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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”



Hepatitis C Management


Hepatitis C, fatty liver disease, and hepatic drug toxicity are the most common liver problems seen by primary care physicians and other health care providers. Hepatitis C virus (HCV) infection is the most common chronic blood-borne viral infection in North America. An estimated 3.9 million persons have been exposed, and 2.7 million have measurable levels of viral RNA. An estimated 38,000 are newly infected annually. More than 5% of certain groups are infected.1 Although the natural history is often benign, over time 20% will develop a serious sequela, such as severe fibrosis, cirrhosis, end-stage liver disease, or hepatoma. Some will have an extrahepatic manifestation, such as lichen planus, leukocytoplastic vasculitis, membranoproliferative glomerulonephritis, porphyria cutanea tarda, or B-cell lymphoma.

The substantial morbidity, mortality, and economic burden associated with HCV infection are responsible for the striking worldwide public health impact of this condition. Currently, HCV infection is responsible for an estimated 8,000 to 10,000 deaths annually in the United States, and that number is predicted to triple in the next 10 to 20 years. HCV-related disease is the leading indication for liver transplantation in the United States. The decision to treat patients with chronic HCV infection should be made after many factors have been considered and each case has been individualized.

It is important for all health care practitioners to understand effective strategies to establish or exclude a diagnosis of HCV infection and to interpret tests correctly. Effective treatment rests importantly on recognition of the attributes that influence disease progression; they include host factors such as age, obesity, comorbidities (eg, chronic renal failure, coinfection with human immunodeficiency virus [HIV]), and others. Viral properties such as genotype play an important role in treatment choices and outcomes. A thorough understanding of the pharmacology and pharmacodynamics of the agents used in treatment and management of side effects is also important.

Testing for Possible, Suspected, or Documented HCV Infection


  • A positive enzyme immunoassay (EIA) is usually followed by HCV RNA testing to confirm antibody specificity and to document active infection.
  • A negative HCV RNA assay in a patient with a positive EIA indicates that either the infection has resolved or the initial EIA was a false positive. The distinction can be made by a recombinant immunoblot assay.
  • Although EIA is generally regarded as the initial test for HCV, in some special circumstances HCV RNA testing should be performed regardless of EIA results.

Since the hepatitis C virus was cloned in 1989, technological advances in molecular biology have led to the development of several serologic and molecular tests to determine the presence of HCV. Clinicians and clinical investigators now have the ability to detect the virus and identify its subtypes, which facilitates the management of patients with chronic HCV infection.

Four categories of hepatitis C laboratory tests are available: (1) liver enzyme tests, (2) tests to detect antibodies to HCV, (3) tests to detect the virus, and (4) HCV genotyping.


The two liver enzymes that are measured in the evaluation of patients with HCV infection are alanine aminotransferase (ALT), also known as serum glutamate pyruvate transaminase (SGPT), and aspartate aminotransferase (AST), also known as serum glutamic oxaloacetic transaminase (SGOT) (Table 1).

Table 1

Range of normal ALT and AST values



10 to 32 U/L
9 to 24 U/L


Both sexes:

8 to 20 U/L

The reference values for normal AST and ALT levels can vary among laboratories. In general, most laboratories have used asymptomatic "normal" individuals for these determinations. It has become increasingly clear that the presence of obesity, obesity-related nonalcoholic fatty liver disease, and female gender can affect the level of ALT.2 Furthermore, liver enzyme levels can fluctuate over time, and the presence of one normal value is not sufficient to determine ALT levels. Finally, liver histology may not always correlate with ALT values. Compared with patients who have elevated ALT levels, HCV-infected patients with normal ALT values appear to have liver disease that is at an earlier histologic stage and less active. However, 25% to 30% of such patients have significant histologic fibrosis, with 5% to 10% having bridging fibrosis or cirrhosis.3

Simultaneous elevations of aminotransferase levels indicate some degree of hepatocellular injury. However, the absence of any elevation does not rule out significant injury or hepatic fibrosis. Liver enzyme tests do not reveal the cause of hepatic injury or reflect the true status of hepatic function.4,5 In patients with risk factors for HCV infection and abnormal liver enzyme levels, HCV infection is probable but not certain. Thus, liver enzymes are neither sensitive nor specific for the diagnosis of HCV infection.


The need to test a patient for HCV infection should be based on the patient's risk of having contracted the virus.

HCV is spread primarily by contact with blood and blood products. Blood transfusions and the use of shared or unsterilized needles and syringes have been the primary means of HCV transmission in the United States. With the advent of routine blood screening for HCV antibody in the United States in 1991, transfusion-related transmission has almost disappeared, leaving injection-drug use as the most common risk factor for contracting HCV. Nevertheless, many patients acquire HCV without any known exposure to blood or any drug use. There appears to be a slightly increased risk of HCV infection among people with high-risk sexual behavior, multiple partners, and sexually transmitted diseases, as well as among people who use shared equipment to take cocaine intranasally.6,7

Individuals with any risk for HCV infection should be considered for HCV testing according to the following risk categories:7

High risk. High-risk individuals include injection-drug users and those who received clotting factors prior to 1987. All these individuals should be tested for HCV infection.

Intermediate risk. Individuals at intermediate risk include hemodialysis patients, those with undiagnosed liver problems, and those who received blood transfusions and/or solid organs before 1992. All these individuals should be tested for HCV. Infants born to infected mothers are also at intermediate risk; testing is recommended when they reach the age of 12 to 18 months.

Low risk. Although health care and public safety workers are considered to be at low risk, testing for HCV is recommended after a possible exposure. Individuals who have sexual relations with an infected steady partner might be at low risk, but testing should still be considered.

Regardless of the test results, all at-risk patients should also be provided with counseling and continuing follow-up.1,4,5,8-11


Antibody tests are serologic assays that are based on the immunologic characteristics of HCV.12,13 The two types are (1) the enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA), and (2) the recombinant immunoblot assay (RIBA).

EIA. EIA is the initial serologic test used for HCV screening. Its sensitivity and specificity are excellent, and its positive predictive value in high-risk patients is quite high. A patient with a positive EIA is presumed to have HCV infection until proven otherwise; EIAs cannot distinguish between resolved and active infection. HCV antibodies usually become detectable 8 weeks following exposure. Several EIAs are available (Table 2).

Table 2

EIAs for specific HCV antigens



Abbott HCV EIA 2.0

Core, NS3, NS4

Abbott HCV EIA 3.0

Core, NS3, NS4, NS5

Abbott IMx HCV 3.0

Core, NS3, NS4, NS5

Abbott AxSYN HCV 3.0

Core, NS3, NS4, NS5

Bio-Rad Monolisa Anti-HCV

Core, NS3, NS4

Bio-Rad Access HCV Ab Plus

Core, NS3, NS4, NS5

Innogenetics Innotest HCV Ab IV

Core, NS3, NS4, NS5

Ortho HCV 3.0 ELISA

Core, NS3, NS4, NS5

Ortho Vitro Anti-HCV

Core, NS3, NS4, NS5

False positives are rare now, but they were common with earlier generations of these assays. When false positives do occur, they usually do so in patients with autoimmune liver disease or hypergammaglobulinemia who have normal liver enzyme levels and no risk factors for HCV infection. False negatives are also uncommon. When they do occur, they do so in immunosuppressed patients (eg, organ transplant recipients and HIV-positive patients) and in patients on long-term hemodialysis.13-16

The advantages of EIAs are that they are easy to use with automation, their variability is minimal, and they are relatively inexpensive (less than U.S. $50). The primary disadvantage of EIA testing is that detectable antibodies may not be detectable in immunosuppressed patients or early in the course of infection.

RIBA. Because the first generations of EIA tests were plagued by false positives, researchers developed the RIBA as a supplemental semiquantitative assay to refine the specificity of positive anti-HCV EIAs. RIBA can identify false-positive EIA results that are sometimes seen in patients with no apparent risk factors for HCV infection and in patients with other immune system-mediated diseases, such as rheumatoid arthritis. However, RIBAs are becoming obsolete because their function can be performed better by HCV RNA testing.11-18 Currently, the primary purpose of RIBA testing is to distinguish between resolved HCV infection (EIA positive, HCV RNA negative, RIBA positive) and a false-positive EIA (EIA positive, HCV RNA negative, RIBA negative).


Molecular assays such as the HCV RNA test are based on the quantification and characterization of the HCV genome.16-19 The HCV RNA test determines the presence of the virus itself rather than its antibodies. The HCV RNA test measures the amount of HCV RNA in the blood via target amplification with reverse transcriptase polymerase chain reaction (PCR), transcription-mediated amplification (TMA), or a signal amplification technique such as a branched DNA (b-DNA) assay. Amplification is necessary because the amount of virus in serum is generally very low. Regardless of the method of amplification, HCV RNA detection represents definitive proof that an infection exists.16

The sensitivity of the different types of amplification varies. The TMA is the newest of the HCV RNA assays, and it is also the most sensitive.It may have the potential to detect relapsed HCV infection earlier than PCR.16 Although qualitative HCV RNA assays are more sensitive, they do not provide a quantitative value for the viral load.

HCV RNA is customarily done at 12 and 24 weeks during the treatment course, at the end of treatment, and 6 months after treatment has been completed.11,16 In the past, comparison of viral levels between assays was impossible. Adoption of standardized units of measurement (IU/mL) has eliminated this problem.16,17,19 It should be borne in mind that differences in HCV viral load of 0.5 log or less are within the range of testing variability and may not have clinical significance.

Several PCR-, TMA-, and b-DNA-based commercial assays are currently available. The U.S. Food and Drug Administration (FDA) has approved two qualitative HCV RNA assays: the manual Amplicor® version 2.0 assay and the semi-automated Cobas Amplicor™ version 2.0 assay, both of which are marketed by Roche Molecular Systems. The only quantitative HCV RNA assay that has been approved by the FDA is the Versant™ HCV RNA version 3.0 assay, marketed by Bayer Diagnostics.

Recently it has been shown that total HCV core antigen levels correlate with HCV RNA levels. However, the utility of the HCV core antigen assay and its application to clinical practice have not yet been established.14


The ability of HCV to undergo high rates of mutation allows it to escape the effects of the immune system and to resist the impact of antiviral therapy. High rates of mutation coupled with the absence of an efficient repair mechanism have resulted in a great deal of genetic heterogeneity among HCV strains. The genetic heterogeneity of HCV is reflected in a variety of genotypes (30% to 50%), subtypes (15% to 30%), isolates (5% to 15%), and HCV quasispecies (1% to 5%). In the spectrum of this genetic heterogeneity, quasispecies indicates that in an infected individual, HCV circulates as a population of viruses that are very similar (1% to 5% differences in base pair).

HCV is classified according to different genotypes (genotypes 1 through 6) based on differences in genomic sequences. Identification of a particular HCV genotype does not predict the natural history of the disease but does have important ramifications for the likelihood of response to therapy and therapy duration. For example, patients with genotypes 2 and 3 generally respond better to treatment and do not need as long a course of therapy. On the other hand, patients with HCV genotype 1 have lower rates of response and require a longer duration of therapy (this is discussed in more detail in the section on Treatment of Uncomplicated Chronic HCV Infection).

HCV genotypes are determined by restriction fragment length polymorphism (RFLP), by direct sequence analysis, or by reverse hybridization to genotype-specific oligonucleotide probes. Once the HCV genotype has been identified, there is no need to repeat the test. HCV genotyping assays have not yet received FDA approval.

Different genotypes are more common in some areas of the world than in others (Figure 1).20 For example, genotype 1 is most common in the United States (accounting for 70% to 75% of all cases), followed by genotype 2 (10% to 15%). Genotypes 2 and 3 are more common in Europe than in the United States, and genotype 4 is most common in North Africa and the Middle East.


Different tests have different capabilities in determining the diagnosis, prognosis, and treatment of HCV infection (Tables 3, 4, and 5).

Table 3

HCV Tests



Acute HCV


Chronic HCV

EIA; if EIA is (+), then HCV RNA

Vertical transmission


Occupational exposure




Antiviral Treatment


Decision to treat

EIA, HCV RNA (+), HCV genotyping

Response evaluation

HCV RNA by sensitive assay

Sustained eradication

HCV RNA by sensitive assay




Table 4

HCV Tests








Response & Logic








X (?)



HCV RNA qualitative





HCV RNA quantitative





HCV genotype








X (?)




Table 5

Interpretation of Hepatitis C Testing






No infection



Acute or chronic infection



Early infection
Chronic infection in immunosuppressed



Resolved infection
Chronic infection with low-level viremia
Passively acquired antibody



EIA is the most widely used initial test for HCV infection because of both its accuracy and its low cost (Figure 2).

A positive EIA is usually followed by an HCV RNA test to document active infection. Since HCV RNA levels in patients with chronic HCV infection are within the range of the quantitative assays, many experts evaluate EIA-positive patients with a quantitative HCV RNA assay. In unusual cases, the HCV RNA quantitative test may be negative, but the (more sensitive) HCV RNA qualitative assay will be positive.

A negative qualitative HCV RNA assay in a patient with a positive EIA indicates that either the infection has resolved or the initial EIA was a false positive. The distinction can be made by RIBA. A positive RIBA generally indicates that an infection has cleared spontaneously. A negative RIBA indicates that the initial EIA was a false positive.

Exceptions. EIA is generally regarded as the initial test for HCV. In some cases, HCV RNA testing should be performed following a negative EIA. As mentioned earlier, the presence of conditions associated with diminished antibody production—such as immunosuppression, HIV infection, or the long-term hemodialysis—can lead to a false-negative EIA result.

Another exception to the testing algorithm concerns patients in the early stage of acute HCV infection. At the time of testing, some of these patients may not yet have developed an antibody response, which can take approximately 8 weeks to manifest. In such a case (eg, in a patient who has been recently exposed), the negative EIA may be followed by HCV RNA testing for verification.

The Role of Liver Biopsy in Hepatitis C


  • Serum-based tests are precise and unequivocal, and a positive HCV RNA test confirms HCV infection.
  • In the absence of clinical or laboratory findings suggesting a second liver pathology, a liver biopsy will not alter the diagnosis.
  • Liver biopsy provides useful information about the degree of fibrosis in HCV-infected patients. This information is important for making decisions in the management of HCV infection.
  • Abstinence from alcohol is recommended for those infected with HCV. The effect of mild to moderate alcohol use on liver disease progression in HCV infection is controversial. Mild to moderate alcohol use outside the context of therapy may not be associated with fibrosis.

Liver biopsy plays a central role in the evaluation of chronic liver diseases, including HCV infection. In 1997, a National Institutes of Health (NIH) Consensus Development Conference Panel endorsed liver biopsy prior to the initiation of treatment of HCV infection.21 In 2002, another NIH consensus conference noted:

"Liver biopsy provides a unique source of information on fibrosis and assessment of histology. Liver enzymes have shown little value in predicting fibrosis. Extracellular matrix tests can predict severe stages of fibrosis but cannot consistently classify intermediate stages of fibrosis. Moreover, only liver biopsy provides information on possible contribution of iron, steatosis, and concurrent alcoholic liver disease to the progression of chronic hepatitis toward cirrhosis. . . . Thus, the liver biopsy is a useful part of the informed consent process. . . . Since a favorable response to current antiviral therapy occurs in 80% of patients with genotype 2 or 3, it may not always be necessary to perform liver biopsy in these patients." 22


The histologic features of chronic HCV infection are well defined. Two components are considered: activity and fibrosis.

Activity. Activity is gauged by the number of mononuclear inflammatory cells present in and around the portal areas, and by the number of dead or dying hepatocytes. Changes in activity do not imply progressive disease.

Fibrosis. The fibrotic response to HCV infection is variable. Fibrosis implies possible progression to cirrhosis. In mild cases, fibrosis is limited to the portal and periportal areas. More advanced changes are defined by fibrosis that extends from one portal area to another. The term for this is "bridging fibrosis". In some, this reaction evolves into cirrhosis.

Other histologic changes, such as macrovesicular fat (steatosis),23 may be seen, but they are not particularly useful. A standardized evaluation of liver histology in HCV infection is helpful, and several means have been developed and validated. Each considers the degree of liver pathology from the standpoint of the amount of inflammation and the amount of fibrosis (Table 6).

Table 6

Three common histologic grading and staging scales in HCV infection




Total Score

Histology Activity
Index (HAI)24

0 to 18

0 to 4

0 to 22

Ishak Modified HAI25

0 to 18

0 to 6

0 to 24


0 to 3

0 to 4

0 to 7


Fibrosis, more than inflammation, predicts the progression to irreversible liver disease in HCV infection. The METAVIR system is simple and easy to learn, and it has been extensively validated (Table 7).27

Table 7

METAVIR fibrosis grading scale



No fibrosis


Portal fibrosis


Bridging fibrosis, slight


Bridging fibrosis, marked






For all its advantages, liver biopsy has several important disadvantages. Among them are cost, the risk of complications, the need for additional health care resources, patient and physician aversion to the procedure, inadequate specimen size, and the lack of specific findings.

Cost. Liver biopsy adds between U.S. $1,500 and U.S. $2,000 to the cost of an evaluation.

Complications. Approximately 20% to 50% of patients will experience significant pain following percutaneous liver biopsy. More severe complications—such as pneumothorax, major bleeding, inadvertent biopsy of the kidney or colon, and perforation of the gallbladder—have been reported in a fraction of patients (0.57%). There have even been a few reports of death.28,29

Resources. In most cases, liver biopsy requires the involvement of a physician (usually a gastroenterologist or radiologist) who may not be the treating physician.

Patient aversion. Patients find liver biopsy anxiety provoking, even when the procedure goes well. Some specialists now advise premedication with anxiolytic agents to reduce apprehension—for example, midazolam, 1 to 2 mg IV, or lorazepam, 1 mg po, before the procedure. Some use meperidine, 12.5 to 25 mg IV, before biopsy to improve comfort. Additional narcotic analgesia may be necessary if post-biopsy pain is more than mild.

Physician aversion. A recent survey of 112 gastroenterologists in the southeastern United States revealed that between one-quarter and one-third do not perform liver biopsies because they are concerned about complications and low reimbursement.30 These respondents said they refer patients to a radiologist for liver biopsy. More than three-quarters (77%) routinely biopsy all HCV-infected patients before treatment, and the others biopsy selected HCV-infected patients to assist in decision-making. Only 3.6% do not biopsy any patients before treatment. Post-treatment biopsies are performed much less frequently. Seven percent of the surveyed physicians routinely biopsy all patients after treatment. Ultrasonography is used as a guide to biopsy selection site by nearly one-half (47%), although it is used by only 5% when the biopsy is performed by the gastroenterologist.

A recent observational study of 166 HIV/HCV-coinfected injection-drug users in France found that 45% underwent liver biopsy during a 5-year follow-up period; factors predictive of liver biopsy were high social support, complete abstinence from drugs, lack of immunosuppression, male gender, lack of multiple incarcerations, recent onset of drug use, and increased liver enzyme levels.31

Specimen size.
The amount of liver tissue obtained by needle biopsy represents no more than 1/30,000 of the liver volume. It is apparent that such a small sample will only represent the state of the liver for processes that are uniformly distributed. Several studies indicate that fibrosis may not be uniformly represented in each biopsy specimen. Postmortem studies in cirrhotics indicate that known cirrhosis will often be absent in a single core of liver tissue and that up to three specimens may be needed.32,33

A recent study of "virtual biopsy specimens" confirmed that the amount of liver tissue available for the pathologist to review is critical.34 A biopsy length of 15 mm was 65% accurate in scoring the degree of fibrosis; a biopsy length of 25 mm was 75% accurate. Specimens longer than 15 mm that contain six or more portal areas correlate better with biochemical surrogate markers of fibrosis than do smaller specimens.35

Most studies have ignored the impact of the width of the biopsy specimen. Colloredo et al have shown that the use of fine needles (internal diameter; 1 mm) impedes accurate staging of fibrosis, probably because of the decreased number of portal areas available in such specimens.36 Similarly, in a study of 149 paired liver biopsy specimens, Brunetti et al concluded that fine-needle biopsy had unsatisfactory discriminant ability and systematically underscored histologic variables compared with coarse-needle biopsy.37 Thus, both the length and the width of the biopsy specimen have been shown to be important in reducing diagnostic error. Many have suggested that five to eleven portal areas should be included before the pathologist can stage HCV-infected livers accurately. A single core of liver tissue obtained with a "biopsy gun" with a needle notch length of 1.7 cm may be expected to result in significant under-reporting of fibrosis. Scheuer recently published an excellent summary of this issue.38

Lack of specific findings. All histologic abnormalities in HCV infection—individually and collectively—are seen in other viral and nonviral liver diseases. Even interpretation of fibrosis requires caution. A previous heavy user of alcohol, abstinent for several months prior to liver biopsy, may have significant hepatic fibrosis. Without concurrent changes of steatohepatitis, the fibrosis might be erroneously ascribed to HCV when, in fact, alcohol may have been more important in the activation of stellate cells and consequent fibrosis.


The utility of liver biopsy in routine cases of HCV infection has been challenged on the basis that clinical and laboratory parameters alone provide sufficient information to make a decision for or against antiviral therapy.39 Liver biopsy is not necessary to establish the diagnosis of HCV infection. Serum-based tests are precise and unequivocal, and a positive HCV RNA test confirms infection. In the absence of other clinical or laboratory findings suggesting the possibility of a second liver pathology, a liver biopsy will not alter the diagnosis. A study at the Cleveland Clinic found that no case of HCV infection diagnosed by serum-based tests was overturned by liver biopsy findings.40 Moreover, in only 2% of cases was an additional liver diagnosis made.


Cirrhosis is found in approximately 29% of unselected cases of HCV infection that come to biopsy.40 Clinical and laboratory tests are relatively weak predictors of the extent of liver damage caused by HCV infection. The number of HCV-infected patients whose liver disease staging (either advanced fibrosis or, conversely, no fibrosis) can be confidently predicted by the AST:ALT ratio, the international normalized ratio (INR), and the platelet count is low. A published cirrhotic discriminant score (Bonacini) for the clinical diagnosis of cirrhosis correctly established or excluded a diagnosis of cirrhosis in only 23% of cases.40 In the remainder, liver biopsy was critical for proper staging. These findings have recently been confirmed by other groups.39,41 Others have also found that predicting severe cirrhosis or fibrosis on the basis of laboratory tests (eg, AST:ALT ratio, platelet counts, and measurements of hyaluronic acid, fibronectin, pseudocholinesterase levels, etc) is not sufficiently sensitive.42

Recently, new attempts to stage hepatitis C according to serum-based indices have been offered. Investigators have suggested that biochemical markers of liver fibrosis in patients with HCV infection allow for satisfactory staging of disease in many, if not most, HCV-infected patients.43 The fibrotest has been used to assess the histologic effects of antiviral therapy.35 Table 8 lists those markers that have been combined in various ways to detect fibrosis.

Table 8

Indirect assessment of cirrhosis



Markers of hypersplenism
     WBC, platelets, Hgb

AST:ALT ratio

Markers of portal hypertension
     Ascites, varices, portosystemic


Imaging features

AST:platelet ratio

Surgical view



Gamma glutamyl transpeptidase

Gamma globulin





Manganese superoxide dismutase


Procollagen III nucleoprotein

Type IV collagen




Although the calculated fibrosis score rises with increasing degrees of histologic fibrosis, the overlap in serum-based scores in different histologic METAVIR grades limits the clinical utility of this approach (Figure 3).

Others have proposed a simpler model,44 based on an AST:platelet ratio index calculated as follows:

AST:platelet ratio index = [(AST/ULN)/platelet count] X 100

where the platelet count is expressed as 109/L and ULN stands for upper limit of normal. This index, if properly validated, may be clinically useful.


The need for liver biopsy in HCV infection should be predicated on the type of information that is being sought for an individual patient. The presence or absence of cirrhosis is clinically relevant in many cases where therapy with antivirals is being considered. All other features being constant, the presence of bridging fibrosis or cirrhosis markedly reduces the expected response rate to antiviral therapy. Major shifts in expected outcomes are far from trivial and will often alter the clinical decision to treat.45 In addition to identifying a lesser chance of successful viral elimination, the goal of prevention of cirrhosis becomes moot if cirrhosis is present on pretreatment biopsy. Additional management changes often mandated by finding cirrhosis include entry into surveillance programs for hepatocellular carcinoma and for esophageal varices.

Liver biopsy remains an important tool in the baseline evaluation of the HCV-infected patient. A specimen of sufficient length (15 mm) and width (1.4 mm) that contains at least six portal areas is desired. How frequently sequential biopsies should be performed in the HCV-infected patient, if at all, has not been established. There appears to be little need for routine biopsies following a course of antiviral therapy. Authorities differ in clinical practice with respect to follow-up biopsies at various intervals to restage the liver in HCV infection. We do not recommend routine follow-up biopsies.

Viral Kinetics as a Predictor of Response to Therapy, and the Implications for Treatment Duration


  • Interferon (IFN) alfa acts by inhibiting viral production. The extent of inhibition is referred to as effectiveness. This inhibition gives rise to a rapid first-phase viral decline.
  • The Second-phase viral decline is dependent on the degree of IFN effectiveness and the rate of clearance of HCV-producing liver cells.
  • With current therapy of pegylated IFN and ribavirin, failure to clear virus at 3 months predicts nonresponse.

The treatment of chronic HCV infection with interferon (IFN) has improved rates of sustained virologic response from 10% to more than 50% during the past 10 to 15 years. This increase occurred as a result of (1) prolonging therapy from 6 months to 12 months, (2) adding ribavirin to IFN therapy, and (3) pegylating IFN such that IFN blood levels are maintained at higher levels over a week of therapy. Another possible factor was the institution of weight-based dosing.

However, IFN treatment is associated with many significant side effects that are difficult to tolerate over 12 months of therapy, and upward of 10% of patients, even those in hepatitis C treatment centers, are unable to finish the entire 12-month course. Moreover, among genotype 1-infected patients, who account for 70% of infected patients in the United States, only 40% to 50% of highly selected study patients achieve a sustained virologic response with pegylated IFN (PEG-IFN) and ribavirin.49,50

In patients with genotype 2 and 3 viral infection, sustained virologic response rates exceed 80% with 6 months of PEG-IFN alfa and ribavirin therapy.49,50 However, such favorable rates are not seen in patients who are infected with genotype 1a or 1b virus. Over the past decade, we have come to recognize that a number of viral and host factors may account for the diminished response to treatment in these patients. These factors include the size of the initial viral load, body mass index, and race.


Among patients with genotype 1 disease, those who have a high initial viral load do not respond to treatment as well as those with a lower viral load. Our understanding of viral dynamics and the effects that drugs have on them has dramatically improved since the introduction of mathematical models to study HCV, human immunodeficiency virus (HIV), and hepatitis B virus (HBV) infections. The pioneering work of Perelson, Ho, Neumann, and others has had a significant impact on our understanding of the HIV life cycle and on means by which we can improve treatment response.

Working with Perelson and Neumann, clinicians at the University of Illinois at Chicago attempted to understand the life cycle of HCV—and how IFN-based therapy interferes with that cycle—by using a mathematical model that describes viral infection. Their initial observations51,52 and research by Zeuzem et al53 demonstrated that IFN alfa caused a rapid reduction in viral serum levels (0.5 to 2.0 log) within 24 hours of the administration of a single dose (Figure 4). This reduction proved to be dose-dependent.51,52 After the initial decline, viral decay slowed (Figure 4) and became highly variable among patients, despite daily doses of IFN alfa-2b over a month of treatment.51,52 This slower phase was referred to as the second phase of viral clearance, thus establishing the biphasic model of viral kinetics (Figure 5).


The best explanation for the initial rapid decline in viral levels during the first 24 to 48 hours is that IFN inhibits either viral production, viral release, or both in a dose-dependent manner.52 To account for this rapid decline, the viral serum half-life must be short. Indeed, the calculated serum half-life of HCV averages 3 hours, which is eight-fold less than the calculated half-life of HBV. The symbol ε was adopted to represent the effectiveness of IFN in inhibiting viral production; it is expressed as a percentage. An effectiveness of 90% reflects a 1.0-log drop in viral levels within 24 hours; a 99% effectiveness represents a 2.0-log drop within 24 hours.

It is interesting that the mean effectiveness of IFN is more than 99.5% (>2.5-log decline) in patients with genotype 2 or 3 infection and 95% (1.5-log decline) in patients with genotype 1 infection—a log difference of greater than 1.0.54 The combination of this finding and the more rapid rate of second-phase viral decline seen in genotype 2- and 3-infected patients represents a mathematical explanation for the greater rate of viral clearance in genotype 2- and 3-infected patients. The mathematical conclusion that IFN lowers HCV levels in part by inhibiting viral production and/or release has been substantiated in the subgenomic HCV culture model, in which viral production and/or release is inhibited by IFN in a dose-dependent manner.


The second phase of viral decline was initially theorized to be attributable in part to the immune eradication of virus-producing hepatocytes (mathematical symbol: δ). Thus, the rate of the second-phase viral decline was dependent on δ and the extent of IFN effectiveness. Recent studies that involved frequent ALT measurements early in treatment suggest that eradication of virus-producing cells by necrosis probably does not completely explain the second-phase viral decline.55 A more likely explanation is that the second phase reflects the sterilization of virus-producing hepatocytes by immune system-related mechanisms (ie, cytokines). IFN has been shown to sterilize HBV-infected hepatocytes by inducing the T-cell cytokines that inhibit viral production.


Bergmann et al56 and Herrmann et al57 recently showed that there is a third phase of viral decline, which is seen in 30% to 60% of patients who are treated with IFN with or without ribavirin. Herrmann et al compared the viral kinetics in genotype 1-infected patients treated with PEG-IFN alfa-2b with or without 800 mg/d of ribavirin. They found that the first and second phases of viral decline, the calculation of effectiveness, and δ were similar in the two treated groups. However, they noted that a third phase of viral decline occurred in a substantial number of patients in both groups 7 to 28 days after the initiation of treatment. The rate of decline during this third phase was significantly faster in those patients who received ribavirin. The authors proposed a modified mathematical model and designated the letter M to represent enhanced infective-cell loss. As δ is a pretreatment calculation, the new model would indicate that δ could be modified during treatment. They hypothesized that the third phase reflected an upregulation of the immune system by ribavirin, which has been suggested by others.

In preliminary studies, Bergmann et al showed that 30% of patients treated with IFN experienced a third-phase viral decline.56 They noted that the third phase was initiated when serum viral levels fell to a certain "set point," which suggested that the "paralyzed" immune system was activated when serum viral levels fell to a certain level. Such a finding has been seen in HBV-infected patients, in whom it has been shown that the T-cell system becomes activated as HBV levels decline.


These early kinetic observations are clinically significant because some patients do not experience a significant decline in viral level until after 1 month of therapy with PEG-IFN and ribavirin. Whether this change in viral decline reflects an activation of the immune system or a change in IFN effectiveness needs to be assessed by careful kinetic analysis that accounts for changes in IFN blood levels over time.

Nonetheless, these observations may help explain the recent findings of Davis et al,58 who examined early viral predictors of response with data from a large international treatment trial of PEG-IFN alfa-2b and ribavirin.49 They found that 100% of patients who did not experience more than a 2.0-log decline in HCV RNA levels by 12 weeks failed to respond despite 9 additional months of therapy with PEG-IFN alfa-2b and ribavirin. Of those patients who did experience at least a 2.0-log decline at week 12, 72% went on to achieve a sustained response. The viral level and decline at 1 month was not an accurate predictor of failure to achieve a sustained response, a finding that might reflect the fact that some patients do not undergo a third-phase viral decline until after week 4. Davis et al proposed an algorithm for viral testing that involved measuring viral levels at baseline and at weeks 12 and 24 in genotype 1-infected patients. Based on the high rate of cure in genotype 2- and 3-infected patients, they suggested that viral levels need not be measured during therapy; instead, they recommended that they be measured 6 months after the completion of therapy.

In a large clinical trial of PEG-IFN alfa-2a plus ribavirin, Fried et al found that only 2 of 63 patients (3.2%) who did not experience more than a 2-log decline in viral levels at week 12 went on to achieve a sustained virologic response.50

Finally, viral kinetics may also be relevant in understanding the lower response rate to treatment seen in African Americans, as well as ways to overcome it. One emerging theory is that the change in second-phase viral decline associated with ribavirin therapy might be explained by ribavirin-induced lethal mutagenesis, by which ribavirin is believed to inhibit the infectivity of uninfected cells. Such an effect would have greater impact in patients in whom IFN is less effective. This might explain why a 0% response rate to IFN monotherapy among African American patients increases to a 25% rate of sustained virologic response when ribavirin is added. Because ribavirin takes 3 to 4 weeks to reach plasma steady state, there may be a theoretical advantage to beginning ribavirin therapy 2 or 3 weeks before IFN is started. Further research on this theory is eagerly awaited.


Treatment of Uncomplicated Chronic HCV Infection


  • Pegylated interferon (PEG-IFN) combined with ribavirin is the best currently available therapy for HCV infection.
  • Several predictors of treatment response have been identified, including HCV genotype.
  • An absence of serum HCV RNA 6 months after discontinuation of therapy predicts durable viral eradication.
  • Treatment of patients with chronic HCV infection is associated with significant side effects, although most of these are not serious or life-threatening.
  • Adjunctive use of hematopoietic growth factors shows promise for managing the anemia and neutropenia associated with anti-HCV therapy, but further studies are warranted.

It has been estimated that approximately 3% of the world's population is infected with HCV.59 This represents nearly 170 million persons worldwide.59 In the United States, the prevalence of anti-HCV is 1.8%; 74% of these patients exhibit HCV RNA positivity. This corresponds to 2.7 million chronically infected persons in the United States alone.1

The substantial morbidity, mortality, and economic burden associated with HCV infection are responsible for the striking worldwide public health impact of this condition. Currently, HCV infection is responsible for an estimated 8,000 to 10,000 deaths annually in the United States, and that number is predicted to triple in the next 10 to 20 years. HCV-related disease is the leading indication for liver transplantation in the United States. The decision to treat patients with chronic HCV infection should be made after many factors have been considered and each case has been individualized (see "The Team Approach to Hepatitis C Management").


Pegylated interferons (PEG-IFNs)—which are produced by the conjugation of IFN and a polyethylene glycol molecule—represent a recent therapeutic advance in the treatment of HCV infection. This modified formulation of IFN has resulted in improved therapeutic effectiveness over unmodified IFN, likely because its sustained action is the result of a long half-life. Trials of PEG-IFN in combination with ribavirin have established its safety and efficacy.

Combination therapy with nonpegylated IFN alfa and ribavirin—until recently considered to be the treatment of choice for chronic hepatitis C—is less convenient and probably less effective. Fewer than 40% of patients achieve a durable benefit, ie, a sustained virologic response, defined as the absence of serum HCV RNA 6 months after the end of treatment, as measured by a sensitive assay with a lower limit of detection of at least 50 IU/mL.

Progress has been slower in the development of non-IFN-based therapies for HCV infection, including protease inhibitors, helicase inhibitors, ribozymes, antisense therapies, cytokine-based therapies, and T-cell-based therapeutic vaccines. Overall, advances in the development of therapies for HCV infection have been hindered by the lack of dependable cell culture systems and an adequate animal model. Furthermore, variations in the response to IFN treatment by different viral genotypes and differences in the type or vigor of immune responses may represent other obstacles to the development of a uniformly effective therapy or vaccine.


The typical HCV-infected patient for whom therapy is well established is an adult who has chronic infection (ie, evidence of infection for at least 6 months). The typical patient has elevated serum transaminase levels, detectable serum HCV RNA, and histologic evidence of liver injury in the absence of decompensated cirrhosis. In addition, other liver diseases or confounding comorbid conditions have been excluded. For the typical HCV-infected patient, IFN-based therapeutic regimens have been found to be safe and often effective.


In the 1980s, even before HCV was identified, therapy with IFN alfa was shown to be associated with normalization of transaminase levels in patients with non-A non-B hepatitis.60 In 1989, the results of two controlled clinical trials that evaluated the efficacy of IFN treatment in chronic HCV infection were published.61,62 In both trials, patients received 1 to 3 million IU of IFN alfa-2b three times weekly for 6 months. Complete biochemical remission was achieved in half of these patients. However, in almost 50% of the responders, serum transaminase levels returned to pretreatment levels 6 to 12 months after IFN therapy was discontinued.

In 1997, Carithers and Emerson published a meta-analysis of randomized trials in which IFN alfa-2b—in regimens of at least 2 million IU three times weekly for a minimum of 24 weeks—was given to IFN-naive patients.63 They concluded that IFN alfa is effective in treating chronic HCV infection. A biochemical sustained response—that is, normalization of ALT levels by 6 months following discontinuation of therapy—was achieved in 23% of the treated group, compared with only 2% of the untreated group (p < 0.001).


Ribavirin is an oral nucleoside analog with activity against a broad spectrum of DNA and RNA viruses. When used alone, it has little or no activity against HCV. Both direct antiviral and immune modulatory effects have been proposed as mechanisms of action.64 Placebo-controlled studies of ribavirin monotherapy in patients with chronic HCV infection found that although 20% to 40% of patients had a biochemical response at the end of therapy, none had a virologic response.65

In the mid-1990s, small pilot studies suggested that treatment with IFN and ribavirin for 6 months was more effective than treatment with IFN alone. A meta-analysis of individual patient data from four European centers found that the efficacy of IFN and ribavirin combination therapy was two- to three-fold greater than the efficacy of IFN alone.66 Also, two randomized controlled trials published in 1998 showed that the combination of IFN alfa-2b and ribavirin produced better rates of sustained virologic and biochemical response in patients with HCV infection who were given it as initial treatment (IFN-naive patients) and in those who had experienced a virologic relapse after a previous course of IFN monotherapy.67,68 Sustained virologic response rates ranged from 31% to 38% when combination therapy was given as the initial treatment, and the sustained virologic response rate was 49% when it was given for relapse. These rates are three to five times as high as those achieved with monotherapy.


PEG-IFNs were recently approved in the United States and Europe for the treatment of chronic HCV infection. The rationale for developing anti-HCV agents that have a longer half-life (which PEG-IFN does) is based on the dynamics of the viral response to IFN. A substantial decrease in viral load occurs during the first 24 hours following a single injection of IFN alfa-2b. However, viral counts begin to rebound at 48 hours, suggesting that longer-acting medications may be more appropriate for these patients.52 Because pegylation prolongs the half-life of IFN, only one dose per week is required to maintain effective levels in the blood (vs. three doses per week with standard IFN).52

The results of three large trials of PEG-IFN alfa-2a and alfa-2b therapy in patients with chronic HCV infection established its superiority over conventional IFN alfa.45,69,70. Overall, sustained viral eradication was achieved in 25% to 39% of patients who were treated with PEG-IFN (alfa-2a or alfa-2b) monotherapy, compared with only 7% to 19% of those who received standard IFN. In all trials, the incidence of adverse effects among patients who received PEG-IFN was similar to that among patients who received standard IFN.

In one of these trials, Zeuzem et al randomly assigned 531 HCV RNA-positive patients with chronic HCV infection without cirrhosis to receive either PEG-IFN alfa-2a (180 µg weekly for 48 weeks) or IFN alfa-2a (6 million IU three times weekly for 12 weeks, followed by 3 million IU three times weekly for 36 weeks).69 PEG-IFN alfa-2a was associated with a significantly greater virologic response than standard IFN. Sustained virologic and biochemical responses were achieved in 38% of the patients treated with PEG-IFN (compared with only 17% of those treated with standard IFN), which was similar to the results seen in patients who were given the combination of standard IFN and ribavirin.

In the second trial, Heathcote et al randomly assigned patients with chronic HCV infection who had cirrhosis to receive either 90 or 180 µg of PEG-IFN alfa-2a weekly or standard IFN alfa-2a (3 million IU three times weekly) for 48 weeks.45 They found that a sustained virologic response was achieved by 30% of the patients who received PEG-IFN at 180 µg weekly.

The third trial of PEG-IFN included 1,219 patients with chronic HCV infection who were assigned to receive standard IFN alfa-2b (3 million IU three times weekly) or PEG-IFN alfa-2b given in one of three doses (0.5, 1.0, or 1.5 µg/kg body weight once weekly).70 Sustained virologic response was substantially greater with PEG-IFN alfa-2b at the doses of 1.0 or 1.5 µg/kg compared with standard IFN alfa-2b (23% to 25% vs.