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NATAP at AASLD: HIV - HCV co-infection

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  • claudine intexas
    NATAP www.natap.org ... AASLD - American Association for the Study of Liver Diseases 27-31 October 2000, Dallas HIV at AASLD Report for NATAP from Douglas T.
    Message 1 of 1 , Nov 3, 2000
      NATAP
      www.natap.org
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      AASLD - American Association for the Study of Liver
      Diseases
      27-31 October 2000, Dallas

      HIV at AASLD
      Report for NATAP from Douglas T. Dieterich M.D.
      Clinical Associate Professor of Medicine
      NYU SChool of Medicine
      Chief of Gastroenterology and Hepatology
      Cabrini Medical Center
      New York City

      This year I count 17 abstracts that involve HIV
      and several others
      that
      pertain to people with HIV infection. The usual count
      at this meeting
      is 3-4
      abstracts, so that amounts to a substantial and
      probably statistically
      significant increase. The liver world is beginning to
      discover HIV. The
      infectious disease world is also beginning to discover
      the liver and
      both
      fields will benefit from this collaboration. The cross
      fertilization of
      scientists is a well known fact and much HIV
      technology and expertise
      is
      moving into the field of hepatitis C and hepatitis B.
      Indeed, the
      principles
      of combination therapy and viral resistance are being
      applied to the
      treatment of both liver viruses. The immunology of
      hepatitis B and C
      also is
      being explored with the same tools that are used in
      HIV. From the HIV
      perspective, there is clear acceptance of hepatitis B
      and C as an
      opportunistic infection that needs to be taken
      seriously and studied in
      an
      organized, large-scale fashion. As a traveler in both
      camps, i.e. a
      card-ca
      rrying member of the International AIDS Society both
      USA and
      internationally,
      the Infectious Disease Society of America and the
      American Association
      for
      the Study of Liver Diseases, I am delighted at these
      developments and
      even
      more delighted to tell you about them.
      In alphabetical order, let�s start with
      hepatitis B. There
      are only
      three abstracts that concern hepatitis B and HIV, but
      two are landmark
      studies, albeit small. The University of Miami has
      reported on 4 liver
      transplants performed in HIV+ patients all with
      hepatitis B. It is
      early to
      draw any conclusions this point, but the first two
      patients are at 13
      months
      and 3 months out and are doing well. All patients were
      required to have
      at
      least 500 CD4 cells and have HIV <400 copies. In
      addition to those 4,
      there
      are reports that four have been done in Pittsburgh, 2
      in San Francisco
      and 1
      in New York. These are carefully selected patients in
      the beginning,
      almost
      guaranteed to do well. Living related donor
      transplants probably have a
      role
      in HIV patients as well. That is an operation that
      takes the right lobe
      (usually) of the donor (usually a blood relative) and
      transplants it
      into the
      recipient. This procedure is still new and requires a
      recipient who is
      not
      too ill. It also carries some risk of dying for the
      donor (<1%). The
      other
      abstract that is hopeful is Benhamou�s report of
      adefovir treatment of
      30 HIV
      infected patients who had lamivudine (3TC) resistant
      hepatitis B. He
      reported
      on the 10 mg dose of adefovir which is the hepatitis B
      dose and his
      patients
      had a mean 3 log drop in HBV DNA in 12 weeks. That is
      also a short term
      report, but encouraging nonetheless for people who
      have resistant HBV.
      The
      only small piece of bad news, was a British abstract
      that noted that
      during
      immune reconstitution, 2 patients had seroconversion
      reactions from
      Hepatitis
      B e Antigen to Antibody and that was accompanied by a
      flare of clinical
      hepatitis, but a resolution of the hepatitis B. The
      other 2 patients
      had a
      reactivation of hepatitis B when coming off HIV
      medication.
      As for hepatitis C, there was more information.
      Two presentations
      commented on the natural history of hepatitis C. The
      first was from
      Paris and
      dealt with cirrhosis. They looked at about 300
      cirrhotics about 50 of
      whom
      had HIV for a mean time of 28 months (1 month to 13
      years). Overall,
      the HIV+
      patients were more likely to be younger, have a
      history of IV drug use
      and to
      drink more than 5 drinks per day. (That is the French
      definition of
      excess
      alcohol). Mean CD4 was 324 and 28% had viral load <200
      copies. (75%
      were
      receiving HAART). The death rate at 3 years was 56% in
      the HIV+ group
      and 19%
      in the HIV negative group, which was significant. The
      risk factors for
      early
      death were HIV, 3.4 times, alcohol 2.3 times and age
      >40 years. This
      demonstrates even in people with end stage liver
      disease, that HIV has
      a
      serious effect on the outcome of hepatitis C.
      Mark Sulkowski from Johns Hopkins presented his
      data on the HIV
      clinic at
      Hopkins. 45% had HCV and 49% were self- described
      alcohol abusers. Of
      the HCV
      patients 92% were genotype 1. However, 97% of the
      African Americans
      were
      genotype 1 versus 80% of the Caucasians. 48% of the
      liver biopsies
      showed at
      least grade 3 fibrosis, on the Ishak scale, which
      shows that half of
      the
      patients were well on their way to cirrhosis. Risks
      for cirrhosis in
      this
      HIV/HCV cohort were alcohol, 5.2 times, Caucasian race
      5.9 times and
      female
      sex 6.5 times. Of particular note was that HIV <400
      copies was a risk
      (2.9
      times) for cirrhosis. This flies in the face of
      previous data. However,
      we
      also know that controlling HIV does nothing for HCV
      and this may just
      be
      confirming that piece of data. This is a very
      interesting finding and
      deserves follow up and confirmation.
      The immunology of HIV and HCV was explored in an
      abstract from
      Bruce
      Walker�s lab at Harvard. Interestingly enough,
      virtually all of the
      patients
      were able to mount an effective immune response to
      HIV, but most were
      not
      able to mount a broad and strong response to HCV. This
      implies that HCV
      is an
      even more wily adversary than HIV and expert at
      avoiding the immune
      system�s
      response to its presence. This theme was echoed in
      numerous abstracts
      in HIV
      negative patients that demonstrated that the size and
      breadth of the
      cell-mediated immune response in HCV patients is the
      key to both
      beating the
      acute infection and eradicating the chronic infection.
      From the Bronx VA, a report of the prevalence
      of HIV in HCV
      positive
      patients revealed that 21% were positive for HIV in
      contrast to a
      European
      report that in 1998 57% of HCV patients were HIV
      infected. Also from
      the VA
      system, although Manhattan this time, Ed Bini reported
      on the Quality
      of Life
      of HCV patients compared to HIV patients. The HCV
      patients have a
      significantly reduced quality of life when compared to
      HIV patients.
      Coinfected patients are not worse and actually fall in
      between HCV and
      HIV
      mono-infected patients. The reasons for this are not
      at all clear. In a
      small
      study of 25 HIV/HCV coinfected patients from
      Jacksonville, the only new
      finding was that of increased lymphoid follicles on
      liver biopsy. That
      may
      warrant further investigation, especially when
      combined with the data
      from
      Texas on ballooning of hepatocytes associated with
      protease inhibitor
      use.
      That was an interesting finding and also unexplained.
      There may be
      something
      else going on in the liver of coinfected patients that
      we are not
      understanding yet.
      From Barcelona, a small treatment trial of
      coinfected
      hemophiliacs
      showed a sustained virological response rate of 32%
      with combination
      interferon TIW and ribavirin. Side effects were
      standard and HIV RNA
      nor CD4
      counts did not significantly change on therapy. They
      did see a
      significant
      amount of anemia from the ribavirin (about a 2 gram
      drop) which our
      group
      would treat with epoietin alfa, although they did not
      indicate if they
      did.
      With the data from McHutchison, in HIV negative
      patients that the
      sustained
      virologic response was significantly lower (24% vs.
      42%) in people who
      took
      less than 10.6 mg/kg per day of ribavirin, (basically
      800 mg for a 165
      pound
      man), it becomes even more important to keep ribavirin
      doses at or
      above 800
      mg. A randomized trial of epoietin alfa versus
      standard of care (dose
      reduction) in HCV patients treated with ribavirin
      showed a dramatically
      higher hemoglobin (by 3 grams) in the treated group.
      Maybe even more
      important was that they were able to take more
      ribavirin 986 mg per day
      versus 682 mg in the dose reduction group. By
      implication, this should
      impact
      the sustained virologic response. An identical study
      is just beginning
      in
      HIV+ patients to study epoietin alfa. A study from
      Pavia looked at
      daily
      interferon monotherapy and showed us a high drop out
      rate and poor
      response.
      This will be eclipsed with peg interferon in the near
      future. The
      evidence
      is building that combination treatment with interferon
      and ribavirin is
      both
      safe and effective in HIV patients, the only issue
      being anemia, which
      is
      treatable. However these are mostly single center
      small 15-30 patient
      studies, but there are about 10 of them now. The
      larger scale trials
      are
      underway and we should have data from them in a year
      or so.

      (Edit. Note from Jules Levin: Overall, it is not clear
      to me that
      coinfected
      persons will respond as well to HCV therapy as
      individuals infected
      with HCV
      alone. As Dr Dieterich says the studies so far in
      coinfected persons
      are
      small. I think the response rates to HCV therapy for
      people with HIV
      will
      vary between individuals based on their situations.
      Some individuals
      will
      respond as well as those with HCV alone. In some
      people HCV may have
      progressed more quickly because HIV can cause HCV to
      progress more
      quickly
      and they may not respond as well to HCV therapy,
      particularly if their
      CD4
      nadir is low. African Americans have a poor virologic
      response rate to
      combination HCV therapy. Most African Americans are
      genotype 1 (in one
      study
      96% were genotype 1. One small French study suggests
      that HCV
      progression
      slowed or stopped in individuals on HAART. But a
      number of treaters
      I've
      spoken with aren't convinced of these results. As Dr
      Dieterich says,
      larger
      ongoing studies ought to be revealing).

      Finally, a good study of NNRTI toxicity was
      presented by our
      group
      with Ron Palmon who is a second year medical resident
      at NYU/Bellevue
      doing
      most of the presenting. He looked at the liver
      toxicity of delavirdine,
      nevirapine and efavirenz in our cohort of largely
      urban gay white
      males,
      using a computerized database. He found that there
      were no significant
      differences in the incidence of liver toxicity with
      the possible
      exception of
      delavirdine, which elevated bilirubin more than the
      other two. Overall
      the
      conclusion was that this class of HIV drugs was
      relatively safe for the
      liver. On the opposite side of the ocean, in Glasgow,
      Triangle
      pharmaceutical
      was presenting FTC 302 which looked at FTC versus 3TC
      plus D4T and
      either
      nevirapine for viral loads <100,000 or efavirenz for
      viral loads >
      100,000.
      This was a largely black largely female population in
      South Africa.
      Severe
      liver toxicity was seen in 0/83 patients on efavirenz,
      but in 58/385
      (15%) of
      the patients on nevirapine, 2 of whom died of liver
      failure. This
      agrees with
      the INCAS, VIRGO and ATLANTIC trials, which had liver
      toxicity for
      nevirapine
      of 15%, 16% and 17% respectively. Why there is such
      great disparity
      between
      trials is not at all clear. There is clustering of
      liver toxicity in
      the 1-2%
      range in some trials and in the 15% range in others.
      The mechanism of
      NNRTI
      liver toxicity is not well understood and may be
      related to the
      allergic
      reaction to nevirapine, which seems to be more common
      in women. Another
      liver
      toxicity related abstract came from Ireland. Bohan and
      colleagues
      showed that
      HCV seems to cause a deletion of a mitochondrial gene
      and that it is
      associated with more fatty liver and fibrosis than
      when it does not
      happen.
      This is particularly pertinent to mitochondrial
      toxicity of nucleoside
      analogues in HIV patients because HCV may begin to
      injure mitochondria
      and
      make coinfected patients more susceptible to
      mitochondrial toxicity. A
      1999
      article using electron microscopy also showed
      mitochondrial injury in
      92% of
      HCV patients, setting them up for nucleoside analogue hepatotoxicity.

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