Teaching Procedural Skills Amy S. Oxentenko, MD, FACP, FACG, AGAF Mayo Clinic, Rochester.
Viral Hepatitis C: The Final Countdownginurse.com/Library/CourseMaterial/Saab_Hepatitis C...The...
Transcript of Viral Hepatitis C: The Final Countdownginurse.com/Library/CourseMaterial/Saab_Hepatitis C...The...
Viral Hepatitis C:The Final Countdown
Sammy Saab, MD, MPH, AGAF, FACG, FAASLDProfessor of Medicine and Surgery
Head, Outcomes Research in HepatologyDavid Geffen School of Medicine at UCLA
Disclosures
• Speaker Bureau/Consultation– AbbVie, Bayer, BMS, Gilead, Intercept, Merck, Salix
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Objectives
• List the diagnostic criteria for hepatitis C (HCV)
• Define the natural history of HCV
• Review the treatment options for HCV
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4
Acute and Chronic Disease Burden
HAV HBV HCV
Acute infections +++ ++ +
Chronic infections - ++ +++
Deaths due to chronicliver disease/year - ++ +++
5
Hepatitis C Virus
6
Hepatitis C Screening
HCV ELISA Test(Antibody)
Positive Negative
HCV RNA
Positive Negative
Stop
Infected Not infected
• 67 year old woman found to have hepatitis C infection on routine screening.
• Remote history of blood transfusionn
• Asymptomatic
• Normal physical examination
Case Presentation
• HBsAg ~ negative
• HCVAb ~ positive
• HCV RNA ~ 800,000
• HCV genotype 1a
Case Presentation (continued)
• ALT 32
• Total bilirubin 0.6
• Albumin 4.4
• Platelet 179
• AFP 4.7
Hepatitis C Prevalence Estimates
Polaris Observatory HCV Collaborators. Lancet 2017.
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HCV Is Nearly 4 Times as Prevalent as HIV and HBV in the United States
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus.Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C; 2010.
Prevalence of Chronic Viral Infections
Num
ber i
nfec
ted 4,000,000
3,000,000
2,000,000
1,000,000
0
1.1 M~21%
HIV
~0.8-1.4 M
~65%
HBV
~2.7-3.9 M
~75%
HCV
UndiagnosedDiagnosed
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Baby Boomers Account for 82% of HCV Cases in the United States
1. Smith BD, et al. [AASLD abstract 394]. Hepatology.. 2011;54(4):554A. 2. Smith, et al. American Association for the Study of Liver Disease Liver Meeting, San Francisco, CA. 2011. 3. Ly, et al. Ann Intern Med. 2012.
Estimated Prevalence by Age Group
Num
ber w
ith c
hron
ic H
CV
infe
ctio
n (m
illion
s)
Birth Year Group
0
1.4
1.2
1.0
0.8
0.6
0.4
0.2
1990+1980s1970s1960s1950s1940s1930s1920s<1920
HCV Testing Screening Recommendations, United States, 1998
CDC Recommendations• Ever injected illegal drugs • Received clotting factors <1987• Received blood/organs <July 1992• Ever on chronic hemodialysis• Evidence of liver disease
(elevated ALT)• Infants born to HCV infected mothers• HIV infection
MMWR 1998;47 (No. RR-19)
Revised HCV Screening Recommendations, United States, 2012
• Adults born during 1945 through 1965 should receive one-time testing for HCV without prior ascertainment of HCV risk factor
• All persons with identified HCV infection should receive a brief alcohol screening and intervention as appropriate, followed by referral to appropriate care and treatment services
Hepatitis C Testing among Baby Boomers at UCLA
14Castrejon et al. Open Forum Infectious Diseases 2017.
Increases in HCV Infection Among Young Persons Who Inject Drugs (<30 Years Old)
MMWR Morb Mortal Wkly Rep. 2015;64:453-8.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
2006 2007 2008 2009 2010 2011 2012
No.
of C
ases
Per
100
,000
Po
pula
tion
Nonurban Urban
*
Hepatitis C virus detection rate increasing among Kentucky Women and Children
Koneru A, et al. MMWR Morb Mortal Wkly Rep 2016.
Natural History of Hepatitis C Infection
Adapted from Chen SL, Morgan TR. Int J Med Sci. 2006;3:47-52.
*20%-30% of individuals are symptomatic. HCC=hepatocellular carcinoma.
Acute Infection*Chronic Infection75%-85%
Clearance of HCV RNA15%-25%
ExtrahepaticManifestations
Cirrhosis10%-20% over 20 years
HCC1%-4% per year
Decompensated Cirrhosis
5-yr survival rate 50%
Hepatitis C Is Leading Cause of Liver Transplants in the US
Available at: http://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/03_%20liver_12.pdf.
Primarycauseofdiseaseamongadultlivertransplantrecipients,2011
All others22.3%
Acute hepatic necrosis
Alcoholic liver disease
17.6%
HCV23.5%
Cholestatic disease
Metabolic liver disease
Malignancy20.9%
2.5%4.0%
All others26.4%
Acute hepatic necrosis
Alcoholic liver disease23.2%
HCV30.1%
Cholestatic disease
HBV
Malignancy
2.6%2.8%
Primarycauseofdiseaseamongadultsonthelivertransplantwaitlist,2011
6.0%
9.0%
9.1%
Extrahepatic Manifestations of Chronic Hepatitis C
• Hematologic: Mixed cryoglobulinemia(10%–25% of HCV patients)*
• Renal: Glomerulonephritis
• Dermatologic:– Porphyria cutanea tarda*
– Lichen planus*
– Cutaneous necrotizing vasculitis
• Diabetes
• Depression
Management of Hepatitis C. NIH Consensus Statement, 2002.
Staging Hepatitis C
Normal Cirrhotic
Stage 1 2 3 4
Liver Biopsy ElastographySerum Biomarkers
Diagnosing Cirrhosis
Routine Imaging
Physical Examination
Implication of Cirrhosis
• Might– impact choice of antiviral therapy– affect treatment duration– necessitate the use of ribavirin
• Natural history of cirrhosis– assess for decompensation– Screen for hepatocellular carcinoma
1
2
3Other
Mixed
Molecular Tests Genotype
• 6 genotypes• Significance
– Treatment response– Duration of treatment
Evaluation of Patents with Hepatitis C Infection• Motivation and adherence• Prior treatment• Quantitative PCR for HCV RNA• HCV genotype• Liver associated tests
– ALT/AST, bilirubin, albumin, total proteins– Platelets
• Exclusion of other liver disease• Ensure immunity to HAV, HBV• Baseline imaging• Evaluation of fibrosis
– Serum marker panels (e.g. Fibrosure, Fibrospect, Hepascore)– Tissue elastography: Fibroscan, ARFI, MRI elastography
Combination of Direct Acting Agents
Protease Inhibitor(‘previr’)
NS5AInhibitor(‘asvir’
PolymeraseInhibitor(‘buvir’)
Ribavirin
At least 2 agents used
Hepatitis C Therapies in 2017
Primary factors influencing choice:1. HCV genotype2. Prior HCV Treatment3. Cirrhosis, especially if
decompensated4. Renal disease5. Insurer Preference
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Sofosbuvir-Velpatasvir
Simeprevir + Sofosbuvir
Ledipasvir-Sofosbuvir
Glecaprevir -pibrentasvir
Sofosbuvir-velpatasvir-Voxilaprevir
Daclatasvir + Sofosbuvir
Elbasvir-Grazoprevir
SVR Rate ≥ 90%
Choosing Among HCV RegimensProvider/patient preferences
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Shortduration
Simple
Few side effects
Highest efficacy
Hepatitis C Can be Cured
• HCV RNA remains in the cytoplasm and does not integrate into host DNA– Unlike HBV, HIV
Hepatitis C Virus
viral RNA
Host CellNucleusHost DNA
Sustained Virologic Response Is Associated With Reduction in All-Cause Mortality
van der Meer AJ, et al. JAMA. 2012
All-
Cau
se M
orta
lity
(%)
All-Cause Mortality
Time (y)
p<0.001
Non-SVR SVR
An international, multicenter, long-term follow-up study from 5 tertiary care hospitals in Europe and Canada of 530 advanced fibrosis/cirrhotic HCV
patients treated with IFN-based regimen between 1990-2003
SVR is Associated with ReducedMortality, HCC and Transplant
• Achieving SVR was associated with:– 62–84% reduction in all-cause mortality– 68–79% reduction in risk of HCC– 90% reduction in risk of liver transplant
Meta-analysis of 129 studies of IFN-based therapy in 34,563 HCV patients
02468
101214
02468
101214
02468
101214
5-year Risk of Death(All Cause)
5-year Risk of HCC
5-year Risk of Liver Transplant
Patie
nts
(%)
SVR No SVR
4.5
10.5
3.6
11.3
1.3
10
2.9
9.3
5.3
13.9
0.9
10
02.2
0.2
7.3
0.62.7
General Cirrhotic HIV/HCV General Cirrhotic HIV/HCV General Cirrhotic HIV/HCV
Adam P, et al. J Viral Hepatol 2016
Cirrhosis Regression and Fibrosis Reduction Following Sustained Viral Response
Prospective study of patients with pre-treatment cirrhosis and an SVR with IFN-based therapy (enrolled in 2009-2010) to assess the impact of SVR on the full spectrum of histopathologic features of HCV-related cirrhosis. N=38, median f/u 67 months (range, 54-110 months).
D’Ambrosio R, et al. Hepatology. 2012.
Sample Liver Biopsy
Pre-treatment (F4) Post-treatment (F3)
Cirrhosis Regression in 61% of Patients
7
1438
15
0%
20%
40%
60%
80%
100%
Pre-treatment Post-treatment
F1 F2 F3 F4
2
Fibrosis Reduction§ After treatment, the area of fibrosis decreased in 34/38 (89%) of patients§ Post-treatment liver biopsies showed a significantly reduced area of fibrosis, with a median individual decrease of 71.8%
Pretreatment HbA1c Post-treatment HbA1c
Mean difference in HbA1c drop in SVR vs. no SVR groups
P Value
All Patients
No SVR 7.27 (1.6) 7.08 (1.5)
SVR 7.20 (1.5) 6.82 (1.3) -0.18 0.03
Patients with pretreatment HbA1c > 7.2%
No SVR 8.54 (1.2) 7.89 (1.6)
SVR 8.54 (1.2) 7.56 (1.3) -0.33 0.02
Patients with pretreatment HbA1c ≤ 7.2%
No SVR 6.1 (0.7) 6.4 (1.06)
SVR 6.2 (0.6) 6.3 (0.9) -0.15 0.04
Patients with cirrhosis
No SVR 7.2 (1.5) 6.9 (1.4)
SVR 7.1 (1.5) 6.8 (1.3) -0.02 0.8
Patients without cirrhosis
No SVR 7.4 (1.6) 7.3 (1.6)
SVR 7.2 (1.4) 6.8 (1.2) -0.33 0.005
Hum J et al, Diabetes Care 2017
Impact of Hepatitis C Cure on HbA1c (%)
Benefits Risks
Improve survival Unable to receive HCV+ grafts
Removal from transplant list Risks of Resistance if no SVR
Decrease portal hypertension Adverse effects
No post-transplant reinfection Retreatment options
What is the Point of New Return?
MELDChildPugh HCC
Renal failure
Suraweera and Saab. Hepatology 2017
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Gynecomastia
AscitesPitting edema
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Esophageal varices Gastric varices
Therapy Indications for TreatmentCirrhosis Dialysis DAA -Treatment
experienced Compensated Decompensated
SOF/LED ± R X XSOF/SIM XEBV/GZR ± R X XSOF/DAC ± R X XSOF/VEL ± R X XSOF/VEL/VOX X XGLE/PIB X X X
FDA – Approved Treatment Regiments forPatients with HCV Genotype 1
Abbreviations: DAA – Direct acting agent; SOF ~ sofosbuvir; LED ~ ledipasvir; SIM ~ simeprevir; DAC ~ daclatasvir; R ~ ribavirin; 3-D ~ Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir ; VEL ~ velpatasvir; VOX ~ Voxilaprevir; GLE ~ glecaprevir; PIB ~ pibrentasvir.
Efficacy of SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients
Roberts, EASL 2017, SAT-280
97 97 97 99 100 96 95 100 100 100
0
20
40
60
80
100
SVR
12 (%
)
GT 4
11
431445
150155
3636
126132
3941
222228
Total GT 1 Total
GT 1a GT 1b GT 2 GT 3 GT 5 GT 6 Other
11
66
6869
The SVR12 rate was 97% (431/445) in DAA-experienced patients treated with SOF/VEL/VOX for 12 weeks; Rates were similar regardless of genotype
Integrated Efficacy Analysis of POLARIS-1 and -4
Puoti M, et al. J Hepatol 2017. Rockstroh J, et al. J Hepatol 2017.
SVR
12 (%
)98 99 98 95 93
100 100
Overall GT1 GT2 GT3TN
GT4 GT5 GT6
808828
383387
193197
177186
4346
22
1010
Efficacy of Glecaprevir and Pibrentasvir for 8 Weeks in GT1-6 TN/TE Patients without Cirrhosis
Abbreviations: TN ~ treatment-naïve; TE ~ treatment-experienced with IFN or pegIFN± RBV, or SOF + RBV ± pegIFN. Data pooled from arms of SURVEYOR-II and EXPEDITION-1.
• GT1, 2, 4-6 TN/TE and GT3 TN patients received glecaprevir and pibrentasvir for 12 weeks• GT3 TE patients received glecaprevir and pibrentasvir for 16 weeks
99 99 100 98 100 100 100
0
20
40
60
80
100
Overall GT1 GT2 GT3TN
GT4 GT5 GT6
SVR
12 (%
)
8990
3131
3940
22
1616
77
184186
Efficacy of Glecaprevir and Pibrentasvir for 12 or 16 Weeks in GT1-6 Patients with Compensated Cirrhosis
4547
96
GT3TE
Puoti M, et al. J Hepatol 2017. Rockstroh J, et al. J Hepatol 2017.
Abbreviations: TN ~ treatment-naïve; TE ~ treatment-experienced with IFN or pegIFN± RBV, or SOF + RBV ± pegIFN. Data pooled from arms of SURVEYOR-II and EXPEDITION-1.
Genotype Strategies
2 SOF/VEL SOF/R SOF/VEL/VOX GLE/PIB
3 SOF/VEL SOF/R SOF/DAC ± R SOF/VEL/VOX GLE/PIB
4 SOF/VEL SOF/LDV 2-D ± R SOF/VEL/VOX GLE/PIB
5-6 SOF/VEL SOF/LDV SOF/VEL/VOX GLE/PIB
Abbreviations: SOF ~ sofosbuvir; LED ~ ledipasvir; R ~ ribvavirin; 2-D – ombitasvir, paritaprevir+ritonavir; R-ribavirin; VEL ~ velpatasvir; VEL ~ velpatasvir; VOX ~ Voxilaprevir; GLE ~ glecaprevir; PIB ~ pibrentasvir.
FDA – Approved Treatment Regiments forPatients with HCV non-Genotype 1
Treatment of Hepatitis C Genotype 1Direct Acting Agent Nonresponders
DAA Prior Exposure Approved Therapies
NS3/4A alone
NS5A alone Gle/ PibX 16 weeks Sof/ Vel/ Vox
X 12 weeks
NS5A + NS3/4A Sof/ Vel/ VoxX 12 weeks
Abbreviations: SOF ~ sofosbuvir; LED ~ VEL ~ velpatasvir; VEL ~ velpatasvir; VOX ~ Voxilaprevir; GLE ~ glecaprevir; PIB ~ pibrentasvir.
Model-Based Predictions The Changing Burden of Hepatitis C Virus Infection
Kabiri M et al. Ann Intern Med. 2014
Improving the HCV Test and Cure Continuum: High Drug Costs are Not the Only Barrier
0
20
40
60
80
100
All HCV infected
anti-HCV tested
HCV care HCV RNA Treated SVR
1.6 M(50%) 1.2 M
(38%)750,000(23%)
360,000(11%) 200,000
(6%)
Holmberg S, et al. IDSA 2015
Perc
ent
Patie
nts
(%)
Eliminating Hepatitis C in Liver Transplant Recipients
0%
20%
40%
60%
80%
100%
2013 2014 2015 2016
Year
Prop
ortio
n of
Tra
nspl
ant
Rec
ipie
nts
with
Hep
atiti
s C
Health Measures in Patients with Hepatitis C
• NO SMOKING• Minimal to no alcohol• Don’t share toothbrushes/razors • Lose weight if overweight• Tell your doctor about ALL medications, herbal products• Be proactive about getting treated• Don’t get lost to follow-up if your doctor says you need to do so:
consequences can be disastrous
Extended Hepatitis C Care Continuum
Falade-Nwulia O, Silkowshi M. J Hepatol 2017.
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Conclusions
• Viral hepatitis diagnosed through blood serological tests.
• Goal of therapy for hepatitis C is cure
• Hepatitis C can become rare disease through antiviral therapy