Infectious Diseases Conference

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Infectious Diseases Conference

• Charles de Comarmond MD
• May 24th 2004

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Case 1

• 45 year old AAM with HIV infection diagnosed 5
  years ago. Routine hepatitis serology revealed a
  positive HCV antibody
• His CD4 count is 550 and viral load is 55,000.
  His CD4 nadir is 450 and he is ART naïve
• HCV genotype 1a, and HCV PCR 660,000
• Has mild elevation in transaminase with AST85,
  ALT 90
• Reports occasional ETOH use.

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• What is the next step?
• Liver US demonstrated mildly enlarged liver with
  no evidence of cirrhosis
• Liver biopsy was reported as grade 1, stage 2
• Should this patient be treated for his chronic
  hepatitis C infection?
• Should he be started on ART prior to hepatitis C
  treatment?

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Case 2

• A 38 year old WF female is referred for
  evaluation of positive hepatitis serology.
• She reports a remote history of IV drug use.
• Her HIV serology is negative. She denies any
  alcohol consumption.
• HCV genotype 2b and viral load 1200000
• Has abnormal transaminase AST150, ALT200

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Case 2

• Reports a 2 year Hx of major depression
• Liver US demonstrated moderately enlarged liver
  with evidence of mild cirrhosis
• Liver biopsy was reported as grade 2, stage 2

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Case 2

• Was the liver biopsy necessary?
• Should this patient be treated for her chronic
  hepatitis C infection?
• Is her major depression a contraindication for
  initiating HCV treatment?

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Case 3

• 56 year old WM with chronic hepatitis C
  co-infected with HIV. Patient is ART experienced,
  CD4 170, VL 350
• Genotype 1a, HCV VL 2,000000. Has cirrhosis,
  Liver Bx grade 3, stage IV.
• Elevated AST 250, ALT300
• No ascites on abdominal ultrasound

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Case 3

• Should Interferon/Ribavarin be initiated for
  chronic hepatitis C infection?
• Is presence of cirrhosis a contra-indication for
  initiation of treatment?

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Case 4

• A 42 year old HIV patient co-infected with
  hepatitis C infection was started on
  interferon/ribavarin therapy. Last HIV VLlt50.
• Genotype 1b, viral load 190,000 at the start of
  therapy. Liver Bx grade 2, stage 3
• Tolerating ART and hepatitis treatment well
  except for mild anemia and neutropenia
• At 12 weeks HCV viral load is 20,0000 (1.6 log
  decrease from baseline)

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Case 4

• Should hepatitis C treatment be discontinued?
• Is there any benefit in continuation of therapy
  for patients who do not achieve early virologic
  response?

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Case 5

• A 56 year old WM with chronic HCV genotype 2a, is
  started on interferon/ribavarin weight based
  dosing
• After 4 weeks of treatment his hemoglobin drops
  from 14 g/dl to 10 g/dl. His WBC is 1500 with ANC
  of 500
• He reports mild shortness of breath on exertion,
  denies any fevers

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Case 5

• Should hepatitis C treatment be discontinued?
• What is the role of erythropoietin and G-CSF in
  the treatment of drug induced anemia and
  neutropenia?

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Objectives

• Indications for initiation of HCV treatment
• Role of liver biopsy
• Role of early viral response for discontinuation
  of HCV treatment
• Late responders and continued therapy in
  non-responders
• Indications for discontinuation of therapy

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Indications for initiation of HCV treatment

• All patients with chronic HCV infection are
  potential candidates for antiviral therapy
• The goals of therapy
• Prevent hepatitis C-related death
• Prevent morbidity from decompensated liver
  disease
• Mitigate extrahepatic syndromes associated with
  chronic hepatitis C viremia
• There are no prospective studies proving that
  antiviral therapy prolongs life

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Indications for initiation of HCV treatment

• Goal of eliminating viral infection is not the
  same as the goal of prolonging life or
  ameliorating life.
• 80 of persons infected with HCV may be
  asymptomatic throughout life
• Defending a reason to treat vs. having a good
  reasons for failure to treat

NIH Consensus Development Conference Statement.
Management of Hepatitis C2002. Bethesda, MD
NIHJune 10-12, 2002
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Indications for initiation of HCV treatment

• Particular risks of progressive fibrosis
• Age over 40 years at time of infection
• History of alcoholism
• Elevated AST/ALT
• Necroinflamatory activity on liver biopsy
• Fibrosis on liver biopsy
• Coinfection with HIV
• Males with BMIgt25kg/m2

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Indications for initiation of HCV treatment

• Evaluate for
• Symptoms
• Degree of liver disease
• Risk of future progression
• Likelihood of response to therapy
• Likelihood of adhering to therapy
• Likelihood of tolerating therapy

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Indications for initiation of HCV treatment

• Recommended for patients with an increased risk
  of developing cirrhosis.
• Detectable HCV RNA levels higher than 50 IU/mL
• Liver biopsy with portal or bridging fibrosis
• Moderate inflammation and necrosis
• Persistently elevated ALT values gt 6 months

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Criteria for treatment

• Persistently elevated ALT for at least 6 months
• Liver biopsy compatible with diagnosis of chronic
  hepatitis
• No other serious underlying conditions
• No evidence of hepatic failure
• Bilirubin lt 4mg/dl, albumin gt 3g/dl
• PT lt 3 secs prolonged
• Platelet count gt 70,000/mcl
• WBC gt 3,000/mcl
• ANC gt 1,500/mcl

NIH Consensus Development Conference Statement.
Management of Hepatitis C2002. Bethesda, MD
NIHJune 10-12, 2002
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Role of liver biopsy

• Liver enzymes have little value in predicting
  fibrosis
• Extracellular matrix tests can predict severe
  stages of fibrosis
• Liver biopsy provides information on possible
  contribution of iron, steatosis, and concurrent
  alcoholic liver disease to the progression of
  chronic hepatitis toward cirrhosis
• Biopsy not required in genotype 2 and 3

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Role of liver biopsy

• Activity (grade)
• Activity is gauged by extent of mononuclear
  inflammatory cells and by the number of dead or
  dying hepatocytes
• Changes in activity do not imply progressive
  disease
• Fibrosis (stage)
• Fibrosis implies possible progression to
  cirrhosis.
• Limited to the portal and periportal areas in
  mild cases.
• More advanced changes are defined by "bridging
  fibrosis"
• This reaction evolves into cirrhosis.

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Grading and staging
Hepatology. 1996 Aug24(2)289-93.
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METAVIR
Hepatology. 1996 Aug24(2)289-93.
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Role of liver biopsy

• Cirrhosis is found in approximately 29 of
  unselected cases of HCV infection by biopsy.
• Usual clinical and laboratory tests are
  relatively weak predictors of the extent of liver
  damage caused by HCV infection.

Hepatology. 2001 Jan33(1)196-200
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Role of liver biopsy

• The need for liver biopsy should be predicated on
  the type of information being sought for an
  individual patient
• The presence or absence of cirrhosis is
  clinically relevant in many cases where therapy
  is being considered
• Presence of bridging fibrosis or cirrhosis
  markedly reduces the expected response rate to
  antiviral therapy

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Role of liver biopsy

• Major shifts in expected outcomes are far from
  trivial and will often alter the clinical
  decision to treat
• The goal of prevention of cirrhosis becomes moot
  if cirrhosis is present on pretreatment biopsy
• Management changes mandated by finding cirrhosis
  include entry into surveillance programs for
  hepatoma and for esophageal varices.

N Engl J Med. 2000 Dec 7343(23)1673-80
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FIBROTEST

• New attempts to stage HCV according to
  serum-based indices
• Biochemical markers of liver fibrosis allow for
  satisfactory staging of disease
• The Fibrotest has been used to assess the
  histologic effects of antiviral therapy
• 90 sensitivity and 88 positive predictive value
  for the diagnosis of bridging fibrosis or
  moderate necroinflammatory activity

Lancet. 2001 Apr 7357(9262)1069-75.
Hepatology. 2003 Aug38(2)481-92.
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Role of early viral response for discontinuation
of HCV treatment

• End of treatment virologic responders The
  patients have had no detectable HCV RNA at the
  end of treatment
• Nonresponders No response to antiviral
  treatment HCV RNA remains positive throughout
  therapy
• Relapsers Responders, who are HCV RNAnegative
  at the end of treatment, but HCV RNA positive
  after treatment is stopped
• Sustained responders (SVR) Negative HCV RNA 6
  months after treatment has been discontinued
• Improved liver histology Interferon therapy is
  associated with improvement in inflammation.
  Occurs not only in those who clear HCV RNA but
  also in those who remain positive for the virus

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Role of early viral response for discontinuation
of HCV treatment
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Overall sustained viral response rates
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SVR with genotype 1
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SVR by genotype 1 and VL
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Role of early viral response for discontinuation
of HCV treatment

• Definition of EVR at 12 weeks of antiviral
  treatment
• Lack of detectable HCV RNA
• 2 log drop in in the level of HCV RNA

Hepatology 200338645-652
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NR/EVR
SVR/EVR
Hepatology 200338645-652
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Week 12 2 log drop or negative HCV RNA
YES
NO
N778 (80.6)
N187 (19.4)
SVR
SVR
NO SVR
N526 (67.6)
N252 (32.4)
N184 (98.4)
N3 (1.6)
Hepatology 200236S145
37
Late responders and continued therapy in
non-responders

• Three ongoing trials
• HALT-C Hepatitis C antiviral long term treatment
  against Cirrhosis (PEG- Interferon
  alfa-2aribavarin)
• COPILOT Colchicine Verses PEG-Intron Long Term
• EPIC Evaluation of PEG-Intron in Chronic
  Hepatitis C Cirrhosis

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Late responders and continued therapy in
non-responders

• Data from pooled analysis of 4 small trials
• All treatment-naïve patients using paired biopsy
  specimens
• Patients with SVR had best histologic outcome
• 36 of non-responders had reduction in
  inflammatory index

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Gastroenterology 2002 1221303-1313
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SVR after retreatment of nonresponders
Hepatology 200133231-240
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Treatment of chronic HCV with cirrhosis

• 271 patients with cirrhosis or bridging fibrosis
  randomly assigned to receive subcutaneous
  treatment with
• 3 million units of interferon alfa-2a (88)
• 90 µg of peginterferon alfa-2a once weekly (96)
• 180 µg of peginterferon alfa-2a once weekly (87).
  
• Treatment lasted 48 weeks and was followed by a
  24-week follow-up period
• Efficacy assessed by measuring HCV RNA and AST
  and by evaluating liver-biopsy specimens
• A histologic response was defined as a decrease
  of at least 2 points on the 22-point Histological
  Activity Index.

N Engl J Med. 2000Volume 3431673-1680
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Treatment of chronic HCV with cirrhosis

• Rate of SVR at week 72 by intention-to-treat
  analysis
• 8 treated with interferon alfa-2a
• 15 treated with 90 µg of peginterferon alfa-2a
• 30 treated with180 µg of peginterferon alfa-2a
• P0.001 for the comparison between 180 µg of
  peginterferon alfa-2a and interferon alfa-2a

N Engl J Med.2000Volume 3431673-1680
43
Treatment of chronic HCV with cirrhosis

• 184 patients with paired liver-biopsy specimens,
• Rates of histologic response at week 72
• 31 treated with interferon alfa-2a
• 44 treated with 90 µg of peginterferon alfa-2a
• 54 treated with 180 µg of peginterferon alfa-2a
• P0.02 for the comparison between 180 µg of
  peginterferon alfa-2a and interferon alfa-2a

N Engl J Med. 2000Volume 3431673-1680
44
Histologic response
The Lancet 2003 3642095-2100
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Indications for discontinuation of therapy

• Failure to achieve EVR at 12 weeks
• 2 log decrease in HCV PCR
• Adverse effects to antiretroviral treatment
• Constitutional
• Hematologic
• Neuropsychiatric
• Poor adherence
• 80-80-80 rule (63 vs. 54 SVR)

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Adverse effects to antiretroviral treatment

• Constitutional
• Flu-like symptoms
• Fatigue
• Insomia
• Other
• Injection site reactions (23-75)
• Dermatologic
• Alopecia (22-36)

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Adverse effects to antiretroviral treatment

• Other
• Endocrine
• Ophthalmologic
• Pulmonary
• Pulmonary infiltrates, bronchiolitis obliterans,
  interstitial pneumonitis
• Gastrointestinal
• Cardiovascular
• Autoimmune
• ITP, thyroiditis, rheumatoid arthritis,
  interstitial nephritis

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Adverse effects to antiretroviral treatment

• Hematologic
• Anemia Ribavirin dosedependent effect
• Accumulation of ribavirin triphosphate ?
  erythrocytes unable to metabolize ribavirin
  triphosphate ? depletion of ATP ? impairment of
  antioxidant defense ? oxidative membrane changes
  ? Premature removal of erythrocytes
  reticuloenothelial system
• Hemoglobin drop 3g/dL in 56 of patients
• Begins 1 2 weeks after initiation of treatment
• Max drop in first 6-8 weeks of treatment

Hepatology 200031997-1004
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Adverse effects to antiretroviral treatment

• Neutropenia
• 95 of patients experience neutropenia
• 45 decrease in neutrophils from baseline within
  2 weeks of initiation of antiviral therapy
• Neutropenia not associated with severe infections
• Thrombocytopenia
• Seen in 33 on combination therapy

Ann Intern Med. 2004140346-355New Engl J Med
2002347975-982
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Peginterferon alfa-2b/ribavirin dose modification
guidelines
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Peginterferon alfa-2a dose modification guidelines
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Ribavirin dose modification guidelines
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Role of erythropoietin and G-CSF for drug induced
anemia and neutropenia

• Limited data available
• Reduction in fatigue associated with anemia
• Potentially higher SVR rates

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Neuropsychiatric

• Prevalence of depression in chronic HCV patients
  estimated to be 35-57
• 30-60 of patients experience a major depressive
  episode on interferon

Gastroenterology 20031241711-1719 Hepatology
2000311207-1211
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Neuropsychiatric

• Depression is seen in 16-36 of patients taking
  ribavirin
• Beck Depression Inventory in combination with
  General Health Questionnaire have a PPV of 70-80
  for depression in HCV infected patients

N Engl J Med. 19983391485-1492 Am J Psychiatry
19991561120
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VA hospital admissions HCV status
Gastroenterology 2002 123476
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Treatment of depression

• Antiviral treatment need not be discontinued in
  patients with depression
• SSRIs are the drugs of choice
• Some patients may require psychiatric evaluation
  and treatment

Psychosomatics 200041439-441 N Engl J Med.
2001344961-966
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Is treatment cost effective?

• The probability of patients with chronic HCV
  developing cirrhosis over a 30-year period ranges
  from 13 to 46 for men and from 1 to 29 for
  women
• The incremental cost-effectiveness of combination
  therapy with pegylated interferon
• For men
• 26 000 to 64 000 per QALY for genotype 1
• 10 000 to 28 000 per QALY for other genotypes
• For women
• 32 000 to 90 000 for genotype 1
• 12 000 to 42 000 for other genotypes

JAMA, Jul 2003 290 228 - 237
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Is treatment cost effective
JAMA, Jul 2003 290 228 - 237
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Key points

• All patients with chronic HCV infection are
  potential candidates for antiviral therapy
• There are no prospective studies proving that
  antiviral therapy prolongs life
• The need for liver biopsy should be predicated on
  the type of information being sought for an
  individual patient
• Biopsy not required in genotype 2 and 3
• EVR is a good predictor of SVR

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Key points

• Patients with compensated cirrhosis may benefit
  from antiviral treatment
• Continued antiviral treatment of nonresponders
  and relapsers may improve histologic activity
• Close monitoring for adverse events is necessary
  during antiviral treatment
• Antiviral treatment may be cost effective