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Infection with Hepatitis C Virus Genotype 4 in the United States

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    NATAP - www.natap.org Infection with Hepatitis C Virus Genotype 4 in the United States Journal of Clinical Gastroenterology Jan 2004; 38(1):68-71 Andre C.
    Message 1 of 1 , Jan 29, 2004
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      NATAP - www.natap.org

      Infection with Hepatitis C Virus Genotype 4 in the United States

      Journal of Clinical Gastroenterology Jan 2004; 38(1):68-71

      Andre C. Lyra, MD; Sunil Ramrakhiani, MD; Bruce R. Bacon, MD; Adrian
      M.
      Di
      Bisceglie, MD

      From the Division of Gastroenterology and Hepatology, Department of
      Internal
      Medicine, Saint Louis University, St. Louis, MO.


      Background: Hepatitis C virus genotype differences seem to be of
      considerable
      clinical significance because they affect responses to antiviral
      therapy. HCV
      genotype 4 is rare in the United Sates and there are few published
      data
      regarding response to therapy in patients with HCV genotype 4
      infection.

      Objectives: To assess epidemiologic factors associated with HCV
      genotype 4
      infection in United States and to describe the response rate to
      therapy
      with the
      combination of alpha interferon and ribavirin.

      Methods: All hepatologists in our Division were asked for information

      about
      patients they had treated with HCV genotype 4. In addition, we
      searched
      the
      computer database from Saint Louis University Hospital in the last 40

      months
      (1999 to 2002). Twenty HCV genotype 4 patients were identified. A
      retrospective
      chart review was performed to collect information about their
      demographics, risk
      factors for acquisition of infection, baseline laboratory studies and

      response to antiviral therapy.

      Results: A risk factor for exposure to HCV was noted in 14 cases
      (70%);
      12
      patients had a history of illicit drug use, whereas a history of
      blood
      transfusion was detected in three cases; 1 patient had both risk
      factors. Only 4 of 20
      individuals had fibrosis stage 3 or 4 on liver biopsy. Seventeen
      patients were
      treated, 14 of whom completed therapy; 10 patients were sustained
      responders.

      Conclusions: As with other HCV genotypes, most patients with HCV
      genotype 4
      in the United States acquire the infection through intravenous drug
      use, liver
      disease is often mild to moderate in severity and 59% of our patients

      had a
      sustained virologic response after combination therapy with
      interferon
      and
      ribavirin.

      PATIENTS and METHODS

      Hepatitis C virus (HCV) is the most common chronic blood-borne
      infection in
      the United States, with the prevalence of anti-HCV in the general
      population of
      the United States being 1.8%. 1 This corresponds to an estimated 3.9
      million
      individuals having been infected with HCV. The striking genetic
      heterogeneity
      of the RNA genome of HCV is well recognized. This genetic diversity
      extends to
      include 6 major genotypes, over 80 subtypes and minor variants
      referred
      to as
      "quasispecies". 2 The occurrence of HCV genotypes tends to vary with
      geographic region. Thus, HCV genotype 1 accounts for approximately
      two-thirds of
      HCV-infected individuals in the United States. The next most common
      is
      genotype 2
      (14%), followed by genotype 3 (6-8%). 3, 4 In one study the
      prevalence
      of HCV
      genotype 4 infection among 438 patients from 10 tertiary referral
      centers
      across the United States was 1.1%. 3

      HCV genotype differences seem to be of considerable clinical
      significance
      because they affect responses to antiviral therapy. In particular, it

      is well
      known that patients infected with HCV genotypes 2 and 3 respond much
      better to
      antiviral therapy than those infected with genotype 1. 5 HCV genotype
      4
      appears
      to be prevalent in the Middle East and Central Africa, where it has
      been
      reported to be frequently associated with cirrhosis and a poor
      response
      to
      interferon. 6, 7 There are few published data from the United States
      regarding
      response to therapy in patients with HCV genotype 4 infection. The
      aim
      of the present
      study is to assess epidemiologic factors associated with HCV genotype
      4
      infection in the United States and to determine the response to
      therapy
      with the
      combination of alpha interferon and ribavirin.
      PATIENTS AND METHODS

      We retrospectively studied patients with HCV genotype 4 infection who

      were
      referred to Saint Louis University. All hepatologists in our Division

      were asked
      for information about patients they had treated with HCV genotype 4.
      In
      addition, we searched the computer database from Saint Louis
      University
      Hospital in
      the last 40 months (1999 to 2002). There were 1250 tests for HCV
      genotyping
      that were performed during this period; 8 patients (0.6%) were found
      to
      have
      genotype 4. In total, we were able to identify 20 patients who were
      infected
      with HCV genotype 4. All had anti-HCV and HCV RNA detectable in
      serum.
      A
      retrospective chart review was performed to collect information about

      their
      demographics, risk factors for acquisition of infection, baseline
      laboratory studies
      including liver biopsy results, and response to antiviral therapy.

      Serum HCV RNA levels and HCV genotyping assays were performed by 2
      commercial
      clinical laboratories. HCV RNA levels were determined in most cases
      using the
      Amplicor HCV version 1.0 kit from Roche (Branchburg, NJ), however the

      results
      are not comparable between the 2 laboratories. In 12 cases, the HCV
      was
      genotyped by sequencing and phylogenetic analysis of PCR products
      from
      the NS5B
      region; and in 8 cases HCV genotyping was performed by restriction
      fragment
      length polymorphisms (RFLP) analysis of 5` untranslated region
      (5`UTR).

      Sixteen patients were treated with interferon and ribavirin in
      combination at
      standard doses (alpha interferon 3 million units 3 times a week and
      ribavirin
      1,000 to 1,200 mg per day based on body weight). One of these 16
      patients was
      a previous non-responder to interferon mono-therapy. Two patients
      were
      treated with pegylated interferon and ribavirin. The other 2 patients

      were not
      treated. HCV RNA was assessed at baseline and at 3, 6, 12, and 18
      months after
      starting treatment. Patients who still had detectable HCV RNA by PCR
      at
      6 months
      were defined as non-responders and their therapy was stopped.
      Patients
      who had
      undetectable HCV RNA by PCR at 6 months were treated for an
      additional
      6
      months. Sustained biochemical and virologic response was defined as
      normal ALT and
      negative HCV RNA 6 months after therapy was stopped.

      RESULTS

      The baseline demographics, liver biopsy, and laboratory data from
      these
      patients are summarized: risk factors���55% IDU (n=11), cocaine
      snorting 10% (n=2),
      30% (n=6) >1 million copies/ml; mean ALT 95 U/L (range 15-202); stage

      of
      fibrosis���11 stage 2, 5 stage 1, 2 stage 3, 2 stage 4. Fourteen
      patients were white,
      most of them born in the United States. Four patients were African
      American, 1
      was an Egyptian who had immigrated to the US approximately 30 years
      ago, and
      1 was a black woman from Zaire who had just immigrated to the United
      States.
      They were all adults and half were men. A risk factor for exposure to

      HCV was
      noted in 14 cases (70%); a history of illicit drug abuse including
      intravenous
      drug use and snorting cocaine was obtained from 12 patients, whereas
      a
      history
      of blood transfusion was detected in 3 cases; 1 patient had both
      illicit drug
      use and blood transfusion as risk factors. In the patient of Egyptian

      nationality, the patient from Zaire, and in 4 other patients, no
      source
      of HCV
      infection could be identified. HCV RNA was detectable in serum of all

      cases, but
      because 2 different laboratories performed the assays mean values
      could
      not be
      calculated. The baseline HCV RNA was above 1 million copies per ml in
      6
      patients. Most of the patients had mild to moderate liver disease on
      biopsy and only 4
      individuals had bridging fibrosis or cirrhosis present.
      Interestingly,
      one of
      these patients with cirrhosis was the subject of Egyptian
      nationality.
      He has
      since developed hepatocellular carcinoma.

      Thirteen patients have completed 6 to 12 months of therapy. An
      additional
      patient completed 8 months of treatment and then discontinued therapy

      because of
      side effects. Two patients discontinued therapy a few weeks after
      starting due
      to adverse reactions, whereas 1 patient was lost to follow-up. Two
      patients
      were not treated and another is still on the second month of
      treatment
      with
      pegylated interferon and ribavirin. Seven of the 14 individuals who
      completed
      treatment (50%) had undetectable HCV RNA at 3 months of therapy. Ten
      of
      the 14
      patients (71%) are sustained responders whereas 4 were non-responders

      (29%).
      When excluding from analysis the patient who is still on the second
      month of
      therapy, overall 10 of 17 treated patients (59%) had a sustained
      virologic
      response. Interestingly, the patient who was treated for only 8
      months
      was a
      sustained responder, and 1 patient with cirrhosis at liver biopsy who

      was an African
      American also had a sustained response after using the combination of

      pegylated
      interferon and ribavirin. The subject who was re-treated with
      combination
      therapy was a sustained responder also. Sustained responders
      frequently
      had
      baseline serum HCV RNA levels below 1 million copies/ml and negative
      HCV RNA by
      qualitative PCR at 3 months of therapy. In addition, 8 out of 10
      sustained
      responders had hepatic stage of fibrosis 1 or 2. On the other hand, 3

      out of 4
      non-responders had baseline serum HCV RNA levels higher than 1
      million
      copies/ml
      and all 4 had detectable HCV RNA at 3 months of therapy. Of note, the

      patient of
      Egyptian nationality was a non-responder.

      DISCUSSION

      We describe patients infected with HCV genotype 4 who seem to be
      different
      from those in countries from the Middle East where this genotype is
      prevalent.
      Thus, most of our patients were white, born in the United States and
      12
      of 20
      (60%) appeared to have acquired HCV through illicit drug abuse,
      including
      intravenous drug use and snorting cocaine. Reports from Western
      European countries
      have also encountered a high rate of HCV transmission through
      intravenous drug
      use in subjects with HCV genotype 4. Therefore, in a study from Spain

      10 of
      11 individuals found to be infected with this HCV genotype were
      intravenous
      drug users. 8 In French populations, 36% to 65% of HCV genotype 4
      infections have
      occurred through intravenous drug abuse. 9, 10 On the other hand, in
      a
      study
      from Kuwait where there was a high proportion of subjects of Egyptian

      nationality, none of the patients was an intravenous drug user. 11

      In addition, most patients in this small cohort had mild to moderate
      liver
      disease and only 4 had bridging fibrosis or cirrhosis present. This
      is
      also in
      contrast to studies from the Middle East and Africa where HCV
      genotype
      4 is
      frequently associated with cirrhosis. Interestingly, the only patient

      of Egyptian
      nationality from our study had no identifiable source of the HCV
      infection
      and had cirrhosis at liver biopsy.

      Our patients had a remarkably high rate of response to antiviral
      therapy with
      the combination of interferon and ribavirin. Thus, 10 of 14 (71%)
      individuals
      who completed approximately 12 months of therapy had a sustained
      virologic
      response. Interestingly, 4 of these 9 responders had normal ALT
      levels
      before
      treatment, however, these are baseline levels and we are not aware of

      other ALT
      measurements in the 6 months preceding the start of therapy. On the
      other
      hand, in the study from Kuwait, the sustained virologic response rate

      of
      individuals with HCV genotype 4 who completed combination therapy was

      42%, whereas in a
      study from Egypt it was 21%. 11, 12 Other previous studies of
      antiviral
      treatment have also shown a poor response rate with interferon
      therapy
      alone. 6, 13
      The reasons for the better response to therapy in our patients are
      unclear
      but might be related to the differences in populations mentioned
      previously.
      Therefore, our patients are from a different ethnic background and
      appear to have
      had a different source of HCV infection in comparison to patients
      from
      the
      Middle East.

      Differences in ethnicity have been described to interfere with
      response
      to
      therapy for hepatitis C viral infection. Thus, African Americans seem

      to have a
      worse overall response to interferon treatment than whites. 14
      Moreover, most
      of our patients had mild to moderate histologic liver disease, low
      HCV
      viral
      load before treatment, and one of the sustained responders was
      treated
      with
      pegylated interferon, which has been reported to improve the response

      rate to
      combination therapy. Possibly, the association of all these factors
      favored the
      response to treatment. It is also important to consider the
      possibility
      of
      patient selection bias secondary to the small number of subjects.
      Nevertheless, it
      should be noted that HCV genotype 4 is rare in the United States with

      the
      prevalence being reported to be as low as 1.1% among subjects who are

      referred to
      tertiary centers. In our center, the incidence rate seemed to be
      around
      0.6%
      in a 3-year period. Therefore, the few cases that are described here
      probably
      reflect reasonably well the patients infected with HCV genotype 4 who

      are
      referred to our center.

      In conclusion, we report 20 patients who were infected with HCV
      genotype 4
      and were evaluated in Saint Louis University. Most of these
      individuals
      acquired
      the infection through intravenous drug use, had mild to moderate
      histologic
      liver disease, and had a sustained virologic response after
      combination
      therapy
      with interferon and ribavirin.

      REFERENCES

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      hepatitis C virus infection in the United States, 1988 through 1994.
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      Engl J Med.
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      2. Farci P, Purcell RH. Clinical significance of hepatitis C
      virus
      genotypes and quasispecies. Semin Liver Dis. 2000; 20:103-126.
      3. Lau JY, Davis GL, Prescott LE, et al. Distribution of
      hepatitis
      C
      virus genotypes determined by line probe assay in patients with
      chronic
      hepatitis
      C seen at tertiary referral centers in the United States. Ann Intern
      Med.
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      hepatitis
      C
      virus RNA and genotype from 6807 patients with chronic hepatitis C in

      the United
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