HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we...

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Transcript of HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we...

Page 1: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA
Page 2: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

HCV Cascade of Care

In order to eliminate HCV, we will need to: Find people with HCV infection

Screen with antibody testing HCV RNA for antibody positive to diagnose chronic infection

Link them to HCV care Inform them of their diagnosis Evaluate readiness/appropriateness of treatment Refer them to appropriate provider

Treat them with antivirals Achieve sustained virologic response (SVR)

Diagnosed with HCV

Linked to Care

Access to Treatment

Prescribed HCV

TreatmentAchieved

SVR

HCV = hepatitis C virus.

Page 3: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

HCV Continuum of Care: Identifying Priorities to Improve Outcomes

Yehia BR et al. CROI 2014. Boston, MA; #669; Holmberg SD. N Engl J Med. 2013;368:1859-1861; Pawlotsky JM. J Hepatol. 2015;62:s87-s99.

Chronic HCV-Infected

Diagnosed and

Aware

Prescribed HCV

Treatment

HCV RNA Confirmed

Underwent Liver Biopsy

Access to Outpatient

Care

Achieved SVR

Treatment Cascade for People with Chronic HCVInfection, Prevalence Estimates with 95% CI

100% 50% 43% 27% 17% 16% 9%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%3,500,000

Half of whom are estimated to be PWID, homeless, immigrants, or incarcerated

Unaware of diagnosis

CI = confidence interval; PWID = persons who inject drugs.

Page 4: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Conduct free testing at Avella pharmacies and/or in institutions implementing the Collaborative Hepatitis C Care Program

Tactics Press release Informational handouts CarePoints flyer Copromotions

Hepatitis Testing Day

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Bob Has a Question

What is Hepatitis

C ?

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The Role of Pharmacists in Viral Hepatitis

“The Action Plan for the Prevention, Care & Treatment of Viral Hepatitis 2014–2016,” prepared by US Department of Health and Human Services, identified pharmacists as key stakeholders in the continuum of care of those living with viral hepatitis.

CDC: Pharmacists can reduce fragmentation of care, lower healthcare costs, and improve patient health outcomes. There are many opportunities for pharmacists beyond the

traditional role of dispensing and managing medications.

CDC = Centers for Disease Control and Prevention.

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Kabiri M et al. Ann Intern Med. 2014;161:170-180. For educational purposes only.

“Our study underscores the need for more-aggressive screening strategies to reduce the burden of HCV infection.”

HCV Projected to Be aRare Disease by 2036

Estimated HCV prevalence in the US from 2001–2050

Screening strategies that work today may not work tomorrow.DAA = direct-acting antiviral agent.

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HCV/HIV Coinfection Outbreak in Indiana

84% Coinfected with HCV

HIV = human immunodeficiency virus.

Page 9: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Goals of Therapy for Hepatitis C

Sustained virologic response Undetectable HCV RNA 3–6 months after

completing treatment Delay progression of advanced liver

disease Liver fibrosis regression

Treatment is prevention Intravenous drug users Women of childbearing age

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Hepatitis C: Beyond the Liver

Cacoub et al. J Hepatol. 2016;65:s82-s94. For educational purposes only.

Page 11: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Source: American Association for the Study of Liver Diseases (AASLD) HCV Guidance:Recommendations for Testing, Managing and Treating Hepatitis C.

Recommendations for When and in Whom to Initiate Treatment• Treatment is recommended for all patients with chronic HCV infection, except those

with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert.Rating: Class I, Level A

Benefits of Treatment at Earlier Fibrosis Stages (Metavir Stage Below F2)Initiating therapy in patients with lower-stage fibrosis augments the benefits of SVR. In along-term follow-up study, 820 patients with Metavir stage F0 or F1 fibrosis confirmed bybiopsy were followed up for up to 20 years (Jezeuel, 2015). The 15-year survival rate wasstatistically significantly better for those who experienced an SVR than for those whosetreatment had failed or for those who remained untreated (93%, 82%, and 88% respectively;P = .003). The study results argue for consideration of earlier initiation of treatment.SEveral modeling studies also suggest a greater mortality benefit if treatment is initiatedat fibrosis stages prior to F3 (Ovrehus, 2015); (Zahnd, 2015); (McCombs, 2015).

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Treatment Selection: Raising the Bar

0102030405060708090

100

SVR

%

GT 1 GT 2

95%–100%

93% 93%–99%

94%–99%

95%–100%

99%–100%

Data from McHutchison J. N Engl J Med.1998;339;1485; Fried MW. N Engl J Med. 2002;347:975; Poordad F. N Engl J Med. 2011;364:119; Jacobson IM. N Engl J Med. 2011;364:2405; Jacobson IM. Lancet. 2014;384:403; Lawitz E. N Engl J Med. 2013;368:1878; Afdhal N. N Engl J Med. 2014;370:1889; Feld JJ. N Engl J Med. 2014;370:1594; Sulkowski MS. N Engl J Med. 2014;370:211; Feld JJ N Engl J Med. 2015;373:2599-2607.

DCV = daclatasvir; EBR = elbasvir; GT = genotype; GZR = grazoprevir; LDV = ledipasvir; OPrD = ombitasvir, paritaprevir, ritonavir, and dasabuvir; RBV = ribavirin; SMV = simeprevir; SOF = sofosbuvir; VEL = velpatasvir.

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Clinical Trials Versus Clinical Practice

Randomized Controlled Trial Homogenous population Optimal compliance Excludes complex patients Excludes comorbidities

Real World Heterogeneous population Real-world compliance Includes complex patients (PWID, psychiatric, etc) Multiple comorbidities

Efficacy vs Effectiveness

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Real-world Results Mirror Those of Clinical Trials

Cohort Regimen N* SVR Naïve (%)

SVR Experienced (%)

SVR Cirrhosis (%)

TARGET LDV/SOF 8 weeks 154/-/- 97 -- --LDV/SOF 12 weeks 627/-/239 97 -- 96

TRIOLDV/SOF 8 weeks 263/-/- 95 -- --LDV/SOF 12 weeks 632/-/121 95 -- 84 LDV/SOF 24 weeks -/-/329 NA -- 92

VALDV/SOF 8 weeks 2027/-/- 94 -- --LDV/SOF 12 weeks 2899/933/925 95 96 92 LDV/SOF 24 weeks 141/479/473 92 95 93

Hepather

SOF/DCV±RBV 12 weeks 66/82/118 89 91 90

SOF/DCV±RBV 24 weeks 59/349/442 88 97 96

Israel PrOD±RBV -/-/253 -- -- 99

German PrOD±RBV 208/322 /252 96 97 95

*N for naïve/experienced/cirrhotic.NA = not applicable.

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Real World: GT 1, Treatment-Naïve, Noncirrhotic Patients Can Be

Treated for 8 Weeks

Tsai N. HEP DART 2015. December 6-10, 2015; Wailea, HI. For educational purposes only.

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Evaluation of Newer Drug Therapies for Hepatitis C at a Specialty Pharmacy

Retrospective chart review

Determine if clinical trial data differs from “real-world” data

based on SVR12 rates at a specialty pharmacy

(N = 578)

SVR12 from SP GT 1a = 91%GT 1b = 90%GT 2 = 89%GT 3 = 95%

SVR12 from Clinical Trials GT 1a = 97%GT 1b = 97%GT 2 = 93%GT 3 = 59%

Overall, SVR12 at SP confirms clinical trial data (91% for both groups when aggregating GT)

Cirrhotic patients had a higher SVR12 (91%) vs clinical trials (84%) Headache was the most commonly reported AE, but 2-fold lower than

PI Medicare had the highest coverage rate at 85% with Medicaid at the

lowest, 30%AE = adverse event; SP = specialty pharmacy.

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Conclusions: Real-World Evidence

Several real-world studies confirm efficacy and safety of DAA treatment

All ethnicities and patient populations can be treated with high cure rates

New treatments will continue to reduce treatment duration and provide alternatives for any patients who fail first-line DAAs

Page 18: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Patient Y

50-year-old African American male, diagnosed with chronic hepatitis C. Referred for treatment evaluation

Medical history: Hypertension, diabetes Social history: unmarried, lives alone; smokes

cannabis and cigarettes daily; drinks alcohol on weekends – binge pattern; remote IVDU and opiate use

IVDU = intravenous drug use.

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Prescription Process

PA = prior authorization.

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Prescription Process

Tx = treatment.

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Further Workup for HCV Treatment

Assess for barriers to adherence Health literacy Substance use disorders Untreated mental health conditions

Assess for drug-drug interactions

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Patient Data Compliance Safety

Laboratory test values Patient-specific data Skills of daily living and

physical information Compliance rate Discontinuation and

reasons why Drug-specific outcomes at

targeted levels

How often is patient missing doses? Why?

Has patient discontinued therapy? Why?

Has patient been referred to HCP or manufacturer patient support?

What disposition?

Which patients have experienced (1) ED visit/hospitalization or (2) new medical condition?

Which patients need refills? QOL issues/opportunities Correlate outcomes

differences to prescriber, patient, therapy, outcome

Side Effects? Missed Doses? Discontinued?

Push/Pull and Checks to Assure Information Provided and Aggregated

RPh RPh RPh RPh Office visit

Office visit

• Assess health status

• Register patient• Educate patient• Calendar/cadence

Clinical Framework Shares

ED = emergency department; HCP = healthcare provider; QOL = quality of life; RPh = Registered Pharmacist.

Page 23: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Proposed Reasons for Nonadherence to HCV Treatment Pill burden Side effects of HCV medications

GI distress Fatigue

Substance use disorders Lack of social support

Transportation Financial instability/inability to work Perceived efficacy of therapy

GI = gastrointestinal.

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SMS Integration

SMS = safety management system.

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Patient-Level Barriers to Treatment

Internal VA Data; July 2016.

Deceased3%

Psychosocial needs16%

Unstable medical

comorbidity31%

Patient determinant

50%

Unstable mental health

2%

Homeless, unstable housing

18%

Alcohol or substance

abuse61%

Psycho-social

comorbidity

19%

Patient deferred or

declined75%

Nonadherent/no follow-up

20%

Other 5%

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eHealth Engagement

AdhereTech

Collects and Sends

Bottles use sensors and worldwide cellular chip to passively send real-time data

1

Records and Analyzes

AdhereTech’s system receives and analyzes data in real time

2

Fully Customizableand Automated Interventions

Customizable alerts (on-bottle lights/chimes, text and phone calls to patients/caregivers) delivered in real time

3

Displays and Integrates

Secure online dashboard displays all info and API for full integration of real-time data

4

API = application program interface.

Page 27: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Proteus ProgramPatient eHealth Engagement

Specialty medications in future scope

Engage patients by monitoring true adherence

Optimize therapies by capturing objective data and allow provider involvement

Improved outcomes by measuring treatment outcomes

IEM = Ingestion Event Marker; PPM = Proteus Personal Monitor.

Page 28: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Stepwise Barriers to Hepatitis C Treatment

HCV Infection Diagnosis

Referral toSpecialist

TreatmentInitiation

McGowan CE et al. Liver Int. 2012;32:s151-s156.

BarriersAsymptomatic disease

Poor awareness/educationLack of medical coverageHCP failure to screen/test

BarriersNonadherence

HCP failure to identifyneed for referral

Logistical concernsLimited specialist

availability

BarriersPatient fears/misunderstandings

StigmatizationSubstance abuse

Psychiatric comorbidityFinancial concern

Transportation/logistical concernCommunication difficulties

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Patient Copay vs Out-of-Pocket Trends

Steady decrease in patient co-pay in 2015 due to deductibles/coinsurance Third quarter of 2015 had patient OOP costs < $20 per month

OOP = out-of-pocket. For educational purposes only.

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Patient Out-of-Pocket Costs

$730.66

$469.48

$108.02

$24.62$0.33 $4.31 $13.31 $2.34

$773.63

$462.86

$108.26

$24.94$33.29$4.36 $10.20 $2.34

Sofosbuvir Simeprevir Peginterferon alfa-2a

Ribavirin

Medicare Medicare with assistanceCommercial Commercial with assistance

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ARS Question

TRUE or FALSE: Patients with mental health disorders and/or active substance use disorders have lower SVR rates than those without these conditions.

A. TrueB. False

Page 32: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Real-World SVR in Patients with Mental Health and Substance Use Disorders

SVR %Mental health diagnosis ever

No

Yes

91.6 (5201/5679)

89.8 (12 408/13 825)

Anxiety

Bipolar

Depression

PTSD

Schizophrenia

90.3 (2983/3305)

90.3 (908/1006)

89.8 (6046/6734)

89.3 (3558/3985)

89.7 (689/768)Alcohol abuse – No

Alcohol abuse – Yes

90.8 (13 690/15 085)

88.7% (3919/4419)Hard drug use – No

Hard drug use – Yes

90.5 (16 117/17 800)

87.6 (1492/1704)Backus LI et al. Antivir Ther. 2016. PTSD = posttraumatic stress disorder.

Page 33: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

VA’s Hepatitis C Treatment Considerations: Principles for Patient Selection

for HCV Treatment Ongoing substance use involving alcohol, illicit drugs,

and/or marijuana, or participation in an opioid replacement program, should not be an automatic exclusion criterion for HCV treatment.

There are no published data supporting a minimum length of abstinence or showing that these patients are less likely to achieve SVR with HCV treatment if they remain adherent. However, in some patients, substance use or alcohol use disorders may need to be addressed prior to initiation of HCV treatment because of the risk of nonadherence and reinfection.

US Department of Veterans Affairs. Chronic hepatitis c virus (HCV) infection: treatment considerations. Hepatitis.va.gov Web site. Available at: http://www.hepatitis.va.gov/provider/guidelines/hcv-treatment-considerations.asp. Updated March 8, 2017.

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Patient Y

Physical examination: BMI 32 kg/m2

General: Obese, no stigmata of advanced liver disease

Laboratory tests: Hepatitis C RNA 3 million IU/mL AST/ALT 2 x ULN Hepatitis A antibody negative Hepatitis B surface antibody (-), core antibody (+) Platelet count 125 000/cm2

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; ULN = upper limit of normal.

Page 35: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

ARS Question

Which of the following patient-specific factors are most relevant to drug therapy selection?

A. Concomitant medications, resistance testing results, absence of cirrhosis

B. Treatment-naïve, age, genotype subtypeC. Genotype subtype, resistance testing results,

presence of cirrhosis, concomitant medications D. Gender, genotype subtype, HCV RNA

Page 36: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Individualizing Treatment Paradigms

Comorbid Conditions: HIV, HBV

Renal/Hepatic Impairment

Drug Interactions

HBV = hepatitis B virus.

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Linking the Silos

Specialty pharmacy Healthcare silos

• Which patients have experienced (1) ED visit/hospitalization or (2) new medical condition?

• Which patients need refills?• QOL issues/opportunities• Correlate outcomes differences to

prescriber, patient therapy, outcomes

Safety and Outcomes Compliance and Benefits • What step therapy, PA, and

CPBs?• How often is patient missing

doses? Why?• Has patient discontinued

therapy? Why?• Has patient been referred to

HCP or manufacturer patient support?

• What disposition?

Patient Data• Laboratory test values• Patient-specific data• Skills of daily living and

physical information• Compliance rate• Discontinuation and reasons

why• Drug-specific outcomes at

targeted levels

Physician Payor Pharma

RESULTS:• Communication• Safety• Adherence• Improved

outcomes

CPB = clinical policy bulletin.

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Hepatitis C Clinical Management Process

Day 1: Hepatitis C Program Enrollment (Opt-in/out) Outbound Patient Call• Introduction to the patient for whom

we are a specialty pharmacy• Outline services we offer• Explain relationship with their

clinician

Day 10: Mid-Therapy Assessment –Outbound Patient Call • Clinical pharmacist to review the

following if necessary:• Review of medication• Review of disease state,

adverse drug effects• Management of adverse drug effects • Adherence/persistence education• Clinician notified if necessary

Day 24: Refill/Wellness Check –Outbound Patient Call• Review of medication• Review of disease state• Depression screen• Management of adverse drug effects • Adherence/persistence education and

screening tool• Coordinate refill• Clinician notified if necessary

Page 39: HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we will need to: Find people with HCV infection Screen with antibody testing HCV RNA

Renal and Hepatic ConsiderationsRenal Hepatic

DCV No adjustment needed No adjustment neededEBR/GZR No adjustment needed,

including hemodialysisNo adjustment needed with mild impairment (CTP A). Contraindicated in moderate/severe impairment (CTP B or C)

LDV No adjustment needed No adjustment needed

OPrD No adjustment needed No adjustment needed with mild impairment (CTP A). Contraindicated in moderate/severe impairment (CTP B or C)

RBV CrCl 30–50 mL/min: 200 mg qd alternating with 400 mg qd CrCl <30 mL/min or HD: 200 mg qd

Although renally cleared, CTP B and C patients may have preexisting anemia; RBV 600 mg/day or lower is recommended as an initial dose

SMV Not evaluated in CrCl <30 mL/min

Should not be used in patients with moderate or severe impairment (CTP B or C) due to higher SMV exposures

SOF CrCl <30 mL/min or end-stage renal disease: Not recommended

No adjustment needed

VEL No adjustment needed No adjustment neededCrCl = creatinine clearance; CTP = Child Turcotte Pugh score; HD = hemodialysis; qd = every day.

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Potential for HCV Drug InteractionsOmbitasvir/ritonavir/paritaprevir

and dasabuvir

Simeprevir

Elbasvir/grazoprevir

Daclatasvir

LDV/SOF SOF/VEL

SOFLower

Higher

Amiodarone

PPIs

• Antiepileptics• Anti-

mycobacterials• Statins• HIV

medications

PPI = proton pump inhibitor.

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Effect of Proton Pump Inhibitor Use with LDV/SOF

98 989293 97

89

0102030405060708090

100

TARGET TRIO VA

SVR

%

No PPI PPI97

909084

0102030405060708090

100

TRIO VA

PPI qd PPI bid

Terrault. AASLD, 2015, 94, TARGET; Afdhal. EASL 2016; LBP519,TRIO; Backus LI. Antivir Ther. 2016; VA.

P = .03 P = .008P < .05 P = .008

bid = twice a day.

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ADE Volume for HCV

020406080

100120

10

109

22

0 015

018

6 13

2016 AEs by Volume

ADE = adverse drug event.

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Recommendations for Patient Y

Reduce/eliminate alcohol intake Cessation of cannabis and tobacco

Offer mental health consultation – patient refused (initially)

Vaccine to prevent hepatitis A Counseled on likelihood of advanced liver

disease (low platelet count) Watch for HBV reactivation

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Baseline Variables that May Influence Treatment Selection and Response

Viral Factors

• HCV genotype (GT 1, 2, 3, 4, 5, 6)• Genotype subtype (GT 1a vs 1b)• HCV RNA• Resistance-associated variants/substitution

(RAV or RAS)

HostFactors

• Race/ethnicity• IL28B (CC, CT, TT)• Body mass index• Comorbidities

Stage of Liver

Disease

• Noncirrhotic• Compensated cirrhosis (CTP A)• Decompensated cirrhosis (CTP B or C)

AASLD/IDSA HCV Guidelines.

CTP = Child-Turcotte-Pugh Score: A = 5–6 points; B = 7–9 points; C = 10–15 points.

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HCV Genotype

6 genotypes: GT 1–6 Subtypes (a, b, c)

GT 1a: Most common in US GT 1–3: Broad geographic

representation GT 4–6: Cluster

geographically Treatment regimen differs

based on genotype.

GT 1a52%

GT 1b18%

GT 216%

GT 312%

GT 4–6: 2%

Manos MM et al. J Med Virol. 2012;84:1744-1750.

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HCV Regimens by GenotypeRegimen Class GT 1 GT 2 GT 3 GT 4 GT 5/6

Elbasvir/grazoprevir (EBR/GZR) NS5A/PI

Ombitasvir/paritaprevir/ritonavir NS5A/PI

Ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD)

NS5A/PI/ NS5B

Daclatasvir + sofosbuvir (DCV+SOF) NS5A/PI

Ledipasvir/sofosbuvir (LDV/SOF) NS5A/NS5B

Simeprevir + sofosbuvir (SMV+SOF) PI/NS5B

Sofosbuvir/velpatasvir (SOF/VEL) NS5B/NS5A

Sofosbuvir + ribavirin (SOF+RBV) NS5B

AASLD/IDSA HCV Guidelines; FDA package labeling. PI = protease inhibitor.

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9097 92 90

99 99.5 98 100

0

20

40

60

80

100

OPrD OPrD + RBV EBR/GZR EBR/GZR

GT 1a GT 1b

SVR

%

12-week treatment duration

GT 1a Versus GT 1b

Ferenci P et al. N Engl J Med. 2014;370:1983-1992; Zeuzem S et al. Ann Intern Med. 2015;163:1-13; Kwo P et al. EASL 2015.

(Naïve, with or without

cirrhosis)

(Experienced, with or without

cirrhosis)

(Naïve, without cirrhosis)

For certain regimens, GT 1a is associated with higher rates of virologic failure than GT 1b.

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ARS Question

Which of the following statements with regards to hepatitis C and liver disease is TRUE? A. Liver biopsy should be done in everyone before

treatment to determine if cirrhosis is presentB. Serum biomarkers are not useful in determining

stage of liver diseaseC. Normal liver function tests do not exclude liver

diseaseD. Ribavirin should be used in all patients with known

cirrhosis

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Staging of Liver Disease Important to identify cirrhosis

Most major complications of chronic HCV occur in patients with cirrhosis.

Cirrhotic patients achieve the greatest magnitude of benefit from treatment.

Cirrhotic patients require closer follow-up, additional follow-up (eg, liver cancer screening).

Presence of cirrhosis can affect HCV treatment regimen.

Early stages of fibrosis are difficult to detect without biopsy or specialized tests.

Diagnosis of compensated cirrhosis can be subtle. Can be present even with normal exam, imaging,

and laboratory tests – normal tests do not exclude cirrhosis

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Serum biomarkers: FIB-4: Uses AST, PLT, age; FIB-4 >3.25: 97% specificity; PPV of 65% for advanced fibrosis APRI uses AST, PLT; APRI >2.0: sensitivity 46%, specificity 91% for predicting cirrhosis Platelets: <140 000–150 000/µL FIBROSpect, FibroSURE

Options for Liver Fibrosis AssessmentSeveral Staging Methods Are Used

Liver biopsy: Gold standard; rarely done now

Abdominal CT/MRI, US: Can demonstrate cirrhotic morphology, portal hypertension

Elastography: Proprietary algorithm using biochemical markers of hepatic fibrosis

Sterling RK, et. al. Hepatology. 2006;43:1317-1325; Lin ZH et al. Hepatology. 2011;53:726-736; Chou R. Ann Intern Med. 2013;158:807-820.

APRI = AST-to-platelet ratio index; CT = computed tomography; FIB-4 = Fibrosis-4 calculator; MRI = magnetic resonance imaging; PLT = platelet; PPV = positive predictive value; US = ultrasound.

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Cirrhosis Considerations: Preferred Regimen, Need for RBV, and Duration

DCV+SOF LDV/SOF OPrD EBR/GZR SOF+SIM SOF/VEL

GT 1a(TN or TE)Noncirrhotic 12 weeks 12 weeks 12 weeks

+RBV(-)RAS: 12 weeks 12 weeks 12 weeks

GT1b GT 1b(TN or TE)Noncirrhotic

12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks

NOTE: Not all alternative regimens are listed; in CTP B or C initiate RBV at 600 mg/day.TE = treatment experienced (prior peginterferon/RBV ± PI); TN = treatment naïve.

GT 1a(TN or TE)Cirrhotic

Alternative24 weeks

±RBV

12 weeks;add RBV if

TE

Alterna-tive 24 weeks

add RBV

(-)RAS: 12 weeks; add RBV if HCV

PI experienced

Alterna-tive

24 weeks ±RBV

12 weeks

GT 1b(TN or TE)Cirrhotic

Alternative24 weeks

±RBV

12 weeks;add RBV if

TE 12 weeks 12 weeks

Alterna-tive 24 weeks±RBV

12 weeks

Cirrhosis, CTP B or C

12 weeks +RBV

12 weeks +RBV

AASLD/IDSA HCV Guidelines.

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Impact of Treatment History on Efficacy (GT 1)

0102030405060708090

100

SVR

%

Naïve Experienced

Poordad F. N Engl J Med. 2011;364:1195; Jacobson IM. N Engl J Med. 2011;364:2405; Jacobson IM. Lancet. 2014;384:403; Lawitz E. N Engl J Med. 2013;368:1878; Afdhal N. N Engl J Med. 2014;370:1889; Feld JJ. N Engl J Med. 2014;370:1594; Sulkowski MS. N Engl J Med. 2014;370:211; Feld JJ et al. N Engl J Med. 2015;373:2599-2607.

(PEG-IFN or HCV PI)

BOC = boceprevir; PEG/PEG-IFN = peginterferon; TVR = telaprevir.

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HCV Data – Who Is Being Treated?

For educational purposes only.

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HCV Treatment History Naïve Experienced

Type of experience Duration and need for ribavirin

Prior Peg-IFN/RBV

Prior HCV Protease Inhibitor

Prior Sofosbuvir

Prior NS5A Inhibitor

Increasing challenges for retreatment

No impact on

outcome

Minimal/No impact

Some impact

Greater impact

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Recommendations for Baseline Resistance Testing in Naïve Patients

Regimen Population Test Recommendation if RAS Present

EBR/GZR GT 1a, naive NS5A Extend therapy to 16 weeks and add weight-based ribavirin

SMV+SOF GT 1a with cirrhosis NS3 – Q80K Use alternative regimen

DCV+SOF GT 1a with cirrhosis NS5A Add weight-based ribavirin

SOF/VEL GT 3 with cirrhosis NS5A – Y93 Add weight-based ribavirin

LDV/SOF GT 1a with cirrhosis

ConsiderNS5A

Add weight-based ribavirin and/or extend therapy from 12 to 24 weeks

Key Points:GT 1a vs GT 1b – different clinical impact

Cirrhosis – Cannot afford to fail!AASLD/IDSA HCV Guidelines; FDA Labeling; Feld JJ. AASLD 2016; US Department of Veterans Affairs. Chronic hepatitis c virus (HCV) infection: treatment considerations. Hepatitis.va.gov Web site. Available at: http://www.hepatitis.va.gov/provider/guidelines/hcv-treatment-considerations.asp. Updated March 8, 2017.

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Patient Y

Declined liver biopsy, MELD = 7 Continued to use marijuana daily; did decrease

alcohol intake to abstinence Agreed to mental health evaluation

Antidepressant, sleep aid Patient took ledipasvir/sofosbuvir for 12 weeks Week 4 HCV RNA – undetectable Week 12 HCV RNA – undetectable Compliant with follow-up and medications 12 weeks posttreatment: HCV RNA undetectable

MELD = Model for End-stage Liver Disease.

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Individualized Treatment

Genotype

1a or 1b

2

3

4

5/6

Treatment History

Naïve

Experienced

Cirrhosis

Yes

No

Regimen

NS3/4 PI

NS5A

NS5B

Need for ribavirin

Variables

Baseline HCV RNA

Renal/ Hepatic

impairment

Other comorbid-

ities

Drug interactions

Duration

8 weeks

12 weeks

16 weeks

24 weeks

Particularly important

forGT 1a, GT 3

Can affect

likelihood of

response

Different clinical impact

Know the exceptionsNuances

impact selection

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Duration of Treatment: Know the Exceptions to 12 Weeks

AASLD/IDSA HCV Guidelines.

Duration Regimen Scenario

8 weeks LDV/SOF • Naïve, noncirrhotic with HCV RNA <6 million IU/mL, mono-infected

16 weeks EBR/GZR

• GT 1a with baseline NS5A resistance (add RBV)• GT 4 with prior treatment experience (add RBV)

24 weeks

DAC+SOF• GT 1a or 1b cirrhotic (alternative)• GT 2 prior SOF experience (alternative)• GT 3 cirrhotic (add RBV if experienced or Y93H present)• GT 3 prior SOF experience (add RBV)

LDV/SOF

• GT 1a or 1b cirrhotic with prior Peg/RBV experience (alternative)

• GT 1 cirrhotic with prior SOF or HCV PI experience • GT 1 or GT 4 decompensated cirrhotic who is RBV ineligible

or failed prior SOF

OPrD • GT 1a cirrhotic (add RBV) (alternative)

SMV+SOF • GT 1 prior NS5A experience (add RBV)

SOF/VEL • GT 1 or GT 3 prior NS5A experience (add RBV)

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Prior Authorization Edit for Sofosbuvir and Simeprevir

Goals:1. Clinical evaluation of each fill2. Prevent wastage

4th fills denied for GT 1

TOTAL SAVINGS OF $106542

212 internal PAs submitted

3 claims denied due to inappropriate request• Request for 4th fill

Avella Intervention

Clinical Pharmacist Review

December 2014

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Considerations for Genotype 2SOF/VEL DCV*+SOF

Alternative

NaïveNoncirrhoticCirrhosis 12 weeks 12 weeks

16–24 weeksPeg-INF/RBV experienced

NoncirrhoticCirrhotic

12 weeks12weeks

12 weeks16–24 weeks (VA: add RBV)

SOF experiencedNoncirrhotic orcirrhotic

12 weeks; add RBV 24 weeks ± RBV

*Not FDA-approved for GT 2.

AASLD/IDSA HCV Guidelines; Feld JJ et al. N Engl J Med. 2015;373:2599-2607. US Department of Veterans Affairs. Chronic hepatitis c virus (HCV) infection: treatment considerations. Hepatitis.va.gov Web site. Available at: http://www.hepatitis.va.gov/provider/guidelines/hcv-treatment-considerations.asp. Updated March 8, 2017.

ASTRAL-1 SVR 100% (104/104)ASTRAL-2 SVR 99% (133/134)

Baseline RASs have NO impact No need for baseline testing

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Population SOF/VEL DCV+SOFNaïve, noncirrhotic 12 weeks 12 weeks

Naïve, cirrhoticPerform RAS testing

12 weeks; add RBV if Y93H

present

24 weeks; add RBV if Y93H present(FDA/VA: 12–16 weeks

+RBV)Peg/RBV experienced, noncirrhotic 12 weeks 12 weeks

Peg/RBV experienced, cirrhosis 12 weeks +RBV 24 weeks +RBV

(FDA/VA: 12 weeks +RBV)SOF experienced, noncirrhotic or cirrhotic 12 weeks +RBV 24 weeks +RBV

Recommendations for Genotype 3

AASLD/IDSA HCV Guidelines; FDA Labeling; VA HCV Treatment Considerations; Foster GR et al. N Engl J Med. 2015; Nelson DR et al. Hepatology. 2015; Leroy V et al. Hepatology. 2016.

If CTP-A or Peg/RBV experienced: Test for NS5A RAS and add RBV if Y93H present

If SOF experienced or CTP-B or C: Add RBV

90%–97% SVR

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Key Monitoring Guidance HCV RNA before treatment and at week 4 If detectable at week 4, reassess at week 6

CBC if receiving ribavirin (at least every 4 weeks) Liver panel and serum creatinine (at week 4 and as needed) ALT OPrD: Before treatment and at week 4; if elevated at week 4,

reassess at week 6 and week 8 EBR/GZR: Before treatment and at week 8; if elevated at week 8,

reassess at week 12 and as needed while treatment continues HBV reactivation HBsAg, HBV DNA, ALT between weeks 4 and 8 or for unexplained

ALT increase on treatment Cirrhotics Clinical signs of decompensation

Pregnancy testing if receiving ribavirin

AASLD/IDSA HCV Guidelines; FDA package labeling. CBC = complete blood cell count; HBsAg = surface antigen of hepatitis B virus.

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Decompensated Cirrhosis

96% 94% 100% 100%

85%

0%10%20%30%40%50%60%70%80%90%

100%

GT 1 1a 1b GT2 GT3

SVR

%

SOF/VEL + Ribavirin x 12 weeks (n = 87)

4/4 11/1314/1451/5465/68

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ClinicalPatient eHealth Engagement

HCV data collection

Current state requires manual process Future state is Medivo

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Provider PortalReal-time Customer Insights and Status

Tracks prescriptions real time through each step of the fulfillment

Quickly find a patient, treatment status, and any required action steps

Easily accessible and secure from any computer

Insights into individual patients and overall practice

FedEx tracking of shipments

RESULTS:

Over 25% of ongoing referring providers now use the portal

Portal users send 2.7 times more prescriptions each month vs nonusers of portal

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Case: Patient Relapsed on Ledipasvir/Sofosbuvir x 8 Weeks

HEPATITIS C VIRAL RNA GENOTYPE 1 NS5A DRUG RESISTANCE

HCV NS5a subtype: 1a

Daclatasvir resistance: Probable

Ledipasvir resistance: Probable

Ombitasvir resistance: Probable

Elbasvir resistance: Probable

Velpatasvir resistance: Not predictedMutations detected: L31M, Y93H

For patients that have failed NS5A regimens:Defer treatment until fall 2017

Retreat with combination DAA “cocktails” Add RBV

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All-Oral Regimens for HCV InfectionRegimen Component Classes GenotypesGrazoprevir/elbasvir Protease inhibitor + NS5A inhibitor 1, 4

Ombitasvir/paritaprevir/ritonavir Protease inhibitor + NS5A inhibitor 4

Ombitasvir/paritaprevir/ritonavir + dasabuvir

Protease inhibitor + NS5A inhibitor + polymerase inhibitor 1

Sofosbuvir + daclatasvir Nucleotide polymerase inhibitor + NS5A inhibitor 1, 3

Sofosbuvir/ledipasvir Nucleotide polymerase inhibitor + NS5A inhibitor 1, 4, 5, 6

Simeprevir + sofosbuvir Nucleotide polymerase inhibitor + protease inhibitor 1

Sofosbuvir/velpatasvir Nucleotide polymerase inhibitor + NS5A inhibitor 1, 2, 3, 4, 5, 6

Glecaprevir/pibrentasvir Protease inhibitor + NS5A inhibitor 1, 2, 3, 4, 5, 6

Sofosbuvir/velpatasvir/voxilaprevir Nucleotide polymerase inhibitor + NS5A inhibitor+ Protease inhibitor 1, 2, 3, 4, 5, 6

Grazoprevir/ruzasvir /MK3682 Protease inhibitor + NS5A inhibitor+ Nucleotide polymerase inhibitor 1,2,3

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Hepatitis C Mobile AppInforming gastroenterology practices on changes in

treatment options

› Interactive, searchable by genotype and medication

› Provides treatment history, dose, duration, response-guided therapy, SVR rate, and clinical study references

“Having access to all of this prescribing information in an easy-to-use app streamlines the process of identifying optimal treatment recommendations”Kevin Prince, MD, Internal Medicine, UMC of Southern Nevada

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New Regimens

VOXNS3/4Aproteaseinhibitor

VEL NS5Ainhibitor

SOF Nucleotidepolymerase

inhibitor

GLE PIBCollectively: G/P

Ruzasvir(MK-8408)

Grazoprevir(MK-5172)

MK-3682

Sofosbuvir/Velpatasvir/Voxilaprevir (VOX) Pan-genotypic activity against GT 1–6, including

most RASs Once-daily, oral, fixed-dose combination

(400/100/100 mg) Diarrhea, PPI interaction

Glecaprevir/Pibrentasvir Pan-genotypic activity against GT 1–6 High barrier to resistance; potent against common

NS3 polymorphisms (80, 155, and 168) and NS5A polymorphisms (28, 30, 31, and 93)

Three 100 mg/40 mg pills (300 mg/120 mg) once daily

No dose adjustment for CKD

MK3682/Grazoprevir/Ruzasvir Activity against GT 1–3 Two 225 mg/50 mg/30 mg tablets (450/100/60

mg) once daily High barrier to resistance; potent against

NS5A DAA failuresCKD = chronic kidney disease.

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New DAA Studies from AASLDSOF/VEL/VOX Study Population SVR

POLARIS-1 12 weeks for NS5A inhibitor-experienced GT 1–6 96% (91%–100%)

POLARIS-2 8 weeks for DAA-naive GT 1–6 95% (92%–95%)

POLARIS-3 8 weeks for cirrhotic GT 3 96% (91%–100%)

POLARIS-4 12 weeks for DAA-experienced (no NS5A inhibitors) GT 1–6 97% (94%–100%)

GLE/PIB

ENDURANCE-1 8 or 12 weeks for noncirrhotic patients with GT 1 99%

ENDURANCE-2 12 weeks for noncirrhotic patients with GT 2 99%

ENDURANCE-4 12 weeks for noncirrhotic patients with GT 4–6 99%

SURVEYOR-II Part 3 12 or 16 weeks for patients with GT 3 ± TE ± cirrhosis 91%–98%

EXPEDITION-IV 12 weeks for patients with GT 1–6 and stage 4/5 CKD 98%

MK-3682/GZR/RZR

C-CREST Part B 8/12/16 weeks ± RBV for GT 1–3 ± TE ± cirrhosis8 wk: 86%–98%

12 wk: 97%–100%16 wk: 95%–100%

C-SURGE 16 or 24 weeks ± RBV for GT 1 – relapsing on DAAs 16 wk: 91%–98%24 wk: 92%–100%

Bourlière M et al. AASLD 2016. Abstract 194; Jacobson IM et al. AASLD 2016. Abstract LB12; Foster GR et al. AASLD 2016. Abstract 258; Zeuzem S et al. AASLD 2016. Abstract 109; Zeuzem S et al. AASLD 2016. Abstract 253; Kowdley KV et al. AASLD 2016. Abstract 73; Asselah T et al. AASLD 2016. Abstract 114; Wyles DL et al. AASLD 2016. Abstract 113; Gane EJ et al. AASLD 2016. Abstract LB11; Lawitz E et al. AASLD 2016. Abstract 110; Serfaty L et al. AASLD 2016. Abstract 112; Wyles DL et al. AASLD 2016. Abstract 193.

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MK-3682/GZR/RZR for DAA Relapses

Wyles DL et al. AASLD 2016. Abstract 193.

100

80

60

40

20

0Perc

ent o

f Pat

ient

s w

ith H

CV

RN

A<

15 IU

/mL

n/N =

16 wk +RBV24 wk without RBV

98 100

43/44 30/30

98 100

43/44 38/38

91 92

40/44 45/49

TW4 SVR4 SVR8

No impact of NS5A or NS3 RAVs on SVR4, including Y93 RAVs

Previous regimens: LDV/SOF 12–24 weeks, 61%; LDV/SOF 8 weeks, 15%; GZR/EBR 12 weeks, 24% NS5A RAVs, 84%; NS3 RAVs, 65%; 4% of patients had ≥3 NS5A RAVs; 55% had dual NS5A and NS3 RAVs

TW4 = treatment week 4.

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Treatment Questions for 2017 Ideal treatment duration and to what extent treatment

can be shortened to <12 weeks Ongoing requirement for ribavirin in subgroups Treatment of genotype 3 Ideal timing of treatment and ideal regimen in

patients with decompensated cirrhosis and those awaiting liver transplant

Treatment options for patients with genotypes 2, 3, 5, 6 and renal failure where sofosbuvir-based treatment is contraindicated

Optimal treatment of DAA failures Is there a MELD cutoff for treatment of

decompensated cirrhosis +/- HCC?HCC = hepatocellular carcinoma.

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2017 and Beyond “The next generation of HCV drugs will be the

last generation. Apart from, maybe, a few more compounds with characteristics similar to those of the current drugs currently at the late clinical development stages, no further HCV drug development effort is on-going.”

“National plans should now be universally implemented to screen and diagnose HCV-infected patients, provide them with efficient care, educate those at high risk of reinfection about its prevention, and make the world almost free of hepatitis C by 2030.”

Pawlotsky. Gastroenterology. 2016;151:587-590.