Hepatology Update

1
Hepatology Update

• Sanjeev Arora M.D.
• Distinguished Professor of Medicine
• Director Project ECHO
• Department of Internal Medicine
• University of New Mexico Health Sciences Center,
• Albuquerque NM 87131-0001
• Tel [phone]
• E-mail sarora_at_salud.unm.edu

2
Estimated 170 Million Persons With HCV Infection
Worldwide

• Europe
• 8.9 million
• (1.03)

• Western Pacific
• 62.2 million
• (3.9)

• Americas
• 13.1 million
• (1.7)

• Southeast Asia
• 32.3 million
• (2.15)

• Eastern Mediterranean
• 21.3 million
• (4.6)

• Africa
• 31.9 million
• (5.3)

• World Health Organization. Wkly Epid Rec
  .199974425-427. World Health Organization.
  Hepatitis C Global Prevalence Update. 2003.
  Farci P, et al. Semin Liver Dis. 200020103-126.
  Wasley A, et al. Semin Liver Dis. 2000201-16.

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Future Burden of Hepatitis C Related Morbidity
and Mortality in the US

• Markov model of health outcomes
• Of 2.7 M HCV infected persons in primary care
• 1.47 M will develop cirrhosis
• 350,000 will develop liver cancer
• 897,000 will die from HCV-related complications

Rein D, et al. Dig Liver Dis 2010.
4
Mortality associated with Hepatitis B,
Hepatitis C, and HIV United States, 1999 2008
From K Ly et al, Ann Intern Med 2012
156271-8
5
NEW CDC Recommendation

• Adults born during 1945 through 1965 should
  receive one-time testing for HCV without prior
  ascertainment of HCV risk factor
• Benefits of therapy
• Reduces risk of liver cancer by 70
• Reduces risk of all-cause mortality by 50

6
Screening for HCV infection in Adults USPSTF
Recommendations

• Released June 24, 2013
• USPSTF Grade B recommendation
• Adults at high risk
• Adults born 1945-1965
• Grade B
• Co-pay support (ACA)
• Priority for performance measures, and changes
  in EMR
• Consistent with CDC recommendations

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HCV Test, Care, and Cure Continuum
50
38
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6
11
Holmberg S, et al, NEJM, 2013)
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Educate Communities
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HCV Testing Algorithm
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HCV antibody Positive and HCV RNA negative
patients

• If liver function tests are normal no further
  testing or follow up required
• Patients who have attained sustained viral
  response with treatment need not have repeated
  tests for HCV RNA to confirm a cure
• If liver function tests are elevated evaluate for
  other etiologies of liver disease

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Treatment Rates Are Low

• Estimated that treatment will prevent only 14.5
  of potential liver-related deaths caused by HCV
  between 2002 and 2030 if 2009 trends continued

Volk ML, et al. J Hepatol. 2009501750-1755.
12
Treatment Reduces All-Cause Mortality in Patients
With Advanced Fibrosis
Van der Meer AJ, et al. JAMA. 20123082584-2593.
13
Impact of Treatment on HCC
Van der Meer AJ, et al. JAMA. 20123082584-2593.
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Impact of Treatment on Liver Failure
Van der Meer AJ, et al. JAMA. 20123082584-2593.
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Management of the Patient with Hepatitis C
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Approach to the Patient with Newly Diagnosed HCV

• Patients need to be educated on
• the natural history of disease
• modes of transmission of
• how to avoid transmission to family members
• the availability of effective treatment
• the promise of new highly effective and safe
  interferon free treatments in the near future
• Screen for depression
• Reassurance
• Patients may benefit from referral to a support
  group

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Additional Measures for Newly Diagnosed Patients
with HCV

• Vaccinate for hepatitis A and hepatitis B
• Counsel for weight loss if appropriate. Obesity
  increases likelihood of liver fibrosis
• Recommend avoiding doses of acetaminophen
  exceeding 1-2 grams per day
• Determine presence or absence of cirrhosis
• NSAIDs should be avoided in patients with
  advanced fibrosis or cirrhosis

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Measures to Avoid Transmission of Hepatitis C

• Avoid Sharing Razors or Toothbrushes
• Cover Bleeding Wounds
• Stop Injection Drug Use
• Advise Not to Share Needles and Paraphernalia
• Advise Not to Donate Blood, Organs, Tissue or
  Semen

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Sexual Transmission of HCV

• Risk of Sexual Transmission is Low in Monogamous
  Heterosexual Relationships
• Many Experts do not Recommend Barrier Protection
  for Couples that are in a Monogamous Long Term
  Relationship
• Patients with Multiple Sexual Partners, and
  Patients with HIV Should Use Barrier Protection

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Steps to Slow Progress of Liver Disease

• Obesity and Smoking Increase Liver Fibrosis
• Daily Marijuana Use Increases Fibrosis
  Progression Rate. Odds Ratio 3.4 (1.5 -7.4)
• Patients Should be Counseled to
• Lose Weight if Necessary
• Stop Smoking
• Discontinue Marijuana Use
• Hu KQ J Hepatol. 2004 Jan40(1)147-54
• Hu SX J Clin Gastroenterol. 2009
  Sep43(8)758-64
• Mallat A J Hepatol. 2008 Apr48(4)657-65
• Hezode C Hepatology. 2005 Jul42(1)63-71

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Hepatitis C and Alcohol

• Hepatitis C Infection Rates in Alcoholics are
  Significantly Higher Than Controls
• Alcohol Use in Patients with HCV Infection
  Increases Fibrosis Progression Rate, Risk for
  Liver Cancer and Overall Mortality
• Abstinence from Alcohol is Recommended
• Educate on Synergistic Damage to liver by Alcohol
  and HCV
• Refer to Alcohol Rehab Programs if appropriate
• Coelho-Little ME Alcohol Clin Exp Res.
  199519(5)1173
• Chen CM Alcohol Clin Exp Res. 200731(2)285
• Delarocque-Astagneau E Ann Epidemiol.
  200515(8)551
• Hassan MM Hepatology. 200236(5)1206

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Screening for Depression

• Mental health screening prior to initiating HCV
  therapy is recommended
• Patients infected with HCV have increased rates
  of depression
• depression and other psychiatric illnesses may
  worsen during interferon-based treatment
• active and untreated mental health issues can
  interfere with adherence to HCV treatment

Weinstein AA. Psycosomatics. 2011 52127-32.
Lee DH. Dig Dis Sci. 1997 42186-91. Morasco
BJ, J Affect Disord. 2007 Nov 103(1-3)83-90.
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Screening for Depression

• An evaluation prior to therapy serves as a
  baseline if psychiatric issues develop during HCV
  therapy.
• Family and social support issues should be
  explored to improve patient adherence to therapy.
  
• We recommend the use of the Patient Health
  Questionnaire (PHQ-9), a standardized depression
  screening tool, before and during HCV treatment.
• IFN-induced depression responds rapidly to
  treatment Prophylactic antidepressants are
  required only for patients with a history of
  depression or anxiety disorders or history of
  IFN-induced depression.

Weinstein AA. Psycosomatics. 2011 52127-32.
Lee DH. Dig Dis Sci. 1997 42186-91. Morasco
BJ, J Affect Disord. 2007 Nov 103(1-3)83-90.
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Baseline Studies in Persons with Chronic HCV
Infection

• CBC, PT, INR
• Comprehensive metabolic panel including LFTs
• Serum ferritin level, serum iron and total iron
  binding capacity
• Urine analysis
• HCV genotype and subtype
• Quantitative HCV RNA
• Hepatitis A serology (total or IgG)
• Hepatitis B serology (HepBsAg, HepBsAb, HepBcAb)
• HIV Antibody
• For Patients not interested or being considered
  for treatment repeat liver function tests every
  3-6 months. It is not necessary to repeat HCV RNA
  or genotype

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Additional Diagnostic Studies in Selected Patients

• Serum Ceruloplasmin (Wilsons Disease)
• Serum ANA and Anti Smooth Muscle Antibody
  (Autoimmune Hepatitis)
• Serum Cryoglobulins
• IL-28 B testing CC Genotypes CC at the
  rs12979860 polymorphic site have higher rates of
  Sustained Viral Response (Ge D, Fellay J
  Nature. 2009 461(7262)399-401.)

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HCV and Diabetes Mellitus

• Meta analysis of 34 studies
• Pooled estimators indicated significant DM risk
  in HCV-infected cases in comparison to
  non-infected controls.
• Retrospective studies(OR(adjusted)1.68, 95 CI
  1.15-2.20)
• Prospective studies (HR(adjusted)1.67, 95 CI
  1.28-2.06)
• Excess DM risk was also observed in comparison to
  HBV-infected controls (OR(adjusted)1.80, 95 CI
  1.20-1.40)
• Suggestive excess risk of DM observed in
  HCV/HIV cases in comparison to HIV controls
  (OR(unadjusted)1.82, 95 CI 1.27-2.38).
• Data suggests a potential direct viral role in
  promoting DM risk

• White DL J Hepatol. 200849(5)831

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Patients with Extrahepatic Manifestations should
be prioritized for treatment

• Essential Mixed Cryoglobulinema
• Leukocytoclastic vasculitis
• B Cell Non Hodgkins Lymphoma
• Porphyria Cutanea Tarda
• Necrolytic acral erythema
• Renal Disease
• Membranoproliferative glomerulonephritis
• Membranous nephropathy
• Nephrotic syndrome

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Classical Cryoglobulinemia-related small vessel
vasculitis with erythematosus palpable
maculopapular rash in a HCV positive patient
composed of monoclonal and polyclonal gamma
globulins.
http//openi.nlm.nih.gov/
Room Temperature 4 degrees C
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Membranoproliferative Glomerulonephritis
There is increased lobulation, intracapillary
hypercellularity (including neutrophil
infiltration), and thickening of the capillary
walls Need to get permission to use
http//www.kidneypathology.com.ar/07.htm
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Does the Patient Have Advanced Fibrosis or
Cirrhosis?
F0 F1 F2 F3 F4

• Metavir Staging
• Stage F0 No Fibrosis
• Stage F1 Portal fibrosis
• Stage F2 Bridging fibrosis with few septa
• Stage F3 Bridging fibrosis with many septa
• Stage F4 Cirrhosis

• Bedossa P, Poynard T Hepatology. 199624(2)289

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Diagnosis of Cirrhosis Changes Approach to
Patients with HCV

• Screen for HCC every 6 months
• Evaluate for esophageal varices with endoscopy
• Avoid all hepatotoxic drugs
• Refrain from use of NSAIDs including aspirin,
  ibuprofen, naproxen, and others due to an
  increased risk of gastrointestinal bleed,
  potential for renal toxicity, and impaired
  response to diuretic therapy.
• Prioritize for treatment
• Recommend weight loss for obese patients
• Avoid use of aminoglycosides for treatment of
  infections

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Findings Suggestive of Cirrhosis

• Clinical exam
• Spider nevi, palmar erythema, gynecomastia, firm
  liver on palpation, splenomegaly
• Noninvasive diagnostic tests suggesting cirrhosis
• Low platelet count (150 thousand)
• Low serum albumin, AST/ALT ratio gt1
• Prolonged prothrombin time
• High APRI score or Fibrosure test score
• Ultrasound transient elastography
• Platelets lt 150 thousand
• Neutropenia
• Liver biopsy

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Commonly Used Biochemical Tests to Assess
Severity of Liver Disease

• AST to Platelet Ratio Index (APRI score)
• FibroTest (Europe) and FibroSure (United States
• MELD (Serum Bilirubin, Serum Creatinine and
  international normalized ratio for prothrombin
  time -INR)

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AST to Platelet Ratio Index (APRI score)

• APRI (AST elevation/platelet count) x 100
• A patient has an AST level of 80 IU/L in a lab
  with an ULN 40 IU/L. AST Elevation is 80/402.
  Platelet count is 130,000/mm3. APRI score is
  (2/130) x 100 1.54
• APRI score gt 1.0 has a sensitivity of 76 and
  specificity of 72 for cirrhosis
• Area Under ROC curve is 0.80

• Lin ZH et al Hepatology. 201153(3)726, Castera
  L . Gastroenterology . 201214212931302

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Ultrasound based Transient Elastography
(FibroScan)

• The more stiff/fibrotic the liver the faster the
  wave propagates.
• Liver Biopsy 1/50,000 of liver, Fibroscan 1/500
  of liver
• Is quick, painless and reproducible

• Friedrich-Rust M, et al. Gastroenterology 2008
  134960.

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All HCV Patients Should be Considered for
Treatment

• Decision for an Individual Based On Risk/Benefit
• Fibrosis stage type of assessment/accuracy
• Likelihood of SVR
• IL28B, IFN-response characteristics
• Likelihood to tolerate IFN additional AEs
• Stage of life
• Age, family planning, job, finances
• Other factors
• Transmission risk, extra hepatic manifestations
• Patient Preference

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SVR Rates with PegIFN/RBV According to Genotype

• 76-82

• 42-46

• Genotype 1

• Genotype Non-1

• Adapted from Strader DB et al. Hepatology.
  2004391147-1171.

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(No Transcript)
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DAAs Uniquely Target Hepatitis C Virus
Potential targets for antiviral intervention in
the HCV lifecycle and their location in the HCV
genome
Receptor binding and endocytosis
Transport and release
Fusion and uncoating
N3/4 protease inhibitors (telaprevir, boceprevir)
Viral assembly
RNA replication
Translation and polyprotein processing
NS5B polymerase inhibitors Cyclophilin inhibitors
Adapted from Manns MP, et al. Nature reviews.
Drug discovery. 20076(12)991-1000.
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Treatment Naïve Protease Inhibitors
IM Jacobson et al. N Eng J Med 2011
3642405-2416. F Poordad et al. N Engl J Med
2011 3641195-1206
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Sample of Investigational HCV Regimens
Regimens with one DAA PEG-IFN alfa/RBV
Regimens with two DAAs ( PEG-IFN alfa and/or
RBV)
IFN-free regimens

• GS-7977 RBV
• Daclatasvir GS-7977
• Daclatasvir Asunaprevir RBV
• ABT-450/r ABT-072 RBV
• ABT-450/r ABT-333 RBV
• BI-201335 BI-207127 RBV
• Mericitabine Danoprevir/r RBV
• GS-5885 GS-9451 Tegobuvir RBV
• Alisporivir RBV

• ABT-072, -333 (NNIs)
• ABT-450 (PI)
• BI201335 (PI)
• Daclatasvir (NS5A)
• Asunaprevir(PI)
• Danoprevir (PI)
• Mericitabine (NI)
• GS-7977 (NI)
• Tegobuvir (NNI)
• TMC-435 (PI)
• Alisporivir (Cyp)

• GS-9526 (PI) tegobuvir
• Daclatasvir Asunaprevir
• VX-222 (NNI) telaprevir

NNI non-nucleoside NS5B inhibitor, NI
nucleoside NS5B inhibitor, PI protease
inhibitor, RBV ribavirin, NS5A replication
complex inhibitor Cyp cyclophilin inhibitor, r
ritonavir
EASL 2012 program http//www2.kenes.com/liver-cong
ress/Pages/Home.aspx
42
Simeprevir and Faldaprevir New Protease
Inhibitors Naïve Patients
M Manns European Association for the Study of
Liver Disease 2013. P Ferenci European
Association for the Study of Liver Disease 2013.
43
Nucleoside/tide Analog Polymerase Inhibitors Are
Chain-Terminators
Primer strand
RNA chain cannot be elongated
5
5
3
Template strand
44
Sofosbuvir - Neutrino Trial (Genotype 1, 4,5,6)
Treatment Naïve

• Sofosbuvir Pegylated Interferon Ribavirin for
  12 weeks (n327)
• SVR Rate 90
• (genotype 1 89, cirrhosis 80)

E Lawitz N Engl J Med 2013 3681878-1887
45
Fission Trial (Genotype 2 and 3 naïve patients)N
Engl J Med 2013 3681878-1887 May 16, 2013

SVR12, Sofosbuvir/Riba(n 256) Peginterferon/Riba(n 243)

Genotype 2 97 78
No cirrhosis 98 82
Cirrhosis 91 62
Genotype 3 56 63
No cirrhosis 61 71
Cirrhosis 34 30
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Preliminary Results of New Interferon Free
Regimens in Phase 2 Trials
Regimen SVR Rate Duration in Weeks
Sufosbuvir Ledipasvir RBV gt95 8-12
ABT450/r ABT267 ABT333 RBV 12 90
Faldaprevir 207127 RBV (GT1B) 90 12-24
DCV ASV BMS-791325 88-94 12-24
Presentations at European Association of Study of
Liver Disease and Press releases
47
Characteristics of New Generation DAA Regimens

• Antiviral activity seen in all genotypes
• High Barrier to Resistance
• Higher SVR rates and shorter treatment duration
• Oral, IFN-free, combination regimens have less
  side effects and higher SVR rates
• Patients with cirrhosis and decompensated
  cirrhosis will benefit from less toxic regimens

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Two New Protease Inhibitors in Development

• Greatly improved Hb profile with simeprevir and
  faldaprevir vs boceprevir/telaprevir with no
  significant increase over pegIFN/RBV
• Simeprevir Once a day with Peg Ribavirin
  SVR-80
• Generally well tolerated no added safety signals
  with triple therapy
• Faldaprevir Once a day with Peg Ribavirin
  SVR-80
• Generally well tolerated (clinically benign and
  transient bilirubin increases with 240 mg dose
  higher incidence of gastrointestinal events and
  rash)

1. Lawitz E, et al. EASL 2013. Abstract 1411. 2.
Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson
D, et al. EASL 2013. Abstract 6. 4. Jacobson I,
et al. EASL 2013. Abstract 61. 5. Jacobson I, et
al. EASL 2013. Abstract 1425. 6. Manns M, et al.
EASL 2013. Abstract 1413. 7. Ferenci P, et al.
EASL 2013. Abstract 1416.
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HCV Treatment Based on Individualized
Risk-Benefit Analysis

• Treat now
• Triple therapy substantially increases SVR rates
• Successful treatment may arrest progression of
  liver disease
• Earlier treatment has higher success rates
• Uncertainty about timelines for approval and
  reimbursement

• Defer
• Current PIs are imperfect
• Complex regimens (TID, lead-in)
• Challenging adverse events
• Unsuccessful treatment may reduce subsequent
  treatment success
• Next-wave DAAs may achieve
• Higher cure rates
• Shorter treatment duration
• Improved safety and tolerability
• IFN-free treatment
• Better resistance profile
• Activity in non-GT1

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Summary

• Educate the patient on preventing transmission of
  virus and ways to slow progress of liver disease
• Vaccinate for Hepatitis A and Hepatitis B
• Determine if the patient has advanced fibrosis or
  cirrhosis
• Non invasive tests such as APRI score and
  Transient Elastography are useful to assess
  extent of liver fibrosis
• Successful treatment of patients with advanced
  fibrosis is life saving.
• New Treatments in the next 12-18 months will have
  increased efficacy and reduced toxicity