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Can Persons With Decompensated Cirrhosis Be Treated for HCV?

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  • claudine intexas
    Can Persons With Decompensated Cirrhosis Be Treated for HCV? Brief Summary: Below are two studies reported at Dallas on this important and controversial
    Message 1 of 2 , Dec 29, 2000
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      Can Persons With Decompensated Cirrhosis Be Treated
      for HCV?

      Brief Summary:
      Below are two studies reported at Dallas on this
      important and
      controversial question. The first study discussed
      below looks at
      treating individuals who appear more advanced in
      disease stage as they
      are on waiting lists for transplants. Less than half
      of the patients
      screened for the study met the criteria. The rate of
      adverse events were
      high: in 15 individuals, there were 23 complications
      and 20 were severe
      (thrombocytopenia & leucopenia were most common). One
      patient died from
      a fatal complication. But individuals were capable of
      a virologic
      response. The second study below looks at individuals
      who appear not to
      be as progressed in their liver disease and the
      investigator also saw a
      viral response, but the complications and side effects
      were not as
      severe. Investigators in this study used an increasing
      dosing approach
      to try for tolerability. Achieving RNA clearance
      appeared to be related
      to the ability to achieve full dosing for at least 3
      months preferably
      for 6 months. Of the 4 patients, for whom data is
      available so far, able
      to achieve SVR prior to transplant they remain RNA-
      after transplant.

      A Pilot Study of the tolerability and efficacy of
      antiviral therapy in
      patients awaiting liver transplantation for Hepatitis
      C
      Gregory Iverson, Univ of Colorado Health Science
      Ctr, Denverr, CO;
      Thomas Trouillot, James Trottier, Justin Skilbred,
      UCSHC, Denver, CO;
      Arthur Halprin, Carol McKinley, Univ of Colorado
      Health Science Center,
      Denver, CO; Barbara Fey, Cathy Ray, James Epp, UCSHC,
      Denver, CO

      Patients were recruited from the waiting lists at 5
      hospital centers:
      Baylor University Med Ctr in Dallas; Mayo Clinic in
      Rochester, Minn; Mt
      Sinai Med Ctr in NYC; Univ of Cal, SF; Univ of
      Nebraska, Omaha.

      The purpose of the study was to determine whether
      pretransplant
      antiviral therapy is practical by studying the
      tolerability and efficacy
      of interferon a2b (IFN) with or without ribivarin
      (RBV), in patients
      with decompensated hepatitis C awaiting transplants.
      So, this group of
      patients is likely to be more advanced in their
      disease stage than the
      group in the next study.

      Patients had to be on the active waiting list at one
      of these centers
      with a status 2b (Child-Pugh class C). They had to be
      at or near the top
      of the list so the transplant was imminent. They had
      to have HCV-RNA
      positive by PCR and no antiviral therapy within the
      last 12 weeks prior
      to enrollment in this study.

      Patients were excluded for:

      Severe renal insufficiency, serum creatinine >2.0
      mg/dL

      Platelet count <45,000

      Hemoglobin <11 gm

      Absolute neutrophil <1250

      INR > 2.0

      Patients were randomized to one of 3 arms:

      A: IFN 2b, 1 million units subq. Daily
      B: IFN 2b, 3 MU 3x/week
      C: IFN 2b, 1 MU daily + RBV 400 mg twice daily

      Laboratory values were checked at baseline, days 1, 3
      and 7 and then
      weekly. HCV-RNA was quantified using a coomercial bDNA
      signal
      amplification assay (HCV Quantiplex 2.0 Chiron). Lower
      limit of
      sensitivity of the assay was 0.2 x 106 vEq/ml.
      Genotype was performed
      by PCR.

      IFN DOSE REDUCTION

      IFN dose was reduced if neutrophil count was <750,
      platelet count
      <45,000 and RBV dose was capped at 400 mg per day if
      hemoglobin was <10
      gm.

      DRUGS DISCONTINUED

      IFN was stopped if
      --neutrophil count was <500, or
      --platelet count <20,000

      RBV stopped if hemoglobin was <8.5 gm

      Both drugs were stopped if serum creatinine >3.0 mg/dL

      Less than half of the patients screened for this study
      met entry
      criteria, so they were a sick group in general. The
      most common reasons
      for exclusion were thrombocytopenia and leukopenia.

      Fifteen patients were enrolled: 3 in arm A and 6 in
      arms B & C. The
      genotypes were:

      1a- 7

      1b- 1

      1a/b- 3

      2a/c- 1

      3a- 1

      untypeable- 2

      BASELINE VIRAL LOAD

      Undetectable- 3 patients

      <5.0 (5 million) vEq/ml- 6 patients

      5.0-10 vEq/ml- 1

      >10 vEq/ml- 5

      VIRAL RESPONSE

      4/12 patients (33%) with detectable viral load at
      baseline achieved
      undetectable VL on treatment

      A (1 MU IFN daily): 1 patient was in arm A with
      genotype 1 and had
      undetectable VL after 2 weeks

      B ( 3 MU IFN 3x/wk): 2 patients in this arm achieved
      undetectable VL: 1
      person with genotype 3a after 3 days on therapy and 1
      person with
      genotype 2a/c after 2 weeks

      C (IFN 1 MU daily+RBV 400 mg bid): only 1/6 achieved
      undetectable
      (genotype 1) and that occurred after 2 weeks on
      therapy

      6/12 patients (50%) had a decrease in VL of <1 log

      Two patients at the time of closing the study went on
      to
      transplantation. One patient had undetectable VL by
      bDNA assay at the
      time of transplant but within 1 month the VL went up
      to 42 million. The
      second patient started with a VL of 4 million at
      baseline which dropped
      to 1.14 million while on therapy. One month after
      transplant the VL was
      8.41 million.

      ADVERSE EVENTS

      The author said the take home message from this study
      was that there
      were a large number of adverse events, and this was
      the major concern.
      In the 15 patients there were 23 adverse events, 20 of
      which were
      severe. Thrombocytopenia was the most common (n=8).
      Leukopenia was
      frequent (n=4). There was an equal distribution across
      all treatment
      arms. And they all resolved with dose
      reduction/discontinuation.

      Other adverse events occurring during the study:

      hepatic encepholopathy (n=3) with out any other
      obvious precipitating
      causes

      severe nausea/vomiting (n=2)

      hyperbilirubinemia (n=1) from a baseline 3-4 to level
      of 13

      new onset of hypothyroidism (n=1)

      acute pancreatitis (n=1) manifested by low level
      elevations in serum
      lipase/amylase which resolved with reduction of drugs

      INFECTIOUS COMPLICATIONS

      The author said the scary part of the study was the
      infectious
      complications occurring. He said most of these
      patients run into
      problems with infections. There were 2 patients with
      such complications.
      They were quite alarmed when one patient developed
      septic (presence of
      toxins in the blood or tissues) arthritis of a toe,
      secondary to S.
      aureus. This responded to antibiotic therapy. Another
      patient developed
      a culture negative empyema that progressed to
      multi-system organ
      failure, refractory hypotension and death despite
      aggressive
      (antibiotic) medical therapy.

      AUTHOR'S SUMMARY:

      Undetectable VLs are attainable

      Adverse events are the rule and most patients don't
      meet criteria (to
      sick) for treatment

      Dose reduction/discontinuation is common as only 4
      patients were able to
      complete 4 weeks therapy

      1 fatal infectious complication

      CONCLUSIONS:

      In this group of patients who are already at high
      risk, fatal
      complications can occur

      Undetectable VLs can occur and tolerability is low

      But treatment of decompensated cirrhotics is possible.
      The next study
      discusses treatment in patients at an earlier stage
      and that may be a
      key

      Treatment of Decompensated Cirrhotics with a
      Low-Accelerating Dose
      Regimen of Interferon alfa-2b and Ribivarin (LADR):
      Safety & Efficacy
      Jeffrey Crippin, Baylor University, Dallas, Tx;
      Patricia Scheidner,
      Mt Sinai Med Ctr, NY, NY; Norah Terrault, Univ of CAL,
      SF, CA; Tim
      McCashland, Univ of Nebraska Med Ctr, Omaha. NE; M
      Charlton, Mayo
      Clinic, Rochester, MN

      Jeffrey Crippin reported on this pilot preliminary
      study, and the author
      suggested keeping that in mind if considering treating
      patients in
      similar circumstances. The author gave a little
      background and the
      reasons for his study. Patients with cirrhosis are
      expandng the waiting
      list for liver transplantation throughout the world.
      Current medical
      strategies are ineffective in preventing recurrence of
      HCV or in
      treating post transplant hepatitis C. Often, Hepatitis
      C can recur
      following transplantation. Everson said treatment
      after transplant is
      unlikely to clear HCV-RNA. The number of transplants
      performed for
      recurrent, progressive, allograft Hepatitis C is
      increasing. Hepatitis C
      is the number one indication for liver
      transplantation. Therefore,
      aggressive approaches designed to eradicate hepatitis
      C in patients with
      advanced liver disease awaiting transplant are needed.

      However, the most effective antiviral therapy,
      combination interferon
      plus ribivarin, is relatively contraindicated due to
      fear of
      precipitation of decompensation of liver disease or
      development of
      dangerous cytopenias. This study's aim was to explore
      the safety and
      efficacy of treating advanced chronic hepatitis C with
      decompensated
      liver disease with combination IFN+RBV.

      So, there are two main reasons to potentially treat
      patients with
      decompensated cirrhosis. If patients can clear HCV RNA
      they may improve
      or stabilize liver function and maybe they can come
      off transplant list.
      For other patients who may not yet be transplant
      patients, stopping or
      reversing disease progression may be possible.

      The specific aims of the study were to determine if a
      low accelerating
      dosing approach (LADR) could clear HCV-RNA, if it's
      tolerable (side
      effects, dose adjustments, dropouts, use of G-CSF for
      low WBC and
      erythropoeitin), and if treatment reduces the risk of
      post-transplant
      recurrence of HCV.

      Study patients (n=86) were eligible for in the
      hepatology clinics of the
      University of Colorado Health Sciences Center, and
      were started on the
      LADR protocol.

      DEMOGRAPHICS
      (half of patients are transplant candidates and 40%
      are on waiting list)

      Age: 24-66 years

      Male- 52, female 34

      Prior history of alcohol: 50%

      Genotype 1: 77%

      Biopsy proven cirrhosis: 62%

      Clinical cirrhosis: 24%

      Non-cirrhosis but had bridging fibrosis: 14%

      63% had one or more of these complications:

      Variceal hemorrage: 21%

      Ascites; 44%

      SBP: 7%

      Encepholopathy: 34%

      42 patients underwent endoscopy and 64% of them had
      documented varisces

      Lab studies indicated that 43% had albumin < 3.5 g/dl,
      52% had INR >1.2,
      33% had bilirubin >2 mg/dl, and 68% had platelet count
      <130,000.

      LADR Protocol:

      Initial therapy: IFN-2b 1.5 MU tiw + Ribivarin 600
      mg/day

      After 2 weeks they tried to increase IFN dose to 3 MU
      tiw (full dose),
      if therapy was tolerable and WBC and platelet count
      were stable

      After 4 weeks they tried to increase RBV dose to 200
      mg/day, on a weekly
      basis in trying to reach goal of 1000 to 1200 mg/day
      RBV (full dose),
      based upon patient weight, tolerance, to medications,
      and hemoglobin
      level

      Granulocyte-colony-stimulating factor (G-CSF) and
      human recombinant
      erythropoeitin were given as needed to maintain PMN
      >800 and hemoglobin
      >10 g/dl, respectively

      CBC and Biochemistry done every 2 weeks and HCV PCR
      done every 3 months

      The goal was to achieve standard full dose therapy of
      3 MU 3x/week IFN
      plus 1000/1200 mg/day RBV.

      TREATMENT OUTCOME

      75 enrolled and began treatment. Some patients had
      transplants and some
      were non-adherent

      21 patients dropped out

      25 patients cleared RNA on treatment (<100 copies)

      of the 25 that cleared RNA 12 relapsed and treatment
      was discontinued

      29 were viral non-responders

      6 had sustained virologic response for >6 months

      3 have virologic response but follow-up is <6 months

      4 are in the last 3 months of treatment

      DROPOUTS & COMPLICATIONS

      There were 21 dropouts, 19 related to side effects and
      2 due to
      non-compliance. The most common were fatigue,
      neuropsychiatric symptoms,
      and cytopenias.

      Serious intercurrent illnesses occurred in 6 patients:
      encephalopathy
      (n=3), responded to lactose; sepsis (n=2) (pathogens
      or toxins in blood
      or tissues) (one patient died related to sepsis; one
      patient had staff
      abscess at injection site); 1 GI bleeding.

      G-CSF was used in 21 patients (28%) and erythropoeitin
      in 1 patient, so
      there was not much trouble with anemia in this
      protocol.

      RATE OF CLEARANCE of RNA

      Everson reported clearance rates in several ways:

      all patients (intent-to-treat) 25/86- 29%

      enrolled patients 25/75- 33%

      enrolled minus dropouts (as-treated)- 46%

      CHARACTERISTICS of RESPONDERS

      Everson stressed two points: The statistically
      significant ability to
      respond for genotype 1; and the response capacity
      based upon reaching
      full dose (see table below). He mentioned that being
      able to take full
      dose for at least 3 months was important to achieving
      response.

      Responders
      Nonresponders p-value
      Age (mean. Yr) 52.5 50.2
      NS
      M:F 15:10 34:16
      NS
      Cirrhosis 64% 56%
      NS
      Decompensation 64% 56%
      NS
      Genotype 1 52% 88%
      <.001

      DOSE EFFECT

      Full dose >6 months 48% 30% .13
      Full dose 3-6 months 24% 18%
      Inadequate dose 28% 52%

      The effect of dose on response was evident only in
      Genotype 1 patient
      <.05

      RNA CLEARANCE in GENOTYPE 1

      RELATIONSHIP TO DOSE

      There were 57 patients with genotype 1. 23 never got
      to full dose for 3
      months or more and only 2 cleared HCV*.

      N % SVR (n)
      Full dose >6 months 8/23 35% 2
      Full dose 3-6 months 3/11 27% 0
      Reduced dose * 2/23 9% 0

      RNA CLEARANCE in GENOTYPE 2, 3, 6

      The relationship to dose was not as evident.

      N % SVR (n)
      Full dose >6 months 3/4 75% 1
      Full dose 3-6 months 4/4 100% 1
      Reduced doses 5/10 50% 2*

      These 2 sustained responders received 12 months of
      treatment.

      RESULTS with LIVER TRANSPLANTATION

      19 of the 86 patients were transplanted. All the
      patients who were RNA+
      before transplant (including relapsers &
      nonresponders) were RNA+ after
      transplant (so far 12 patients). Of the 4 SVRs for
      whom data is
      available so far remain RNA- after transplant. And
      they have basically
      normal ALT & liver function.

      SUMMARY by Everson:

      This is a preliminary pilot study, but they saw 33% of
      patients (25/75),
      particularly for genotype 2/3 patients. For genotype 1
      patients, it's
      important to achieve full dosing to clear RNA for at
      least 3 months.
      With pegylated IFN becoming available they may be able
      to achieve
      reasonable response rates of approaching 50%.

      Sustained viral remission is rare (12%). Once you stop
      treatment the
      relapse rate is high. But if patients are able to
      achieve SVR, they do
      not appear to relapse post-transplant.

      Dropouts are common (50%).

      Serious complications occurred in 8%. I think Everson
      said he would
      expect this rate of complications in this population
      anyway.

      G-CSF required in 28% and Epo in 1%.

      CONCLUSIONS:

      LADR is warranted in decompensated cirrhotics

      Genotype 1 patients who become RNA negative on
      treatment should be
      maintained on IFN+RBV until time of transplant

      If treatment is withdrawn in a responder, monitor for
      relapse and
      consider reinstitution of therapy

      Everson speculates that clearance of HCV-RNA will:
      - Slow disease progression
      - Improve hepatic function
      - Reduce risk of post-transplant occurrence of
      Hepatitis C

      __________________________________________________
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