Diagnosis, management, and treatment of hepatitis C: An update
Authors: Marc G. Ghany, Doris B. Strader, David L. Thomas, Leonard B. Seeff
Journal: Hepatology (2008)

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 therefore willing to withhold or delay treatment if liver histology displays minimal to moderate fibrosis stage ≤2 (Table 7), 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 (Table 7) 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.77 The earlier views that persons with genotype 1 infection and persistently normal aminotransferase values did not require a liver biopsy because they were believed to have minimal liver disease, and that treatment may actually be harmful, are no longer valid.78 It is now apparent that as many as a quarter of such individuals have significant fibrosis,78-81 and that treatment response is similar to that of individuals with abnormal serum aminotransferase levels.82-84 Therefore, the decision to perform a liver biopsy should be based on whether treatment is being considered, taking into account the estimated duration of infection and other indices of advancing liver disease (e.g., the platelet count), the viral genotype, and the patient's willingness to undergo a liver biopsy and motivation to be treated. If the biopsy is not performed and treatment not undertaken, the patient should continue to be monitored at least annually and a biopsy performed if the aminotransferase values become abnormal and other indicators of progressing liver disease become apparent. Recommendations 7. A liver biopsy should be considered in patients with chronic hepatitis C infection if the patient and health care provider wish information regarding fibrosis stage for prognostic purposes or to make a decision regarding treatment (Class IIa, Level B) 8. Currently 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 IIb, Level C). Natural history studies indicate that 55% to 85% of individuals who develop acute hepatitis C will remain HCV-infected.76, 85, 86 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.87, 88 Prospective studies of women and children infected at a young age and followed for 20 to 30 years report low rates of cirrhosis, 1% to 3%.75, 89-92 Retrospective studies of patients referred to tertiary care facilities document higher rates of cirrhosis, 20% to 25%, but this figure may be inflated by referral bias.93, 94 Progression to cirrhosis may be accelerated in persons who are of older age, who are obese, who are immunosuppressed (e.g., HIV co-infected), and who consume more than 50g of alcohol per day, although the precise quantity of alcohol associated with fibrosis progression is unknown.95-98 Persons with HCV-related cirrhosis are at risk for the development of hepatic decompensation (30% over 10 years) as well as hepatocellular carcinoma (1% to 3% per year).99 Identifying individuals at risk for developing 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.94, 96, 100 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, Table 7) 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. (See section on Treatment of Patients with Kidney Disease). 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).71, 72 Several types of virological responses may occur, labeled 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.102 Graphic display of virological responses. RVR, rapid virological response (clearance of HCV from serum by week 4 using a sensitive PCR-based assay); EVR, early virological response (≥2 log reduction in HCV RNA level compared to baseline HCV RNA level or HCV RNA negative at treatment week 12); SVR, sustained virological response (HCV RNA negative 24 weeks after cessation of treatment); relapse, reappearance of HCV RNA in serum after therapy is discontinued; nonresponder, failure to clear HCV RNA from serum after 24 weeks of therapy; partial nonresponder, 2 log decrease in HCV RNA but still HCV RNA positive at week 24; null nonresponder, failure to decrease HCV RNA by < 2 logs after 24 week of therapy. 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.72, 105-107 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 currently recommended therapy of chronic HCV infection is the combination of a 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.71-73 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 μg/kg/week dosed according to body weight (Fig. 2). 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 Virological responses to pegylated interferon and ribavirin in the two U.S. Registration trials.71, 72 ETR, end-of-treatment response; SVR, sustained virological response. Peginterferon alfa-2a is administered at a fixed dose of 180 μg/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.73 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 sufficient provided an EVR is achieved, these results need to be confirmed.111 Patients with genotypes 5 and 6 are underrepresented in trials of peginterferon and ribavirin due to their limited worldwide frequency. A recent retrospective analysis of the treatment of patients w