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Liver Transplantation: What's New?

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    American Association for the Study of Liver Diseases 52nd Annual Meeting [Medscape, 2001. © 2001 Medscape, Inc.] Liver Transplantation: What s New? Michael R.
    Message 1 of 1 , Dec 8, 2001
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      American Association for the Study of Liver Diseases
      52nd Annual Meeting
      [Medscape, 2001. � 2001 Medscape, Inc.]

      Liver Transplantation: What's New?

      Michael R. Lucey, MD
      Introduction
      Two prominent themes were evident during the
      proceedings of the 52nd Annual Meeting of the American
      Association for the Study of Liver Diseases: (1)
      living-donor liver transplantation (LDLT) between
      adults, and (2) hepatitis C virus (HCV) infection in
      liver transplant recipients.
      This summary reviews a series of presentations that
      advanced our understanding of these important topical
      issues.

      Adult-to-Adult Living-Donor Liver Transplantation
      Brown and colleagues[1] presented the results of a
      survey on the practice of adult-to-adult LDLT in the
      United States. The survey derived from a National
      Institutes of Health-sponsored workshop on LDLT held
      in December 2000, and concentrated on characteristics
      of donors, donor evaluation, and donor outcome.
      Eighty-six of the 112 United Network for Organ Sharing
      (UNOS)-certified liver transplant programs responded.
      The respondents accounted for more than 90% of all
      transplants (cadaveric and live donors) being carried
      out in the United States at that time.

      The survey revealed that 43 (50%) centers had already
      completed at least 1 adult-to-adult LDLT; 33 of the
      remaining transplant programs indicated that they were
      planning to start adult-to-adult LDLT. By November
      2000, 449 adult-to-adult LDLTs had been completed, and
      13 centers had done more than 10. Among donors, 75%
      were family members, 11% were spouses, and 14% were
      friends. The so-called "good Samaritan" donor was
      rare. Typically, the evaluation included assessment by
      a hepatologist, a medical social worker, and a
      psychiatrist, and rarely involved an ethicist.
      Regarding the use of invasive tests, 14% of programs
      never did liver biopsies on potential donors, 60% used
      biopsy selectively, and 26% of programs biopsied
      everyone who met initial criteria. In contrast, the
      majority (60%) of programs reported that they
      performed angiograms in all likely donors, with 26%
      using angiography selectively, and 14 never obtaining
      angiograms at all. Fifty percent of programs did not
      send donors to intensive care following surgery. The
      complications recorded included 1 donor death,
      reoperation in 4% of cases, and significant biliary
      morbidity in 8%.

      Although fewer data were recorded on recipient
      characteristics and outcome, these investigators noted
      that only 7 recipients did not meet criteria for a
      cadaveric donor. The rates of vascular and biliary
      complications in recipients of adult-to-adult LDLT
      were appreciable: 109 (24%) and 41 (8%), respectively.


      Commentary
      As discussed above, these findings represent important
      data showing the emergence of a new technology. The
      inclination to participate in this technologic
      evolution is strong, and almost all transplant centers
      have begun or plan to start adult-to-adult LDLT. Donor
      evaluation practices are highly variable, as shown by
      the lack of consensus on donor liver biopsy. The
      survey also indicates that the morbidity for donor and
      recipient is considerable. Up until this point, the
      selection criteria for recipients have remained the
      same as those used for reception of a cadaveric donor,
      but whether this will continue to be the case is
      questionable.

      Hepatitis C in Liver Transplantation
      Forman and colleagues[2] presented data from a
      retrospective review of the UNOS database from 1992
      through 1998. When the database was confined to
      patients with known HCV antibody serology, informative
      data were available on 11,036 primary graft
      recipients. Potential interactions between HCV status,
      donor and recipient characteristics, year of
      transplantation, and outcome were assessed using Cox
      proportional-hazards analysis.
      Using this methodology, these investigators identified
      an unexpected interaction (significant at the P < .001
      level) between recipient sex, HCV infection, and
      transplant outcome. Specifically, female recipients
      who were anti-HCV-positive had a significantly worse
      graft and patient survival than did female recipients
      who were anti-HCV-negative -- graft survival was 56%
      less and patient survival was 51% less in this former
      group. This interaction was not accounted for by
      either the sex of the allograft donor, or by a
      preponderance of chronic cholestatic disorders such as
      primary biliary cirrhosis, among the female recipients
      who were HCV-negative.

      Commentary
      The above interaction was a surprising and unexplained
      result, especially because female sex is associated
      with less aggressive HCV infection in the absence of
      liver transplantation. The strength of the UNOS
      database is its size, giving it the capacity to
      identity previously unrecognized and unrecognizable
      associations. Its weakness is that many potentially
      interesting data are not included.
      The present study "begs" for more information, such as
      causes of death or graft loss among anti-HCV-positive
      and -negative women. Elucidating the mechanism of the
      negative interaction between female sex and HCV on
      outcome after liver transplantation may provide new
      insights into HCV infection.

      Control of HCV Infection Before LDLT
      At last year's meeting, 2 groups presented data on the
      difficulty of eradicating HCV in anticipation of
      cadaveric liver transplantation -- the so-called
      "preemptive therapy."[3] One problem posed by
      preemptive therapy is that the interval for treatment
      is dictated by the availability of a cadaveric donor
      organ, and not by the virologic response to therapy.
      Halprin and coworkers[4] provided an interesting
      variant on preemptive therapy by reporting on a single
      center's experience administering anti-HCV
      chemotherapy to candidates due to undergo LDLT. This
      experience is important for at least 2 reasons. First,
      as demonstrated, the LDLT allows the timing of
      transplantation to be coordinated with the planned
      antiviral therapy. Second, there are anecdotal data to
      suggest that HCV infection may impair the regeneration
      of the recipient right lobe. Thus, eradication of HCV
      before the LDLT would obviate this problem.

      Dynamics of HCV Immediately After Liver
      Transplantation
      Forns and coworkers[5] described the kinetics of HCV
      during the perioperative period. Twenty patients with
      HCV-induced cirrhosis were studied before operation,
      in the anhepatic phase, and at frequent intervals
      thereafter.
      The study authors found that the circulating hepatitis
      C viral load declined during the anhepatic phase, and
      demonstrated a continued decline after reperfusion.
      The median decline during the anhepatic phase was 0.73
      log10, and during reperfusion was 1.35 log10. The
      median interval to nadir levels was 16 hours after the
      start of the transplant. HCV became undetectable in
      occasional samples in only 2 patients. After this
      initial phase, there was a variable response of
      circulating HCV. Quantitative levels of HCV rose to
      pretransplant levels in 10 recipients, remained at a
      low plateau in 4, and showed a further decline in 6.
      Five of the latter 6 subjects manifesting a
      second-phase decline were among the 8 recipients whose
      immunosuppressive protocol did not include
      corticosteroids.

      Evolution of HCV quasispecies was analyzed in 9
      recipients. Approximately equal numbers of patients
      maintained their pretransplant profile of predominant
      quasispecies as those in whom new or poorly
      represented quasispecies became dominant in the
      initial 120 hours.

      Commentary
      These elegant data show that there is a dynamic flux
      in circulating HCV levels during and immediately after
      liver transplantation. These data suggest that the
      nadir of circulating HCV occurs after reperfusion, and
      may be influenced by choice of immunosuppressive
      agent. Additionally, these findings suggest that
      initiation of antiviral therapy in the first 24 hours
      after transplantation may afford the best opportunity
      to control the virus.

      Early Treatment of HCV After Liver Transplantation
      Also during last year's meeting, Didier Samuel
      presented results from a randomized controlled trial
      of combination therapy for HCV after liver
      transplantation using interferon alfa-2b and
      ribavirin.[3] In this study, treatment was introduced
      at least 6 months after transplantation.
      Administration of combination antiviral therapy early
      after liver transplantation is hindered by the renal
      clearance of ribavirin, as many patients have some
      degree of renal impairment after liver
      transplantation.
      During this year's meeting proceedings, Manzarbeitia
      and colleagues[6] presented preliminary results on the
      use of interferon monotherapy with pegylated
      interferon alfa-2a (40 kd; PEGASYS). Study entry was
      restricted to patients who were positive for HCV RNA
      in serum and had undergone primary liver
      transplantation 3 weeks or less before randomization.

      Data were presented on 33 subjects of a projected
      recruitment of 50, who were randomized to receive
      either 180 mcg pegylated interferon alfa-2a
      subcutaneously per week or no antiviral treatment. To
      date, 9 subjects in each treatment arm have completed
      24 weeks of observation. The side-effect profile was
      similar in both groups. At week 24, 44% of the treated
      group had shown a 2 log10 decline in circulating
      virus, and HCV RNA was undetectable in 22%. No subject
      in the untreated group demonstrated a 2 log10 decline
      in HCV RNA, and HCV was detectable in all untreated
      subjects.

      Commentary
      Although these are preliminary data, they nevertheless
      suggest that it may be possible to ameliorate the
      circulating hepatitis C viral load by administration
      of currently available antiviral agents. The results
      of this and other clinical trials will be awaited
      eagerly.
      Findings reported by Forns and colleagues, as
      described above, suggest that initiation of antiviral
      therapy even earlier in the course of posttransplant
      management may be useful. Given the complexity of
      management of patients in the immediate postoperative
      phase, the use of powerful antivirals after liver
      transplantation -- especially early in the
      postoperative period -- should be confined to
      carefully conducted clinical trials.

      References
      1. Brown RS, Richardson M, Lai M, Everhart J, Russo
      MW, Hoofnagle JH. Adult living donor liver
      transplantation (LDLT) in the US: Results of a survey
      from the NIH LDLT meeting. Hepatology. 2001;34:235A.
      [Abstract 245]
      2. Forman LM, Lewis JD, Berlin JA, Lucey MR. The
      interaction of recipient gender and hepatitis C
      infection on patients and allograft survival after
      orthotopic liver transplantation. Hepatology.
      2001;34:244A. [Abstract 283]
      3. Lucey MR. Liver transplantation and hepatitis C
      infection. Medscape Conference Summaries from the
      American Association for the Study of Liver Diseases
      51st Annual Meeting. 2000. Medscape Gastroenterology.
      Available at:
      http://www.medscape.com/Medscape/CNO/2000/AASLD/Story.cfm?story_id=1786.
      Accessed November 21, 2001.
      4. Halprin A, Trotter JF, Everson GT, et al.
      Post-transplant eradication of hepatitis C by
      pre-transplant treatment in living donor liver
      transplant recipients. Hepatology. 2001;34:244A.
      [Abstract 284]
      5. Forns X, Garcia M, Feliu A, et al. Hepatitis C
      virus (HCV) kinetics and quasispecies evolution during
      and immediately after liver transplantation.
      Hepatology. 2001;34:362A. [Abstract 760]
      6. Manzarbeitia C, Tepermann L, Chalasani N, et al.
      Peginterferon alfa-2a (40KD) (Pegasys) as prophylaxis
      against hepatitis C infection recurrence after liver
      transplantation (LT): preliminary results of a
      randomized, multicenter trial. Hepatology.
      2001;34:406A. [Abstract 938]


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