HBV

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HBV Powered By Docstoc
					Jeffery W. Spray, Pharm.D., BCPS
      Clinical Pharmacy Specialist
        Winchester Medical Center
Objectives
   Identify risk factors associated with
    development of viral hepatitis
   Explain pathophysiologic mechanisms
    associated with the development of acute and
    chronic hepatitis
   Describe patients most likely to benefit from
    vaccination against HAV and HBV
   Design an initial treatment regimen for a
    treatment naïve patient with HCV
   List the primary adverse effects associated
    with agents used in the treatment of viral
    hepatitis
Hepatitis A
   Risk factors for development
       Long stays in endemic countries/areas
       Men who have sex with men
       Injecting drug users
       Persons working with nonhuman primates
       Contact with child or employee in child care
        center
   Primarily occurs through person to person
    contact
     Oral inoculation of fecally excreted virus
     Ingestion of contaminated food/water
Viral Hepatitis relative modes of
transmission
   Fecal-Oral        Sexual Transmission
     HAV +++           HBV +++
     HEV +++           HDV ++
   Parenteral          HGV +
    Transmission      Perinatal
     HBV +++          Transmission
     HCV +++           HBV +++
     HDV ++            HCV +
     HGV ++            HDV +
     HAV +           Unknown
                        HBV +
                        HCV +
HAV Pathophysiology
 Self limiting disease, up to 6 months in
  duration causing inflammatory damage
  to the liver
 3 stages
     Incubation
     Acute hepatitis
     Convalescence
HAV Pathophysiology
   Incubation
     Duration: 15-50 days, avg. 25-30 days
     Peak viral excretion 2 weeks before onset of
      jaundice
     Viremia and elevated liver enzymes occurs
      soon after infection
     Viral antigens can be found in hepatocytes
     Host usually asymptomatic
HAV Pathophysiology
   Acute Hepatitis
     Preicteric phase (before jaundice) 5-7 days
      ○ Nonspecific influenza-like symptoms – anorexia,
        nausea, fatigue, fever, and malaise
          Mild disease – mild elevations of bilirubin, gamma
           globulin, ALT, and AST
     Icteric phase 4-30 days
      ○ Significant liver dysfunction, interruption of
         bilirubin metabolism and flow
      ○ Sx’s: fever, RUQ abdominal pain, nausea,
         vomiting, dark urine, light colored stool
      ○ AST, ALTs 4x ULN
   Convalescence
HAV Pathophysiology
 Liver injury is immune mediated through
  cytotoxic T cells
 Death of hepatocytes results in viral
  elimination and resolution of clinical
  illness
 IgM is formed shortly after infection
  (usually detectable 5-10 days)
 IgG antibodies formed 2-6 months,
  confer lifelong immunity
HAV Treatment
 Supportive Care
 Liver Transplant for pt that develop
  fulminant hepatitis
 Avoid hepatotoxic agents
     Acetaminophen, alcohol
HAV Prevention
   Immunoglobulin
     Administered IM provides 3-5 months of
      protection
      ○ Used for patients who might have been exposed
        or travellers to endemic areas
   Vaccines
     Children after 12-18 months routinely
      vaccinated
     At risk adults should be vaccinated
     Pt with chronic liver disease due to higher risk of
      complications
   Handwashing
Acute HBV
   Acute HBV
     Often asymptomatic (70% of adults, 90% of
      children)
     Incubation period 1-4 months
     Sx/Symptoms (last 1-3 months)
     ○ Nausea, anorexia, fatigue, low-grade fever,
       right upper quadrant pain
     ○ Jaundice can occur, but usually when
       symptoms resolving
     ○ Myalgias, joint pain, urticaria
Acute HBV
 Treatment - supportive
 AST and ALT may rise up to 20,000 IU/L
    ○ Typically peak 2 weeks prior to jaundice

 Elevated Bilirubin
 Mild anemia
 Most of the liver damage is related to
  immune response, not direct viral damage
 Fulminant hepatic failure only occurs in 1%
  of patients
Chronic HBV
 Defined as presence of HBsAg for 6
  months
 4 phases
     Immune tolerant
      ○ High HBV DNA, HBeAg, and transaminases
      ○ Incubation period, can last for years
     Immune response
      ○ Inflammatory cascade
      ○ Causes destruction of HBV infected hepatocytes
      ○ High risk of progression to cirrrhosis and cancer
Chronic HBV
   4 stages cont.
     Inactive carrier state
      ○ End of viral replication
      ○ HBeAg becomes negative and transaminase
        levels normalize
      ○ Most adults reach this phase rapidly
      ○ Can have flares of disease
     Immune stage
      ○ Clearance of HBsAg, HBV DNA undetectable
      ○ Only occurs in 3% of patients
   Lifetime risk of developing cirrhosis or
    cancer 15%-25%
Relative Risk of developing HCC from
HBV
HBV Prevention
   Vaccination
     All children and adolescents, as well as high risk
      adults
      ○   Hx STD
      ○   Household contact with HBV carrier
      ○   Healthcare workers
      ○   IV drug users
      ○   Men who have sex with men
      ○   Sexual partners of HV infected persons
      ○   High risk sexual practices
     3 injection series
      ○ Protection achieved in 90% of adults
      ○ Booster only for immunocompromiseds
HBV Prevention
   Vaccination
     All children and adolescents, as well as high risk
      adults
      ○   Hx STD
      ○   Household contact with HBV carrier
      ○   Healthcare workers
      ○   IV drug users
      ○   Men who have sex with men
      ○   Sexual partners of HV infected persons
      ○   High risk sexual practices
     3 injection series
      ○ Protection achieved in 90% of adults
      ○ Booster only for immunocompromiseds
Immune Globulin
 BayhepB
 HyperHEP B
 Nabi-HB
 Nabi-HB NovaPlus
 HepaGam B
Goals of Tx for chronic HBV
infection
 Eradication or suppress HBV
 Short term
     Limit hepatic inflammation
     Decrease risk of fibrosis and/or
     decompensation
   Long term goals
     Prevent transaminase flares and long term
      compensation
     Prolong survival
     Loss of HBeAg
HBV Treatment
   Indications for treatment
     HBeAg and transaminase levels > twice
      normal
     Presence of HBV DNA and transaminase
      levels > twice normal
     Moderate to severe hepatitis on liver biopsy
     Presensce of HBV and cirrhosis
   Goals of Tx
     Erradicate or permanently suppress HBV
HBV Indications for Treatment
 HBeAG +, ALT > 2x ULN or hepatitis on
  biopsy – Lamivudine or interferon
 HBeAG -, ALT > 2x ULN – tx only if
  hepatitis seen on biopsy or HBV DNA
  >105 copies/ml
     Failure to respond to interferon, can tx with
     lamivudine
   Decompensated liver disease – only use
    lamivudine
Diagnostic Tests for HBV
Test           CHB HBeAg    CHB HBeAg    Inactive Carrier
               Positive     Negative
HBsAg          +            +            +
Anti-HBs       -            -            -
HBeAg          +            -            -
anti-HBe       -            +            +
anti-HBc       +            +            +
IgM anti-HBc   -            -            -
HBV DNA        >2x104       >2x103       < 2x103
               IU/ml(>105   IU/ml(>104   IU/ml(<104
               copies/ml)   copies/ml)   copies/ml)
ALT level      Elevated     Elevated     Norma
HBeAg   HBV DNA    ALT    Treatment strategy
        (IU/ML)

+       > 20,000   <2 x   Observe; consider treatment when ALT becomes elevated;
                   ULN    Consider biopsy in persons 40 years, ALT persistently high
                          normal-2x ULN, or with family history of HCC.; Consider
                          treatment if HBV DNA 20,000 IU/ml and biopsy shows
                          moderate/severe inflammation or significant fibrosis
+       > 20,000   >2 x   IFN/pegIFN , LAM, ADV, ETV or LdT may be used as initial
                   ULN    therapy; End-point of treatment – Seroconversion from HBeAg to
                          anti-HBe
                          Duration of therapy: IFN-: 16 weeks; PegIFN-: 48 weeks;
                          LAM/ADV/ETV/LdT: minimum 1 year, continue for at least 6
                          months after HBeAg seroconversion; IFN non-responders /
                          contraindications to IFN 3 ADV/ETV; IFN-/peg IFN-,
-       > 20,000   >2 x   LAM, ADV, ETV or LdT may be used as initial therapy; End-point
                   ULN    of treatment – not defined; Duration of therapy: IFN-/pegIFN-: 1
                          year; LAM/ADV/ETV/LdT: 1 year

-       > 20,000   1-2 x treat if liver biopsy shows moderate/severe inflammation or
                   ULN significant fibrosis
-       < 20,000   WNL    Observe, treat if HBV DNA or ALT becomes higher

+/-     Detect-    Cirrh Comp.: HBV DNA 2,000 IU/ml—Treat, LAM/ADV/ETV/LdT may
        able       osis be used as initial therapy
                          Decomp.: LAM (or LdT) ADV or ETV preferred. Refer
                          for liver transplant
Interferon-alpha
   MOA
     Interferon induced production intracellular
      enzymes such as 2'5'-OAS and protein kinase
      that inhibit of viral replication by activation of
      endoribonucleases that cleave viral RNA
      ○ translation of viral proteins is inhibited.
     Contraindications
      ○ Neutropenia, Thrombocytopenia, Depression,
        Decompensate cirrhosis, Alcohol or drug abuse
     Predictors of response
      ○ Low HBV DNA levels, Elevated transaminases,
        Lack of fibrosis, Female, HIV Negative, genotype
        A or B
Dosing IFN alpha
   Dosing
     Adults is 5MUdaily or 10 MU thrice weekly
     Children 6 MU/m2 thrice weekly (max. of 10
      MU)
   Duration
     HBeAg positive chronic hepatitis B is 16 to 24
      weeks
     HBeAg-negative chronic hepatitis B should be
      treated for at least 12 months, and one study
      suggested that 24 months treatment may
      increase the rate of sustained response
IFN Monitoring
 Blood counts and liver panel monitored
  every 4 weeks, thyroid stimulating hormone
  (TSH) and HBV DNA levels every 12
  weeks, and, if initially HBeAg-positive,
  HBeAg/anti- HBe every 24 weeks during
  treatment.
 Blood counts, liverpanel, TSH and HBV
  DNA, and if initially HBeAg positive,
  HBeAg/anti-HBe should be tested every 12
  weeks during the first 24 weeks post-
  treatment.
PEG – IFN alpha
 PEG molecule allows for longer t50 for
  the medication and less frequent dosing
 Dosing 180mcg weekly for 48 weeks
 Similar AE as regular IFN
 Growing evidence of improved efficacy
  over standard IFN
Lamivudine
   MOA
     synthetic nucleoside analogue, is phosphorylated intracellularly
      to its active 5'-triphosphate metabolite, this is incorporated into
      viral DNA HBV polymerase, resulting in DNA chain termination
   AE
     Common
       ○ Endocrine metabolic: Lipodystrophy (less common)
       ○ Gastrointestinal: Decrease in appetite, Nausea and vomiting,
         Vomiting
       ○ Neurologic: Headache
       ○ Other: Fatigue
     Serious
       ○ Endocrine metabolic: Lactic acidosis, Some fatal cases
       ○ Gastrointestinal: Pancreatitis, Especially children; some fatal
         cases
       ○ Hepatic: Hepatomegaly, Some fatal cases, Relapsing type B viral
         hepatitis
Lamivudine
   Dosing
     100mg po qday
   Predictors of response
     Elevated transaminase (ALT>100)
     Low viral loads
   Response
     Quicker than Interferon
     But not always sustained
   Resistance
     Can occur after 6mo of work
     See increase in HBV DNA and ALT
     Lower durability of response
Adefovir
   MOA
     phosphorylated to the active metabolite by cellular
      kinases which inhibits HBV DNA polymerase by
      competing with the natural substrate and by causing DNA
      chain termination after its incorporation into viral DNA.
   AE
     Common
      ○ Dermatologic: Pruritus, Rash
      ○ Gastrointestinal: Abdominal pain, Diarrhea, Flatulence,
      ○ Neurologic: Asthenia, Headache
     Serious
      ○ Renal: Renal failure, Renal impairment
   Dosing
     10mg po qday
Adefovir
   Predictors of Response
     reduction in serum HBV DNA
     HBeAg-positive patients with high pretreatment
      ALT were more likely to undergo HBeAg
      seroconversion
   Resistance
     Resistance occurs at a slower rate during
      adefovir treatment compared to lamivudine and
      no adefovir-resistant mutations were found after
      1 year of treatment in the patients who
      participated in the Phase III trials
     genotypic resistance exceeding 20% after 2
      years of treatment
Entecavir
   MOA
     phosphorylated to the active form which inhibits hepatitis B viral
      polymerase activities including base priming, reverse
      transcription of negative strand pregenomic mRNA, and
      synthesis of positive strand of hepatitis B DNA.
   AE
     Common
       ○ Gastrointestinal: Nausea
       ○ Neurologic: Dizziness, Headache
       ○ Other: Fatigue
     Serious
       ○ Hepatic: Recurrent hepatitis
   Dosing
     Tx naïve: 0.5mg daily
     Others: 1mg daily
Entecavir
   Predictors of Response
     HBV DNA levels and in inducing histologic
     improvement in Asians and Caucasians, and
     across HBV genotypes A-D and a wide
     range of pretreatment HBV DNA and ALT
     levels; HBeAg seroconversion rates were
     lower in patients with normal ALT,
   Resistance
     7% of patients after 48 weeks and in 16%
     after 96 weeks of treatment in the phase III
     trial of lamivudine refractory patients.
Telbivudine
   MOA
     synthetic thymidine nucleoside analog with activity against hepatitis B virus
       by competitive inhibition of viral DNA polymerase (reverse transcriptase).
       Once incorporated into viral DNA by hepatitis B polymerase, DNA chain
       termination results
   AE
     Common
      ○ Gastrointestinal: Abdominal pain (12% )
      ○ Musculoskeletal: Finding of creatine kinase level, grade 3/4 (9% )
      ○ Neurologic: Headache (11% )
      ○ Respiratory: Nasopharyngitis (11% ), Upper respiratory infection (14% )
      ○ Other: Malaise and fatigue (12% to 18% )
   Dosing
     600mg daily
   Predictors of Response
     week 24 virologic response was the most important predictor of virologic
       and biochemical responses as well as resistance at week 96
   Resistance
     resistance rate is substantial and increases exponentially after the first year
       of treatment
Tenofovir
 MOA: structurally similar to adevofir
 More robust response than adefovir in
  small studies, also active against HIV
 Postive results for patients HBeAG +
  and –
 Not as much increase in SCr as seen in
  HIV studies, but did have increased
  LFTs compared with adefovir
Management of Resistance
   Lamivudine Resistant
     Add adefovir or tenofovir
     Switch to emtricitabine/tenofovir
   Adefovir resistance
     Continue adefovir and add lamivudine or tebivudine
     Switch to or add entecavir (if no prior lamivudine
      resistance)
   Entecavir Resistance
     Switch to or add adefovir or tenofovir
     Swtich to emtrictitabine/tenfovir
   Telbivudine resistance
     Continue and add adefovir or tenofovir
     Swtich to emtrictitabine/tenfovir
Oral HBV Treatment Algorithm
Special Populations
   Cirrhosis
     HBV DNA levels less than 2000
      ○ Treat with entecavir or tenofovir
      ○ Monitor
     HBV DNA levels above 2000
      ○ Entecavir or tenofovir
     Decompensated
      ○ Consider treatment
Special Populations Cont
   HIV Coinfection
     Can have altered biochemical markers of
     infection
      ○ i.e. HBV DNA detectable, but HBsAg negative
     Higher rate of lamivudine resistance
     HAART must be started in addition to
     treatment for HBV
      ○ Tenofovir and lamivudine or emtricitabine
      ○ Avoid monotherapy for HBV
     If HAART is not able to be started can treat
     with IFN
Special Populations Cont
   Immunosuppression/Chemotherapy
     Pt often under reactivation during chemo,
      can be life threatening
     Close monitoring of HBV + during chemo
      therapy reccomended
     Can prophylax with lamivudine prior to
      chemo and for 6 months or longer
      depending on HBV DNA levels
HCV Epidemiology
   Risk Factors
     Clotting factor use prior to 1987
     Long term hemodialysis
     Injection drug use
     Frequent percutaneous exposures
     Health care workers
     Blood transfusions or organ transplant prior
      to 1992
     Birth from infected mother
     Multiple sex partners
HCV Pathophysiology
   Acute HCV
     Often asymptomatic, 25% of patients
        develop malaise, anorexia, and jaundice
       Incubation last 50 days
       Viremia occurs 3 weeks after exposure
       ALT elevated within 4-12 weeks
       70% of patients will develop chronic disease
       Detection
        ○ Antibody linked HCV tests can be negative
         initially, but usually postive after 3 months
HCV Pathophysiology
   Chronic HCV
     Usually asymptomatic until develop fibrosis,
      cirrhosis, ESLD, and HCC
      ○ 10-30% develop cirrhosis
      ○ 1-5% develop cancer
     If symptomatic: fatigue, malaise, anorexia,
      weight loss
     DX: anti-HCV via EIA, positive viral RNA
     Extra-heaptic symptoms
      ○ Cryoglobulinemia, cutaneous vasculitis, renal
        disease, neuropathy, lymphoma, Sjogren’s
        syndrome
HCV Treatment
   Goal                       Candidates for
     Eradicated virus          Therapy
     Prevent progression        >18yo
      of cirrhosis                + liver biopsy
     Reduced                    Abnormal ALT
      hepatocellular             + HCV viral load
      carcinoma
     Reduce need to
                               Response
      transplant                 Type 1 – 40%
     Enhance survival           Types 2&3 – 80%
HCV Treatment
   Contraindications
     Major, uncontrolled depressive illness
     Decompensate cirrhosis
     Acute substance abuse
     Autoimmune disease
     Untreated hyperthyroidism
     Pregnancy
     Advanced cardiac or pulmonary disease
     Known hypersensitivity to drugs
HCV Treatment
   Predictors of Response
     Genotype 2 or 3
     Low baseline viral loads (< 2 million
        copies/ml)
       Younger age (<40 yo)
       Lower body weights (< 75 kg)
       Early virologic response (EVR)
       Mild disease on liver biopsy
       Therapy adherence (>80%)
HCV Treatment
 Standard Interferon
 Pegylated interferon alfa 2b (Peg Intron)
 Pegylated interferon alfa 2a (Pegasys)
 Ribavirin (Rebetol, Copegus)
HCV Treatment
   Optimal treatment
     Peginterferon alfa and ribavirin
   Ribavarin
     Genotype 1
      ○ <75kg = 1000mg, >75mg = 1200mg
     Genotype 2
      ○ 400mg twice daily
   Interferon
     Peginterferon-a2a – 180mcg SQ qweek
     Peginterferon-a2b – 1.5mcg/kg SQ qweek
Hepatitis C
   Candidates for          Goal
    Therapy                     Eradicated virus
     >18yo                     Prevent progression
     + liver biopsy             of cirrhosis
     Abnormal ALT              Reduced
     + HCV viral load           hepatocellular
                                 carcinoma
                                Reduce need to
                                 transplant
                                Enhance survival
Acute HCV Treatment
   Supportive
     Healthy diet
     Maintaining fluid balance
     Avoid hepatotoxic drugs and alcohol
Treatment outcome definitions
   Response
     Reduction in HCV RNA to undectable levels and
     normalization of ALT during treatment and 6mo
     post completion
   Non-response
     HCV RNA remains detectable or ALT fails to
     normalize during course of tx
   Relapse
     HCV RNA becomes undetectable and ALT
     normalized during treatment, but either ALT or
     HCV RNA re-emerge in the 6 months after
     therapy
Who to Treat
   Candidates for Therapy
     >18yo
      + liver biopsy
      ○ Moderate to severe hepatitis with septal or bridging fibrosis
     Abnormal ALT
     + HCV viral load
     Compensated Liver Disease
      ○   Bili < 1.5g/dL
      ○   INR < 1.5
      ○   Alb >3.4g/dL
      ○   Plt > 75,000k/mm3
      ○   No evidence of encephalopathy
     Acceptable hematological and biochemical indices
      ○ Hgb > 13g/dL (12g/dL for females)
      ○ Neutrophil count > 1.5k/mm3
      ○ SCr < 1.5 mg/dL
Contraindications
   Major, uncontrolled depressive illness
   Decompensate cirrhosis
   Acute substance abuse
   Autoimmune disease
   Untreated hyperthyroidism
   Pregnancy
   Advanced cardiac or pulmonary disease
   Known hypersensitivity to drugs
   Retinopathy
   Seizure disorder
   Immunosuppressive treatment
Predictors of Response
   Genotype 2 or 3
   Low baseline viral loads (< 2 million copies/ml)
   Younger age (<40 yo)
   Lower body weights (< 75 kg)
   Early virologic response (EVR)
   Mild disease on liver biopsy
     Lack to steatosis
     Lack of fibrosis
   Therapy adherence (>80%)
   Non-African American ethnicity
   Compliant
Which patient would you select
        for treatment?
HCV Patient A
 33yof hx of illicit drug use, mother of 5
  month old, currently living with parents,
  limited income, uninsured, facing possible
  incarceration, highly motivated to begin
  treatment, lives 10 miles from clinic
 Labs
     HCV type 1
     Low viral load
     Moderately elevated AST/ALT
     Biopsy pending
HCV Patient B
   45 yof with history of illicit drug use, lives with
    mother, motivated to begin treatment, lacks
    insight into disease, PMH significant for severe
    depression with pyschotic symptoms, currently
    moderately controlled, has health insurance,
    lives 20 miles from clinic
   Labs
       HCV type 2
       Low viral load
       LFTs normal
       Biopsy shows active inflammatory process and
        minimal fibrosis
HCV Patient C
 55yom, unemployed, lives with wife and
  mother, hx of depression well controlled
  and seeing psychiatrist, hx of IV illicit
  drug use making venipuncture very
  difficult, lives 45miles from clinic
 Labs
       HCV type 2
       Low Viral load
       Mildly elevated AST/ALT
       Biopsy not done
HCV Treatment
 Standard Interferon
 Pegylated interferon alfa 2b (Peg Intron)
 Pegylated interferon alfa 2a (Pegasys)
 Ribavirin (Rebetol, Copegus)
Optimal Treatment
   Optimal treatment
     Peginterferon alfa and ribavirin
     48 weeks for Genotype 1
     24 weeks for Genotypes 2 and 3
   Ribavirin
     Genotype 1
      ○ <75kg = 1000mg, >75mg = 1200mg
     Genotype 2
      ○ 400mg twice daily
   Interferon
     Peginterferon-a2a – 180mcg SQ qweek
     Peginterferon-a2b – 1.5mcg/kg SQ qweek
Ribavirin (Rebetol, Copegus)

   MOA: inhibition of the capping of mRNA
     reduction of intracellular guanosine triphosphate
      (GTP) pools and inhibition of viral RNA and protein
      synthesis
   AE:
     Common
      ○ Dermatologic: Pruritus, Rash
      ○ Gastrointestinal: Indigestion, Loss of appetite, Nausea
      ○ Neurologic: Headache, Headache, Inhalation; health-
        care workers administering ribavirin
      ○ Ophthalmic: Conjunctivitis
      ○ Other: Fatigue
AE Cont
  ○ Serious
     Cardiovascular: Bradyarrhythmia, Inhalation, Cardiac arrest,
      Hypotension
     Gastrointestinal: Pancreatitis, Fatal and nonfatal
     Hematologic: Hemolytic anemia, Cardiac and pulmonary
      events have occurred, Thrombotic thrombocytopenic purpura
      (less than 1%)
     Hepatic: Hepatotoxicity, Hyperammonemia,
      Hyperbilirubinemia, Increased erythrocyte destruction, Liver
      failure, oral, in combination with peginterferon alfa-2a (2%)
     Immunologic: Bacterial infectious disease, oral, in combination
      with peginterferon alfa-2a (<1%)
     Psychiatric: Suicide, oral, in combination with peginterferon
      alfa-2a (<1%)
     Respiratory: Complication of respiratory therapy procedure,
      Drug precipitation, Respiratory arrest preceding cardiac arrest,
      Inhalation
HCV Treatment
   Interferon
     IFN-a2a, IFN-a2b, IFN aflacon-1
      ○ Non-pegylated forms are no longer
        reccomended
     Peginterferon-a2a (Pegasys) and
     peginterfern-a2b (PEG-Intron)
      ○ Addition of PEG to structure increased t1/2
     MOA – activation of tyrosine kinases and up
     regulation gene products that produce of
     immunomodulating, antiviral, and
     antiproliferative effects
HCV Treatment
Interferon AE
   Early                      Neuropsychiatric
     Fever, Chills,             Irratability, mood
      myalgias, fatigue,          lability, depression,
      malaise, nausea,            tearfulness, delerium,
      sleep disturbances,         parathesisas,
      abdominal pain,             seizures, psychosis
      diarrhea, Headache,      Autoimmune
      appetite changes
                                 Hepatitis, thyroid
   Hematologic                   dysfunction,
     Neutropenia, TCP,           thyroiditis,
      anemia                      arthropathy, DM,
                                  psoriasis
HCV Treatment
   Interferon AE
     Chronic Fatigue            Low grade fevers
     Infections                 Decreased libido
     Increased sleep            Alopecia
     Anorexia                   Hypertriglyceridemia
     Weight Loss                Irritability
     Myalgias                   Anxiety
     Attention span deficits    Depression
Monitoring Therapy
   Baseline Evaluation
     Liver Evaluation – Liver Biopsy, HCV Genotype,
        HCV RNA
       Hematologic Test: WBC, ANC, Plt, Hgb, HCT
       Liver Function Tests: ALT, AST, Bilirubin
       Biochemical Tests: Cr, Glucose, BUN, etc
       Thyroid Tests: TSH, T4
       Clinical Evaluation: Mood evaluation, weight
        evaluation, adverse events, adherence, eye
        exam, cardiac examination, medical history,
        Child-Pugh Score
       Pregnancy screening
Monitoring Cont
   Week 1-2: Hematologic Tests, LFTs, Clinical
    evaluation
   Week 4: Hematologic Tests, LFTs, Biochemical
    tests, Clinical Evaluation, Pregnancy Test
   Week 6: Hematologic Tests, LFTs, Clinical
    evaluation
   Week 8: Hematologic Tests, LFTs, Biochemical
    tests, Clinical Evaluation, Pregnancy Test
   Week 12: HCV RNA, Hematologic Tests, LFTs,
    Biochemical test, Thyroid Tests, Clinical Eval,
    Pregnancy test
   Weeks 24, 48, 72: HCV RNA
Early Virologic Response
   Definition
     At week 12 at least a 2-log decline from
     baseline HCV RNA level
 65% of patients with EVR achieve SVR
 97% of patient that do not achieve EVR
  fail to achieve SVR
Efficacy of Treatment
   Peg-IFN alfa and ribavirin
     Sustained Virologic Response (SVR) seen in
      54-56% of patients overall
     Genotype 1
      ○ 42-52% SVR
     Genotype 2 or 3
      ○ 76-84%
 Not known is weight based superior to
  fixed dose regimens
 Some advocate for pt with high levels of
  HCV RNA and genotype 3 to be treated for
  48 weeks
Efficacy of Treatment
   Need to make case by case
    determination of duration of treatment
     Consider predictors of response
   Genotype 4
     PEG-IFN alpha and full dose ribivarin (1000-
     1200mg) for 48 weeks
      ○ No significant trials evaluating this regimen
Short Course Therapy
   PEG-IFN Alfa 2b and Ribavirin for 12 vs. 24
    weeks in HCV Genotypes 2 or 3
     NEJM 21005; 352:2609-17
     Prospective trial that randomized pt with EVR at
      week 4 to only receive 12 weeks of treatment
     Results: shorter course was equally effective in
      achieving SVR
   PEG-IFN Alfa-2a and Ribavarin for 16 or 24
    weeks in HCV Genotype 2 or 3
     NEJM 2007; 357: 124-34
     Prospective trial comparing 16 vs 24 weeks of
      treatment
     Results: 16 week treatment was inferior to 24 weeks
      in terms of SVR
Side effect management
   Flu Like Symptoms
     Non-steroidal anti-inflammatories (ibuprofen, naproxen)
   Insomnia
     Sleep promoting agents (diphenhydramine, zolpidem)
   Depression
     Antidepressants
   Neutropenia
     Dose reduction
     Colony stimulating factors not recommended
   Anemia
     Dose reduction
     EPO
  Agents on the Horizon
Protease Inhibitors                 Polymerase-nucleoside/nonnucleoside
                                    inhibitors
Telaprevir (Vertex) Boceprevir      PF00868554 (Pfizer)
(Schering Plough/Merck)             Idenix 184/-IDX136/316
TMC435350 (Tibotec)                 ANA598 (Anadys)
ITMN-191/R7227 (Roche)              BI 207127 NNPI (BI)
MK7009 (Merck)                      MK-3281 NNPI (Merck)
B1201355 (BI)                       ABT-072/333 NNPI (Abbott)
SCH 900518 (Schering)               GS-9190 NNPI (Gilead)
BMS790052 (BMS NS5A)
Other Novel Agents
•IV Silibin – silimarin (milk
thistle)
•Debio025, NIM811, SCY635
(cyclophilin inhibitors)
•Nitazoxanide (unknown mode
of action)
•Taribavirin (ribavirin analogue)
Protease Inhibitors
   MOA – interrupt catalytic site or blocking
    protein interactions
   Agents:
     Telaprevir
     750mg po q8h
      ○ In people with hepatitis C who were new to treatment
        (treatment-naive):
          Up to 75% achieved a viral cure with telaprevir-based
           combination therapy, compared to 44% of people who
           received pegyalted interferon and ribavirin alone
          A majority (58% in ADVANCE and 65% in ILLUMINATE) were
           eligible to reduce their treatment time by half -- from 48 weeks
           to 24 weeks
          Data showed there was no benefit to extending total treatment
           from 24 weeks to 48 weeks in people whose virus was
           undetectable at weeks 4 and 12 with telaprevir-based therapy
   Bocepravir –
     800mg po Q8H
     Respond 2 Trial
      ○ Standard therapy without boceprevir: SVR 21%
      ○ Response-guided therapy with boceprevir 59% (37%
        improvement)
      ○ Fixed-duration therapy with boceprevir: 67% (45%
        improvement)
     Sprint 2 trial
      ○ Standard therapy without boceprevir: 38% (40% for non-
        blacks and 23% for blacks)
      ○ Response-guided therapy with boceprevir: 63% (67% and
        42%, respectively)
      ○ Fixed duration therapy with boceprevir: 66% (69% and
        53%, respectively).
Polymerase Inhibitors
   MOA – similar to antiretrovirals
     Nucleoside inhibitors target catalytic sites
      and act as chain terminators
     Nonnucleosides are allosteric inhibitors
   Agents
     R7128 – 85% of pt achieved SVR compared
      to placebo
     R7128 and R7227 (INFORM-1 Trial) –
      combo of agents for 14 days, followed by 48
      weeks of SOC
Ribavarin Analogues
   Taribavirin under investigations
     Still trying to figure out an optimal dose to
      achieve efficacy
     Early studies did not show benefits
     Ongoing trials showing initial benefits with
      less anemia
Other direct acting agents/ Novel
Compounds
   Debio 025 – synthetic, cyclosporine analogue
     Has shown significant ability to lower RNA levels
     Still evaluating need for loading doses
   Nitazoxanide
     Patients receiving nitazoxanide had higher response
      rates than those taking placebo by 12 weeks, but not
      at 4 weeks:
     RVR: 12% in nitazoxanide arm vs 19% in placebo
      arm; SVR: 44% vs 32%, respectively.
     SVR rates were consistently higher for nitazoxanide
      recipients in difficult-to-treat patient sub-
      groups: High baseline viral load (> 800,000 IU/mL):
      41% vs 29% respectively; African-Americans: 38%
      vs 20%, respectively
Proposed New Treatment Algorithm
 Class I: treatment naïve, IT, G2/3, G1
  low viral load, and/or CC allele
 Class II: treatment naïve, IT, G1 high
  viral load, or CC/TT allele
 Class III: G1/4 and G 2/3 relaspers and
  nonresponders to current SOC who
  became undectable by week 12
 Class IV: Class IIIs who do not become
  undectable by week 12, IFN
  interolerance and treatment failure
Proposed treatment Regimens
 Class 1: SOC x 24 weeks
 Class 2: PI + SOC x 24 weeks
 Class 3: PI + SOC x 48 weeks
 Class 4: PI + other agents – lifetime
  suppression
Other Hepatitis Viruses
   HDV – aka Delta hepatitis
       Causes acute or chronic infection
       Usually associated with HBV coninfection
       Similar transmission modes at HBV
       Treatment
        ○ Possibly role for low dose interferon
   HEV
     Acute infection only
     Rare in US
     Associated with oral fecal contamination
   HGV
       Similar to HCV in structure
       Transmitted via blood exposure
       Seen in 6% of HBV cases and 10% of HCV infections
       Unknown pathology in humans
Questions?

				
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