HCV difference in life cycle?

[Andiamo1]

Does anyone know why it is possible to cure HCV, but not HIV?  It was explained to me as a difference in the virus life cycle, but the explanation given me had some misconceptions that I would like to clarify.

[merryBe]

you bring up an interesting point that has had me perplexed for sometime.

I have not of the indicators, high BP, HIV etc, yet I have 13 large white spots in my brain and neuropathy elsewhere.

Based on the latest things I've read, and what you just posted, can you explain why no mention is made of this possibility to patients?

Is there a way to test the spinal cord fluid or blood that would tell if such spots in the brain were HCV, so that a brain biopsy would not be necessary.

All my neurologist would say is...I don't know what's causing it. Yet I feel HCV patients should have the right to to tested and told if this is happening to them.

thanks for all and any input.

mb

[zazza]

Since you got my post deleted where I told where you had gotten your information about interferon from, I expect you to be woman enough to answer my question yourself.

I know of course by now that there exists no link to back your statements up, so I guess that is why you meet my inquiry with silence.

[Proactive]

From the last line of the above post
"Finally, the enhanced third phase in patientsKidney diet - dialysis patients treated with IFN-alpha in combination with RBV versus patientsKidney diet - dialysis patients treated with IFN-alpha alone can be explained by a mutagenic effect of RBV against HCV."

Kind of goes hand and hand with coming into the third phase of viral decline at the opitmun ribavirin dosage..I'm convinced my rbv dosage increases at week 4 and 8 were as critical to my svr as the treatment extension was..

[Proactive]

I have always thought viral response to the interferon was pretty much as described here.I had thought it was more triphasic than biphasic..
"When patients chronically infected with hepatitis C virus (HCV) are placed on antiviral therapy with pegylated interferon (IFN)-alpha or IFN-alpha plus ribavirin (RBV), HCV RNA generally declines in a biphasic manner. However, a triphasic decline has been reported in a subset of patients. A triphasic decline consists of a first phase (1-2 days) with rapid virus load decline, followed by a "shoulder phase" (4-28 days) in which virus load decays slowly or remains constant, and a third phase of renewed viral decay. We show that by including the proliferation of both uninfected and infected cells, a viral kinetic model can account for a triphasic HCV RNA decay. The model predicts that a triphasic decline occurs only in patients in which a majority of hepatocytes are infected before therapy. The shoulder phase does not represent the intrinsic death rate of infected cells, but rather the third phase slope is close to the intrinsic death rate of infected cells when overall drug efficacy is close to 1. CONCLUSION: Triphasic responses can be predicted from a generalization of existent viral kinetic models through the inclusion of homeostatic proliferation of hepatocytes. This generalized model can also explain the viral kinetics seen in flat partial responders. Finally, the enhanced third phase in patients treated with IFN-alpha in combination with RBV versus patients treated with IFN-alpha alone can be explained by a mutagenic effect of RBV against HCV."
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17596864&ordinalpos=144&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[Proactive]

"Kinetics of hepatitis C virus RNA load during pegylated interferon alpha-2a and ribavirin treatment in naïve genotype 1 patients"
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1343582

viral load decline chart from the above
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1343582&rendertype=figure&id=F1

[Proactive]

"Dynamics of Hepatitis C Viremia following Interferon-a Administration"
http://www.journals.uchicago.edu/doi/pdf/10.1086/515309

[desrt]

MKAndrew has been researching (and speculating about) HCV for years. He's the first to admit that many of the speculations in his blog during the last 6 years have been dead ends - but he has a great talent for putting many of these issues into easily understood 'layman's' terms. At this point I value his opinion as much as I do many of the 'heavy' doctors.

[comeagain]

What is this is?? !! Is MK Andrews a doctor don´t think so is Cowriter a doctor dont think so,  but if you didn´t know you sure as hell would thought they were when reading this litany.
No they are two amateur docs very knowledgeable I´m sure but still no docs.
We better  hold on here a second are they speculating and mixing own thoughts with medical fact but not clearly telling what is what.

That could be dangerous in my opinion. I really would like to hear what  Dr Dieterish  dr Pearl , Shiffman , Jacobson or Bergs or any other heavy dr thinks about  this kind of presentation (formulation)  and which facts are correct and which are not !

We are all  forum polices sometimes aint we, if  I` m out in the blue here please police me right back.

ca

[Andiamo1]

I have not seen any studies that quantify interferon resistance, but Dr D did tell me that I should treat longer due to my age impacting my ability to react to interferon and stimulate my own immune system.

So it would not be interferon resistance in the strict sense of the word, but does say that our own ability to deliver interferon to the virus and the ability of our immune system to react to interferon and attack the virus play a strong role in the success of our treatment;  perhaps as much or more of a role than the ability of HCV to resist interferon.

[Rockerforlife]

To me...the term" interferon resistance " would mean a total nul-responder to the drug...someone who does not have a 2 log drop in 24 weeks to me is interferon resistance ...just my 2 cents worth

[zazza]

Still waiting for a link from you.

[Mr Liver]

Thanks for looking up the thread. I checked it out as well as other links in it and didn't really see anything which showed that 'people' are interferon resistant. I saw many references by those posting about intereferon resistance in reference to the host, but that was all. I've read numerous studies on interferon resistance and have never seen one that referred to the host as being interferon resistant. If there is a study which uses the definition in this context  I'd really like to read it to see how the definiton is arrived at. Thanks again for the link.
ML

[Willy50]

I hope that this helps some.  Also included within the thread Jim included some other links that will be worthwhile.  

I think I'll let the heavy hitters field the answer for you....at least in part.  I'll have to read these also since I am trying to stay up on the issue.  Thought I'd get them out here though to keep things moving.

best,
Willy

http://www.medhelp.org/posts/show/345189

[Mr Liver]

"And if somebody is interferon resistant"

I've never heard of a person being interferon resistant, only the virus. Where are you drawing this definition from ?
ML

[Andiamo1]

I was under the belief that the reason HCV is curable is that it spends more of its life cycle in the bloodstream and therefore more accessible when treated.  It was not a well founded theory on my part, so thanks for the help in clarifying that and thank you all for the thoughtful input.
Eric

[Rockerforlife]

i believe the Hep virus cuases cancer INDIRECTLY..the poor old liver cant filter the toxins from the body....and    voila...cancer

[Willy50]

Actually, this is what I was referring to;

http://www.medhelp.org/posts/show/724750

from Schering Plough

As part of its long-term commitment to hepatitis C therapy, Schering-Plough also is developing SCH 900518 ("518"), a next-generation HCV protease inhibitor. A Phase IIa study with 518, known as the NEXT-1 study, is currently ongoing. The company said that 518 has been shown to be 10 times more potent in-vitro than other protease inhibitors currently in Phase III development and has the potential for once daily dosing. 518 also has shown decreased emergence of resistance in vitro. Given its pharmacokinetic (PK) profile, the company anticipates that 518 may be active against some HCV strains that are resistant to other protease inhibitors. Phase I proof of concept studies with 518 in treatment-naive patients and those who failed prior treatment, both as monotherapy and in combination with peginterferon (without ribavirin), demonstrated enhanced antiviral activity, with up to 4 log10 and 5 log10 decreases in circulating HCV, respectively.
-----------------------------------------------------------------------------

Vertex has 2 second generation drugs in development but has refused to comment on their efficacy other than to say that they are "competitive".   I'm sure that we will hear more about that fairly soon, but even a successful second generation compound will face a slow approval process. One thing that should speed approval process is that IF Vertex were to be approved....then would not that become the new SOC?  IF so...... that would mean that the new "control arms" in in some studies (with TVR) might become 24 weeks instead of 48 weeks?  

best,
Willy

[Rockerforlife]

Infection
Some viruses are linked to certain cancers. For example, people with persistent infection with the hepatitis B virus or the hepatitis C virus have an increased risk of developing cancer of the liver. Another example is the link between the human papilloma virus (HPV virus) and cervical cancer. Most (possibly all) women who develop cervical cancer have been infected with a strain (sub-type) of the HPV virus at some point in their life. But, most viruses and viral infections are not linked to cancer.

[Rockerforlife]

most viruses and viral infections are not linked to cancer.
In many cases it is likely that a combination of factors such as genetic make-up, exposure to a carcinogen, age, diet, the state of your immune system, etc, play a part to trigger a cell to become abnormal, and allow it to multiply 'out of control' into a cancer.



http://www.patient.co.uk/showdoc/27000577/

[CoWriter]

"I see that Rocker posted an article in which (it was claimed) that a Sherring-Plough 2nd generation PI in development was said to be 10X more powerful (in vitro) than existing PI's.(meaning Telaprevir and Boceprevir, presumably) "
---------------------------

By adding ritonavir, an HIV anti-viral that strongly inhibits CYP3A, they boosted the bioavailability of Telaprevir more than that.  But the issue then becomes one of possible toxicity.

Co



Pharmacokinetic enhancement of the hepatitis C virus protease inhibitors VX-950 and SCH 503034 by co-dosing with ritonavir.

Kempf DJ, Klein C, Chen HJ, Klein LL, Yeung C, Randolph JT, Lau YY, Chovan LE, Guan Z, Hernandez L, Turner TM, Dandliker PJ, Marsh KC.
Global Pharmaceutical Research & Development Division Abbott, Abbott Park, IL, USA.

Inhibitors of hepatitis C virus (HCV) protease have shown marked antiviral activity in short-term clinical studies in HCV-infected individuals. The interaction of the investigational HCV protease inhibitors VX-950 and SCH 503034 with ritonavir, a potent inhibitor of cytochrome P450 3A, was studied in vitro and in vivo. In rat and human liver microsomes, the metabolism of VX-950 and SCH 503034 was strongly inhibited by the presence of 4 microM ritonavir. Upon co-dosing either VX-950 or SCH 503034 with ritonavir in rats, plasma exposure of the HCV protease inhibitors was increased by > 15-fold, and plasma concentrations 8 h after dosing were increased by > 50-fold. A human pharmacokinetic model of VX-950 co-administered with low-dose ritonavir suggested that improved efficacy and/or dosing convenience may be feasible by pharmacokinetic enhancement with ritonavir.

[jacksonblue]

numerous cancers have been related to virus and bacteria small sample jc virus colon cancer hpv cervical hepatitis liver herpes type 8 karposi epstein bar to 4 types cancer non hodgkins and lymphomas stomach cancer bacteria at least 30 percent of all cancer related to this and list just keeps growing then there is a genectic component maybe 30 percent of cancer related to food and enviroment

[jdwithhcv]

"...all the research funds in the past have pumped into cancer cures ...(which there is none and will never be)"
---------------------------------------------------------------

Acturally, there are cures for several different kinds of cancer!

[Rockerforlife]

Reason why we are behind in a more effective cure for hepatitis is because all the research funds in the past have pumped into cancer cures ,,,(which there is none and will never be)..cancer is caused by the chemicals in our food and water...also all the cash went to AIDS cures.....its about time the new PI`s are on the way...

Sorry for posting on youir thread..

I AM NOT A HIGH JACKER

[Willy50]

Co:
"But were they null responders, or were they "non-responders" because they were under-dosed, their dose was reduced or interrupted, etc?"
------------------------------------------------------  

We will soon see, or at least better see. In the past it was virtually impossible to know exactly how and why people failed.  Unless one had meticulous records of weekly viral loads, dosing records, etc it was a matter of supposition.

When the people who failed Prove 1 and Prove 2 (the SOC control arm "failures"; all geno 1 naives) were given the opportunity to be placed into rollover arms in which they were given triple therapy.   We will be able to see all the classic groups of treatment failures (from null responder to relapsers) respond when given triple therapy.  When they classify a person a null responder they will have fairly detailed records to prove it.  It will then be followed up with detailed response rates to triple therapy given to the exact same people who had prior failed SOC.

Given the response rates of Prove 3 with past treatment failures I am hopeful that we will see null responders be converted into responders and perhaps even SVR success stories.

I am not trying to argue the point about interferon resistance but I would like to open up the possibility that even so called "null or non response" to SOC does not mean that one may not be able to be cured using protease or polymerase inhibitors (in conjunction with IFN & RBV)  I think sometimes people attribute null response to interferon resistance.  (I understand that presumably all interferon resistant people will be null responders (to current SOC) but that not all null responders are therefore interferon resistant.  Does that sound right to you?)

I see that Rocker posted an article in which (it was claimed) that a Sherring-Plough 2nd generation PI in development was said to be 10X more powerful (in vitro) than existing PI's.(meaning Telaprevir and Boceprevir, presumably)

At some point the inhibitors may become effective enough that interferon (or RBV) will be dropped from treatment.  That day may be here sooner than we think. Trials for such treatments may soon start several pharma's.  Vertex had one planned on in 2009 I believe

By the way..... Vertex (well, actually Tibotech) will have a European trial which will utilize the SOC "lead in" before dosing Telaprevir on past treatment failures, null responders included.  Figure over 18 months to get the trial started, dosed for a year and a 6 month wait for an "official" SVR PCR.

http://www.hivandhepatitis.com/hep_c/news/2008/102408_b.html

best,
Willy