HCV - Best Practice.

Best Practices for HCV Infection
Before and After the Cure
Supported by an independent educational

grant from Gilead Sciences Medical Affairs
Simply Speaking® Hepatitis “Best Practices for HCV Infection Before and After the Cure” is
Copyrighted 2020 by Practice Point Communications, unless otherwise noted. All rights reserved.
Content Development Faculty
Nancy Reau, MD, FAASLD, AGAF
Chief, Section of Hepatology
Richard B. Capps Chair of Hepatology
Associate Director, Solid Organ Transplantation
Rush University Medical Center
Chicago, Illinois
• Disclosures
– Employment/Salary: None
– Research Grants/Investigator: GenFit, Gilead Sciences, Intercept
– Consultant: Gilead Sciences, Merck
– Speakers Bureau, Faculty, Peer Reviewer: None
– Advisory Committee/Board: AbbVie, Gilead Sciences, Intercept
– Stockholder: None
– Royalty: None
– Honoraria: None
– Other: None
2
Learning Objectives
(CME/CNE/CPE)
• Upon completion of this educational activity, participants should be better able to:
– Discuss the changing demographics of HCV in the United States
– Select appropriate regimens to cure patients with hepatitis C infection according to the American Association
for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) recommendations
– Select appropriate management approaches for liver-related complications and HCV reinfection in patients
who achieved a sustained virologic response
3
Updated
Slide
Overview
• Changing epidemiology/demographics of patients with HCV infection in the United States

• Patient profiles
• Management after the cure
4
CDC (2013-2016):
Estimated HCV Prevalence Among Adults in the United States
• HCV antibody positive (including past and current infection)

– Number: 4.1 million (95% CI 3.4-4.9)
– Prevalence: 1.7% (95% CI 1.4-2.0)
• HCV RNA positive (including current infection)

– Number: 2.4 million (95% CI 2.0-2.8)
– Prevalence: 1.0% (95% CI 0.8-1.1)
Estimated adult US population in 12/2016: 245 million.

Datasets analyzed:
National Health and Nutrition Examination Survey (noninstitutionalized civilian population).
Combination of literature reviews and population size estimation approaches (incarcerated people, unsheltered homeless people, active-duty
military personnel, and nursing home residents).
Hofmeister MG, et al. Hepatology. 2019;69:1020-1031. 5
Update on WHO HCV Elimination 2030 Targets
• 2030 targets
Global Progress Towards Meeting
– 90% diagnosed WHO HCV Elimination Targets
2019 Status
– 80% treated
– 65% reduced mortality
– 90% reduction in HCV incidence
• Countries on track to meet targets

– Egypt, France, Ireland, Spain, Switzerland
On track
Working towards
• United States is not on track to meet all targets
Not on track
by 2030 (extrapolated from 2019 data)
The Polaris Observatory HCV Collaborators. 1/2020. https://cdafound.org/dashboard/polaris/dashboard.html. 6

CDC:
National HCV Progress Report 2020 Goals
Goal: Reduce the Rate of Acute HCV Goal: Reduce the Rate of HCV-Related
Infections to 0.25 per 100K Population Deaths to 4.17 per 100K Population
1.2 5.5
Age-Adjusted Rate per 100K Population

1.04
1 0.98 5.03 5.01
Cases per 100K Population
5 4.94 4.91
4.82
0.81
0.8 4.64
0.72 0.73
4.5 4.42
0.6 0.60
4.13
4 Goal
0.42 4.17
0.4
0.29
3.5
0.2 Goal
0.25
0 3
2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
CDC. National Viral Hepatitis Progress Report 2020. https://www.cdc.gov/hepatitis/policy/NationalProgressReport.htm. 7

AASLD-IDSA:
HCV Screening Recommendations
Recommendations for 1-Time HCV Testing

• 1-time, routine, opt-out for all individuals ≥18 years of age
• 1-time for all persons <18 years of age with behaviors, exposures, or conditions/circumstances associated with an
increased risk of HCV infection
• Annual HCV testing for all PWIDs and MSM with HIV who have unprotected sex
Risk Behaviors Risk Exposures Other Medical Conditions

Past or current injection drug use Chronic hemodialysis HIV infection
Intranasal illicit drug use Getting tattoo in an unregulated setting Sexually active persons about
to start PrEP
MSM Persons with recognized exposures
(needle-sticks, mucosal exposures) Unexplained chronic liver disease
and chronic hepatitis including
Birth to an infected mother persistently abnormal ALT
Recipients of transfusions/organ Solid organ donors (deceased/living)
transplants
Recipients of clotting factors (prior to 1987)
Ever incarcerated
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. Version November 6, 2019. 8
CDC (2020): New
Slide
Recommendations for HCV Screening Among Adults
• Universal HCV screening (except in settings where

HCV prevalence is <0.1%)
– At least once in a lifetime for all adults ≥18 years of age
– All pregnant women during each pregnancy
• 1-time HCV testing regardless of age or setting

prevalence, including among persons with recognized
conditions or exposures
• Routine periodic testing for persons with ongoing risk
factors, while risk factors persist
• Any person requesting HCV testing
Schillie S, et al. MMWR Recomm Rep. 2020;69:1-17 9

U.S. Preventive Services Task Force: Updated
Citation
Recommendations for HCV Screening
• All adults aged 18 to 79 years should be screened for HCV

– Includes asymptomatic adults (including pregnant women) Important Considerations
without known liver disease
• Communicating that screening is voluntary and
– 1-time screening for most adults (periodic screening for undertaken only with the patient's knowledge
persons with continued risk of HCV infection)
• Informing patients about HCV infection
– Expands the population to be screened beyond adults born
– How it can (and cannot) be acquired
between 1945 and 1965 and others of high risk
– Meaning of positive and negative test results
• Suggests consider screening persons <18 and >79 years
– Benefits and harms of treatment
of age who are at high risk for infection (eg, current or past
injection drug use) • Providing patients the opportunity to ask
– Limited evidence to determine how often to screen questions and to decline screening
10
United States Preventive Services Task Force. JAMA. 2020;323:970-975.
HCV Disease Epidemiology in the United States
• Data from 2 national laboratory companies

representing the majority of patients screened Changing Profile of Persons Testing
for HCV antibody and/or tested for HCV RNA HCV RNA-Positive in the United States
100
from 2013-2016 2013 (n=186,823)
85% 2016 (n=313,422)
– HCV antibody screening results (n=17,149,480)
80 75%
– HCV RNA test results (n=1,592,984)
Distribution (%)
– HCV RNA positive: 57% (n=914,285) 60
• From 2013 to 2016, there was an increasing

number of young patients and patients with 40 36%
31%
milder disease being diagnosed with HCV 25%
28%
19% 18% 17%
• In 2016 (n=469,550) 20 15%
11% 13%
– Untreated, treatment-naïve (66%)
0
– Treatment-naïve, initiated treatment (19%) <40 ≥40 F0 F1 F2 F3/4
Age Strata Fibrosis Stage
(years)
Chirikov VV, et al. Adv Ther. 2018;35:1087-1102. 11
Rate of Acute HCV Infections Continues to Increase AmongUpdated
Slide
Those <40 Years of Age in the United States (2009-2018)
• New acute HCV infections in 2018 Acute HCV Rate in US 2001-2018

3.5 Age group (years)
– Reported cases (n=3621)
20-29
3 30-39
– Estimated (n=50,300, adjusted for under-
Rate (per 100,000 population)

40-49
ascertainment and under-reporting) 50-59
2.5 ≥60
• 3-fold increase in new cases since 2009
2
– Reflects new infections associated with rising rates
of injection-drug use 1.5
• Most newly acquired acute HCV infections 1

occurred among young, white, PWIDs, who live
in non-urban areas (ie, Appalachian, 0.5
Midwestern, and New England states) 0

2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Year
Ryerson AB, et al. MMWR Morb Mortal Wkly Rep. 2020;69:399-404. 12

PROP UP: Current Medical Comorbidities at the Time of
Initiating DAA Therapy in Real-World Setting
60
Patients reporting ≥1 comorbidity: 90%
50% 49% Median number of comorbidities/patient: 4
50
Strongest/most frequent predictors of
43% worse
40 patient-reported outcomes: disability,
unemployment, current use of psychiatric
Cohort (%)
medications
32% 31% 30%
30
20%
20 18% 17% 16%
10
0
Joint High Blood Muscle Vision Loss/ Sleep Chronic Pain Diabetes/ Asthma/ Hearing Loss High
Pain Pressure Aches Problems Disorder/ Disorder/ High Blood COPD or Problems Cholesterol
Insomnia Orthopedic Sugar
Observational study in the United States (n=1600; 2016-2017) conducted in 11 medical centers (9 academic hepatology and 2 private gastroenterology).
PROP UP: Patient-Reported Outcomes Project of HCV-TARGET.
Evon DM, et al. PLoS One. 2018;13(8): e0196908. 13
Clinical Benefit of HCV Cure With DAA Therapy
• Reduction in overall mortality regardless of severity of liver disease

– Advanced liver disease: 79% reduction
– Non-advanced liver disease: 59% reduction
• 84% reduction in incident hepatocellular carcinoma
• Decrease in liver inflammation (reduced AST/ALT levels)
• Reduction in liver fibrosis progression
• Reduces symptoms and mortality from extra-hepatic manifestations
• Substantially improved quality of life
AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. Version November 6, 2019.

Backus LI, et al. Hepatology. 2019;69:487-497.
Ioannou GN, et al. Gastroenterology. 2019;156:446-460. 14
HCV Linkage to Care in the US (2013-2016)
• Data from two large national laboratory companies

HCV Antibody Positive
• HCV linkage of care cascade
2013 2016
HCV antibody (screening) HCV RNA (diagnosis) (n=179,144) (n=287,130)
Underwent an 45 77
HCV RNA test (%)
See HCV
specialist or PCP
HCV Antibody Positive and
Underwent an HCV RNA Test
Receive HCV treatment 2013 2016
(n=80,615) (n=221,090)
• Patients HCV antibody positive and administered HCV RNA test
HCV RNA positive (%) 64 64
were longitudinally followed
Saw specialist (%) 21 17
– Only a minority of HCV RNA positives saw a specialist
• Age cohorts
– Baby boomers (48 to 71 years of age)
– Young adults (18 to 38 years of age)
Reau N, et al. Hepatology. 2018;68(suppl S1):892A-893A. Abstract 1567. 15

Young Adults Who Were HCV RNA Positive:
Linkage to Care in the US (2016)
Linked to Specialist Linked to Primary Care Physician

100% 100%
100 100
Proportion of HCV RNA Positive (%)
Proportion of HCV RNA Positive (%)

80 80
60 60
40%
40 40
20 20
9%
23% 2% 5% 2%
0 0
HCV RNA Saw Received HCV RNA Saw Primary Received
Positive Specialist Treatment After Positive Care Physician Treatment After
(n=42,263) Specialist Visit (n=42,263) Primary Care
Physician Visit
Patients HCV antibody positive and administered HCV RNA test were longitudinally followed.
Specialist (gastroenterology/hepatology/infectious disease).
Primary care physician (general practitioner/family medicine/internal medicine).
Reau N, et al. Hepatology. 2018;68(suppl S1):892A-893A. Abstract 1567. 16
Updated
Slide
Overview
– Treatment-naïve PWID
• Management after SVR
17
PWID:
21-Year-Old Male With Asymptomatic, Elevated ALT
Acute HCV diagnosed
Screened for HCV when presenting to

ER for overdose Considerations
Tobacco Alcohol Recreational
Comorbidities Use Use Drugs
Should he be treated for acute HCV?
None None Rare Injection heroin
• No symptoms
• ALT 578 U/L Employment Status Relationship Status

Unemployed Single, lives with parents
• Has been injecting heroin for the past 3 to
4 months prior to visit
18
Interpretation of Blood Tests for Diagnosis of
Acute HCV Infection
Test Interpretation for Diagnosis of Acute HCV

HCV antibody Test may be negative during first 6 weeks after exposure
Seroconversion maybe delayed or absent in immunosuppressed persons
Presence of HCV antibody alone does not distinguish between acute versus chronic infection
HCV RNA Viral fluctuations >1 log10 IU/mL may indicate acute HCV infection
HCV RNA maybe transiently negative during acute HCV infection
Presence of HCV RNA alone does not distinguish between acute versus chronic infection
ALT Fluctuating ALT peaks suggest acute infection

ALT maybe normal during acute HCV infection
ALT maybe elevated due to other liver insults, such as alcohol consumption

AASLD-IDSA Guidelines:
Management of Acute HCV Infection
• Pre-exposure or post-exposure prophylaxis with antiviral therapy is not recommended
• In the setting of acute HCV infection

– HCV treatment should be initiated without awaiting spontaneous resolution
• Owing to high efficacy and safety, the same regimens that are recommended for chronic HCV infection are
recommended for acute infection
– Counseling to avoid hepatotoxic insults, including hepatotoxic drugs (eg, acetaminophen) and alcohol
consumption, and to reduce the risk of HCV transmission to others
– Referral to an addiction medicine specialist if acute HCV infection is related to substance use

Clinical Trials for the Treatment of Acute or Recent HCV
• Elbasvir/grazoprevir (adults with HIV who develop acute HCV genotype 1 or 4 infections)
– DAHHS-2 II: phase 3, open-label trial, 8-week course (Netherlands; NCT02600325)
– SAHIV: phase 2, open-label trial, 8-week course (France; NCT02886624)
• Glecaprevir/pibrentasvir (adults with recent HCV infection [<12 months])

– TARGET-3D Part II: phase 3, open-label study, 6-week course (NCT02634008)
– TARGET-3D Part III: phase 3, open-label trial, 4-week course (NCT02634008)
• Sofosbuvir/velpatasvir (PWIDs with recent HCV infection [<12 months])

– REACT: phase 3, randomized, international study, either 6 or 12 week course (NCT02625909)
www.clinicaltrials.gov. 21
PWID: 21-Year-Old Male Presents After Completing
2nd Inpatient Rehabilitation for Opioid Use
Diagnosed with chronic HCV
Patient wants treatment, should he be

treated for chronic HCV? Considerations
• HCV genotype 1a Comorbidities Use Use Drugs
None None Rare Past injection
– HCV RNA 1.2 million IU/mL heroin
• ALT 124 U/L

Employment Status Relationship Status
• FibroSure: F0 Unemployed Single, lives with parents
• Reports not using heroin

• Not taking opioid substitution therapy
22
Interventions for Enhanced HCV Treatment
• Integrated HCV care, substance

use and psychiatric services
delivered by multidisciplinary team
• Biomarkers in place of liver
stiffness measurement
• DAA access
• Cash incentives
• Peer support
OAT: opioid agonist therapy.

DOT: directly-observed therapy.
NEPs: needle-exchange programs.
CBOs: community-based organizations.
Bajis S, et al. Int J Drug Policy. 2017;47:34-46.
Gowda C, et al. Curr Hepatol Rep. 2018;17:111-120.
23
Ward K, et al. Open Forum Infect Dis. 2019;6(4):ofz166.
PREVAIL 1:
Intensive Models of HCV Care for PWID
• Randomized, controlled trial conducted at 3 opioid agonist

therapy programs in Bronx, New York (n=158; 2013-2017) SVR Rates
100 98%
– HCV genotype 1 on opiate agonist therapy 94%
90%
– Injection drug use (75%)
80
• Randomized groups
– Individual treatment (n=51): self-administer all HCV medications 60
SVR (%)
– Group treatment (n=48): attend weekly treatment group
– DOT (n=51): receive observed oral doses by nursing staff 40
• All models of onsite HCV care delivered to PWID in OAT

programs resulted in high SVR, despite ongoing drug use 20
– HCV treatment completion rate: 97% (no differences among groups)

0
Individual Group DOT
Treatment Treatment
OAT: opioid agonist therapy.
DOT: directly-observed therapy.
Akiyama MJ, et al. Ann Intern Med. 2019;170:594-603. 24
ANCHOR Study:
HCV Therapy in PWIDs
• Prospective, open-label, observational study set

Baseline Characteristics
at a harm reduction organization drop-in center in
Washington, DC (n=100 enrolled) Patients
(n=100)
– Chronic HCV infection Median age (years) 58
– Opioid use disorder Male (%) 76

Black (%) 93
– No decompensated cirrhosis or contraindicated DDIs
Cirrhosis (%) 33
• HCV regimen Unstable housing (%) 51
Prior incarceration (%) 92
– Sofosbuvir/velpatasvir
Government benefits/no income source (%) 42/50
• Achievement of SVR12 ≥Daily IDU (%) 59
Medication assisted treatment (%) 33
• Adherence measures
Receptive sharing of IDU equipment (%) 29
– Viral load, interruptions in treatment, completion of Hazardous drinking (%) 40
medication, end of treatment timing
Rosenthal ES, et al. Clin Infect Dis. 2020;Feb 3. [Epub ahead of print]. 25
ANCHOR Study:
SVR12 Rates (ITT) in PWIDs
SVR12 (n=100; ITT): 82%

Yes No
P=0.0001 P=0.4
100 P=0.0001 P=0.5 95%
91% 89% 88%
83%
80 75%
SVR Rate (%)
63%
60
40
20
62 20 12 70 82 0% 39 21
68 32 16 84 92 (0/8) 41 24
0
OAT Use at SVR Interruption Completion of ≥2 Bottles Finishing 12 Weeks
on Treatment of HCV Therapy Treatment On-Time
OAT: opioid agonist therapy. Versus Late
Did not achieve SVR (n=18): viral relapse (n=11); lost to follow-up (n=3), incarceration (n=1), died (n=3).
ANCHOR Study:
Conclusions
• High uptake of buprenorphine collocated with HCV treatment

– On buprenorphine (86%): at baseline (33%) or initiated prior to week 24 (53%)
• PWIDs had high rates of completion of DAA therapy and achieved high SVR12 rates
• Achieving SVR
– Not associated with baseline opioid agonist therapy, on-treatment drug use, or imperfect daily adherence
– Significantly associated with completion of at least 8 weeks of sofosbuvir/velpatasvir and being on opioid
agonist therapy at week 24
• Concurrent initiation of opioid agonist therapy with HCV treatment can result in high rates of SVR
while reducing risks associated with drug use
VA Cohort: Elbasvir/Grazoprevir in Patients Who Receive
Opioid Substitution Therapy
• Retrospective analysis (n=611; 2016-2017)

SVR12 Rate
– US VA Corporate Data Warehouse 100 97%
96% 96% 96%
– HCV genotype 1 with opioid use disorder or ≥1 prescription
for opioid substitution therapy 80
• Baseline characteristics
– Age (62 years), black (53%), male (96%), treatment-naïve 60
SVR (%)
(90%), genotype 1a (47%), HCV RNA >800K IU/mL (68%)
– Cirrhosis (35%), diabetes (34%), CKD stage 4-5 (85%), 40
drug/alcohol abuse (90%/77%), concomitant anti-
psychiatric medication (71%)
20
• SVR rates were high and comparable to phase 3
586 273 417 529
clinical trials 611 286 434 548
0
Overall Genotype Any Anti- History of
– Consistently high SVR12 rates across all subgroups 1a Psychiatric Drug Abuse
Medication
Kramer J, et al. J Hepatol. 2019;70(suppl):e112. Abstract PS-182. 28

C-EDGE Co-STAR Part B:
Injection Risk Behavior in Patients on Opioid Agonist Therapy
• Part A (n=296)
Reinfection Rate
– HCV genotype 1, 4, or 6 on opiate agonist therapy 5
– Received elbasvir/grazoprevir: SVR 97%
Rate per 100-Person-Years

4
• Part B: open-label (n=149 with 30 months of follow-up)
– Reinfection rate: 1.8 per 100 person-years
3 2.8
– Number of reinfections (n=10: spontaneous clearance [2],
persistent infection [8; 4 re-treated and achieved SVR12]) 2 1.8
• HCV reinfection among patients on opioid agonist therapy
following DAA therapy is uncommon, despite ongoing 1
drug use 0.3
0
Overall Yes No
Injection Drug Use
Grebely J, et al. Hepatology. 2018;68(suppl S1):35A. Abstract 52. 29

Updated
Citation
HCV Reinfection Following SVR in PWIDs
• Meta-analysis (36 studies)

Factors Associated With HCV Reinfection
– Prospective (n=26), retrospective (n=10)
Adjusted
– Treatment setting: drug treatment service (36%), community Rate Ratio
(95% CI)
clinic (19%), tertiary care (8%), prison (6%), primary care (3%),
mixed setting (28%) Median/mean follow-up (per year increase) 0.94*
Versus opioid substitution therapy and no
• Reinfection rate (per 100 person-years) drug use
Drug use
– Recent injecting or non-injecting drug use: 5.9 With opioid substitution therapy 3.47*
No opioid substitution therapy 3.74*
– Recent injecting drug use: 6.2 Unknown use of opioid substitution therapy 6.81*
– Opioid substitution therapy ± recent drug use: 3.8
*P<0.001.
• Post-treatment HCV reinfection rate was associated with
recent drug use/opioid substitution therapy status
– Highest rate: recent drug use, not receiving OST
Hajarizadeh B, et al. J Hepatol. 2020;72:643-657. 30

AASLD-IDSA Guidelines:
PWID
• Annual HCV testing is recommended for PWID with no prior testing, or past negative testing and
subsequent injection drug use
– Depending on the level of risk, more frequent testing may be indicated
• Substance use disorder treatment programs and needle/syringe exchange programs should offer
routine, opt-out HCV-antibody testing with reflexive or immediate confirmatory HCV-RNA testing
and linkage to care for those who are infected
• PWID should be counseled about measures to reduce the risk of HCV transmission to others
• PWID should be offered linkage to harm reduction services when available, including
needle/syringe service programs and substance use disorder treatment programs
• Active or recent drug use or a concern for reinfection is not a contraindication to HCV treatment
• At least annual HCV-RNA testing is recommended for PWID with recent injection drug use after
they have spontaneously cleared HCV infection or have been successfully treated

PWID: 21-Year-Old Male Presents After Completing
2nd Inpatient Rehabilitation for Opioid Use
Diagnosed with chronic HCV
If the patient was female would this

change the treatment decision? Considerations
• HCV genotype 1a Comorbidities Use Use Drugs
None None Rare Past injection
– HCV RNA 1.2 million IU/mL heroin
• ALT 124 U/L

• FibroSure: F0 Unemployed Single, lives with parents
• Reports not using heroin

• Not taking opioid substitution therapy
32
Updated
Slide
Overview
– Treatment-naïve woman of child-bearing age
33
HCV and Women
• Women living with HCV who are of child-bearing age: ~40%
• 2011-2014 in the United States

– Number of births/year: ~3.9 million
– Detection of HCV infection in pregnant women: 0.73% (~29,000 women giving birth)
– Vertical transmission: 5.8% (1700 infants born with HCV)
Ly KN, et al. Ann Intern Med. 2017;166:775-782.

Society for Maternal-Fetal Medicine. Am J Obstet Gynecol. 2017;217:B2-B12.
Benova L, et al. Clin Infect Dis. 2014;59:765-773.
HCV Infection Among Reproductive-Aged Women
and Children in the United States (2006-2014)
• Analysis of NNDSS (2006-2014)

Proportion of Confirmed HCV Cases
– Women 15 to 44 years of age (n=171,801) (NNDSS 2006-2014)
25
2010 2014
– Children 2 to 13 years of age (n=1869)
21%
20
• Number of HCV cases among women of 18% 18%
Proportion (%)
reproductive age doubled from 2010 to 2014
(from ~15 to 31K/year) 15
– Similar trends seen for acute and past/current 11%

10 10%
HCV infections 9% 9%
7%
• Number of HCV cases among children 5
remained stable from 2006-2014 (~200/year)
0
Total Acute Past/Current Children
(n=171,801) (n=4133) (n=167,668) (n=1869)
Women Aged 15-44 Years With HCV
NNDSS: National Notifiable Diseases Surveillance System.
Ly KN, et al. Ann Intern Med. 2017;166:775-782. 35
Updated
Slide
Recommendations for Universal HCV Screening in Pregnancy
• AASLD
– As part of prenatal care, all pregnant women should be tested for HCV infection, ideally at the initial visit
• CDC
– All pregnant women during each pregnancy (except in settings where HCV prevalence is <0.1%)
• USPSTF
– Pregnant adults should be screened

Schillie S, et al. MMWR Recomm Rep. 2020;69:1-17
United States Preventive Services Task Force. JAMA. 2020;Mar 2. [Epub ahead of print]. 36
HCV Treatment-Naïve:
28-Year-Old White Female
Diagnosed during prenatal visit (P0G1)
Confirmed genotype 1a
Considerations
• HCV RNA: 1.2 million IU/mL
• ALT/AST: 76/82 U/L Comorbidities Use Use Drugs
GERD None Stopped after None
• Fibrosis F0-1 positive History of IDU
pregnancy test (clean for 6
• 24 weeks pregnant years)
What next? Employment Status Relationship Status

Part-time employment Recently married
• Monitor patient?
• Initiate antiviral therapy?
37
HCV Treatment and Pregnancy
• Women of reproductive age with known HCV infection should be counseled about the benefit of
DAA therapy prior to pregnancy
– Improve health of mother and eliminate the low risk of MTCT
– Antiviral therapy is recommended before considering pregnancy whenever practical and feasible
• There are no data from large-scale trials on the use of DAAs during pregnancy
– Despite lack of a recommendation, treatment can be considered on an individual basis after patient-
physician discussion about the potential risks and benefits
– Ribavirin: teratogenic
• Women who become pregnant while on DAA therapy

– Discuss the risks/benefits of continuing therapy
– If exposed to ribavirin, report maternal and fetal outcomes to the ribavirin pregnancy registry
(http://www.ribavirinpregnancyregistry.com/)
MTCT: mother-to-child-transmission.
Vertical Transmission of HCV
• MTCT is the leading cause of HCV infection in children

HCV Vertical Transmission Rates
– 33% to 50% of MTCT appears to occur in utero prior to the last
month of pregnancy
(HCV-Antibody Positive Mothers)
15
– Remainder occurs either in last month of pregnancy or during
delivery Adjusted OR: 2.56
(P=0.002)
– Few children born to HCV-infected mothers are tested 10.8%
(95% CI 7.6, 15.2)
Proportion (%)
• Meta-analysis of MTCT rates of HCV (2011-2014) 10
– HCV-infected mothers without (17 studies) and with (8 studies)
HIV coinfection
5.8%
– Overall MTCT rate is low (5.8%) (95% CI 4.2, 7.8)
• Risk of MTCT increased in mothers with HIV coinfection

5
• High maternal HCV RNA levels increases risk of transmission
• Limited data on MTCT infections that progress to chronic

HCV (some estimate: 3%-5%)
0
HIV-Negative HIV-Positive
MTCT: mother-to-child-transmission. (n=2017) (n=496)
Society for Maternal-Fetal Medicine. Am J Obstet Gynecol. 2017;217:B2-B12.
Benova L, et al. Clin Infect Dis. 2014;59:765-773.
AASLD-IDSA Recommendations for Monitoring HCV-Infected
Women During Pregnancy
Recommendations for HCV-Infected Women

Initiation of prenatal care
HCV RNA and routine liver function tests to assess the risk of MTCT and degree of liver disease
Administer prenatal and intrapartum care that is appropriate for their individual obstetric risk(s)
Pruritus or jaundice
High index of suspicion for intrahepatic cholestasis of pregnancy
Assess ALT, AST, and serum bile acids
Cirrhosis
Counsel on the increased risk of adverse maternal and perinatal outcomes
Antenatal and perinatal care should be coordinated with a maternal-fetal medicine (ie, high-risk pregnancy)
obstetrician
MTCT: mother-to-child-transmission.
AASLD-IDSA Recommendations for HCV in Children
Recommendations for Testing of Perinatally Exposed Children and Siblings of HCV-Infected Children
All children born to HCV-infected women should be tested for HCV infection
Test using an antibody-based test at or after 18 months of age
Testing with an HCV-RNA assay can be considered in the first year of life,
but the optimal timing of such testing is unknown
Repetitive testing by HCV RNA prior to 18 months of age is not recommended
Anti-HCV positive children after 18 months of age

Test with an HCV-RNA assay after age 3 to confirm chronic HCV infection
Siblings of children with vertically-acquired chronic HCV should be tested for HCV infection,
if born from the same mother

HCV Treatment-Naïve:
28-Year-Old White Female, Former PWID
Ready to start HCV therapy
Follow-up visit 2 years after giving birth

(child tested HCV negative at 18 months) Considerations
• HCV RNA level is re-evaluated: 1.8 million IU/mL Comorbidities Use Use Drugs
• ALT/AST: 80/84 U/L GERD None Stopped during None
pregnancy History of IDU
• Fibrosis F1 (clean for 6
years)
• Medications: multivitamin infusion, proton-pump
inhibitor, combined oral contraception
At-home mother Married 3 years
What are your initial management thoughts?
• Any reason to defer therapy?
• Which regimen?
42
Potential Times During the Pregnancy Care Cascade
for DAA Therapy
Before Postdelivery After

Mother Pregnancy
Pregnancy
Breastfeeding* Breastfeeding
Child Infancy
(<3 years of age)
Childhood
Use of HCV DAA therapy

Approved
Not approved
*AASLD-IDSA, ACOG, CDC, Society for Maternal-Fetal Medicine:

Breastfeeding is safe in women with HCV infection, but recommend women abstain from breastfeeding if their nipples are damaged, bleeding, or cracked, or in
the context of HIV coinfection. 43
Treatment-Naïve Adult Patients:
AASLD-IDSA Recommended HCV Regimens
• SVR12 rates for all

Treatment Duration
recommended regimens for (weeks)
HCV genotype 1: ≥95%
No Compensated
Genotype Regimen Cirrhosis Cirrhosis
1 Glecaprevir/pibrentasvir 8 8
Sofosbuvir/velpatasvir 12 12
Ledipasvir/sofosbuvir 8* or 12 12
Elbasvir/grazoprevir 12† 12†
*Only for patients who are HIV-uninfected and have a baseline HCV RNA <6M IU/mL.
†
Only for genotype 1a patients without baseline NS5A RASs for elbasvir.

DDI Potential Between Common Gastrointestinal Acid-Reducing
Agents and Preferred HCV Direct-Acting Antiviral Agents
Glecaprevir/ Sofosbuvir/ Ledipasvir/ Elbasvir/ Sofosbuvir/Velpatasvir/

Pibrentasvir Velpatasvir Sofosbuvir Grazoprevir Voxilaprevir
Antacids  
Cimetidine 
Esomeprazole 
Famotidine 
Lansoprazole 
Omeprazole 
Pantoprazole 
Rabeprazole 
Ranitidine 
No clinically significant interaction expected Potential weak interaction Potential interaction Do not coadminister
https://www.hep-druginteractions.org/. 45
Treatment-Naïve Children and Adolescents:
• Glecaprevir/pibrentasvir (300/120 mg qd) for 8 weeks

– Adolescents aged ≥12 years or weighing ≥45 kg
– Any genotype, without cirrhosis or with compensated cirrhosis (Child-Pugh A)
• Ledipasvir/sofosbuvir (weight-based dosing) for 12 weeks

– Children aged ≥3 years
– Genotypes 1, 4, 5, or 6
– Without cirrhosis or with compensated cirrhosis (Child-Pugh A)

DDI Potential Between Hormonal Contraception and
Preferred HCV Direct-Acting Antiviral Agents

Desogestrel     
Dienogest     
Drospirenone     
Estradiol   
Etonogestrel (implant)     
Etonogestrel (vaginal ring) x    
Levonorgestrel (COC) x   
Levonorgestrel (implant, IUD)     
Levonorgestrel (POP)   
Levonorgestrel
(emergency contraception)     
Norethindrone     
No clinically significant interaction expected Potential weak interaction Do not coadminister
Updated
Slide
Overview
– Treatment-naïve woman with renal impairment
48
HCV and Renal Failure:
63-Year-Old Female With Renal Impairment
No symptoms or complaints
HCV treatment-naïve
Considerations
• HCV genotype 1b
– HCV RNA 5.8 million IU/mL Comorbidities/Other Use Use Drugs
• Fibrosis score: F2 (FibroSure) Type 2 diabetes, hypertension None None None
and hyperlipidemia,
• Laboratory results postmenopausal
– AST/ALT: 50/65 IU/L
– Total bilirubin: 0.65 mg/dL
Not employed Married
– Platelets: 160,000/mm3
– Hemoglobin: 13.2 g/dL
– Creatinine clearance: 50 mL/min
– HbA1c: 6.7%
Does the patient’s renal function impact your

HCV treatment decisions? 49
HCV and US VA Cohort:
Incidence and Progression of Chronic Kidney Disease
• Chronic HCV infection was associated with

Adjusted Hazard/Odds Ratios
– 15% higher incidence of decreased renal (HCV positive versus negative)
function 2.5
2.17
Hazard/Odds Ratio of Outcomes

(2.13-2.21)
– 98% higher hazard of ESRD 1.98
(1.81-2.16)
2
– 2.2-fold higher mortality
1.5
• Similar results found in propensity matched 1.15
1.22
(1.19-1.26)
(1.12-1.17)
cohort analysis
1
0.5
0
eGFR ESRD Mortality eGFR Slope
<60 mL/min <-5 mL/min
Adjusted for age, gender, race/ethnicity, baseline GFR, comorbidities (diabetes, hypertension, cardiovascular disease, congestive heart failure, cerebrovascular disease,
peripheral vascular disease, lung disease, dementia, rheumatic disease, malignancy, HIV/AIDS, depression, systolic BP, diastolic BP, body mass index),
sociodemographic parameters (income, marital status, service connection, compliance, drug compliance, number of visits, number of medications and ACEI/ARB
usage). 50
Molnar MZ, et al. Hepatology. 2015;61:1495-1502.
German Hepatitis C-Registry: DAA Therapy in
HCV Patients With Advanced Chronic Kidney Disease
• Real-world cohort (2014-2015; n=5733)

eGFR (mL/min) Before and After Treatment
– Genotype 1/3 (79%/11%)
End of Treatment
• Overall SVR rates (ITT) by eGFR (mL/min) 0-15 16-30 31-60 61-90 >90
– 0-15 (85%), 16-30 (84%), 31-60 (91%), >60 (90%) Baseline
0-15 96% -- -- 4% --
• eGFR improvement with HCV therapy: 7%
– Deterioration to <30 mL/min: <1% (9/4527) 16-30 -- 55% 39% 6% --
• Similar incidence of adverse events among patients

31-60 -- 2% 66% 26% 6%
with eGFR above and below 30 mL/min
– More serious adverse events and treatment <1% -- 7% 75% 18%
61-90
discontinuations were seen with RBV use
>90 <1% <1% <1% 17% 82%
Regimens:
Sofosbuvir + RBV; simeprevir + sofosbuvir ± RBV; daclatasvir + sofosbuvir ± RBV; ledipasvir/sofosbuvir ± RBV; ombitasvir/paritaprevir/r + dasabuvir ± RBV.
51
Wiegand J, et al. Eur J Gastroenterol Hepatol. 2019;31:1424-1431.
DDI Potential Between Common Lipid-Lowering Agents and
Preferred HCV Direct-Acting Antiviral Agents

Atorvastatin x x
Bezafibrate     
Ezetimibe   
Fenofibrate     
Fish oils     
Fluvastatin x
Gemfibrozil x  
Lovastatin x x
Pitavastatin  x
Pravastatin x 
Rosuvastatin x x
Simvastatin x x
What If the Patient Had Severe Renal Failure?
Creatinine clearance: 29 mL/min (not on dialysis)
HCV treatment-naïve
Considerations
• HCV genotype 1b
– HCV RNA 5.8 million IU/mL Comorbidities/Other Use Use Drugs
Type 2 diabetes, hypertension None None None
• Fibrosis score: F2 (FibroSure) and hyperlipidemia,
postmenopausal
• Laboratory results
– AST/ALT: 50/65 IU/L Employment Status Relationship Status
– Total bilirubin: 0.65 mg/dL
– Platelets: 160,000/mm3
– Hemoglobin: 13.2 g/dL
– HbA1c: 6.7%
53
Treatment-Naïve Patients:
• No dose adjustment is required in

Duration (weeks)
patients with CKD stage 1, 2, ,3, 4, or 5
No Compensated
– In November 2019, the FDA amended the Genotype Regimen Cirrhosis Cirrhosis
package inserts for sofosbuvir-containing 1 Glecaprevir/pibrentasvir 8 8
regimens to allow use in patients with Ledipasvir/sofosbuvir 8* or 12 12
renal disease, including those with an Elbasvir/grazoprevir 12† 12†
eGFR ≤30 mL/min and those on dialysis
2/3 Glecaprevir/pibrentasvir 8 8
Sofosbuvir/velpatasvir 12 12‡
4 Glecaprevir/pibrentasvir 8 8
Ledipasvir/sofosbuvir 12 12
Elbasvir/grazoprevir 12 12
*Only for patients who are HIV-uninfected and have a baseline

HCV RNA <6M IU/mL. 5/6 Glecaprevir/pibrentasvir 8 8
†
Only for genotype 1a patients without baseline NS5A RASs for elbasvir. Sofosbuvir/velpatasvir 12 12
‡
In genotype 3: only for patients without baseline NS5A RAS Y95H. Ledipasvir/sofosbuvir 12 12
What If the Patient Had Severe Renal Failure?
Patient requests pre-emptive kidney

transplant Considerations
• Do you treat HCV pre-transplant or defer Comorbidities/Other Use Use Drugs
until after kidney transplantation? Type 2 diabetes, hypertension None None None
and hyperlipidemia,
• Would having a living donor impact your postmenopausal
treatment decision?
• Would the presence of cirrhosis change Not employed Married
your treatment decision?
55
DAA-Based Regimens and Kidney Transplantation:
Treating or Not Treating HCV Before Transplant
Treat Before Transplant Do Not Treat Before Transplant

Patient can remain active on waitlist during therapy Efficacious in posttransplant setting
HCV cure is likely HCV cure eliminates HCV-positive donor option

• Possible longer life expectancy • Longer wait time
• Possible decreased risk of • May limit choice of deceased organs
- Progressive liver disease • May lose transplant opportunity
- Posttransplant glomerulonephritis • Inadvertently shorten life expectancy
- New-onset diabetes after transplant • Increased kidney discard rate
Avoids drug-drug interactions with Potential drug-drug interactions necessitates very close
immunosuppression
immunosuppression monitoring
Public health risk reduction
Calogero A, et al. Biomed Res Int. 2019;2019:4674560.

Awan AA, et al. Clin Gastroenterol Hepatol. 2019;Jul 31. [Epub ahead of print].
Morales JM, et al. Clin Transplant. 2019;33(12):e13739. 56
63-Year-Old Female With Severe Renal Impairment
If post-transplant HCV treatment is

preferred, which regimen? Considerations
• Glecaprevir/pibrentasvir ± RBV Comorbidities/Other Use Use Drugs
Type 2 diabetes, hypertension None None None
• Elbasvir/grazoprevir and hyperlipidemia,
postmenopausal
• Sofosbuvir + NS5A inhibitor
57
Post-Kidney Transplantation:
• SVR rates ≥95%

Treatment-Naïve and Non-DAA Experienced
– Glecaprevir/pibrentasvir (MAGELLAN-2 in liver
Kidney Transplant Patients
and kidney transplant recipients) (With or Without Compensated Cirrhosis)
– Sofosbuvir/velpatasvir (phase 2 study in liver Duration
transplant recipients; ASTRAL-1 and 3 studies) Genotype Regimen (weeks)
– Ledipasvir/sofosbuvir (phase 2 study in kidney 1-6 Glecaprevir/pibrentasvir 12
Sofosbuvir/velpatasvir 12
transplant recipients)
1, 4, 5, or 6 Ledipasvir/sofosbuvir 12
Alternative regimen for genotypes 1 or 4: elbasvir/grazoprevir (without NS5A RASs).

Drug-Drug Interactions:
DAAs and Immunosuppressants
Glecaprevir/ Sofosbuvir/ Ledipasvir/

Pibrentasvir Velpatasvir Sofosbuvir Daclatasvir
Anti-proliferative
Azathioprine    
Mycophenolate    
Calcineurin inhibitors
Cyclosporine   
Tacrolimus   
mTOR inhibitors
Everolimus    
Sirolimus   
IL-2 receptor antagonists
Basiliximab    
Sofosbuvir/velpatasvir: no dose adjustment required when given with cyclosporin or tacrolimus (Summary of Product Characteristics).
*May require a dosage adjustment, altered timining of administration, or additional monitoring. DDI: drug-drug interaction.
59
https://www.hep-druginteractions.org/.
Updated
Slide
Overview
– Treatment-experienced man with decompensated cirrhosis
60
HCV and Decompensated Cirrhosis:
64-Year-Old, HCV Treatment-Experienced Male
Patient presents for HCV therapy
Failed prior sofosbuvir + RBV therapy

Medical Considerations
• HCV genotype 1b
Esophagogastroduodenoscopy MRI
– HCV RNA 6.0 million IU/mL Small esophageal varices No HCC
Small perihepatic ascites
• Is this patient compensated?
Laboratory Test Results
• Would you treat HCV in this patient?
AST/ALT: 55/34 IU/L
Total bilirubin: 1.8 mg/dL
• Other considerations? Albumin: 3.5 g/dL
Platelets: 65,000/mm3
– HCV NS5A drug resistance assay? AFP: 8 ng/mL
INR: 1.7
– Evaluate for orthotopic liver transplantation? Creatinine: 0.2 mg/dL
MELD: 17
• Which HCV regimen?
61
Patients With HCV and Decompensated Cirrhosis:
• SVR rates ≥95%

Decompensated Cirrhosis
(includes CTP class B and class C patients who may or may not be
candidates for liver transplantation, including those with HCC)
Duration
Genotype Regimen (weeks)
Failed prior sofosbuvir- or NS5A-inhibitor based therapy
1-6 Sofosbuvir/velpatasvir + RBV (weight-based) 24
1, 4, 5, or 6 Ledipasvir/sofosbuvir + with low initial RBV dose (600 mg)* 24
*Increase as tolerated to weight-based dose.

AASLD-IDSA:
All Patients With HCV Infection and Decompensated Cirrhosis
• It is critical to understand that decompensating events place patients at higher risk of further
complications and death compared with patients with compensated cirrhosis
• Moderate or severe hepatic impairment; Child-Turcotte-Pugh class B or C
– Should be referred to a medical practitioner with expertise in that condition, ideally in a liver transplant center
– Regimens not recommended

• Any protease inhibitor-containing regimen (eg, glecaprevir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir)
• Interferon-based regimens

Updated
Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During
Slide
the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement
• Goals of the document

– Provide data on what is currently known about COVID-19
– How these data may impact hepatologists, liver transplant providers, and their patients
• Aim of consensus statement

– Provide a template for the development of clinical recommendations and policies to mitigate the impact of
the COVID-19 pandemic on liver patients and healthcare providers
• Recommendations have been created to protect our patients, communities, and healthcare workers
– Will be updated as new information becomes available
Fix OK, et al. Hepatology. 2020;Apr 16. [Epub ahead of print]. 64

ASTRAL-4: SVR12 Rates With Sofosbuvir/Velpatasvir ± RBV in
HCV Genotype 1-4 or 6 With Decompensated Cirrhosis
• Phase 3, open-label trial

SVR12 With Sofosbuvir/Velpatasvir
– Treatment-naïve or -experienced with decompensated in HCV Genotype 1 Patients
cirrhosis
HCV subtype: 1a 1b
• MELD: <10 (34%), 10-15 (61%); mild-moderate ascites (78%),
100 100%
median HCV RNA 5.9 log10 IU/mL; median eGFR 90 mL/min 94% 93%
88% 89% 88%
• Sofosbuvir/velpatasvir ± RBV* for 12 weeks;
80
sofosbuvir/velpatasvir for 24 weeks
• Virologic failure in genotype 1b
Patients (%)
60
– 12 weeks, no RBV: 11%
– 12 weeks, RBV: 0% 40
– 24 weeks, no RBV: 6%
20
• Most common adverse events
– All patients: fatigue (29%), nausea (23%), headache (22%)
0
12 Weeks 12 Weeks 24 Weeks
– RBV patients: anemia (31%) No RBV RBV No RBV
(n=90) (n=87) (n=90)
*Weight-based RBV dosing.
Curry MP, et al. N Engl J Med. 2015;373:2618-2628. 65
SOLAR-1 and -2: SVR12 Rates With Ledipasvir/Sofosbuvir +
RBV in Decompensated Cirrhosis
• Pre-transplant cohort (n=212)

SVR12 Rates: Pre-Transplantation
– HCV genotype 1 or 4 Ledipasvir/sofosbuvir + RBV
12 weeks 24 weeks
– Median HCV RNA: 5.9-6.4 log10 IU/mL; median 100
92%
MELD: 12-13; median eGFR: 64-85 mL/min 86% 84%
81%
80
• Ledipasvir/sofosbuvir + RBV* for 12 or 24
weeks
SVR12 (%)
60
• Duration of therapy or HCV subtype (1a or 1b)
did not impact SVR12 rates
40
• Improvement to CTP A Relapse Relapse Relapse Relapse
(n=7) (n=2) (n=3) (n=3)
– CTP B: 40% 20
– CTP C: 12%
*RBV dosing: fibrosing cholestatic hepatitis, Metavir F0-F3, CTP A (weight-based 1000- 0
1200 mg/day); CTP B and C pre- and post-transplant (dose escalation 600-1200 mg/day).
CTP B CTP C
(n=56|52) (n=43|48)
Gane EJ, et al. Hepatology. 2015;62(suppl S1):722A-723A. Abstract 1049.
Charlton M, et al. Gastroenterology. 2015;149:649-659.
66
Manns M, et al. Lancet Infect Dis. 2016;16:685-697.
Survival Benefits of DAA Therapy in Patients With
• Survival model to predict mortality in HCV

Patients
patients with decompensated cirrhosis
OPTN SOLAR-1, -2
• Expected (no DAA therapy): OPTN data Validation Cohort ASTRAL-4
(n=899) (n=463)
• Observed (SVR12 with DAA therapy) Male (%) 69 70
– SOLAR-1, -2 (ledipasvir/sofosbuvir ± RBV) Age (years) 53 57*

Ascites (%) 76 81
• Genotype 1 or 4 (treatment-naïve or -experienced)
Hepatic encephalopathy (%)
• CPT B/C 1-2/3-4 61/1.8 64/1.5
• Post-liver transplantation Sodium (mEq/L) 137 137*

Creatinine (mg/dL) 1.0 0.9*
– ASTRAL-4 (sofosbuvir/velpatasvir ± RBV)
INR 1.4 1.3*
• Genotype 1-6 (treatment-naïve or -experienced) Bilirubin (mg/dL) 2.3 2.2
• CPT B MELDNa 15.9 14.5*
Albumin (g/dL) 3 2.9*
*P<0.01 versus OPTN.
OPTN: Organ Procurement and Transplantation Network.
67
Kim WR, et al. J Hepatol. 2018;68(suppl S1):S84-S85. Abstract PS-151.
Survival Benefits of DAA Therapy in Patients With
• In comparison with expected mortality, decompensated

HCV cirrhosis patients treated with ledipasvir/sofosbuvir Observed Versus Expected Deaths
or sofosbuvir/velpatasvir experienced fewer deaths in DAA-Treatment Patients
70
– Difference was significant in less than 120 days Expected (n=54)
60
Observed (n=25)
– By end of the first year, standardized mortality ratio for
observed to expected deaths: 0.46 (risk reduced by 54%)
Number of Deaths
50
• Predictors of 1-year mortality: aHR (95% CI)
40
– Age (year): 1.03 (1.01-1.05)
Mortality
Reduced
– Albumin: 0.41 (0.31-0.55) 30 by 54%
– Na: 1.15 (1.06-1.25)

20
– MELDNa: 1.17 (1.13-1.20)
10
– Hepatic encephalopathy stage
P<0.05
• 1-2: 1.48 (1.08-2.03) 0
0 50 100 150 200 250 300 350
• 3-4: 3.58 (2.03-6.31)
Days From Treatment Initiation
OPTN: Organ Procurement and Transplantation Network.
68
Kim WR, et al. J Hepatol. 2018;68(suppl S1):S84-S85. Abstract PS-151.
BC Hepatitis Testers Cohort:
Impact of SVR on Long-Term Risk of HCC
• HCC incidence (per 1000 person-years)

Cumulative HCC Incidence
– SVR versus no SVR: 1.1 versus 7.2
0.1
Gray’s test
• Factors associated with HCC among SVR patients P<0.0001
(adjusted hazard ratios) No SVR
Cumulative Incidence (%)

0.08
– Age
• 50-59: 4.4 (95% CI: 1.69, 11.47)

0.06
• ≥60: 4.4 (95% CI: 1.26, 15.31)
– Male: 3.3 (95% CI: 1.14, 9.61) 0.04

– Cirrhosis: 3.2 (95% CI: 1.17, 8.98)
• Need for continued HCC surveillance 0.02 SVR
– Post SVR patients with advanced disease and older age

0
0 2.5 5.0 7.5 10.0 12.5
Median follow-up: 5.6 years. Years
HCC cases detected: SVR (n=29); no SVR (n=145).
Janjua NZ, et al. J Hepatol. 2017;66:504-513. 69
HCV and Decompensated Cirrhosis:
64-Year-Old, HCV Treatment-Experienced Male
HCV regimen chosen
Based on the week-4 results, what next? Ledipasvir/sofosbuvir + RBV 1000 mg/day
for 12 weeks
• Stop HCV therapy
Progress During HCV Therapy
• Add spontaneous bacterial peritonitis Week 2 HCV RNA 56 IU/mL
prophylaxis Hemoglobin declined to 9 g/dL, RBV dose
reduced from 1000 to 600 mg/day
• Increase RBV dose Week 4 HCV RNA <15 IU/mL, but detectable
Detection of more ascites
• Increase HCV therapy to 24 weeks Bilirubin increased to 3.5 mg/dL
(direct 1.5 mg/dL)
• Stop worrying, complete the 12-week
regimen
70
Patients With HCV and Decompensated Cirrhosis:
(includes CTP class B and class C patients who may or may not be
candidates for liver transplantation, including those with HCC)
Duration
Genotype Regimen (weeks)
RBV eligible
RBV Ineligible
1-6 Sofosbuvir/velpatasvir 24
1, 4, 5, or 6 Ledipasvir/sofosbuvir 24
Failed prior sofosbuvir- or NS5A-inhibitor based therapy

*Increase as tolerated to weight-based dose.

Updated
Slide
Overview
– Man who failed prior NS5A-inhibitor based therapy
72
HCV Treatment-Experienced:
52-Year-Old Black Male
Failed 8 weeks of ledipasvir/sofosbuvir
Recent laboratory results?

• HCV genotype 1b
Considerations
• HCV RNA: 8.2 million IU/mL Tobacco Alcohol Recreational
Comorbidities Use Use Drugs
• ALT: 115 U/L
Depression None 1 to 2 drinks/day HCV infection
• Liver elastography: 13.1 kPa associated with IDU
– CTP score: 5
– MELD score: 5 Employment Status Relationship Status
Which regimen for HCV treatment? Stable employment Single, lives alone
Other testing?
• Resistance test results
– Q30R, Y93H
• Esophagogastroduodenoscopy: small esophageal varices
• Right upper quadrant ultrasound: no HCC, no ascites
73
Long-Term Follow-Up of Emergent NS5A RASs With
Ledipasvir-Containing Regimens
Persistence of Treatment-Emergent NS5A RASs in Non-SVR12 Patients

100 99%
95%
86%
80
Patients (%)
60
40
20 16%
0
Baseline At Failure* 48 96
(n=76) (n=73) (n=55) (n=58)
Presence of NS5A RASs NS5A RASs During Registry Study
(Follow-Up Week)
*RASs in non-SVR12 patients after receiving ledipasvir without sofosbuvir who were then enrolled in a 3-year follow-up registry study.
Deep sequencing (1% cut-off).
74
Wyles D, et al. Antivir Ther. 2018;23:229-238.
POLARIS-1:
Overall SVR12 Rates in NS5A Inhibitor-Experienced Patients
Sofosbuvir/Velpatasvir/Voxilaprevir (Genotypes 1-6)
100 99% 100 98% 100% 97%

96% 96% 94%
93%
80 80
SVR12 (%)
SVR12 (%)
60 60
40 Break- Break- 40
Through Through
(n=1) (n=1)
Relapse Relapse
20 (n=6) (n=6) 20
253 140 113 42 199 9 120 70
263 142 121 43 208 9 127 72
0 0
Overall No Cirrhosis Cirrhosis No Any NS3 NS5A NS3 +
RASs RAS Only Only NS5A
Double-blind, phase 3 trial (NS5A inhibitor-experienced, compensated cirrhosis allowed): sofosbuvir/velpatasvir/voxilaprevir for 12 weeks.
No placebo patients achieved an SVR12.
*P<0.001 for superiority versus pre-specified goal of 85% for sofosbuvir/velpatasvir/voxilaprevir.
75
Bourlière M, et al. N Engl J Med. 2017;376:2134-2146.
TRIO Network:
Real-World Experience With Sofosbuvir/Velpatasvir/Voxilaprevir
• Cohort analysis (n=173)

SVR12 Rates (ITT)
– HCV treatment-experienced
100 96% 95%
94% 94%
91%
– HCV genotype 1-6 89%
80
– Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks
Patients (%)
– Prior NS5A inhibitor experienced: 77%
60
• Overall SVR12 (ITT): 94%
40
– Virologic failures (n=3)
• Genotype 1a, cirrhosis (n=2)
20
– High SVR12 rates regardless of prior HCV 163 88 19 17 10 16
173 92 20 19 11 17
antiviral regimen 0
Overall LDV/SOF SOF/VEL EBR/GZR PrOD Other SOF
±RBV ±RBV ±RBV Regimens
Prior Regimen
Bacon B, et al. J Hepatol. 2019;70(suppl):e209. Abstract THU-116. 76

VA National HCV Clinical Case Registry:
Real-World Experience With Sofosbuvir/Velpatasvir/Voxilaprevir
• Observational, ITT cohort analysis

SVR12 Rates (ITT)
– HCV genotype 1-4 Genotype: 1 2 3 4
100% 100% 100%

– Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks 100
91% 90% 91% 91% 92% 93% 91%
89%
– Prior NS5A experienced: 99% 83%
80
• Overall SVR12: ≥90%
Patients (%)
– High SVR12 rates regardless of prior HCV 60
antiviral drug class for genotypes 1, 3, and 4
40
• Lower SVR12 rates
– Genotype 2 with prior NS5A, NS5B, or
20
NS5A/NS5B experience (SVR12 ≤90%)
429 18 42 12 140 5 21 7 289 13 21 5
473 20 46 12 157 6 23 7 316 14 23 5
– Genotype 1, 2, and 3 with prior sofosbuvir/ 0
Overall Yes No
velpatasvir experience (SVR12 83%-86%)
Cirrhosis Status
Belperio PS, et al. J Viral Hepat. 2019;26:980-990. 77

Prior DAA Failure:
• RAS testing is recommended in

advance of retreatment of HCV Prior Regimen Failure Genotype
NS3 PI + PR
• All regimens are administered for Glecaprevir/pibrentasvir 1
12-weeks for no cirrhosis and Sofosbuvir/velpatasvir 1
Ledipasvir/sofosbuvir (compensated cirrhosis only) 1
compensated cirrhosis except where
noted
Non-NS5A Inhibitor, Sofosbuvir-Containing
• SVR12 rates for all recommended Glecaprevir/pibrentasvir (16 weeks for genotype 3) 1, 2, 3
regimens: ≥95% Sofosbuvir/velpatasvir 1b, 2
Sofosbuvir/velpatasvir/voxilaprevir 1a
NS5A Inhibitor DAA-Experienced

Sofosbuvir/velpatasvir/voxilaprevir 1, 2, 3*, 4, 5†, 6†
*Add RBV for genotype 3 with compensated cirrhosis who failed prior NS5A inhibitor.
†
Except experience with glecaprevir/pibrentasvir.
Updated
Slide
Overview
79
HCV Cure With DAA Therapy Achieves New
Slide
Clinically Relevant Endpoints
• Reduce rate of new infection
• Prevent development of cirrhosis
• Reverse cirrhosis
• Reverse decompensation
• Reduce risk of liver cancer
• Reduce liver-related mortality
• Reduce overall mortality

Ioannou GN, et al. Gastroenterology. 2019;156:446-460. 80
VA Cohort: New
Slide
Impact of SVR With DAA Treatment on Risk of HCC
• Retrospective cohort study (n=62,354) Survival Free of HCC

1 No cirrhosis, SVR
– Initiating HCV therapy between 1999 and 2015
• IFN only (58%), DAA+IFN (7%), and DAA only (35%) Cirrhosis
SVR
– Electronic health care database
No Cirrhosis
• Key baseline characteristics among the DAA
Survival
No SVR
only cohort 0.9
– Age (61 years), male (97%), genotype 1 (85%),

cirrhosis (24%), decompensated cirrhosis (7%)
• HCC incidence (≥3 months after DAA initiation) Cirrhosis
No SVR
• SVR rate with DAA only: 91%
0.8
• DAA-induced SVR was associated with a 71% 0 0.5 1.0 1.5 2.0
Time Since Start of DAA (years)
reduction in HCC risk
ACLD: advanced chronic liver disease.
Ioannou GN, et al. J Hepatol. 2018;66:25-32. 81
Risk Factors Most Frequently Associated With New
Slide
Liver Cancer After SVR
• Among those with cirrhosis

– Portal hypertension
– Diabetes
Cirrhosis – Alcohol use
– Older age ≥65 years
– [Elevated GGT]
– [AFP elevation at end of DAA therapy
Ravaioli F, et al. Dig Liver Dis. 2018;50:573-579.

Chang, KC, et al. J Antimicrob Chemoth. 2012;67:2766-2772.
Huang C, et al. J Hepatol. 2014;2014;61:67-74
Toyoda H, et al. J Gastroenterol Hepatol 2015;30:1183-1189.
El-Serag HB, et al. Hepatology. 2016;64:130-137.
Kanwal F, et al. Gastroenterology. 2017;153:996-1005. 82
New
Slide
Post-SVR Management by Pre-Treatment Stage of Fibrosis
Pre-treatment Stage of Fibrosis
Intermediate
Intermediate Stage
Stage
Low
Low Stage
Stage (F2) Advanced
Advanced Stage
Stage
(F2)
(F0-1)
(F0-1) (F3-F4)
(F3-F4)
Monitor
Monitor for
for progression
progression
No
No further
further monitoring
monitoring Long-term
Long-term follow-up
follow-up
to
to advanced
advanced fibrosis
fibrosis
needed;
needed; release
release back
back HCC
HCC surveillance
surveillance
to
to PCP
PCP Variceal
Variceal surveillance
surveillance
Regression
Regression Progression
Progression
Terrault NA, et al. J Hepatol. 2016;65(1 suppl):S120-S129. 83

Key Counseling Messages: New
Slide
“Keep the Liver in Good Shape”
Prevention of fatty liver

 Optimize weight
Safe levels of alcohol
 Prevent/treat diabetes
 None if advanced
 Treat dyslipidemia fibrosis
Cannabis Use Caution with

• Non-daily use Supplements/ Herbals
 Awareness of potential
for hepatotoxicity
Coffee: It’s good!
 > 3 cups per day associated with
lower risk of progression
Terrault NA, et al. J Hepatol. 2016;65(1 suppl):S120-S129. 84

Updated
Slide
Summary
• Patients with active HCV infections with a detectable viral load are at increased risk of death due to
hepatic and extrahepatic diseases
• Chronic HCV patients with active infection may benefit from antiviral treatment, once diagnosed, to
reduce overall mortality
• Direct-acting, oral agents have high HCV cure rates, few adverse events, and negligible treatment-
emergent resistance
• Patients with advanced fibrosis/cirrhosis require monitoring for disease progression after cure
• Counseling messages related to liver health and prevention of reinfection important
85
CME/CNE/CPE Credit
• Please return to the CME/CNE/CPE activity page for the Simply Speaking Hepatitis Lecture
Library at www.PracticePointCME.com
– Click on the ‘Claim Credit’ button associated with this archived PowerPoint presentation
– Complete the brief posttest and evaluation form
– Upon successful completion of the posttest (ie, 80% accuracy), you will be able to print your CME/CNE/CPE
certificate for 1 credit hour
• Please visit us at www.PracticePointCME.com to review other archive presentations in the Simply
Speaking Hepatitis Lecture Library of interest and receive additional CME/CNE/CPE credit
86

HCV - Best Practice.

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HCV - Best Practice.

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Best Practices for HCV Infection

Before and After the Cure

Supported by an independent educational

• Changing epidemiology/demographics of patients with HCV infection in the United States

• Management after the cure

• HCV antibody positive (including past and current infection)

– Prevalence: 1.7% (95% CI 1.4-2.0)

• HCV RNA positive (including current infection)

– Prevalence: 1.0% (95% CI 0.8-1.1)

Estimated adult US population in 12/2016: 245 million.

• Countries on track to meet targets

The Polaris Observatory HCV Collaborators. 1/2020. https://cdafound.org/dashboard/polaris/dashboard.html. 6

Age-Adjusted Rate per 100K Population

CDC. National Viral Hepatitis Progress Report 2020. https://www.cdc.gov/hepatitis/policy/NationalProgressReport.htm. 7

Recommendations for 1-Time HCV Testing

Risk Behaviors Risk Exposures Other Medical Conditions

• Universal HCV screening (except in settings where

– All pregnant women during each pregnancy

• 1-time HCV testing regardless of age or setting

Schillie S, et al. MMWR Recomm Rep. 2020;69:1-17 9

• All adults aged 18 to 79 years should be screened for HCV

• Data from 2 national laboratory companies

• From 2013 to 2016, there was an increasing

• New acute HCV infections in 2018 Acute HCV Rate in US 2001-2018

Rate (per 100,000 population)

• Most newly acquired acute HCV infections 1

Midwestern, and New England states) 0

Ryerson AB, et al. MMWR Morb Mortal Wkly Rep. 2020;69:399-404. 12

• Reduction in overall mortality regardless of severity of liver disease

– Non-advanced liver disease: 59% reduction

• 84% reduction in incident hepatocellular carcinoma

• Decrease in liver inflammation (reduced AST/ALT levels)

• Reduction in liver fibrosis progression

• Reduces symptoms and mortality from extra-hepatic manifestations

• Substantially improved quality of life

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. Version November 6, 2019.

• Data from two large national laboratory companies

– Baby boomers (48 to 71 years of age)

– Young adults (18 to 38 years of age)

Reau N, et al. Hepatology. 2018;68(suppl S1):892A-893A. Abstract 1567. 15

Linked to Specialist Linked to Primary Care Physician

Proportion of HCV RNA Positive (%)

Acute HCV diagnosed

Screened for HCV when presenting to

• ALT 578 U/L Employment Status Relationship Status

Test Interpretation for Diagnosis of Acute HCV

ALT Fluctuating ALT peaks suggest acute infection

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. Version November 6, 2019. 19

• Pre-exposure or post-exposure prophylaxis with antiviral therapy is not recommended

• In the setting of acute HCV infection

AASLD-IDSA. http://www.hcvguidelines.org/full-report-view. Version November 6, 2019. 20

– SAHIV: phase 2, open-label trial, 8-week course (France; NCT02886624)

• Glecaprevir/pibrentasvir (adults with recent HCV infection [<12 months])

– TARGET-3D Part III: phase 3, open-label trial, 4-week course (NCT02634008)

• Sofosbuvir/velpatasvir (PWIDs with recent HCV infection [<12 months])

Diagnosed with chronic HCV

Patient wants treatment, should he be

• ALT 124 U/L

• Reports not using heroin

• Integrated HCV care, substance

OAT: opioid agonist therapy.

• Randomized, controlled trial conducted at 3 opioid agonist

– DOT (n=51): receive observed oral doses by nursing staff 40