Diagnosis, management, and treatment of hepatitis C: An update # † ‡

This document has been approved by the AASLD, the Infectious Diseases Society of America, and the American College of Gastroenterology. 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;1 (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. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart association Practice Guidelines).3, 4 AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; ANC, absolute neutrophil count; anti-HCV, antibody to HCV; AST, aspartate aminotransferase; CKD, chronic kidney disease; CTP, Child-Turcotte-Pugh; EIA, enzyme immunoassay; ETR, end-of-treatment response; EVR, early virological response; FDA, U.S. Food and Drug Administration; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; PEG, polyethylene glycol; RVR, rapid virological response; SVR, sustained virological response; ULN, upper limit of normal. 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.6 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. The optimal approach to detecting HCV infection is to screen persons for a history of risk of exposure to the virus, and to test selected individuals who have an identifiable risk factor.10 Currently, injection drug use is the primary mode of HCV transmission in the U.S; thus, all persons who use or have used illicit injection drugs in the present or past, even if only once, as well as intranasal drug users who share paraphernalia, should be tested for HCV infection.7, 11, 12 Individuals who have received a blood or blood component transfusion or an organ transplant before 1992 should also be tested. With the introduction of sensitive tests to screen blood donors for HCV antibodies in 1992, transfusion-transmission of HCV has become rare.12, 13 Persons with hemophilia should be tested for HCV infection if blood products were received before 1987, after which time, viral inactivation procedures were implemented.14 Similarly, individuals with unexplained elevations of the aminotransferase levels (alanine and/or aspartate aminotransferase; ALT/AST), those ever on hemodialysis, children born to HCV-infected mothers, or those with human immunodeficiency virus (HIV) infection should be tested for the presence of HCV infection.15-17 Other potential sources of HCV transmission include exposure to an infected sexual partner or multiple sexual partners, exposure among health care workers to HCV-contaminated blood and blood products, and tattooing.12, 15, 18-23 The prevalence of HCV infection is consistently higher among persons with multiple sexual partners, whereas sexual transmission of HCV between monogamous partners is uncommon.11, 18 Thus, although it is prudent to counsel HCV-infected persons to notify their current partners of their HCV status, they should be informed that the risk of sexual transmission is sufficiently low19 that many authorities do not advise the use of barrier protection among monogamous couples.18 Nevertheless, between 1% and 5% of monogamous sexual partners of index HCV cases test positive for anti-HCV. There is no need for HCV-infected persons to limit ordinary household activities except for those that might result in blood exposure, such as sharing a razor or toothbrush. The hepatitis C virus is not transmitted by hugging, kissing, sharing of eating utensils or breastfeeding. Folk medicine practices, including acupuncture and ritual scarification, as well as body piercing, tattooing and commercial barbering are potential modes for transmission of HCV infection when performed without appropriate infection control measures.24-28 Transmission of HCV infection by body piercing is, however, rare and many HCV infected persons who have undergone body piercing acquired their infection by other means.23, 29-33 Therefore, there is no need to routinely test persons who have received tattoos or undergone piercings in the absence of other risk factors, particularly if these procedures have taken place in licensed establishments. Because symptoms are generally absent in individuals with chronic HCV infection, recognition of infection requires risk factor screening, which should be done whenever it is possible to link with appropriate HCV testing and counseling.10 Table 2 outlines the list of persons who should be routinely screened for HCV infection.15 For some groups, such as those with a history of injection drug use or persons with hemophilia, the prevalence of HCV is high (≈90%). For other groups (recipients of blood transfusions prior to 1992), the prevalence is moderate (≈10%). For still others, (persons with needle stick exposure, sexual partners of HCV-infected persons), the prevalence is low (1% to 5%). ○ Persons with HIV infection ○ Persons with hemophilia who received clotting factor concentrates prior to 1987 ○ Persons who have ever been on hemodialysis ○ Persons with unexplained abnormal aminotransferase levels ○ Persons who were notified that they had received blood from a donor who later tested positive for HCV infection ○ Persons who received a transfusion of blood or blood products ○ Persons who received an organ transplant Recommendation 1. As part of a comprehensive health evaluation, all persons should be screened for behaviors that place them at high risk for HCV infection. (Class I, level B). 2. Persons who are at risk should be tested for the presence of HCV infection (Table2) (Class I, level B). Good clinical practice dictates that persons found to be HCV-infected are counseled regarding prevention of spread of the virus to others. Because exposure to infected blood is the primary mode of transmission, it is essential to inform HCV-infected individuals that precautions should be taken to avoid the possibility of exposing others to contact with their blood. This is particularly important for injection drug users who are the leading source of HCV infection, because their transmission route is primarily via sharing of needles and other infected implements. Table 3 outlines the measures to avoid HCV transmission. Recommendation 3. Persons infected with HCV should be counseled on how to avoid HCV transmission to others, as indicated in Table3 (Class I, level C) 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 viral nucleic acid. These assays have no role in the assessment of disease severity or prognosis. 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 aggammaglobulinemia or in patients on hemodialysis.35-37 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.40, 41 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.42, 43 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 is now the preferred unit to report test results.44, 45 For monitoring purposes, it is important to use the same laboratory test before and during therapy. 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 a sequence divergence of 30% among isolates.46 Genotype 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.47 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.48 The diagnosis of acute or chronic HCV infection generally requires testing of serum for both antibody 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 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 (Table 6). 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 recent known risk exposure, with exacerbation of chronic HCV infection, or with an acute hepatitis of another etiology 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 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. Recommendation 4. Patients suspected of having acute or chronic HCV infection should first be tested for anti-HCV (Class I, Level B.) 5. HCV RNA testing should be performed in: a) Patients with a positive anti-HCV test (Class I, Level B) b) Patients for whom antiviral treatment is being considered, using a sensitive quantitative assay (Class I, Level A) c) Patients with unexplained liver disease whose anti-HCV test is negative and who are immunocompromised or suspected of having acute HCV infection (Class I, Level B). 6. HCV genotyping should be performed in all HCV-infected persons prior to interferon-based treatment in order to plan for the dose and duration of therapy and to estimate the likelihood of response (Class I, Level A) 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.49 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.50-54 (Table 7). The two more common non-HCV conditions that might affect disease progression and possibly impede treatment response are steatosis49, 55, 56 and excess hepatocellular iron.57 Identifying either of these two features does not preclude initiating treatment, but their presence provides additional information regarding the likelihood of response to treatment.58-60 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.61, 62 The procedure is not without risks (including pain, bleeding and perforation of other organs),63, 64 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.66 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.66 The recently developed transient elastography that uses ultrasound and low frequency elastic waves to measure liver elasticity67 has improved the ability to define the extent of fibrosis without a liver biopsy, particularly when combined with other noninvasive markers.68 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 now 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.69, 70 A liver biopsy may be unnecessary in persons with genotypes 2 and 3 HCV infection, since more than 80% of them achieve a sustained virlogical response (SVR) to standard-of-care treatment. There is, however, an ongoing debate about whether a biopsy is warranted for persons infected with HCV, genotype 1, whose response to such treatment approximates 50% among Caucasians and 30% among African Americans.71-73 Even more uncertain is whether there is need for a liver biopsy in persons infected with the other less common genotypes (4 through 6). Thus, 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 to or treatment if liver minimal to moderate fibrosis stage (Table if the infection is known to have been These individuals are regarded as having liver disease that may not be for their However, treatment is for those with more advanced fibrosis stage (Table be however, that while information from a biopsy is the procedure is not for on treatment. performed and treatment is a common is to the liver biopsy 4 to years later and to treatment should there be evidence of disease The that persons with genotype 1 infection and aminotransferase values not a liver biopsy because they were to have minimal liver and that treatment may be are no longer is now that as many as a of such individuals have and that treatment response is to that of individuals with abnormal serum aminotransferase Therefore, the decision to a liver biopsy should be based on whether treatment is being considered, into the estimated duration of infection and other of liver disease (e.g., the the viral and the to a liver biopsy and to be the biopsy is not performed and treatment not the patient should continue to be at least and a biopsy performed if the aminotransferase values become abnormal and other of liver disease become A liver biopsy should be considered in patients with chronic hepatitis C infection if the patient and health care information regarding fibrosis stage for or to a decision regarding treatment (Class Level B) available noninvasive tests may be useful in defining the presence or absence of advanced fibrosis in persons with chronic hepatitis C infection, but should not replace the liver biopsy in routine clinical practice (Class Level history studies that to of individuals who acute hepatitis C will resolution is more common among infected and than among persons who are when they acute HCV infection has for the infected persons as well as for their the are at risk for progression to cirrhosis and/or the are at risk of the infection through exposure to the The risk of cirrhosis from 5% to over of to studies of and children infected at a and followed for to years report low of 1% to studies of patients to care document higher of to but this may be by to cirrhosis may be in persons who are of who are who are immunosuppressed (e.g., HIV and who more than of although the of with fibrosis progression is Persons with cirrhosis are at risk for the development of over as well as hepatocellular carcinoma (1% to Identifying individuals at risk for disease is the preferred approach is to the of fibrosis on liver biopsy, using a such as the or Persons with no or minimal fibrosis stage and stage have a low risk for and death the next to However, the presence of fibrosis stage Table is an important of progression to cirrhosis and an indication for with HCV can also cause including mixed and is an indication for HCV antiviral therapy of the stage of liver on of Patients with The of therapy is to and death from HCV infection. Because of the of chronic HCV infection over it has been difficult to that therapy of liver treatment are by a virological rather than a clinical can be of serum ALT of HCV RNA from serum by a sensitive and in necroinflammatory score with no in fibrosis Several of virological may to their to treatment. The most important is the sustained virological response as the absence of HCV RNA from serum by a sensitive PCR assay weeks following of therapy (Table This is generally regarded as a although liver has been identified years if cirrhosis at the time of an of virological RVR, rapid virological response of HCV from serum by 4 using a sensitive EVR, early virological response in HCV RNA level to HCV RNA level or HCV RNA negative at treatment SVR, sustained virological response RNA negative weeks after of of HCV RNA in serum after therapy is failure to HCV RNA from serum after weeks of 2 in HCV RNA but still HCV RNA positive at failure to HCV RNA by 2 after of therapy. virus at the of either a or of therapy is to as an end-of-treatment response An does not that an will be but is for it to A rapid virological response as HCV RNA at 4 of treatment, using a sensitive test with a lower limit of detection of IU/mL, a high likelihood of an An early virological response is as a or absence of serum HCV RNA at 12 of therapy with the to achieve an is the most of not an viral is useful for predicting whether or not an is likely to to the of HCV RNA while still on therapy, while virological is the of HCV RNA in serum after treatment is and an was Persons who to serum HCV RNA by at least 2 after weeks of therapy are while those whose HCV RNA levels by but become are to as The currently recommended therapy of chronic HCV infection is the of a and The of this was based the results of three clinical that the of this treatment over standard and not these three of therapy, namely the appropriate dose of the the optimal duration of therapy and the need for a for patients with genotype 1 and genotype 2 and 3 There are two licensed in the United NJ), with a polyethylene to the standard and with a to the standard The of these two of The optimal dose of based on the is to body the dose of used in the was at a of patients with genotype 1 infection that for patients for patients to for patients to and for patients but was more to and in the two U.S. ETR, end-of-treatment response; SVR, sustained virological is at a dose of 180 with to for those who and for those who The the two of an in the more a in the rate as to treatment. A third that the optimal duration of treatment should be based on the viral The established that patients with genotype 1 should be for weeks with standard whereas patients with genotypes 2 and 3 be with low dose for For patients with HCV genotype 4 infection, treatment with for weeks to be the optimal as in a of from another of treatment with a dose of has that weeks duration of therapy is an is these results need to be Patients with genotypes and 6 are in of and to their A recent analysis of the treatment of patients