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New Insights Into the Mechanisms of Anemia During Interferon Alfa/Ribavirin Therapy

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    www.medscape.com Hemolysis and Bone Marrow Suppression: New Insights Into the Mechanisms of Anemia During Interferon Alfa/Ribavirin Therapy
    Message 1 of 1 , Sep 14, 2002
      www.medscape.com

      Hemolysis and Bone Marrow Suppression: New Insights Into the
      Mechanisms of Anemia During Interferon Alfa/Ribavirin Therapy
      Faculty/Chairperson: Mark S. Sulkowski, MD; Educational Reviewer:
      Chris S. Jackson, Jr, MD


      Release Date: August 30, 2002; Valid for credit through August 30,
      2003

      Editorial Content produced by AdvancMed
      Copyright � 2002 AdvancMed

      This CME activity, "Hemolysis and Bone Marrow Suppression: New
      Insights Into the Mechanisms of Anemia During Interferon
      Alfa/Ribavirin Therapy," was originally offered as a monograph
      certified for CME.


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      Program Overview and Learning Objectives
      Target Audience
      This educational monograph is intended for hepatitis C-treating
      clinicians.


      Learning Objectives
      Upon completion of this activity, participants should be able to:
      Describe hepatitis C treatment options.
      Synthesize clinical data supporting recommended ribavirin dosing
      strategies for attaining optimal SVR rates.
      Delineate the definition and parameters of anemia in IFN/RBV-treated
      hepatitis C patients.
      Analyze the mechanisms of anemia related to IFN/RBV therapy.

      Credit Hours Available
      Physicians - up to 1.5 hour(s) of AMA PRA category 1 credit





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      Table of Contents
      Epidemiology

      HCV Routine Screening Recommendations

      Diagnostic Tools

      References



      Natural History

      Public Health Significance

      References



      Pharmacologic Management of Hepatitis C

      Interferon

      Standard Interferon alfa/Ribavirin Combination Therapy

      Pegylated Interferon alfa Monotherapy

      Pegylated Interferon alfa/Ribavirin Combination Therapy

      PEG IFN alfa-2b plus RBV

      PEG (40 kDa) IFN alfa-2a plus RBV

      References



      Importance of Achieving and Maintaining Ribavirin Dose During Therapy
      Strategies to Improve Clinical Effectiveness

      Ribavirin Concentration and Viral Response

      RBV Dose Reduction and Viral Response

      Adverse Effect Profile of IFN/RBV Therapy

      Anemia Caused by IFN/RBV Combination Therapy

      Management of Anemia During IFN/RBV Therapy

      Mechanism of Ribavirin-Associated Anemia

      Bone Marrow Suppression Due to IFN in Patients Receiving IFN Therapy
      With or Without RBV

      References



      Summary



      --------------------------------------------------------------------------------


      Hemolysis and Bone Marrow Suppression: New Insights Into the
      Mechanisms of Anemia During Interferon Alfa/Ribavirin Therapy
      Epidemiology

      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).



      HCV Routine Screening Recommendations

      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 Tools

      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.



      References

      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.



      Natural History


      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.



      Public Health Significance

      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.


      References

      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.



      Pharmacologic Management of Hepatitis C

      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.



      Interferon

      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).



      Standard Interferon alfa/Ribavirin Combination Therapy

      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.



      Pegylated Interferon alfa Monotherapy

      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).



      Pegylated Interferon alfa/Ribavirin Combination Therapy

      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.



      PEG IFN alfa-2b plus RBV

      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 �g/kg once a week (higher dose PEG IFN)
      plus RBV 800 mg/day (n = 511) or
      PEG (12 kDa) IFN alfa-2b 1.5 �g/kg once a week plus RBV 1000 or 1200
      mg/day for 4 weeks, then 0.5 �g/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 �g/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.



      PEG (40 kDa) IFN alfa-2a plus RBV

      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 �g subcutaneously once a week plus RBV
      1000-1200 mg/day (n = 453)
      PEG (40 kDa) IFN alfa-2a 180 �g 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 �g subcutaneously once a week plus RBV
      800 mg/day for 24 weeks
      PEG (40 kDa) IFN alfa-2a 180 �g subcutaneously once a week plus RBV
      1000-1200 mg/day for 24 weeks
      PEG (40 kDa) IFN alfa-2a 180 �g subcutaneously once a week plus RBV
      800 mg/day for 48 weeks
      PEG (40 kDa) IFN alfa-2a 180 �g 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.



      References

      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.



      Importance of Achieving and Maintaining Ribavirin Dose During Therapy
      Strategies to Improve Clinical Effectiveness

      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.



      Ribavirin Concentration and Viral Response

      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.


      RBV Dose Reduction and Viral 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.



      Adverse Effect Profile of IFN/RBV Therapy

      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).



      Anemia Caused by IFN/RBV Combination Therapy

      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.



      Management of Anemia During 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).



      Mechanism of Ribavirin-Associated Anemia

      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.



      Bone Marrow Suppression Due to IFN in Patients Receiving IFN Therapy
      With or Without RBV

      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/�L, range 140 to 258) compared to those
      receiving IFN/RBV (70 x 103 reticulocytes/�L, 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.



      References

      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).



      Summary

      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.



      --------------------------------------------------------------------------------


      Faculty and Disclosures


      Authors
      Mark S. Sulkowski MD
      Assistant Professor of Medicine, Division of Infectious Diseases,
      Department of Medicine, Johns Hopkins University, Baltimore,
      Maryland.

      Disclosure: Grants/Research Support: Roche Pharmaceuticals,
      Schering-Plough, Ortho Biotech Products, LP.
      Honoraria: Roche Pharmaceuticals, Schering-Plough, Ortho Biotech
      Products, LP.

      Hemolysis and Bone Marrow Suppression: New Insights Into the
      Mechanisms of Anemia During Interferon Alfa/Ribavirin Therapy
      Faculty/Chairperson: Mark S. Sulkowski, MD; Educational Reviewer:
      Chris S. Jackson, Jr, MD


      Release Date: August 30, 2002; Valid for credit through August 30,
      2003

      Editorial Content produced by AdvancMed
      Copyright � 2002 AdvancMed

      This CME activity, "Hemolysis and Bone Marrow Suppression: New
      Insights Into the Mechanisms of Anemia During Interferon
      Alfa/Ribavirin Therapy," was originally offered as a monograph
      certified for CME.

      Faculty affiliations and disclosures are at the end of this activity.


      -------------------------------------------------------------------------------

      Program Overview and Learning Objectives
      Target Audience
      This educational monograph is intended for hepatitis C-treating
      clinicians.


      Learning Objectives
      Upon completion of this activity, participants should be able to:
      Describe hepatitis C treatment options.
      Synthesize clinical data supporting recommended ribavirin dosing
      strategies for attaining optimal SVR rates.
      Delineate the definition and parameters of anemia in IFN/RBV-treated
      hepatitis C patients.
      Analyze the mechanisms of anemia related to IFN/RBV therapy.

      Credit Hours Available
      Physicians - up to 1.5 hour(s) of AMA PRA category 1 credit





      Instructions for Credit
      Participation in this self-study activity should be completed in
      approximately 1.5 hours. To successfully complete this activity and
      receive credit, participants must follow these steps during the
      period from August 30, 2002 through August 30, 2003.


      Make sure you have provided your professional degree required in
      order to issue credit. If you haven't, click here. For information on
      applicability and acceptance of continuing education credit for this
      activity, please consult your professional licensing board.
      Read the target audience, learning objectives, and faculty
      disclosures.
      Study the educational activity online or printed out.
      Read, complete, and submit answers to the post test questions and
      evaluation questions online. Participants must receive a test score
      of at least 70%, and respond to all evaluation questions to receive a
      certificate.
      When finished, click "submit."
      After submitting the activity evaluation, you may access your online
      certificate by selecting "View/Print Certificate" on the screen. You
      may print the certificate, but you cannot alter the certificate. Your
      credits will be tallied in the CME Tracker.


      --------------------------------------------------------------------------------


      Accreditation Statements

      For Physicians


      AdvancMed is accredited by the Accreditation Council for Continuing
      Medical Education to provide continuing medical education for
      physicians.

      AdvancMed designates this educational activity for a maximum of 1.5
      hours in category 1 credit toward the AMA Physician's Recognition
      Award. Each physician should claim only those hours of credit that
      he/she actually spent in the educational activity.



      This activity is supported by an educational grant from Ortho
      Biotech.





      Legal Disclaimer
      The material presented here does not necessarily reflect the views of
      Medscape, the CME provider, the companies providing educational
      grants or the authors and writers. These materials may discuss uses
      and dosages for therapeutic products that have not been approved by
      the United States Food and Drug Administration. All readers and
      continuing education participants should verify all information and
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      --------------------------------------------------------------------------------


      Table of Contents
      Epidemiology

      HCV Routine Screening Recommendations

      Diagnostic Tools

      References



      Natural History

      Public Health Significance

      References



      Pharmacologic Management of Hepatitis C

      Interferon

      Standard Interferon alfa/Ribavirin Combination Therapy

      Pegylated Interferon alfa Monotherapy

      Pegylated Interferon alfa/Ribavirin Combination Therapy

      PEG IFN alfa-2b plus RBV

      PEG (40 kDa) IFN alfa-2a plus RBV

      References



      Importance of Achieving and Maintaining Ribavirin Dose During Therapy
      Strategies to Improve Clinical Effectiveness

      Ribavirin Concentration and Viral Response

      RBV Dose Reduction and Viral Response

      Adverse Effect Profile of IFN/RBV Therapy

      Anemia Caused by IFN/RBV Combination Therapy

      Management of Anemia During IFN/RBV Therapy

      Mechanism of Ribavirin-Associated Anemia

      Bone Marrow Suppression Due to IFN in Patients Receiving IFN Therapy
      With or Without RBV

      References

      Summary


      Faculty and Disclosures


      Authors
      Mark S. Sulkowski MD
      Assistant Professor of Medicine, Division of Infectious Diseases,
      Department of Medicine, Johns Hopkins University, Baltimore,
      Maryland.

      Disclosure: Grants/Research Support: Roche Pharmaceuticals,
      Schering-Plough, Ortho Biotech Products, LP.
      Honoraria: Roche Pharmaceuticals, Schering-Plough, Ortho Biotech
      Products, LP.


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