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6536Hepatitis C Virus Genotyping/Clinical Significance of Hepatitis C Virus Genotypes

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  • claudine intexas
    Jul 30, 2001
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      Infections in Medicine�

      Abstracts in Hepatitis:
      Recent Findings in the Journals
      Steven K. Herrine, MD, Series Editor, Jefferson
      Medical College, Philadelphia
      [Infect Med 18(5):248-250, 2001. � 2001 Cliggott
      Publishing Co., Division of SCP/Cliggott
      Communications, Inc.]


      Hepatitis C Virus Genotyping
      Clinical Significance of Hepatitis C Virus Genotypes
      Zein NN., Clin Microbiol Rev. 2000;13:223-235.
      On the basis of phylogenic analysis of nucleotide
      sequences, multiple genotypes and subtypes of
      hepatitis C virus (HCV) have been identified.
      Characterization of these genetic groups is likely to
      facilitate and contribute to the development of an
      effective vaccine against infection with HCV.
      Differences among HCV genotypes in geographic
      distributions have provided investigators with an
      epidemiologic marker that can be used to trace the
      source of HCV infection in a given population. HCV
      genotype 1 may represent a more aggressive strain and
      one that is less likely to respond to interferon
      treatment than is HCV genotype 2 or 3. However, these
      observations require confirmation before HCV
      genotyping can be used in clinical settings.

      Editorial Comment
      Since its identification as the source of most non-A,
      non-B hepatitis in the early 1990s, HCV has been noted
      to be unique in its ability to escape eradication by
      the immune system. Antibody testing has allowed
      effective screening of the blood supply as well as
      identification of clinical infection in patients.
      Therapy has improved over the past decade but remains
      far less effective than desired by clinicians. Efforts
      to develop a vaccine against HCV have met with only
      slow and limited progress. The heterogeneity of the
      HCV genome accounts in part for many of these clinical
      findings. This in-depth and extraordinarily
      well-written review provides information on HCV
      genotypes, including information on techniques used in
      identifying genotypes, classification systems,
      association with persistence of infection, natural
      history, and treatment. Genotyping is performed most
      accurately through phylogenic analysis of a specific
      portion of the patient's HCV genome. Commercial assays
      for this purpose are available, but they are limited
      in their ability to distinguish between some genomic
      subtypes. Serologic genotyping is able to reliably
      distinguish type 1 infection from non-type 1
      infection, a task important in determining probability
      of therapeutic response. Significant geographic
      differences are seen in genotype distribution. Types
      1a and 1b are predominant in North America and Europe.
      Type 2c is most commonly seen in northern Italy, while
      type 3a appears to be predominant in injection drug
      users in Europe and the United States. Types 4, 5, and
      6 are seen mostly in Africa and the Middle East, South
      Africa, and Hong Kong, respectively. Types 7 to 11 are
      seen in Southeast Asia and Oceania. Such observations
      have proved useful in tracing the epidemiology of the
      epidemic. The author describes the controversy
      regarding the prognostic value of HCV genotyping. Some
      investigators believe that type 1a carries a higher
      risk of fibrotic progression and hepatocellular
      carcinoma, while others point to duration of infection
      as the more important factor. The higher rate of
      interferon-based therapy response in non-type 1
      genotypes has been well described and is summarized in
      the article.

      Serum HCV RNA Levels May Fluctuate
      Fluctuation Patterns of HCV-RNA Serum Level in
      Patients With Chronic Hepatitis C
      Arase Y, Ikeda K, Chayama K, et al., J Gastroenterol.
      The serum level of hepatitis C virus (HCV) RNA is
      clinically important as a predictor of the response to
      interferon (IFN) therapy in patients with chronic
      hepatitis C. If serum HCV RNA levels fluctuate during
      follow-up and IFN therapy is begun at the time of a
      low HCV RNA level, the IFN therapy may be more
      effective. We evaluated the fluctuation of HCV RNA
      serum levels for 2 years in 212 patients with chronic
      hepatitis C, who were not treated with IFN and had HCV
      genotype 1b and an HCV RNA level of 10 mEq/mL or more
      at first consultation. The HCV RNA level was measured
      monthly for 2 years with an HCV branched-chain DNA
      (bDNA) probe assay. We classified HCV RNA patterns
      into 3 types by the ratio of maximum HCV RNA level (a)
      to minimum HCV RNA level (b). In pattern 1 (constant
      type, 151 patients; 71.2%), the a/b ratio ranged from
      1 to 5. In pattern 2 (slight fluctuation type, 46
      patients; 21.7%), the a/b ratio ranged from 5 to 10.
      In pattern 3 (severe fluctuation type, 15 patients;
      7.1%), the a/b ratio was 10 or more. Next, we
      evaluated the factors associated with the 3 patterns.
      Acute exacerbation of chronic hepatitis was regarded
      as an increase in serum alanine aminotransferase (ALT)
      level to more than 250 IU/L. The incidence of acute
      exacerbation for a 2-year follow-up was 13.9% (21 of
      151) in pattern 1, 19.6% (9 of 46) in pattern 2, and
      53.3% (8 of 15) in pattern 3. Multivariate analysis
      showed that acute exacerbation was the most important
      factor in the manifestation pattern 3. In conclusion,
      we found that about 70% of patients had a constant HCV
      RNA level for 2 years and that a few patients had
      severe fluctuation of serum HCV RNA level after acute
      exacerbation of chronic hepatitis.

      IFN-based therapy for chronic HCV infection, although
      improving, is made difficult by low response rates,
      high rates of side effects, and significant relapse
      rates. It is widely believed that some patients'
      illness may not progress to a significant extent over
      years, thus obviating the need for therapy. It
      behooves the clinician to be able to predict IFN
      responsiveness in order to aid the decision between
      treatment and watchful waiting. The most reproducible
      factors that are able to predict virologic response
      are genotype and viral load. Genotypes other than
      types 1 and 4 are much more likely to respond, while
      patients with lower viral loads enjoy a similar
      advantage. The lack of standardized measures of HCV
      RNA has hampered the ability to fully understand the
      implications of viral load. This study by a group of
      Japanese investigators proceeds on the premise that
      viremia can fluctuate and that treating patients when
      their viremia is at "low tide" may increase response
      rates. Unfortunately, the report stops short of
      investigating the above hypothesis. The study
      population was chosen to be those patients with high
      viral loads and a resistant genotype (1a).
      Observations were made using the first-generation bDNA
      probe assay. Three patterns of viral load fluctuation
      were identified; the group with the widest fluctuation
      was found to have more episodes of "acute
      exacerbation" of ALT levels. The investigators then
      reach the unwarranted conclusion that patients with
      acute exacerbation have a "high possibility" of HCV
      eradication with IFN therapy. Besides study design
      difficulties, such as the use of bDNA measurements,
      IFN monotherapy, and the unsubstantiated syndrome of
      "acute exacerbation" of HCV infection, this paper
      illustrates the difficulty in accepting the paradigm
      of chronic HCV infection as an infectious disease
      rather than a hepatic disease. Convincing data that
      viral load and genotype have an association with
      hepatic histology have never been demonstrated. Only
      by correlating viral measures with outcomes, such as
      inflammation, fibrosis, and survival, can we
      accurately measure our success

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