Transcript HCV

Hepatitis C Update
Primary Care Guidance
Michael J. Tan, MD, FACP, FIDSA
Associate Professor of Internal
Medicine
Northeast Ohio Medical University
Summa Health System
Akron, OH
Objectives
• Review basic epidemiology of HCV
• Understand testing and interpretation of HCV labs
• Review new therapeutics
• Primary source for recommendations is IDSA-AASLD, accessible from
www.hcvguidelines.org
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What is HCV?
• Non-A, Non-B
• small, single stranded, enveloped RNA virus
o Family: Flaviviridae
• Genera: Hepacivirus, HCV
• Genera: Flavivirus: Dengue, Yellow Fever, WNV
• Targets hepatocytes
• Blood-borne
• 2-3% of world’s population (130-170mil)
• US <2%, Egypt > 10%
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Hepatitis C Virus
• Primary target hepatocytes
• Genome encodes a polyprotein consists of 3011 amino acids
– Structural (core, E1, E2)and Non-structural (regulatory NS2, NS3, NS4A/B, NS5A/B)
proteins
– Robust viral replication ~10 trillion particles/day
– RNA-dependent RNA polymerase-lacks proofreading and no DNA intermediates
– Does not integrate into host genomes (vs. HIV)
HIV vs. HCV
• RNA virus-Retrovirus
• CD4, macrophages, dendritic
cells
•  mutation rate
• Blood-borne, moderate sexual
transmission
• Fatal if untreated
• Treatable not curable
• Many drugs
• Life-long therapy
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RNA virus-Flavivirus
Hepatocytes
 mutation rate
Blood-borne, low sexual
transmission
Might be fatal (cirrhosis, HCC)
Both treatable AND potentially
curable
Few drugs (more to come)
Finite duration
Hepatitis C Virus
• Genotypes 1 to 6, multiple subtypes
• Geographical distribution differences around the world
• Genotypes important to stratify duration and dosing
– Genotype 1 harder and longer therapy
– Genotype 2,3 “easier” and shorter duration
– Less important with new and more potent agents
Geographic distribution of hepatitis C virus genotype. (Adapted from Fang JW, Chow V, Lau JY: Virology of hepatitis C virus. Clin Liver Dis 1997;1:493 - 514.)
(Adapted from Fang JW, Chow V, Lau JY: Virology of hepatitis C virus. Clin Liver Dis 1997;1:493 - 514.)
Viral Hepatitis
Cleveland Clinic,, Current Clinical Medicine, ${parentCitation.chapternum}, 539-551
Copyright © 2010 Copyright © 2009, 2010 by The Cleveland Clinic Foundation. Published by Saunders, a imprint of Elsevier Inc.
HCV Genotype (used to) matter
• Genotype 1 historically the most difficult type to treat
– Unfavorable characteristics
• Advanced fibrosis, especially cirrhosis
• African-American
• IL-28B CT or TT genotype
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Polymorphism encodes gene products for IFN-III
Favorable response to CC genotype
• Baseline high viral load
• Prior non-responders
• New agents might relegate above characteristics, except for cirrhosis
• Traditional risk factors
 Illegal drug injection (once or a
few times many years ago)
 Clotting factors before 1987
 Hemodialysis
 Abnormal ALT
 Prior transfusions or organ
transplantations before July 1992
 HCW after needle sticks or
mucosal exposures with HCV +
blood
 Children born to HCV + women
• Traditional risk factors
 Illegal drug injection (once or a few times many
years ago)
 Clotting factors before 1987
 Hemodialysis
 Abnormal ALT
 Prior transfusions or organ transplantations
before July 1992
 HCW after needle sticks or mucosal exposures
with HCV + blood
 Children born to HCV + women
 “Adults born during 1945-1965 should received onetime testing for HCV without prior ascertainment of HCV
risk”
 Brief alcohol screening and intervention, if indicated
 HIV-infected patients
Staging
Histologic Stages of HCV Infection.
Lauer GM, Walker BD. N Engl J Med 2001;345:41-52.
Liver staging
• Important to identify cirrhotic patients
o Higher incidence of HCC
• Initiate surveillance, risk still present even patient is cured
o Decreased response rate
o Risk of liver decompensation (while on therapy)
o Candidacy for response-guided therapy (1st generation protease inhibitors:
boceprevir and telaprevir)
Distribution of hepatic fibrosis in patients with chronic hepatitis C virus infection and normal
or persistently elevated serum alanine aminotransferase (ALT) levels.
Shiftman M L et al. J Infect Dis. 2000;182:1595-1601
© 2000 by the Infectious Diseases Society of America
Distribution of hepatic fibrosis in patients with chronic hepatitis C virus infection and normal
or persistently elevated serum alanine aminotransferase (ALT) levels.
Shiftman M L et al. J Infect Dis. 2000;182:1595-1601
© 2000 by the Infectious Diseases Society of America
ALT not reliable to predict severity of liver
disease
Liver Biopsy
• Still considered as gold standard
• Might be replaced by serum markers
• Values:
o Best way to assess fibrosis
o Assess other liver disease(s)
o Definitive staging
Liver Biopsy
• Cons:
o Invasive
o Relative more expensive than serum markers
o Expertise in acquiring specimen and interpreting histopathology
• Adequacy of specimen
• Which classification is used (Metavir, Ishak, etc.)
o Bleeding risk
Fig. 5
Source: Journal of Hepatology 2007; 47:598-607 (DOI:10.1016/j.jhep.2007.07.006 )
Copyright © 2007 Terms and Conditions
Liver Biopsy-size matters!!
>3 cm
1.5 cm
1 cm
22.4±4.9
10.3±2.2
6.4±1.2
Mild (≤6)
80 (49.7%)
97 (60.2%)
133 (86.6%)
Moderate (7-12)
62 (38.5%)
63 (39.1%)
28 (17.4%)
Severe (≥13)
19 (11.8%)
1 (0.6%)
0
Mild (1-2)
95 (59%)
110 (68.3%)
120 (80.1%)
Moderate (3-4)
48 (29.8%)
39 (24.2%)
24 (14.9%)
Severe (5-6)
18 (11.2%)
12 (7.4%)
8 (4.9%)
No. of portal
tracts
Complete
Grading
Staging
Colloredo et al. Journal of Hepatology 39 (2004):239-244
FibroSure
• Serum biomarkers as surrogate to test for fibrosis
• Non-invasive
• Biochemical markers: α2 macroglobulin, haptoglobin, bilirubin, GGT,
apolipoprotein A1 and ALT
• Coupled with patient’s age and gender and using a proprietary artificial
intelligence algorithm to generate a score
FibroSure
• Provides a numerical quantitative estimate of liver fibrosis ranging 0.00 to 1.00corresponds to Metavir scroing F0-F4
o F0=no fibrosis, F1= portal fibrosis, F2= bridging fibrosis with septa, F3=
bridging fibrosis with many septa, F4= cirrhosis
• Provides a numerical quantitative estimate of necroinflammatory activity from
0.00 to 1.00 corresponds to A0 to A3
o A0= no activity, A1= minimal activity, A2= moderate activity, A3= severe
activity
FibroSure
• Correlates fairly well with liver biopsy
• Multiple studies indicated AUROC predictive value between 0.70 to 0.80
• Should not be used:
o Hemolysis, acute hepatitis, autoimmune hepatitis, low haptoglobin, genetic
liver disease
• Discordant liver biopsy vs. FibroSure
o Biopsy size (<15 mm)
Hepatitis C More Background
• Risks
o About 10% spontaneous clearance
o Non-cleared—risk of cirrhosis, liver failure, HCC
• Previous treatments: Peg-Interferon + Ribavirin
o Treatment up to 12mos
o Sustained virologic response:
• Genotype 1: 70% (less with HIV)
• Genotype 2-3: 80-90% (less with HIV)
o Anemia
o Influenza-like illness
o Depression
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Treatment
Ghany et al. Hepatology, Vol. 49, April 2009
Therapy
• For decades only two major classes of medications: interferon and ribavirin
o Standard IFN-1991; Pegylated IFN-early 2000s
• Response rate poor to fair at best (genotype 1 especially)
• Moderately significant side-effects
• Direct Acting Anti-virals (DAAs)-2011 revolutionized treatment paradigm
Ribavirin
• Nucleoside purine analogs
• 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide
• Broad spectrum of DNA and RNA viruses
– Exact mechanism on HCV not clear
• Major metabolite ribavirin-5’-triphosphate
– Erythrocytes lack necessary enzymes to degrade metabolite-leads to 
accumulation of metabolites
– Exerts oxidative damage to cell membrane and increased extra-vascular
hemolysis by RE system
Gilbert et al. AAC, Aug 1986, p.201-205
Evolution of HCV Therapy
McHutchison NEJM 1998; 339:1485-1492
Fried NEJM 2002; 347:975-982
Manns Lancet 2001; 358:958-965
Boceprevir
Telaprevir
Simeprevir
Asunaprevir
Sofosbuvir
Ledipasvir
Daclastavir
Organization of the hepatitis C virus (HCV) genome and polyprotein. ( A ) Organization of the HCV genome with nontranslated RNA segments shown as
lines and the open reading frame as a box; the region encoding the nonstructural proteins required for replication is shaded. ( B ) Functional organization
and processing of the viral polyprotein, showing approximate membrane topologies of the mature HCV proteins. Sites of cleavage by host cell and viral
proteases are indicated by triangles. (Redrawn from Lemon SM, Walker C, Alter MJ, et al. Hepatitis C virus. In: Knipe DM, Howley PM, eds. Fields’
Virology, 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:1253.)
(Redrawn from Lemon SM, Walker C, Alter MJ, et al. Hepatitis C virus. In: Knipe DM, Howley PM, eds. Fields’ Virology, 5th ed. Philadelphia: Lippincott
Williams & Wilkins; 2007:1253.)
Viral Hepatitis C
Alter, Miriam J., Tropical Infectious Diseases: Principles, Pathogens and Practice, CHAPTER 65, 427-432
Anti-Hep C
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4/2011, Recommended for approval
5/2011, Telaprevir, boceprevir-APPROVED!
Approval for recurrence/treatment
New Agents for HCV
o Combination with PEG-IFN, RBV
o Anemia biggest AE
• Apparently better SVR than standard of care
• Cost? Role? Efficacy in HIV?
Anti-Hep C-Boceprevir
• N Eng J Med 2011;364:1195-206.
o Boceprevir for untreated HCV Genotype 1
• Gp 1: pegIFN-RBV + Placebo 44wks
• Gp 2: peg IFN-RBV + boceprevir 24 wks
• Gp 3: peg IFN-RBV + boceprevir 44wks
o SVR non-black: Gp 1 40% vs Gp 2 67% vs Gp 3 68%
o SVR black: 23% vs 42% vs 53%
o Anemia 13% controls vs 21% boceprevir
SVR rates improve with new DAAs
Adapted from: Poordad et al. NEJM 2011;364:1195; Jacobson et al. NEJM 20111:364:2405; Bacon et
al. NEMJ 2011;364:1207; Zeuzem et al. NEJM 2011;364:2417
Side-effects
• Boceprevir
o Fatigue
o Anemia
o Nausea
o Dysgeusia
• Telaprevir
o Anemia
o Rash
o Fatigue
o Pruritis
o Nausea
o Diarrhea
o Vomiting
o Hemorrhoids
o Anorectal discomfort
Sofosbuvir (SOF, GS-7977)
 HCV-specific uridine nucleotide NS5B polymerase inhibitor (chain
terminator)
 Potent antiviral activity against
HCV genotypes 1–6
 High barrier to resistance
 Once-daily, oral, 400-mg tablet
 Favorable clinical pharmacology
profile
 No food effect
 Renally cleared - limited potential for drug interactions
 No CYP3A/4 metabolism
 limited potential for drug interactions
 Generally safe and well tolerated in clinical studies to date (>3000
patients)
Gilead
Anti-HCV
• Simeprevir (Janssen)
o Oral 150mg q24 x12wk + Peg/Rib x24wk.
o SVR 79-80%
o Approval for naïve and treatment experienced Genotype 1
o Once daily pill option
o APPROVED
• Sofosbuvir (Gilead)
o Once daily nucleotide analogue
o Approval in chronic HCV in adults with GT2, 3
• PEGIFN + Riba + sofosbuvir, Chronic HCV 1 and 4 treatment Naïve
• Riba + sofosbuvir, Chronic HCV 2, 3 (24wk)
• SVR in as little as 12 weeks Sup or non-inf to current treatments.
Sofosbuvir
• Indications
o Genotype 1 and 4: P/R/SOF x 12 weeks
• If INF ineligible: SOF + RBV x 24 weeks
o Genotype 2: RBV + SOF x 12 weeks
o Genotype 3: RBV + SOF x 24 weeks
o Hepatocellular carcinoma awaiting transplant: RBV + SOF up to 48 weeks
o HIV/HCV co-infection
Simeprevir (Olysio)
• NS3/4A protease inhibitor
• Combination therapy with PEG-IFN/RBV for genotype 1 only
• Treatment naïve/prior relapses:
o 12 weeks then 12 more weeks with P/R
• Partial/null responders and cirrhotics:
o 12 weeks then 36 more weeks with P/R
Simeprevir
• Off label use-combination of sofosbuvir + simeprevir (sim-sof combo)
o As recommended by recent AASLD/IDSA joint guidelines for IFN intolerant GT-1
patient
o Significant: interferon free!
o Data derived from ongoing study COSMOS
ledipasvir/sofosbovir (Harvoni)
• Approved for genotype 1 in adults
• One tablet (90/400) PO q24h
o Naïve with or without cirrhosis 12 wk
o Experienced without cirrhosis 12 wk
o Experienced with cirrhosis 12 wk
• Interferon sparing
• AE:
o Fatigue, Headache, nausea, diarrhea, insomnia
• GT-1 96-99% SVR with minimal relapse
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DAA
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sofosbuvir + velpatasvir (Epclusa) daily
elbasvir + grasoprevir (Zepatier) (HCV Geno 1 or 4) (Daily)
daclatasvir (Daklinza,)
paritaprevir/ritonovir/ombitasvir (daily) + dasabuvir (twice/day) (Viekira Pak)
sofosbuvir (Sovaldi)
ledipasvir + sofosbuvir (Harvoni)
Simeprevir (Olysio)
When and in Whom to Initiate Therapy?
• All patients with chronic HCV except those with short life expectancies that cannot be
remediated by treating HCV, by transplantation, or by other directed therapy.
o Prioritization tables have been removed
• Earlier treatment leads to augmented benefit of SVR
• Treatment in setting of fibrosis or cirrhosis and reduce decompensation
New Diagnosis
• HCV Ab +
o Check HCV Viral Load
o Check HCV Genotype
o Check CBC, BMP, LFT, Thyroid, Coags, Fibrosis score
Recommendations
• Guidelines change frequently. Visit http://www.hcvguidelines.com
• Treatment Naïve/Treatment Experienced
o Know the genotype
o Know state of cirrhosis
o Select therapy
o Most treatments are 12 weeks, some 24wks
• Few have ribavirin
• Few if any have PEG-IFN
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www.hcvguidelines.com
Monitoring
• Drug-Drug interactions
• HCV Geno/Subtype, Quantitative HCV
• Within 12 weeks prior to start
o CBC, INR, LFT, Calculated GFR
o TSH (if IFN)
• During therapy
o CBC, Creat, GFR, LFT after4 weeks
o TSH q12k weeks if IFN
o Discontinue Tx for 10 fold rise in ALT at week 4.
• If less than 10 fold rise, check LFT wk 6 and 8
• Quantitative @ 4 weeks, and 12 weeks after completion, +/- 24 weeks after
completion.
HCV and HIV
• Still want to treat HIV fully
• Follow guidelines for HCV
o Watch for drug interactions with HAART
HCV
• Decompensated disease has recommendations but should be done with consultation
with liver specialist
• Post-liver transplant has recommendations
• Specific recommendations for patients with impaired crt cl <30
• Acute infection?
o HCV Ab and HCV RNA (viral load)
o Pre-exposure prophy and post-exp prophy not recommended
o F/U VL for clearance, no treatment for spontaneous clearance. (min 6 mos)
Monitoring
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If HCV detectable @ wk 4, repeat at wk 6
If HCV increases 10 fold at week 6, stop therapy
If comes down at week 6 and 8, no recommendation
Check serum HCG
RBV not recommended in pregnancy
No SVR:
o LFT, CBC, INR for disease progression
o Surveillance for HCC q6mos
o Endoscopic surveillance for varices if cirrhosis
o Evaluate for retreatment as new alternatives become available.
SVR Achieved
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No fibrosis (f/u as if no HCV)
Check Quant if ongoing risk of HCV or if unexplained hepatic dysfunction
If F3 or F4, ultrasound 2x/year surveillance for HCC
Baseline endoscopy for varices if cirrhosis
Assess for other causes of liver disease in those who develop persistently abnormal
LFT after SVR
• Not recommended to prospectively monitor for HCV recurrence in those receiving
immunosuppressive therapy.
Conclusions
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HCV is a huge problem
Cases on increase, especially with screening
Therapy is easier than it used to be
Cure is possible
Cost is an issue