Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

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Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to

Alfa-Interferon and Ribavirin

(Am J Gastroenterol Feb 2006;101:399-402)

Case Reports

Milazzo, M.D.1, Mara Biasin, Ph.D.2, Nadia Gatti, M.D.1, Luca

Piacentini, Ph.D.2, Fosca Niero, M.D.3, Barbara Zanone Poma, Ph.D.1,

Massimo Galli, M.D.1, Mauro Moroni, M.D.1, Clerici, M.D.2, and

Agostino Riva, M.D.1

Immunomodulation of thalidomide is represented by the

antiinflammatory effect through inhibition of tumor necrosis factor

α and costimulatory effect on human CD8+ T cells. We investigated

the efficacy and safety of a 24-wk course of thalidomide at a dosage

of 200 mg/day in eight patients with HCV chronic hepatitis

nonresponders to interferon α plus ribavirin. We observed a

significant mean decrease of serum aminotransferases and γ-

glutamyltransferases of 39% and 61%, respectively (p= 0.017 and

0.02). Tumor necrosis factor-αin vitro production in mononuclear

cells decreased with thalidomide in all the subjects (p= 0.028).

Perforin- and granzyme-specific mRNA expression increased under

thalidomide without statistical significance. A positive correlation

between biochemical and immunological parameters was observed with

higher increase of granzyme and perforin values in patients showing

reduction of aminotransferases. Finally upregulation of T-helper 1

cytokine expression as mean interferon γ/IL-10 ratio was evidenced.

Thalidomide was well tolerated. In conclusion, thalidomide was able

to reduce liver enzymes in six out of eight patients with chronic

hepatitis C and to reduce tumor necrosis factor α production,

representing a promising new approach for the treatment of HCV

infection.

INTRODUCTION

The immunopathogenesis of liver damage in chronic hepatitis C is due

to cytolytic and noncytolytic mechanisms mediated by cytotoxic T

lymphocytes (CTL) and inflammatory cytokines (1, 2). Thalidomide

exerts antiinflammatory activity primarily by the inhibition of tumor

necrosis factor (TNF)-α; a potent costimulatory effect of

thalidomide on human CD8+ T cells in vitro has been also described

(3, 4). Its immunomodulating effects include increased production of

IL-12, IL-2, and IFN-γ (5, 6).

We evaluated the safety and the effects of thalidomide in the

treatment of eight subjects with HCV chronic hepatitis.

PATIENTS AND METHODS

Eight HCV-infected patients with active chronic hepatitis,

nonresponders or relapsers to a previous treatment with IFN-α and

ribavirin, were treated with thalidomide at a daily dose of 200 mg

for 24 wk. They had no HBV or HIV coinfection and had stopped IFN and

ribavirin at least 6 months before enrollment.

A liver biopsy was performed within 3 months of enrollment; serum

liver enzymes were monitored monthly during the study period and

serum quantitative HCV-RNA was measured every 3 months. The study was

approved by our Institutional Ethical Committee, a written informed

consent was obtained from all the patients.

Evaluation of mRNA Specific for Cytolytic Molecules and Cytokines

Total RNA was extracted from peripheral blood mononuclear cells

(PBMC) and was reverse transcribed. Perforin, granzyme, IL-10, and

IFN-γ were evaluated by RealTime PCR, were expressed as Π" Π" Ct and

presented as ratios between the target gene mRNA and the GAPDH

housekeeping mRNA.

TNF-α Production

PBMC were cultured with PMA at a concentration of 1 ng/mL and

ionomycin at a concentration of 500 ng/mL for 48 h. TNF-α was

measured by enzyme-linked immunosorbent assay (ELISA, Amersham

Biosciences, UK).

Statistical Analysis

Continuous data were analyzed by the Student's t-test and by Wilcoxon

nonparametric test.

RESULTS

The characteristics of the patients are shown in Table 1. High

prevalence of HCV genotype 1 (75%) and high degree of fibrosis were

detected (mean ± standard deviation (SD) Knodell activity score: 6.2

± 2.4; mean ± SD Knodell fibrosis score: 4.4 ± 1.5). The mean ±

SD ALT level before thalidomide was 164.9 ± 66 IU/L.

Thalidomide was generally well tolerated; the majority of the

patients referred constipation and drowsiness and one patient (No. 2)

developed mild peripheral neuropathy.

We observed a mean decrease of serum ALT of 39% at wk 24 compared to

pretreatment levels (from mean value ± SD of 164.9 ± 66 IU/L to

100.6 ± 25 IU/L, p= 0.017 95% CI: 19.1-109.3; Fig. 1A). Gamma-

glutamyl-tranferases (GGT) showed a mean decrease of 61% (from mean

value ± SD of 127.6 ± 87 IU/L to 49 ± 28 IU/L, p= 0.02; 95% CI:

14.8-128.1 Fig. 1B). Six of the eight patients showed a decrease of

serum transaminases, the remaining two did not show significant

change of liver enzymes. It is noteworthy that after interruption of

thalidomide the mean values of ALT and γGT returned close to

pretreatment levels (Fig. 2).

No significant change of serum HCV-RNA was observed.

No detectable histologic modification for both necroinflammatory and

fibrosis scores was evidenced in the four patients who accepted to

undergo liver biopsy at the end of treatment.

Immunological Results

Granzyme- and perforin-specific mRNA levels increased after 24 wk of

thalidomide without reaching statistical significance (Fig. 3A and

. A higher increase of granzyme and perforin values were observed

in patients with reduction of ALT: from 3,952 N fold to 6,889 N fold

(p= 0.028, 95% CI: 691-5176) and from 1,920 N fold to 2,405 N fold

(p= 0.46), respectively, while no increase was observed in subjects

without biochemical response. Moreover, therapy resulted in an

upregulation of Th1 cytokine expression as mean ± SD IFN-γ/IL-10

ratio changed from 8.1 ± 5 to 13.0 ± 14.7 (p= 0.43; Fig. 3C).

Finally in vitro TNF-α production decreased from a mean ± SD value

of 3,530 ± 2,224 pg/mL to 2,397 ± 1,905 pg/mL at wk 24 of

treatment. (p= 0.028, 95% CI: 170.3-2094.2; Fig. 3D).

DISCUSSION

To our knowledge this is the first study to employ thalidomide in the

treatment of hepatitis C. We observed a significant decrease of ALT

and γGT levels during a 24-wk course of treatment. No effect on HCV

viremia and no histological improvement were observed.

At the dosage of 200 mg/day thalidomide was well tolerated and no

rise of aminotransferases was seen after starting the drug, as

previously reported in one patient (7).

Interestingly the most significant decrease of ALT was observed in

patients with higher pretreatment levels. These data could be

explained by the antiinflammatory activity on nonspecific immune

activation responsible of liver damage and possibly by the

costimulatory effect that thalidomide determines on activated CTL

immune response (3, 4, 8).

We found an increased IFN-γ/IL-10 mRNA ratio with thalidomide

administration, suggesting a cytokine shift from Th2 to Th1, although

the limited number of patients and the high individual variability do

not allow a conclusive interpretation.

A recent study has shown that etanercept, an anti-TNF agent, used as

an adjuvant to interferon and ribavirin therapy seems to enhance

viral clearance in chronic hepatitis C (9). Several studies have

demonstrated the anti-TNF activity of thalidomide in vitro and in

vivo and we accordingly detected a reduced TNF-α production by

stimulated PBMC in vitro. Moreover thalidomide was reported to

accelerate the recovery from experimental cirrhosis in rats, probably

mediated by TNF-α suppression in the liver (10). We did not find

histologic improvement in the four follow-up liver specimens, but

longer follow-up might be necessary to determine a late beneficial

effect.

Thalidomide due to its immunomodulatory characteristics might

represent a new pharmacologic approach to chronic HCV infection.

Future investigations might focus on the association of thalidomide

with IFN or possibly with IFN and ribavirin to evaluate the potential

improvement of the current therapeutic regimens.

[Guest guest]

When I first read this, I noted it as something to talk to my doctor about. Then I checked the web for more data on Thalidomide. This drug was developed by a pharma company, and prior to being banned in the early sixties was used to treat nausia in pregnant women. There were some terrible side effects. I'm not a pregnant woman, and I try this someday, but I much prefer natural or extracts from naturally occuring substances. This post is not intended to take away form the validity of 's post, nor the validity of the study being sited. I just wanted to add information to it. , please continue to post all the good news you find. It not only gives us hope, but shows us that there are thousands of people out there working to help us. You are an angel ! Bless you and the things you do for us here. Eat well, sleep well,

be well! elizabethnv1 wrote: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interferon and Ribavirin(Am J Gastroenterol Feb 2006;101:399-402)Case Reports Milazzo, M.D.1, Mara Biasin, Ph.D.2, Nadia Gatti, M.D.1, Luca Piacentini, Ph.D.2, Fosca Niero, M.D.3, Barbara Zanone Poma, Ph.D.1, Massimo Galli, M.D.1, Mauro Moroni, M.D.1, Clerici, M.D.2, and Agostino Riva, M.D.1Immunomodulation of thalidomide is represented by the antiinflammatory effect through inhibition of tumor necrosis factor α and costimulatory effect on human CD8+ T cells. We investigated the efficacy and safety of a 24-wk course of thalidomide at a dosage of 200 mg/day in eight patients with HCV chronic hepatitis nonresponders to interferon α plus

ribavirin. We observed a significant mean decrease of serum aminotransferases and γ-glutamyltransferases of 39% and 61%, respectively (p= 0.017 and 0.02). Tumor necrosis factor-αin vitro production in mononuclear cells decreased with thalidomide in all the subjects (p= 0.028). Perforin- and granzyme-specific mRNA expression increased under thalidomide without statistical significance. A positive correlation between biochemical and immunological parameters was observed with higher increase of granzyme and perforin values in patients showing reduction of aminotransferases. Finally upregulation of T-helper 1 cytokine expression as mean interferon γ/IL-10 ratio was evidenced. Thalidomide was well tolerated. In conclusion, thalidomide was able to reduce liver enzymes in six out of eight patients with chronic hepatitis C and to reduce tumor necrosis factor α production, representing a promising new approach for the treatment of

HCV infection.INTRODUCTION The immunopathogenesis of liver damage in chronic hepatitis C is due to cytolytic and noncytolytic mechanisms mediated by cytotoxic T lymphocytes (CTL) and inflammatory cytokines (1, 2). Thalidomide exerts antiinflammatory activity primarily by the inhibition of tumor necrosis factor (TNF)-α; a potent costimulatory effect of thalidomide on human CD8+ T cells in vitro has been also described (3, 4). Its immunomodulating effects include increased production of IL-12, IL-2, and IFN-γ (5, 6).We evaluated the safety and the effects of thalidomide in the treatment of eight subjects with HCV chronic hepatitis.PATIENTS AND METHODS Eight HCV-infected patients with active chronic hepatitis, nonresponders or relapsers to a previous treatment with IFN-α and ribavirin, were treated with thalidomide at a daily dose of 200 mg for 24 wk. They had no HBV or HIV coinfection and

had stopped IFN and ribavirin at least 6 months before enrollment.A liver biopsy was performed within 3 months of enrollment; serum liver enzymes were monitored monthly during the study period and serum quantitative HCV-RNA was measured every 3 months. The study was approved by our Institutional Ethical Committee, a written informed consent was obtained from all the patients.Evaluation of mRNA Specific for Cytolytic Molecules and CytokinesTotal RNA was extracted from peripheral blood mononuclear cells (PBMC) and was reverse transcribed. Perforin, granzyme, IL-10, and IFN-γ were evaluated by RealTime PCR, were expressed as ?#34;?#34;Ct and presented as ratios between the target gene mRNA and the GAPDH housekeeping mRNA.TNF-α ProductionPBMC were cultured with PMA at a concentration of 1 ng/mL and ionomycin at a concentration of 500 ng/mL for 48 h. TNF-α was measured by enzyme-linked immunosorbent

assay (ELISA, Amersham Biosciences, UK).Statistical AnalysisContinuous data were analyzed by the Student's t-test and by Wilcoxon nonparametric test.RESULTS The characteristics of the patients are shown in Table 1. High prevalence of HCV genotype 1 (75%) and high degree of fibrosis were detected (mean ± standard deviation (SD) Knodell activity score: 6.2 ± 2.4; mean ± SD Knodell fibrosis score: 4.4 ± 1.5). The mean ± SD ALT level before thalidomide was 164.9 ± 66 IU/L.Thalidomide was generally well tolerated; the majority of the patients referred constipation and drowsiness and one patient (No. 2) developed mild peripheral neuropathy.We observed a mean decrease of serum ALT of 39% at wk 24 compared to pretreatment levels (from mean value ± SD of 164.9 ± 66 IU/L to 100.6 ± 25 IU/L, p= 0.017 95% CI: 19.1-109.3; Fig. 1A). Gamma-glutamyl-tranferases (GGT) showed a mean decrease of 61%

(from mean value ± SD of 127.6 ± 87 IU/L to 49 ± 28 IU/L, p= 0.02; 95% CI: 14.8-128.1 Fig. 1B). Six of the eight patients showed a decrease of serum transaminases, the remaining two did not show significant change of liver enzymes. It is noteworthy that after interruption of thalidomide the mean values of ALT and γGT returned close to pretreatment levels (Fig. 2).No significant change of serum HCV-RNA was observed.No detectable histologic modification for both necroinflammatory and fibrosis scores was evidenced in the four patients who accepted to undergo liver biopsy at the end of treatment.Immunological ResultsGranzyme- and perforin-specific mRNA levels increased after 24 wk of thalidomide without reaching statistical significance (Fig. 3A and . A higher increase of granzyme and perforin values were observed in patients with reduction of ALT: from 3,952 N fold to 6,889 N fold (p= 0.028, 95% CI:

691-5176) and from 1,920 N fold to 2,405 N fold (p= 0.46), respectively, while no increase was observed in subjects without biochemical response. Moreover, therapy resulted in an upregulation of Th1 cytokine expression as mean ± SD IFN-γ/IL-10 ratio changed from 8.1 ± 5 to 13.0 ± 14.7 (p= 0.43; Fig. 3C).Finally in vitro TNF-α production decreased from a mean ± SD value of 3,530 ± 2,224 pg/mL to 2,397 ± 1,905 pg/mL at wk 24 of treatment. (p= 0.028, 95% CI: 170.3-2094.2; Fig. 3D).DISCUSSION To our knowledge this is the first study to employ thalidomide in the treatment of hepatitis C. We observed a significant decrease of ALT and γGT levels during a 24-wk course of treatment. No effect on HCV viremia and no histological improvement were observed.At the dosage of 200 mg/day thalidomide was well tolerated and no rise of aminotransferases was seen after starting the drug, as previously reported in one

patient (7).Interestingly the most significant decrease of ALT was observed in patients with higher pretreatment levels. These data could be explained by the antiinflammatory activity on nonspecific immune activation responsible of liver damage and possibly by the costimulatory effect that thalidomide determines on activated CTL immune response (3, 4, 8).We found an increased IFN-γ/IL-10 mRNA ratio with thalidomide administration, suggesting a cytokine shift from Th2 to Th1, although the limited number of patients and the high individual variability do not allow a conclusive interpretation.A recent study has shown that etanercept, an anti-TNF agent, used as an adjuvant to interferon and ribavirin therapy seems to enhance viral clearance in chronic hepatitis C (9). Several studies have demonstrated the anti-TNF activity of thalidomide in vitro and in vivo and we accordingly detected a reduced TNF-α production

by stimulated PBMC in vitro. Moreover thalidomide was reported to accelerate the recovery from experimental cirrhosis in rats, probably mediated by TNF-α suppression in the liver (10). We did not find histologic improvement in the four follow-up liver specimens, but longer follow-up might be necessary to determine a late beneficial effect.Thalidomide due to its immunomodulatory characteristics might represent a new pharmacologic approach to chronic HCV infection. Future investigations might focus on the association of thalidomide with IFN or possibly with IFN and ribavirin to evaluate the potential improvement of the current therapeutic regimens.It's a pleasure having you join in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/Happy

Posting

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If I read this right, Thalidomide is being used not for nausea during TX, but it's helping the body to destroy the virus and actually relieving liver inflammation, plus it appears to be shrinking tumors. They're testing this on people who have failed to respond to interferon, or who have a genotype that doesn't respond well to the normal drug combo.

I remember reading an article about ten years ago that the drugs was being used in south America again for the treatment of something or other (sorry, I can't remember what) but it's use was really controversial.

WulfeMom

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

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[Guest guest]

If I read this right, Thalidomide is being used not for nausea during TX, but it's helping the body to destroy the virus and actually relieving liver inflammation, plus it appears to be shrinking tumors. They're testing this on people who have failed to respond to interferon, or who have a genotype that doesn't respond well to the normal drug combo.

I remember reading an article about ten years ago that the drugs was being used in south America again for the treatment of something or other (sorry, I can't remember what) but it's use was really controversial.

WulfeMom

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

I am using the free version of SPAMfighter for private users.It has removed 19886 spam emails to date.Paying users do not have this message in their emails.Try SPAMfighter for free now!

No virus found in this outgoing message.

Checked by AVG Free Edition.

Version: 7.1.371 / Virus Database: 267.15.1/250 - Release Date: 2/3/2006

[Guest guest]

Thalidomide was used for the nausea of pregnancy over in Europe and motion sickness but it caused devastating birth defects .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

I am using the free version of SPAMfighter for private users.It has removed 19886 spam emails to date.Paying users do not have this message in their emails.Try SPAMfighter for free now!

No virus found in this outgoing message.Checked by AVG Free Edition.Version: 7.1.371 / Virus Database: 267.15.1/250 - Release Date: 2/3/2006

[Guest guest]

was that the only side effects tho? current tx is also very bad

for unborn babies, you have to promise not to get pregnant, OR

get someone pregnant while you are on Interferon and riba....

if it's helpful otherwise maybe they've finally found a good use

for the Thalidomide?

Sara

Re: Thalidomide in the

Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to

her horror stories of taking care of thalidomide babies and the

terrible birth defects . I somehow doubt that thalidomide is ever

going to be used . But as a researcher I am obligated to post

what current research so I did. But I would advocate against this

drug .

------------------------------------------------------------------------------

I am using the free version of SPAMfighter for private users.

It has removed 19886 spam emails to date.

Paying users do not have this message in their emails.

Try SPAMfighter for free now!

It's a pleasure having you join in our conversations. We hope

you have found the support you need with us.

If you are using email for your posts, for easy access to our

group, just click the link--

http://groups.yahoo.com/group/Hepatitis_C_Central/

Happy Posting

[Guest guest]

It was also used in Australia in the 60's. I have a sister who was born with defects that we're assuming was due to this so-called miracle drug back then! Thankfully my sisters birth defects were only minor by comparison with others.

anne

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

[Guest guest]

Your sister was very lucky .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

[Guest guest]

Your sister was very lucky .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

[Guest guest]

Oh yes Liz, we know! It affected her spine causing klippel-feil syndrome and scholiosis. Strangely it affected her hand too. She was born without a thumb on one hand. All things considered, yes, she was very lucky.

anne

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .