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

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 goal of treatment is to prevent complications of HCV infection; this is principally achieved by eradication of infection. Accordingly, treatment responses are frequently characterized by the results of HCV RNA testing. Infection is considered eradicated when there is a sustained virologic response (SVR), defined as the absence of HCV RNA in serum by a sensitive test at the end of treatment and 6 months later. Persons who achieve an SVR almost always have a dramatic earlier reduction in the HCV RNA level defined in some studies as a 2-log drop or loss of HCV RNA 12 weeks into therapy, referred to as an early virologic response (EVR). Continued absence of detectable virus at termination of treatment is referred to as end of treatment response (ETR). A patient is considered to have relapsed when HCV RNA becomes undetectable on treatment but is detected again after discontinuation of treatment. Persons in whom HCV RNA levels remain stable on treatment are considered nonresponders, while those whose HCV RNA levels decline (e.g., by >2 logs), but never become undetectable, are referred to as partial responders. Improvement in liver histology, including improvement in fibrosis, has been observed in patients receiving interferon or pegylated interferon (peginterferon) in combination with ribavirin, particularly in those with an SVR to therapy.59 There have been substantial improvements in the success of HCV treatment (Fig. 1), and there are currently several treatments approved by the FDA (Table 6). In randomized clinical trials, the highest overall SVR rates have been achieved with the combination of weekly subcutaneous injections of long-acting peginterferon alfa and oral ribavirin, which represents the current standard of care. Milestones in therapy of chronic hepatitis C. IFN, interferon; RBV, ribavirin; PEG, pegylated interferon; m, months. Peginterferons are produced by binding of the inert polyethylene glycol moiety to interferon molecules, thus decreasing renal clearance, altering metabolism, and increasing the half life of the peginterferon molecule.60 There are 2 licensed products in the United States, the 12-kd peginterferon alfa-2b (Peg-Intron, Schering-Plough Corporation, Kenilworth, NJ) and the 40-kd peginterferon alfa-2a (Pegasys, Hoffmann-La Roche, Nutley, NJ). Because of their prolonged half lives, they can be administered by subcutaneous injection once weekly. In large, randomized, controlled trials, higher SVR rates have been achieved with the combination of weekly injections of peginterferon alfa plus oral ribavirin given twice daily than with interferon alfa given by injection 3 times a week together with ribavirin or peginterferon alfa used alone.31, 32 In these trials, peginterferon alfa-2b was dosed by weight (1.5 μg/kg was FDA approved) and coupled with 800 mg of ribavirin; peginterferon alfa-2a was given as a fixed dose of 180 μg along with a weight-adjusted, higher dose of ribavirin (1,000 mg if ≤ 75 kg and 1,200 mg if > 75 kg). In a third randomized controlled trial, 180 μg of peginterferon alfa-2a was used with either 800 mg or the higher, weight-adjusted doses of ribavirin.33 Since the 2 peginterferon alfa compounds have not been compared in a randomized controlled trial using similar ribavirin doses, their relative efficacies cannot be assessed. However, there were similar indicators of treatment response and adverse events. It should be noted that data believed to be useful for establishing treatment recommendations were not always replicated for both forms of peginterferon. For example, the design of the peginterferon alfa-2a study was the only one capable of determining that a treatment duration of 6 months is sufficient for persons infected with HCV genotypes 2 or 3.33 Nevertheless, recommendations have been broadened to encompass both peginterferon preparations. Overall response rates to peginterferon plus ribavirin, and response according to genotype and pretreatment HCV RNA levels, are shown in Figs. 2,3, and 4. The likelihood of achieving an SVR can be predicted by pretreatment patient characteristics, as well as by the EVR. In all prospective treatment studies, genotype is the strongest predictor of response. In the above-mentioned randomized, controlled studies of peginterferon alfa-2b and ribavirin, SVR rates were higher in patients who had genotype-2 or genotype-3 HCV infections, lower pretreatment HCV RNA levels (Fig. 2), younger ages, lower body weights, and absence of bridging fibrosis and cirrhosis.31-33 In persons who were treated with peginterferon alfa-2a together with ribavirin, the independent variables associated with an SVR included genotype non-1 (Fig. 3), age less than 40 years, and body weight less than 75 kg.32 The majority of patients in the first 2 peginterferon combination trials who had genotype-non-1 infection31, 32 were infected with genotype 2 or 3, but a small number were infected with genotypes 4, 5, and 6. In these 2 registration trials, in patients with genotype-1 infections, SVRs were 42% to 46%, while the response rates in those with genotype 2 or 3 were higher—76% to 82%. In the study that evaluated peginterferon alfa-2a, the data were analyzed further by combining genotype and viral load.32 Persons with genotype 1 and a high viral load (>2 × 106 copies/mL, equivalent to ≈800,000 IU/mL) who received the combination of peginterferon alfa-2a and ribavirin had an SVR of 41%, whereas the rate among those with genotype 1 and a low viral load (≤2 × 106 copies/mL) who were treated with the same regimen was 56%. In contrast, in persons with genotypes 2 and 3 and a high viral load who were given peginterferon alfa-2a and ribavirin, the SVR rate was 74%, while those with genotypes 2 and 3 and a low viral load who were treated similarly had an SVR of 81%. Sustained virologic response rates with peginterferon alfa-2b (PegIFN) and ribavirin (RBV) therapy for 48 weeks according to genotype and viral concentration.31 Sustained virologic response rates with peginterferon alfa-2a (PegIFN) or interferon alfa-2b (IFN) and ribavirin (RBV) according to genotype.32 Sustained virologic response rates in recipients of peginterferon alfa-2a (PegIFN) and 2 different doses of ribavirin (RBV) for 24 or 48 weeks.33 In African American patients with genotype-1 infection, SVR rates are typically lower than in Caucasians,61, 62 although precise estimates are not currently available for the combination of peginterferon alfa and ribavirin. In the study of peginterferon alfa-2a with ribavirin, the predictability of an SVR based on the EVR was assessed.32 Defined at week 12 as an at least 2-log decline from baseline of the HCV RNA level, 65% of patients with an EVR subsequently achieved an SVR. Conversely, among those who did not have an EVR, 97% failed to develop an SVR. Similar data were noted in the study that used peginterferon alfa-2b together with ribavirin.63 Among treated persons who had an EVR, 72% ultimately achieved an SVR; of those who did not have an EVR, none developed an SVR. The optimal treatment duration and ribavirin dose were investigated in a multicenter, randomized, controlled trial in which all persons received peginterferon alfa-2a at a dose of 180μg while patients in the 4 arms received either 24 or 48 weeks of ribavirin at doses of either 800 mg or the higher, weight-based dose of 1,000 or 1,200 mg daily (Fig. 4).33 Data were analyzed taking into account not only the HCV genotype, but also the pretreatment viral load (> or ≤ 2 × 106 copies/mL) of those with genotype 1. In patients with genotype 1 with low-level viremia, the SVR was highest in those who had received the higher ribavirin dose and who were treated for 48 weeks (61%). This regimen was also optimal for patients with genotype 1 and a high viral load: 46% achieved an SVR. In contrast, in patients with genotype 2 or 3, regardless of the pretreatment viral load, no differences were detected with the 4 treatment regimens, suggesting that peginterferon alfa-2a plus ribavirin at a dose of 800 mg given for 24 weeks is adequate.33 Those typically associated with interferon alfa, such as neutropenia, thrombocytopenia, depression, hypothyroidism and hyperthyroidism, irritability, concentration and memory disturbances, visual disturbances, fatigue, muscle aches, headaches, nausea and vomiting, skin irritation, low-grade fever, weight loss, insomnia, hearing loss, tinnitus, interstitial fibrosis and hair thinning. "Flu-like" symptoms and depression appeared to occur significantly less frequently with peginterferon alfa-2a plus ribavirin than with interferon alfa-2b plus ribavirin.32 Those typically associated with ribavirin, such as hemolytic anemia, fatigue, itching, rash, sinusitis, birth defects, or gout. Because of the concern of birth defects from the use of ribavirin, it is imperative that persons who receive the drug use strict contraception methods both during treatment and for a period of 6 months after treatment. Deaths reported in association with the use of interferon alfa and ribavirin include suicide, myocardial infarction, sepsis, and stroke. Growth factors, such as epoetin and granulocyte colony-stimulating factor (G-CSF) have been used to counteract the adverse events of ribavirin and interferon, respectively. However, currently there are insufficient data to recommend their routine use as a means to avoid or ameliorate peginterferon and ribavirin dose reductions in clinical practice. Adverse events tend to be more severe in the initial weeks of treatment and often can be managed with analgesics, such as acetaminophen (<2.0 grams/d) or nonsteroidal anti-inflammatory drugs; antidepressants, such as serotonin uptake inhibitors; and, occasionally, growth factors. Current recommendations for treatment of persons with chronic hepatitis C are derived from data gathered in the randomized, controlled registration trials p