Natural History Of HCV/ 2000-2010

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Natural History Of HCV/ 2000-2010

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Natural History Of HCV

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Hepatitis C in Children (Natural History)

Children’s Hospital http://www.fda.gov/ohrms/dockets/ac/01/slides/3744s1_04_Jonas/sld001.htm

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Treatment of Chronic Hepatitis C: Impact on Natural HistoryEmmet B. Keeffe, M.D.Chief of Hepatology and Co-Director of Liver Transplant ProgramStanford University School of MedicinePDF (download)

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,Natural History of Hepatitis C /2000

,Dr. Leonard B. Seeff (Division of Digestive Diseases and Nutrition, NIDDK, NIH):

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The natural history of hepatitis C continues to be a controversial issue because of the lack of clarification of long-term outcome. Although it is widely accepted that approximately 80% of persons who become infected fail to clear the virus and progress to chronic infection, the uncertain extended outcome has prompted divergent views. Clearly, some infected persons recover completely; some remain HCV viremic without biochemical evidence of liver damage; some seem to have a static form of chronic hepatitis characterized by persistently elevated aminotransferase levels without overt symptoms or disease advancement; some progress over a difficult-to-define period to histologic fibrosis and cirrhosis; some have long-term stable cirrhosis identified only through liver biopsy; some have progressive cirrhosis that culminates in liver failure; and, finally, some develop hepatocellular carcinoma. The uncertainties lie in the relative frequencies

and rates of development of these various sequelae. Indeed, the major questions are whether progression is linear and whether advancement through these increasingly severe manifestations is inevitable (31).The only means of accurately defining outcome is to conduct well-designed, long-term, prospective studies that begin with onset of acute HCV infection and follow participants over a sufficiently extended period. Such studies must use careful clinical, biochemical, serologic, and histologic assessment. However, there are numerous impediments to accomplishing these aims. Onset of acute hepatitis C is rarely recognized owing to lack of symptoms; chronic HCV infection similarly is generally a silent condition; and the course of the disease is often markedly protracted, spanning 20 to 40 years before the final outcome is reached. Moreover, the circumstance of exposure (for example, transfusions, parenteral drug use, hemophilia, or hemodialysis) may

itself be associated with reduced life expectancy, thus competing with HCV for morbidity and mortality.Strategies used to examine this issue have included prospective transfusion-related studies that begin with acute hepatitis C; retrospective studies that prospectively track persons with established chronic hepatitis C; and a combination of the two—retrospective-prospective (nonconcurrent prospective) studies—that requires identification of a definitive acute hepatitis outbreak in the past, with subsequent patient recall followed by long-term prospective evaluation. The prospective study approach describes the natural history of acute hepatitis C, whereas the retrospective study delineates the natural history of chronic hepatitis C. Obstacles to the first approach include the difficulty in identifying a large study cohort with acute hepatitis C and the time required to complete follow-up. The second approach introduces the problem of

selection bias—namely, the focus on patients with already established chronic liver disease and the omission from analysis of persons who were infected earlier but who spontaneously recovered or were not ill enough to consult a physician.Prospective Studies of Acute Hepatitis CEarly studies focused on persons with transfusion-associated hepatitis C (32-36). None of the studies had more than 14 years of follow-up, and none included a noninfected control group. Composite analysis of these studies reveals that clinical symptoms were identified in approximately 10% of patients, cirrhosis was found in about 20% (range, 8% to 24%), and hepatocellular carcinoma was rare. Liver disease appeared to be responsible for death in approximately 3% of patients (range, 1.6% to 6.0%). These studies clearly identified liver-related morbidity and mortality but in generally modest frequencies. Their

limitations, however, were the relatively small numbers of patients included in each study and the short follow-up.Retrospective Studies of Chronic HepatitisIn three important studies (37-39), a far bleaker picture emerged. Despite the relatively short follow-up (4 to 11 years), these studies reported symptoms in far greater frequency, cirrhosis in a higher proportion of patients (30% to 46%), a remarkably high frequency of hepatocellular carcinoma (11% to 19% of patients), and a significantly high rate of liver-related death. Of note, a considerable number of the patients in the U.S. study already had end-stage cirrhosis or hepatocellular carcinoma when they were first seen (39). The impact of these results must, however, be tempered by the fact that they represent the worst-case scenario by focusing only on persons with already well-established chronic liver disease. Despite this

“referral bias,†the accrued data nevertheless underscore how serious the condition is once cirrhosis develops.Retrospective-Prospective StudiesThree studies can be classified as retrospective-prospective studies. The first, an ongoing study from Ireland, involved an outbreak of acute hepatitis C in more than 50 000 young women who had received HCV-contaminated anti-D immunoglobulin (40). In a follow-up report 17 years later, three quarters of the women were symptomatic, mainly with fatigue; serum enzyme values were normal in more than 40% of patients; and, most important, liver biopsies revealed fibrosis, which was mostly mild in 51% but represented cirrhosis in 2%. This surprising result has been attributed to the fact that these were young, healthy, nondrinking women, who seem to be at less risk than older, alcohol-imbibing men (31).

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*** Updated 2009/ : Progression Of Hepatitis C/Irish Women Study/31 Years Later,The second study followed persons from several early transfusion-related studies in whom acute hepatitis C had developed (41). Patients with acute hepatitis in these studies were combined and compared with a matched group of controls who did not undergo transfusion and did not have cirrhosis so that morbidity and mortality could be studied long-term. Analysis at 18 years (41) and 23 years (42) revealed no difference between the two cohorts with respect to overall mortality but showed a slight and slowly increasing difference in liver-related mortality (Figure 3). Follow-up for morbidity in living patients revealed that one fourth seemed to have had spontaneous resolution; in the

remainder, viremia persisted, and only half of these patients had accompanying aminotransferase elevations. Liver biopsies revealed cirrhosis in 15% of patients; clinical symptoms were confined almost exclusively to patients with cirrhosis. These data are in accord with a recent report from Germany showing that mortality is increased in persons with chronic hepatitis C only if they have cirrhosis (43).

Survival of 100% is shown as 1 on the y axis. Survival curves comparing patients with non-A, non-B transfusion-associated, predominantly type C hepatitis (solid line); matched transfusion recipients without hepatitis (controls) (dashed line); and the general U.S. population (dotted line).

The final study is an almost 50-year follow-up of young military recruits on a U.S. Air Force base in Wyoming, from whom blood samples were obtained between 1948 and 1954 as part of a study of a streptococcal infection outbreak . Among the few persons found to be infected with HCV, less than 20% have died or have liver disease. Taken together, these data suggest that approximately 15% to 20% of persons who acquire HCV infection progress to potentially serious end-stage liver disease, the critical sequela being cirrhosis. The remainder are likely to die of causes other than liver disease. Moderator: T. Jake Liang, MD;Discussants: Barbara Rehermann, MD;Leonard B. Seeff, MD; andJay H. Hoofnagle, MD+ Author Affiliations

This ArticleAnn Intern Med February 15, 2000 vol. 132 no. 4 296-305

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..Journal of Viral Hepatitis, 2006, 13, 297-302

2006/ Fibrosis progression in initially mild chronic hepatitis C: 36% with F1 Progress to F3 or cirrhosis

"PEG-IFN plus Ribavirin, the current standard of therapy for hepatitis C,..... use in HCV carriers with no/minimal liver fibrosis has been questioned mainly because this has been assumed to be a benign, stable condition with minimal risk of progression to 'clinically significant' liver disease......All our patients had the final liver biopsy taken more than 5 years after the initial one and almost two-thirds of them showed fibrosis progression, development of advanced fibrosis/cirrhosis being observed in 27% including more than one-third of those with F1 (portal fibrosis) in the initial biopsy. These results clearly indicate that chronic hepatitis C is a progressive disease in many patients who initially present with no/minimal fibrosis and that progression to advanced fibrosis does occur in a significant number of cases within 5-10

years.....Progression to F3 or cirrhosis was seen in 36% of those with F1 initially.....Fibrosis is facilitated by older age and alcohol and associated with inflammatory activity and ALT levels.....By multivariate analysis high alcohol intake (>40 g/day) and steatosis correlated independently with fibrosis progression (data not shown)......The ALT profile during follow-up was also found to have a significant association with fibrosis progression. Thirty-one patients had persistently normal ALT during the entire follow-up period and nine of them (29%) showed fibrosis progression (3 from F0 to F1, 5 from F1 to F2 and 1 from F1 to F3) compared with 55 of 75 (73.3%) of those with elevated ALT.. Antiviral therapy should be considered in mild chronic hepatitis C."

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..2006 / Natural History

Int J Med Sci 2006; 3:47-52 ©Ivyspring International PublisherReview

The Natural History of Hepatitis C Virus (HCV) Infection

L. Chen1 2, R. 1 2 1. Gastroenterology Section, VA Medical Center, Long Beach, California2. Division of Gastroenterology and Hepatology, University of California-Irvine, Irvine, California

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2008 / Natural History of HCV-Related Cirrhosis after Liver Transplantation

Over the course of years or decades, chronic hepatitis C virus (HCV) infection can lead to severe liver disease including cirrhosis and hepatocellular carcinoma, which in advanced cases may necessitate a liver transplant.Unfortunately, HCV typically infects the new donor liver soon after transplantation. Recurrent HCV after transplantation can lead cirrhosis in the graft in up to 30% of patients within 5 years. Continue Reading.................

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2008/Assessment of Prognosis of Cirrhosis: General Principles and Natural History of Cirrhosis

General Principles and Natural History of Cirrhosis

Any patient with cirrhosis carries a risk of specific life-threatening complications such as variceal bleeding, sepsis, or hepatorenal syndrome. There is also a significant risk of nonspecific life-threatening complications due to the frequent association of comorbidities. The general course of the disease is characterized by a longstanding phase of compensated cirrhosis, followed by the occurrence of specific complications. It has been shown that 10 years after diagnosis, the probability of developing decompensated cirrhosis is ∼60%, ascites being the most frequent complication (∼50%).[1] Once patients have developed the first episode of decompensation, complications tend to accumulate and life expectancy is markedly reduced. The course of cirrhosis is extremely variable from patient to patient due to several factors, including hepatic synthetic function (or “hepatic reserveâ€), the cause of cirrhosis, the possibility of stopping or slowing the underlying damaging process to the liver, and the occurrence of liver malignancy. Therefore, establishing a prognosis in a given patient with cirrhosis remains a challenging issue. In addition to the simple estimation of life expectancy, more complex issues must be taken into account, such as the capacity of a cirrhotic patient to withstand a given therapeutic intervention, or whether a given therapeutic option offers an acceptable chance of survival. Over the last couple of decades, additional complex issues have emerged with the generalization of liver transplantation, namely, the optimal timing for transplantation and, on a collectivity basis, the optimization of allocation policy in a context of organ

shortage.Even though the course of cirrhosis varies according to several factors, the need for prognostic models and scoring systems is obvious in order to manage individuals faced with different therapeutic options. Scoring systems are even more crucial for managing populations of patients in the setting of transplantation, for instance. Major efforts have been made in recent years to achieve these goals and develop prognostic tools which are detailed below. Hepatocellular carcinoma (HCC) will not be discussed in this article.

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2008/ The Natural History Of 'Healthy-HCV rs'

http://www.medicalnewstoday.com/articles/122830.php

A normal liver is observed in about 10% of HCV infected patients and the natural history of these so-called "healthy-HCV carriers" is not fully defined. An article published in the World Journal of Gastroenterology addresses the question of the evolution of theses "healthy-HCV carriers". In this research lead by Dr Sobesky R and his colleagues from the Unit of Hepatology, Hospital Cochin, Paris, the authors try to determine factors associated with fibrosis progression in HCV-infected patients without significant initial pathological lesions. After a median interval of 4 years, there is no fibrosis progression in 66% of patients. By multivariate analysis, fibrosis progression was associated with elevated transaminases, body mass index upper to 25, and the time interval between 2 biopsies. This study confirms the concept that the natural history of chronic hepatitis in this group of subjects is characterized by a very slow or no fibrosis progression. We can differentiate in these "asymptomatic carriers" a sub-group of patients with elevated transaminases and overweight, which is exposed to fibrosis progression. Moreover, theses patients with a higher risk of liver fibrosis progression should receive an antiviral therapy. HCV-infected patients with overweight should be informed of the risk of liver fibrosis progression and the need of dietetic councils.

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2009/ EXPERT COMMENTARYYear : 2009 Volume : 1 Issue : 1 Page : 33-37

Association between hepatitis C and hepatocellular carcinoma

Jesuino de Oliveira Andrade1, Argemiro D'Oliveira1, ngela Carvalho Melo2, Emmanuel Conrado De Souza2, Carolina Alves Costa Silva1, Raymundo Parana11 Department of Medicine of Federal University of Bahia, Brazil2 Faculty of Medicine of State University of Santa Cruz, Bahia, BrazilClick here for correspondence address and emailDate of Web Publication29-Jun-2009

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Natural History Genotypes

June 25 2010/ Natural history of chronic hepatitis C: Genotype 1 versus genotype 6

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Natural History Mild Fibrosis

2010/Mild Liver Fibrosis in HCV/Progression Progression of Initially Mild Liver Fibrosis in People with Chronic Hepatitis

SUMMARY: People with chronic hepatitis C who have absent or mild liver fibrosis early in the course of disease can go on to develop advanced liver damage, according to a study described in the January 18, 2010 advance online edition of the Journal of Viral Hepatitis. Study investigators suggested that older patients and those with high alanine transaminase (ALT) levels should consider early antiviral therapy, as they are at higher risk for disease progression.

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2010/ Predictors of histological activity and fibrosis in chronic Hepatitis C infection: A study from North India

Sompal Singh1, Ruchika Gupta1, Veena Malhotra1, Shiv K Sarin21 Department of Pathology, G.B. Pant Hospital, New Delhi-110 002, India2 Department of Gastroenterology, G.B. Pant Hospital, New Delhi-110 002, IndiaClick here for correspondence address and emailDate of Web Publication12-Jun-2010

IntroductionAfter discovery of Non-A, Non-B hepatitis (NANB) in 1975, it took another 14 years to identify hepatitis C virus (HCV) as its predominant causative agent. [1] Throughout the world, at least six main groups (genotypes) of sequence variants of HCV have been described, along with their more closely related sub-groups (subtypes). [2]Recent reports in literature suggest that genomic heterogeneity of HCV have a significant influence on disease

severity and response to interferon (IFN) treatment. [3] In some studies, Type 1b, has been shown to be associated with more severe hepatic disease than other genotypes, however other studies have refuted this. [4],[5] Rare studies have evaluated other predictive factors, including age at diagnosis, moderate/ severe steatosis and alcohol intake for severity of fibrosis. [6],[7] Although there are a few studies on the distribution of various HCV genotypes in India, [8],[9],[10] there is a lack of studies exploring the relationship of HCV genotypes, if any, with the disease severity in Indian patients. A recent study by Hissar et al.[11] in 2006 showed that there was no significant association between HCV genotype and degree of fibrosis or histological activity. However, they failed to analyze their data by multivariate analysis to evaluate other factors, which may act as predictors of histological activity and fibrosis in patients with chronic hepatitis C infection. The influence of other risk factors may be the cause of the existing discrepancy in literature. The available data in literature shows that the proportion of various HCV genotypes is different in India compared to the western countries. Hence, a study of the

influence of HCV genotypes on the severity of chronic HCV infection in Indian patients is essential.The present study aims at identifying the role of HCV genotypes and other predictors of disease severity in chronic HCV infection in Indian patients. Continue reading.......................

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