ezetimibe effect on interferon genes and increase of response

[stef2011]

http://www.journal-of-hepatology.eu/article/S0168-8278(11)60460-1/pdf

457
EZETIMIBE IMPROVES EFFICACY OF PEGIFN AND RIBAVIRIN
THERAPY VIA ACCELERATION OF IFN-MEDIATED ISG15
CONJUGATION SYSTEM
M. Nakamuta1, M. Yada2, K. Notsumata3, N. Tanaka3, R. Yada1,
M. Kohjima1, K. Gotoh1, T. Yoshimoto1, N. Fukushima1,
K. Fukuizumi1, K. Kawabe1, T. Mizutani1, N. Harada1, S. Morizono4,
N. Sakamoto5, M. Enjoji6. 1Gastroenterology, Clinical Research
Center, Kyushu Medical Center, National Hospital Organization,
Fukuoka, 2Hepatology, Aso Iizuka Hospital, Iizuka, 3Internal Medicine,
Fukui-ken Saiseikai Hospital, Fukui, 4Internal Medicine, Saiseikai
Fukuoka Hospital, Fukuoka, 5Gastroenterology and Hepatology, Tokyo
Medical and Dental University, Tokyo, 6Clinical Pharmacology, Faculty
of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
E-mail: ***@****
Background and Aim: Lipid metabolism in the liver reportedly
affects innate immunity and hepatitis C virus (HCV) replication.
Ezetimibe, an HMG-CoA reductase inhibitor, is used as an adjuvant
to PegIFN and ribavirin therapy. It inhibits Nieman-Pick-C1-like-1,
which is abundantly expressed in the liver. Here, we investigated
ezetimibe’s effect on subgenomic HCV replication, and its efficacy
when co-administered with PegIFN and ribavirin therapy.
Method: Samples from 334 HCV-1 high-titer patients treated with
PegIFN/RBV, of whom 44 received ezetimibe and 290 did not,
were used to study ezetimibe’s efficacy as an adjuvant. Patients’
HCV RNA-negativity (defined as early viral response [EVR]: less
than 50 IU/ml by Amplicore method) was tracked from the start of
treatment to the 12th week.
We also studied Huh7/Rep-Feo, an HCV-replicon cell line
expressing a selectable chimeric reporter protein of firefly luciferase
and neomycin, which was cultured with ezetimibe and IFNa.
Reporter protein expression was measured by luciferase assay;
expression levels of related genes were measured by quantitative
real-time PCR.
Results: In the clinical study, EVR occurred in 65.9% of patients
receiving ezetimibe, but only 45.2% of patients who did not
(P = 0.002). In the Huh7 cells, ezetimibe suppressed luciferase
activity in a dose-dependent manner, while enhancing IFNa’s
repression of HCV replication. To study this repressive mechanism,
we measured expression of several genes related to innate
immunity. Interferon singly induced ISG15, activating enzyme
Ube1L and conjugating enzyme UbcH8. Ezetimibe enhanced ISG15
expression singly and in combination with IFNa. Reportedly,
IFN-mediated ISGylation of HCV-NS5A inhibits HCV replication in
subgenomic replicon cells. These results suggest that ezetimibe may
accelerate the IFN-mediated ISG15 conjugation system.
Conclusions: Ezetimibe shows synergistic anti-HCV effect with
IFNa in subgenomic system by accelerating the IFN-mediated ISG15
conjugation system. Ezetimibe may be a promising adjuvant for
PegIFN and ribavirin therapy against chronic HCV infection.

[stef2011]

no they only work to improve pegintf response, they might even allow some non-responders to respond to peg

they are totally useless with antivirals:

i tried nitazoxanide with entecavir and it did make hbvdna from around detectable 0-21iu/ml to always undetectable (when i stopped it hbvdna rebounded so i added tdf) but the effect on hbsag was small and only transient

ezetimibe with etv plus tdf had no effect on hbsag

[mer971]

Good news, Do you think that this drug can be used together with antivirals,also for people that don't have cholesterol or high blood pressure?

[stef2011]

good study on ntz just published
Titolo: IMMUNOMODULATORY EFFECTS OF NITAZOXANIDE AND RELATED MOLECULES
Autori: GNUDI, FEDERICA
Tutor: CLERICI, MARIO SALVATORE
Supervisori e coordinatori: CLERICI, MARIO SALVATORE
Data di discussione: 3-feb-2014
Abstract: Background: Nitazoxanide (Alinia®, NTZ) and its active circulating metabolite tizoxanide (TIZ) belong to a new class of anti-infective agents active against parasites, anaerobic bacteria, and viruses. Nowadays, NTZ is licensed in the United States for the treatment of diarrhea caused by Cryptosporidium parvum and Giardia lamblia in adults and children older than twelve months of age. The amplitude of the spectrum of pathogens targeted by NTZ and new-generation non-nitro thiazolides, makes it very unlikely that the action of these compounds is mediated by a pathogen-specific mechanism(s), suggesting instead that thiazolides act as immunomodulants. To date, the potential effect of these compounds on immune responses has nevertheless not been analysed. In particular, because innate immunity and type 1 interferons are pivotal in early and effective antiviral immune responses that are not antigen-restricted, it is plausible to hypothesize that thiazolides could potentiate this arm of the immune system. To verify this possibility, we performed extensive in vitro analyses on the immunomodulatory effects of TIZ and the second generation non-nitro thiazolide RM4848 using two different models of viral infection: Influenza and HIV-1. Methods: Peripheral blood mononuclear cells (PBMCs) from 20 healthy donors were stimulated with influenza virus antigen (FLU) or infected with HIV-1BaL strain and cultured in presence/absence of TIZ or RM4848. Thiazolide effects on innate immunity were examined by evaluating TLRs expression on monocytes, IFN-secretion by dendritic cells, cytokine and chemokine production, mRNA expression of multiple genes involved in TLR, type I IFN and in cholesterol metabolism pathways. Results: Thiazolides are associated with strong immunomodulatory effects. Notably, these compounds, both in FLU-stimulated and in HIV-1-infected cells, significantly increase: 1) TLR-expression on monocytes, 2) IFN production, 3) chemokine and cytokine production, 4) mRNA expression of different genes operating in the TLR and type I IFN pathways, 5) genes involved in cholesterol metabolism and efflux. Conclusions: Data herein show that thiazolides are potent type I IFN inducers, triggering a selective activation of several IFN-stimulated gene (ISG) pathway. Thus, increased expression of innate antiviral factors and the different modulation of genes involved in cholesterol metabolism and efflux suggest a new mechanism of action mediated by thiazolides.
Parole chiave: thiazolides ; influenza ; HIV-1 ; nitazoxanide
Settori scientifico disciplinari: MED/04 - Patologia Generale
Citazione: IMMUNOMODULATORY EFFECTS OF NITAZOXANIDE AND RELATED MOLECULES : corso di MEDICINA MOLECOLARE / Federica Gnudi ; tutor: M. Clerici ; coordinatore: M. Clerici. - Milano : Università degli studi di Milano. DIPARTIMENTO DI FISIOPATOLOGIA MEDICO-CHIRURGICA E DEI TRAPIANTI, 2014 Feb 03. ((26. ciclo, Anno Accademico 2013.

[stef2011]

another hcv trial using higher ezetimibe dose at 20mg per day combo to keep an eye on

http://trialx.com/curebyte/2014/04/29/pilot-study-of-ezetimibe-for-chronic-hepatitis-c-virus-hcv-infection/

Clinical Trial Conditions: Chronic Hepatitis C
Treatments in this Clinical Trial : Ezetimibe
Clinical Trial Phase: Phase 1
Eligible Clinical Trial Participant Age : Between 18 years to 100 years
Can Healthy Volunteers Participate: No
Clinical Trial Lead Sponsor: Pontificia Universidad Catolica de Chile
Detailed Clinical Trial Description: Infection by hepatitis C virus (HCV) affects more than 170 million people in the World and
80.000 in Chile. It causes more deaths than HIV infection in the US and is a leading cause
for liver transplantation in Chile. Even though treatments are evolving with new direct
antiviral agents (DAAs) that are increasing response rates, there are several issues with
these new approaches, including increased toxicity, need for using interferon and ribavirin,
complex algorithms of treatment, high cost, limited effectivity in certain groups (liver
transplant patients) and drug interactions. Treatments targeted at host factors required for
the viral cycle are becoming increasingly explored as an alternative or complement to DAAs.
It has been recently described that Niemann-Pick C1-like 1 (NPC1L1), the intestinal receptor
of cholesterol, serves as an entry factor for HCV. NPC1L1 is, therefore, a key transporter
in the enterohepatic cycle of cholesterol. NPC1L1 can be blocked with ezetimibe, which is
an approved and generally safe drug used for the management of hypercholesterolemia. Our
hypothesis posits that blocking HCV entry to the hepatocyte or intestinal HCV reabsorption
with ezetimibe may have an antiviral effect. In the study, we will administer ezetimibe 20
mg/d to 20 patients with stable chronic hepatitis C for 12 weeks and assess changes in HCV
RNA and core antigen in plasma, bile and feces.
The clinical trial information was obtained from http://clinicaltrials.gov/ct2/show/NCT02126137

[stef2011]

thank you very much for your explanation

i guess my friend is having a strong immune boost by ezetimibe/ntz add on since he even got hypothyroid with very severe sides like it happens with hcv patients.although now that hbsag is very low he is feeling better

[studyforhope]

The enhancement of ifn effects by additional drugs that stimulate interferon sensitive genes is interesting. But the disappointment with gs9620 points to the need of caution with these approaches.

In the end a permanent control of the small remnant HBV infection without external therapy will only be achieved by a resident permanent class I T cell memory population. The formation of this can be induced with ifn if the other two factors, the availability of effective epitopes in the remnant virus and the de novo production of effective lymphocyte clones from the thymus are present.

The long term reduction of the viral load by antivirals reduces the overstimulation and resulting apoptosis and anergy of available T cell clones.
In patients where the epitope availability is good and which consequently show a low cccDNA and hbsag level even before ifn stimulation, the additional push by interferon can activate dormant clones into effective activity leading to a permanent control situation without the need of external therapy.

[stef2011]

sorry i meant first 3 months he was having hbsag increase and no response

[stef2011]

what do you think of the IFN-mediated ISG15 conjugation system accelaration by ezetimibe?

i have a friend of mine on sequential tdf (3years) plus pegintf and he was having total non response, first 3 weeks of combo hbsag increased from about 2500iu/ml to over 7000iu/ml and he was having no sides effect from interferon at all

i suggested him to add ezetimibe 20-50mg daily and nitzoxanide 500mg bid to tdf+pegintf and the same day he started this combo he felt very bad with fever and the usual intf sides effects.by 3 weeks hbsag was 2500iu/ml and now responding to peg very well with 1 log decline at 24 weeks

can we say this was just coincidence or ISG15 conjugation system or nitazoxanide might have done the difference?of course we just share ideas here, too little data to draw conclusions

thanks

[stef2011]

this confirms ezetimibe effect irrespective of hbv receptor for liver cells entrance.
now we only miss a suggested dose and since there is no toxicity or relevant sides high doses are probably better