HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we...
Transcript of HCV Cascade of Care HCV Asembia slides v3.pdf · HCV Cascade of Care In order to eliminate HCV, we...
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.
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.
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
Bob Has a Question
What is Hepatitis
C ?
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.
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.
HCV/HIV Coinfection Outbreak in Indiana
84% Coinfected with HCV
HIV = human immunodeficiency virus.
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
Hepatitis C: Beyond the Liver
Cacoub et al. J Hepatol. 2016;65:s82-s94. For educational purposes only.
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).
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.
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
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.
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.
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.
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
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.
Prescription Process
PA = prior authorization.
Prescription Process
Tx = treatment.
Further Workup for HCV Treatment
Assess for barriers to adherence Health literacy Substance use disorders Untreated mental health conditions
Assess for drug-drug interactions
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.
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.
SMS Integration
SMS = safety management system.
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%
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.
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.
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
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.
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
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
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.
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.
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.
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
Individualizing Treatment Paradigms
Comorbid Conditions: HIV, HBV
Renal/Hepatic Impairment
Drug Interactions
HBV = hepatitis B virus.
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.
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
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.
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.
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.
ADE Volume for HCV
020406080
100120
10
109
22
0 015
018
6 13
2016 AEs by Volume
ADE = adverse drug event.
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
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.
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.
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.
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.
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
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
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.
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.
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.
HCV Data – Who Is Being Treated?
For educational purposes only.
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
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.
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.
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
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)
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
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
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
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.
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
ClinicalPatient eHealth Engagement
HCV data collection
Current state requires manual process Future state is Medivo
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
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
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
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
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.
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.
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.
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.
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.