Treatment of Viral Hepatitis - PowerPoint by lzq12436

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									Treatment of Viral Hepatitis


          Paul Y Kwo, MD
   Associate Professor of Medicine
Medical Director, Liver Transplantation
Gastroenterology/Hepatology Division
Indiana University School of Medicine
              Human Hepatitis Viruses
                 Human Hepatitis Viruses
Virus   Genome                    Genome Envelope   Family / genus
                                  size (kb)
HAV     RNA                        7.5       -      Picornaviridae
        positive sense,                              hepatovirus
        single stranded, linear
HBV     DNA                        3.2      +       Hepadnaviridae
        partially double
        stranded, circular
HCV     RNA                        9.6      +       Flaviviridae
        positive sense,                              hepacivirus
        single stranded, linear
HDV     RNA                         1.7     +       Unclassified
        positive sense,                             (viroid), delta virus
        single stranded, linear
HEV     RNA                         7.5      -      Unclassified,
        positive sense, single                      togavirus and
        stranded, linear                            alpha virus-like
                      Hepatitis B Virus
                              Nucleic Acid: 3.2 kb DNA
                              Classification: Hepadnaviridae
                              Multiple serotypes and genotypes
            42 nm               A-H
                              Enveloped
           22 nm              In vitro model: primary
                                 hepatocyte culture and
        HBsAg
                                 transfection of cloned HBV DNA

42 nm             HBcAg       In vivo replication: in cytoplasm,
                                 cccDNA in nucleus; hepatocyte
                     HBsAg
                                 and other tissues, human and
        HBV DNA                  other primates
        22 nm
      Prevalence of HBsAg Carrier State




                        >8%
                        2-8%
                        <2%




WHO
                                    Hepatitis B by Year, United States, 1966 - 2000
                                                                               HBsAg
                               14                                           screening of
                                                                              pregnant Infant Immunization
Cases per 100,000 Population




                                                          Vaccine                         recommended
                               12                         licensed             women
                                                                           recommended
                               10                                                           OSHA Rule enacted
                                                                                                 Adolescent
                                8
                                                                                                Immunization
                                6                                                              recommended

                                4                                                     Decline among
                                                                     Decline among       injecting
                                2                                    MSM & HCWs         drug users

                                0
                                    1967 1970 1973 1976 1979 1982 1985 1988 1991 1994 1997 2000

                               Source: NNDSS                     Year
                        HBV: How Do People Get
                              Infected?
  Hepatitis B is transmitted by contact with blood or body
   fluids of an infected person

  The main ways of getting infected with HBV are:
        Perinatal (from mother to baby at birth)
        Child-to-child transmission
        Unsafe injections and transfusions
        Sexual contact
  HBV is 50 to 100 times more infectious than HIV

  Household contact is a documented risk factor
From http://www.who.int/vaccines/en/hepatitisb.shtml. Accessed 09/20/06.
American Journal of Epidemiology Vol. 132, No. 2: 220-232.
     HBV: How Do People Get Infected?

                  Asian Americans                                            Non-Asian Americans
  Mother to baby at time of birth
                                                                  Adult sexual activity (~54% of cases)
  (most cases)

  Within household (virus can survive for at
                                                                  IV drug use (~20% of cases)
  least 7 days outside body)

  Reuse of nonsterilized needles and syringes
  in poor healthcare facilities

  Traditional medicine
  (acupuncture, coining, cupping)




From http://liver.stanford.edu/Edu/Edu_stat.php. Accessed 09/10/06.
Centers for Disease Control and Prevention. Hepatitis B. In: Atkinson W et al, eds. Epidemiology & Prevention
of Vaccine-Preventable Diseases. 8th ed, Washington DC: Public Health Foundation; 2005:191-212.
HBV - Epidemiology

               Risk of Chronic Infection
        100

         80

         60
   %
  Risk 40

         20

          0
              Neonates   Infants   Children   Adults
                         Age at Infection
   Hepatitis B Virus Infection, United States
New infections /year 1985-90         438,000
1999                                 125,000
Deaths from acute liver failure 1999 300
Persons ever infected (1990)         4.9%
Persons with chronic infection      1.25 million
HBV-related chronic liver disease   4% - 14%
Deaths from chronic disease/year    ~ 5,000
Life-time risk of death due to HCC or cirrhosis ~30%
HBV - Natural History

         Cumulative Probability of Developing HCC in
        Patients with HBsAg + Compensated Cirrhosis
           20




           15
       %

           25




             0
                 0   1     2      3      4    5     6   7   8   9   10
                                             Year

 Fattovich, et al., Hepatology 1995; 21:77
HBV - Diagnosis


  Serological Markers         Clinical Significance
  HBsAg                       Acute/Chronic infection
  Anti-HBc IgM                Acute infection
  HBeAg                       High infectivity
  Anti-HBe                    Low infectivity
  Anti-HBs                    Immunity
  Anti-HBc IgG and HBsAg      Chronic infection
  Anti-HBc IgG and anti-HBs   Resolved infection
                     Hepatitis B Virus
                  Wild Type and Mutants
 Wild type
   Usual HBeAg (+) hepatitis
 Precore mutation (27% U.S. patients)
   Abolishes HBeAg production
 Core promoter mutation (44% U.S. patients)
   Down-regulates HBeAg production
 Treatment-induced mutations
   Lamivudine: M204V/I +/- L180M and others (YMDD)
   Adefovir: N236T and A181V/T
   Entecavir: I169, T184, S202 and M250 (only with treatment of patients with
    lamivudine mutations)
                     HBV Genotypes
 HBV classified into 8 genotypes (A-H)
   A: North America, Western Europe and Africa
   B and C: Asia
   D: Southern Europe, Africa and India
   E: West Africa
   F: Central and South America and Alaska
   G: United States, France and Germany
   H: Central America
 B associated with less active disease, slower
  progression, and lower incidence of HCC than C
 A and B respond better to IFN than C and D
 Genotype does not predict on-treatment response
  to oral agents
      Natural Course of Chronic HBV
                 Infection
                  HBeAg

                                       Anti-HBe
HBV
DNA




ALT


       Immune         Immune     Inactive    Reactivation
      Tolerance      Clearance    Carrier
                                    HBV DNA During Different Stages
                                              of CHB
   MAJOR RESULTS                                          MAJOR RESULTS
    HBeAg(+) patients                                     HBeAg(+) patients with sustained
                                                          HBeAg loss: (a) spontaneous, and
                                                          (b) IFN-related




                                                          Log10 HBV DNA (copies/mL)
   Log10 HBV DNA (copies/mL)




                               11                                                     11
                               10                                                     10
                                9                                                      9
                                8                                                      8
                                7                                                      7
                                6                                                      6
                                5                                                      5
                                4                                                      4
                                3                                                      3
                                2                                                      2
                                1                                                      1
                                0                                                      0
                                                                                           (a)   (b)   (a)   (b)   (a)   (b)
                                     1st    2nd     3rd
                                           Sample                                            1st          2nd            3rd
                                                                                                         Sample

Chu CJ, et al. Hepatology 2002;36:1408-1415
                 REVEAL: Baseline HBV DNA
                and Liver Disease Progression
Prospective, multicenter, observational cohort
                     study
                                              1991-1992: 7 Taiwanese townships
                                             Individuals aged 30-65 years eligible
                                                          (N = 89,293)


                                                 HCC-free individuals enrolled
                                                        (n = 23,820)


    Excluded if cirrhotic within 6 months

                           Cirrhosis Analysis                                      HCC Analysis
                               (n = 3774)                                           (n = 3653)
                      2004: 42,115 PYs follow-up                            2004: 41,779 PYs follow-up
                     395 cirrhotic patients (10.5%)                          164 HCC patients (4.5%)



Chen CJ, et al. JAMA 2006;295:65-73.
Iloeje UH, et al. Gastroenterology 2006;130:678-686.
        REVEAL Study: HBV DNA Levels and Long-
                   Term Outcomes
                                                        Viral Load at Baseline
                               < 300 (Undetectable)              10,000-99,999                  1 Million
                               300-9,999                         100,000-999,999

                     Cumulative incidence of HCC                                     Multivariate-adjusted
                           (%) (n = 3653)                                     relative risk of cirrhosis (n = 3482)
             20                                                         12
                                                                                                                   10.6
                                                                                                             9.7
                                                                        10
                                                        14.89%
             15
                                                   12.17%                 8

             10                                                           6

                                                                          4                      3.6
               5                          3.57%                                          2.0
                                                                          2
                      1.30% 1.37%                                                  1.0
               0                                                          0
Chen CJ, et al. JAMA. 2006;295:65-73.
Iloeje UH, et al. Gastroenterology. 2006;130:678-686.
HBV

         Indications for HBV vaccination

       HBIG and HB vaccine to infants of HBsAg+
        mothers

       Routine vaccination of infants and adolescents

       Catch-up vaccination of children

       Vaccination of adults at risk of infection
    Surrogate Clinical Markers for
        Hepatitis B Outcomes
Liver histology Improves                   Serum HBV DNA declines




                           Prevention of
                              Death,
                             Cirrhosis,
                             and HCC




      Seroconversion (loss of HBeAg,         ALT normalization
          production of anti-HBe)
Cirrhosis Reversal Following
   Lamivudine Rx in HBV




                          Courtesy of Ian Wanless, MD.
                       HBV Treatments 2007
                     Interferon or 4 oral agents
        Interferon            Lamivudine                 Adefovir
        Pegylated IFN         Telbivudine                Entecavir
Pros    Finite duration of    Oral                      Oral
         therapy
                               Negligible side           Effective against
        Durable response        effects                   lamivudine-resistant
         post treatment                                    mutants
        Resistant mutants                                Resistant mutants not
         not reported                                      reported at 1 year


Cons    Injection             Long / indefinite         Long / indefinite
                                duration of                duration of therapy
        Frequent side          therapy
         effects                                          Long-term renal
                               Resistant mutants          toxicity unknown
                               Higher with
                                lamivudine/telbivudine
                     Treatment Recommendations
                        for HBeAg(+) Patients
       ALT           HBV DNA                         Recommendations
                                           No treatment, monitor1,2,3
  ≤2 × ULN                  +
                                           Grey zone: ALT 1–2 x ULN or
                                           intermittently elevated; liver biopsy →
                                           moderate/severe inflammation or
                                           advanced fibrosis → treatment1

  >2 × ULN                  +              Observe × 3–6 months; treat if no
                                           spontaneous HBeAg
                                           seroconversion1,2,3
                                           Immediate treatment if bilirubin
                                           increases3 or decompensation1,3

HBV DNA: + defined as >100,000 copies/mL
Guidelines: 1AASLD; 2EASL; 3APASL
                                        Baseline ALT and Response to
                                        Treatment of HBeAg(+) Patients

                                        50
               % HBeAg Seroconversion




                                        40
                                                                                     Placebo
                                                                                     LAM
                                        30                                           IFN
                                                                                     LAM + IFN
                                        20


                                        10


                                         0
                                              1-2 x ULN      2-5 x ULN   > 5 x ULN
                                                          Baseline ALT

Perrillo RP, et al. Hepatology 2002;36:186-194.
                 Treatment Recommendations
                     for HBeAg(-) Patients

    ALT                HBV DNA             Recommendations
≤2 × ULN        <100,000 copies/ml No treatment, monitor1,2,3
                                    Grey zone: ALT 1–2 X ULN; HBV
                                    DNA 10,000 – 100,000 copies/mL
                                    Liver biopsy → moderate/severe
                                    inflammation or advanced
                                    fibrosis → treatment1

>2 × ULN        >100,000 copies/ml Treatment1,2,3

HBV DNA: < or >100,000 copies/mL
Guidelines: 1AASLD; 2EASL; 3APASL
                              Treatment Algorithm
                    Patients with Compensated Disease
                                        HBeAg Positive


            HBV DNA                                                      HBV DNA
          <20,000 IU/mL                                                ≥20,000 IU/mL


                                                         ALT Normal                      ALT
                                                                                       Elevated


• No treatment                            • Monitor ALT every 3-12           • Treat
                                            months (immune                   • Adefovir, entecavir,
• Monitor every 6–12 months                 tolerant)                          peginterferon, and
                                          • Consider biopsy, if age            possibly telbivudine are
                                            >35–40, and treat if               first-line options
                                            significant disease


Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
                              Treatment Algorithm
                 Patients with Compensated Disease
                                       HBeAg Negative


            HBV DNA                                                     HBV DNA
           <2,000 IU/mL                                                ≥2,000 IU/mL


                                                         ALT Normal                      ALT
                                                                                       Elevated


• No treatment                            • Monitor ALT and HBV              • Treat
                                            DNA, or                          • Adefovir, entecavir,
• Monitor every 6–12 months
                                          • Consider biopsy, since             peginterferon, and
                                            ALT often fluctuates,              possibly telbivudine are
                                            and treat if significant           first-line options
                                            disease                          • Long-term treatment
                                                                               required (oral agents)

Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
Treatment Algorithm
Patients with Compensated Cirrhosis

             HBV DNA                       HBV DNA              HBV DNA
             <2,000 IU/mL                  (PCR)                ≥2,000 IU/mL



                                   • Treat with adefovir or entecavir
                                   • May be a role for combination therapy
                                   • Significant clinical consequences associated with
                                     lamivudine resistance in this population


       • May choose to treat or observe
       • If treat: adefovir or entecavir, or combination Rx
       • May be a role for combination therapy


Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
 Management of Antiviral Resistance HBV
Prevention
• Avoid unnecessary treatment
• Initiate treatment with potent antiviral that has low rate of
drug resistance or with combination therapy
• Switch to alternative therapy in patients with primary non-
response
Monitoring
• Test for serum HBV DNA (PCR assay) every 3-6 months
during treatment
• Check for medication compliance in patients with virologic
breakthrough
• Confirm antiviral resistance with genotype testing
                 Antiviral HBV Drug Resistance
                                Potential Treatment

        Resistant Drug                                 Rescue Therapy
                                    Continue lamivudine and add adefovir or tenofovir*
      Lamivudine-R
                                    Switch to emtricitabine/tenofovir*

                                    Continue adefovir and add lamivudine or telbivudine
      Adefovir-R                    Switch to or add entecavir (if no prior LAM-R)
                                    Switch to emtricitabine/tenofovir*
                                    Switch to or add adefovir or tenofovir*
      Entecavir-R
                                    Switch to emtricitabine/tenofovir*
                                    Continue telbivudine and add adefovir or tenofovir*
      Telbivudine-R
                                    Switch to emtricitabine/tenofovir*

     *Not approved by FDA.
Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962, and
Lok ASF, McMahon BJ. Hepatology. 2007;45:507-539.
       Bottom Line: When to Start Therapy:
           1) Elevated HBV DNA Level
             2) ALT Level above ULN



The Threshold and Guidelines for treating HBV are
falling and dynamic
Hepatitis C: A Global Health Problem
               170-200 Million Carriers Worldwide



                                                              Far East Asia
                           Western        Eastern                 60 M
                           Europe         Europe
     US                                    10 M
                            5M
   3-4 M
                                                       South East Asia
                                                          30-35 M

    Americas                     Africa
    12-15 M                     30-40 M



                                                                    Australia
                                                                     0.2 M


                                                    World Health Organization, 1999.
    Hepatitis C Virus Infection in the US

   New infections (cases)/year
      1985–1989                      242,000
      2003                          30,000
   Deaths from acute liver failure   Rare
   Persons ever infected (1.8%)      3.9 million (3.1–4.8)*
   Persons with chronic infection     2.7 million (2.4–3.0)*
   HCV-related chronic liver disease 40%–60%
   Deaths from chronic disease/year 10,000



                         *95% Confidence Interval
  Prevalence of HCV Antibody NHANES III

                                                        90s       00s
                     2,000,000
        Prevalence




                     1,500,000

                     1,000,000

                       500,000

                                 0
                                     6-11   12-19    20-29    30-39   40-49   50-59   60-69   70-79   80+


                                                    Age distribution

Adapted from Alter MJ, et al.,. N Engl J Med. 1999;341:556–562.
               Risk Factors for Acute Hepatitis C
                                                     United States, 1991-1995


                                                                                         Injection Drug Use 43.0%



   Other
   High Risk* 30.0%



*Other High Risk                                                                                   Unknown 1.0%
                                                                                                  Household 3.0%
 16% drug related
 •11% previous drug use                                                                       Occupational 4.0%
   not within last 6 months
 • 5% intranasal cocaine use                                                               Transfusion** 4.0%
 4% history of STDs                                                                                **None in 1995

 1% prison
                                                                                    Sexual (Multiple Partners) 15.0%
 9% lower socio-economic status (fewer years of education)


 Alter MJ. Presented at the NIH Consensus Development Conference, March 24, 1997.
         HCV Infection Testing Algorithm
     for Diagnosis of Asymptomatic Persons
                                                                 EIA for Anti-HCV                               Negative
                                                                                                                               STOP
                                                                                                              (non-reactive)
                                  Positive (repeat reactive)
                                                                                 OR

                                                                             Negative
                    RIBA for Anti-HCV                                                                        RT-PCR for HCV RNA


                 Negative                            Indeterminate                             Positive                  Positive

                               Additional Laboratory                                  Medical
          STOP               Evaluation (e.g. PCR, ALT)                              Evaluation
                          Negative PCR,               Positive PCR,
                           Normal ALT                 Abnormal ALT


Adapted from Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset. Accessed 01/18/03.
MMWR 1998;47 (No. RR 19)
                 HCV Genotypes and Subtypes

       Developed countries           2      Americas + Western Europe



  South Africa

                             5
                                                    1
Middle East
North Africa
                   4


         IVDU
                                            Asia
                              3
  Simmonds P, Journal of Hepatology, 1999   6
                             Chronic HCV Infection
                                           HCV RNA
              1000       + + + + + + + + + + + + +

               800
  ALT (U/L)




                                                    Anti-HCV
               600                                                                Chronic
               400
                                 Symptoms                                        Hepatitis C

               200

                0
                     0   2   4   6    8   10   12   24   1   2   3   4   5   6
                             Weeks                             Months
                                     Time After Exposure
Hoofnagle JH. Hepatology.1997;26:15S-20S.
            Hepatitis C: Spectrum of Disease

                                                        Acute HCV Infection
                                                   85%                    15%

                                   Chronic HCV Infection                Recovery
                            Severe           Moderate      Mild


                            Cirrhosis         Chronic Hepatitis



           HCC             End-Stage
                         Liver Disease




Hoofnagle JH. Hepatology. 1997;26:15S-20S.
HCV-related fibrosis, cirrhosis and
     hepatocellular cancer
                     Why Do We Treat Chronic HCV?
              1000
                                                                                HCC
               800                                                         4+
                                  ALT                                3+
                                                           2+
  ALT (U/L)




                                                    1+
               600                                             Fibrosis   Cirrhosis

                                                    Anti-HCV
               400
                                                    HCV RNA
               200


                 0
                     0    0.5      1        2   5   10 15 20 25 30 35 40 45 50
                                                Years After Exposure
Hoofnagle JH. Hepatology 2002;36:S21-S29.
        Who Should Be Treated for
              Hepatitis C?
• Those with detectable HCV RNA, liver biopsy
 with fibrosis and/or inflammatory changes
• Patients with cirrhosis without decompensation
• Acute hepatitis C
• People with significant extra-hepatic manifestations
of hepatitis C
• A normal ALT may mean less severe disease, but
treatment should be individualized, especially with
improved cure rates
                  HCV Therapy: Definitions

 Rapid Virologic response : Undetectable HCV RNA at
  week 4 of therapy: These individuals may require
  shorter treatment duration
 Early virologic response (EVR): 2 log (99%) reduction in
  HCV RNA level during therapy, usually at week 12
   Accurately predicts non-response to therapy, need to use
    same assay
 Sustained virologic response (SVR): Undetectable HCV
  RNA by PCR testing 24 weeks after stopping therapy
   The best definition of cure at this time
 Non-response: Failure to clear HCV RNA during
  therapy, can be determined during weeks 12-24
        Use of Viral Kinetics to Define
     On-treatment Predictors of Response
HCV RNA




              4                   12                      24
                                 Weeks
          Earlier viral clearnace predicts greater liklihood of
                        sustained response (cure)
                Peginterferon alfa-2b/Ribavirin
                     Virologic Response
              100          IFN/RBV
                           PEG IFN 0.5 + RBV 1000-1200
               80          PEG IFN 1.5 + RBV 800               80   82
                                                          79
    SVR (%)




               60                54*
                     47*   47
               40                                   42†
                                         33†   34
               20


               0
                           All             Genotype 1     Genotype 2/3
*P = .01; †P = .02

Manns MP, et al. Lancet. 2001. 358:958
% of patients with undetectable HCV-RNA
                                          SVR in US Genotype 1 Patients (ITT)
                                          80


                                          60
                                                     40                                      41
                                                                        38
                                          40


                                          20


                                          0
                                               PEG α-2b 1.5 + R,   PEG α-2b 1.0 + R,   PEG α-2a 180 + R,
                                                  N=1019              N=1016              N=1035



PEG-IFN -2b 1.5/RBV vs PEG-IFN -2a 180/RBV, p-value 0.57
PEG-IFN -2b 1.5/RBV vs PEG-IFN -2b 1.0/RBV, p-value 0.20
                                       86
                 2008: “Tailored”
             Treatment for Genotype I

•   A 24 week dosage regimen with Peg-IFN/RBV
    appropriate for genotype 1 CHC patients with a
    rapid viral response (RVR)
•   A 72 week dosage regimen with Peg-IFN/RBV is
    appropriate for “slow responders”
•   Higher doses of RBV may be appropriate for
    certain genotype 1 patients
•   Ribavirin dose will be most important till
    introduction of new molecules for HCV
   Should First Viral HCV-RNA Assessment be
                Done at Week 4?

• Goal with week 12 assessment: Identify non-
  responders early during therapy to determine if
  therapy should be discontinued
   – Avoids additional morbidity in those who will not
     respond
   – Reduces cost
• In 2008,
   – Can we make a determination at 4 weeks as to who is likely
     to respond?
   – Can we identify those genotype 1 patients who might
     respond with only 24 weeks of therapy?
                   Shorter Treatment Duration for HCV-1
                   and Rapid Virologic Response (RVR)
           PEG-IFN 180 g/wk plus RBV 1,000-1,200 mg/day


             366 treatment naïve HCV-1 and HCV-4 pts received
              standard PEG + RBV
             79 (22%) W4 HCV RNA – patients received a total
              of 24 wks of therapy
         100%                                 92%          92%

           80%                                       74%          73%
                           67%
                                                                           24 wks may suffice
           60%                                                           for HCV-1 with LVL and
                                                                           early fibrosis if RVR
           40%

           20%

             0%
                            ITT                LVL   HVL   F0-2   F3-4

Ferenci et al. Hepatology 2005;42(suppl 1):218A.
                              High Dose Ribavirin for HCV
                                       Is there a role in non-responders?
       Genotype 1 naïve patients 48 weeks of treatment
       3 arms : Standard PEG IFN alpha 2 b with
             RBV 800-1400; RBV 800-1400, EPO; RBV1000-1600, EPO
                 70
                 60
                                                                                 *
                 50                                                                               PEG RBV 800-
                 40                                                                               1400
                                                                                                  PEG RBV 800-
                 30                                                                               1400 EPO
                 20                                                                               PEG RBV 1000-
                                                                                                  1600 EPO
                 10
                   0
                             EVR                  EOT                   SVR
Shiffman ML, Price A, Hubbard S, et al. Treatment of chronic hepatitis C virus (HCV) genotype 1 with peginterferon alfa-2b (PEGIFN), high
weight based dose ribavirin (RVN) and epoetin alfa (EPO) enhances sustained virologic response (SVR). Program and abstracts of the 56th
Annual Meeting of the American Association for the Study of Liver Diseases; November 11-15, 2005; San Francisco, California. Abstract 55
   What patients benefit from a longer duration of
                    treatment?

                                                          Non-response to treatment (NR)
     HCV RNA Level




                                                               Partial Response to treatment (NR)


                                                                   Slow response to treatment
                                                                   (SVR, NR or relapse)
                     RVR
                                      EVR
                                  (SVR or relapse)

                           4                         12                            24
                               Treatment Week: PEG IFN Ribavirin

•Those with slow response, early virologic response may benefit
from treatment duration beyond 48 weeks (decreasing relapse)
•? partial responders
        TeraViC-4 Study: Prolonged therapy reduces
               relapse in those without RVR
      510 patients, 78% genotype 1,4
      PEG IFN alfa 2a 180 mcg, RBV 800 mg
      Those without RVR at week 4 randomized (326) to 48 vs 72 weeks

                                70
         HCV RNA undetected %




                                     61 61
                                60           p=.01              p=.003   48 weeks
                                50
                                                  45                44
                                40                                       72 weeks
                                             32
                                30                                28
                                                                         48 weeks
                                20                                       genotype 1
                                10                                       72 weeks
                                                                         genotype 1
                                 0
                                       EOT    SVR            SVR
                                                           Genotype 1
Sanchez-Tapia SJM. Hepatology 2004;40:218A. Abstract No. 126.
            New Strategic Approaches
• Improved pharmacokinetics – eg, PEG-IFN
• Improved routes of administration – albumin-interferon alpha
  (fusion protein of IFN and albumin)
• Reduced toxicity of RBV – eg, viramidine, VX 497
• New molecular targets – protease inhibitors, helicase,
  polymerase inhibitors
    • VX-950, SCH 503034 , MK-7009 (all undergoing clinical
      trials here at IU)
• Antifibrotics/immune modulators/apoptosis
  inhibitors – eg, IFN-, low-dose IFN, thymosin,
  IDN-6556 (caspase inhibitor)
• Supportive agents – eg, epoetin, G-CSF, antidepressants

Have a referral for study or non-study patient to be seen?
pkwo@iupui.edu or call 317-278-1187
                 Maintenance Therapy

Indications                     Goals
 Nonresponse                    Delay
                                  progression
  to best available              Prevent
  therapy                         cirrhosis,
 Advanced                        decompensation, HCC
  fibrosis or                    Avoid liver
                                  transplantation
  cirrhosis                      Improve survival

 CO-PILOT: 0.5 mcg/kg PEG Interferon alfa-2b
 EPIC: 0.5 mcg/kg PEG Interferon alfa-2b
 HALT-C: 90 mcg Peg Interferon alfa-2a
                    HALT C results
 34.1% of patients in the pegylated interferon maintenance arm
  and 33.8% of the control group had reached one of the study
  endpoints (hazard ratio 1.01; P = 0.91; not a significant
  difference).

  Although mean serum ALT and HCV RNA levels decreased
  significantly with treatment (both P < 0.0001), as did
  necroinflammatory changes on liver biopsy (P < 0.0001), there
  was no significant difference observed in rates of any of the
  primary outcomes:

  Death: 6.6% in the treatment group vs 4.6% in the control
  group;

  Hepatic decompensation: 14.3% vs 13.2%, respectively;

  HCC: 2.8% vs 3.2%;

  Increased fibrosis: 28.2% vs 31.9%.
      HCV-Related Liver Transplantation in 2008
   HCV is leading indication for liver transplantation
       500,000 with HCV related cirrhosis in US
   Recurrence is universal; progressive liver injury occurs
   Posttransplantation natural history is variable
    – Short-term survival is good
    – Long-term natural history is not as good
   Management of immunosuppression is controversial
   IFN or RBV monotherapy has limited efficacy
   Combinations of RBV + IFNs or PEG IFN lead to sustained response
    rates that are lower than in non-transplant patients
               Selected Herbs
                  Milk Thistle



 Silymarin (Silybum marianum)

 Used for almost 2000 years

 Reemergence for the therapy
  of liver disease

 Virtually every patient asks about it
                              Selected Herbs
                              Milk Thistle (cont’d)
       Antioxidant/anti-inflammatory effects
       Inhibits lipid peroxidation
       Decreases the activity of tumor
        promoters
       Chelates iron
       Most of the existing clinical trials in
        chronic liver disease have flaws
       Lack of clinical studies in patients with
        HCV infection
Bhatia N, et al. Cancer Lett. 1999;147:77. Flora K, et al. Am J Gastroenterol.
1998;93:139. Patrick L. Alternative Med Review. 1999;4:220.
               What I Tell Patients Who Are
               Diagnosed with Hepatitis C
• Hepatitis C is the major cause of chronic hepatitis in the United States
• Hepatitis C is transmitted primarily by contact with infected blood or
blood products administered through the blood stream
• Sexual transmission and mother-to-fetus transmission are rare
(Centers for Disease Control does not consider HCV to be a sexually
transmitted disease)
• This disease is difficult to transmit to family members
• Alcohol consumption should be minimized, abstinence is
recommended
•Insulin resistance reduces efficacy of interferon based therapy
•Acute hepatitis C is curable almost 100% of the time
        What I Tell Patients Regarding
         Transmission of Hepatitis C
• You should refrain from donating blood, organs, tissues
or semen
• With multiple sexual partners, the use of latex condom
should be encouraged
• Sexual partners of infected patients should be tested for
HCV
• Do not share razors and toothbrushes, but it is not
necessary to avoid sharing meals or utensils
• HCV patients can participate in any social, education or
employment activities
•Pegylated Interferon and ribavirin remains the standard,
and likely will not be replaced for 5 years
         What I Tell Patients Regarding
           Treatment of Hepatitis C
 HCV can be cured in over half of all cases
 Therapy is evolving: week 4 PCR clearance suggests
  shorter duration of treatment may be sufficient with no
  sacrifice in SVR for all genotypes
   24 weeks for genotype 1 low viral load
   12 weeks for genotypes 2 and 3
   Extending therapy beyond 48 weeks in those with who are slow
    responders may reduce relapse

 Future therapies appear promising though interferon
  will remain the backbone of therapy

								
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