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The History of Hepatitis C
Most infected persons are unaware of their exposure to HCV, and do not get diagnosed until many years later. The rate of chronic HCV infection is affected by the person's age at time of infection, gender, race, and viral immune response.
A large proportion of HCV-infected persons, ranging from 75%-85%, develop chronic HCV infection, and are at risk for advanced liver fibrosis, HCV-related extrahepatic complications, cirrhosis and HCC .
The rates of liver fibrosis progression is highly variable, and is influenced by the amount of alcohol consumption, age of initial HCV infection, degree of inflammation and fibrosis on liver biopsy, HIV or HBV coinfection, and comordid conditions.
An estimated 10%-20% of chronic HCV infections advance to end-stage liver disease over one or two decades. Extrahepatic manifestations can occur during chronic HCV infection or cirrhosis, but HCC appears to develop only after cirrhosis is established. Research is ongoing to determine the histological, biochemical, genetic and demographic markers that may further predict the outcome of HCV infections.
What are the chances of persons with HCV infection developing long term infection, chronic liver disease, cirrhosis, liver cancer, or dying as a result of hepatitis C?
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Risk Factors for Developing Chronic HCV Infection
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Risk Factors for Advanced Progression of Liver Fibrosis
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The Natural History Of 'Healthy-HCV Carriers'
What is the Natural History of Hepatitis C?
Natural history of initially mild chronic hepatitis C
New insights in to the natural history of hepatitis C virus infection
Does the Natural History of Hepatitis C Vary According to HCV Genotype?
A Brief History of Hepatitis C
New Hepatitis Guidelines Oct 09
Natural History of Cirrhosis Including: Compensated and Decompensated Cirrhosis
AASLD Nov 2009 (Liver Meeting)
Natural History: HCV symptoms, disease progression and management.
The Natural History Of 'Healthy-HCV Carriers'
Main Category:
Liver
Disease / Hepatitis
Article Date: 24 Sep 2008 - 10:00 PDT
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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Article adapted by Medical News Today from original press release.
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Reference: Sobesky R, Lebray P, Nalpas B, Vallet-Pichard A, Fontaine H,
Lagneau JL, Pol S. Pathological evolution of hepatitis C virus -
"Healthy carriers". World J Gastroenterol 2008; 14(24): 3861-3865
http://www.wjgnet.com/1007-9327/14/3861.asp
Correspondence to: Rodolphe Sobesky, INSERM U 785, Centre
Hépato-Biliaire, Hôpital Paul Brousse, Villejuif 94807, France.
Management of Hepatitis C Virus Infection: Natural History of the Disease
Natural History of the Disease
Chronic hepatitis C develops in most persons who are infected with HCV. Spontaneous clearance of the virus occurs in only 15% to 25% of patients, almost always within the first 6 months of infection. Most acute infections are asymptomatic, and in the past, HCV infection was often not recognized until decompensated liver disease developed.
The natural history of the disease varies. Over a period of 25 years, cirrhosis develops in about 15% to 20% of those infected and can result in severe complications and death. Recent data demonstrate that fibrosis progression accelerates with age.[3] Fibrosis in patients older than 40 to 45 years may rapidly progress despite no significant progression over the preceding decades. Alcohol consumption accelerates the progression to fibrosis or cirrhosis; thus, many health care providers recommend that patients with HCV infection abstain from alcohol consumption.[4] Increased awareness of risk factors has led to earlier detection of HCV infection, before serious liver disease develops.
Risk Factors
Hepatitis C is transmitted parenterally. Most patients currently infected contracted HCV between 1970 and 1989, before screening tests of blood and blood products became routine and when the use of illicit drugs and needle sharing was more widespread. Common risk factors for HCV infection are listed in Table 1 . Other possible risk factors for HCV infection include:
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Reasons for some of these associations are not clear, but many suspect that undisclosed intravenous drug use is frequently a factor.
Despite rigorous screening measures to prevent contamination of blood products, new cases of HCV infection continue to appear. These are associated mainly with intravenous drug use.
Transmission
Some investigators have detected HCV-RNA in almost all body fluids. However, it is found most frequently and at the highest concentration in blood. The presence of HCV-RNA does not always indicate infectivity; in fact, HCV is inactive in bile�and, therefore, stool.[5] Some investigators, but not others,[6] have also detected HCV-RNA in saliva. In any event, contact with the saliva of infected persons is an inefficient mode of transmission. Although the likelihood of transmission through household or casual contact is highly unlikely, patients with HCV infection should keep wounds covered and should not share razors, toothbrushes, or objects that may be contaminated with blood.
A key concern for those infected is whether they can transmit the disease to their sexual partners. HCV infection may be transmitted by sexual intercourse, but this is rare. Sexual transmission is thought to be responsible for fewer than 3% of cases. Breaks in the mucosal barrier, such as those that occur with traumatic intercourse or with genital ulcers, may increase risk of transmission.[5] In addition, patients who are coinfected with HIV appear to transmit HCV to their partners more readily.[5]
No changes in sexual practices are necessary for patients with HCV infection who are in monogamous relationships, according to the CDC. It is recommended, however, that their partners be screened for HCV.[2] For patients with HCV infection who are not in monogamous relationships, the routine use of condoms with each sexual contact is recommended to prevent both transmission of HCV and acquisition of other sexually transmitted diseases.
Improved screening of the blood supply in the United States has dramatically reduced the risk of contracting HCV infection through transfusion. However, this is still a concern in countries that do not screen their blood supply for HCV.
Diagnosis
Patients should be tested for HCV infection if any of the risk factors in Table 1 are present�even if the patient is asymptomatic and has normal levels of liver enzymes. Patients may be reluctant to admit to having risk factors other than blood transfusion, especially during an initial office visit. An effective approach is simply for a physician to give patients a list of risk factors and then to ask whether they consider themselves at risk�without having them specify why.
Once it has been determined that a patient is at risk for HCV infection, an enzyme-linked immunosorbent assay to test for HCV antibody (anti-HCV) should be obtained. Test results may not be positive until 4 to 6 weeks after exposure; thus, the test results of a patient who has acute hepatitis C may be falsely negative. Results may also be negative in persons whose immune systems are depressed or who are receiving hemodialysis. In these persons, a test for HCV-RNA by polymerase chain reaction is necessary to make the diagnosis.
After HCV infection has been diagnosed, it is important to exclude other causes of liver disease and assess liver function. Recommended tests include:
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In persons with a family history of liver disease, with early progression to cirrhosis, or with an atypical presentation, determination of α1- antitrypsin phenotype and ceruloplasmin levels and an antinuclear antibody test with quantitation may be indicated.
Determining the genotype of the HCV infection may be useful in counseling patients about treatment. Six genotypes have been recognized. In the United States, genotypes 1, 2, and 3 account for more than 98% of infections, with genotype 1 being the most common.[7] Although genotype does not correlate with severity of disease, it predicts success with antiviral therapy. Persons infected with genotype 2 or 3 are much more likely to achieve a sustained response after treatment than are those with genotype 1 infection
Determining Disease Severity
Liver biopsy, which remains the gold standard for determining the activity of HCV-related disease, is the only way to assess severity of disease. Liver biopsy can be used to assess the degree of inflammation, stage of fibrosis, and presence of cirrhosis. It is the only reliable predictor of prognosis; liver enzyme levels do not correlate with disease severity and cannot be used for prognosis. Liver biopsy is also helpful in uncovering other causes of liver disease, which may complicate the course of HCV infection.[1] Although not absolutely necessary before beginning treatment, liver biopsy provides information that is highly useful in making therapeutic decisions.
Candidates for Treatment
The treatment of HCV infection is complex, and guidelines change frequently. All persons with hepatitis C are potential candidates for therapy if they have no contraindications. Primary care practitioners who have patients with newly diagnosed infection should consult with a specialist who is active in the treatment of hepatitis C.
Absolute contraindications to interferon therapy include current psychosis or a history of psychosis, severe depression, current alcohol or injection drug use, neutropenia that cannot be corrected with growth factors, severe thrombocytopenia, symptomatic heart disease, decompensated cirrhosis, uncontrolled seizures, and organ transplantation (other than liver). Relative contra-indications include autoimmune disorders and uncontrolled diabetes.
Absolute contraindications to ribavirin therapy include pregnancy or unwillingness to use effective contraception, renal insufficiency, anemia that cannot be corrected with growth factors, hemoglobinopathies, and severe heart disease. Relative contraindications to ribavirin therapy are uncontrolled hypertension and ischemic heart disease.
For persons who have no contraindications, the decision to treat is based on the severity of the disease (determined by liver biopsy results), age, and pretreatment probability of a response. Ultimately, the decision should be made by both the patient and the physician, after appropriate counseling regarding all aspects of treatment, including side effects and expected efficacy rates.
Parameters that predict a favorable response to therapy include[8]:
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The presence of 4 or 5 of these factors greatly increases the odds of a positive response to therapy.
Antiviral therapy is recommended for patients with aggressive disease, determined on liver biopsy (eg, stage 2 to 4 fibrosis). Those with minimal disease have the option of waiting for safer, more efficacious medications, remembering that there is a risk that fibrosis progression may accelerate after age 40 to 45 years.[3] The approach to treatment should be more aggressive in younger patients because the risk of progression over time is greater. Younger persons who have favorable pretreatment parameters, no contraindications to therapy, and aggressive biopsy-proven liver disease are obvious candidates for treatment. Other persons with mild disease may choose treatment or may wait for other, more effective therapies in the future. Repeated liver biopsy at 4- to 5-year intervals is recommended for persons who choose not to be treated.
Treatment
The goal of antiviral therapy is to achieve a sustained viral response (SVR), defined as no detectable virus in the serum 6 months after antiviral therapy is completed. Recent advances in hepatitis C therapy now allow clearance of the infection in more than half of patients treated.
Combination Therapy With Standard Interferon and Ribavirin
The sustained response to interferon monotherapy is low (5% to 15%). Thus, this treatment is of historic interest only. The advent of combination therapy with interferon plus ribavirin, an oral nucleoside analogue, led to marked improvements in efficacy. Approximately 50% of patients who received combination therapy achieved undetectable levels of HCV-RNA during treatment, and SVR occurred in about 41%.[10] However, genotype 1, the most common type of HCV in the United States and Western Europe, is also the least responsive to treatment. Only 29% of patients infected with genotype 1 achieved an SVR after 1 year of interferon-ribavirin combination therapy.[10] In contrast, response rates of up to 66% have been seen in persons infected with genotype 2 or 3.
Pegylated Interferon
The rapid rate of HCV replication and the short half-life (6 hours) of conventional interferon limit the efficacy of this therapy. To improve the pharmacokinetics of interferon, researchers attached a large molecule�polyethylene glycol (PEG)�to increase its half-life. While the concentration of conventional interferon peaks and then declines rapidly after subcutaneous administration, the serum concentration of pegylated interferon increases gradually and does not peak until about 24 hours after injection. This allows for a more even rate of drug delivery.[11]
Pegylation also reduces the renal clearance of interferon. A major advantage of pegylated interferon is that its longer half-life allows for once-weekly dosing�in contrast to conventional interferon, which must be injected 3 times per week.
Two pegylated interferons have been developed: peginterferon alfa-2a and peginterferon alfa-2b. Both are currently approved by the FDA for the treatment of HCV infection. The 2 pegylated products differ mostly in the size and shape of the PEG molecule attached.[11] Peginterferon alfa-2b has a linear 12 kDa PEG molecule, much smaller than the branched 40 kDa PEG chain in peginterferon alfa-2a. This difference in the PEG molecule radically changes the pharmacokinetics of both products. Because of the smaller size of the PEG molecule in pegylated interferon alfa-2b, this product is dosed by weight. Pegylated interferon alfa-2a is administered in a fixed dose, because it has a smaller volume of distribution.
Both pegylated interferons are superior to standard interferon monotherapy in the treatment of HCV infection in patients with all viral genotypes and in African Americans, who are thought to respond poorly to standard interferon therapy. During treatment, viremia resolved in 69% of patients who received peginterferon alfa-2a but in only 28% of those who received standard interferon alfa-2a monotherapy. An SVR was achieved by 39% of patients in the peginterferon alfa-2a group, but of those treated with standard interferon alfa-2a, only 19% achieved an SVR.[12] A trial comparing peginterferon alfa-2b with standard interferon alfa-2b yielded similar results.[13] However, the efficacy of pegylated interferon monotherapy is less than that of combination therapy with standard interferon and ribavirin. For this reason, pegylated in terferon monotherapy is recommended only for patients who cannot tolerate ribavirin.
Combination Therapy With Pegylated Interferon and Ribavirin
Peg interferon alfa-2b (1.5 µg/kg/wk), in combination with ribavirin (800 mg/d), resulted in higher rates of SVR than the combination of standard interferon and ribavirin ( Table 2 ).[14] Peginterferon alfa-2a (180 µg/wk) in combination with riba virin (1000 to 1200 mg/d) yielded similar results.[15] Based on the outcome of these and other studies, the FDA approved a 48-week treatment combination of peginterferon alfa-2b and ribavirin (800 mg/d) for the treatment of patients with HCV infection, regardless of genotype.
Similarly, the FDA later approved peginterferon alfa-2a in combination with weight-based ribavirin (1000 to 1200 mg) for 48 weeks to treat patients with genotype 1 HCV infection. Based on data presented by Hadziyannis and associates,[16] the FDA approved a 24-week treatment period for persons infected with genotype 2 or 3 using fixed-dose ribavirin (800 mg/d) in combination with peginterferon alfa-2a. It is not known whether a 24-week treatment period with a fixed dosage of 800 mg/d of ribavirin in combination with peginterferon alfa-2b is as efficacious as the currently recommended 48-week treatment period.
Recent studies have demonstrated that adherence to therapy is essential in maximizing the response.[17] Patients who are adherent to therapy, defined as taking more than 80% of the interferon dose and more than 80% of the ribavirin dose more than 80% of the time prescribed, are able to achieve SVR rates that exceed 60%.[17] The effect of adherence is most pronounced in genotype 1 patients, in whom a weight-based ribavirin dose is essential to achieve the best possible results. Adherence can be improved by aggressive management of adverse effects, including the use of growth factors to treat bone marrow suppression.
Viral response can be assessed at 12 weeks of therapy, and therapy should be continued in those who achieve a greater than 2log reduction in viral load.[18] Patients who fail to achieve this end point have a less than 2% chance of achieving an SVR with continued therapy. For those patients who have a greater than 2log drop in viral load but who still have detectable virus after 12 weeks of therapy, testing should be repeated at 24 weeks. If virus is still present at 24 weeks, SVR is unlikely with continued therapy. Those in whom the virus has cleared by week 24 should receive a total of 48 weeks of therapy.
Patients infected with genotype 2 or 3 who have no fibrosis detected on a biopsy specimen and who are able to take the recommended doses of peginterferon and ribavirin only need to be treated for 24 weeks. The presence of cirrhosis or delayed viral clearance during the early weeks of treatment may require 48 weeks of therapy in selected patients infected with genotype 2 or 3, although a recent trial suggested that 24 weeks may also be sufficient for this subgroup of patients.[16]
Managing Side Effects of Therapy
Adequate management of adverse effects is essential to promote adherence and achieve an SVR. Table 3 lists effective strategies for minimizing these effects.
Because treatment is long and difficult, extensive patient support greatly enhances adherence. Patients should be well informed of all potential side effects before therapy is started. Patients educated about possible adverse effects are more likely to be emotionally prepared for them and, therefore, more likely to complete the prescribed course of medication. The importance of compliance with follow-up visits for monitoring should be emphasized to the patient. Readily available office staff to answer patient questions and concerns greatly increases patient satisfaction and adherence.
Interferon Adverse Effects
The side-effect profile of the pegylated interferons is similar to that of regular interferon. Adverse effects were seen in 42% of patients who received peginterferon and ribavirin, compared with 34% of those who received standard interferon and ribavirin.[14] However, neutropenia is more common with pegylated interferon than with regular interferon.[19]
Flu-like symptoms are among the most common complaints of patients undergoing interferon therapy. Most experience myalgia, fatigue, headache, and malaise. Some also have fever and rigors. Because interferon raises the body temperature, hydration is extremely important in ameliorating flu-like symptoms. Fortunately, these symptoms tend to lessen after the first few weeks of therapy.
Neuropsychiatric disturbances are also frequent complications of interferon therapy and one of the most common reasons for discontinuation of treatment. Depression (which can be severe and can lead to suicide), insomnia, irritability, and anxiety are seen most often. They result in discontinuation of therapy in 2% to 9% of treatment-naive patients and in 3% of relapsers who are re-treated.[20] Screening for the presence of depression before treatment, monitoring for depression with standardized questionnaires, and aggressive use of antidepressants as soon as signs of mild depression appear can minimize the number of patients who discontinue therapy.
The prevalence of psychiatric disorders is thought to be greater among persons with untreated HCV infection than in the general population, which poses a dilemma for those who wish to be treated.[21] Persons with severe depression, a history of suicidal ideation or attempts, manic-depressive disorder, or other severe psychiatric illness are not candidates for therapy. In select cases, if a patient with a psychiatric disorder is under close monitoring by a psychiatrist, antiviral therapy may be considered.
Involvement of the family is crucial in early detection and management of psychiatric symptoms. Family members may notice irritability, depression, and other symptoms before the patient does.
Injection site reactions are another phenomenon seen with interferon therapy. These usually consist of only localized erythema and are generally a mild inconvenience, not a treatment-limiting event.[14]
Pegylated interferon alfa is a pregnancy category C medication. Standard interferon alfa-2b has also been shown to have abortifacient effects in experimental animals. Use of either product is contraindicated in pregnant women.
Ribavirin Adverse Effects
Ribavirin-associated dermatologic side effects include diffuse or localized rash and pruritus, which may be a cause of drug discontinuation. GI side effects, such as nausea and dyspepsia, often occur as a result of ribavirin therapy.
The teratogenic effects associated with ribavirin necessitate the use of effective contraception during treatment and for 6 months afterward. Patients should be counseled to practice contraception even if only the male partner is receiving therapy. Unwillingness to use reliable contraception is an absolute contraindication to treatment with ribavirin.
Hematologic Adverse Effects
Bone marrow suppression caused by interferon and ribavirin-induced hemolytic anemia are common occurrences. A decrease in hemoglobin levels of at least 2 to 3 g/dL is common and is caused by both hemolysis from ribavirin and bone marrow suppression from interferon, which blunts the reticulocyte response. The decrease in hemoglobin is most pronounced during the first 4 to 8 weeks of therapy and gradually stabilizes thereafter.
Absolute neutropenia may also occur during treatment. This adverse effect is more common in patients treated with pegylated interferon (up to 20% of such patients). Cytopenias are especially common in patients with cirrhosis. However, it was demonstrated in a study that ribavirin and interferon can be used safely in patients with well-compensated cirrhosis, provided they are closely monitored.[22]
Careful monitoring of hematologic parameters is required, especially at the beginning of treatment. A complete blood cell count with differential should be obtained weekly or biweekly for the first 4 to 8 weeks of therapy and monthly thereafter. Because ribavirin-associated anemia may be severe, caution must be used in patients with preexisting anemia or heart disease. Some authorities consider these preexisting conditions to be contraindications to therapy.[1] Management of neutropenia is also critical to successful therapy.
The use of growth factors (epoetin alfa and granulocyte colony-stimulating factor) has been recommended to prevent interferon and ribavirin dose reductions or discontinuations because of bone marrow suppression and hemolysis. A recent study demonstrated that patients who were treated with epoetin alfa were able to maintain higher doses of ribavirin than those who were treated with standard of care.[23] The effect of using growth factors to achieve SVR has not been extensively studied.
Re-treatment After Failed Antiviral Therapy
Patients in whom a first course of antiviral therapy has failed differ in their chances of benefiting from re-treatment according to the type and duration of the first treatment, as well as the type of response achieved during that treatment.
For patients who took a course of interferon monotherapy that was unsuccessful, re-treatment with peg interferon and ribavirin is recommended. The efficacy of interferon monotherapy is less than 10% in most patients and is currently not considered adequate in the re-treatment of HCV infection.
Patients who responded and then relapsed after receiving a course of interferon alfa and ribavirin can expect a 55% chance of SVR if re-treated with peginterferon and ribavirin therapy for 48 weeks. Patients who did not clear virus during treatment with interferon and ribavirin but who experienced a significant decrease in viral load have a 10% to 15% chance of response with re-treatment using peginterferon and ribavirin.[24] In contrast, those who had no significant decrease in viral load during therapy with interferon and ribavirin are unlikely to achieve a response when re-treated with peg interferon and ribavirin.
The decision to re-treat patients in whom standard interferon and ribavirin therapy failed to clear the virus should be based on the severity of their disease and their tolerance of previous therapy. Patients with mild disease on liver biopsy who tolerated previous treatment poorly should probably not be re-treated. Those with advanced fibrosis on biopsy may benefit from additional therapy, even if viral clearance is not achieved.
http://www.medscape.com/viewarticle/479959_9
A. Alberti, , a, b, L. Benvegnùa, S. Boccatoa, A. Ferraria and G.
Sebastiania
a Department of Clinical and Experimental Medicine, University of Padova,
Via Giustiniani, 2, 35128, Padua, Italy
b Venetian Institute of Molecular Medicine, Padua, Italy
Available online 4 August 2004.
Abstract
The hepatitis C virus is a leading cause of chronic liver disease, cirrhosis
and hepatocellular carcinoma in western countries. Chronic hepatitis C is
highly heterogeneous and many patients present with a mild form of liver
disease. Population-based studies have indeed demonstrated that around 50%
of hepatitis C virus carriers have persistently normal ALT and two-third
have mild histological liver lesions. Studies on the natural history of
initially mild chronic disease indicate that the short-term outcome is
always benign. However, progression of liver fibrosis can be observed at
long-term (>5–7 years) follow-up, particularly in those cases who have
elevated and/or fluctuating transaminase levels. Observational prospective
studies and outcome modelling projections indicate that the risk of liver
disease progression towards severe fibrosis/cirrhosis is minimal at 10–15
years in hepatitis C virus carriers with persistently normal ALT, around
5–10% in patients with elevated ALT and F0 (no fibrosis) in the initial
biopsy but >30–40% in chronic carriers with elevated ALT and F1 (portal
fibrosis) in the initial biopsy. Cofactors like age at infection, alcohol,
coinfections and liver steatosis accelerate disease progression. On the
basis of these findings, patients with initially mild chronic hepatitis C
and elevated ALT should be proposed for antiviral therapy in the absence of
contraindications.
Author Keywords: Hepatitis C; HCV; Natural history
Corresponding author. Tel.: +39 049 821 2294; fax: +39 049 821 1826.
Natural History of Chronic HCV Infection:
Introduction:
There are many uncertain issues regarding hepatitis C virus (HCV) infection, chief among which is the question of its natural history. Outcome data are needed for two obvious reasons:(1) the need to inform hepatitis C virus (HCV) carriers of what to anticipate in their future and, if possible, to reassure them about potential sequelae, and (2) the need to make rational decisions regarding treatment with drugs that currently are of only limited therapeutic value. The problem is compounded by the conflicting views held with respect to the natural history, some regarding chronic HCV infection as a universally progressive disease that will inevitably be responsible for serious chronic liver disease or liver disease-related demise provided other disease entities do not intervene first, while others regard it as a progressive disease limited to a minority of infected individuals, its course dictated by as yet not fully defined factors that might promote liver disease progression.
What is recognized is that persons who develop acute HCV infection rarely recover completely, more than 80% of them remaining HCV-infected. The result is progression to chronic hepatitis, generally defined by persistence of serum enzyme abnormalities for at least six months, advancement in a proportion of instances to cirrhosis, and culmination among a few in the development of hepatocellular carcinoma (HCC). What is not well established is the frequency of these changes, the tempo of advancement, and whether or not there are existing factors that curb or promote disease progression.
Basis for Uncertainty Regarding Natural History: The difficulties inherent in attempting to define the natural history of HCV infection are numerous. First, a natural history study requires knowledge of onset of acute disease in order to establish frequency and rate of progression. Unfortunately, onset of acute HCV infection is rarely recognized; in 80% or more of instances, persons with chronic HCV infection do not recall ever having had an illness resembling acute hepatitis. Second, full knowledge of natural history must include long-term evaluation of the entire spectrum of the acute disease, ranging from the mildest to the most severe forms. Because of the paucity of symptoms in most persons infected with HCV, those with the milder disease are generally overlooked, thus biasing outcome data in the favor of those with the more severe illness. Third, a valid study requires equally intense evaluation of a non-infected control group. Again, the lack of symptoms inhibits selection of such a group thus foiling conduct of a case-control study. Fourth, the extraordinarily indolent nature of the disease process in chronic hepatitis C coupled with its highly extended course before sequelae are recognized makes study of the natural history a daunting task, difficult to accomplish. Indeed, the natural history of the disease is generally more extended than the natural history of the clinical investigator. Finally, the disease course is obviously altered if treatment is instituted. Currently, it is almost routine to attempt treatment of most persons with compensated chronic HCV infection. It is these items that have made study of the natural history of hepatitis C so difficult.
Available data therefore have derived either from relatively short term prospective studies beginning from onset of acute disease, mostly transfusion-related, or from study of persons with already established chronic liver disease.
Follow-Up Studies Beginning with Acute Hepatitis: Most such studies have not exceeded 10 to 15 years in duration (with the exception of one which is a 17-year follow-up of an outbreak of HCV infection induced by contaminated immunoglobulin). This time period is obviously insufficient since in two retrospective/prospective studies, one from Japan and one from the U.S.A., progression from apparent acute to chronic hepatitis was estimated to average 10 years, to cirrhosis, 20 years, and to HCC, 30 years, some developing HCC 40 to 50 years after the presumed acute infection. Nevertheless, these studies have yielded useful and important information. In five prospective studies, clinical symptoms have been noted in about 10% of cases, histologic cirrhosis in 15% to 20%, and HCC identified in 0.7% to 1.3%. Mortality ranged from 1.6% to 6.0%. In the 17-year follow-up study of imunoglobulin recipients, outcome was reported to be benign in the majority of instances; 60% did have moderate enzyme abnormalities, but only 1.8% had histologic evidence of severe fibrosis (cirrhosis). These prospective studies thus revealed that during the first two decades following acute infection, liver-related morbidity and death is modest in frequency.
Follow-Up Studies Beginning with Already Established Chronic Liver
Disease:
Not surprisingly, in four such studies, two from Japan , one from the U.S.,
and one from Australia, far more serious sequelae were noted. In the two
studies from Japan, cirrhosis developed in 30% and 42% respectively, and HCC
in 15% and 19%. In the U.S. study, similar devastating outcomes were
identified. Thus, in studies beginning with already identifiable chronic
liver disease, serious sequelae are common. The problem with such studies is
that they are "biased" in the direction of severe forms of the disease;
persons infected with HCV who have no symptoms - perhaps the bulk of cases -
do not come to the attention of investigators in tertiary care or liver
transplantation centers.
More complete information on natural history, therefore, requires a long-term, prospective study that starts at the time of acute infection. Such a study has been progress in the U.S. for the past 8 years, sponsored by the National Institutes of Health (National Heart, Lung and Blood Institute [NHLBI]).
NHLBI Long-Term Follow-Up Study of Transfusion-Associated Non-A, Non-B
(NANB) Hepatitis:
This study aims to determine both mortality and morbidity among infected
transfusion recipients. The study has incorporated all persons who developed
hepatitis, identified by serial serum enzyme monitoring, in five transfusion
studies that had been performed between 1968 and 1980, as well as a matched
control group consisting of approximately twice the number of subjects who
were transfused but did not develop hepatitis. The two groups consisted of
568 cases and 984 controls. Among the cases with an original diagnosis of
NANB hepatitis, 71% were later identified to be anti-HCV reactive by the 2nd
generation ELISA.
Mortality was examined after an average of 18 to 20 elapsed years since transfusion. All-cause mortality was found to be almost identical between the cases and controls (both+50%) regardless of whether the cohorts consisted of the entire group of NANB hepatitis cases or of the hepatitis C cases. Liver-related mortality, derived from examination of death certificates, was significantly higher among the cases than the controls (3.2% vs 1.5%).
Morbidity has been determined by recalling all living subjects (cases and controls) for historical interview, physical examination, and phlebotomy for biochemical, serologic and molecular biologic evaluation. Liver biopsy was performed, whenever possible, among those with biochemically-defined chronic hepatitis. 205 cases and 335 controls were available for analysis, a subgroup of 146 cases having all original (repository) and follow-up sera available, permitting paired analysis of the HCV data. Among the main group, 31% of the cases and 4% of the controls in followup had biochemical evidence of chronic hepatitis while anti-HCV and HCV RNA was found in 53% of the cases and 6% of the controls. Evaluation of the 146 cases with original and follow-up sera revealed that 104 (71%) were originally anti-HCV positive and 42, anti-HCV-negative. Followup of the anti-HCV positive cases showed that one-half remained viremic and had chronic hepatitis, one-fifth remained viremic without biochemical evidence of chronic hepatitis, 15% continued to be anti-HCV positive but negative for HCV RNA and without evidence of chronic hepatitis, and 10% appeared to have recovered completely showing no evidence of chronic hepatitis nor of any serologic marker of the original HCV infection. Among the 42 cases that were originally anti-HCV negative (as well as negative for all other viral hepatitis markers), almost all remained HCV-negative in followup, although 19% had chronic hepatitis as defined by persisting ALT abnormalities.
Liver biopsies among those with chronic hepatitis revealed the presence of chronic hepatitis without cirrhosis in 58% of them, and the presence of cirrhosis in 28%. Correlating the histologic findings with overt clinical evidence of chronic liver disease (splenomegaly, thrombocytopenia, prolonged prothrombin time, ascites, varices), only 5% of those with histologically defined chronic hepatitis alone had observable clinical findings of chronic liver disease, none manifesting advanced chronic liver disease, whereas among those with histologically-established cirrhosis, 70% had clinical findings, 40% of this group having features of advanced chronic liver disease. Thus, advanced liver disease could be found in about 5% of the entire 205 cases in followup, or in 13% of those with biochemical dysfunction of chronic hepatitis.
These data suggest that during the first two decades after initial HCV infection, an indolent disease ensues that is associated with relatively low mortality and relatively low overt clinical morbidity. However, since those with histologic cirrhosis - representing nearly a third of those biopsied or about 10% of the entire case cohort in followup - show features of overt chronic liver disease of mild to moderate severity, this group seems poised for progressive worsening as followup extends into the third and fourth decades after initial infection. Whether those with histologically-defined chronic hepatitis alone will progress to cirrhosis with the passage of time remains to be seen.
Further long-term followup of the above groups is required and, indeed, is in process. In this regard, another study is being conducted to determine mortality and morbidity among young persons who were phlebotomized almost 50 years ago and whose resultant blood samples had been stored in deep freeze over this period of time. Serologic screening of almost 10,000 stored blood samples has revealed the presence of HCV seropositivity in some, and they and a large matched control group are presently being scrutinized for sequelae.
Predictive Factors for Outcome of Chronic HCV Infection:
Since it seems likely that only a limited proportion of HCV-infected
individuals manifest progressive disease, there is speculation that there
may be definable factors that might be predictive of progressive disease.
Viral-related factors that have been examined include viral dose, viral
genotype, and the presence of quasispecies. Host factors scrutinized have
included the age at the time of infection, race, gender, and geographic
location. Extraneous influences sought have included co-infection with other
viruses, exposure to viral contaminants, smoking, and concomitant chronic
alcoholism. Of these, the latter has proven to play the most obviously
important role, but further studies are warranted.
References:
1. Alter MJ. Epidemiology of hepatitis C in the West. Sem Liver Dis
1995;15:5-14.
2. Mansell CJ, Locarnini SA. Epidemiology of hepatitis C in the East. Sem Liver Dis 1995;15:3:15-32.
3. Seeff LB; Natural history of viral hepatitis, type C. Sem Gastrointestinal Dis 1995;6:20-7.
4. Crowe J, Doyle C, Fielding JF, et al: Presentation of hepatitis C in a unique uniform cohort 17 years from inoculation (abstr). Gastroenterology 1995;108:A1054.
http://search.freefind.com/find.html?id=8543868&pid=r&mode=ALL&query=natural+history+of+hcv
Natural History of Hepatitis C
Leonard B. Seeff, M.D.
Introduction
Of the many perplexing issues regarding viral hepatitis, type C, none is more uncertain and, indeed, more controversial than the matter of its natural history. Knowledge of outcome of the disease is critical in order to provide meaningful information to persons who are chronically infected and in order to make judicious and prudent decisions regarding treatment.
In the course of the last decade of study of what was initially referred to as non-A, non-B (NANB) hepatitis, and then more recently, hepatitis C, it had become clear that the vast majority of persons who develop acute hepatitis C-perhaps over 80 percent-remain infected. The consequence of this is progression in many such individuals from acute to chronic hepatitis, advancement in a proportion of instances to cirrhosis, ending in the development by some of hepatocellular carcinoma (HCC). This sequence has been particularly well-recognized among infected persons in Japan,
(1,2) Italy,(3) and Spain. (4) While similar outcomes have been observed among persons infected in the United States, the frequency of termination in end-stage liver disease and particularly HCC has seemed to be less frequent. This has led to two contradictory viewpoints, the first being that all or most chronically infected persons will advance to serious or terminal liver disease if they do not succumb first to another lethal illness, the second holding the position that only a limited proportion of infected persons develop progressive disease, the challenge being to determine which persons will follow this path and the reason or reasons why. Only by conducting appropriate long-term natural history studies is it possible to resolve the conflict.Such studies have been difficult to perform for the following reasons: (l) most persons who develop acute hepatitis C do so in the complete absence of symptoms, thus frustrating the ability to accurately determine onset and hence duration of disease; (2) the total lack or paucity of symptoms at onset of the illness hinders the ability to recognize the full disease spectrum, the focus then being on those with the more severe forms of the illness; (3) the lack of symptoms associated with the acute illness precludes the opportunity to select a noninfected control group to perform appropriate casecontrol followup studies; (4) treatment is now commonplace which has the clear potential of altering the natural history of the disease; and (5) the extremely slow rate of progression of the disease, ranging from 2 to 4 decades, makes it a daunting task for any investigator to embark on the necessary long-term studies. Consequently, most data on natural history have come from relatively short-term followup studies starting with disease onset, from studies that begin with already established chronic liver disease, or from retrospective studies. These approaches tend to focus attention on the more severe form of the dlsease while neglecting the milder cases that may not come to attention, thus creating potential outcome bias.
Prospective Studies Beginning from Disease Onset
Five prospective studies have been reported from the United States and Europe involving persons with transfusion-associated NANB hepatitis, predominantly but not exclusively due to hepatitis C virus (HCV) infection.
(5-9) The mean duration of followup was 8-15 years. About 10 percent of study subjects were reported in followup to have clinical symptoms, histologic cirrhosis was noted in 15-20 percent, and HCC was identified in two of the studies (0.7 percent and 1.3 percent, respectively). Mortality ranged from 1.6-6.0 percent. These studies, with somewhat small numbers and relatively short durations of followup, demonstrated an unequivocal but modest frequency of mortality and morbidity over their limited time courses.More benign data come from a study reported from Ireland of HCV-infection following receipt of HCV-contaminated immunoglobulin products.
(10,11) A followup of 232 infected persons over a 1 7-year period showed that about one-quarter had mild fatigue, none were jaundiced or had hepatosplenomegaly, and about 60 percent had modest enzyme abnormalities. Liver biopsies revealed the presence of chronic hepatitis, mostly mild, in the majority of instances, only 2.4 percent of them showing early cirrhosis and 1.8 percent showing severe fibrosis. The authors concluded from these data that there was minimal evidence of progressive disease.ollowup Studies Beginning with Already Established Chronic Liver Disease
Among three such studies with mean followup periods of 9-15 years, cirrhosis was reported to develop in 8 percent, 30 percent, and 42 percent, and HCC in 15 percent and 19 percent.
(12-14) The high frequency of cirrhosis and HCC was noted in the two studies from Japan. (12,13) It is of more than passing interest that this strikingly high frequency of HCC among persons infected in Japan may not be replicated once they move to other countries. In a recent examination of records in Hawaii over a 25-year period seeking information on HCC among descendants of Japanese immigrants, 28 HCC cases were identified, 24 of which had sera available for serologic evaluation. (15) Fifteen of the 24 had hepatitis B virus markers, while none had HCV markers. This implies that there is either an extremely low prevalence of HCV in Hawaii, or that another factor-cultural, nutritional, environmental-exists in Japan that helps promote carcinogenesis among HCV carriers residing in that country.Two other important studies must be considered in the context of evaluating the natural history of those with already existing chronic hepatitis C. In one from Japan, involving a followup of transfusionassociated chronic NANB/C hepatitis cases, HCC development was found to be common.
(16) Attempting to establish the rate of progression by extending information back to the time of initial infection based on transfusion histories, the investigators estimated that chronic hepatitis emerges after 10 years, cirrhosis after 21.2 years, and HCC after 29 years. In three cases, the interval even exceeded 50 years. In a similar study from the United States, involving an initial and followup evaluation of 131 transfusionassociated cases of chronic hepatitis C, initial evaluation revealed fatigue among 67.2 percent, hepatomegaly among 67.9 percent, histologically-defined "chronic active hepatitis" in 22.9 percent, and HCC in 5.3 percent. (17) During the followup period of 3.9 years, an additional 5.3 percent developed HCC, and 15.3 percent died. Emulating the Japanese study, the investigators estimated that, following acute infection, chronic hepatitis could be identified 13.7+10.9 years later, chronic active hepatitis 18.4+11.2 years later, cirrhosis 20.6+10.1 years later, and HCC, 28.3+11.5 years later. These studies demonstrated two important points: (l) serious outcomes are common in studies that begin with already established endstage or near-endstage chronic liver disease; and (2) the rate of progression is exceptionally slow, serious sequelae generally beginning to emerge only in the third or later decades after initial infection. Therefore, satisfactory information regarding the natural history of chronic hepatitis C can come only from longer-term prospective studies.The National Heart, Lung, and Blood Institute (NHLBI) Long-Term Followup Study of Transfusion-Associated NANB Hepatitis
A long-term followup study has been in progress during the past 8 years directed at evaluating the sequelae of acute NANB hepatitis that had developed among persons participating in five separate transfusion studies conducted in the United States between 1968 and 1980.
(18) In all five studies, hepatitis had been sought by prospective, repetitive serum enzyme monitoring of blood recipients, thus identifying even the entirely subclinical cases. Over 90 percent of these cases were defined as NANB hepatitis, 71 percent of whom were established to be HCV in origin. A total of 568 hepatitis cases were identified and matched with a transfused, non-hepatitis control group (984 subjects) from the same studies, both cohorts then being subjected to long-term followup evaluation.All-cause mortality after an average of 18 years of followup was approximately 50 percent in both the cases and the controls, indicating no difference between cases and controls. Liver-related mortality, based on death certificate analysis, was 3.2 percent for the cases and 1.5 percent for the controls, a difference that was significant even though the frequency was quite low. Of note is that 71 percent of the study subjects who had died as a consequence of liver disease were found after enrollment to be heavy drinkers, some with hospitalizations for this problem. Evaluation of mortality by life-table analysis at the end of 20 years continued to demonstrate no difference on mortality between cases and controls. Furthermore, no difference in mortality could be found when the analysis was restricted to the HCVpositive cases and their controls.
Morbidity is also being assessed by recalling all living patients to determine their current status clinically, biochemically, serologically, and histologically. Two hundred and five cases and 335 controls were available for analysis, with a subgroup of 146 cases among whom all original (repository) and followup sera were available, permitting paired comparisons. Among the main group, certain marked differences were found between cases and controls. This included the frequency of fatigue and hepatomegaly, both found to be present slightly more commonly among cases than controls, the presence of raised serum enzymes (noted in one-third of cases and 4 percent of controls), and the presence of HCV-related hepatitis serology (anti-HCV and HCV RNA in 53 percent of cases and 6 percent of controls). Focusing on the 146 with available original and followup sera, 104 (71 percent) of them could be shown to have originally developed acute HCV-related transfusion-associated hepatitis. In followup of these individuals, one-half remained HCV RNA-positive in association with biochemical evidence of chronic hepatitis; one-fifth remained HCV RNA-positive but without biochemically defined chronic hepatitis; 15 percent showed anti-HCV alone, and 10 percent appeared to have recovered completely, both biochemically and seologically. Followup of the originally HCV-negative cases revealed that 93 percent remained negative, but 19 percent showed chronic hepatitis of undefined etiology.
Liver biopsies revealed the histology of chronic hepatitis alone in 58 percent and of cirrhosis in 28 percent. Correlating the histologic findings with overt clinical evidence of chronic hepatitis, clinical disease could be identified in 5 percent of those with chronic hepatitis alone, but in 70 percent of those with cirrhosis. However, among the latter, only about one-third of those with evident chronic liver disease had clearly advanced or moderately advanced chronic liver disease. Thus, 15-18 years after the initial infection, advanced liver disease could be demonstrated in 5-8 percent of the entire living cohort of NANB hepatitis cases among whom followup could be accomplished, or in 13 percent of those who had been defined biochemically to have chronic hepatitis. These data suggest that, at this juncture in the followup of the transfusion-associated NANB/C hepatitis cases, both mortality and severe morbidity are present, but in relatively low frequency. Moreover, overt morbidity appears confined largely to those with histologically identified cirrhosis. Whether persons with histologically detected chronic hepatitis alone will ultimately advance to cirrhosis and then assume the risks of the cirrhotic group remains to be determined through continued followup.
Another long-term followup study is also in progress that involves approximately 10,000 young Air Force recruits who were phlebotomized between 1948 and 1954 in the course of the evaluation, at that time, of an outbreak of streptococcal infection. The samples had been stored in deep freeze for the past 40-45 years. With their rediscovery, the entire group was tested for the presence of HCV markers. A number of positive samples having been identified, a mortality and morbidity study is now in progress, comparing outcome among those who are positive with those selected as negative controls. This represents a unique opportunity to determine outcome among young persons found to be HCV-positive almost 50 years ago. Data will be presented.
Predictive Factors for Outcome of Chronic HCV Infection
If progression of chronic HCV infection is not inevitable, is it possible to identify factors that might help in predicting outcome? Viral factors that have been examined include viral dose, genotype, and the presence of quasispecies, each of which have been identified as having predictive value, although available data are conflicting.
(19-24) Host-related factors include age, race, gender, and geographic location. Age may play an important role, the rate of progression appearing to be more rapid as the age at the time of infection rises. Geographic location also may be of importance, perhaps related to cultural or environmental differences. Extraneous influences may consist of co-infection with other viruses, exposure to environmental contaminants, smoking, or concomitant chronic alcoholism. Co-infection with hepatitis B has been reported to increase the severity of chronic hepatitis C and the likelihood of development of HCC. (25) Co-infection with HIV has been shown in hemophiliacs to increase HCV RNA levels(26) and to worsen the course of the disease. (27) Co-infection with hepatitis G was earlier considered likely to play a promoting role in disease progression, but careful studies have recently disproved these views. (28,29) Chronic alcoholism quite clearly enhances disease progression, either because it promotes increased viral replication or because it is an additive liver-damaging factor. (30,31) The use of alcohol should be strongly condemned in persons who have chronic HCV infection.Summary
It is quite clear that a proportion of persons with chronic HCV infection will advance in time to cirrhosis and progress eventually to terminal chronic liver disease, in some instances after developing HCC. These are the seriously ill patients seen in tertiary care and liver transplant centers. The perception of the frequency of these adverse events depends, in part, on the stage of the disease at the time that follow-up studies are initiated. If they begin when chronic liver disease has already evolved, the frequency and tempo of progression is found to be high, particularly in some geographic areas such as Japan and Italy. If, however, studies begin with disease onset, serious sequelae seem to be defined less frequently. Current data suggest that during the first two decades after infection, with occasional exceptions, the disease runs an indolent course with relatively low frequencies of mortality and overt morbidity. If cirrhosis has developed during this period, symptomatic disease is more common than is noted when the histology demonstrates chronic hepatitis without cirrhosis. It can be anticipated that future morbidity and liver-related mortality is likely to emerge predominantly from the group that has developed cirrhosis, and this will become apparent as the disease process moves into its third or later decades. Whether progression is enhanced by definable factors is not yet fully established, but it does appear that late age of infection, genotype characteristics, and concomitant alcoholism may play promoting roles. Other promoting factors must continue to be sought. Whether persons with histologic evidence of chronic hepatitis alone at the end of the second decade will ultimately advance to cirrhosis and then assume the increased risks that accompany that lesion needs further evaluation through additional long-term studies. The proportion of cases whose disease remains completely stable is not yet known but might well represent the bulk of cases. The problem at present is that while helpful aggregate data are beginning to emerge, prediction of outcome for the individual case remains difficult to define. Indeed, the need for this information would be reduced if available treatment were more effective, less uncomfortable, and less costly. Continued long-ter n studies both of natural history and treatment strategies are, therefore, sorely needed. Finally, there is critical need for natural history and treatrnent studies involving children and adolescents with chronic HCV infection because of the extended life that awaits them.
References
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Nishioka K, Watanabe J, Furuta S, et al. A high prevalence of the antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan. Cancer 1991;67:429-33.
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Tanaka K, Hirohata T, Koga S, et al. Hepatitis C and hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population. Cancer Res 1991;51:2842-7.
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Colombo M, Choo QL, Del Ninno E, et al. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. Lancet 1989;2:100~8.
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Bruix J, Calvet X, Costa J, et al. Prevalence of antibody to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989;2:1004-6.
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Hopf U, Moller B, Kuther D, et al. Long-term followup of posttransfusion and sporadic chronic hepatitis nonA, non-B and frequency of circulating antibodies to hepatitis C virus. J Hepatol 1990;10:69-76.
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Di Bisceglie AM, Goodman ZD, Ishak, KG, et al. Long-term clinical and histopathological followup of chronic post-transfusion hepatitis. Hepatology 1991;14:969-74.
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Tremolada F, Casarin C, Alberti A, et al. Long-term followup of non-A, non-B (type C) post-transfusion hepatitis. J Hepatol 1992; 16:273-81.
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Koretz RL, Abbey H, Coleman E, Gitnick G. Non-A, non-B post-transfusion hepatitis: looking back in the second decade. Ann Intern Med 1993; 119:110-15 .
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Mattson L, Sonnerborg A, Weiland 0. Outcome of acute symptomatiG non-A, non-B hepatitis: a 13-year followup study of hepatitis C virus markers. Liver 1993; 13 :274-8.
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Crowe J, Doyle C, Fielding JF, et al. Presentation of hepatitis C in a unique uniform cohort 17 years from inoculation (Abstract). Gastroenterology 1995;108:AI 054.
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Power JP, Lawlor E, Davidson F, et al. Hepatitis C viremia in recipients of Irish intravenous anti-D immunoglobulin. Lancet 1994;344:1166-7.
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Takahashi M, Yamada G, Miyamoto R, et al. Natural course of chronic hepatitis C. Am J Gastroenterol 1993;88:240-3.
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Yano M, Yatsuhasi H, Inoue 0, et al. Epidemiology and long-term prognosis of hepatitis C virus infection in Japan. Gut 1993;34(Suppl):S13-S16.
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Roberts JM, Searle JW, Cooksley WGE: Histological patterns of prolonged hepatitis C virus infection. Gastroenterol Jpn 1993;28:901-5.
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Nomura A, Stemmermann GN, Chyou P-H, Tabor E: Hepatitis B and C serologies among Japanese Americans with hepatocellular carcinoma. J Infect Dis 1996;173:1474 6.
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Kiyosawa K, Sodeyama T, Tanaka E, et al. Interrelationship of blood transfusion non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibidy to hepatitis C virus. Hepatology 1990;12:671-5.
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Tong MJ, El-Farra NS, Reikes AR, Co RL: Clinical outcomes after transfusion-associated hepatitis C. N Engl JMed 1995;332:1436 66.
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Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. N Engl J Med 1992;327:1906-11.
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Gretch D, Corey I, Wilson J, et al. Assessment of hepatitis C virus RNA levels by quantitative competetive RNA polymerase chain reaction: high-titer viremia correlates with advanced stage of disease. J Infect Dis 1994;169:1219-25.
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Honda M, Kaneko S, Sakai A, et al. Degree of diversity of hepatitis C virus quasispecies and progression of liver disease. Hepatology 1994;20:1144-51.
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Farci P, Melpolder JC, Shimoda A, et al. Studies of HCV quasispecies in patients with acute resolving hepatitis compared to those who progress ro chronic hepatitis. Hepatology 1996;24:350A.
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Tanaka E, Kiyosawa K, Matsushima T, et al. Epidemiology of genotypes of hepatitis C virus in Japanese patients with type C chronic liver disease: a multi-institution analysis. J Gastroenterol Hepatol 1995;10:538-45.
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Kobayashi M, Tanaka E, Sodeyama E, et al. The natural course of chronic hepatitis C: a comparison between patients with genotypes I and 2 hepatitis C viruses. Hepatology 1996;23:695-9.
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Romeo R, Tommasini MA, Rumi MG, et al. Genotypes in the progression of hepatitis C related cirrhosis and development of hepatocellular carcinoma. Hepatology 1996;24:153A.
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Chiba T, Matsuzaki Y, Abei M, et al. The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. Am J Gastroenterol 1996;91:119-203.
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Eyster ME, Fried MW, Di Bisceglie AM, Goedert JJ. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study. Blood 1994;84:1020-3.
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Eyster ME, Diamondstone LS, Lien JM, et al. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immun Defic Syndr 1993;6:602-10.
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Tanaka E, Alter HJ, Nakatsuji Y, et al. Effect of hepatitis G virus infection on chronic hepatitis C. Ann Intern Med 1996;125 :740 3 .
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Pawlotsky JM, Roudot-Thoravel F, Pellerin M, et al. GBV-C infection in HCV-infected patients: epidemiological characteristics, influence on HCV infection and response to interferon alfa therapy. Hepatology 1996;24:226A.
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Oshita M, Hayashi N, Kasahara A, et al. Increased serum hepatitis C virus RNA levels arnong alcoholic patients with chronic hepatitis C. Hepatology 1994;20:1115-20.
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Noda K, Yoshihara H, Suzuki K, et al. Progression of type C chronic hepatitis to liver cirrhosis and hepatocellular carcinoma-its relationship to alcohol drinking and the age of transfusion. Alcohol Clin Exp Res 1996;20:95A-IOOA
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Health Research Board & Cork University Hospital
Liam Fanning
A viral version of the 'invasion of the body snatchers' - the Hepatitas C virus invades the human liver.
Chronic hepatitis C infection is a ubiquitous disease, affecting over 200
million people worldwide. The hepatitis C virus (HCV) is spread by exposure
to infected blood or blood products. The most striking feature of hepatitis
C virus infection is the tendency toward chronicity. The human leukocyte
associated antigen (HLA) is a host-encoded protein that presents bacterial
and viral proteins to the infected individual's immune system. The HLA has
been shown to influence host response to the HIV and the hepatitis B virus.
Researchers at the Hepatitis C Unit, Cork, Department of Medicine, Cork
University Hospital, have assessed the likely influence of host HLA on the
ability of infected individuals to eliminate the HCV. The study population
was infected from a single source, with a single type of the hepatitis C
virus, and the year of infection was known for each individual. The study
population was equally divided between those who had evidence of exposure to
the HCV, but who had cleared the virus, and those who were persistently
infected with the virus
In a series of experiments, DNA was isolated from the blood of these
individuals. Their genetic profile was determined molecularly at two
specific locations on chromosome 6. Analysis of this genetic data revealed
that presence of a particular HLA group was associated with a greater
likelihood of clearance of the hepatitis C infection. Additional analysis
identified a HLA gene, which was associated with persistent hepatitis C
infection in this study population. Evidence from the study may lead to the
identification of crucial protein segments from the HCV important for immune
system mediated clearance.
Chronic hepatitis C is characterized by persistent viraemia (i.e. the
continuous presence of detectable virus), the natural variation of which is
undefined. Researchers at the Hepatitis C Unit have evaluated the amount of
virus present in the blood over an extended period of patient follow-up and
developed a model for predicting change in viral load over time in their
study population. The results of this research suggest that viral load
appears to increase over time in the chronically infected individual. This
model, which is currently undergoing prospective evaluation, may enable the
prediction of when chronically infected individuals are likely to have a
serum viral load correlated with likely response to anti-viral therapy.
The ongoing goal of the Hepatitis C Unit is to define the viral and host
factors that influence the natural progression of hepatitis C virus
infection.
Contact: Liam Fanning PhD,
Hepatitis C Unit, Department of Medicine, Clinical Sciences Building,
Cork University Hospital;
Tel: +353-21-901281; Fax: +353-21-345300
http://www.irishscientist.ie/2000/contents.asp?contentxml=036Bs.xml&contentxsl=insight3.xs
Does the Natural History of Hepatitis C Vary According to HCV Genotype?
It is well known that individuals with genotype 1 hepatitis C virus (HCV) do not respond as well to interferon-based therapy as those with genotypes 2 or 3, but less is known about the effect of genotype on the natural history and progression of hepatitis C.
As reported in the March 2007 Journal of Viral Hepatitis, researchers with the HCV National Register Steering Group in the United Kingdom assessed whether HCV genotype might influence the clinical outcome of infection.
They analyzed serum
samples from 749 individuals enrolled in the UK HCV National Register, and
extracted clinical outcome information from the database.
Logistic regression analysis was used to investigate the effect of HCV genotype
on viral clearance, comparing HCV RNA positive and negative subjects. The same
method was used to investigate whether HCV genotype was associated with
histological stage of liver disease.
Results
• The prevalence of HCV genotype 1 among patients who spontaneously cleared the virus was 69%, compared with 51% among those who remained HCV RNA positive.
• Patients with genotype 1 were more likely to be HCV RNA negative than those with other genotypes (OR 0.47; P = 0.003).
• Among subjects with continued detectable HCV RNA, genotype 1 patients were more likely to have histological scores above the median (OR 2.03; P = 0.03).
Conclusion
"HCV [geno]type 1 infection was more often HCV RNA negative," the authors concluded, "suggesting that spontaneous clearance may occur more commonly with this type." However, they added, "Among the [HCV] RNA-positive infections, [geno]type 1 infection may be more aggressive than [geno]types 2/3.
03/30/07
References
H E Harris, K P Eldridge, S Harbour, and others (HCV National
Register Steering Group). Does the clinical outcome of hepatitis C infection
vary with the infecting hepatitis C virus type? Journal of Viral Hepatitis
14(3): 213-220. March 2007.
http://www.hivandhepatitis.com/hep_c/news/2007/033007_a.html
A Brief History of Hepatitis C
Alan Franciscus, Editor-in-Chief
The management and care of hepatitis C has come a long way in the last decade. While there are still many unanswered questions, we have a much better understanding of hepatitis C transmission, prevention, disease progression and treatment. This article will focus on a brief review of the history of hepatitis C and the major strides made in treating HCV since the identification of the virus.
Prior to 1990
It is impossible to really know the origins of hepatitis C since there are
no stored blood samples to test for the virus that are older than 50 years.
However, given the nature of the evolution of all viruses, hepatitis C has
probably been around for hundreds of thousands of years or more before
evolving into the current strains.
Some experts speculate that since HGV/GBV-C, a close relative of HCV,
originated in Old and New World primates, the beginnings of HCV might be
traced back to 35 million years ago. However, this is just speculation and
it is impossible to corroborate these theories at the present time. On
firmer ground is the prediction that the different subtypes of HCV
originated approximately 200 years ago and that the six main genotypes of
HCV most likely had a common ancestor approximately 400 years ago. However,
it has also been pointed out that it is difficult to limit the origin of HCV
to such a short period of human history because the virus is found in remote
areas all over the world. As well, the virus is mainly spread by direct
blood to blood contact, making it difficult to spread and evolve
rapidly—especially considering that the main transmission routes (blood
product use and needle use) have only been in existence for a short period
of time.
1957
Scientists discovered the antiviral properties of interferon, a naturally
occurring substance in 1957. It was named interferon since it has the
ability to 'interfere' with viral replication. Three different types of
interferon were identified—alfa, beta and gamma. While it was found that
there is only one form of beta and gamma interferon, it was discovered that
there were many forms of alfa interferon. Interferon was approved to treat a
variety of disorders including hairy cell leukemia, and Kaposi's sarcoma.
1960-1970's
Scientists developed blood tests to identify hepatitis B (1963) and
hepatitis A (1973), but many of the blood samples taken for post-transfusion
illness tested negative for hepatitis A and hepatitis B.
Given that the mode of transmission (blood transfusion) was the same,
scientists classified the unidentified cases as non-A, non-B hepatitis. It
is now believed that approximately 90-95% of cases previously classified as
non-A, non-B were actually hepatitis C.
In the 1980's, investigators from the Centers for Disease Control (headed up
by Daniel W. Bradley) and Chiron (Michael Houghton) identified the virus. In
1990, blood banks began screening blood donors for hepatitis C, but it
wasn't until 1992 that a blood test was perfected that effectively
eliminated blood transfusion supply. Now the risk of contracting hepatitis C
through a blood transfusion is approximately .001%. Prior to the screening
of the blood supply for hepatitis C, approximately 300,000 Americans
contracted hepatitis C through blood transfusions or blood products.
Treatment Timelines
1991 - FDA approves first alfa interferon (Schering's
Intron A) to treat hepatitis C.
1992 - FDA approves first interferon (Schering- Intron A)
to treat hepatitis B.
1996 - FDA approves alfa interferon (Roche- Roferon A ) to
treat hepatitis C.
1997 - FDA approves consensus interferon (Amgen- now
InterMune-Infergen) to treat hepatitis C.
The general treatment protocol was to inject 3 million units of interferon,
three times a week for 48 weeks. Sustained virological response rates
(negative viral load 6 months post-treatment) were approximately 9% for
genotype 1 and 30% for genotypes 2 and 3.
Treatment Breakthrough
1998 - FDA approves Rebetron (Schering's Intron A plus
ribavirin) for the treatment of hepatitis C.
Ribavirin is a synthetic nucleoside analogue with a broad spectrum of
antiviral activity that was initially developed as a possible treatment of
HIV. As it turned out, ribavirin was not effective against HIV, but it was
found that it did have antiviral activity against several flaviviruses (a
family of viruses that includes hepatitis C), and it was studied as a single
agent for the treatment of hepatitis C. In some small studies, ribavirin was
found to reduce serum ALT levels, but that it had no effect on the hepatitis
C virus. The clinical findings that ribavirin reduced ALT levels led to the
studies of combination ribavirin and interferon therapy. It was found that
ribavirin when combined with interferon produced a snygery that proved to be
a major breakthrough for treating hepatitis C. Ribavirin (in a mist form) is
also approved for the treatment of respiratory syncytial virus (RSV)
infection in children.
The treatment with combination therapy consists of interferon (Intron A - 3
million units thrice weekly) plus ribavirin (800-1200mg/day). The clinical
trials conducted on combination therapy also determined the duration of
treatment for genotype 1 as 48 weeks and 24 weeks for genotypes 2 and 3.
Overall sustained virological response rates are genotype 1 - 29% (high
viral load - 27%); genotypes 2 and 3 - 62% (high viral load - 60%).
A New Era in the Treatment of Hepatitis C
Synthetic interferon is a protein that is broken down rapidly by the body
within 12 to 24 hours after injection. The standard protocol for interferon
was to inject 3 times a week. The synthetic interferon was eliminated by the
body, and, without further interferon available, the body could not suppress
or kill the virus.
Pegylation is a process that attaches polyethylene glycol (a biologically
inert compound) strands to the interferon molecule making it less likely to
be cleared from the bloodstream. The benefit of increased concentrations of
interferon levels is that these help to constantly suppress the virus and
increase the likelihood of a sustained virological response.
2001
Peg-Intron (Schering’s pegylated interferon alpha-2b) was the first
pegylated interferon FDA approved to treat hepatitis C. Peg-Intron is a
powder that needs to be reconstituted (with a sterilized solution) before it
can be injected. Peg-Intron also needs to be dosed by a person's body
weight.
The sustained virological response rates for Peg-Intron monotherapy are 14%
for genotype 1, and 47% for genotypes 2 and 3.
PEG-Intron plus Rebetol (ribavirin) was also approved in 2001 to treat
hepatitis C. Sustained virological response rates are 42% for genotype 1
(high viral load - 30%) and 82% for genotypes 2 and 3.
2002
Pegasys (Roche's pegylated interferon alpha-2a) was approved to treat
hepatitis C in 2002. Pegasys comes in a ready made solution (does not need
to be reconstituted) and in a dose fixed at 180 micrograms regardless of a
person's weight.
The sustained virological response (SVR) rate for Pegasys is 28% for
genotype 1, and 56% for genotypes 2 and 3. People with advanced fibrosis or
compensated cirrhosis (a group that is more difficult to treat) achieved a
SVR of 20%. This clinical trials on cirrhotic patients also showed that
Pegasys reduced liver inflammation and scarring in treatment responders and,
to a lesser degree, in non-responders. Data from this trial and other
conventional interferon clinical trials led to the NIH HALT C trial that is
studying the role of interferon in reducing liver inflammation and slowing
or 'stopping/halting' liver disease progression.
In 2002 Pegasys plus Copegus (Roche's brand of ribavirin) was also approved
for treatment of hepatitis C. Sustained virological response rates for
genotype 1 are 46-51% (high viral load 41-45%) and 76-78% for genotypes 2
and 3.
It is clear that we have come a long way in a relatively short period of
time in the understanding of HCV disease and the therapies used to treat it.
We are by no means close to completely understanding and treating hepatitis
C, but with increased research it is clear that we will have many more
answers within the next 5-10 years and perhaps discover a medication that
will be effective for treating everyone with hepatitis C.
2008
Pegasys Or Pegintron?
Roche responds to announcement of 'IDEAL' hepatitis C trial results
2000 B.C. First recorded references to hepatitis
epidemics.
1947 F.O. MacCallum, using human volunteers, differentiates hepatitis A,
which is spread by contaminated food and water, from hepatitis B, which is
spread by blood.
1963 Baruch Blumberg and Harvey Alter discover Aa, the Australian antigen
(later called HBsAg).
1967-1968 Blumberg, Kazuo Okochi, Alfred Prince, Alberto Vierrucci, and
colleagues report that Aa is involved in the development of hepatitis B.
1969 Irving Millman and Blumberg devise a concept and through the Fox Chase
Cancer Center receive a patent for using Aa to prepare a hepatitis B
vaccine.
1970 D. S. Dane discovers whole hepatitis B virus particles in blood samples
examined with the electron microscope.
1972 Laws are passed in the United States requiring testing of donor blood
for HBsAg antigen.
1973-1974 Stephen Feinstone and colleagues and Maurice Hilleman and
colleagues discover and describe hepatitis A virus.
1975 Wolf Szmuness and Hilleman and colleagues begin tests of the hepatitis
B vaccine.
1977 Mario Rizzetto and John Gerin discover hepatitis D.
1980-1981 Subunit hepatitis B virus vaccine derived from blood serum is
developed by Hilleman and colleagues, proved effective and licensed for
general use.
1983 Mikhail Balayan describes the hepatitis E virus.
Hepatitis time Line
1983-1986 Subunit hepatitis B virus vaccine derived from yeast is developed
by William Rutter and colleagues and approved for use.
1989 Daniel Bradley provides Chiron with non A-non B hepatitis serum from
chimpanzees; Michael Houghton and colleagues discover a single virus,
publish the genetic sequence of the viral agent, and change the name to
hepatitis C.
1990 Blood screening for hepatitis C begins.
1996 The first hepatitis A vaccine, made by Merck, is licensed for general
use; another hepatitis A vaccine, developed by SmithKline Beecham, is proved
to be effective
Download 2009 HCV Updates
Dr.
Galati Discussed Hepatitis C Updates
Two recent studies examined the natural history
of liver cirrhosis in individuals with viral hepatitis. In the May issue of
Gut, L. Benvegnu and colleagues investigated the progression and
outcome of initially compensated cirrhosis in a cohort of 312 Italian
patients with hepatitis B (43 patients), C (254 patients), or both (15
patients), followed for an average of about eight years. Tests were
performed every six months to assess liver disease progression and identify
major complications. During the follow-up period, 102 patients (about 33%)
developed at least one complication. The most common were hepatocellular
carcinoma (HCC, a type of liver cancer; about 21%), ascites (about 20%),
gastrointestinal bleeding (about 5%), and encephalopathy (about 2%). About
20% experienced liver disease progression as evidenced by an increased
Child-Pugh cirrhosis score. About 19% died from liver disease during
follow-up, most (70%) due to HCC. The authors concluded that HCC was “the
most frequent and life-threatening complication, particularly in HCV
positive cases.”
The same month in the Journal of Hepatology, Ramon Planas and
colleagues from Spain reported on the natural history of decompensated
cirrhosis in patients with hepatitis C. Two hundred patients were followed
from their first hospitalization for hepatic decompensation; average
follow-up was about three years. The most common initial complications
related to decompensation were ascites (48%), gastrointestinal bleeding
(about 33%), severe bacterial infection (about 15%), and encephalopathy
(5%). During follow-up, about 17% developed HCC and about 43% died. “Once
decompensated HCV-related cirrhosis was established,” the researchers
concluded, “patients showed not only a very high frequency of readmissions,
but also developed decompensations different from the initial one.”
http://www.hcvadvocate.org/news/newsRev/2004/HJR-1.11.html#3
NATURAL HISTORY OF COMPENSATED CIRRHOSIS
This study was presented at the EASL
liver meeting in Madrid by a Greek research group from the University
of Crete. The aim of this study was to define the natural history of
compensated cirrhosis and analyze age, sex and cirrhosis etiology at
diagnosis to identify prognostic factors available at diagnosis which
might influence the time or decompensation or survival.
The authors retrospectively analyzed data of 306 compensated cirrhotic
patients from diagnosis to decompensation and, death, using the log
rank test and univariate Cox PH models.
RESULTS: 54.9% of the patients were males, 47.06% were <64
years old. 56 had alcoholic cirrhosis, 17 had alcoholic cirrhosis with
a viral infection, 45 had HBV cirrhosis, 145 had HCV cirrhosis and 43
had cryptogenic cirrhosis. 150 patients (49.02%) became decompensated
within the study period. Median time to decompensation was 58 months
(95% CI 51 and 65 months). Patients with HCV cirrhosis had longer
times to decompensation than the other groups (81 months).
65% of all patients remain compensated 3 years after diagnosis,
reduced to 34% after 7 years. 70 patients (22.88%) died within the
study period. The median survival time was 126 months (95% CI 103 to
149 months). The prognostic factors available at diagnosis that were
found to have a significant effect on decompensation and survival time
were sex (p = 0.0024 and p = 0.0007) and etiology of cirrhosis (p <
0.0001 and p = 0.0024). The authors found that females with HCV
cirrhosis have the longest time until decompensation and the longest
survival times.
http://www.natap.org/2002/easl/day9.htm
Compensated cirrhosis: natural history and prognostic
factors.
Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, Caballeria
J, Rodes J, Rozman C.
To investigate the natural history of compensated cirrhosis, 293 consecutive
patients without previous major complications (ascites, jaundice,
encephalopathy or gastrointestinal hemorrhage) were studied in terms of
morbidity (probability of developing decompensated cirrhosis during
follow-up) and survival. Patients were diagnosed by liver histology between
1968 and 1980. Median follow-up was 63 months. Decompensation of cirrhosis
was considered when a patient first developed one of the major complications
of the disease. Ten years after diagnosis, the probability of developing
decompensated cirrhosis and the survival probability rate were 58 and 47%,
respectively. A multivariate survival analysis (Cox's regression model)
using clinical, biochemical and histological data obtained at diagnosis
disclosed seven factors that predicted prognosis: serum bilirubin; serum
gamma-globulin concentration; hepatic stigmata; prothrombin time; sex; age,
and alkaline phosphatase. According to the contribution of each one of these
factors to the final model, a prognostic index was constructed that allows
calculation of the estimated survival probability. The predicting value of
this index was validated by a split sample testing technique.
PMID: 3804191 [PubMed - indexed for MEDLINE]
Natural history of decompensated hepatitis C virus-related cirrhosis.
A study of 200 patients. Hepatol. 2004 May;40(5):823-30.
Planas R, Balleste B, Antonio Alvarez M, Rivera M, Montoliu S, Anton Galeras J, Santos J, Coll S, Maria Morillas R, Sola R. Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain.
BACKGROUND/AIMS: Since few data are available concerning the clinical course of decompensated hepatitis C virus (HCV)-related cirrhosis, the aim of the present study was to define the natural long-term course after the first hepatic decompensation.
METHODS: Cohort of 200 consecutive patients with HCV-related cirrhosis, and without known hepatocellular carcinoma (HCC), hospitalized for the first hepatic decompensation.
RESULTS: Ascites was the most frequent first decompensation (48%), followed by portal hypertensive gastrointestinal bleeding (PHGB) (32.5%), severe bacterial infection (BI) (14.5%) and hepatic encephalopathy (HE) (5%). During follow-up (34+/-2 months) there were 519 readmissions, HCC developed in 33 (16.5%) patients, and death occurred in 85 patients (42.5%). The probability of survival after diagnosis of decompensated cirrhosis was 81.8 and 50.8% at 1 and 5 years, respectively. HE and/or ascites as the first hepatic decompensation, baseline Child-Pugh score, age, and presence of more than one decompensation during follow-up were independently correlated with survival.
CONCLUSIONS: Once decompensated HCV-related cirrhosis was established, patients showed not only a very high frequency of readmissions, but also developed decompensations different from the initial one. These results contribute to defining the natural course and prognosis of decompensated HCV-related cirrhosis. PMID: 15094231 [PubMed - in process]