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News 2004

2003 Research News and Articles

HCV News Archives 2001-2002

 

  Individualized Versus Standard Treatment in Hepatitis C

Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C
  Italian Study Links Tobacco Use and Hepatitis C to Development of Non-Hodgkin’s Lymphoma
  Optimal Dosing Frequency of Pegylated Interferon Alfa-2b (PegIntron) Monotherapy
  12 Weeks of Peginterferon Alfa-2b (PegIntron) and Ribavirin Combination Therapy Shown as Effective as 24 Weeks of Treatment in HCV Patients with Genotype 2 or 3 Virus Who Had an Early Virological Response to Therapy
  Trial Results of 'PEGASYS' Plus Ribavirin 'COPEGUS', a Combination Therapy for Hepatitis C, Presented at the 41st Annual Conference of the Japan Society of Hepatology

 

  SourceURL: http://www.gastrohep.com    

Individualized Versus Standard Treatment HCV

An improvement in virologic efficacy was not achieved with the available individualized treatment options, reports the latest issue of the Journal of Hepatology. Dr Stefan Zeuzema and colleagues aimed to increase virologic response rates by individualized treatment according to the early virologic response. The researchers frequently quantified serum Hepatitis C virus-RNA in 270 patients with chronic Hepatitis C. The patients were treated with peginterferon alfa-2a 180 μg per week and ribavirin 1000-1200 mg per day. Virologic response occurred in 60% of the individualized arm vs 66% in the standard treatment - Journal of Hepatology The team classified patients after 6 weeks as rapid, slow, flat, or null responders. The researchers subsequently randomized patients within each viral kinetic class to continue therapy either with an individualized or standard regimen. Individualized therapy comprised peginterferon monotherapy of 48 weeks or a shorter combination therapy of 24 weeks for 171 rapid responders. Triple therapy with histamine 1mg per day for 48 weeks or prolonged combination therapy of 72 weeks was given to 65 slow responders. The researchers gave 10 flat responders triple therapy, and 22 null responders received high-dose peginterferon 360 μg per week plus ribavirin. The team found that overall end-of-treatment and sustained virologic response rates were 77% in the individualized arm and 77% in the standard treatment arm. The researchers noted that sustained virologic response was 60% in the individualized arm versus 66% in the standard treatment arm. Histamine in addition to peginterferon and ribavirin did not improve virologic response rates in patients with flat response rates. In addition, the team observed that high-dose peginterferon plus ribavirin did not improve virologic response rates in null responders. Dr Zeuzema's team concludes, “An improvement in virologic efficacy was not achieved with the available individualized treatment options.” J Hepatol 2005: 43(2): 250-7 http://www.hcvadvocate.org/news/newsRev/2005/NewsRev-109.html#7

 

NATAP - http://www.natap.org

Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C

....we show a significant relationship between daily cannabis use and fibrosis progression in patients with ongoing CHC. We believe that patients with ongoing CHC should be strongly advised to abstain from daily cannabis use.....

Hepatology
July 2005

Christophe Hézode 1 6, Françoise Roudot-Thoraval 2 6, Son Nguyen 1 5, Pascale Grenard 5, Boris Julien 5, Elie-Serge Zafrani 3 5, Jean-Michel Pawlostky 4 6, Daniel Dhumeaux 1, Sophie Lotersztajn 5, Ariane Mallat 1 5 *
1Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France
2Department of Public Health, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France
3Department of Pathology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France
4Department of Virology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France
5INSERM, U581, Université Paris XII, Hôpital Henri Mondor, Créteil, France; and
6INSERM, U635, Hôpital Henri Mondor, Créteil, France

ABSTRACT
Cannabinoids present in Cannabis sativa (marijuana) exert biological effects via cannabinoid receptors CB1 and CB2. We recently demonstrated that CB1 and CB2 receptors regulate progression of experimental liver fibrosis.

We therefore investigated the impact of cannabis smoking on fibrosis progression rate in patients with chronic hepatitis C (CHC).

Two hundred seventy consecutive untreated patients with CHC of known duration undergoing liver biopsy were studied.

Demographic, epidemiological, metabolic, and virological data were recorded, and detailed histories of cannabis, alcohol, and tobacco use over the span of hepatitis C virus infection were obtained. Fibrosis stage, steatosis, and activity grades were scored according to Metavir system.

Patients were categorized as noncannabis users (52.2%), occasional users (14.8%), or daily users (33.0%), and the relationship between cannabis use and fibrosis progression rate (FPR) or fibrosis stage was assessed.

On multivariate analysis, six factors were independently related to a FPR greater than 0.074 (median value of the cohort):
--daily cannabis use (OR = 3.4 [1.5-7.4]),
--Metavir activity grade A2 or higher (OR = 5.4 [2.9-10.3]),
--age at contamination of more than 40 years (OR = 10.5 [3.0-37.1]),
--genotype 3 (OR = 3.4 [1.5-7.7]),
--excessive alcohol intake (OR = 2.2 [1.1-4.5]), and steatosis (OR = 2.0 [1.0-4.1]).

Daily cannabis use was also an independent predictor of a rapid FPR (>0.15) (OR = 3.6 [1.5-7.5]).

Finally, severe fibrosis (F3) was also predicted by daily cannabis use (OR = 2.5 [1.1-5.6]; P = .034), independently of Metavir activity grade, excessive alcohol intake, age at liver biopsy, steatosis, and tobacco smoking.

In conclusion, daily cannabis smoking is significantly associated with fibrosis progression during CHC. Patients with ongoing CHC should be advised to refrain from regular cannabis use.

INTRODUCTION
Cannabis (Cannabis sativa, marijuana), the most common recreational drug used in the Western world,[13] is the source of more than 60 cannabinoid compounds that bind two G protein-coupled receptors, CB1 and CB2.[14][15] CB1 receptors predominate in the brain and are responsible for the psychoactive effects of -9-tetrahydrocannabinol, the main active component of cannabis, whereas CB2 receptors are mainly expressed in cells of the immune system.[14][15] Expression of both receptors has also been demonstrated in a variety of peripheral tissues.[16] We recently found that CB1 and CB2 receptor expression undergo marked induction in the human liver with cirrhosis.[17-19] We also demonstrated that CB1 receptors strongly enhance experimental liver fibrogenesis, while CB2 receptors exert opposite antifibrogenic effects.[17-19] The present study was therefore undertaken to determine the clinical relevance of these experimental findings. To this aim, we investigated the impact of cannabis smoking on fibrosis progression in patients with CHC.

AUTHOR DISCUSSION
The present study investigates the impact of cannabis use on the natural history of CHC in a large series of patients with untreated CHC and known disease duration. Using multivariate analysis, we identify daily cannabis smoking as an independent predictor of FPR, in contrast to occasional cannabis use. In keeping with these results, severe fibrosis (F3) is also independently related to daily cannabis use.

Major factors previously incriminated in fibrosis progression during CHC were identified as predictors of FPR and fibrosis stage, in addition to daily cannabis smoking, as expected. Older age at infection and chronic excessive alcohol intake are consistently considered primary determinants of fibrosis progression,[4][6][7][20][23][24] and the relationship between fibrosis stage and necroinflammatory grade has been documented in both longitudinal and cross-sectional studies.[3][12][25][26] Steatosis is also a recognized factor associated with severe fibrosis[11][27][28] and emerged as an independent predictor of FPR in our study, while being close to significance for the prediction of severe fibrosis. An impact of genotype 3 was found in analyses based on FPR, independently of steatosis, and was absent when considering fibrosis stage. This finding is rather unusual, because the majority of previous studies found no effect of viral genotype on fibrosis progression.[29] We considered the possibility of a confounding effect related to an interaction between daily cannabis use and genotype 3. However, in daily users of cannabis, the proportion of patients with a FPR greater than 0.074 or greater than 0.15 was not significantly different in patients with genotype 3 compared with patients who had other genotypes (data not shown; P = .411 and .583, respectively). In addition, there was no impact of genotype 3 on the prevalence of severe fibrosis in daily cannabis users (P = .411). Overall, discrepant results obtained with respect to viral genotype deserve additional investigation in further studies.

Our study closely investigated possible confounders of cannabis impact. Arguably, the shorter duration of HCV infection in cannabis users compared with nonusers may result in overestimation of FPR in daily cannabis users. However, daily cannabis use was also independently related to fibrosis stage. Moreover, occasional cannabis smoking did not emerge as an independent predictor of FPR, although this group of patients had similar disease duration compared with daily users. As reported in several studies, prevalence of excessive alcohol intake was high in cannabis users.[13] Nevertheless, it should be noted that there was a significant relationship between fibrosis stage and daily cannabis use in the subgroup of patients with low disease-time alcohol intake. This finding therefore allows us to rule out a confounding effect of alcohol on cannabis impact. Ongoing use of illicit drugs other than cannabis is another potential confounding factor that was excluded at enrollment. An influence of maintenance treatment by methadone or buprenorphine in former IVDU was investigated and ruled out via univariate analysis. Finally, tobacco smoking was also taken into account, given the conflicting results of recent studies.[12][30]

Several limitations of the study must be acknowledged. As in several previous reports,[6][9][24][31] fibrosis progression rate was calculated from a single liver biopsy and estimated disease duration. Potential inaccuracy in the presumed date of infection[32] was limited by exclusive enrollment of patients with a previous history of a single, well-identified route of exposure. The assumption of linearity of FPR has recently been disputed in a report suggesting late acceleration of fibrogenesis.[23] However, our findings are strongly supported by the fact that daily cannabis use was also identified as an independent predictor of fibrosis stage. Disease-time cannabis history recording is also subject to potential inaccuracy. Therefore, this possible bias was minimized by categorizing patients according to the pattern of cannabis use (none, occasional, or daily) rather than a quantitative estimation of usage. Uncertainties in quantification of disease-time alcohol intake were also controlled by grouping patients according to two types of behavior.

Life prevalence of cannabis use has increased steadily over the past 30 years in the Western world.[33][34] A recent survey from the National Institutes of Health also shows that within a period of 10 years, there has been a significant increase in cannabis use among 45- to 64-year-old men and women.[35] In our study, cannabis use was recorded using a standardized questionnaire covering the span of HCV infection. Daily and occasional use of cannabis was reported in 32% and 17% of patients, respectively, and predominantly involved former IVDU, as expected. These findings are in keeping with the notion that prolonged cannabis use for up to 20 years predominantly occurs in near-daily and daily users.[36-38]

There have been great advances in the understanding of mechanisms of action of plant-derived cannabinoids in recent years. Biological effects are elicited by two G protein-coupled cannabinoid receptors, CB1 and CB2, that also bind endogenous lipidic cannabinoid ligands with autocrine and paracrine effects.[14][15] Although the central properties of cannabinoids such as mood regulation, stimulation of appetite, and analgesia are best known, the peripheral effects of the compounds are becoming increasingly recognized.[16] In this respect, it has been shown that endogenous activation of the cannabinoid system plays a role in the pathogenesis of portal hypertension associated with cirrhosis via CB1-dependent splanchnic vasodilation.[39][40] We recently demonstrated that the cannabinoid system is involved in experimental liver fibrogenesis.[17-19] Along this line, results of the present study are in keeping with our experimental data demonstrating the profibrogenic role of CB1 receptors.[18][19] Indeed, we found a strong induction of CB1 receptor expression in samples of human livers with cirrhosis, predominating in liver fibrogenic cells. Moreover, we showed that mice genetically invalidated for the CB1 receptor display reduced fibrosis following chronic intoxication with carbon tetrachloride compared with wild-type littermates. These data suggest that CB1-receptor antagonism may open new therapeutic avenues in the treatment of liver fibrosis.[19]

In conclusion, we show a significant relationship between daily cannabis use and fibrosis progression in patients with ongoing CHC. We believe that patients with ongoing CHC should be strongly advised to abstain from daily cannabis use. This recommendation might be particularly beneficial in difficult-to-treat patients.


 

 
 
Italian Study Links Tobacco Use and Hepatitis C to Development of Non-Hodgkin’s Lymphoma

Italian researchers have reported that smoking and hepatitis C virus (HCV) increases the incidence of non-Hodgkin’s lymphoma (NHL). This study was published in the July 2005 issue of the International Journal of Cancer .[1]

Non-Hodgkin’s lymphomas are a group of diseases of generally unknown etiology. However, the incidence of NHL, especially low-grade NHL has been increasing in the general population. In contrast to other malignancies, there has been no clear association between alcohol and tobacco use and the incidence of NHL.

Previous U.S. studies have evaluated the incidence of NHL in smokers and nonsmokers and concluded that there is no association between tobacco use and NHL in men or women.[2],[3] However, two studies have shown an increased incidence of follicular lymphoma in smokers.[4],[5] These authors point out that many of the past epidemiology studies have been flawed by not considering sub-types of NHL and usually only distinguish NHL from Hodgkin’s lymphoma. In one of these studies, NHL subtypes were evaluated in 601 patients and smoking histories were compared with 718 control patients without NHL. These researchers reported that the increased risk of follicular lymphoma appears to be associated with increased intensity and duration of smoking, and cumulative lifetime exposure to smoking. They reported a 50% increased risk for 16-33 pack-years and an 80% increased risk with 34 pack years or greater. There was no increased risk for the other NHL subtypes. In the second study, data on over 6,500 cases of NHL showed only an increase incidence of follicular NHL and not other cell types.

Studies from Italy, but not from the United States, have also shown an increased incidence of NHL in patients with HCV infection. Some researches suspect that this correlation can only be observed in populations where HCV is highly prevalent.

Italian researchers have evaluated the effects of HCV and smoking on the incidence of NHL. In this recent study, conducted between 1999 and 2002, researchers used a case-controlled study to examine the association of HCV, smoking habits and NHL. The study was focused in two areas of northern and southern Italy. Study participants included 225 newly diagnosed NHL patients and 504 control subjects, who had been diagnosed with a variety of non-cancerous, non-autoimmune and non-tobacco related conditions.

Results of the study found that current, heavy smokers (more than 20 cigarettes per day) had more than twice the risk of developing NHL than patients who had never smoked. This risk was consistent in all age groups and among both genders. Further analysis demonstrated that current and heavy smokers were also at higher risk of developing more aggressive and higher grades of NHL. The increased risk of developing intermediate and high-grade lymphomas was 25 fold among smokers with a lower risk for low grade NHL. Hepatitis C virus also increased the incidence of NHL independent of the smoking effect. There was a four fold overall risk of developing NHL in current heavy smokers who were HCV-positive.

Comments: These data may be applicable to U.S. smokers who carry HCV making such individuals at a significantly greater risk of developing NHL. However, these data are at odds with most published reports showing only an increased incidence of follicular lymphoma with smoking. The striking increase in aggressive lymphomas with smoking is unique to this study and needs to be evaluated in other populations. There is a possibility that this is a unique population with a high prevalence of HCV and smoking.

References:
 

[1]Talamini R, Polesel J, Montella M, et al. Smoking and Non-Hodgkin’s Lymphoma: Case-Control Study in Italy. International Journal of Cancer. 2005;115:606-610.

[2]Bracci PM and Holly EA. Tobacco use and non-Hodgkin’s lymphoma: results from a population-based case-control study in the San Francisco Bay Area, California. Cancer Causes Control. 2005;16:333-346.
[3]Willett EV, Smith AG, Dovey GL, et al. Tocacco and alcohol consumption and risk of non-Hodgkin’s lymphoma. Cancer Causes Control. 2004;15:771-780.
[4]Morton LM, Holford TR, Leaderer B, et al. Cigarette smoking and risk of non-Hodgkin’s lymphoma subtypes among women. British Journal of Cancer. 2003;89:2087-2092.
[5]Morton LM, Hartge P, Holford TR, et al. Cigarette smoking and risk of non-Hodgkin’s lymphoma: a pooled analysis from the International Lymphoma Epidemiology Consortium (interlymph). Cancer Epidemiol Biomarkers Prev. 2005;14:925-933.

http://professional.cancerconsultants.com/oncology_main_news.aspx?id=34524

 

Optimal Dosing Frequency of Pegylated Interferon Alfa-2b (PegIntron) Monotherapy

Pegylated interferon alfa-2b/PEG-IFN-alfa2b (PegIntron) has been shown to provide superior efficacy to IFN-alfa2b in patients with chronic hepatitis C (predominantly genotype 1) infection as measured by viral clearance. This study was conducted to determine the optimal dosing regimen of PEG-IFN-alfa2b required to obtain a maximum decrease of hepatitis C viral RNA.

This was a 24-week, open-label, multicenter, parallel-group, randomized, active-controlled trial in the United Kingdom, France, and Israel. Individuals (n = 61) with chronic hepatitis C infection, genotype 1, received IFN-alfa2b 3 mIU 3 times weekly for 24 weeks, or PEG-IFN-alfa2b 1.5 or 3.0 ìg/kg/wk, as total weekly full or split doses, for 12 weeks.

At week 12, serum RNA titer was measured, and all PEG-IFN-alfa2b patients continued with 1.5 ìg/kg/wk for a further 12 weeks.

Results

· Mean serum hepatitis C RNA levels decreased in all groups at weeks 12 and 24.

· PEG-IFN-alfa2b 1.5 ìg/kg/wk was superior to IFN-alfa2b in decreasing mean serum hepatitis C RNA (P < .05 at week 12).

· The efficacy of split-dose PEG-IFN-alfa2b 1.5 or 3.0 ìg/kg/wk regimens was not significantly different from full-dose PEG-IFN-alfa2b 1.5 ìg/kg/wk.

· However, there was a significant decrease in neutrophil count in groups receiving PEG-IFN-alfa2b 3.0 ìg/kg/wk or lower, multiple-dose per week regimens.

According to the authors, “PEG-IFN-alfa2b 1.5 ìg/kg once weekly is the optimal dosing frequency for patients with chronic hepatitis C with predominantly genotype 1 infection.”

“More frequent dosing or increasing the dose to 3.0 ìg/kg/wk did not result in improved antiviral effects, but did decrease neutrophil counts.”

06/29/05

Reference
Y Lurie and others. Optimal Dosing Frequency of Pegylated Interferon Alfa-2b Monotherapy for Chronic Hepatitis C Virus Infection. Clinical Gestroenterology and Hepatology 3(6): 610-615. June 2005.

http://www.hivandhepatitis.com/hep_c/news/2005/ad/062905_d.html

 
  12 Weeks of Peginterferon Alfa-2b (PegIntron) and Ribavirin Combination Therapy Shown as Effective as 24 Weeks of Treatment in HCV Patients with Genotype 2 or 3 Virus Who Had an Early Virological Response to Therapy
 

Results of a new Italian study published in the current issue of the New England Journal of Medicine show that a shorter, 12-week course of therapy with peginterferon alfa-2b (PegIntron) and ribavirin combination therapy was as effective as a 24-week course for patients with hepatitis C virus (HCV) genotype 2 or 3 who had an early virological EVR) to treatment.

“Early Virologocal Response” is defined as HCV RNA undetectable (negative) after  4 weeks of therapy.

The shorter regimen was not only highly effective in these patients, with 85 percent achieving a sustained virological response (SVR), but it also was associated with fewer side effects and, consequently, less frequent withdrawals from therapy.

In addition, patients assigned to 12 weeks of treatment were less likely to require a dose reduction. Maintaining the therapeutic dose is important for achieving a sustained virological response.

This open-label clinical trial was conducted in 14 centers in Italy as an investigator-sponsored study without financial support from industry.

“Our findings suggest that patients with chronic hepatitis C genotype 2 or 3 infection who have undetectable virus after 4 weeks of treatment with peginterferon alfa-2b and ribavirin achieve high response rates with only 12 weeks of therapy and do not require 24 weeks of treatment,” said Alessandra Mangia, M.D., Gastroenterology Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo.

“Tailoring treatment so that those with an early response are given a shorter course may make therapy more appealing to patients, sparing the expense and inconvenience of extended treatment, without adversely affecting outcomes,” noted Dr. Mangia.

Most patients treated today for chronic HCV genotype 2 or 3 receive 24 or 48 weeks of therapy. Although these schedules are effective, side effects increase with the length of treatment.

Abstract from the NEJM Article:

Researchers hypothesized that in patients with hepatitis C virus (HCV) genotype 2 or 3 in whom HCV RNA is not detectable after 4 weeks of therapy, 12 weeks of treatment is as effective as 24 weeks.

A total of 283 patients were randomly assigned to a standard 24-week regimen of peginterferon alfa-2b at a dose of 1.0 µg per kilogram weekly plus ribavirin at a dose of 1000 mg or 1200 mg daily, on the basis of body weight.

Of these, 70 patients were assigned to the 24-week regimen (standard-duration group) and 213 patients to a variable regimen (variable-duration group) of 12 or 24 weeks, depending on whether tests for HCV RNA were negative or positive at week 4.

The primary end point was HCV that was not detectable by polymerase-chain-reaction (PCR) assay 24 weeks after the completion of therapy.

Results

·  In the standard-duration group, 45 (64 percent) patients had HCV that was not detectable by PCR assay at week 4, as compared with 133 (62 percent) in the variable-duration group (difference [the rate in the standard-duration group minus that in the variable-duration group], 2 percent; 95 percent confidence interval, –11 to 15 percent).

·  Fifty-three patients (76 percent) in the standard-duration group and 164 patients (77 percent) in the variable-duration group had a sustained virologic response (difference, –1 percent; 95 percent confidence interval, –13 to 10 percent).

· Fewer patients in the variable-duration group receiving the 12-week regimen had adverse events and withdrew than in the group receiving the 24-week regimen (P=0.045).

· The rate of relapse (defined as HCV not detectable at the end of treatment but detectable at the end of follow-up) was 3.6 percent in the standard-duration group and 8.9 percent in the variable-duration group (P=0.16).

· Overall, the rate of sustained virologic response was 80 percent among patients with HCV genotype 2 and 66 percent among those with genotype 3 (P<0.001).

In conclusion, the authors write, “A shorter course of therapy over 12 weeks with peginterferon alfa-2b and ribavirin is as effective as a 24-week course for patients with HCV genotype 2 or 3 who have a response to treatment at 4 weeks.”

06/24/05

Reference
A Mangia and others. Peginterferon Alfa-2b and Ribavirin for 12 vs. 24 Weeks in HCV Genotype 2 or 3. The New England Journal of Medicine 352(25): 2609-2617. June 23, 2005.

http://www.hivandhepatitis.com/hep_c/news/2005/ad/062405_a.html

 
 
Trial Results of 'PEGASYS' Plus Ribavirin 'COPEGUS', a Combination Therapy for Hepatitis C, Presented at the 41st Annual Conference of the Japan Society of Hepatology

 

TOKYO, June 17, 2005 - Chugai Pharmaceutical Co., Ltd. [Head Office: Chuo-ku, Tokyo; President Osamu Nagayama (hereinafter, Chugai)] announced today that the results from phase III clinical trial conducted in Japan for combination therapy using pegylated interferon alpha-2a (genetic recombination) [hereinafter, "PEGASYS®"], hepatitis C treatment currently marketed by Chugai, plus ribavirin, which is currently developed also by Chugai, had been announced at the 41st Annual Conference of the Japan Society of Hepatology held in Osaka on June 16 and 17.  The following are the outlines of the results.
 
Key Results of the Study
1. Genotype 1b patients with no previous interferon treatment
A 61% efficacy rate (sustained virological response rate at 24 weeks after final treatment) was achieved from the ribavirin combination therapy arm with genotype 1b and no previous interferon treatment, which was significantly higher than the efficacy rate of 26% observed from the "PEGASYS®" monotherapy arm.  Notably, a 59% efficacy rate was achieved in patients with genotype 1b with high viral load (HCV-RNA load over 100 KIU/mL) who received the ribavirin combination therapy.

Efficacy Rates for Patients with Genotype 1b and No Previous Interferon Treatment
"PEGASYS®" plus ribavirin combination therapy "PEGASYS®" monotherapy
Total efficacy rate 61% (60/99) 26% (26/101)
Patients with high viral load 59% (57/96) 24% (23/96)
Patients with low viral load 100% (3/3) 60% (3/5)
 

 

2. Patients with previous interferon treatment
A 54% efficacy rate for ribavirin combination therapy was achieved with patients who were previously treated with interferon but did not respond or relapsed.  Also, a 51% efficacy rate was achieved with nonresponders of genotype 1b and high viral load, who are considered to be the most difficult to treat.
 
About the Phase III Study Design
The trial was to examine the efficacy and safety profile of "PEGASYS®" plus ribavirin combination therapy, conducted at 43 medical institutions in Japan, enrolling 300 patients with intractable chronic hepatitis C.

1. A total of 201 patients with Genotype 1, who were previously untreated by interferon, were assigned to receive 180mcg "PEGASYS®" once weekly plus daily ribavirin (600-1,000mg, depending on body weight) or 180mcg "PEGASYS®" once weekly plus placebo.

2. A total of 100 patients who were previously treated with conventional interferon but did not respond to treatment (so called "nonresponder") or patients who responded but then relapsed (so called "relapser") were treated with 180mcg "PEGASYS®" once weekly plus daily ribavirin (600-1,000 mg depending on body weight).

Safety Profile
The most common adverse events observed during clinical trials were influenza-like symptoms such as fever and fatigue and abnormal laboratory values such as neutropenia and thrombocytopenia.  The overall adverse event profile was similar in the two treatment arms, "PEGASYS®" monotherapy arm and the "PEGASYS®" plus ribavirin combination therapy arm.
While the occurrence of decreased hemoglobin were higher in the ribavirin combination therapy arm compared to that in the monotherapy arm, withdrawal rates due to adverse events or occurrence rates of serious adverse events were similar in both arms.

Withdrawal Rates due to Adverse Events
"PEGASYS®" plus ribavirin combination therapy "PEGASYS®" monotherapy
Withdrawal rate 12% (12/99) 15% (15/101)
 

 

Reference

[About chronic hepatitis C]
Caused by hepatitis C virus (HCV) infection, the disease can lead to critical outcome, eventually in the long course progressing to liver cirrhosis or liver cancer.  It is estimated that two million HCV carriers exist today in Japan.  The deaths caused by liver cirrhosis and liver cancer in 1999 were 45,000, 70% of which are reported to be attributable to HCV.

[About peginterferon alpha-2a]
The benefits of PEGASYS are derived from its large 40 kilodalton (KD) branched-chain polyethylene glycol (PEG) construction, which allows for once-weekly treatment by sustained drug levels.  In Japan, this drug was approved in October 2003 with indication for a single-agent treatment of intractable chronic hepatitis C and is now marketed under the trade name of "PEGASYS®".

[About ribavirin]
Outside Japan, this drug is used as an anti-virus therapy for treatment of various types of infectious diseases.  The ribavirin used in this trial is a ribavirin tablet (overseas trade name: "COPEGUS®") developed by F. Hoffmann-La Roche for use in combination with "PEGASYS®" for chronic hepatitis C.

[About KD (kilo Dalton) - a molecular weight unit]
KD is a unit to measure the mass of large molecular compounds such as protein. K (kilo) means a thousand.

[About genotype]
Genotype is the classification of genes of the hepatitis C virus.  The Dominant genotypes in Japanese patients are 1b, 2a, and 2b. 1b in particular accounts for 70% of the total chronic hepatitis C in Japan and is considered to be difficult to treat.

 
   

 

   

July 08 2005