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a Department of
Gastroenterology, Royal Berkshire Hospital, London Road, Reading
RG5 5AN, UK, b Institute
of Liver Studies, King's College London, Bessemer Road, London
SE5 9PJ, UK, c The Liver
and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham B15
2TH, UK
Correspondence to: Dr J C L Booth.
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1.0 Guidelines |
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 Top
 1.0 Guidelines
 2.0 Background
3.0 Diagnosis
4.0 Treatment
5.0 Future research
6.0 Appendix
Guideline recommendations
References
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1.1 THE NEED FOR GUIDELINES
Hepatitis C virus (HCV) is a major health care concern in the UK
affecting some 200 000 to 400 000 individuals. The majority of these
patients will have chronic HCV infection and many will develop chronic
liver disease with the risk of developing cirrhosis and hepatocellular
carcinoma (HCC). Successful treatment will arrest the progression of
liver disease and so prevent the serious complications of chronic HCV
infection. In addition, treatment will reduce the numbers of HCV
infected individuals.
The relatively high cost of treatment enforces the need for a systematic approach for this condition so that resources are used most effectively. The development of clinical guidelines is important, as these will assist purchasing authorities, providers, clinicians, primary care groups, and patients in making decisions about appropriate treatment.
1.2 THE DEVELOPMENT OF GUIDELINES:
RIGOUR OF DEVELOPMENT/SYSTEMATIC CRITICAL REVIEW OF THE LITERATURE
1.2.1 Guideline development group
The development of these clinical guidelines follows a workshop
held at the Royal College of Physicians on 3 December 1997. This
meeting was jointly coordinated by the NHS Executive, the Royal College
of Physicians, the British Society of Gastroenterology, British Liver
Trust, and the British Association for the Study of the Liver (BASL).
The workshop was attended by hepatologists, gastroenterologists,
histopathologists, virologists, general practitioners, clinical nurse
specialists, patient representatives, health care economists, and NHS
managers. Attendants were chosen to represent key professional
disciplines and interest groups likely to be affected by the
guidelines. The literature was reviewed by a clinician attending the
workshop and the guidelines written under the guidance of a steering
committee, which met regularly during the development process. The
document was circulated to both clinicians (including gastroenterologists and hepatologists) and non-clinicians for comments
before the final guidelines were drawn up (see appendix). The
guidelines were presented at the 1999 BASL meeting in London where
consensus was achieved on some of the more controversial issues.
1.2.2 Strategy
The literature was searched comprehensively so as to include the
most up to date literature. Literature searched included results of
randomised control trials (RCTs), meta-analyses, prospective and
retrospective studies, and in some instances from evidence obtained
from expert committee reports or opinions. Where possible a judgement
is made on the quality of information used to generate the guidelines.
Categories of evidence are classified:
A RCTs, meta-analyses, or systematic reviews;
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| Bprospective, retrospective, or cross sectional studies;
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| Cexpert opinion.
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1.2.3 Context and content
The guidelines are intended to improve the patient's management
from first diagnosis to completion of a course of antiviral therapy and
during follow up. Patient preferences must be sought and decisions made
jointly by patient and health carer based on the risks and benefits of
any therapeutic intervention.
1.2.4 Application and presentation
The national guidelines will be used as a framework for local
groups to develop according to local needs.
1.2.5 Statement of intent
The guidelines should not be regarded as the standard for medical
care for all patients. Individual cases must be managed on the
basis of all clinical data available for that case and are subject to
change as scientific knowledge advances.
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2.0 Background |
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Top
1.0 Guidelines
2.0 Background
3.0 Diagnosis
4.0 Treatment
5.0 Future research
6.0 Appendix
Guideline recommendations
References
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2.1 EPIDEMIOLOGY
2.1.1 Prevalence
Since the discovery of HCV and the development of diagnostic
tests, almost all of the non-A non-B (NANB) post transfusion hepatitis
(PTH) cases have been shown to be due to HCV
infection.1-7 HCV has been encountered worldwide with WHO
estimates of 170 million infected patients worldwide, and up to 90% of
these will progress to chronic liver disease.8 In total,
130 countries worldwide have reported HCV infection.
2.1.2 Parenteral transmission
The main route of HCV transmission is parenteral, and the majority
of patients will give a history of either intravenous drug abuse or a
blood/blood product transfusion prior to anti-HCV testing. In 1989, Zuckerman reported the presence of anti-HCV antibody in 85% of PTH
patients, 60-80% of haemophiliacs receiving blood products, 60-70%
of cases of chronic liver disease with a history of blood transfusion,
and 50-70% of intravenous drug abusers.13 Application of
second generation diagnostic tests and polymerase chain reaction (PCR)
suggest that some of these values are underestimates.14 Long term follow up indicates that a large proportion of those patients
infected by blood or blood product transfusion will develop chronic
viral carriage.15 16
2.1.3 Non-parenteral transmission
2.1.3.1 Sexual transmissionEpidemiological studies show
low rates of HCV infection in high promiscuity groups such as
prostitutes, homosexuals, and patients with sexually transmitted
diseases22-24 and suggest a limited role for sexual
transmission. A more recent study showed a seropositivity rate of
11.7% in human immunodeficiency virus (HIV) positive homosexuals who
did not have a history of transfusion or IVDU suggesting that sexual
transmission occurs and may be facilitated by coinfection with
HIV.25 Although Alter and colleagues4
suggested in 1989 that heterosexual contact was responsible for a
proportion of acute NANB cases, more recent studies have failed to
support these findings.26 27 Indeed Hsu and
colleagues28 were unable to detect HCV by PCR in semen,
urine, stool, or vaginal secretions. The overall rate of anti-HCV
positivity appears to be low in sexual partners of HCV infected
haemophiliacs29 unless there is coexistent HIV infection.
In one study intraspousal infection was confirmed by sequence analysis
of the E1 gene30 although the risk of transmission in long
term monogamous relationships is less that 5%.31 32 However, multiple sexual partners, sexually transmitted disease clinic
attendance, and prostitution are associated with an increased risk of
HCV infection.33
The risk of vertical
transmission seems to be low (<6% of children becoming HCV positive)
unless the mother is HIV positive or has a particularly high level
viraemia.34-37 Breast feeding has not so far been
implicated in HCV transmission and the virus has not been found in
breast milk.38 39
2.1.3.3 Alternative routes of transmissionIn families,
unapparent parenteral exposure may occur, perhaps by sharing razors or
toothbrushes. HCV has been found in saliva39-41 and in
one study NANB was thought to have been transmitted from chimpanzees by
saliva.42 Studies of non-sexual household contacts of HCV
seropositive patients have reported seroprevalence rates varying from
0.5% to 13%.43 44
2.2 NATURAL HISTORY OF HEPATITIS C
VIRUS INFECTION
Subclinical HCV infection is the rule with only 10% of patients
reporting an acute illness associated with jaundice. HCV infection rarely causes fulminant hepatitis45 46 but severe acute
HCV infections have been reported in liver transplant
recipients,19 patients with underlying chronic liver
disease, and in patients coinfected with hepatitis B virus
(HBV).47 Although the acute illness is usually mild, a
high proportion of patients progress to chronic liver
disease.8 In a study of 135 patients with PTH, 77%
developed chronic disease and of the 65 patients with sequential liver
biopsies, 32% had developed cirrhosis after a mean follow up of 7.5 years.16 Only 1% of these patients had histological
remission with the remaining patients having chronic active (CAH) or
chronic persistent hepatitis (CPH). However, in the same year Seeff
et al published a long term follow up study of patients with post transfusion NANB hepatitis.48 A
total of 568 patients with PTH and two control groups of 526 and 458 patients who had received transfusions without developing hepatitis were studied. After an average follow up of 18 years, mortality related
to liver disease was 3.3% in PTH cases compared with 1.5% in the
control groups and the majority of deaths occurred in patients with
associated alcoholism. It appears therefore that most patients who
develop progressive disease do so slowly.
In 1995 Tong et al published a study of 131 PTH cases referred to a centre between 1980 and 1994.49 A total of 101 patients underwent liver biopsy a mean of 22 years post transfusion. Twenty seven (20.6%) had chronic hepatitis, 30 (22.9%) had CAH, 67 (51.1%) had cirrhosis, and seven (5.3%) had HCC after mean time intervals from transfusion of 14, 18, 20, and 28 years, respectively. During the follow up period, 20 (15.3%) patients died, 19 (95%) from complications of cirrhosis or the development of HCC. Thus persistent post transfusion HCV infection does lead to progressive liver disease and in some patients death from related liver failure or the development of HCC although long term follow up studies are required to assess the contribution of HCV to morbidity and mortality. However, most studies have been conducted at referral centres, reflecting the severe end of the disease spectrum, so that the true numbers of patients with non-progressive or mildly progressive liver disease are unknown.
Viral factors associated with more rapidly progressive disease include high level viraemia,50 genotype 1 (especially 1b),51 and the degree of viral genetic diversity (quasispecies).52 53 Route of transmission may be important as patients infected via blood transfusion tend to have more histologically active liver disease.27 Other host factors such as immune deficiency,54 excess alcohol,55 56 and coinfection with HBV47 and HIV57 may also influence the rate of disease progression.
There is a variable rate of fibrosis progression with a median time from infection to cirrhosis of approximately 30 years (range 13-42 years).58 Independent factors associated with an increased rate of fibrosis progression include age at infection greater than 40 years, daily consumption of 50 g or more of alcohol, and male sex. There was no association between fibrosis progression and genotype.
In HCV associated compensated cirrhotics, five year survival is over 90% and 10 year survival 80%.59 A five year follow up showed that the risk of developing HCC was 7% (1.4% per year) and 18% decompensated. After decompensation, prognosis is poor with 50% survival at five years.
2.3 CLINICAL SPECTRUM OF DISEASE
Infection with the hepatitis C virus results in a variety of
hepatic and extrahepatic diseases. In a minority of patients, infection
results in an acute hepatitis with symptoms resembling other forms of
acute hepatitis.4 The mean incubation period is seven
weeks and symptoms, if present, last for 2-12 weeks. There are however
few reliable studies on the natural history of acute HCV and although
the minority of patients clear the virus, the precise numbers are not known.
Patients with chronic HCV often have no symptoms but may complain of non-specific symptoms such as fatigue, muscle aches, anorexia, right upper quadrant pain, and nausea. Symptoms and signs of chronic liver disease occur later in the disease. However, some patients with chronic HCV cirrhosis remain asymptomatic. Thus the presence of symptoms is a poor marker of the severity of liver disease.
2.4 EXTRAHEPATIC MANIFESTATIONS
HCV infections have been associated with a number of immunological
disorders including autoimmune hepatitis, Sjogren's syndrome, lichen
planus, thyroiditis, membranous glomerulonephritis, and polyarteritis
nodosa.60 HCV is associated with essential mixed cryoglobulinaemia.61-63
Recognition of HCV involvement in disorders such as cryoglobulinaemia and idiopathic thrombocytopenic purpura64 will allow consideration of IFN therapy for these non-hepatic as well as hepatic diseases.
2.5 HEPATITIS C VIRUS AND ALCOHOL
There are high rates of HCV antibody positivity among alcoholic
patients.65 66 Most antibody positive patients are also HCV RNA positive and some studies suggest higher levels of HCV RNA in
this group of patients,67 although this remains to be confirmed. The presence of anti-HCV antibodies is associated with more
severe liver disease in alcoholic patients.
The importance of alcohol in chronic HCV infection was shown in the recent study of Poynard et al showing that daily consumption of more than 50 g of alcohol is associated with an increased rate of fibrosis progression.58
2.6 HEPATITIS C VIRUS AND
HEPATOCELLULAR CARCINOMA
HCV infection is associated with a large proportion of HCCs. In
southern Europe and Japan, 50-75% of HCCs are associated with HCV.65 68-70 HCV may cause HCC as a consequence of
cirrhosis or as a result of chronic necroinflammation rather than
having any direct carcinogenic effects. Unlike HBV, HCV does not
integrate into the host's DNA. The majority, if not all, of patients
with HCV associated HCC have established cirrhosis. Both HBV
coinfection and excess alcohol seem to have an additional effect on the
development of HCC.71 72
The natural history of disease progression is slow in HCV related liver disease with estimates of 20-30 years' duration of infection prior to the development of HCC.49 In patients with established cirrhosis the rates of development of HCC range between 1% and 7% per year.59 73 The role of antiviral therapy in preventing the development of HCC in HCV infected cirrhotics is controversial.73
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3.0 Diagnosis |
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Top
1.0 Guidelines
2.0 Background
3.0 Diagnosis
4.0 Treatment
5.0 Future research
6.0 Appendix
Guideline recommendations
References
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3.1 DIAGNOSTIC SEROLOGICAL ASSAYS
The discovery of HCV in 198974 led to the development
of an antibody diagnostic assay based on viral recombinant peptides. The first generation tests incorporated a fused antigen of human superoxide dismutase (SOD) and HCV polypeptide (C100-3) used in an
enzyme linked immunosorbent assay (ELISA).75 The first
generation assay lacked sensitivity and specificity prompting the
development of second generation assays incorporating antigens from the
nucleocapsid (C22) and NS3 (C33) genomic regions. Third generation
assays (ELISA-3) have since been introduced incorporating antigens from
the putative nucleocapsid, NS3, NS4, and NS5 regions. ELISA-3 tests
have a sensitivity of 97% and have shortened the mean time to
seroconversion by 2-3 weeks.76 ELISA-3 tests are now the
most widely used screening tests for HCV77 78 but despite
the improved specificity, confirmation of positive results is still
required as a significant proportion of positive tests will represent
false positive results. The false positive rate is especially important
in low prevalence settings where the number of false positives may
exceed the number of true positives.
A positive ELISA test in a patient with chronic liver disease is probably enough to diagnose HCV infection and a confirmatory antibody test may not be needed. Confirmatory PCR testing of serum for HCV RNA is suggested for this group of patients.
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3.2 CONFIRMATORY ASSAYS
By immobilising HCV antigens on to nitrocellulose strips,
recombinant immunoblot assays were developed (for example, Chiron RIBA,
Chiron Diagnostics, Emeryville, California, USA) for confirmation of
positive ELISA results. A first recombinant immunoblot assay (RIBA-100)
was developed with separately immobilised C100-3, 5-1-1, and SOD antigens.
Second generation RIBA tests were developed with antigens from nucleocapsid (C22) and NS3 (C33) in addition to C100-3 and 5-1-1. Both chimpanzee79 80 and human studies81-84 have suggested that second generation tests allow earlier detection of HCV infection in acute cases and are more frequently positive in chronic cases. A positive second generation RIBA result is associated with HCV viraemia by PCR in 88-98% of cases.85-87
A positive RIBA test is associated with reactivity with two or more of the antigens, and in the majority (63%) of cases88 reactivity to all four antigens is detected. An indeterminate result shows reactivity to any one antigen. Several studies have shown that reactivity with c100-3 or 5-1-1 alone is rarely associated with PCR positivity and can be regarded as falsely positive.86 88-90 The majority of patients with lone antibody to c33 and about half of those with antibody to c22 will be PCR positive and therefore represent true positive results.86 88 89 91 92
Third generation RIBA tests have been developed incorporating synthetic C22 and C100-3, recombinant C33, and a recombinant NS5 antigen expressed in yeast to replace 5-1-1. This later version has been shown to be positive in most RIBA-2 indeterminate cases90 93 and to correlate better with HCV viraemia.94 However, despite the improved sensitivity of this test, indeterminate results have been observed and HCV RNA is detected in 58% of these cases.95 Thus patients with indeterminate RIBA-3 results must be evaluated for evidence of viral replication and liver disease.
Following a positive antibody test, patients should be referred to the nearest specialist service for further clinical assessment. Specialist clinicians will be responsible for the care of these patients and will ensure some uniformity of approach while facilitating data collection, audit, and research.
3.3 THE POLYMERASE CHAIN REACTION
Initial PCR for HCV detection used primers derived from
heterogeneous non-structural regions of the virus. The development of
primers from the highly conserved 5' non-coding region greatly enhanced
the detection of HCV RNA by PCR.96 The sensitivity of PCR
detection was further enhanced by the development of PCR primers
producing shorter PCR products.96 The sensitivities of
most PCR assays is in the range of 500-1000 equivalents per ml.
Direct detection of the virus using PCR is needed in patients recently infected with the virus and in immunosuppressed individuals who may be antibody negative. In addition, PCR is useful for determining the status of patients with indeterminate antibody profiles and for monitoring antiviral therapies. The sensitivities and specificities of the commercially available PCR tests are very high. Intermittent viraemia is unusual in patients untreated with IFN so enhancing the significance of a negative PCR result.97
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3.4 LIVER TESTS
The use of routine liver tests to screen for chronic HCV infection
is of limited value as about 50% of HCV infected (anti-HCV and PCR
positive) patients will have normal transaminase values. Despite normal
liver tests these viraemic patients should not be considered "healthy
carriers" as the majority will have histological evidence of
necroinflammatory liver disease with or without
cirrhosis.98 Other studies have shown that transaminase
levels can be helpful in predicting severity of liver disease, with
higher levels associated with more advanced histology, but that they
are of limited value in an individual patient.99 The value
of monitoring transaminases is limited with levels fluctuating from
normal to abnormal over time.
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3.5 LIVER HISTOLOGY
Liver biopsy is usually performed before initiation of antiviral
treatment and remains the most accurate measure of the extent of liver
disease. Liver biopsy is usually done in patients with evidence of
chronic HCV infection with abnormal transaminases who are being
considered for antiviral therapy. In addition, histological information
is useful when other diagnoses such as alcohol induced liver disease
are being considered.
The role of liver biopsy in patients with normal transaminases is less clear. Several studies have shown that patients with normal transaminases often have evidence of significant liver disease on liver biopsy. In one study, 11% of 54 patients with CAH or active cirrhosis had normal alanine aminotransferase (ALT) levels,100 and in another more than 50% of patients with CAH, CPH, or cirrhosis had normal ALT levels.101 Liver biopsy may be considered in HCV positive patients with normal liver function tests (LFTs) and positive for HCV RNA who are being considered for treatment.
In a further study the use of clinical parameters to predict cirrhosis was found to be inaccurate with a correct diagnosis in less than one third of cases.102 In the absence of a less invasive measure of fibrotic liver disease, liver histology remains the gold standard for the assessment of the severity of liver disease.
The biopsy appearance at presentation does not predict the rate of disease progression in an individual non-cirrhotic patient but biopsies taken every 2-3 years may be useful in predicting outcome if there is progressive accumulation of fibrous tissue.
Some patients will test positive for antibody to HCV, have abnormal LFTs, but will be PCR negative: these patients should be screened for other liver diseases including autoimmune hepatitis and haemochromatosis. Anti-HCV positive patients found to be PCR negative with normal ALT levels should probably be followed up annually until the natural history (virological and biochemical relapse rate) is better known: liver biopsy may be recommended if there is a return of viraemia or a flare up of liver enzymes.
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Liver biopsy is probably not indicated after a course of treatment in the majority of patients. A repeat liver biopsy at a remote time interval will provide information on disease progression in both responders and non-responders but the precise timing is not clear.
3.6 ASSESSMENT OF VIRAEMIA
Measuring the level of HCV RNA in blood samples has been widely
reported with some studies showing varying levels with changes in
LFTs103 and others suggesting stable levels in individual patients prior to treatment.97 However, the role of HCV
quantitation in determining disease course remains unclear but the
results of recent trials suggest that levels of viraemia are important in tailoring IFN/ribavirin combination therapy. The level of HCV viraemia can be measured by quantitative PCR103-105 or by
signal amplification techniques such as branched DNA assay.
3.7 GENOTYPING
Analysis of the conserved 5'NCR allowed the distinction of
three major groups, types 1, 2, and 3. Analysis of samples from around
the world led to the discovery of other genotypes. Type 4 HCV was found
predominantly in the Middle East and Egypt,106 and type 5 sequences were found only in South Africa.107 108 More
recently type 6 has been described from Hong Kong.109
Phylogenetic analysis of the NS5 region has allowed the classification of HCV into six major genetic types and a number of subtypes. So far there has been no overlap in sequence variability between the different classes with nucleotide homologies of 88-100% between isolates, 74-86% between subtypes, and 56-72% between types.
Typing can be performed in several ways, either serologically with specific peptide ELISAs (serotyping)110 or by analysis of PCR products. The latter can be carried out by direct sequencing,111 112 with type specific primers113 on the basis of restriction fragment length polymorphisms114 or with sequence specific DNA probes (genotyping).115 Genotype helps predict the rate of disease progression116 117 and response to antiviral treatment.118 119
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4.0 Treatment |
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Top
1.0 Guidelines
2.0 Background
3.0 Diagnosis
4.0 Treatment
5.0 Future research
6.0 Appendix
Guideline recommendations
References
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4.1 COUNSELLING
The diagnosis of HCV causes considerable anxiety to patients and
it is therefore essential that all patients receive adequate counselling from a health carer with knowledge and experience in this
field. The natural history, treatment options, and likelihood of
success should be discussed. Patients should be reassured that HCV
infections are not usually associated with other infections such as HBV
or HIV. Although the precise role of sexual transmission remains to be
established,26 32 120 121 because up to 5% of spouses
of infected patients are infected,30 31 122 couples in
new relationships should be advised to use barrier contraception. In
established relationships the small risk of transmission should be
explained and the couple should be reassured and left to decide whether
to change their sexual practices. The risk of vertical transmission
seems to be low (<6% of children becoming HCV positive) unless the
mother is HIV positive or has a particularly high level viraemia.34-36 Mothers should be advised that breast
feeding is probably safe and that so far HCV RNA has not been
demonstrated in breast milk.38 39
Patients must also be screened for their suitability to receive IFN and ribavirin therapy. The decision to treat must be taken jointly by the physician and patient, based on careful consideration of a number of different factors.
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Counselling regarding transmission
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Patients should probably not be offered IFN if there is a history of depressive illness, psychosis, untreated autoimmune thyroid disease, neutropenia and/or thrombocytopenia, organ transplantation other than liver, symptomatic heart disease, decompensated cirrhosis, uncontrolled seizures, or evidence of ongoing alcohol or intravenous drug abuse. Patients should have access to reliable refrigeration to store IFN and be able and willing to make regular clinic visits. Adequate warning should be given of the usual initial effects of IFN (fever and malaise) and in particular absence from work may be necessary during the early stages of treatment. Administration prior to sleep with a predose of 0.5-1 g of paracetamol in the initial weeks of treatment may reduce "flu-like" symptoms associated with initial IFN therapy. Severe side effects from either IFN or ribavirin are infrequent but they may be reversible and dose modulation may successfully reduce the occurrence of side effects while maintaining therapy. Women should be advised not to conceive during a course of IFN.
Ribavirin is contraindicated if there is evidence of end stage renal failure, anaemia, haemoglobinopathy, severe heart disease, uncontrolled hypertension, and for women, where appropriate pregnancy (a pregnancy test prior to treatment is advisable), or no reliable method of contraception. Both men and women should be advised to avoid conception during and for six months after IFN/ribavirin combination treatment.
These guidelines apply to adults over 18 years of age; the upper age limit where treatment should be given is unclear but perhaps 65 or 70 years would be reasonable.
The management of patients needs to take into account the differing patient groups according to their transmission routes. These groups include current and ex-injecting drug users, blood or blood product recipients (some identified by HCV lookback), and those with unknown or unapparent transmission (for example, sexual, vertical, household, or occupational). These patient groups may well need different approaches to the way they are managed.
For many current IVDUs there are multiple contraindications to therapy, in addition to concern that continued or recommencing intravenous drug use will result in reinfection with HCV. Some patients may respond to a multidisciplinary approach and antiviral treatment may be considered within the context of detoxification and rehabilitation programmes. Many patients with a history of injecting drugs fail to reattend for follow up after the initial diagnosis of HCV.123 Although current IVDUs should not be treated, some patients on oral methadone and particularly those individuals who are committed to rehabilitation programmes may be considered for treatment.
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The group of patients infected by blood products is similar to that infected by blood but may already be affected by the dissemination of HBV or HIV. There is debate about the health impact of HCV on patients with genetic clotting disorders as well as the need for intervention, including liver biopsy, monitoring, or non-intervention.124 The risks and costs of performing liver biopsy may be greater than in other groups of patients and in many of these patients the consequences of the clotting disorder or of coinfection with HBV or HIV are more of a health concern than chronic HCV. The management of patients coinfected with HIV is also controversial, particularly in view of recent developments in antiviral therapy.
An estimated 2-5% of chronic HCV infected patients have no behavioural risks but all of the above routes may be the source of possible transmission along with others such as tattooing and poor sterilisation of reused medical instruments.
Significant numbers (up to 40%) of patients do not accept treatment or complete the full course of treatment or follow up,123 particularly those patients with a history of injecting drugs. Even in those with moderately severe disease, a significant number (42%) did not want to undergo treatment.
The role of patient support groups at the local and national level is to be encouraged and perhaps facilitated in the primary care setting. The British Liver Trust organise a national support group network and help in starting up new groups (telephone 01473-276326).
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4.2 TREATMENT: GENERAL MEASURES
4.3 ANTIVIRAL THERAPY The treatment of HCV has evolved from the use of single agent IFN to the use of combination treatment using IFN and ribavirin.
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4.4 INTERFERON MONOTHERAPY
Numerous studies have now been published to evaluate different
IFNs, dosing regimens, and response definitions. The disparate study
designs and data analysis make interpretation of the results and
comparison with other studies difficult. Few trials have included more
than 100 patients per treatment group.125
The goal of treatment is the achievement of sustained (24-48 weeks post treatment cessation) transaminase and virological response (PCR negative) with histological improvement. Most of the treatment trials have used similar doses of between 1 and 3 million units (MU) of IFN three times a week for periods of 3-6 months. A dose of 3 MU is more efficacious than 1 MU.126 In addition, only those patients receiving 3 MU had significant improvements in liver histology. Alberti et al have shown that 6 MU three times a week leads to a higher proportion of patients with normal ALT at the end of treatment compared with those treated with 3 MU three times a week.127 Another study using 10 MU three times a week suggested that sustained response rates could be as high as 50% although there is a greater risk of treatment failures due to side effects.128
Longer treatment regimens of 12 or 18 months also resulted in greater numbers of sustained responders. In one study with a three year follow up period, treatment for 48 weeks led to a sustained biochemical response in 57.1% of patients compared with 15.4% in patients treated with the same dose for 24 weeks.129 One large trial studied 329 patients treated initially with 3 MU three times a week for six months and then randomised to a further one year of 3 MU or 1 MU three times a week or no further treatment.130 A total of 303 patients were randomised and the study end points were normalisation of ALT at the end of treatment during a follow up period of 19-42 months and improvement in histology at the end of treatment. Patients treated with 3 MU for 18 months were more likely to have normal ALT at the end of treatment (p=0.008), during follow up (p=0.02), and to have improved histological activity scores at the end of treatment (p=0.02).
The majority of patients (>90%) with sustained response seem to maintain normal ALT with negative HCV-RNA in prolonged follow up (1-6 years).131 The histological appearances also improve and in some patients the liver becomes normal.
Poynard at al published a meta-analysis of more than 100 randomised IFN trials125 in 1996. The study analysed placebo controlled trials as well as trials using different IFN regimens. Trials were included if they were clearly randomised, using IFN alone, and were using at least one of the following clinical end points: normalisation of ALT during and at the end of treatment (complete ALT response), sustained ALT normalisation (sustained ALT response 6-18 months post treatment cessation), and improvement in histological lesions when biopsy after treatment was compared with biopsy before treatment. Trials were only included if the dose of IFN was at least 3 MU three times per week with a duration longer than six months. All patients were IFN naive.
4.4.1 Interferon versus placebo
Using the standard regimen, 3 MU three times per week for six
months, sustained response rates were 22% compared with a natural course of 1%. The response rates were improved when treatment was
continued for 12 months, with sustained response in 38% compared with
2% in controls. In a smaller number of studies using six months of
treatment, histological improvement was demonstrated in 67% versus
14% in the control group (p<0.001). The discrepancy between ALT and
histological responses may reflect a natural tendency towards a
decrease in histological activity but also may be due to the marked
variability in histological end points.
4.4.2 Dose effect
In the trials studied for the effects of different doses of IFN,
there was no significant difference between 3 or 6 MU given for six
months although there was a tendency for greater response rates in the
group taking the higher dose. However, there was a significant
improvement in response rates at 12 months for the higher dose in terms
of complete response (p=0.005) and sustained response (p<0.001). The
mean sustained response rate in the 6 MU group was 46% versus 28% in
the 3 MU group. However, dose reduction due to side effects was more
common in patients treated with doses of more than or equal to 5 MU
(22%) compared with those on 3 MU (9%) (p=0.01). Preliminary data
suggest that the dose of interferon should be adjusted to take the
patient's weight into account.
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4.4.3 Duration effect
In the meta-analysis, longer duration of treatment did not
significantly effect the numbers of patients with complete ALT response
but did alter the rate of sustained response. At standard doses of 3 MU
the mean sustained response rate in the 12-18 month group was 35%
versus 14% in the six month group (p<0.001). The mean sustained
response for the higher dosing regimen (6 MU) was 49% for 12-18
months of treatment compared with 29% in the six month group
(p<0.001).
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4.4.4 Type of interferon
Four forms of alfa-IFN have been evaluated in adequate numbers of
HCV infected patients: alfa-2b, alfa-2a, alfa-n1, and consensus IFN
(CIFN). Both alfa-2b and alfa-2a are produced by recombinant DNA
techniques using a strain of Escherichia
coli genetically engineered to possess
plasmid DNA containing an IFN gene from a human leucocyte. Alfa-2b
differs from alfa-2a by a single amino acid. IFN alfa-n1 is a mixture
of nine IFN subtypes produced from a human B lymphoblastoid cell line
while CIFN was produced by scanning subtypes of IFN and assigning the
most frequently observed amino acid at each position to form a
consensus molecule.
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4.5 INTERFERON/RIBAVIRIN COMBINATION
THERAPY
Ribavirin is a nucleoside analogue that is well absorbed orally
and has broad antiviral activity against a variety of DNA and RNA
viruses. Ribavirin is administered in doses of 1000-1200 mg/day
depending on body weight (above/below 75 kg).
4.5.1 Ribavirin monotherapy
Initial pilot studies with ribavirin revealed encouraging results
with significant biochemical responses during treatment but there was
always relapse following treatment withdrawal. There was no effect on
HCV viraemia.134 135
4.5.2 Combination therapy
Initial pilot studies revealed encouraging results with the
combination of IFN and ribavirin,139 particularly in
patients who had relapsed after an initial course of
alfa-IFN.140 Studies in IFN naive patients also showed
beneficial effects of combination treatment over IFN alone. Two
European studies revealed improved sustained response rates of 47% and
60% in the combination groups when compared with IFN
alone.141 142
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4.6 WHO TO TREATACCORDING TO
BIOPSY
The decision of whether to treat is complex. As the treatment is
relatively expensive and may not cure most cases, patients need to be
selected as those most likely to respond to treatment and also those in
whom the impact of treatment is greatest, in terms of halting disease
progression and preventing complications. Decisions about treatment
should be made after liver biopsy has been performed and patients
classified into mild, moderate, or severe disease categories according
to histological appearances. Histological appearances are classified as
mild if the fibrosis score (stage) is less than or equal to 2/6, and if
the necroinflammatory score (grade) is less than or equal to 3/18.
If the fibrosis score is 3-5/6 and/or the necroinflammatory score is
greater than 3/18, the appearances are described as moderate. If the
fibrosis score is 6/6, the biopsy is cirrhotic irrespective of
necroinflammatory score.
All liver biopsies should be examined by a histopathologist with experience in liver pathology and who can apply the recently reformed grading and staging scores.146 Some pathologists prefer to base the assessment of severity of hepatitis on individual components of the grading system. In this case mild hepatitis can be defined as having scores for interface hepatitis and for lobular hepatitis of 0 or 1 out of 4. Confluent necrosis should be absent (score 0). Any grade of portal inflammation is acceptable.
In patients with mild slowly progressive disease, it may be best to withhold treatment until more efficacious treatments are available. Others would regard this as the best time to treat, perhaps resulting in higher numbers of responders, and others would argue that the virus rather than the disease process needs to be treated and so all infected patients need to be considered for treatment.
4.6.1 Mild disease
Patients with mild disease at presentation represent up to 25% of
patients attending for consideration of treatment. These patients are
potentially infectious, and despite minimal disease on liver biopsy,
may suffer long term consequences of chronic liver disease.
Alternatively, treating these generally clinically well patients with
expensive drugs with potentially serious side effects may well be
inappropriate unless there is clear evidence of disease progression
over time.
4.6.2 Moderate disease
This group of patients are the most important group as successful
treatment is likely to have the greatest impact by hopefully preventing
progression to cirrhosis and its complications. Therefore, all patients
with moderate or severe inflammatory activity with or without fibrosis
and any patient with fibrosis not amounting to cirrhosis on liver
biopsy should be offered treatment.
4.6.3 Cirrhotics
HCV cirrhotics are an important group of patients and studies have
shown that liver complications are responsible for 70% of the
mortality of HCV cirrhotics.59
Initial studies
suggested a poorer response to IFN monotherapy in cirrhotic compared
with non-cirrhotic patients.149 A recent review of 26 published trials that separated cirrhotic patients from non-cirrhotics
revealed a reduced rate of ALT normalisation during therapy (27%
compared with 53%).150 In a smaller group of patients the
rate of viral clearance was also reduced (5-10% compared with
20-35%). The poor response is more often due to failure to respond
rather than to relapse following an initial response. Sustained
response rates of 29% (24 weeks) and 36% (48 weeks) have been
achieved with IFN/ribavirin combination treatment suggesting that
treatment may well be justified in this subgroup of patients with
notoriously poor response to IFN monotherapy.145 Other
studies have assessed the effects of IFN on clinical events in
cirrhotics. In one study only 16% of treated patients were rendered
PCR negative on treatment; in the follow up period of up to seven years
HCC was detected in 4% of treated compared with 38% of control
patients (p=0.002).73 In two other studies the tendency to
develop HCC was reduced in patients treated with IFN, with a
particularly strong effect in those few patients with sustained biochemical and virological responses.151 152 However,
these results need to be confirmed in larger studies using
IFN/ribavirin combination with longer follow up periods.
4.6.3.2 Decompensated cirrhosisThe probability of
survival after decompensation is about 50% at five
years.59 There are few data on the use of antiviral therapy in decompensated HCV cirrhotics.
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4.7 PREDICTORS OF RESPONSE
Several factors have been implicated but their accuracy in
predicting a response in individual patients has been poor.
However, some physicians exclude patients from treatment if they
have one or more of the pretreat- ment markers associated with a
reduced likelihood of response in an attempt to improve response rates and efficiency of antiviral treatment.
4.7.1 Pretreatment factors
Both host and viral factors have been identified by
either univariate or multivariate analyses. One initial study suggested a more favourable outcome in young females and in patients with lower
pretreatment ALT levels.126 Other studies have failed to link female sex to better response but have confirmed that younger patients tend to respond more favourably127 and that
pretreatment ALT and 
-glutamyltransferase levels tend to be lower in
responders.153 The better response in younger patients may
reflect a shorter duration of infection in association with less severe
histological lesions. Indeed, several studies have shown that absence
of cirrhosis and low fibrotic histological scores are associated with
better treatment outcomes.119 127 One study reported the
biochemical response rates in patients treated with IFN for 12 months
according to the presence or absence of cirrhosis. Within a six month
follow up period, 5.3% of cirrhotics compared with 40.5% of
non-cirrhotics showed sustained normal ALT levels.149
Other studies have shown that the hepatic iron content of
non-responders (1156±283 µg/g dry weight) tends to be higher
compared with responders (638±118 µg/g dry weight;
p<0.05).154
Patients with suspected HCV infection
should be tested for anti-HCV by an up to date (currently third
generation) ELISA test. (Recommendation grade B.)