Research Articles 2003
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Following Treatment
with Interferon and Ribavirin, Fibrosis Regression Is Greater in HCV
Genotype 1 Sustained Responders But Also May Decrease in Non Responders Interferon and ribavirin decrease necro-inflammation in chronic hepatitis C with or without virological clearance; however, reversibility of fibrosis remains to be established. Researchers at the Upstate Medical University in Syracuse, New York evaluated the effect of combination therapy on virological and liver histopathological outcomes in 52 treatment-naive patients and 79 patients unresponsive to interferon monotherapy with predominantly genotype 1 chronic hepatitis C. One hundred four patients completed interferon and ribavirin treatment after 24-48 weeks. Fifty-six paired liver biopsies (mean biopsy interval 28 months) were assessed by the Ishak score. Sustained virological responses were 37% in naive patients and 22% in re-treated patients. In virological responders and nonresponders, fibrosis and necroinflammation scores decreased by -0.91 (P = 0.04) and -0.5 (P = 0.02) and by -2.8 (P = 0.001) and -0.66 (P = 0.06), respectively. The authors conclude, “Interferon and ribavirin had greater benefit for fibrosis when associated with clearance of HCV RNA. Treatment strategies in virological nonresponders who show fibrosis regression should include consideration of maintenance therapy, if such treatment eventually proves to benefit histological outcomes.” 08/08/03
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Sustained Viral Response to
Treatment Is Associated with a Reduction of Steatosis in Genotype 3 HCV
Patients It has been suggested that hepatitis C virus (HCV) and especially genotype 3 is associated with steatosis. In this study, researchers in France assessed the effect of treatment with peginterferon alfa-2b or interferon alfa-2b (PEG-Intron and Intron A, respectively) and ribavirin (Rebetol) on steatosis. The investigators analyzed the database on 1,428 naive patients who were included in a large, international, multicenter, randomized trial randomized trial. A single pathologist scored steatosis at baseline and 24 weeks after the treatment. At baseline, steatosis was present in 935 of 1,428 patients (65%), including 175 (83%) of 210 patients with genotype 3 versus 760 (62%) of 1,218 with other genotypes (P <.001). The variables associated with steatosis in logistic regression were genotype 3 (P <.001), triglycerides greater than 1.7 mmol/L (P <.001), body mass index greater than 27 (P <.04), age greater than 40 years (P <.001), and septal fibrosis (P =.007). In genotype 3-infected patients, steatosis was associated with high viral load and with lower serum cholesterol. Steatosis was associated with lower sustained response rate, even after taking into account other factors (P <.001). Among virologic responders, steatosis was much improved in genotype 3, improvement of at least 1 grade in 77%, and disappearance in 46% compared with other genotypes, 46% and 29%, respectively (P <.001 both comparisons). In genotype 3 responders, the baseline low serum cholesterol was corrected by treatment (P <.001). This study confirms the high prevalence (65%) of steatosis among patients with chronic hepatitis C and the association with genotype 3, overweight, high fasting serum glucose, triglycerides, male gender, and age. The authors conclude, “For the first time, it has been clearly demonstrated that effective treatment of HCV leads to a reduction or disappearance of liver steatosis. The impact was particularly observed in patients with HCV genotype 3 infection. Like other studies, we found that genotype 3 was more strongly associated with steatosis (83% of 210 patients in the present cohort) than other genotypes.” “This study, like previous publications, also suggests that steatosis induces a mechanism of resistance to interferon and ribavirin combination treatment. This mechanism is unknown but seems independent of other known response factors (genotype 1, high viral load, extensive fibrosis) as well as independent of metabolic factors assessed in this study (BMI, serum glucose, and triglycerides).” “In conclusion, the better understanding of factors related with steatosis will permit us to improve the management of patients. In patients infected with genotype 3 HCV, most of them will be sustained responders, and the steatosis will disappear in half of them. In contrast, in patients infected by non-3 genotype HCV, steatosis is mainly associated with metabolic factors. The management of overweight, diabetes, and hypertriglyceridemia must be particularly encouraged.” 08/06/03
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Dynamics of alanine aminotransferase during hepatitis C virus treatment.Hepatology. 2003 Aug;38(2):509-17. Ribeiro RM, Layden-Almer J, Powers KA, Layden TJ, Perelson AS. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM; and Department of Medicine, University of Illinois at Chicago, Chicago, IL. Studies of the kinetics of hepatitis C virus (HCV) decline during interferon (IFN)-based therapy have led to insights into treatment efficacy. However, the kinetics of serum alanine aminotransferase (ALT), an enzyme used as a surrogate of liver damage, have not been closely monitored, and it is not known if they correlate with those of HCV RNA. Here we describe the associations between ALT and HCV dynamics. We analyzed 35 patients treated daily with 10 mIU IFN-alpha2b with or without ribavarin for 28 days followed by standard IFN/ribavirin therapy. Patients exhibited 4 patterns of ALT change: (1) exponential decay of ALT, (2) transient increase in ALT followed by a decrease to pretreatment or normal levels, (3) increase in ALT to a new level, and (4) no significant change. By simultaneously modeling HCV and ALT dynamics, we successfully fit the observed changes. We found ALT decays with t(1/2) = 12.7 hours. The transient increase in ALT observed in some patients suggested a mild hepatotoxic effect of IFN. However, patients with a smaller initial ALT increase achieved higher rates of viral negativity by week 72 (P =.02). The week-4 ALT decline correlated with the HCV log drop (P =.006) and the efficacy of therapy (P =.025). In conclusion, our results suggest the use of ALT as a surrogate marker for treatment effect in patients with elevated ALT. PMID: 12883496 [PubMed - in process]
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A Simple Index Can Predict Both
Significant Fibrosis and Cirrhosis in HCV Patients Information on the stage of liver fibrosis is essential in managing chronic hepatitis C (CHC) patients. However, most models for predicting liver fibrosis are complicated and separate formulas are needed to predict significant fibrosis and cirrhosis. The aim of the current study, conducted at the University of Michigan Medical School, was to construct one simple model consisting of routine laboratory data to predict both significant fibrosis and cirrhosis among patients with CHC. Consecutive treatment-naive CHC patients who underwent liver biopsy over a 25-month period were divided into 2 sequential cohorts: training set (n = 192) and validation set (n = 78). The best model for predicting both significant fibrosis (Ishak score >/= 3) and cirrhosis in the training set included platelets, aspartate aminotransferase (AST), and alkaline phosphatase with an area under ROC curves (AUC) of 0.82 and 0.92, respectively. A novel index, AST to platelet ratio index (APRI), was developed to amplify the opposing effects of liver fibrosis on AST and platelet count. The AUC of APRI for predicting significant fibrosis and cirrhosis were 0.80 and 0.89, respectively, in the training set. Using optimized cut-off values, significant fibrosis could be predicted accurately in 51% and cirrhosis in 81% of patients. The AUC of APRI for predicting significant fibrosis and cirrhosis in the validation set were 0.88 and 0.94, respectively. The authors conclude, “Our study showed that a simple index using readily available laboratory results can identify CHC patients with significant fibrosis and cirrhosis with a high degree of accuracy. Application of this index may decrease the need for staging liver biopsy specimens among CHC patients.” 08/06/03
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Enzyme Therapy Attacks Liver Tumors in
Second Phase Study
Author: John C. Martin Author Date: 8/4/2003
New research by a group of Italian doctors has
found that a protein in the body can degrade an amino acid that certain
tumors rely on for their growth.(1) The result is complete tumor remission
in some cases. The protein, known as arginine deiminiase, attacks the
amino acid arginine, which circulates in the body and is needed by tumors
to help fuel their growth.
Though the study was small, ADI, the Italian
doctors found, either prevented disease recurrence, or blocked tumor
growth in the 19 patients with liver cancer who took part in the trial.
A simultaneous Phase II trial is being
conducted by doctors at the M.D. Anderson Cancer Center in Houston.
"We have seen major decreases in the tumor
masses, and a dramatic increase in the quality of life of our patients,"
said Francesco Izzo, M.D., of the Pascale National Cancer Institute, who
took part in the study. "They feel so much better, and are leading much
more productive lives."
"The treatment with ADI is no more painful
than a vaccination, and any toxic effects are very mild, and essentially
non-significant," Izzo said, in a statement.
How ADI Works: The drug is given as a
continuous injection, circulates in the bloodstream, and essentially
eliminates tumor-nourishing arginine from the body. While healthy tissues
and cells can survive without arginine, tumor cells possess a mutation, or
abnormality, that forces them to rely on the protein. The result is tumor
starvation and shrinkage.
Research Impetus: The Phase II trial was
launched with patients who had the major form of liver cancer known as
hepatocellular carcinoma (HCC), whose tumors were rapidly growing, and who
only had a few months to live. Currently, effective treatments for HCC are
limited.
What prompted the research? "We were looking
at the nutritional requirements of certain tumors, and this was based on
historical data, really, extending back over the past 70 years that showed
that certain tumors require arginine for growth," said Mike Clark, Ph.D.,
in a telephone interview.
Clark is president and CEO of Phoenix
Pharmacologics, a biotechnology company that is sponsoring the research.
More specifically, Clark and his team of
scientists found that tumors related to hepatocellular carcinoma and some
melanomas rely on this protein for growth, adding that at least two other
groups of independent researchers reached the same conclusion.
"Based on this information, we developed
arginine deiminase as a treatment for these tumors," Clark told Priority
Healthcare.
Clark views this therapy as "a deadly 'rifle
shot' to the tumor cell, and not a 'shotgun blast' that kills normal body
cells along with the tumor cells."
He explained that his company's scientists
first confirmed the effect of ADI in tissue culture, then had positive
findings using mice implanted with human hepatocellular and melanoma
cancers. "Based on that data, which was very promising, we went into
humans," he said.
Complete Remission in Some: In their study,
Izzo and his colleagues treated the 19 patients with ADI once a week for
three months, continuing to follow-up with monthly exams using CT scans.
At the end of the three-month period, two patients went into complete
remission with no clinical evidence of disease, seven experienced a
greater than 50 percent remission of their tumor, and seven had stable
disease with no increase in tumor size.
Three patients showed no response, but Clark
says the reasons are unclear. "Basically, no drug works in everybody a
hundred percent of the time," he said. "We just don't know why some
patients do better than others."
In the six months since treatment was
concluded, 14 patients saw five-fold increases in their survival, compared
to their predicted life expectancy if they had had no treatment, the
Italian doctors reported.
U.S. ADI Trial: Meanwhile, similar benefits
are being seen in an ongoing Phase II trial testing ADI's benefits at M.D.
Anderson Cancer Center in Houston. The therapy was used initially in
patients who had very large liver tumors that could not be removed
surgically, said Steven Curley, M.D., head of GI Surgical Oncology, who is
taking part in the study. "Shrinkage of the tumor enabled complete
surgical resection of the tumor, and allowed the patient to live a normal
life, including a continued career and work schedule," Curley explained,
in a statement.
He says ADI may become not only an effective
single treatment for hepatocellular carcinoma, but also in combination
with other drugs and treatment approaches for patients with liver cancer
tumors, as well as those associated with other cancers.
Several Phase III clinical trials, typically
the final phase before drugs are submitted to the FDA for approval, are
expected to begin at different sites in the U.S., Europe and in Taiwan
later this year involving larger numbers of patients, Clark said.
1. Izzo F et al. Phase I/II testing of
pegylated arginine deiminase in subjects with hepatocellular carcinoma.
39th Annual Meeting of the American Society of Clinical Oncology (ASCO).
2003 May 31-Jun 3. Chicago, IL.
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