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

2

Objectives

• List the diagnostic criteria for hepatitis C (HCV)

• Define the natural history of HCV

• Review the treatment options for HCV

3

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.

10

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

11

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

26

Sofosbuvir-Velpatasvir

Simeprevir + Sofosbuvir

Ledipasvir-Sofosbuvir

Glecaprevir -pibrentasvir

Sofosbuvir-velpatasvir-Voxilaprevir

Daclatasvir + Sofosbuvir

Elbasvir-Grazoprevir

SVR Rate ≥ 90%

Choosing Among HCV RegimensProvider/patient preferences

27

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

34

Gynecomastia

AscitesPitting edema

35

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.

47

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