Diagnosis, management, and treatment of hepatitis C† (2004)

HCV, hepatitis C virus; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HIV, human immunodeficiency virus; anti-HCV, HCV antibody; RNA, ribonucleic acid; PCR, polymerase chain reaction; TMA, transcription-mediated amplification; FDA, Food and Drug Administration; HCC, hepatocellular carcinoma; SVR, sustained virologic response; EVR, early virologic response; ETR, end of treatment response; peginterferon, pegylated interferon; G-CSF, granulocyte colony-stimulating factor; HAART, highly active antiretroviral therapy; ddI, didanosine; GM-CSF, granulocyte-macrophage colony-stimulating factor. These recommendations provide a data-supported approach. They are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (Medline search); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines1 ; (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 Guidelines2; the guideline procedures of the Infectious Diseases Society of America3; and (4) the experience of the authors in the specified topic. These recommendations are fully endorsed by the AASLD, the Infectious Diseases Society of America, and the American College of Gastroenterology. 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. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1). The hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease. In the United States, the Centers for Disease Control and Prevention estimates that there are more than 2.7 million people with ongoing HCV infection.5 HCV is the leading cause of death from liver disease in the United States.6 The purpose of this article is to provide clinicians with approaches to the diagnosis, management, and prevention of HCV infection. The optimal methods of detecting HCV infection are to screen populations for history of risk and to test selected individuals with an identifiable risk factor. With careful questioning, an HCV risk factor can be identified in more than 90% of cases.7 The primary source of HCV transmission is HCV-infected blood or blood products. In the United States, injection drug use is the chief mode of transmission, and anyone who has ever injected illicit drugs should be tested.5, 7 Persons should also be tested if they received a blood or blood component transfusion or organ transplant before 1992, when sensitive tests were first used to screen donors for HCV antibodies. Since that time, HCV infection is rarely transmitted by transfusion.8 Other potential sources of HCV transmission include exposure to an infected sexual partner or multiple sexual partners, frequent exposure to infected blood among health care workers, and perinatal exposure.9-11 Although HCV prevalence rates are consistently higher in persons with multiple sexual partners, sexual transmission of HCV between monogamous partners is rare.7 Thus, while it is common to counsel HCV-infected persons to notify their current partners of their HCV status, they should be told that the risk of sexual transmission is sufficiently low12 that many authorities do not advise use of barrier precautions (i.e., latex condoms). Testing of sexual partners, therefore, is done chiefly for reassurance. There is no need to curtail ordinary household activities except those that might result in blood exposure, such as sharing a razor or toothbrush. HCV is not transmitted by hugging and the sharing of eating utensils. Although a monogamous sexual relationship carries a low risk of transmission of HCV infection, as noted above, the risk is higher in persons involved with multiple sexual partners. Persons with hemophilia should be tested for HCV infection if blood products were received before 1987, when viral inactivation procedures were implemented. It is also advisable to test persons for HCV infection if they have evidence of otherwise unexplained elevations of aminotransferase levels (alanine and/or aspartate aminotransferases; ALT /AST), have ever been on hemodialysis, or have human immunodeficiency virus (HIV) infection.10 Other situations that have been suggested to carry a risk for HCV transmission include certain folk medicine practices (acupuncture, ritual scarification), body piercing, tattooing, and even commercial barbering.13-17 Some studies of HCV infection have reported associations with commercial tattooing, suggesting possible acquisition of HCV infection in this setting.18-20 Most studies of body piercing have not differentiated between ear piercing and piercing of other body parts. As a result of discrepancies in study design, definitive conclusions regarding risks associated with these forms of percutaneous exposures are problematic, although the risk, if present, is likely to be low. Thus, there is no need to routinely test persons who have received tattoos or undergone piercing, particularly if these procedures have taken place in licensed establishments. Table 2, adapted from recommendations published by the Centers for Disease Control, Atlanta, Georgia,10 outlines the list of persons who should be routinely tested for HCV infection. For some of these categories (e.g., injection drug users, persons with hemophilia), the HCV prevalence is high (≈90%); for others (e.g., recipients of blood transfusions prior to 1992), the prevalence is moderate (≈10%). For still others (e.g., persons exposed by needle stick, sexual partners of HCV-infected persons), it is quite low (2%-5%). 1. Persons who should be tested for HCV infection are listed in Table 2(Grade, III). Persons found to be HCV-infected need to be counseled regarding prevention of spread of the virus to others. Good clinical practice dictates that all persons identified as infected with HCV be informed that transmission to others occurs through contact with their blood and that they should therefore take precautions against the possibility of such exposure. Although this advice applies to all HCV-infected persons, it has particular importance for injection drug users who are the leading source of HCV infections. Circumstances requiring counseling are shown in Table 3. 2. Persons infected with HCV should be counseled on how to avoid HCV transmission to others, as indicated in Table 3(Grade, III). Utilizing the tests described in Table 4, several strategies can be employed to detect HCV infection. In clinical practice, the usual approach is to test initially for antibodies to HCV (anti-HCV), then to use HCV ribonucleic acid (RNA) to document viremia. Because most persons with ongoing HCV infection have HCV RNA levels in the range of the quantitative assays and because the quantity of HCV RNA is useful to know before providing and monitoring HCV treatment,21 many experts routinely obtain quantitative rather than qualitative HCV RNA tests to confirm the presence of viremia.22 However, quantitative HCV RNA tests are generally not as sensitive; therefore, some experts prefer a qualitative HCV RNA test either as the primary test or to confirm a positive HCV antibody result in patients with a negative result by quantitative assay.23, 24 A negative sensitive RNA test in a person with HCV antibodies most likely indicates that the HCV infection has resolved. Other interpretations are that the anti-HCV immunoassay is falsely positive, the HCV RNA test is falsely negative, or rarely, that a person has intermittent or low-level viremia. The recombinant immunoblot assay has limited usefulness in clinical practice but may establish the cause of a positive anti-HCV immunoassay in a person with undetectable HCV RNA.24 A negative immunoblot result indicates that a positive anti-HCV immunoassay result represented a false positive result and that no further testing is needed. A positive immunoblot result followed by two or more instances in which HCV RNA cannot be detected using a licensed, qualitative assay suggest that HCV infection has resolved and no further HCV testing is indicated. There are instances in which a negative anti-HCV does not exclude HCV infection in patients with suspected liver disease. These include acute HCV infection or immunosuppressed states. HCV RNA testing can be used to establish acute HCV infection after an exposure because HCV RNA can be detected in 1 to 2 weeks, while antibodies to HCV are detectable an average of 8 weeks later.25-27 HCV RNA testing can also be used to test for HCV infection in persons with negative HCV antibody results who are known to have conditions associated with diminished antibody production, such as HIV infection and chronic hemodialysis.23 HCV RNA can be detected in the blood using amplification techniques such as polymerase chain reaction (PCR) or transcription-mediated amplification (TMA).28 The Food and Drug Administration (FDA) has approved 2 PCR-based tests for qualitative detection of HCV RNA: (1) Amplicor Hepatitis C Virus Test, version 2.0, and (2) Cobas Amplicor Hepatitis C Virus Test, version 2.0 (Roche Molecular Systems, Branchburg, NJ), which have lower limits of detection of approximately 50 IU/mL. Other commercially available nonapproved assays are used by some diagnostic laboratories. Quantitative assays (Table 4) ascertain the quantity of HCV RNA in blood using either target amplification (PCR, TMA) or signal amplification techniques (branched DNA assay). The level of HCV RNA in blood helps in predicting the likelihood of response to treatment, and the change in the level of HCV RNA during treatment can be used to monitor response. The results should be reported in international units to standardize data,29 although the dynamic ranges differ and the results can be difficult to compare between assays, as noted in Table 4. Because a change in the HCV RNA level is used to monitor treatment response, it is important at the outset of treatment to obtain the actual level rather than simply a report indicating that the level exceeds an upper limit of detection, since HCV RNA levels sometimes are above the linear range of currently available assays. In addition, the same quantitative test should be used while on therapy to avoid confusion. The only quantitative test that has currently received FDA approval is Versant HCV RNA version 3.0 (Bayer Diagnostics, Tarrytown, NY) (Table 4). There are 6 major HCV genotypes.30 Although genotype does not predict the outcome of infection, it does predict the likelihood of treatment response, and, in many cases, determines the duration of treatment.31-33 Genotyping can be performed by direct sequence analysis, by reverse hybridization to genotype-specific oligonucleotide probes, or by the use of restriction fragment length polymorphism. Two tests, not yet FDA approved, are currently available for clinical use: (1) the Trugene HCV 5'NC Genotyping Kit (Visible Genetics, Toronto, Canada), which is based on direct sequencing followed by comparison with a reference sequence database, and (2) the line-probe assay (Inno LiPA HCV II, Innogenetics, Ghent, Belgium), which is based on reverse hybridization of PCR amplicons on a nitrocellulose strip coated with genotype-specific oligonucleotide probes.34-36 Once the genotype is identified, the test need not be repeated. Current commercial tests fail to identify the genotype in a small proportion (<3 %) of HCV-positive persons,37 and a similarly low proportion (1%-4%) may display mixed genotypes.37, 38 3. Patients suspected of having chronic HCV infection should be tested for HCV antibodies. (Grade, II-2) 4. HCV RNA testing should be performed in (a) patients with a positive anti-HCV test (Grade, II-2); (b) patients for whom antiviral treatment is being considered, using a quantitative assay (Grade, II-2); (c) patients with unexplained liver disease whose anti-HCV test is negative and who are immune-compromised or suspected of having acute HCV infection (Grade, II-2). 5. HCV genotype should be determined in all HCV-infected persons prior to treatment in order to determine the duration of therapy and likelihood of response (Grade, I). The role of liver biopsy in the management of patients with chronic hepatitis C is currently being debated. In the initial treatment trials of hepatitis C, a liver biopsy was regarded as an important parameter in helping to guide management and treatment, particularly at a time when response to treatment was low. More recently, with the improvement of treatment effectiveness, the value of the liver biopsy has been questioned because of the potential risks of the procedure and the concern of sampling error.39 This has prompted some to challenge the need for biopsy and to suggest that the procedure may not be necessary as a prelude to treatment. However, since current therapy is effective in clearing virus in only about one half of those treated, and since treatment is associated with costs and adverse events, there are likely many individuals in whom therapy can be safely deferred. The liver biopsy furnishes information about the staging of fibrosis and the degree of hepatic inflammation, histopathological features that are helpful to both the patient and the provider for predicting the natural history of disease and thus the relative urgency of therapy.40-42 Three scoring systems for defining the degree of inflammation (grading) and the extent of fibrosis (staging) have been devised, 2 of which—the Metavir scoring system43 and the Ishak grading system44—have received the greatest attention. The components of these systems are shown in Table 5. Using the degree of fibrosis as one component of the basis for therapy, treatment is generally advised if the liver biopsy displays a Metavir score of ≥ 2 or an Ishak score of ≥ 3. Some experts, in considering the need for treatment, also assess the intensity of liver inflammation. However, there are no established guidelines for how to combine the degrees of liver fibrosis and inflammation. Moreover, measurement of liver fibrosis, and especially liver inflammation, can be compromised by sampling error and by difficulties in the histopathologic interpretation. In most studies, the extent of liver fibrosis is an independent predictor of treatment response. Patients with milder degrees of fibrosis generally respond more favorably to treatment than do patients with more advanced fibrosis (bridging fibrosis or cirrhosis).45, 46 However, the need for treatment in such patients is lower than it is for those with advanced fibrosis. The cost-effectiveness of treating patients with no liver fibrosis has been questioned, since the prognosis even without therapy is excellent, further underscoring the importance of accurately staging the severity of liver disease.47 Clinical, laboratory and radiological findings can identify many patients with cirrhosis, but not those with lesser degrees of fibrosis.48 Thus, in persons without strong clinical evidence of cirrhosis, a liver biopsy is useful in providing information about the extent of liver damage associated with chronic infection, the feature that remains the best predictor of prognosis. Although liver fibrosis markers are commercially available, they are currently insufficiently accurate to support their routine use.49 Until sensitive serum markers can be developed that will define all stages of fibrosis and mirror the information derived from liver biopsy, the procedure remains the only means of defining the severity of damage from HCV infection in many patients. After weighing the risks, benefits and costs of existing HCV treatments and of liver biopsy, most experienced clinicians routinely obtain a liver biopsy in patients with HCV genotype-1 infection to guide recommendations for treatment. Patients infected with HCV genotypes 2 and 3, however, have a high likelihood of response and, therefore, some advocate treating all such patients regardless of severity of liver disease without resorting to liver biopsy. For patients with no or little fibrosis (i.e., Metavir score <2 or Ishak score <3), in whom treatment is often deferred, liver biopsy can be used to monitor progression of liver disease. An interval of 4 to 5 years between biopsies may be needed to measure change in such patients.50 Although the spectrum of liver fibrosis tends to be worse in persons with elevated blood levels of aminotransferases than in those with normal aminotransferase levels,51 14% to 24% of persons with persistently normal values have more-than-portal fibrosis on liver biopsy. These persons may have progressive liver disease over time despite persistence of normal aminotransferase values.51, 52 In individuals with normal aminotransferase values and extensive hepatic fibrosis (bridging fibrosis or cirrhosis), treatment should be considered, and liver biopsy is the only available method to obtain the necessary information to guide this decision. In patients with chronic infection and clinical signs of advanced cirrhosis, liver biopsy may add little to the clinical impression and may be riskier than in healthier patients. 6. Regardless of the level of ALT, a liver biopsy should be done when the results will influence whether treatment is recommended, but a biopsy is not mandatory in order to initiate therapy (Grade, III). 7. A liver biopsy may be obtained to provide information on prognosis (Grade, III). Natural history studies indicate that 55% to 85% of persons who develop acute hepatitis C will remain HCV-infected. Among these individuals, 5% to 20% are reported to develop cirrhosis over periods of approximately 20 to 25 years.53, 54 The higher percentage figure of 20% may not reflect the cirrhosis rate in the general population of HCV-infected persons because these data originate largely from studies in tertiary-care settings, and hence may represent referral bias. Persons with HCV-related cirrhosis are at risk for developing end-stage liver disease (a risk of approximately 30% over 10 years) as well as hepatocellular carcinoma (HCC) (a risk of approximately 1% to 2% per year).55 The 15% to 45% of persons with acute hepatitis C who do recover (HCV RNA not detected in their blood) are not subject to long-term complications and do not need treatment. In general clinical practice, however, acute hepatitis C is uncommonly recognized; the majority of patients already have chronic hepatitis C. In persons with persistent infection, evolution to cirrhosis is the primary concern, usually requiring the passage of 2 or more decades, and occurring more often in persons infected at older ages (particularly men), those who drink more than 50 grams of alcohol each day, those who are obese or have substantial hepatic steatosis, and those with HIV coinfection.56-58 More-than-portal fibrosis on liver biopsy (Metavir ≥2 or Ishak ≥3) is an important predictor of future progression of liver disease and the need for HCV treatment.40, 41, 57 Infection with HCV can also be associated with a variety of extra-hepatic manifestations, chief of which is the induction of abnormal circulating proteins called cryoglobulins. The pathologic consequence, termed mixed cryoglobulinemia, is the development of vasculitis, which is associated with certain skin manifestations and internal organ damage that predominantly affects the kidney. The presence of symptomatic cryoglobulinemia is an indication for HCV antiviral therapy, regardless of the stage of liver disease. The of treatment is to complications of HCV this is by of infection. treatment are by the results of HCV RNA Infection is when there is a sustained virologic response as the of HCV RNA in serum by a sensitive test at the end of treatment and 6 Persons who an have a in the HCV RNA level in some studies as a or of HCV RNA weeks therapy, to as an early virologic response of detectable virus at of treatment is to as end of treatment response A patient is to have when HCV RNA undetectable on treatment but is detected after of treatment. Persons in whom HCV RNA levels remain on treatment are while those whose HCV RNA levels (e.g., by but are to as in liver including improvement in fibrosis, has been in patients or pegylated in with particularly in those with an to There have been substantial in the of HCV treatment and there are currently several treatments approved by the FDA (Table In clinical the rates have been with the of of and which the current of care. in therapy of chronic hepatitis C. interferon; pegylated interferon; are by of the to thus and the half of the There are 2 licensed products in the United States, the and the Because of their half they can be by injection In higher rates have been with the of of than with by injection a with or used In these was by was FDA and with of was as a of with a higher of if and if In a of was used with either or the of Since the 2 have not been in a using their relative cannot be However, there were of treatment response and adverse It should be noted that data to be useful for treatment recommendations were not for both forms of For the of the study was the only one of that a treatment duration of 6 is for persons infected with HCV genotypes 2 or recommendations have been to both response rates to and response to genotype and HCV RNA are shown in and 4. The likelihood of an can be by patient as well as by the In all treatment studies, genotype is the predictor of response. In the studies of and rates were higher in patients who or HCV lower HCV RNA levels lower body and of fibrosis and In persons who were with with the independent associated with an genotype than and body than The majority of patients in the first 2 trials who were infected with genotype 2 or 3, but a small were infected with genotypes 4, and 6. In these 2 in patients with genotype-1 were to while the response rates in those with genotype 2 or were to In the study that the data were further by genotype and viral Persons with genotype 1 and a high viral to who received the of and an of the rate among those with genotype 1 and a low viral who were with the same was In in persons with genotypes 2 and and a high viral who were and the rate was while those with genotypes 2 and and a low viral who were similarly an of virologic response rates with and therapy for weeks to genotype and viral virologic response rates with or and to virologic response rates in recipients of and 2 of for 24 or In American patients with genotype-1 infection, rates are lower than in although estimates are not currently available for the of and In the study of with the of an based on the was at as an at from of the HCV RNA of patients with an an among those who not have an EVR, to develop an data were noted in the study that used with Among persons who an EVR, an of those who not have an EVR, developed an The optimal treatment duration and were in a in which all persons received at a of while patients in the 4 received either 24 or weeks of at of either or the of or were not only the HCV but also the viral or 2 of those with genotype 1. In patients with genotype 1 with low-level the was in those who received the higher and who were for weeks This was also optimal for patients with genotype 1 and a high viral an In in patients with genotype 2 or 3, regardless of the viral no were detected with the 4 treatment suggesting that at a of for 24 weeks is associated with such as and and and skin fibrosis and and to with than with associated with such as or Because of the concern of from the use of it is that persons who the drug use methods both during treatment and for a of 6 after treatment. reported in with the use of and include and such as and granulocyte colony-stimulating factor have been used to the adverse of and However, currently there are data to their routine use as a means to avoid or and in clinical to be more in the initial weeks of treatment and often can be with such as or such as and, Current recommendations for treatment of persons with chronic hepatitis C are derived from data in the trials