http://www.medhelp.org/posts/show/393732?post_id=post_2325287
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Hepatology. 1996 Jul;24(1):21-6.
Improved sustained response following treatment of chronic hepatitis C by gradual
reduction in the interferon dose.
Shiffman ML, Hofmann CM, Luketic VA, Sanyal AJ, Contos MJ, Mills AS.
Hepatology Section, Medical College of Virginia, Richmond, Va 23298, USA.
Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with
a high rate of relapse. IFN is thought to exert its effect against HCV via direct
viral inhibition and immune stimulation. We have hypothesized that relapse
following termination of therapy results from the sudden withdrawal of this
immune modulatory effect and that gradual reduction in the IFN dose may decrease
the incidence of relapse. One hundred six patients with chronic HCV were enrolled
into this 24-month controlled, randomized prospective trial. All were treated
with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who
achieved biochemical response were randomized to either stop or taper IFN
gradually at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU (all
three times a week). 0.5 mU twice weekly and then once weekly. Liver histology
was assessed by Knodell index and HCV RNA was measured by a quantitative
polymerase chain reaction (PCR) assay. Of the 92 patients who completed the
initial 6 months of IFN treatment, 47 (51%) achieved biochemical response.
Twenty-one of these patients were randomized to stop IFN treatment and 25 to
taper (1 drop-out). At randomization patients were well matched with respect to
age, sex, race, serum alanine transaminase (ALT), and liver histology.
Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN
treatment compared with only 60% who tapered IFN (P= .04).
Virological relapse
occurred in 90% of patients who stopped and only 48% of persons who tapered IFN
therapy.
At completion of the 24-month study patients who achieved long-term
sustained biochemical response had a significantly lower mean Knodell score (3.5
vs. 6.5) and a significantly greater number were HCV RNA negative in serum (85%
vs. 18%) compared with relapsers.
We conclude that gradual reduction in IFN dose
is associated with a SIGNIFICANT HIGHER RATE OF SUSTAINED RESPONSE and clearance
of HCV RNA from serum compared with abruptly stopping treatment. This in turn is
associated with a significant improvement in hepatic histology supporting the
premise that response to IFN therapy can prevent progression to cirrhosis.
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by HR
It needs to be understood that when stopping IFN, a new form of antiviral defense against possible HCV remnants needs to take hold and establish itself - the adaptive Tcell response, that up to this point was greatly aided by the direct effect of IFN on the hepatocytes and the local intrahepatic immune cells. With this IFN aid gone all the burden is on the Tcell response, that will typically get stronger if more remnant viruses are seen ( if they can be seen now, because new epitopes are now present) - with incredible sensitivity, but it takes time to come to full swing and it can furthermore, at this very critical moment, be paralyzed by the prominent absence of innate signals needed to get adaptive Tcell responses going after IFN is abruptly missing from the equation. Here is one more specific EXAMPLE how the Tcell effect depends on the presence of some Interferon: The presentation of the viral epitopes is performed - as described in detail in an earlier post- by the cellular proteasome and the class I MHC molecules that bind the peptide and bring it to the surface for recognition by the "cognate" Tcell receptors of the "cognate" Tcell patrolling the liver.
IFN has a strong influence on the intensity of expression - the number of proteins produced per cell - of the MHC class I proteins. Less IFN - less MHC, less presentations- less recognition - less killing of remnant virus infected cells, less general intrahepatic antiviral milieu by the gammaIFN secretion of these Tcells....
If you abruptly stop the enormous whipping up of the hepatocyte MHC production it will likely go into lower than normal mode for a while being so used to the whip...thus temporarily HCV remnants become invisible to the Tcell system.
If you taper AFTER the end of the full standardized tx period, then you will never have to ask yourself in case you still relapse, if it was the premature tapering that caused it. Tapering in this fashion can certainly cause no propensity for relapse, rather the opposite. Then at least you have done all you could under the circumstances.
What type of tapering schedule?
Each week one half of the previous dose would get you down in a "geometrical" fashion, as opposed to a linear one. 16mcg 8 4 2 1 1/2 1/4 1/8 Stop.
From patients reporting the "feel" of tapering down, each reduction feels quite good. As a matter of fact, some who stopped abruptly reported negative side effects from the counterswings of the system used to all that IFN. The point is, that tapering is not a useless extension of tx sides, but rather a gentle readjustment of the complex immune regulatory pathways directly or indirectly depending on IFN.
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http://www3.interscience.wiley.com/cgi-bin/fulltext/106594360/PDFSTART
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by geterdone
So, form what I gather is that the immune systems is weakened by the onslaught of the virus and subsequent chronic condition of the same over time, which has pushed the natural producing INF to below normal levels by the HVC blocking mechanisms IRF-3 which is initiated by the RIG-1 and keeps it at that state of alteration during the infection cycle, but with the induction of the synthetic interferon, it raises it and keeps it at a artificially higher level during treatment but when abruptly stopped at the EOT there is a void or lag time because coming off of the interferon is in such a short duration and is faster than the immune system; which has been depressed for a long period of time by the HVC blockade has not had the time to regenerate its cellular pathways to start producing its own natural interferon, which may take a week, month or longer, who knows but the bottom line is that during that time any weakened stragglers or super virions left behind may have the golden opportunity to start replication and faster because of the absents or lack of natural acting interferon. So the tapering off of the interferon would allow all the systems to readjust theoretically at the same controlled time and at some point there would be an equilibrium point reached between the synthetic interferon and the autoimmune response interferon in which any weakened remaining remnants of the virus would be put into check or eradicated.
jasper
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by Gauf
I will add lactoferrin near EOT. It significantly boosts the immune system, I think it a prudent addition to SOC at the END of treatment. Instead of stopping cold turkey at EOT on the soc drugs (like I did on the last 2 txs'), I plan to taper down and give my own immune system some help coming back online. As soon as I start to taper, I will add the lactoferrin to help. Camel Lactoferrin is 30x stronger than bovine, so I will try that. HR thinks this plan cerrtainly couldn't hurt, and may just help.
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