Transcript 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:

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: 505-272-2808
E-mail: [email protected]
Estimated 170 Million Persons With HCV
Infection Worldwide
•Europe
•Western
Pacific
•8.9 million
•Americas
•62.2 million
•(1.03%)
•(3.9%)
•Southeast Asia
•13.1 million
•(1.7%)
•Africa
•Eastern
Mediterranean
•31.9 million
•21.3 million
•(5.3%)
•(4.6%)
•32.3 million
•(2.15%)
•World Health Organization. Wkly Epid Rec .1999;74:425-427. World Health Organization. Hepatitis C:
Global Prevalence: Update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin
Liver Dis. 2000;20:1-16.
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
o 1.47 M will develop cirrhosis
o 350,000 will develop liver cancer
o 897,000 will die from HCV-related complications
Rein D, et al. Dig Liver Dis 2010.
Mortality associated with Hepatitis B,
Hepatitis C, and HIV
United States, 1999 – 2008
* From: K Ly et al, Ann Intern Med 2012; 156:271-8
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%
Screening for HCV infection in Adults:
USPSTF Recommendations
• Released June 24, 2013
• USPSTF Grade B recommendation
o Adults at high risk
o Adults born 1945-1965
• Grade B –
o Co-pay support (ACA)
o Priority for performance measures, and changes in EMR
• Consistent with CDC recommendations
HCV Test, Care, and Cure Continuum
50%
38%
23%
11%
Holmberg S, et al, NEJM, 2013)
6%
Educate Communities
HCV Testing Algorithm
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
Treatment Rates Are Low
• Estimated that treatment will prevent only 14.5% of potential liverrelated deaths caused by HCV between 2002 and 2030 if 2009 trends
continued
Volk ML, et al. J Hepatol. 2009;50:1750-1755.
Treatment Reduces All-Cause
Mortality in Patients With Advanced
Fibrosis
Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.
Impact of Treatment on HCC
Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.
Impact of Treatment on Liver
Failure
Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.
Management of the Patient
with Hepatitis C
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
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
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
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
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 Jan;40(1):147-54
Hu SX: J Clin Gastroenterol. 2009 Sep;43(8):758-64
Mallat A: J Hepatol. 2008 Apr;48(4):657-65
Hezode C: Hepatology. 2005 Jul;42(1):63-71
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. 1995;19(5):1173
Chen CM: Alcohol Clin Exp Res. 2007;31(2):285
Delarocque-Astagneau E: Ann Epidemiol. 2005;15(8):551
Hassan MM: Hepatology. 2002;36(5):1206
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; 52:127-32.
Lee DH. Dig Dis Sci. 1997; 42:186-91.
Morasco BJ, J Affect Disord. 2007 Nov; 103(1-3):83-90.
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 IFNinduced depression.
Weinstein AA. Psycosomatics. 2011; 52:127-32.
Lee DH. Dig Dis Sci. 1997; 42:186-91.
Morasco BJ, J Affect Disord. 2007 Nov; 103(1-3):83-90.
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
Additional Diagnostic Studies in
Selected Patients
• Serum Ceruloplasmin (Wilson’s 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.)
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 1.272.38).
• Data suggests a potential direct viral role in promoting DM risk
•White DL: J Hepatol. 2008;49(5):831
Patients with Extrahepatic Manifestations
should be prioritized for treatment
•
•
•
•
•
•
Essential Mixed Cryoglobulinema
Leukocytoclastic vasculitis
B Cell Non Hodgkin’s Lymphoma
Porphyria Cutanea Tarda
Necrolytic acral erythema
Renal Disease
– Membranoproliferative glomerulonephritis
– Membranous nephropathy
– Nephrotic syndrome
Classical Cryoglobulinemia-related small vessel vasculitis with
erythematosus palpable maculopapular rash in a HCV positive patient
composed of monoclonal and
polyclonal gamma globulins.
Room Temperature
4 degrees
http://openi.nlm.nih.gov/
Membranoproliferative Glomerulonephritis
There is increased lobulation, intracapillary hypercellularity (including
neutrophil infiltration), and thickening of the capillary walls
Need to get permission to use:
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
•Bedossa P, Poynard T Hepatology. 1996;24(2):289
•Stage F4 – Cirrhosis
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
Findings Suggestive of Cirrhosis
• Clinical exam
– Spider nevi, palmar erythema, gynecomastia, firm liver on
palpation, splenomegaly
• Noninvasive diagnostic tests suggesting cirrhosis
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–
–
–
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–
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Low platelet count (150 thousand)
Low serum albumin, AST/ALT ratio >1
Prolonged prothrombin time
High APRI score or Fibrosure test score
Ultrasound transient elastography
Platelets < 150 thousand
Neutropenia
• Liver biopsy
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)
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 80/40=2.
Platelet count is 130,000/mm3. APRI score is:
(2/130) x 100 = 1.54
• APRI score > 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. 2011;53(3):726, Castera L . Gastroenterology . 2012;142:1293–
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; 134:960.
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
SVR Rates with PegIFN/RBV
According to Genotype
100
•76%-82%
80
60
•42%-46%
40
20
0
•Genotype 1
•Genotype Non-1
•Adapted from Strader DB et al. Hepatology. 2004;39:1147-1171.
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
Fusion and
uncoating
Transport
and release
α- glucosidase
Inhibitors
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. 2007;6(12):991-1000.
Treatment Naïve: Protease Inhibitors
IM Jacobson et al. N Eng J Med 2011; 364:2405-2416.
F Poordad et al. N Engl J Med 2011; 364:1195-1206
Sample of Investigational HCV
Regimens
Regimens with two DAAs
(± PEG-IFN alfa and/or
RBV)
Regimens with
one DAA + PEG-IFN alfa/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
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

Go to Home
EASL 2012 program
http://www2.kenes.com/liver-congress/Pages/Home.aspx
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.
Go to Home
Nucleoside/tide Analog Polymerase
Inhibitors Are Chain-Terminators
NI Chain-terminator
Primer strand
5’
G
C
C
3’
C
G
G
A
U
RNA chain cannot
be elongated
NI
G
A
C
G
5’
Template strand
Go to Home
Sofosbuvir - Neutrino Trial
(Genotype 1, 4,5,6) Treatment Naïve
• Sofosbuvir + Pegylated Interferon + Ribavirin
for 12 weeks (n=327)
SVR Rate: 90%
(genotype 1: 89%, cirrhosis 80%)
E Lawitz : N Engl J Med 2013; 368:1878-1887
Go to Home
Fission Trial (Genotype 2 and 3 naïve
patients)
N Engl J Med 2013; 368:1878-1887 May 16, 2013
SVR12, %
Sofosbuvir/Riba Peginterferon/Riba
(n = 256)
(n = 243)
Genotype 2
97
78
•No cirrhosis
98
82
•Cirrhosis
Genotype 3
91
56
62
63
•No cirrhosis
61
71
•Cirrhosis
34
30
Go to Home
Preliminary Results of New
Interferon Free Regimens in Phase 2
Trials
Regimen
SVR
Rate
>95%
Duration
in Weeks
8-12
ABT450/r + ABT267 + ABT333 + RBV
12
~90%
Faldaprevir + 207127 + RBV (GT1B)
90%
12-24
DCV + ASV +BMS-791325
8894%
12-24
Sufosbuvir + Ledipasvir + RBV
Presentations at European Association of Study of Liver Disease
and Press releases
Go to Home
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
Go to Home
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.
Go to Home
Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract 1416.
HCV Treatment Based on
Individualized Risk-Benefit Analysis
Treat now
Defer
 Triple therapy substantially
increases SVR rates
 Current PIs are imperfect
 Successful treatment may arrest
progression of liver disease
 Earlier treatment has higher
success rates
 Uncertainty about timelines for
approval and reimbursement
–
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
Go to Home
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
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