Faculty/Chairperson: Mark S. Sulkowski, MD; Educational Reviewer: Chris S. Jackson, Jr, MD

Release Date: August 30, 2002

Hepatitis C virus (HCV) is a spherical, enveloped, RNA virus of the Flaviviridae family. Its genome is a positive, single-stranded RNA molecule that replicates at a rate of 10 trillion new virions per day. A highly heterogeneous virus, HCV has approximately 70% homology between all isolates. As HCV replicates, RNA-dependent polymerases often introduce random nucleotide errors, which over time, result in slow genetic evolution of the virus (Neumann, 1998). Six major genotypes and over 90 subtypes characterize this resultant HCV genetic diversity. The most treatment resistant genotype, HCV genotype 1, accounts for an estimated 75% of HCV infections in the United States (CDC, 1998). Furthermore, within individual patients, hepatitis C exists as a swarm of closely related variants known as quasispecies; preliminary data suggest that the complexity of the quasispecies may contribute to viral resistance to interferon-based therapies (Farci et al, 2001) (Figure 1).

Figure 1. Hepatitis C Virus.

Hepatitis C infects approximately 5% to 10% of the global population, or approximately 170 million persons worldwide. In the United States alone, roughly 4 million individuals are infected with HCV, with an average acquisition rate of 28,000 people per year.

Individuals who contract hepatitis C have an 85% chance of developing persistent or chronic HCV infection, which is associated with an increased risk of progressive liver disease leading to cirrhosis and, in some cases, hepatocellular carcinoma (HCC), end-stage liver disease (ESLD), or death. Currently, HCV-related liver disease is the leading indication for liver transplantation in the United States. The Centers for Disease Control and Prevention (CDC) estimates that there are 2.7 million chronically-infected HCV persons in the United States, accounting for more than 8000 to 10,000 deaths per year (CDC, 1998).

Hepatitis C shares the transmission and behavioral risk factors associated with human immunodeficiency virus (HIV) and hepatitis B virus (HBV). However, unlike HIV or HBV, sexual transmission of HCV is relatively inefficient, and while clearly possible, sexual transmission of HCV is uncommon. While transfusion of blood products was once an important route of transmission in the United States, the incidence of transmission has decreased dramatically with the implementation of antibody screening and, more recently, nucleic acid testing. Currently, injection drug use accounts for at least two thirds of new cases of HCV in the United States. While the incidence of HCV infection has decreased to less than 30,000 cases per year, the CDC estimates that nearly 2% of the US population is infected with HCV, with the highest prevalence rates observed among African American males (9%) and individuals between 30 and 49 years of age (Alter et al, 1999).

Based on the current understanding of HCV transmission, the CDC recommends routine HCV antibody screening among persons with acknowledged high-risk behaviors and for those who have experienced HCV exposure.

HCV Screening Recommendations

• Persons who have ever injected recreational drugs, including those who experimented many years ago and who do not consider themselves drug users
• Persons with certain medical conditions, including those who
  • Received clotting factor concentrates produced prior to 1987
  • Ever underwent chronic hemodialysis
  • Have persistently abnormal ALTs
• Persons who received an organ transplant before July 1992
• Persons who were notified that they received blood from a donor who subsequently tested positive for HCV infection
• Persons who received a blood transfusion or blood component before July 1992
• Healthcare, emergency medical, and public safety workers after needle stick, sharp, or mucosal blood exposure to HCV-positive blood
• Infants over 12 months of age born to HCV-positive mothers.

Additionally, patients who test positive for HIV are included in this high-risk group. Related primarily to the mutuality of the IV drug use risk factor, the prevalence rate of HCV in the HIV-infected population is approximately 40% (MMWR, 1998).

Diagnostic assays for detection and assessment of infection with and exposure to HCV have become increasingly sensitive and specific with successive versions. Assays may be classified as either serologic tests, which detect antibodies formed against HCV-specific antigens, or virologic tests, which detect HCV RNA when active viral infection is present. Additional tests, such as liver biopsy, may be indicated to stage the progression of liver disease due to HCV infection.

Serologic tests, such as the second or third version anti-HCV enzyme immunoassay (EIA), are inexpensive, easy to perform, reliable, and specific when used on high-risk populations. Following acute infection with HCV, antibody response (ie, seroconversion) to HCV can be detected at approximately 10 weeks following exposure. It is important to note that a positive serologic assay indicates exposure and immune response to the HCV virus, but does not indicate whether the virus is active or resolved (MMWR, 1998). Accordingly, confirmatory testing is recommended for all persons with a reactive HCV EIA. In low-risk populations, such as blood donors, the positive predictive value of the EIA is limited and confirmation with an additional antibody test, the recombinant immunoblot assay (RIBA), may be recommended to determine a true positive test in this group. Conversely, in high-risk populations, such as injection drug users, the positive predictive value of the EIA is excellent, and confirmation with specific virus testing is recommended.

Virologic tests, such as the polymerase chain reaction (PCR) and the branched-chain DNA (bDNA) assays, can be either qualitative (detecting the presence or absence of HCV RNA) or quantitative (determining the number of HCV RNA copies per milliliter of serum). Hepatitis C RNA may be detected as early as 1 to 2 weeks following HCV exposure, and typically is detectable in those with chronic HCV infection. Since PCR assays are not well standardized in their specificity and sensitivity, it is important to use the same testing methodology when monitoring the course of HCV treatment (MMWR, 1998).

Following confirmation of active infection (ie, the detection of plasma HCV RNA), many hepatologists recommend liver biopsy to assess the degree of histologic disease progression. Histologic disease due to HCV can be classified in terms of grading (to assess the degree of necroinflammatory activity) and staging (to determine the amount and location of liver fibrosis). While there are many widely used classification systems, the Ishak-modified Knodell histological activity index (HAI) is commonly used in research and clinical practice. This system describes necroinflammatory activity using a grading scale of 0 to 18, where grade zero represents the absence of necroinflammation and grade 18 represents established portal inflammation, and using a staging scale of 0 to 6, where stage 0 represents the absence of hepatic fibrosis and stage 6 represents established cirrhosis.

Batts K, Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg Path. 1995;19:1409-1417.

Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Morb Mortal Wkly Rep. 1998;47:1-39.

Farci P. Hepatitis C virus: the importance of viral heterogeneity. Clin Liver Dis. 2001;5:895-916.

Ishak K, Baptista A, Biancho L, et al. Histologic grading and staging of chronic hepatitis. J Hepatol. 1995;22:696-699.

Neumann A. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon alfa therapy. Science. 1998;282:103-107.

National Institutes of Health Consensus Development Conference Panel Statement. Management of hepatitis C. Hepatology. 1997;26(suppl 1):2S-10S.

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Figure 2. Natural History of HCV Infection.

Persistent viremia affects approximately 85% of those infected with HCV; some of these chronically infected persons will develop progressive liver disease (Figure 2). Some studies predict that progression to fibrosis and cirrhosis will occur in roughly 20% of patients, and further, progression to HCC will occur in 25% of fibrotic/cirrhotic patients. However, other individuals infected with HCV may have a cirrhotic-free course of illness without clinical consequence in their lifetime (Seeff, 2000).

In general, following acute infection, only 20% to 25% of individuals experience classic symptoms of hepatitis, and approximately 15% of infected individuals will clear hepatitis C viremia spontaneously (Alter et al, 1999; NIH Consensus Statement, 1997). Frequently among those with chronic hepatitis C, neither patients nor their healthcare providers recognize symptoms until the disease has progressed to decompensated cirrhosis. In a study of 2235 chronically-infected HCV patients with biopsy-detected hepatic fibrosis, Poynard and colleagues reported that rapid progression of hepatic fibrosis was associated independently with older age at time of infection (>40 years), male gender, longer duration of infection, and consumption of greater than 50 grams of alcohol daily (Poynard et al, 1997).

In a meta-analysis, Graham and coworkers found that HIV coinfection was associated with a 2-fold increased risk of cirrhosis and a 2-fold increased risk of ESLD compared to those without HIV infection (Graham, 2001). Conversely, virologic parameters, such as plasma HCV RNA level and HCV genotype, have not been associated with HCV disease progression. Based on these data, persons infected with HCV should be advised to abstain from alcohol. However, Wong and colleagues estimate that less than 5% of Americans with HCV infection are aware of their HCV status, and the majority have not been tested or diagnosed with chronic HCV infection (Wong et al, 2000). Accordingly, heightened HCV public health initiatives are needed to encourage the diagnosis and management of HCV.

Nearly 4 million Americans are chronically infected with HCV, representing a substantial public health burden. First, persons with chronic viremia provide a reservoir for ongoing HCV transmission, particularly among those who use injection drugs. Second, estimates suggest that the impact of HCV-related liver disease will increase dramatically over the next 10 to 15 years, with approximately 20,000 to 30,000 deaths due to HCV annually. Finally, the economic impact of HCV will increase significantly due to the cost of medical care for those with advanced liver disease and lost productivity of those with chronic illness. In fact, conservative estimates place the cost of HCV-related healthcare at nearly $600 million currently, and estimates indicate that without effective treatment, these costs will triple over the next 15 to 20 years. Wong and coworkers (2000) calculated that the indirect costs related to disability and mortality are projected at 3.09 million years of life lost. Societal costs of premature mortality of persons younger than 65 are predicted to be $54.2 billion, with disability costs from decompensated cirrhosis and HCC projected at $21.3 billion. It is likely that these figures underestimate morbidity and mortality costs, as they do not consider accelerated HCV progression in older patients, those with coinfection with HBV or HIV, or those individuals exhibiting excessive alcohol consumption. Figure 3 outlines the future long-term morbidity, mortality, and cost estimates that might be expected from cases of hepatitis C that existed before 1991 alone (Wong et al, 2000).

Figure 3. HCV-Related Projections for the Years 2010 to 2019.

Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States: 1988 through 1994. N Engl J Med. 1999;341:556-562.

Alter MJ. Epidemiology of hepatitis C in the West. Semin Liver Dis. 1995;15:5-14.

Management of Hepatitis C. NIH Consensus Statement. 1997;March 24-26:15(3).

Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus. Clin Infect Dis. 2001;33:562-569.

Hoofnagle J. Hepatitis C: the clinical spectrum of disease. Hepatology. 1997;26:15SW-20S.

Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825-832.

Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med. 2000;132:105-111.

Wong J, McQuillan G, McHutchison J, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. American J Public Health. 2000;90:1562-1569.

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When weighed against the economic and societal burden of potential future complications, treating the chronically-infected HCV patient prior to the onset of symptomatic disease favors a positive cost-benefit ratio and a notably reduced risk of cirrhosis, HCC, and ESLD.

Treatment options for patients with chronic HCV have evolved from interferon (IFN) monotherapy to combination therapy with IFN and ribavirin (RBV) to combination therapy with pegylated interferon (PEG IFN) and RBV. When 24 to 48 weeks of combination therapy with IFN and ribavirin was adopted as the standard of care for HCV treatment, sustained virologic response (SVR) rates rose from approximately 20% in monotherapy to approximately 40% in combination therapy. Along with improvements in SVR, patients experienced half the rate of relapse following combination therapy compared with that observed with monotherapy (McHutchison et al, 1998; Poynard et al, 1998).

Interferon alfa-2a and IFN alfa-2b comprise the primary IFNs available for treatment in the HCV-infected patient. Naturally occurring small protein molecules, endogenous alfa IFNs are produced and secreted by T cells and fibroblasts in response to viral-induced leukocytes. Specific cell surface membrane receptors bind IFN (endogenous and exogenous) proteins; the binding of IFN to the receptor produces a complex sequence of intracellular events, including the induction of enzymes (Figure 4).

Figure 4. Proposed Antiviral Effects of Interferon.

The events that follow include:

• Direct inhibition of HCV replication in virus-infected hepatocytes via
  • Prevention of viral binding of HCV to the hepatocyte wall
  • Inhibition of HCV cell entry
  • Prevention of rapid uncoating of the nucleocapsid within the cytoplasm
• Suppression of viral cell proliferation
• Enhancement of the macrophage phagocytic activity
• Augmentation of the cytotoxic activities of T lymphocytes

(Drug Facts and Comparisons, 2001; Davis et al, 1999).

 

 

Ribavirin is an orally available guanosine nucleoside analogue with limited antiviral activity against a broad array of RNA and DNA viruses, prompting its investigation in persons with chronic HCV infection. Unfortunately, RBV monotherapy has no impact on HCV RNA, and while significant decreases in serum alanine aminotransferase (ALT) levels have been observed, these were not sustained once therapy was discontinued (Di Bisceglie et al, 1995). Nonetheless, RBV was studied in combination with IFN alfa-2b in persons with chronic HCV infection. In separate studies, McHutchison and colleagues and Poynard and coworkers randomized patients to receive IFN alfa-2b plus RBV or placebo for 24 or 48 weeks. The combination of IFN alfa-2b plus RBV resulted in SVR rates of 41% in persons infected with HCV genotype 1 and 67% in those infected with HCV genotypes 2 or 3, nearly 2-times greater than the SVR rate observed in those receiving IFN alfa-2b plus placebo (McHutchison et al, 1998; Poynard et al 1998). Combination therapy with IFN alfa-2b and RBV 1000 mg (body weight 75 kg) or 1200 mg (body weight>75 kg) daily in 2 divided doses was approved by the FDA in 1998, replacing IFN alfa monotherapy as the standard of care for the treatment of persons chronically-infected with HCV.

 

 

Interferon alfa is rapidly absorbed, has a high volume of distribution, and is rapidly cleared by the kidneys. Although initial clinical trials employed a standard regimen of IFN alfa 3 MIU thrice weekly, viral kinetic studies conducted by Neumann and colleagues demonstrated the greatest anti-HCV effect when IFN alfa was administered at 10 MIU daily, suggesting that IFN alfa was being delivered at doses that were too low and given too infrequently (Neumann et al, 1998). To address the inadequacies of standard IFN, researchers examined the effect of adding polyethylene glycol (PEG) to the IFN alfa molecule. The addition of the nontoxic water-soluble polymer (composed of repeating methyl groups) to IFN increases the half-life of the molecule, providing continuous exposure over a 1-week period. In addition, PEG IFNs have enhanced pharmacokinetic and dynamic properties, including improved absorption and volume of distribution and decreased renal clearance. More importantly, in clinical trials, patients with chronic hepatitis C who received PEG IFN alfa-2a or alfa-2b achieved SVR rates that were nearly 2-fold greater than those observed among patients receiving standard IFN alfa-2a or alfa-2b (Lindsay, 2001; Zeuzem, 2001; Heathcote, 2001).

 

 

Recently, randomized controlled trials have demonstrated that the addition of RBV to PEG IFN therapy is more effective than either PEG IFN monotherapy or standard IFN/RBV combination therapy, leading to the FDA approval of PEG IFN (12 kDa) alfa-2b/RBV combination therapy. In addition, PEG IFN (40 kDa) alfa-2a/RBV combination therapy currently is under FDA review for approval.

 

 

Manns et al, 2001

In a randomized open-label international trial, Manns and colleagues (2001) studied 1530 patients with chronic HCV infection, randomly assigning them into one of three 48-week treatment groups:

• Standard IFN alfa-2b 3 MIU subcutaneously once a week plus RBV 1000 or 1200 mg/day (n = 505)
• PEG (12 kDa) IFN alfa-2b 1.5 µg/kg once a week (higher dose PEG IFN) plus RBV 800 mg/day (n = 511) or
• PEG (12 kDa) IFN alfa-2b 1.5 µg/kg once a week plus RBV 1000 or 1200 mg/day for 4 weeks, then 0.5 µg/kg once a week (lower dose PEG IFN) plus RBV 1000 or 1200 mg/day (n = 514).

Patients who received higher dose PEG IFN had a significantly higher SVR rate (54%) than the other 2 treatment groups, which were each 47% (P = .01).

Genotype 1 patients demonstrated an SVR rate of 42% when treated with higher dose PEG IFN, vs SVR rates of 34% and 33% in the lower dose PEG IFN and standard IFN groups, respectively. Genotype 2 and 3 patients achieved SVR rates of approximately 80% in all 3 treatment groups (Figure 5).

Figure 5. Sustained Virologic Response by HCV Genotype.

In addition, Manns and coworkers found that SVR was higher among patients who received more RBV per day, expressed as the number of milligrams per kilogram of body weight per day. In a subset analysis, they found that the SVR was higher among patients who received more than 10.6 mg/kg of RBV daily (~800 mg for a 70 kg person) (Figure 6).

Figure 6. Sustained Virologic Response by Treatment Regimen and Ribavirin Dose.

The authors concluded that PEG (12 kDa) IFN alfa-2b 1.5 µg/kg per week and ribavirin given at doses >10.6 mg/kg per day for 48 weeks was more effective than standard IFN and ribavirin.

 

 

Fried et al, 2001

Similarly, Fried and coworkers conducted a multicenter, partially blinded, randomized clinical trial for the treatment of chronic hepatitis C among persons who had not been treated previously.

Patients were randomized into one of three 48-week treatment groups

• PEG (40 kDa) IFN alfa-2a 180 µg subcutaneously once a week plus RBV 1000-1200 mg/day (n = 453)
• PEG (40 kDa) IFN alfa-2a 180 µg subcutaneously once a week plus placebo (n = 224)
• IFN alfa-2b 3 MIU TIW plus RBV 1000-1200 mg/day (n = 444)

The SVR rate was 56% in the PEG IFN alfa-2a plus RBV group, significantly higher than the 45% SVR observed in the IFN alfa-2b/RBV combination group and the 30% SVR observed in the PEG IFN alfa-2a monotherapy group (P = .001) (Figure 7).

Figure 7. Sustained Virologic Response by Treatment Regimen.

Among patients infected with HCV genotype 1, the SVR rate was 46% in the PEG (40 kDa) IFN alfa-2a plus RBV group, which was significantly higher than the SVR observed in the standard IFN/RBV group (37%) and in the PEG (40 kDa) IFN alfa-2a/placebo group (21%). Similarly, among patients infected with HCV genotypes 2 and 3, SVR rates were highest in the PEG (40 kDa) IFN alfa-2a/RBV groups (Figure 8).

Similar to the study by Manns and colleagues, Fried and coworkers concluded that PEG (40 kDa) IFN alfa-2a plus RBV was more effective than standard IFN/RBV for patients with HCV genotype 1. However, these studies left important questions unanswered regarding the appropriate duration of therapy in persons infected with HCV genotypes 2 or 3 and the most effective daily dose of RBV.

Figure 8. Sustained Virologic Response Rates by Treatment Regimen and HCV Genotype.

To address these outstanding clinical issues, Hadziyannis and colleagues conducted a multicenter, double-blind, randomized, controlled clinical trial among persons chronically infected with hepatitis C who had not previously been treated.

Study participants (N = 1284) were randomized to one of four treatment groups, which compared 2 dosing schemes of RBV (800 mg/day versus 1000-1200 mg/day) and 2 treatment durations (24 weeks vs 48 weeks). Randomization was stratified by HCV genotype, HCV RNA level (viral load), and geographic region.

• PEG (40 kDa) IFN alfa-2a 180 µg subcutaneously once a week plus RBV 800 mg/day for 24 weeks
• PEG (40 kDa) IFN alfa-2a 180 µg subcutaneously once a week plus RBV 1000-1200 mg/day for 24 weeks
• PEG (40 kDa) IFN alfa-2a 180 µg subcutaneously once a week plus RBV 800 mg/day for 48 weeks
• PEG (40 kDa) IFN alfa-2a 180 µg subcutaneously once a week plus RBV 1000-1200 mg/day for 48 weeks

Hadziyannis and colleagues reported that among persons infected with HCV genotype 1, the SVR rate was greatest among those treated with PEG (40 kDa) IFN alfa-2a/high dose RBV (1000-1200 mg) for 48 weeks, whereas among those with HCV genotype 2 or 3, shorter duration of therapy (24 weeks) and low dose RBV (800 mg/day) revealed comparable SVR rates to standard IFN/RBV therapy (Figure 9).

Figure 9. Sustained Viral Response Rates by HCV Genotype, Ribavirin Dose and Treatment Duration.

However, longer duration of HCV therapy was associated with more adverse events, leading to higher rates of withdrawal from therapy (Figure 10).

Figure 10. Rate of Withdrawal From Therapy by Ribavirin Dose and Treatment Duration.

In addition, the rate of RBV discontinuation for clinical adverse events and/or laboratory abnormalities was significantly higher among those treated for 48 weeks compared with 24 weeks (Figure 11).

Figure 11. Rate of RBV Discontinuation by Ribavirin Dose and Treatment Duration.

Based on these data, it is recommended that persons infected with HCV genotype 1 be treated with PEG IFN plus higher dose RBV (1000-1200 mg/day) for 48 weeks, whereas those with HCV genotype 2 or 3 should be treated for 24 weeks. However, the higher rates of adverse effects and dose reduction and/or discontinuation of RBV observed among those treated for 48 weeks and among those receiving higher dose RBV clearly indicate the need for the development of strategies to reduce side effects, improve quality of life, and prevent the need for RBV dose reduction among patients treated with PEG IFN alfa/RBV.

 

 

Bacon BR, Rauscher JS, Smith-Wilkaitis NL, Koehler KM. IFN-RBV combination sustained response in previous IFN monotherapy nonresponders. Hepatology. 1999; 30:372A.

Bodenheimer HC Jr, Lindsay KL, Davis GL, et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology. 1997;26:473-477.

Davis GL, Esteban-Mur R, Rustgi V, et al. IFN alfa-2b alone or in combination with RBV for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1493-1499.

Davis GL. Combination therapy with interferon alfa and ribavirin as retreatment of interferon relapse in chronic hepatitis C. Semin Liver Dis. 1999;19(suppl 1):51.

Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123:897-903.

Drug Facts and Comparisons: 55th Edition. St. Louis: Facts and Comparisons; 2001:1622-1631.

Fried M, Shiffman ML, Reddy R, et al. Pegylated (40 kDa) interferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III randomized, actively controlled, multicenter study. Digestive Disease Week. Atlanta, Georgia. May 20-23, 2001(oral presentation, Presidential Plenary Session).

Hadziyannis SJ, Cheinquer H, Morgan T, et al. Peginterferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III, randomized, doubleblind, multicentre study examining the effect of duration of treatment and ribavirin dose. European Association for the Study of the Liver (EASL). Madrid, Spain. April 18-21, 2002 (Oral presentation, Abstract 356).

Heathcote EJ, Balart LA, Shiffman ML, et al. Pegylated interferon alfa-2a is superior to interferon alfa-2a in improving posttreatment histologic outcome in chronic hepatitis C. J Hepatol. 2000;32(suppl, pt 2) (Abstract 246).

Manns M, McHutchison J, Gordon S, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001;358:958-965.

McHutchison JG, Gordon SC, Schiff ER, et al. IFN alfa-2b alone or in combination with RBV as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-1492.

McHutchison JG, Poynard T. Combination therapy with interferon plus ribavirin for the initial treatment of chronic hepatitis C. Semin Liver Dis. 1999;19 (suppl 1):57-65.

Poynard T, Marcellin P, Lee SS, et al. Randomised trial of IFN alpha 2b plus RBV for 48 weeks or for 24 weeks versus IFN alpha 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet. 1998;352:1426-1432.

 

 

Beyond the data from Hadziyannis and colleagues (2002), additional clinical and pharmacokinetic studies provide further evidence of the importance of achieving and maintaining adequate RBV therapy during HCV treatment.

 

 

In a study of the pharmacokinetic and pharmacodynamics of RBV among patients with chronic HCV receiving standard IFN/RBV, Jen and coworkers (2000) examined the relationship between RBV serum concentrations and anemia among 1105 patients over the first 24 weeks of therapy. They reported that the RBV concentration increased with body weight but decreased when the patient exceeded 40 years of age. More importantly, higher serum RBV concentrations at treatment week 4 were associated with a higher rate of viral response at treatment week 24. Jen and coworkers also found that higher RBV concentrations at week 4 were associated with a greater reduction of hemoglobin (Hb) concentration and a lower Hb nadir concentration, suggesting changes in Hb concentration may correlate roughly with serum RBV concentrations. In a multivariate logistic regression model, Jen and colleagues reported that week 24 viral response was associated with non-1 HCV genotype, lower pretreatment HCV RNA level, patient age, and higher RBV concentrations at week 4 of therapy (Figure 12).

Figure 12. Ribavirin Concentration and Virologic Response.

 

 

To evaluate the effects of RBV dose reduction on SVR rates among patients with chronic hepatitis C receiving standard IFN/RBV, McHutchison and coworkers conducted a retrospective analysis of data from two large clinical trials (N = 316) (McHutchison et al, 1998; Poynard et al, 1998). The investigators analyzed the percentage of total doses of IFN and RBV received and the duration of treatment in these patients. Genotype 1 patients received 48 weeks of combination therapy while patients with genotypes 2 and 3 received 24 weeks of combination therapy. Retrospective analysis of data revealed 63% of the 316 patients received their dosage for the expected duration. Of patients who received greater than or equal to 80% of the prescribed medication greater than or equal to 80% of the time, SVR rates were as follows:

• All patients: 48%
• Genotype 1: 37%
• Genotype 2 and 3: 100%.

These data represent an improvement over the results obtained in the original intent to treat (ITT) analyses:

• All patients: 41%
• Genotype 1: 29%
• Genotype 2 and 3: 76%.

Accordingly, adherence to both IFN and RBV is important in patients receiving combination therapy; hepatitis C care providers should aim to facilitate adherence, avoid dose reduction of IFN and RBV, and support patients through the entire treatment course.

 

 

For many patients, the ability to achieve greater than or equal to 80% of the intended RBV dose, greater than or equal to 80% of the intended IFN dose, for greater than or equal to 80% of the intended duration is limited substantially by adverse effects related to both IFN and RBV. The majority of patients experience some side effects during therapy, with the intensity varying greatly among individual patients. Typical side effects experienced by patients receiving combination therapy are outlined below.

Side Effect Profile of (PEG) Interferon

• Flu-like symptoms (38% - 68% incidence in patients)
  • Headache
  • Fatigue or asthenia
  • Myalgia, arthralgia
  • Fever, chills
• Nausea (25% - 46%)
• Diarrhea (17% - 26%)
• Alopecia (32% - 36%)
• Psychiatric symptoms (17% - 34%)
  • Depression
  • Mood lability
• Injection-site reaction (7% - 75%)
• Thyroiditis (5.5% - 10.9%)
• Lab alterations:
  • Leukopenia (8% - 18%)
  • Anemia (9% - 13%)
  • Thrombocytopenia (1% - 3%)

(Manns et al, 2001; Poynard et al, 1998; McHutchison et al, 1998; Davis et al, 1998).

While the management of side effects during IFN/RBV therapy requires a comprehensive approach, the remainder of this program will focus on the multifactorial mechanisms of anemia observed among patients with chronic HCV receiving combination (PEG) IFN/RBV therapy.

Side Effect Profile of Ribavirin

• Hemolytic anemia
• Teratogenicity (rare)
• Cough and dyspnea (approximately 25%)
• Rash and pruritus (approximately 29%)
• Insomnia (approximately 40%)
• Anorexia (approximately 40%)

(Poynard et al, 1998; McHutchison et al, 1998; Davis et al, 1998).

 

 

The most notable adverse effect of RBV therapy is the development of a dose-dependent, extravascular hemolytic anemia, which is reversible with the discontinuation of the drug. The majority of patients receiving IFN/RBV experience a decrease in their Hb levels, which may be associated with fatigue, reduced exercise tolerance, and decreased quality of life.

Sulkowski and colleagues (2000) performed a retrospective analysis of pooled data from two combination therapy IFN/RBV clinical trials involving 655 treatment-naive and experienced patients receiving RBV with daily or thrice weekly IFN therapy as described below:

• Study 1: IFN alfa-naive patients were randomized to receive RBV 1000-1200 mg/day based on body weight with IFN alfa 3 MIU daily or thrice weekly for 48 weeks
• Study 2: IFN alfa-experienced patients were randomized to receive RBV 1000 mg/day with IFN alfa 3 MIU daily or thrice weekly for 4 weeks followed by thrice weekly dosing for 48 weeks.

Hemoglobin levels were determined at treatment weeks 0, 1, 2, and 4, and then monthly to week 48, and post-treatment weeks 4, 8, 12, 24, and 48. Ribavirin was reduced to 600 mg for a Hb less than 10 g/dL.

Study results demonstrated 10.3% of all patients had a Hb level of less than 10 g/dL. The incidence of Hb less than 10 g/dL was approximately 5-fold higher in women (20%, 95% CI: 13.7-27.5) than in men (4.8%, 95% CI: 2.9-7.5%); consequently, women required dose reduction of RBV more frequently than men.

Furthermore, the majority (56%) of patients experienced a significant reduction in Hb levels, defined as a decrease of greater than 3 g/dL from baseline levels, and more than 1/3 of patients experienced a greater than 25% reduction in Hb levels. Compared to women, men were significantly more likely to experience a decrease in Hb of greater than 3 g/dL during combination therapy (60% of men, 44% of women, RR 1.4, 95% CI: 1.2-1.6). Sulkowski and colleagues also observed that approximately 10% of men and 5% of women lost more than 5 g/dL of Hb during IFN/RBV therapy (Figure 13).

Figure 13. Magnitude of Hb Decline by Gender.

Sulkowski and colleagues evaluated the recovery of Hb following RBV dose reduction. One hundred and two patients required RBV dose reduction to 600 mg/day due to anemia, with a mean Hb level of 10.7 g/dL. The mean increase in Hb level at 4 to 8 weeks following dose reduction was 1.1 g/dL.

In a multivariate logistic regression analysis, the loss of greater than 27% of the baseline Hb level was associated independently with decreased creatinine clearance, higher baseline Hb levels, and increased age.

Thus, while only 10.3% of patients experienced a decline in Hb levels to less than 10 g/dL, the majority of men and women on IFN/RBV therapy experienced substantial reductions in their Hb levels of more than 25% from their pretreatment Hb levels. Researchers hypothesize that substantial relative declines in Hb may contribute significantly to the adverse effects on energy level and quality of life experienced by many patients receiving IFN/RBV therapy.

 

 

According to the manufacturer's labeling for IFN alfa-2b/RBV, dose reduction or discontinuation of RBV is recommended for patients experiencing significant anemia during therapy.

RBV dose adjustment guidelines for a hemoglobin level <10 g/dL

• Hemoglobin >10 g/dL -- make no therapeutic changes
• Hemoglobin 8.5-10 g/dL -- begin decreasing RBV to control anemia and
• Hemoglobin <8.5 g/dL -- stop RBV.

Myocardial ischemia associated with coronary artery disease (CAD) places persons with CAD at increased risk of harm related to IFN/RBV-induced anemia. For this reason, patients with a cardiac comorbidity should be referred to a cardiologist for a cardiac evaluation to determine the risk/benefit ratio for undergoing an anemia-provoking therapy for HCV.

Patients with CAD

• Refer patients to cardiologist for CAD treatment
• Evaluate hemoglobin frequently during initial months of therapy

(Rebetron (TM) [package insert]. Kenilworth, NJ: Schering Corp;1998).

 

 

To understand the mechanisms of RBV-associated anemia, De Franceschi and colleagues studied patients undergoing therapy with RBV or IFN/RBV. Previous studies on the steady-state pharmacokinetics of RBV demonstrated that RBV concentrations in red blood cells (RBCs) greatly exceed those observed in plasma. RBV is transported permeant for the nucleoside transporter in human RBCs. Once inside the RBCs, RBV is converted to the corresponding RBV-triphosphate by adenosine kinase, producing a relative deficiency of adenosine triphosphate (ATP). Because RBCs lack the enzymes necessary to remove the RBV-triphosphate, these metabolites become trapped in the erythrocytes, unable to permeate the cell membrane, and are eliminated very slowly from erythrocytes (half-life 40 days). De Franceschi and colleagues hypothesized that RBV may be responsible for membrane oxidative damage by depleting ATP levels, which may indirectly affect the cells antioxidant defense mechanisms, promoting premature extravascular RBC removal similar to that observed in other conditions, such as sickle cell disease and G6PD deficiency.

To test this hypothesis, De Franceschi and colleagues evaluated indicators of erythrocyte oxidative susceptibility, such as hexosemonophosphate shunt (HMS) in vitro and in vivo among eleven patients who received either RBV 1000 mg or 1200 mg/day alone or in combination with standard IFN 5 MIU thrice weekly.

Both treatment groups demonstrated a decrease in hemoglobin levels and an increase in reticulocyte count during the first 60 days of treatment evaluation period. In the presence of RBV, red blood cell ATP levels were markedly decreased after a 12-hour incubation period. In addition, De Franceschi and coworkers reported that erythrocyte sodium-potassium (Na-K) pump activity was decreased significantly, while potassium-chloride (K-CL) cotransport and its dithiotreitol-sensitive fraction, malondialdehyde, and methemoglobin levels were increased significantly. There was an increase in aggregated 3 bands in RBV-treated patients, which was associated with a significantly increased binding of autologous antibodies and complement C3 fragments.

According to the data, these researchers concluded that RBV therapy is associated with increased RBC susceptibility to oxidation through depletion of RBC ATP content and an increase in the HMS. In vivo, this RBV-associated increase in RBC oxidative susceptibility is associated with phagocytic, extravascular destruction of RBC within the reticuloendothelial system (RES).

In addition to the hemolytic properties of RBV therapy, data from primate studies suggest RBV may have a negative affect on erythrocyte progenitor cells in the bone marrow. Both Canonico (1984) and Cosgriff (1984) evaluated the effects of RBV on bone marrow in rhesus monkeys, determining that RBV led to erythroid hypoplasia with suppression of late erythroid precursors in the bone marrow. These changes in bone marrow were reversible with the withdrawal of RBV.

Taken together, these data indicate that, in humans, RBV therapy is associated with an extravascular hemolytic anemia through increased RBC oxidative membrane damage, leading to the premature extravascular destruction of the RBCs by the RES. In addition, based on primate studies, RBV therapy may be associated with suppression of erythroid precursors in the bone marrow.

 

 

In addition to the development of RBV-associated anemia, several studies suggest that patients receiving IFN or IFN/RBV therapy also experience IFN-associated suppression of hematopoesis, which may contribute to the decreases in Hb observed in patients receiving INF/RBV for the treatment of hepatitis C.

In the 3 large clinical trials comparing IFN alfa-2b alone to IFN alfa-2b plus RBV (Davis et al, 1998; McHutchison et al, 1998; Poynard et al, 1998), patients randomized to IFN and placebo experienced a small decrease in Hb levels (mean of approximately 1 g/dL), which was not associated with an increase in the reticulocyte count, suggesting that IFN monotherapy causes a decrease in Hb levels due to bone marrow suppression. In contrast, patients randomized to receive IFN and RBV experienced a substantial decrease in Hb levels (mean of >3 g/dL), which was associated with a brisk increase in reticulocyte count, indicative of a hemolytic anemia with an appropriate increase in RBC production (Figure 14).

Figure 14. Anemia Associated With Combination IFN/RBV Therapy.

More recently, several studies indicated that the reticulocytosis observed in patients with RBV-related hemolysis is blunted by the concurrent IFN-related bone marrow suppression. In the above described study by De Franceschi and colleagues, the in vivo hematologic effects of RBV alone or in combination with IFN were evaluated in 11 patients. While the average Hb decrease was similar among the 6 patients receiving RBV 1000-1200 mg daily and the 5 patients receiving IFN 5 MIU thrice weekly and RBV 1000-1200 mg daily, the increases observed in the reticulocyte count at day 60 of treatment were significantly higher among those receiving only RBV (196 x 10³ reticulocytes/µL, range 140 to 258) compared to those receiving IFN/RBV (70 x 10³ reticulocytes/µL, range 33-124) (P = .002). These data suggest that IFN may limit the ability of the bone marrow to respond to ongoing hemolysis.

Similarly, Rendo and coworkers (2000) carefully evaluated parameters associated with anemia among 50 patients with chronic hepatitis C who were treated with IFN alfa-2b 3 MIU thrice weekly and RBV 1200 mg/day for a duration of 48 weeks. They observed significant anemia, defined as a decrease in Hb of greater than 2 g/dL, in 39 patients (68%) and measured the reticulocyte count, serum transferrin receptor (STR), haptoglobin, lactate dehydrogenase (LDH), and direct Coombs tests to determine the primary mechanisms of anemia. They defined the failure to increase both the reticulocyte count and STR as indicative of inhibition of the bone marrow erythroprogenitor cells, whereas a hemolytic anemia was defined as an increase in these parameters.

Rendo and colleagues observed that the primary mechanism appeared to be RBV-related hemolysis in 58% of patients, whereas 42% exhibited a pattern consistent with bone marrow suppression. Comparing the primary hemolysis group with the erythroprogenitor cell inhibition group, mean reticulocyte percentage was 4.3% (+/- 1.9%) and 2.4% (+/- 0.8%) (P < .001), respectively. Rendo and colleagues concluded that while many patients receiving IFN/RBV exhibit a pattern indicative of a primary hemolytic anemia, a significant proportion have evidence of an inadequate erythroprogenitor cell response indicative of IFN-related bone marrow suppression.

Taken together, these data suggest that the majority of patients treated with IFN/RBV develop a substantial (>3 g/dL) decrease in Hb during therapy and that, in many patients, the decrease in hemoglobin is due to RBV-related hemolysis and IFN-related bone marrow suppression of erythroprogenitor cells, representing a "mixed" anemia.

 

 

Canonico PG, Kastello MD, Cosgriff TM, et al. Hematological and bone marrow effects of ribavirin in rhesus monkeys. Toxico Appl Pharmacol. 1984;74:163-172.

Cosgriff TM, Hodgson LA, Canonico PG, et al. Morphological alterations in blood and bone marrow of ribavirin-treated monkeys. Acta Haematol. 1984;72:195-200.

Davis GL, Esteban-Mur R, Rustgi V, et al. IFN alfa-2b alone or in combination with RBV for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1493-1499.

De Franceschi L, Fattovich G, Turrini F, et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology. 2000;31:997-1004.

Hadziyannis SJ, Cheinquer H, Morgan T, et al. Peginterferon alfa-2a in combination with ribavirin: efficacy and safety results from a phase III, randomized, doubleblind, multicentre study examining the effect of duration of treatment and ribavirin dose. European Association for the Study of the Liver (EASL). Madrid, Spain. April 18-21, 2002 (Oral presentation, Abstract 356).

Jen JF, Glue P, Gupta S, et al. Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Therapeutic Drug Monitoring. 2000;22:555-556.

McHutchison JG, Poynard T, Harvey J, et al. The effect of dose reduction on sustained response in patients with chronic hepatitis C receiving interferon alfa-2b in combination with ribavirin. Hepatology. 2000; 32:223A(Abstract 247).

McHutchison JG, Gordon SC, Schiff ER, et al. IFN alfa-2b alone or in combination with RBV as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-1492.

Poynard T, Marcellin P, Lee SS, et al. Randomised trial of IFN alpha 2b plus RBV for 48 weeks or for 24 weeks versus IFN alpha 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet. 1998;352:1426-1432.

Rebetron (TM) [package insert]. Kenilworth, NJ: Schering Corp;1998.

Rendo P, Rosso A, Gomez F, et al. Anemia in patients with chronic hepatitis C treated with ribavirin and interferon. Antiviral Therapy. 2000;5(suppl 1):C96.

Sulkowski M, Wasserman R, Ball L, et al. Changes in hemoglobin during therapy with interferon alfa-2b plus ribavirin in IFN alfa-naive and IFN alfa-experienced patients. AASLD. 2000:368A(Abstract 834).

 

 

Chronic hepatitis C infection represents a significant problem affecting approximately 4 million Americans. Effective treatment strategies are needed to prevent the development of long-term complications such as ESLD and HCC in a substantial proportion of HCV-infected patients over the next 15 to 20 years. Recent studies have demonstrated that PEG IFN alfa-2b and alfa-2a plus RBV therapy are associated with eradication of hepatitis C in approximately 80% of patients infected with HCV genotype 2 or 3, and 42% to 51% of those infected with HCV genotype 1. However, these studies indicate that successful therapy in HCV genotype 1 infected patients requires longer duration of therapy (48 weeks) and higher RBV dosing (1000-1200 mg daily). In these prospective studies, the ability of patients to effectively take PEG IFN and adequate doses of RBV is limited substantially by adverse effects including anemia, fatigue, and decreased quality of life, particularly over a 48-week treatment course.

Current studies indicate that the development of treatment-related anemia adversely impacts the ability of patients to complete the intended duration of therapy, and, among those infected with HCV genotype 1, to maintain adequate RBV dosing. Understanding the underlying mechanisms of anemia in patients receiving IFN/RBV will permit clinicians treating patients with hepatitis C to recognize the role of RBV-related hemolysis and IFN-related bone marrow suppression in the development of anemia, and permit the use of strategies to maintain Hb levels without RBV and/or IFN dose reduction. Strategies to maintain RBV dosing and decrease the adverse effects of therapy are expected to translate into improved SVR rates among HCV-infected patients receiving PEG IFN and RBV therapy.