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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.
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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
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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
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