decay is attributed to the progressive loss of infected cells. Here we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found that the second phase slope of viral decline to be strongly correlated with the treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Since telaprevir is not known to increase the death rate of infected cells, our results suggest the second phase slope of viral decline is driven not only by the death of infected cells but may also involve other mechanisms, such as a treatment effectiveness-dependent degradation of intracellular viral RNA. As a consequence of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended. (HEPATOLOGY 2011.).
Copyright © 2011 American Association for the Study of Liver Diseases.
PMID: 21384401 [PubMed - as supplied by publisher]
Second phase HCV RNA decline during telaprevir based therapy increases with drug effectiveness: Implications for treatment duration
Hepatology. 2011 Mar 7. doi: 10.1002/hep.24272. [Epub ahead of print]
Guedj J, Perelson AS.
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos 87545, USA.
Abstract
Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase decay to the treatment effectiveness, whereas the second phase decay is attributed to the progressive loss of infected cells. Here we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found that the second phase slope of viral decline to be strongly correlated with the treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Since telaprevir is not known to increase the death rate of infected cells, our results suggest the second phase slope of viral decline is driven not only by the death of infected cells but may also involve other mechanisms, such as a treatment effectiveness-dependent degradation of intracellular viral RNA. As a consequence of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended. (HEPATOLOGY 2011.).
Copyright © 2011 American Association for the Study of Liver Diseases.
PMID: 21384401 [PubMed - as supplied by publisher]
hi Robert - the following is from
http://www.*****************/index.php/news/pb/19244
FRIDAY, April 8 (HealthDay News) -- Analysis of the kinetics of telaprevir treatment for hepatitis C virus (HCV) shows a rapid second-phase viral decline, which may allow for shorter duration of treatment, according to a study published online March 7 in Hepatology.
Jeremie Guedj, Ph.D., and Alan S. Perelson, Ph.D., from the Los Alamos National Laboratory in New Mexico, examined second-phase HCV viral decline during treatment with telaprevir. Two aspects of telaprevir treatment were investigated: the effect of varying regimens of telaprevir monotherapy in 28 participants, and the comparison of telaprevir monotherapy in eight patients with telaprevir plus interferon therapy in eight patients. Using a new viral kinetic model, and assuming that drug resistance can be avoided, the treatment time needed to eliminate all virus and infected cells was estimated.
The investigators found that the second-phase viral decline was associated with the effectiveness of treatment, and was approximately four times more rapid with telaprevir than interferon-based therapies. In the predictive model, assuming 95 percent of the patients are fully compliant, the last virus particle could be eliminated within seven weeks, and the clearance of remaining infections in the hepatocytes by no more than 10 weeks. This time would be extended if doses were missed.
"Using a new viral kinetic model that allowed for an improved description of the changes in antiviral treatment effectiveness, the second phase of viral decay was found to be very rapid compared with second phases observed in patients treated with interferon alone, with no differences according to the treatment regimen," the authors write.
http://www.*****************/index.php/news/pb/19244
FRIDAY, April 8 (HealthDay News) -- Analysis of the kinetics of telaprevir treatment for hepatitis C virus (HCV) shows a rapid second-phase viral decline, which may allow for shorter duration of treatment, according to a study published online March 7 in Hepatology.
Jeremie Guedj, Ph.D., and Alan S. Perelson, Ph.D., from the Los Alamos National Laboratory in New Mexico, examined second-phase HCV viral decline during treatment with telaprevir. Two aspects of telaprevir treatment were investigated: the effect of varying regimens of telaprevir monotherapy in 28 participants, and the comparison of telaprevir monotherapy in eight patients with telaprevir plus interferon therapy in eight patients. Using a new viral kinetic model, and assuming that drug resistance can be avoided, the treatment time needed to eliminate all virus and infected cells was estimated.
The investigators found that the second-phase viral decline was associated with the effectiveness of treatment, and was approximately four times more rapid with telaprevir than interferon-based therapies. In the predictive model, assuming 95 percent of the patients are fully compliant, the last virus particle could be eliminated within seven weeks, and the clearance of remaining infections in the hepatocytes by no more than 10 weeks. This time would be extended if doses were missed.
"Using a new viral kinetic model that allowed for an improved description of the changes in antiviral treatment effectiveness, the second phase of viral decay was found to be very rapid compared with second phases observed in patients treated with interferon alone, with no differences according to the treatment regimen," the authors write.
Eureka said- Sounds good in theory, and maybe the case for some situations, but doesn't jive for me.
That explanation could certainly be applied in cases of early responders, slow-response, and possibly even relapse, but would not explain those situations where there is significant viral decline during treatment but no undetected attained.
------------------------
This is what happened in Joe's case. He is a geno1b, over 50, cirrhotic. Even though Alinia helped his interferon response enough to get him to a 2 log drop in 12, which wasn't achieved in the 1st two tries, it couldn't get him to nondetectable although he tried for 60 weeks. The lowest he went was 80 and then it just bounced around in the hundreds.
That seems to fit better with what GoofyDad said about a compromised immune system.
Ev
That explanation could certainly be applied in cases of early responders, slow-response, and possibly even relapse, but would not explain those situations where there is significant viral decline during treatment but no undetected attained.
------------------------
This is what happened in Joe's case. He is a geno1b, over 50, cirrhotic. Even though Alinia helped his interferon response enough to get him to a 2 log drop in 12, which wasn't achieved in the 1st two tries, it couldn't get him to nondetectable although he tried for 60 weeks. The lowest he went was 80 and then it just bounced around in the hundreds.
That seems to fit better with what GoofyDad said about a compromised immune system.
Ev
Hmm, it sounded a bit odd to me too. Thanks all for the opinions.
I guess the bottom line is, like everything, there are multiple reasons. My current theory is that they are just TOUGH LITTLE BASTARDS and there are TRILLIONS of them. After all, I guess if they were "easy to kill" it wouldn't take 48 weeks to try and "be sure".
In the end, all any of us can do is do the grind, wait six months, and hope there is still no trace. There are no shortcuts and no other way at the present time.
Being an engineer, I want definitive, absolute answers to everything. It kills me when none seem to exist. But I guess I'm just going to have to accept the fact that we really don't know, stay the course, hope the reels spin up "triple 7's" for me in the end.
And thanks all for the well wishes! Onward and upward.
Robert
I guess the bottom line is, like everything, there are multiple reasons. My current theory is that they are just TOUGH LITTLE BASTARDS and there are TRILLIONS of them. After all, I guess if they were "easy to kill" it wouldn't take 48 weeks to try and "be sure".
In the end, all any of us can do is do the grind, wait six months, and hope there is still no trace. There are no shortcuts and no other way at the present time.
Being an engineer, I want definitive, absolute answers to everything. It kills me when none seem to exist. But I guess I'm just going to have to accept the fact that we really don't know, stay the course, hope the reels spin up "triple 7's" for me in the end.
And thanks all for the well wishes! Onward and upward.
Robert
Haaayyyy...Congratulations!!!
And uuhhh!...You all really get deep!...
And my boyfriend thinks I am an analyzer...
He gets mad at me for doing a little reseach on the web and consulting in you all for peace of mind in the meantime...
I can certainly attest to and am sure that a lot of you know more than most doctors out there...
Be Well and Stay Well!!!...
Becky
And uuhhh!...You all really get deep!...
And my boyfriend thinks I am an analyzer...
He gets mad at me for doing a little reseach on the web and consulting in you all for peace of mind in the meantime...
I can certainly attest to and am sure that a lot of you know more than most doctors out there...
Be Well and Stay Well!!!...
Becky
And geeeeez....dropping a "still UND and bloods at lowest levels since..." as an aside! Congratulations!! :)
Trish
Trish
Just off the top without thinking it through too deeply - if that were the case, there would be no difference in response rates between the different genotypes, there wouldn't be a different response due to ethnicity, IR, BMI, etc.
Then you look at the ILB28 test - where your genetic variation predicts your chances of clearing. That doesn't have much to do with how easy the virus is to locate in the body.
Then you look at drug development and what they're focusing on and it's not on drugs that are superior HCV-seeking missiles, it's drugs that attack the various mechanisms of the HCV virus. Interferon and ribavirin are only so effective and I really doubt it's simply because they aren't as good at hide-and-seek as the PI's / DAA's being developed, it's because they're more effective at destroying the mechanisms that allow the virus to survive and replicate.
This doesn't really answer your question but rather speaks to his response/theory. Can't say that I'm buying that one.
Then you look at the ILB28 test - where your genetic variation predicts your chances of clearing. That doesn't have much to do with how easy the virus is to locate in the body.
Then you look at drug development and what they're focusing on and it's not on drugs that are superior HCV-seeking missiles, it's drugs that attack the various mechanisms of the HCV virus. Interferon and ribavirin are only so effective and I really doubt it's simply because they aren't as good at hide-and-seek as the PI's / DAA's being developed, it's because they're more effective at destroying the mechanisms that allow the virus to survive and replicate.
This doesn't really answer your question but rather speaks to his response/theory. Can't say that I'm buying that one.
"the "toughest" to get to" view of things would help explain why cirrhotics are harder to SVR. .
I ran that theory by my hepa, who seems to really know his stuff. He scoffed and said you have to think of the inf as training the immune system, and cirrhotics have a compromised immune system that doesn't learn tricks so well. When I got an RVR, with a cirrhosis dx - he thought the cirrhosis factor lost a lot of weight in the relapse question, and whacked my tx schedule in half. He convinced me I should stop early - I did and he was right. FLguy had a piece in that say too :)
I ran that theory by my hepa, who seems to really know his stuff. He scoffed and said you have to think of the inf as training the immune system, and cirrhotics have a compromised immune system that doesn't learn tricks so well. When I got an RVR, with a cirrhosis dx - he thought the cirrhosis factor lost a lot of weight in the relapse question, and whacked my tx schedule in half. He convinced me I should stop early - I did and he was right. FLguy had a piece in that say too :)
So, when the lab tech sticks a needle in your arm to get blood for the PCR which virons are being sucked into the vial? The easy ones or the ones that just happen to trickle by at the right time? The pcr result is based on the number in an ml of blood. You have about 5,600 mls. Did this nice young doc look like Doogie Howser or PeeWee Herman?
Sounds good in theory, and maybe the case for some situations, but doesn't jive for me.
That explanation could certainly be applied in cases of early responders, slow-response, and possibly even relapse, but would not explain those situations where there is significant viral decline during treatment but no undetected attained.
If indeed all it took was for the virus to re-locate to the bloodstream to effectively be killed by interferon, anyone responding to treatment would either be SVR or relapser. If the elimination of hcv were simply dependent upon on it "trickling" into the bloodstream to meet its death, there would be little utility to PCR testing. Persistent viral presence in blood after measurable significant response makes me think the theory is somewhat questionable. Just my two cents. ~eureka
That explanation could certainly be applied in cases of early responders, slow-response, and possibly even relapse, but would not explain those situations where there is significant viral decline during treatment but no undetected attained.
If indeed all it took was for the virus to re-locate to the bloodstream to effectively be killed by interferon, anyone responding to treatment would either be SVR or relapser. If the elimination of hcv were simply dependent upon on it "trickling" into the bloodstream to meet its death, there would be little utility to PCR testing. Persistent viral presence in blood after measurable significant response makes me think the theory is somewhat questionable. Just my two cents. ~eureka
RBW , this is a good question ...
It does sound plausible, if we are discussing virons that have not become resistant or mutated (another can of worms) ..., my reasoning being .. someone who responds to Inf ..... if somehow the virons were able to work their way into, for example, liver scar tissue, underneath deposits or plaque in our blood veins, or into another body organ that may be partially compromised ... anywhere that our bodies blood flow system might be restricted or compromised ... wouldn't it be harder for the Inf to get into those kind of area's ? Our bodies blood corpuscles don't really flow there 100% , as the damage has already been done .. leaving access from the Inf in our blood stream less likely to penetrate those hard to reach areas ?
As we know, for folks with levels of fibrosis >F1 , or for those over 50 , Tx response and Non Relapse (SVR) is harder to achieve .. why ??, compromised organs, and a lack of blood flow ?? .. enough virons hiding and reproducing in those hard to reach places, that after EOT, and they are still replicating ... slowly leaking out into the system over whatever time frame up to 1 year.... to start the process all over again ... a definite maybe ??
Only my 1 penny's worth ....
It does sound plausible, if we are discussing virons that have not become resistant or mutated (another can of worms) ..., my reasoning being .. someone who responds to Inf ..... if somehow the virons were able to work their way into, for example, liver scar tissue, underneath deposits or plaque in our blood veins, or into another body organ that may be partially compromised ... anywhere that our bodies blood flow system might be restricted or compromised ... wouldn't it be harder for the Inf to get into those kind of area's ? Our bodies blood corpuscles don't really flow there 100% , as the damage has already been done .. leaving access from the Inf in our blood stream less likely to penetrate those hard to reach areas ?
As we know, for folks with levels of fibrosis >F1 , or for those over 50 , Tx response and Non Relapse (SVR) is harder to achieve .. why ??, compromised organs, and a lack of blood flow ?? .. enough virons hiding and reproducing in those hard to reach places, that after EOT, and they are still replicating ... slowly leaking out into the system over whatever time frame up to 1 year.... to start the process all over again ... a definite maybe ??
Only my 1 penny's worth ....
"the "toughest" to get to" view of things would help explain why cirrhotics are harder to SVR.
Guess if we had a straight answer to that we would be a lot closer to 100% cure rate.
b
wk48 of 60
b
wk48 of 60
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