Diagnosis, Management, and Treatment of Hepatitis C: An Update

Diagnosis, Management, and Treatment of Hepatitis C: An Update

These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: (1) a formal review and analysis of the recently published

world literature on the topic (Medline search up to September 2008); (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines; (3) guideline policies, including the American Association for the Study of Liver Diseases’ (AASLD) Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association’s Policy Statement on the Use of Medical Practice Guidelines;2 and (4) the experience of the authors in regard to hepatitis C.

Background

The hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease.5 An estimated 180 million people are infected worldwide. In the United States (U.S.), the prevalence of HCV infection between the years 1999 and 2002 was 1.6%, equating to about 4.1 million persons positive for antibody to hepatitis C (anti-HCV), 80% of whom are estimated to be viremic.7 Hepatitis C is the principal cause of death from liver disease and the leading indication for liver transplantation in the U.S.8 Some calculations suggest that mortality

related to HCV infection (death from liver failure or hepatocellular carcinoma) will continue to increase over the next two decades.9 The purpose of this document is to

provide clinicians with evidence-based approaches to the prevention, diagnosis, and management of HCV infection.

Testing and Counseling

Laboratory Testing

Two classes of assays are used in the diagnosis and

management of HCV infection: serologic assays that detect

specific antibody to hepatitis C virus (anti-HCV) and

molecular assays that detect a viral nucleic acid. These assays

have no role in the assessment of disease severity or

prognosis.

Serologic Assays.

Tests that detect anti-HCV are used both to screen for and to diagnose HCV infection. Anti-HCV can be detected in the serum or plasma using a number of immunoassays. Two enzyme immunoassays (EIAs) are approved by the U.S. Food and Drug Administration (FDA) for clinical use, Abbott HCV EIA 2.0 (Abbott Laboratories, Abbott Park, IL) and ORTHO_ HCV Version 3.0 ELISA (Ortho-Clinical Diagnostics, Raritan, NJ), as well as one enhanced chemiluminescence immunoassay (CIA) VITROS_ Anti-HCV assay, (Ortho-Clinical Diagnostics, Raritan, NJ). The specificity of current EIAs for anti-HCV is greater than 99%.34 False-positive results are more likely to occur when testing is performed among populations where the prevalence of hepatitis C is low. False negative results may occur in the setting of severe immunosuppression such as infection with HIV, solid organ transplant recipients, hypo- or agammaglobulinemia or in patients on hemodialysis

The recombinant immunoblot assay, Chiron RIBA HCV 3.0 SIA (Chiron Corporation, Emeryville, CA) is also FDA approved. This assay was originally developed as a more specific, supplemental assay to confirm the results of EIA testing.38,39 However, specificity is extremely high for third generation EIA results that exceed particular signal/ cutoff ratios (e.g., _3.8 for the above mentioned Ortho and Abbott EIA tests). Given the widespread availability of nucleic acid testing, the role for RIBA testing in HCV diagnosis and management has all but disappeared.

Molecular Assays.

The list of commercial assays available for the detection (qualitative assays) or quantification (quantitative assays) of HCV RNA is shown in Tables 4 and 5. Historically, qualitative assays have been more sensitive than quantitative assays. With the recent availability of real-time polymerase chain reaction (PCR)- based assays and transcription-mediated amplification (TMA) assays, with sensitivities of 10-50 IU/mL, there is no longer need for qualitative assays. A highly sensitive assay with this lower limit of detection is considered appropriate for monitoring during therapy. All currently available assays have excellent specificity, in the range of 98% to 99%. In 1997, the World Health Organization established the first International standard for HCV RNA nucleic acid technology,44 and the IU rather than viral copies are now the preferred unit to report test results. For monitoring purposes, it is important to use the same laboratory test before and during therapy.

Genotyping Assays.

Genotyping is useful in epidemiological studies and in clinical management for predicting the likelihood of response and determining the optimal duration of therapy. The hepatitis C virus can be classified into at least 6 major genotypes (genotypes 1 to

6) based on sequence divergence of 30% among isolates.nGenotype 1 (subtypes 1a and 1b) is the most common in the U.S., followed by genotypes 2 and 3. Less common genotypes (genotypes 4-6) are beginning to be observed more frequently because of the growing cultural diversity within the United States. Several commercial assays are available to determine HCV genotypes using direct sequence analysis of the 5_ non-coding region, that include Trugene 5_NC HCV Genotyping kit (Siemens Healthcare Diagnostics Division, Tarrytown, NY), reverse hybridization analysis using genotype-specific oligonucleotide probes located in the 5’ non-coding region, INNO-LiPa HCV II, (Innogenetics, Ghent, Belgium), and Versant HCV Genotyping Assay 2.0 (Siemens Healthcare Diagnostics Division, Tarrytown, NY). Incorrect typing among the major genotypes is rare (<3%) and mixed genotypes occur but are uncommon. Occasionally (<5%), tested samples cannot be genotyped. This usually results from low viral levels, issues with the PCR amplification step of the assay, or extreme nucleotide variability within the HCV genome

Diagnosis of Acute and Chronic HCV Infection and Interpretation of Assays

The diagnosis of acute or chronic HCV infection generally requires testing of serum for both antibodies to HCV (anti-HCV) and for HCV RNA. A sensitive quantitative HCV RNA assay is recommended for diagnosis because it also provides information on the level of the virus which is helpful in management. The differentiation of acute from chronic HCV infection depends on the clinical presentation: namely the presence of symptoms or jaundice, and whether or not there was a prior history of ALT elevation and its duration. After acute exposure, HCV RNA is usually detected in serum before antibody; HCV RNA can be identified as early as 2 weeks following exposure whereas anti-HCV is generally not detectable before 8-12 weeks. These two markers of HCV infection may be present in varying permutations, requiring careful analysis for interpretation One pattern is the identification of both anti-HCV and HCV RNA in a person with recent elevation of the ALT value. This scenario is consistent with either acute HCV infection when there is a recently known risk exposure, with exacerbation of chronic HCV infection, or with acute hepatitis of another aetiology in a patient with chronic HCV infection. Another pattern is the detection of anti-HCV but with a negative test for HCV RNA. This may represent acute HCV infection during a period of transient clearance of HCV RNA, a false positive or negative result or, more commonly, recovery from HCV infection. Re-testing for HCV RNA 4-6 months later is recommended to confirm the resolution of HCV infection. The reverse scenario — a negative anti-HCV test but a positive result for HCV RNA—is compatible with the early stage of acute infection prior to the development of antibody or may represent a chronic infection in an immunosuppressed individual. Alternatively, it may represent a false positive HCV RNA result. In all circumstances, re-testing for anti-HCV and HCV RNA in 4-6 months should resolve the issue. Finally, if the patient has raised ALT values but the tests for anti-HCV and HCV RNA are negative, both acute and chronic hepatitis C may be excluded and another diagnosis should be considered. Antibody testing should be repeated in 4-6 months for confirmation purposes.

The utility of the Liver Biopsy and Noninvasive Tests of Fibrosis

There are three primary reasons for performing a liver biopsy: it provides helpful information on the current status of the liver injury, it identifies features useful in the decision to embark on therapy, and it may reveal advanced fibrosis or cirrhosis that necessitates surveillance for hepatocellular carcinoma (HCC) and/or screening for varices. The biopsy is assessed for grade and stage of the liver injury, but also provides information on other histological features that might have a bearing on liver disease progression. The grade defines the extent of necroinflammatory activity, while the stage establishes the extent of fibrosis or the presence of cirrhosis. Several scoring systems have been conceived, the most common being the French METAVIR, the Batts-Ludwig, the International Association for the Study of the Liver (IASL) and the Ishak Scoring systems. The two more common non-HCV conditions that might affect disease progression and possibly impede treatment response are steatosis and excess hepatocellular iron. Identifying either of these two features does not preclude initiating treatment, but their presence provides additional information regarding the likelihood of response to treatment

The liver biopsy has been widely regarded as the “gold standard” for defining the liver disease status, but it has drawbacks that have prompted questions about its value. The procedure is not without risks (including pain, bleeding and perforation of other organs), it is subject to sampling error,65 it requires special expertise for interpreting the histopathology, it adds cost to medical care, and it is anxiety-provoking for the implicated person. Thus, efforts are underway to seek alternative means of establishing information on the extent of fibrosis by focusing on noninvasive blood marker panels. These markers are useful for establishing the two ends of the fibrosis spectrum (minimal fibrosis and cirrhosis) but are less helpful in assessing the mid-ranges of fibrosis or for tracking fibrosis progression. The recently developed transient elastography that uses ultrasound and low-frequency elastic waves to measure liver elasticity has improved the ability to define the extent of fibrosis without a liver biopsy, particularly when combined with other noninvasive markers. However, it is not yet ready to replace the liver biopsy since it is not FDA approved, the failure rate is higher in obese patients, and there is no evidence that the transient elastography score can be unexpectedly increased in persons with acute hepatitis who have high necroinflammatory activity but no or minimal fibrosis.

Although the liver biopsy was previously regarded as routine for defining the fibrosis stage in persons with genotype 1 infection,62 the issue is now in a state of flux and possible transition. Supporters of a biopsy cite the difficult nature and high cost of current antiviral therapy and are therefore willing to withhold or delay treatment if liver histology displays minimal to moderate fibrosis stage < 2, especially if the infection is known to have been long-standing. These individuals are regarded as having slowly progressive liver disease that may not be responsible for their ultimate demise74-76 However, treatment is advised for those with more advanced fibrosis stage ≥3. It must be noted, however, that while information obtained from a biopsy is useful, the procedure is not mandatory for deciding on treatment. If performed and treatment is withheld, a common strategy is to repeat the liver biopsy 4 to 5 years later and to reconsider treatment should there be evidence of disease progression

Initial Treatment of HCV Infection

Natural history studies indicate that 55% to 85% of individuals who develop acute hepatitis C will remain HCV-infected. Spontaneous resolution is more common among infected infants and young women than among persons who are older when they develop acute hepatitis.86 Chronic HCV infection has relevance for the infected persons as well as for their contacts: the former are at risk for progression to cirrhosis and/or HCC, the latter are at risk of acquiring the infection through exposure to the virus. The risk of developing cirrhosis ranges from 5% to 25% over periods of 25 to 30 years

Identifying individuals at risk for developing the progressive disease is difficult. Presently, the preferred approach is to assess the degree of fibrosis on liver biopsy, using a validated staging system such as the Ishak, IASL, Metavir or Batts-Ludwig staging systems. Persons with no or minimal fibrosis (Ishak stage 0-2; Metavir, IASL and Batts-Ludwig stage 0-1) have a low risk for liver-related complications and liver-related death (over the next 10 to 20 years). However, the presence of bridging fibrosis (for example Metavir stage 3) is an important predictor of future progression to cirrhosis and therefore an indication for treatment.101

Infection with HCV can also cause extrahepatic diseases including mixed cryoglobulinemia, types II and III. Indeed, symptomatic cryoglobulinemia is an indication for HCV antiviral therapy regardless of the stage of liver disease.

Treatment Objectives and Outcomes.

The goal of therapy is to prevent complications and death from HCV infection. Because of the slow evolution of chronic HCV infection over several decades, it has been difficult to demonstrate that therapy prevents complications of liver disease.

Accordingly, treatment responses are defined by a surrogate virological parameter rather than a clinical endpoint. Short-term outcomes can be measured Biochemically (normalization of serum ALT levels), virologically (absence of HCV RNA from serum by a sensitive PCR-based assay), and histologically(>2 point improvement in necroinflammatory score with no worsening in fibrosis score). Several types of virological responses may occur, labelled according to their timing relative to treatment. The most important is the sustained virological response (SVR), defined as the absence of HCV RNA from serum by a sensitive PCR assay 24 weeks following discontinuation of therapy (Table 8, Fig. 1). This is generally regarded as a “virological cure,” although liver cancer has been identified years later, especially if cirrhosis existed at the time of achieving an SVR.

The undetectable virus at the end of either a 24-week or 48-week course of therapy is referred to as an end-of-treatment response (ETR). An ETR does not accurately predict that an SVR will be achieved but is necessary for it to occur.

A rapid virological response (RVR), defined as undetectable HCV RNA at week 4 of treatment, using a sensitive test with a lower limit of detection of 50 IU/mL, predicts a high likelihood of achieving an SVR.103,104 An early virological response (EVR) is defined as a >2 log

reduction or complete absence of serum HCV RNA at week 12 of therapy compared with the baseline level. Failure to achieve an EVR is the most accurate predictor of not achieving an SVR. Monitoring viral kinetics is thus useful for predicting whether or not an SVR is likely to develop.

Virological breakthrough refers to the reappearance of HCV RNA while still on therapy, while virological relapse is the reappearance of HCV RNA in serum after treatment is discontinued and an ETR was documented. Persons who fail to suppress serum HCV RNA by at least 2 logs after 24 weeks of therapy are null responders, while those whose HCV RNA levels decrease by < 2 logs IU/mL but never become undetectable are referred to as partial nonresponders

The Optimal Treatment of Chronic HCV: Peginterferon Alfa and Ribavirin

The currently recommended therapy of chronic HCV infection is the combination of pegylated interferon alfa and ribavirin. The choice of this regimen was based upon the results of three pivotal, randomized, clinical trials that demonstrated the superiority of this combination treatment over standard interferon alfa and ribavirin. While not directly comparable, these three trials defined several key components of therapy, namely the appropriate dose of the drugs, the optimal duration of therapy and the need for a different regimen for patients with genotype 1 and genotype 2 and 3 infections.

There are two licensed pegylated interferons in the United States, peginterferon alfa-2b (Peg-Intron, Schering Plough Corp., Kenilworth, NJ), with a 12-kd linear polyethylene glycol (PEG) covalently linked to the standard interferon alfa-2b molecule, and peginterferon alfa-2a (Pegasys, Hoffmann-La Roche, Nutley, NJ) with a 40-kd branched PEG covalently linked to the standard interferon alfa-2a molecule.108 The doses of these two forms of pegylated interferons differ.

The optimal dose of peginterferon alfa-2b, based on the original registration trial, is 1.5 mcg/kg/week dosed according to body weight. Although the dose of ribavirin used in the original registration trial was fixed at 800 mg daily, a subsequent community-based study of patients with genotype 1 infection demonstrated that weight-based ribavirin (800 mg for patients _65 kg;

1,000 mg for patients weighing 65 to 85 kg; 1,200 mg for patients weighing 85 to 105 kg; and 1,400 mg for patients weighing_105 kg but_125 kg) was more effective.71,109 Peginterferon alfa-2a is administered at a fixed dose of 180 _g/week given subcutaneously together with ribavirin

1,000 to 1,200 mg daily, 1,000 mg for those who weigh_75 kg and 1,200 mg for those who weigh_75 kg (Fig. 2).72 The registration trial highlighted the two beneficial effects of ribavirin, an improvement in the ETR but, more importantly, a significant decrease in the relapse rate as compared to peginterferon monotherapy treatment. A third randomized trial determined that the optimal duration of treatment should be based on the viral genotype. The study established that patients with genotype 1 should be treated for 48 weeks with peginterferon alfa-2a plus standard weight-based ribavirin, whereas patients with genotypes 2 and 3 could be treated with peginterferon alfa-2a plus low dose ribavirin (800 mg) for 24 weeks. For patients with HCV genotype 4 infection, combination treatment with pegylated interferon plus weight-based ribavirin administered for 48 weeks appears to be the optimal regimen, as concluded in a meta-analysis of six randomized trials.110 While data from another randomized trial of treatment with combination peginterferon alfa-2b plus a fixed dose of ribavirin (10.6 mg/kg per day) has suggested that 36 weeks duration of therapy is sufficiently provided an EVR is achieved, these results need to be confirmed. Patients with genotypes 5 and 6 are underrepresented in trials of peginterferon and ribavirin due to their limited worldwide frequency

Pretreatment Predictors of Response.

Pretreatment predictors of response are useful for advising patients on their likelihood of an SVR. Absence of favourable factors should not be used, however, to deny therapy. Data on predictors of an SVR come from several sources: registration trials which have strict inclusion and exclusion criteria and may not accurately reflect the general population infected with HCV; community-based trials that may not be conducted with the same rigor as registration trials; and Veterans Affairs databases which involve men predominantly and therefore do not reflect the general population with HCV infection. Despite these caveats, multivariate analyses have identified two major predictors of an SVR among all populations studied: the viral genotype and pretreatment viral load. Sustained virological response rates were higher in patients infected with genotype non-1 infection (mostly genotype 2 and 3) and in those with a viral load of less than 600,000 IU/mL. Other less consistently reported baseline characteristics associated with a favorable response include the doses of peginterferon (1.5 µg/kg/week versus 0.5 µg/kg/week) and ribavirin (>10.6 mg/kg), female gender, age less than 40 years, non–African-American race, lower body weight (<75 kg), the absence of insulin resistance, elevated ALT

levels (three-fold higher than the upper limit of normal),

and the absence of bridging fibrosis or cirrhosis on liver

biopsy

Adverse Events.

Almost all patients treated with peginterferon and ribavirin experience one or more adverse events during the course of therapy. Adverse events are a major reason that patients decline or stop therapy altogether. In the registration trials of peginterferon alfa-2a and 2b plus ribavirin, 10% to 14% of patients had to discontinue therapy due to an adverse event. The most common adverse events in these trials were influenza-like side effects such as fatigue, headache, fever and rigors, which occurred in more than half of the patients, and psychiatric side effects (depression, irritability, and insomnia), which occurred in 22% to 31% of patients. Laboratory abnormalities are the most common reasons for dose reduction. Among these, neutropenia (absolute neutrophil count [ANC] of 1500 mm3) was a frequent laboratory abnormality, occurring in 18% to 20% in the two large phase III clinical trials where the dose was reduced 50% for an ANC of 750 mm3 and permanently discontinued for an ANC of <500 mm3 Severe neutropenia, ANC < 500 mm3, occurred in 4% of subjects. Despite the decline in the neutrophil count, serious infections are uncommon125 and granulocyte colony stimulating factor is rarely necessary except in patients with advanced cirrhosis. Anaemia was observed in approximately one-third of patients, reaching a nadir within 6 to 8 weeks. Dose modification for anaemia (haemoglobin level <10 g/dL) was required in 9% to 15% in the two phases III registration trials. Growth factors, such as erythropoietin and darbepoetin, have been used to counter the anaemia associated with peginterferon and ribavirin. Although growth factors improve a patient’s sense of well-being and have reduced the requirement for ribavirin dose reduction, their use has not been shown to improve SVR rates.126-128 In one analysis, the use of a haematological growth factor nearly doubled the cost of treatment for chronic hepatitis C. Although generally safe, erythropoietin and darbepoetin use has been associated with serious side effects including cardiovascular and thromboembolic events, pure red cell aplasia, the progression of certain cancers, and death.130 There has also been a report of a new, orally active thrombopoietin-receptor agonist, called eltrombopag that stimulates thrombopoiesis.131 Given for 12 weeks, it allowed successful therapy of HCV patients who had baseline thrombocytopenia (20,000 to 70,000 mm3), but whether this product will permit patients to complete a full course of therapy has yet to be evaluated. Therefore, routine use of growth factors cannot be recommended at this time and dose reduction is the primary mode for managing cytopenias.

Neuropsychiatric side effects include depression, anxiety, insomnia, emotional lability, mood disorders, frank psychosis, suicidal ideation, actual suicide, and homicide. The most consistent risk factors for developing depression are the presence of mood and anxiety symptoms prior to therapy. A past history of depression and of receiving higher doses of interferon, as well as being female, have been identified as risk factors, but are less reliable ones. Pegylated interferon may induce autoimmune disorders, such as autoimmune thyroiditis, or may worsen preexisting autoimmune disorders. Therefore, the presence of autoimmune conditions prior to treatment is a relative contraindication to therapy. A major dilemma, however, is that chronic HCV infection may present with features that simulate idiopathic autoimmune hepatitis, including the presence of a positive test for antinuclear antibodies. This poses the problem of distinguishing between chronic HCV infection with autoimmune features, for which treatment with antiviral therapy is appropriate, and persons with non-hepatitis C–related autoimmune hepatitis with superimposed chronic HCV infection which requires treatment with immunosuppressive drugs. A helpful distinction is a prior history of autoimmune hepatitis, the presence of other autoimmune conditions and the identification of specific HLA characteristics (See AASLD guidelines for Autoimmune Hepatitis). A liver biopsy may also be helpful. An individualized approach with careful monitoring is recommended if treatment is initiated. With regard to ribavirin, the most common side affects hemolytic anaemia. Since ribavirin is cleared by the kidney, the drug should be used with extreme caution in patients with renal disease and renal failure. Other side effects associated with ribavirin include mild lymphopenia, hyperuricemia, itching, rash, cough and nasal stuffiness. Ribavirin is reported to cause fetal death and fetal abnormalities in animals and thus it is imperative for persons who receive the drug to use strict contraceptive methods both during treatment and for a period of 6 months thereafter. The education of patients and caregivers about side effects and their management is an integral component of treatment and is important for a successful outcome. Interferon-induced depression appears to be composed of two overlapping syndromes — a depression-specific syndrome characterized by mood, anxiety, and cognitive complaints, and neurovegetative symptoms, characterized by fatigue, anorexia, pain and psychomotor slowing. Depression-specific symptoms are highly responsive to serotonergic antidepressants whereas neurovegatative symptoms are not. These symptoms may be more effectively treated with agents that modulate catecholaminergic function. When selecting an agent, consideration should be given to drug-drug interactions, underlying hepatic function, the possibility of drug-induced hepatotoxicity and other adverse side effects

Selection of Patients for Treatment.

Current recommendations for treatment of persons with chronic HCV infection derive from data collected in the randomized registration trials. However, these trials have usually been restrictive in their exclusion criteria and thus have not reflected the general population who require therapy. More data are needed in certain groups such as those with renal disease, depression and active substance abuse, children, and those with HIV/HCV co-infection. As with all decisions in medicine, a balance must be struck between the benefit and risk related to therapy. Application of these principles can be challenging and the relative strength of a recommendation will need to vary accordingly

Characteristics of Persons for Whom Therapy Is Widely Accepted

1. Age 18 years or older, and

2. HCV RNA positive in serum, and

3. Liver biopsy showing chronic hepatitis with significant fibrosis (bridging fibrosis or higher), and

4. Compensated liver disease (total serum bilirubin _1.5 g/dL; INR 1.5; serum albumin _3.4, platelet count 75,000 mm and no evidence of hepatic decompensation (hepatic encephalopathy or ascites), and

5. Acceptable haematological and biochemical indices (Hemoglobin 13 g/dL for men and 12 g/dL for women; neutrophil count 1500 /mm3 and serum creatinine _1.5 mg/dL, and

6. Willing to be treated and to adhere to treatment requirements, and

7. No contraindications

Characteristics of Persons for Whom Therapy Is Currently Contraindicated

1. Major uncontrolled depressive illness

2. Solid organ transplant (renal, heart, or lung)

3. Autoimmune hepatitis or other autoimmune condition is known to be exacerbated by peginterferon and ribavirin

4. Untreated thyroid disease

5. Pregnant or unwilling to comply with adequate contraception

6. Severe concurrent medical disease such as severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes, chronic obstructive pulmonary disease

7. Age less than 2 years

8. Known hypersensitivity to drugs used to treat HCV

Assessment Prior to Treatment and Monitoring During and After Therapy

It is advisable to assess the risk of underlying coronary heart disease, to control preexisting medical problems, such as uncontrolled diabetes and hypertension, and to pre-screen all candidates for symptoms of depression prior to initiating therapy. A number of validated self-rated or clinician-rated scales to assess depression are available. Patients should be monitored during therapy to assess the response to treatment and for the occurrence of side effects. A reasonable schedule would be monthly visits during the first 12 weeks of treatment followed by visits at 8 to 12-week intervals thereafter until the end of therapy. At each visit, the patient should be questioned regarding the presence of side effects and depression. They should also be queried about adherence to treatment. Laboratory monitoring should include measurement of the complete blood count, serum creatinine and ALT levels, and HCV RNA by a sensitive assay at weeks 4, 12, 24, 4 to 12-week intervals thereafter, the end of treatment, and 24 weeks after stopping treatment. Thyroid function should be monitored every 12 weeks while on treatment. Patients who achieve an SVR usually have an improvement in liver histology and clinical outcomes. However, patients who achieve an SVR but who have cirrhosis are at risk for hepatic decompensation and HCC and death in the short term (5 years), and therefore should continue to be monitored periodically, including screening for HCC (See AASLD guidelines on Management of Hepatocellular Carcinoma).144 There is no role for a posttreatment liver biopsy among those who achieve an SVR

Characteristics of Persons for Whom Therapy Should Be Individualized

1. Failed prior treatment (non-responders and relapsers) either interferon with or without ribavirin or peginterferon monotherapy

2. Current users of illicit drugs or alcohol but willing to participate in a substance abuse program (such as a methadone program) or alcohol support program. Candidates should be abstinent for a minimum period of 6 months

3. Liver biopsy evidence of either no or mild fibrosis

4. Acute hepatitis C

5. Coinfection with HIV

6. Under 18 years of age

7. Chronic renal disease (either requiring or not requiring hemodialysis)

8. Decompensated cirrhosis

9. Liver transplant recipients

Non-Responders. Approximately thirty per cent of patients treated with pegylated interferon and ribavirin are unable to clear the virus from the serum. Options for non-responders to pegylated interferon and ribavirin are limited. Retreatment with the same regimen leads to an SVR in fewer than 5% of patients and therefore cannot be recommended. There is no convincing evidence that switching to alternative interferons is effective.146 Maintenance therapy with peginterferon with the goal of delaying or preventing progression to cirrhosis and/or hepatic decompensation is currently being assessed in two ongoing and one completed randomized trials in the U.S.and Europe. Results of one of them, the HALT-C trial, have recently been reported.148 In this trial, although serum ALT levels, HCV RNA and hepatic necroinflammation were statistically significantly reduced in the treated arm, the rates of clinical decompensation and progression to histologic cirrhosis were similar in both the treated and untreated groups, 34.1% and 33.8%, respectively (hazard ratio 1.01). Thus, based on the results of the HALT-C Trial, maintenance low dose peginterferon alfa-2a, 90 mcg per week, is not indicated in patients with hepatitis C who have bridging fibrosis or cirrhosis and who have not responded to a standard course of peginterferon and ribavirin therapy. Until data become available from retreatment studies using alternate regimens, the decision to undergo retreatment should be individualized. Non-responders to peginterferon and ribavirin with advanced fibrosis should follow AASLD guidelines for screening for HCC and varices and be evaluated for liver transplantation if they are appropriate candidates. Patients with mild fibrosis should be monitored without treatment.

For non-responders to standard interferon either with or without ribavirin, retreatment with peginterferon alfa-2a or 2b has been evaluated in three trials. The SVR rates were higher among patients who had previously received interferon monotherapy, ranging from

20% to 40%, and were lower among non-responders to the combination of interferon and ribavirin, ranging from 8% to 10%. Persons more likely to achieve an SVR from retreatment included those with genotype non-1 infection, who had lower baseline HCV RNA levels, who had lesser fibrosis, who were of the Caucasian race, and whose prior treatment had consisted of interferon monotherapy.

Relapsers. In the majority of instances, virological relapse occurs within the first 12 weeks and late relapse, beyond 24 weeks, is extremely uncommon. Patients with virological relapse are likely to respond to the same regimen given a second time but will still experience an unacceptable rate of relapse. For relapsers to standard interferon and ribavirin, two regimens have been evaluated — high dose peginterferon alfa-2b, 1.5 mcg/kg/week with fixed-dose ribavirin 800 mg daily, and low dose peginterferon alfa-2b, 1 mcg/kg/week plus weight-based

ribavirin, 1,000 to 1,200 mg daily. The overall SVR rate was 42% and, although it was higher in the group treated with the higher dose of peginterferon (50%) than in those treated with the lower dose (32%), the number of treated patients was too few to draw meaningful conclusions. Data on the retreatment of relapsers to peginterferon and ribavirin have not been published

Treatment of Persons with Acute Hepatitis C

The response rate to treatment is higher in persons with acute than with chronic HCV infection. However, the optimal treatment regimen and when it should be initiated remains uncertain. There is consistent evidence that treatment reduces the risk that acute hepatitis C will evolve to chronic infection. Studies using high doses of interferon (5-10 million units per day) for at least 12 weeks, or until serum enzymes normalized, report sustained viral response rates of 83% to 100%, which are much higher than any estimates of spontaneous clearance, or of response rates in persons with chronic HCV infection. One meta-analysis considered results of 16 trials that compared interferon therapy with spontaneous resolution of acute hepatitis C. There is remarkable consistency in the superiority of treatment in preventing evolution to chronic HCV infection when compared to observation. Overall, the pooled estimate of the treatment effect was a risk difference of 49% (95% CI 33-65), making it clear that treatment of acute hepatitis C reduces the risk of developing chronic infection.

The optimal regimen to treat acute HCV infection has not been definitively established. In one study from Germany, the most effective regimen at the time was administered to 60 patients diagnosed with acute hepatitis C.381 The majority (85%) presented with symptomatic disease. None of those with asymptomatic acute hepatitis C spontaneously cleared the virus, whereas 52% of those with symptomatic onset lost virus spontaneously, usually within 12weeks. Treatment is given to those who did not spontaneously lose virus, beginning 3 to 6 months after the onset of disease, led to an SVR rate in 81%. Overall, 91% cleared virus either spontaneously or through treatment. The authors concluded that for those with symptomatic acute hepatitis, treatment should be delayed for the first 12 weeks. Further support for delaying treatment for up to

12 weeks came from another multi-centre study of acute hepatitis C in which SVR rates >90% were reported for patients randomized to 12 weeks of peginterferon alfa-2b after delaying 8 or 12 weeks after diagnosis. In contrast, a lower SVR rate (76%) was found for those randomized to delay peginterferon 20 weeks after diagnosis. In another study from Japan, 13 of 15 persons randomized to start within 8 weeks had an SVR compared to 8 of 15 in whom treatment was delayed by 12 months. Collectively, these data suggest that it is reasonable to start treatment within 8-12 weeks after identified acute hepatitis C, and thus patients should be monitored monthly for this purpose. Within this range, treatment might be delayed longer in persons presenting with jaundice and those with fluctuating viremia patterns that are associated with spontaneous clearance, while earlier treatment might be favoured in persons with genotype 1 infection who have high (>800,000 log10 IU/mL) viral loads. There are few studies that address the regimen, dose, or duration. Several case series using variable doses of peginterferon alfa-2b for 12 weeks reported higher SVR rates in persons who received higher doses (>1.2-1.33 µg/kg/ wk). However, aside from a trend toward a higher peginterferon dose, as of this time there are no definitive answers to whether concurrent use of ribavirin improves SVR rates with acute HCV treatment, nor are there data establishing the benefit of peginterferon alfa or the comparability of 12 weeks to longer courses. Although HCV RNA in patients with acute infection generally is cleared from the blood by 8 to 16 weeks in most persons who recover spontaneously, viremia has been observed as late as 48 weeks after acute infection in injection drug users who ultimately clear. Thus, what is offered is an interim set of recommendations that will need modification as more data accumulate.

General Management Issues

An important adjunct to the therapy of HCV is to advise chronically affected persons of measures that might be helpful in reducing or even preventing further fibrosis progression, independent of treatment. Most important is the issue of the potential deleterious effect of alcohol.

There are numerous studies that have reported a strong association between the use of excess alcohol and the development or progression of liver fibrosis and even the development of HCC. Moreover, excess alcohol intake may increase HCV RNA replication and interfere with response to treatment. Controversy exists, however, about the level of alcohol intake that is clearly harmful to the HCV-infected person. It is widely believed that the daily consumption of more than 50 grams of alcohol has a high likelihood of worsening the fibrosis, but there are reports of levels of alcohol intake of less than that amount having a deleterious effect on the liver disease.410 Clearly, for heavy alcohol users, efforts should be undertaken to treat the alcohol abuse and dependence before starting treatment, but treatment is not contraindicated for persons who have an occasional drink of alcohol or who have a past history of alcoholism. Although no consensus opinion exists, it seems reasonable to recommend either the complete suspension of alcohol intake while on treatment or restricting its use to an occasional drink during the course of the treatment. Obesity and its associated nonalcoholic fatty liver disease are believed to play a role in the progression of fibrosis in HCV-infected individuals and response to treatment. It is, therefore, appropriate to counsel those who are overweight (defined by a raised body mass index of >25 kg/m2 or more) to attempt to lose weight. Additionally, weight reduction and improvement in insulin resistance may improve the response to peginterferon plus ribavirin therapy. This is sound advice for its potentially positive impact not only on the liver disease but also on the other conditions associated with being overweight. A single report has suggested that superimposition of hepatitis A virus infection in persons with chronic liver disease, particularly those with hepatitis C, was associated with fulminant hepatitis. Therefore, it is recommended that persons with chronic HCV infection who lack evidence of preexisting antibody to hepatitis A be administered the hepatitis A vaccine. Although no specific recommendation has been advanced for vaccination against hepatitis B, the evidence that persons co-infected with hepatitis B and C have a worse prognosis than those with HCV infection alone suggests that hepatitis B vaccination should be offered to persons who are at risk for exposure to hepatitis B if they lack preexisting antibody

to hepatitis B.

Persons with chronic liver disease including those with hepatitis C frequently use herbal remedies. In a prospective study, 42% of patients with chronic HCV infection

reported using at least one herbal product.417 Silymarin (milk thistle extract) was the most frequently reported herbal remedy used representing 72% of all herbals taken. Similarly, approximately 40% of patients with advanced chronic hepatitis C and prior nonresponse to antiviral therapy who entered the long-term HALT-C treatment trial were found at the baseline visit to have either used herbal products in the past or were continuing to use them even while committing themselves to long-term peginterferon treatment.418 Once again, silymarin was by far the preferred herbal. The benefit of silymarin or other herbal therapies for patients with chronic HCV infection has not been well studied or established. Currently, the NIH is conducting a well-designed scientific study of a standardized formulation of silymarin to determine its effectiveness in persons with chronic hepatitis C who had not responded to conventional medication, as well as among persons with nonalcoholic steatohepatitis (NASH). Of concern is that some herbals, particularly herbal mixtures have been associated with severe hepatotoxicity, fulminant hepatitis and death.419 Accordingly, patients with chronic HCV infection should seek advice from their physician prior to initiating any herbal preparation. Similarly, prescription medications should be limited to the absolute minimum, particularly in those with cirrhosis.

Persons with chronic HCV infection should not share items of personal hygiene such as razors and toothbrushes.

Conclusions

Described above are the current data on testing, diagnosis, decisions regarding whom to treat, and the recommended treatments of patients with chronic HCV infection.

As noted earlier, these represent currently acceptable guidelines; it is recognized that reasonable physicians may deviate from the strategy and remain within acceptable standards of treatment. The issue of treatment of chronic HCV infection is in constant flux. There is highly active clinical research in this area, and new information appears with increasing frequency. Presented here is the current state of the art for management and treatment of persons with chronic HCV infection. However, these recommendations will need to be revised and updated in the future as additional critical and pivotal information becomes available.