Hepatitis C Research
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EFFECT OF
INTERFERON THERAPY ON THE RISK OF HEPATOCELLULAR CARCINOMA AND MORTALITY IN
PATIENTS WITH CHRONIC HEPATITIS C: A LARGE RETROSPECTIVE COHORT STUDY OF
3296 PATIENTS Reported by Jules Levin This study is very interesting although it is a study limited to Japanese patients and does not address coinfected patients. This data comes from the program abstract. The poster itself will be examined for any differences tomorrow. In brief, this study finds- --a viral load reduction, even if its not an ETR or SVR response, may lead to better survival and less risk for liver cancer --patients treated with interferon have significantly lower rates of liver cancer (HCC) than untreated patients --the incidence of HCC in non-responders was no better than in untreated patients (although, it appears to me from the data in the abstract that there was a non-significant difference between non-responders and the control group --untreated) in multivariate analysis including biochemical response in looking at risk for death --but, both sustained responders and those with transient viral response had significantly lower risk for HCC --the overall cumulative survival rate and cumulative liver-specific survival rate were significantly higher in interferon treated patientsthan in untreated patients --higher histological stage--more progressed disease--was an independent factor associated with death from liver-associated causes --interferon decreased risk of death from all causes by 62%, and deaths from liver disease by 59% --overall survival rate was better in interferon treated EFFECT OF INTERFERON THERAPY ON THE RISK OF HEPATOCELLULAR CARCINOMA AND MORTALITY IN PATIENTS WITH CHRONIC HEPATITIS C: A LARGE RETROSPECTIVE COHORT STUDY OF 3296 PATIENTS abstract 171 Yasuharu Imai, Ikeda Municipal Hosp, Ikeda Japan; Akinori Kasahara, Osaka Univ Hosp, Suita Japan; Takeshi Okanoue, Kyoto Prefectural Univ of Medicine, Kyoto Japan; Hirohito Tsubouchi, Miyazaki Med Coll, Miyazaki Japan; Sumio Kawata, Yamagata Univ Sch of Medicine, Yamagata Japan; Shinji Tamura, Osaka Univ Graduate Sch of Medicine, Suita Japan; Kentaro Yoshioka, Nagoya Univ Sch of Medicine, Nagoya Japan; Kendo Kiyosawa, Shinshu Univ Sch of Medicine, Matsumoto Japan; Shinichi Kakumu, Aichi Med Univ Sch of Medicine, Aichi Japan; Kiwamu Okita, Yamaguchi Univ Sch of Medicine, Ube Japan; Norio Hayashi, Osaka Univ Graduate Sch of Medicine, Suita Japan Interferon therapy for chronic hepatitis C has been shown to reduce the risk of hepatocellular carcinoma, especially among virologic and biochemical responders. However, the effect of interferon therapy on mortality remains unclear. We studied the effect of interferon therapy on the development of hepatocellular carcinoma and mortality in patients with chronic hepatitis C. 3296 patients with histologically-proven chronic hepatitis C by the end of 1997 were enrolled. Of these 3025 patients received interferon therapy and 271 patients were untreated. Patients in the interferon treatment group received 4- to 12-month course of interferon. The degree of liver fibrosis was assessed by using the criteria of Desmet and colleagues (F0 to F4). Response to interferon was determined biochemically. The end point of follow-up was the date of the development of hepatocellular carcinoma diagnosed by periodic examination of abdominal ultrasongraphy or computed tomography, date of death or the closing date of the study. Effect of interferon therapy on the risk for hepatocellular carcinoma and mortality was analyzed by using Cox proportional hazard regression. The cumulative incidence of hepatocellular carcinoma was significantly lower in interferon-treated patients than in untreated patients (p = 0.0001). Cox proportional regression analysis revealed that interferon treatment significantly lowered the risk of developing hepatocellular carcinoma by 38% (p = 0.001). Although the cumulative incidence of hepatocellular carcinoma in non-responders and untreated patients did not differ, both sustained responders and transient responders had significantly lower cumulative risk of developing hepatocellular carcinoma (p = 0.0001). The risk ratios for development of hepatocellular carcinoma in patients with sustained response, transient response and no response were 0.16 (95%CI, 0.10 to 0.27), 0.54 (95%CI, 0.37 to 0.94) and 0.91 (95%CI, 0.68 to 1,23), respectively, compared with untreated patients. Both the overall cumulative survival rate and cumulative liver-specific survival rate were significantly higher in the interferon-treated patients than in the untreated patients (p = 0.0001 and p = 0.0001, respectively). In multivariate analysis, older age at diagnosis of chronic hepatitis (p = 0.0001 and p = 0.0001, respectively), male gender (p = 0.0001 and p = 0.0004, respectively) and higher histological stage (p = 0.0001 and p = 0.0001, respectively) were independent factors associated with death from all causes and from liver-specific disease. Interferon treatment significantly decreased the risk of death from all causes by 62% (p = 0.0001) and death from liver-specific disease by 59% (p = 0.0001). The cumulative overall survival rate as well as liver-specific survival rate in the sustained and transient responders was significantly higher than in the untreated patients (p = 0.0001 and p = 0.0001, respectively). Multivariate analysis performed including the factor of biochemical response to interferon demonstrated that the risk ratios of death from all causes and death from liver disease were 0.12 (95% CI, 0.06 to 0.25) and 0.02 (95%CI, 0.003 to 0.17), respectively, in sustained responders, 0.17 (95%CI, 0.09 to 0.33) and 0.13 (95%CI, 0.05 to 0.35), respectively, in transient responders and 062 (95%CI, 0.43 to 0.90) and 0.72 (95%CI, 0.46 to 1.13), respectively, in non-responders, compared with controls. In conclusion, interferon therapy for chronic hepatitis C not only reduces the risk of hepatocellular carcinoma but also improves the long-term survival, especially among biochemical responders. Menopause, Hormone Contraception May Accelerate Liver Fibrosis; Perhaps Hormone Replacement Therapy Can Be Helpful AASLD Dallas, Nov 9-13, 2001 abstract 195. IMPACT OF PREGNANCIES, ORAL CONTRACEPTION AND MENOPAUSE ON LIVER FIBROSIS PROGRESSION IN WOMEN WITH CHRONIC HEPATITIS C Vincent Di Martino, Pascal Lebray, Joseph Moussalli, GH Pitié-Salpêtrière and Réseau VHC Paris-Sud, Paris France; Catherine Buffet, HTMpital Bicêtre et Réseau VHC-Paris Sud, Kremlin-Bicêtre France; Thierry Poynard, GH Pitié-Salpêtrière and Réseau VHC Paris-Sud, Paris France program abstract: During chronic hepatitis C (CHC), liver fibrosis progression is faster in males than in females. Among all the factors involved in such difference, estrogenes may be a major one since experimental data recently supported that estrogenes may have direct antifibrosing effect. The aim of this work was to evaluate the influence of pregnancies, oral contraceptives and menopause on liver fibrosis (F) and fibrosis progression rate (FPR) in HCV-infected women, taking into account confusing factors such as age, alcohol consumption, and BMI. Patients and methods: 472 women with CHC without HBV nor HIV coinfection received an anonymous questionnaire that asked for alcohol and tobacco consumption, presence of diabetes, age at first menstruation, age at pregnancies with or without children, hormonal contraception, age at menopause and its cause if any, and hormonal substitution. These data were completed by those collected in the DOSVIRC database. Liver biopsies performed before antiviral therapy were analyzed using the METAVIR scoring system. The FPR was estimated in case of known date of HCV infection and expressed in milli METAVIR Units of fibrosis per year. Statistical analyses were performed using Kruskall-Wallis rank test and logistic and multiple linear regression models for multivariate analyses. Results: 212 (44%) women completed the questionnaire. 192 (48±1 years old) underwent adequate liver sample, among whom 99 had 1 to 7 pregnancies (0 to 5 children) during 15±1 months, 86 received oral contraceptive(s) during 31±4 months, 95 had menopause 11±1 years before liver biopsy, and 47 received hormonal substitution during 7±1 years. Only one woman had alcohol intake more than 50g/d. In univariate analysis, F score and/or FPR were significantly lower in women who had one or more pregnancies, who received hormonal contraception, who were seen before menopause or who received hormonal substitution, whereas liver necro-inflammatory lesions(A) were not different (table). After adjustment on age and BMI, multivariate analyses showed that menopause was associated with higher F score and FPR, and that pregnancies were associated with lower FPR ; the effect of oral contraceptives was not significant. Conclusion: in women with CHC, menopause accelerates the liver fibrosis progression. Such effect seems prevented by hormonal substitution. Pregnancies may have a long-term beneficial impact on liver fibrosis. editorial note: a pilot study presented at the AASLD Single Conference meeting in June 2001 showed HRT could improve response to HCV therapy for postmenopausal women. |
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SEN Virus Variants Are "Unequivocally Transmitted
By Blood Transfusion" in the US
By Harvey S. Bartnof, MD One of the more recent viruses that potentially has been associated with hepatitis is SEN virus (SEN-V). However, the cause-and-effect link between SEN-V and hepatitis or other disease has been a matter of debate within the research community. Even today, hepatitis can occur after a blood transfusion; yet tests for all known viruses have been negative. Now, researchers from the US National Institutes of Health (NIH) have reported that two SEN-V variants are "unequivocally transmitted by blood transfusion," and that they "might be the causative agent [infecting organism] of post-transfusion hepatitis" [liver infection after a blood transfusion]. If SEN-V causes hepatitis after a blood transfusion in 2000, screening the world blood supply for this virus would be of paramount importance. Co-authors of the report included Drs. T. Umemura and Harvey J. Alter, MD. Dr. Alter and his colleagues found that SEN-V DNA was detected in five of 243 (2.1%) of normal US blood donors, using a PCR (polymerase chain reaction) test. He also found that ten of 262 surgery patients were positive before they had surgery and blood transfusion(s). Among the remaining 252 patients who were negative for SEN-V DNA before surgery, 3% of 97 non-transfused patients became DNA positive after surgery. However, 40% of the remaining 155 patients became SEN-V DNA positive after blood transfusion associated with surgery. That difference was highly statistically significant. Dr. Alter also analyzed the association of SEN-V with hepatitis after transfusion. Among transfusion patients who did not have SEN-V DNA beforehand, new infection with this virus was detected in ten of 12 (83%) patients who developed hepatitis post-transfusion that was not due to hepatitis viruses A, B, C, D or E. New SEN-V infection was also detected in 32 out of 94 (34%) who did not develop hepatitis after transfusion. In addition, new SEN-V infection was detected in 20 of 49 (41%) of patients who developed acute hepatitis C after transfusion. The rate of new infection with SEN-V was significantly higher after transfusion among those who developed hepatitis that was not due to hepatitis viruses A-E (83%) than among those who did not develop hepatitis (34%). The 83% rate also was significantly higher than among those who did not receive a blood transfusion, 3%. Among those patients who developed hepatitis after blood transfusion, infection with SEN-V occurred before or at the same time that the first increase in ALT (alanine aminotransferase, liver enzyme to diagnose hepatitis) occurred. This time relationship is an important part of the reason for the authors' conclusions. Based upon other data, Dr. Alter also reported that less than 5% of persons infected with SEN-V after blood transfusion develop detectable hepatitis. The researchers concluded that the two SEN-V variants are "unequivocally transmitted by blood transfusion." Also, they concluded that the two SEN-V variants are present in approximately 2% of US blood donors. In addition, "The high rate of SEN-V infection in transfusion-associated hepatitis cases [not due to hepatitis A, B, C, D or E] and the temporal association between viremia [SEN-V DNA in blood] and ALT [liver enzyme] elevation suggests that SEN-V might be a causative agent [organism] of post-transfusion hepatitis." They continue, "However, it appears that the majority of SEN-V infected patients do not develop hepatitis." Lastly, "Further studies, particularly of intrahepatic replication [growth in liver cells], are needed to establish causality." This reviewer finds the results somewhat déjà vu to the discovery and documentation of transmission by blood transfusion of HIV, hepatitis B virus (HBV) and hepatitis C virus. Given the potential implications of the current study, one can easily envision future screening of the world blood supply for SEN-V if future studies definitively establish a causal relationship between infection and growth in liver cells. It is currently unknown whether SEN-V is transmitted by sexual contact, needle/"works" sharing, from mother-to-newborn or by breastmilk. 4/26/00 References Umemura T, Alter HJ and others. The incidence of SEN virus infection in transfusion-associated hepatitis. Abstract and poster presentation G018 at the 10th International Symposium on Viral Hepatitis and Liver Disease; April 9-14, 2000; Atlanta, Georgia. Copyright 2001 by HIV and Hepatitis.com. All Rights Reserved Subject: INFO: Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C.
Effect on treatment outcome of coinfection with SEN viruses in patients
with Rigas B, Hasan I, Rehman R, Donahue P, Wittkowski KM, Lebovics E. The newly discovered SEN D and SEN H viruses are transmitted parenterally
and Publication Types: PMID: 11747922 [PubMed - in process] Here is another site to learn more
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Treatment of Chronic
Hepatitis C Howard J. Worman, M.D. Treatment of chronic hepatitis C is presently based on the use of interferon-alpha. Interferon-alpha is a protein that is given by injection, usually three times a week. The addition of ribivirin, a non-specific, orally administered anti-viral agent, improves the efficacy of interferon-alpha. Although interferon-alpha with or without ribivirin works for some patients with hepatitis C, most do not achieve a "sustained response" of undetectable virus in blood 6 months after stopping therapy. Interferon-alpha is also associated with myriad adverse events and is relatively expensive. Ribavirin may also cause side effects. Better drugs are unequivocally needed for the treatment of chronic hepatitis C. What will they likely be? Longer Acting Interferon-alphaThe next drug available for the treatment of chronic hepatitis C will be peginterferon-alpha (sometimes called "pegylated interferon"). The active agent in peginterferon-alpha is the same old interferon-alpha. However, the protein is attached to polyethylene glycol (antifreeze), an inert compound that slows the elimination from the body. More constant blood levels of interferon-alpha are achieved with less frequent injections, usually once a week. This results in enhanced compliance and clinically superior anti-viral activity. Published studies have shown that peginterferon-alpha alone results in "sustained response" rates of 30% to almost 40%. The side effect profile is similar to unmodified interferon-alpha. Preliminary data show that addition of oral ribavirin to pegylated interferon-alpha results in "sustained response" rates of approximately 50%. Hence, pegylation enhances the efficacy of interferon-alpha for the treatment of chronic hepatitis C. The United States Food and Drug Administration (FDA) has recently approved peginterferon-alpha-2b (Peg-Intron, Schering-Plough) for the treatment of chronic hepatitis C. Peginterferon-alpha-2a (Pegasys, Hoffmann La Roche) will likely be approved in the near future. Within a year, the FDA will likely approve the combination of peginterferon-alphas with ribavirin. Clinical trials of peginterferon-alpha with a compound called VX-497 (Vertex Pharmaceuticals) are also in progress. VX-497 has some features similar to ribavirin and inhibits a cellular enzyme know as inosine monophosphate dehydrogenase that may responsible for some of its effects. An even longer acting form on interferon-alpha is currently in early stage clinical testing. This is a fusion protein between albumin and interferon alpha (Albuferon, Human Genome Sciences). Data on its clinical efficacy are not yet available. It is also probable that other long acting preparations of interferon-alpha will be developed in the next few years. Drugs that Affect the Immune Response Against the VirusSeveral drugs known as "immune modifiers" or "immunomodulators" that alter the immune response are being tested in clinical trials for chronic hepatitis C. Some are being studied along with interferon-alpha. There drugs alter the inflammatory response against liver cells infected with the virus; however, their mechanisms of action are poorly understood. Compounds of this type currently being tested in humans include thymosin-alpha-1 (Zadaxin, SciClone Pharmaceuticals) and histamine dihydrocholoride (Ceplene, Maxim Pharmaceuticals). Therapeutic vaccines are also being developed to enhance the immune response against the hepatitis C virus. In contrast to a preventive vaccine, which is likely to be a very long way off for hepatitis C, a therapeutic vaccine is administered to already-infected individuals to stimulate the immune system to fight the infection. Several therapeutic vaccines are in preclinical development for hepatitis C. The most promising of these are DNA vaccines involving injection of DNA copies of the hepatitis C virus's RNA genome, which are taken up by certain immune system cells. These cells then express viral proteins, stimulating an immune response against the virus. These theoretically appealing therapeutic vaccine for hepatitis C remain to be shown effective in human subjects Specific Agents Against Hepatitis C Virus ProteinsA new generation of drugs to treat hepatitis C will be those designed specifically to inhibit functions of the hepatitis C virus. One target for such drugs is the hepatitis C virus RNA genome. Ribozymes are catalytic RNA molecules, some of which can cut other RNA molecules. A ribozyme (Hepatazyme, Ribozyme Pharmaceuticals) has been designed to cleave the hepatitis C virus RNA genome in a region that the virus needs to survive. Its efficacy in cutting hepatitis C virus RNA has been established in the test tube and the drug is now in early clinical trials. ISIS-14803 (Isis Pharmaceuticals) is a antisense inhibitor complementary to a conserved sequence of the hepatitis C virus RNA. This molecule binds to the viral RNA and inhibits the expression of proteins required for replication. ISIS-14803 is currently in early stage clinical trials. A small molecule known as VP-50406 (ViroPharma) has also been demonstrated to inhibit hepatitis C virus RNA in the laboratory and is in early stage clinical development. Inhibitors of a unique structure of the hepatitis C virus RNA necessary for protein synthesis, known as the internal ribosome entry site or IRES, are also under study in the laboratory. Three favorite targets of the hepatitis C virus for pharmaceutical chemists are its N3S RNA polymerase, NS3 RNA helicase and NS5B RNA polymerase. Compounds directed against these targets are in various stages of preclinical development. The targets are all enzymes (proteins that catalyze chemical reactions) essential for hepatitis C virus replication. They are expressed in cells infected with the virus but not in mature viral particles themselves. Armed with knowledge of the three-dimensional structures of these enzymes deduced using X-ray crystallography, scientists can identify molecules that inhibit their activities. NS3 has two parts with distinct enzymatic activities. One part is a protease that cuts a larger precursor protein encoded by the hepatitis C virus RNA into smaller functional proteins. Inhibition of NS3 would result in a failure of the virus to make the smaller proteins necessary for its replication. The other part of NS3 is a RNA helicase that unwinds the hepatitis C viral RNA. RNA unwinding is necessary for its efficient replication and translation into protein. Specific inhibitors of NS3's enzymatic activities would theoretically not influence critical host cell functions, limiting the side effect profiles. NS5B of the hepatitis C virus is an essential RNA-dependent RNA polymerase that copies the virus's RNA genome. Animal cells do not copy RNA; they make RNA copies from DNA. Therefore, specific inhibitors of the NS5B should not affect host cell processes. Of course, one cannot accurately predict the adverse event profile of a given drug until it is tested in human. Drugs designed as best as possible against specific viral targets may still prove to have side effects. However, well-designed drugs directed against the hepatitis C virus RNA, NS3 protease, NS3 RNA helicase and NS5AB RNA polymerase are very likely to be more effective and better tolerated than currently available treatments for hepatitis C. The timeline from the laboratory to the clinic is likely to be several years.
Drugs that Affect the Liver's Response to InjuryChronic hepatitis (inflammation of the liver) can lead to fibrosis (scarring) and cirrhosis (fibrosis plus abnormal regeneration of liver cells). Virtually all of the serious complications of chronic hepatitis C result from cirrhosis. For this reason, several groups are developing drugs to prevent fibrosis and cirrhosis. Recent data suggest that fibrosis, and perhaps even early cirrhosis, may be reversible to some extent. Very little is known about why the liver becomes fibrotic in response to chronic inflammation. Furthermore, it is not known why some individuals infected with the hepatitis C virus develop significant fibrosis or cirrhosis while others never do. Some drugs that may prevent liver fibrosis and cirrhosis are in early clinical trials. IP-501 (Interneuron Pharmaceuticals) is an orally administered anti-fibrotic compound being tested for the treatment of including alcoholic and hepatitis C-induced cirrhosis. Animal models suggest that IP-501 is effective in preventing the development of alcohol-induced cirrhosis, however the exact mechanism by which this compound works is not fully understood. Clinical trials of IP-501 in alcohol-induced liver disease and chronic hepatitis C are underway. Preliminary studies in humans have also shown that interleukin-10 (Schering-Plough) may prevent liver fibrosis in chronic hepatitis C. Clinical trials of interleukin-10 need to be carried out on a larger scale to demonstrate safety and efficacy. Increasing scientific effort is being devoted to the study of liver fibrosis in response to injury and exciting new drugs to prevent it will hopefully be available someday. Re-grow a Damaged Liver?When a liver is damaged beyond repair, the only hope today is orthotopic liver transplantation. However, considerable research effort is being devoted to the study of stem cells. Stem cells are undifferentiated cells, such as those in the early embryo that can be directed to form many different tissues of the body. In the past few of years, investigators have shown that liver stem cells reside in the bone marrow. Theoretically, these bone marrow stem cells can be isolated and grown into hepatocytes and bile duct cells in the laboratory. Some animal studies have also shown that expression of the enzyme telomerase in liver cells enhance their ability to regenerate. Although considerable challenges remain to be overcome, this early stage research provides promise that liver transplantation may someday be a thing of the past. PharacogenomicsSome drugs work in some patients but not in others. Similarly, some drugs have side effects in some patients while others tolerate them well. For example, less than half of patients with chronic hepatitis C have a "sustained response" to treatment with interferon-alpha and many experience intolerable side effects. Most of this is a result of different individuals' different genetic make-ups. Pharmacogenomics is the science of understanding the correlation between an individual patient's genetic make-up and response to a drug. The discipline is evolving rapidly as a result of the extensive work recently completed on sequencing the entire human genome. Phamacogenomics aims to identify genetic markers that predict response to a drug. The genetic markers commonly assessed are known a single nucleotide polymorphisms (SNPs) and haplotypes. SNPs are changes at a single base of DNA between individuals. Haplotypes are linear arrays of slightly different forms of particular genes on a chromosome. By studying populations of patients and their responses to a drug, inheritance of a collection of SNPs or different haplotypes can be correlated with successful treatment, unsuccessful treatment or development of side effects. This knowledge can them be used to "customize" drug therapy for a particular patient based on first examining their DNA.
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