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ezetimibe first results on hbsag quant
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ezetimibe first results on hbsag quant

i just received hbsag quantity now and it lowered for the first time to less than 4000iu/ml in 3 years (all tests in same lab with authomated diluition)

hbsag baseline before ezetimibe 4207iu/ml
(stable around this value in 2012, in previous years up and down from 7300 to 4200iu/ml, never reached less)
hbsag after 9weeks of ezetimibe 3644iu/ml

i have used 10mg dose for about 4weeks and then increased to 50mg daily, no sides, all blood tests normal (alt lowered from 45-50 to 31)

the therapy used is entecavir plus tenofovir and ezetimibe add on

not correlated with therapy or response:
tot cholesterol from 164 to 131-139
ldl from 92 to 71-79
hdl from 61 to 44-39
trigl from 57 to 40

ast-alt lowered from 27-37 to 28-31 one month ago, will recheck this month
34 Comments Post a Comment
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Avatar_m_tn

please comment on these results, i think that monthly hbsag quant may confirm if we are having a good result from ezetimibe, we have only one thing certain from 2009 to 2012 hbsag stable from 4200 to 7300 no matter what we tried (alinia or imiquimod)

would you also add intf to this combo tdf+etv+ezetimibe since imiquimod too failed?liver specialists scheduled intf add on for this year
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Avatar_m_tn
ezetimibe is a drug that lowers cholesterol level, isn't it?

I also noticed that decrease in cholesterol affects hbsAg quantity. Since Oct'12 to Dec'12 I lost 3 kilos and
cholesterol went down from 5.6 to 4.95.
HDL was stable around 1.4 but
LDL went down from 4.1 to 3.0
HbsAg went down from 1795 iU/ml to 1447 iU/ml

I did not take any drugs except for the supplements VitD3 1k a day, LivOn GSH+VITC+AntiAge, changed diet a bit.
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Avatar_m_tn

it may be just a coincidence or improved immune response by those supplements because me and some other members tried simvastatin or red yeast rice supplements in the past and it did lowered chol but no effect on hbsag at all

ezetimibe doesn t work on cholesterol to interfere with hbv but it is thought to interfere with some steps after hbv entry, something before cccdna and hbsag formation.in vitro it did lower cccdna and hbsag but as regards vivo no data yet
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Avatar_m_tn

as regards hcv ezetimibe blocks cellular entry receptors
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Avatar_m_tn
I wonder if HbsAg level will stay if you stop ezetimibe...
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Avatar_m_tn
This looks like a real response that has shifted the daily kinetics of reinfection so that the total cccDNA might be reduced. You took a very high dose, i suspect the regular low dose of 10mg would not have shown much effect.

Since ezetimibe is reported to block virion uptake at a later step it might work synergistic with Myrcludex in reducing the reinfection rate.

The key question is now if a further reduction of surface antigen can be expected, or if this is new setpoint reached with no more progress in infected cell reduction. I think there is a chance that the reduction might continue, similar to what we expect from a properly dosed Myrcludex treatment.

If you see a further drop in upcoming tests, I would definitely recommend to have it as a component add on to the planned IFN therapy. If there is a continuing drop i would not start the IFN as long as the effect shows true progression.

When is your next hbsag quant scheduled?
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Avatar_m_tn

i can do it whatever timepoint now even with no prescription, it is just 7-10€ cost test and can also try higher dosages since no sides in case of furthur decline

what would you suggest monthly test or every 15 days?

thanks

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Avatar_f_tn
I think we need more time points to make a scientific decision but the result is promising.
I can't find any data on toxicology or dosage escalation studies on Ezitimibe, therefore, I will advice not to exceed 50 mg daily dosage  because all the trial with Ezitimibe was 10 mg daily .. This is just my opinion and our great asset Studyforhope can contribute.

    
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Avatar_m_tn
Once monthly testing should give meaningful results. However right mow a retesting in two weeks would be useful to confirm that it was not just a temporary fluctuation in surface antigen expression activity without a true reduction in cccDNA content.
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Avatar_m_tn
I agree that dose increases have to be handled very carefully. Stefano already jumped into uncharted lands with the 50mg dose. I would recommend a test of pancreatic Lipase.

On the other hand, he might not have seen an effect with the standard 10mg dose. It is further possible that he is still in the middle of the dose response curve.
What has to be kept in mind is that this secondary entry inhibitor effect cannot lead directly to an elimination of infected cells. The elimination is depending on ongoing immune mediated infected cell removal or noncytolytic clearance. Once entry blocking is complete, any further dose escalation will achieve nothing but trouble.
But we dont know if the 50mg dose is already causing a near max effect.

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Avatar_m_tn

is pancreatic lipase urgent?if not i ll test in 2 weeks with hbsag quant
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Avatar_f_tn
I have seen article on Ezitimibe viral activities and there is a patent in the USA blocking the use of it and the like group  on treatment of HBV.
There's possibility that 50mg is still ok but it has to be monitored.
Although this drug is designed for liver metabolism, i ll suggest that due to massive increase in the usual recommended daily dosage to do a Kidney function test if its available.
A daily dosage of 50 mg might well be within the tolerable range and the decision to use 10mg for therapeutic effect is design  for long term use.
I am watching closely.
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Avatar_m_tn
50mg / day seamce to be maximum considered in overdoses. Be careful on the dosage.

"In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.



In the event of an overdose, symptomatic and supportive measures should be employed"

from: http://www.rxlist.com/zetia-drug/overdosage-contraindications.htm
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Avatar_m_tn

creatinine-calcium is monitored every month since i started nucs in 2009  and just rechecked after the 50mg dose adding liver function, no change

lipase is the only test i never did, so i ll keep monthly monitoring of all main tests plus lipase

we have two human trials that covered the 50mg dose and the 40mg dose with no toxicity/sides but they were short time, about 1-2 months only
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Avatar_m_tn
One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.

can you link this?it may be good to see tests of this patient, anyway i ll keep 50mg for now and if we see a real continuous decrease will consider higher dose with every 4 weeks full monitoring
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Avatar_m_tn

sorry got the link rxlist.com, good to know no toxicity reported until now

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Avatar_m_tn
I will look more deeper for the details if published.
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Avatar_m_tn
No the lipase is not urgent, but important if you proceed. Regarding kidney function, a more sensitive test for kidney toxicity than creatinine will randum urine microalbumine to creatinine ratio. It will pick up minor disturbances to the glomerular podocytes, the most sensitive and sophisticated cells in the kidney.

The ed50 for ezetimibe in the hepaRG  cells was 18 micromols. If you remember we calculated once the achievable concentration in a human assuming even distribution in the extracellular fluid. It came out too low. But since ezetimibe is preferentially taken up in the liver, it is possible that much higher local concentrations can be achieved.

The most likely mechanism operating is that a membrane component protein that binds to cholesterol in the HBV envelope after the virions have been endocytosed but not yet fused with the endosome membrane for core delivery into the cytosol is blocked by ezetimibe, blocking envelope to membrane fusion and cytosolic core delivery. The nonfused virion is later destroyed in the endolysosome that will form. A similar mechanism is envisioned for myrcludex, except that in this case the binding of the pres1 arms to the bile acid transporter is blocked.

Thus it can be reasonably expected that these two independent mechanisms to prevent core uptake into the cytosol will work synergistically and could greatly enhance each others efficiency.
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Avatar_m_tn
Hey Stefano,

A couple questions for you:

1. You stated your ALT dropped from 45-50 down to 30. How long was your ALT that high. Shouldn't it have normalized with ETV + TDF?

2. I read that Ezetimibe also causes hepatitis and increased ALT/AST?

3. I also read that this is sometimes prescribed with Sivastatin. Is there a reason you chose one over the other?

Lastly I wanted to say you should be careful when trying these things, especially when increasing dosing.
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Avatar_m_tn
1 since 3 months after starting etv.no normalization of ast/alt doesn t happen if there is some immune response

2 no it is not ezetimibe it is the statins added to ezetimibe and in both cases the increase of alt is similar to placebo and due to the dicrease of cholesterol, there are many posts about statins and alt increase.alt normalize continuing statins and does not reflect liver damage

3 that combo is only for those needing to lower cholesterol.the patent over the use of ezetimibe for hbv, hcv recommeds not to combo with statins and to combo with intf

i have full blodd tests plus researchers monitoring, plus we already know 40-50mg dose has no sides for 26weeks so nothing new, the doses over this or for longer periods are something new.
hopefully researchers are trying higher doses too bad they didn t check if there is any toxicity at 100mg or more....the 10mg dose was choosen because there is no incresed effect on cholesterol over this dose, not because of toxicity, and this is bad for us
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Avatar_m_tn

is it useful to activate macrophages by gcmaf to remove hbsag from circulation faster or it can be deleterious now?
i have some left that will expire anyway so i may use it
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Avatar_m_tn
What you really want right now is the removal of infected cells faster than the reinfection rate. Ezetimibe holds the chance of effective entry inhibition, if this is the mechanism operating right now that has reduced yor surface antigen level, then you want to truly know that.
If you activate macrophage removal of surface antigen by phagocytosis increase, then you would possibly not be clear if there is indeed the critical effect of ezetimibe at work.

If the effect on cccDNA is real, it will likely continue, once you are sure of that, you can use GCMAF, whatever help it might offer. But better not blur the picture right now, if your 50mg ezetimibe treatment is able to block reinfection sufficiently to reduce cccDNA by unreplenished attrition, it would be an incredible step forward.
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Avatar_m_tn

ok thanks
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Avatar_m_tn
Here is  a short statement from a paper investigating ezetimibes effect on bile cholesterol in hamsters, but the statement from the discussion  relates to dogs. I show it here, because it might contribute to the question of ezetimibe toxicity.

". Despite this, treatment of dogs with ezetimibe at a very high dose (300 mg·day−1·kg body wt−1) for 1 yr did not result in gallstone formation or any other adverse hepatobiliary effects.It should be noted that these findings were made in dogs maintained on a low-cholesterol, low-fat commercial canine diet."

Obviously, using any dose higher than the approved 10mg/day in humans is experimental and has to be done with great caution, under physician supervision and consent and with extensive monitoring of risk indicators. But it is comforting to know that these dogs tolerated such a gigantic dose for a year.
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Avatar_m_tn
here is the hamster paper, the dog study is in the discussion. Access to this paper is free.

BTW it might seem paradox that the cholesterol transport protein NPD1L1 that is inhibited by ezetimibe, will decrease, not increase biliary cholesterol concentrations, despite the fact that this transporter is intensely enriched in the apical ( biliary, canalicular) side of the hepatocyte, with the obvious function to bring cholesterol back from the bile.
But the primary uptake blockage, with strongly reduced cholesterol transport to the liver under ezetimibe seems to more than compensate for the loss of this reuptake function.

Also note, that the presence of the ezetimibe sensitive receptor on the apical side of the hepatocyte seems at first sight to negate an effect of this cholesterol  transporter on HBV entry inhibition, since the HBV virions obviously enter on the the sinusoidal ( towards the blood), or basolateral side of the liver cell.

Nevertheless, this cholesterol grabbing membrane protein is present on the basolateral side as well due to its fundamental functions in transporting cholesterol from the endosomal compartment into the cytosol.

Thus it sits on the basolateral cell membrane in smaller  concentrations, waiting for the caveolae ( invaginations of the cell membrane) to form and then, with the HBV virions trapped in the resulting endosome and immobilized by their attachment to the bile acid transporter via the preS1 arms, will condense and collect upon the cholesterol molecules in the virion envelope and once sufficient contacts have been made, it will pull the HBV virion  envelope to fuse with the endosome membrane, which will release the HBV core into the cytosol.

This is likely the mechanical basis for the strong entry inhibitory effect that Ulrike Protzner and her team in Munich was able to show in their chimeric HBV mouse model with ezetimibe.

The big problem with this effect is however that 10mg/kg mouse was used.



Here is the hamster paper that containes the dog study in their references.

Am J Physiol Gastrointest Liver Physiol. 2008 October; 295(4): G813–G822.
Published online 2008 August 21. doi:  10.1152/ajpgi.90372.2008
PMCID: PMC2575918
Inhibiting intestinal NPC1L1 activity prevents diet-induced increase in biliary cholesterol in Golden Syrian hamsters
Mark A. Valasek,2 Joyce J. Repa,1,2 Gang Quan,1 John M. Dietschy,1 and Stephen D. Turley1
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Go to:
Abstract

Niemann-Pick C1-like 1 (NPC1L1) facilitates the uptake of sterols into the enterocyte and is the target of the novel cholesterol absorption inhibitor, ezetimibe. These studies used the Golden Syrian hamster as a model to delineate the changes in the relative mRNA expression of NPC1L1 and other proteins that regulate sterol homeostasis in the enterocyte during and following cessation of ezetimibe treatment and also to address the clinically important question of whether the marked inhibition of cholesterol absorption alters biliary lipid composition. In hamsters fed a low-cholesterol, low-fat basal diet, the abundance of mRNA for NPC1L1 in the small intestine far exceeded that in other regions of the gastrointestinal tract, liver, and gallbladder. In the first study, female hamsters were fed the basal diet containing ezetimibe at doses up to 2.0 mg·day−1·kg body wt−1. At this dose, cholesterol absorption fell by 82%, fecal neutral sterol excretion increased by 5.3-fold, and hepatic and intestinal cholesterol synthesis increased more than twofold, but there were no significant changes in either fecal bile acid excretion or biliary lipid composition. The ezetimibe-induced changes in intestinal cholesterol handling were reversed when treatment was withdrawn. In a second study, male hamsters were given a diet enriched in cholesterol and safflower oil without or with ezetimibe. The lipid-rich diet raised the absolute and relative cholesterol levels in bile more than fourfold. This increase was largely prevented by ezetimibe. These data are consistent with the recent finding that ezetimibe treatment significantly reduced biliary cholesterol saturation in patients with gallstones.
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Avatar_m_tn

first weekly test to control for possible toxicity, too keep in mind the tests were made after a very early flight 4am and a flu infection controlled by high dose liposomal vit c 4g (equal to 40g normal vit c) so i was feeling just a bad cold, mild thoatache, mild fever to 37.i will recheck next week in normal situation with no flights, no flu infection

inversion of ast/alt ratio, but both single values were higher before ezetimibe add on)
ast 32
alt  30
bilirubin tot 0.5mg/dl
bilirubin direct 0.2mg/dl
bilirubin indirect 0.3mg/dl

WBC 8.7
RBC LOW  4.44 (normal 4.5-5.8)
plt 175 (130-400)
emoglobin (hgb) LOW 13.6g/dl  (normal 14-18)
hematocrit (hct) LOW 41.4% (normal 42-52)
mcv 93.3fl  normal
mch 30.8    normal
mchc 33g/dl   normal
rdw 13.8%    normal

neutr 73.3% (45-75)  6.4 (1.8-7.5)
lymph 19.7% LOW (20-48) 1.7 (1.2-4)
monocytes 6.2% (2.5-12) 0.5 (0.2-1.0)
mpv 10.6fl   normal
pct 0.184%  normal
pdw 17.1      normal
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Avatar_m_tn

forgot:
creatinine 0.8mg/dl (0.2-1.3)  jaffe
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Avatar_m_tn

the low lympho is very very unusual, never had such a low absolute value and percentage

previous ast with no ezetimibe 27-40
previous alt with no ezetimibe 34-54
but ratio rarely inverted
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Avatar_m_tn
The lymphocytes may be low because you have a cold. Altogether your profile does not show any remarkable abnormalities, liver and kidney parameters seem ok. The lowering of your ALT is somewhat interesting, but itbis too early to place speculative interpretations on this.
The most interesting value will be your next and the following hbsag quants.

I did an in depth analysis of prozers paper on HBV entry suppression in hepaRg cells by Ezetimibe. One surprising detail is, that it should NOT be the Niemann Pick protein cholesterol transporter blocking as one would logically assume, but another yet unknown Ezetimibe sensitive function that is being blocked. This was concluded from the fact , that silencing the niemann pick gene did not prevent entry of HBV. I am not sure if they have done this silencing well enough.
If true, however then the chances that it has in blocking HBV are independent from the results on HCV, which showed, in the human liver chimeric mouse a blocking effect of ezetimibe, but at a dose unreachable in clinical practice. Thus this magic unknown rezeptor that helps pulling HBV virions in the cytoplasm, is still a hopeful target.
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Avatar_n_tn
My hbsag quantity as on 27.10.12 is 759iu/ml.4 months after, the result is 738iu/ml (reduced 21iu/ml in 4 months)    
             hbeag-negative

              Anti-hbsag-0.2

              Hbvdna- <20 IU/ml by COBAS TAQMAN method

              ALT-48 U/L(Cut off value 30-65)  

              AST-34 U/L(Cut off value 15-37)  
All other tests are normal. Now I have been taking baraclude 0.5mg and vitamin d3 supplement only.  As u suggested earler, I propose to take ifn in the coming may after consulting my doctor. Till then can I take ezetimibe 10 or 50 mg to reduce the qhbsag? I expect ur valuable suggestion in thi regard.
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Avatar_m_tn
wait the next few months hbsag tests as studyforhope said, it is too early to say my first hbsag tests declined because of ezetimibe
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Avatar_m_tn
this is very interesting... Keep us posted. This is really good info on Symvastatin..

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Avatar_m_tn
as for high Vitamn D and C intake yes there is all kinds of good info out there... from stopping cancer to slowing down HIV..

We should really start a separate topic on this.. and discuss it more..
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3136921_tn?1380650224
Hi Everyone,

Please keep this on topic.  :)

Thanks!

Steph
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