PIRFENIDONE, IN PATIENTS WITH LIVER CIRRHOSIS

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A PILOT STUDY OF A NOVEL ANTI-INFLAMMATORY AND ANTI-FIBROTIC AGENT,

PIRFENIDONE, IN PATIENTS WITH LIVER CIRRHOSIS

Armendariz-Borunda, University of Guadalajara, OPD Hospital

Civil de Guadalajara, Guadalajara, Jal. Mexico, Mexico; M. Cristina

Islas-Carbajal, Meza, Ana Rincon, University of

Guadalajara,, Guadalajara, Jal. Mexico, Mexico; Arnulfo Alvarez,

University of Guadalajara, Guadalajara, Jal. Mexico, Mexico; Zachary

D. Goodman, Armed Forces Institute of Pathology, Washington, DC;

A.Soledad Sandoval, University of Guadalajara, Guadalajara, Jal.

Mexico, Mexico; Amador Covarrubias, Hospital Civil I Menchaca,

Guadalajara, Jal. Mexico, Mexico; Gil Arechiga, University of

Guadalajara, Guadalajara, Jal. Mexico, Mexico; Leonel García,

University of Guadalajara, OPD Hospital Civil de Guadalajara,

Guadalajara, Jal. Mexico, Mexico.

INTRODUCTION

Pirfenidone (PFD) is an orally bioavailable pyridone derivative that

affects a variety of cytokines, including inhibition of TGF-beta, TNF-

alpha, PDGF, and EGF. PFD has been shown in clinical studies to

improve physiologic parameters in patients with pulmonary fibrosis.

We have previously shown that PFD decreased hepatic fibrosis in two

different rat models of cirrhosis (J of Hepatology 37: 797-805,

2002). Our objective in this pilot clinical study was to evaluate the

safety and preliminary activity of PFD in patients with cirrhosis of

varying etiologies.

METHODS

All patients had histologic and/or clinical evidence of cirrhosis.

PFD was given orally at a dose of 400 mg TID for 12 months. Physical

examination and labs including ALT, AST, bilirubin, albumin and

prothrombin time, platelet count were assessed at baseline and on

monthly basis. HCV RNA levels were measured in patients with chronic

hepatitis C (Cobas Amplicor HCV Monitor v2.0). Liver biopsies were

obtained at baseline and after 12 months of treatment and were read

independently by two hepatopathologists who were blinded to the

biopsy sequence. Modified Histological Activity (HAI) Index of

Knodell and Ishak fibrosis stage were used to assess changes in

necroinflammatory scores and fibrosis stage, respectively. Change in

steatosis was also assessed.

RESULTS

A total of 26 patients with cirrhosis due to hepatitis C (15),

ethanol (8), amyloidosis (1), autoimmune disease (1) and Budd-Chiari

syndrome (1) were included. The mean age was 57 years (range, 29-75)

with 13 males. Liver biopsies at end of therapy showed a 2-point or

greater reduction in the HAI necroinflammatory score in 41% of the

patients. Steatosis decreased in 33% of the patients, was unchanged

in 42% and worsened in 25%. While there was no significant reduction

in the Ishak fibrosis stage, improvement in interstitial fibrosis was

noted. Evidence of cell regeneration was seen in some patients.

HCV RNA levels were measured in 15 patients with chronic hepatitis C.

At 6 months, 9 patients had a decrease in viral load, 2 patients

remained unchanged and 4 patients displayed an increase in viral load

compared to baseline. No patient had a sustained virologic response.

4 out of 15 (27%) HCV patients had normalization of ALT, 7 out of 15

(47%) had decreased ALT values, 1 did not change (7%) and 3 patients

showed a modest increase in ALT (20%). PFD was well tolerated with

the predominant drug-related adverse events being nausea,

photosensitivity rash, and itching occurring in 15% of the patients

and which improved after 2 to 3 months of therapy.

CONCLUSIONS

In this pilot study, treatment of cirrhotic patients with pirfenidone

for one year was well tolerated. A significant reduction in

necroinflammation (= 2-point reduction in HAI grade) and steatosis

was observed in a substantial proportion of patients. A subset of

patients with chronic HCV infection showed on-treatment reduction in

HCV RNA levels. Longer treatment duration or a less cirrhotic patient

population may be needed to demonstrate effects on fibrosis. These

data support conducting clinical studies to evaluate a potential role

of PFD in the treatment of steatosis, or in combination therapy for

chronic hepatitis C. This work was supported by Grants of Marnac, Inc

and InterMune, Inc.

http://www.hcvadvocate.org/news/reports/AASLD_2003-1.html