Updates in Hepatitis C Management Hayley Blackburn, Pharm.D., - - PowerPoint PPT Presentation

Updates in Hepatitis C Management

Hayley Blackburn, Pharm.D., BCACP Montana Pharmacy Association Winter CE

Disclosures

 I have no relevant financial or nonfinancial interests

related to this presentation

Learning Objectives

• 1. Explain the most recent developments in direct-acting

antiviral (DAA) therapy for the treatment of chronic hepatitis C.

• 2. Describe the trends toward non-specialist treatment of

chronic hepatitis C.

Pre-Assessment Questions

• 1. True/false: New direct-acting antiviral combinations are

highly effective against all hepatitis C genotypes.

• 2. True/false: Current data suggests that HCV treatment

provided by a specialist is superior to treatment provided by a non-specialist provider for the majority of those with chronic HCV infection.

1945 2021

Today 1945 1952 1959 1966 1973 1980 1987 1994 2001 2008 2015 1960 - Hepatitis B discovered 1969 - First Hepatitis B vaccine invented 1973 - Hepatitis A discovered

1975 - "Non-A/Non-B" Hepatitis found 1981 - First Effective Hepatitis A Vaccine, Merck develops hepatitis B vaccine 1989 - Hepatitis C Virus Identified 1991 - IFN-alpha is approved for hepatitis C treatment 2011- Telaprevir and boceprevir approved 2013 - Sofosbuvir and simeprevir approved 2016 - Zepatier and Epclusa approved by FDA 2017 – Mavyret and Vosevi approved 2014 - Harvoni approved by FDA 1998 - FDA approves Interferon + Ribavirin for HCV treatment 2001 - FDA approves Peginterferon alfa-2b "Baby Boomers" Vietnam War HIV/AIDS epidemic begins Testing of the blood supply begins

The History of Hepatitis

Hepatitis C Epidemiology

Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol. 2017;2:161-176.

 Approximately 70 million

people living with chronic hepatitis C worldwide

 50% of total infections are

found in 7 countries:

 China  Pakistan  India  Egypt  Russia  United States  Nigeria

Hepatitis C Epidemiology: Reported Cases of Acute HCV in United States

Source: Division of Viral Hepatitis. Statistics and Surveillance

500 1,000 1,500 2,000 2,500 3,000 3,500

Number of cases Year

Based on these data, CDC estimates that more than 41,000 Americans were newly infected with hepatitis C in 2016 alone

Incidence of Acute HCV By Age Group: CDC Surveillance Data 2001-2016

0.5 1 1.5 2 2.5 3 Reported cases/100,000 population Year 0-19 yrs 20-29 yrs 30-39 yrs 40-49 yrs

Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

Opioid Epidemic and HCV Transmission: Reported Acute HCV Infection 2006 to 2012

Suryaprasad AG, et al. Clin Infect Dis. 2014;59:1411-1419.

Incidence of Acute HCV By Age Group: CDC Surveillance Data 2001-2016

0.5 1 1.5 2 2.5 3 3.5 Reported cases/100,000 population Year American Indian/Alaska Native Asian/Pacific Islander Black, Non-Hispanic White, Non-Hispanic

Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

CDC HCV Surveillance Data: Montana

 1026 new cases of

confirmed past or present chronic HCV reported in 2016

Reported Cases of Acute HCV (*Rate per 100,000)

2013 2014 2015 2016 No. Rate* No. Rate* No. Rate* No. Rate*

Montana 16 1.6 13 1.3 15 1.5 20 1.9 US Total 2138 0.7 2194 0.7 2436 0.8 2967 1.0

DHHS National Viral Hepatitis Action Plan

 2020 DHHS goal: Increase the percentage of persons

aware of their hepatitis C virus infection to 66%

 25% reduction in mortality

 CDC, DHHS, and National Academies of Sciences,

Engineering, and Medicine have set a strategy to eliminate viral hepatitis in the US by 2030

• DHHS. National Viral Hepatitis Action Plan 2017-2020.

HCV Screening Recommendations

Population CDC AASLD USPSTF NIH

Born in the US between 1945-1965

X X X X

Any injection of illicit drugs (IVDU/PWID)

X X X X

Received blood transfusion or organ transplant before 1992

X X X X

Chronic hemodialysis

X X X X

Evidence of liver disease

X X X

HIV infection

X X X

HCW after exposure

X X X

Received an unregulated tattoo

X

Children born to HCV+ women

X X X

Incarceration

X X

Intranasal drug use (cocaine)

X X

15-25%

No chronic disease

Progression of Hepatitis C

15%

No chronic disease

Progression of Hepatitis C

Decompensated cirrhosis:

Jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy

Compensated 5% per year

Fibrosis

Source: Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998;28:805-9.

Progression of Hepatitis C

 Higher risk of disease progression:

 HCV acquired after age 40  Male gender  Coinfection with HIV/HBV  Alcohol use

 Lower risk:

 Female gender  Acquired at a younger age

Forecasted Deaths Associated with Chronic HCV

Source: Rein DB, et al. Dig Liver Dis. 2011;43:66-72.

 Projected 1.76 million

people with chronic HCV will develop cirrhosis over the next 50 years

 Predicted to peak at 2030:

 1 million with cirrhosis  131,000 with ESLD  3200 HCV-related transplants

per year

 BUT these numbers are

assuming no widespread treatment of chronic HCV

Treatment Goals: The “SVR”

 SVR12 = undetectable

HCV RNA at 12 weeks after the end of treatment

 SVR12 is the most

indicative of cure

 Patients will also be tested

at 24 and/or 48 weeks after treatment to assess

 Less than 1% will go on to

relapse at 24 or 48 weeks post-treatment if undetectable at 12 weeks

Treatment Goals: The “SVR”

Source: Hepatitis C Online – University of Washington Delayed response Viral relapse

Sustained Virologic Response: Effects on Morbidity and Mortality

 SVR is associated with

significant reductions in liver-related complications and death, as well as a number of other extrahepatic benefits

Source: van der Meer AJ, et al. JAMA. 2012;308:2584-2593.

Benefits of SVR: Beyond the Liver

 Extrahepatic benefits1,2:

 Decreased all-cause mortality  Improved quality of life  Improved control of diabetes/insulin resistance  Improved neurocognition  Improved HCV-related liver transplant outcomes  2018 observational VA study3: HCV treatment associated with a

significant reduction in CVD events

 Veterans treated with either PEG-IFN + RBV (n=4436) or DAA (n=12,667)  7.2% incidence of CVD events in treatment group vs 13.8% in control group

(p<0.0001)

• 1. Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19. 2. Negro F, et al. Gastroenterology. 2015;149:1345-1360.
• 3. Butt AA, et al. Gastroenterology. 2018;49:729-738.

Benefits of SVR: Beyond the Liver

Societal benefits:

 Cost-effective, potentially cost-saving

2017 systematic review: 71% of analyses

found second-generation DAAs to be cost- saving at a discounted price of $60K

 Public health – increase cure rates mean

reduced transmission rates

BUT does not protect against reinfection

Hepatitis C Treatment: The Era of Direct-Acting Antivirals

History of HCV Treatment: Interferon+Ribavirin

Of those that finished treatment,

• nly 40-50%

achieved SVR (NO LONGER USED)

“Sustained Virologic Response” “Early Virologic Response” “Rapid Virologic Response”

Duration of treatment: 24-72 weeks ~up to 50% overall early discontinuation rate

• ~40% discontinued due to intolerance
• ~10% discontinued early due to lack of efficacy

1989 2019

1989 1993 1997 2001 2005 2009 2013

1989 - Hepatitis C Virus Identified

1/1/1989

1991 - IFN-alpha is approved for hepatitis C treatment

1/1/1991

1998 - FDA approves Interferon + Ribavirin for HCV treatment

1/1/1998

2001 - FDA approves Peginterferon alfa-2b

1/1/2001

2011- Telaprevir and boceprevir approved

1/1/2011

2013 - Sofosbuvir and simeprevir approved

1/1/2013

2014 - Harvoni approved by FDA

10/14/2014

2016 - Zepatier and Epclusa approved by FDA

6/8/2016

IFN-only: 6-16% cure IFN/RBV: 34-42% cure Peg-IFN/RBV: 55% cure Peg-IFN/RBV/DAA: 70-90% cure

 Beginning in 2011, rapid advances in product

development for direct-acting antiviral agents that specifically target essential components of viral replication

 NS3 protease inhibitors  NS5A polymerase inhibitors  NS5B inhibitors

 HUGE advantages:

 All oral regimens, 8-24 weeks, well-tolerated  Rapid response in viral load reduction  Well-tolerated with minimal adverse effects:  Headache, fatigue, insomnia, nausea

 SVR Rates: 95-99%

Direct-Acting Antivirals: Combination Products

Direct-Acting Antivirals: Protease Inhibitors

 NS3 Protease

Inhibition:

 Inhibits cleavage of

viral polyprotein into functional protein subunits required for viral replication and assembly

 Inhibitors:

Glecaprevir, grazoprevir, paritaprevir, simeprevir, voxilaprevir

Holmes JA, Thompson AJ. Hep Med. 2015;7:51—70

Holmes JA, Thompson AJ. Hep Med. 2015;7:51—70

Direct-Acting Antivirals: NS5A/NS5B Inhibitors

 NS5B:

 RNA polymerase

responsible for RNA synthesis

 Inhibitors: sofosbuvir,

dasabuvir

 NS5A:

 Modulation of NS5B

activity

 Role in modulation

• f host response?

 Inhibitors:

Daclatasvir, elbasvir, ledipasvir, ombitasvir, pibrentasvir, velpatasvir

Direct-Acting Antivirals: Combination Products

Direct-Acting Antiviral Combo Product Antiviral Activity Cost Ledipasvir/sofosbuvir (Harvoni) G1, G4-6 $72K (12 weeks) Elbasvir/grazoprevir (Zepatier) G1, G4 $54K (12 weeks) Ombitasvir/paritaprevir/ritonavir (Technivie) G4 $76K (12 weeks) Ombitasvir/paritaprevir/ritonavir & dasabuvir (Viekira Pak G1 $84K (12 weeks) Sofosbuvir/velpatasvir/voxilaprevir (Vosevi) Pan-genotypic $75K (12 weeks) Sofosbuvir/velpatasvir (Epclusa) Pan-genotypic $75K (12 weeks) Glecaprevir/pibrentasvir (Mavyret) Pan-genotypic $26K (8-12 weeks)

Choosing Treatment Regimens

 Multiple options of highly effective DAA

regimens– how to choose?

 Choice of treatment regimen

depends primarily on:

• 1. Genotype
• 2. Presence and degree of cirrhosis

Compensated/decompensated?

• 3. Treatment history: naïve or

experienced?

Treatment Decisions: HCV Genotypes

Genotype 1 73% Genotype 2 13% Genotype 3 12% Genotype 4,5,6 2%

Source: Gerner et al. J Clin Microbiol 2012;49(8):3040-3043.

 Genotypes: 1-6

 Genotype 1: most prevalent (subtypes 1a/1b)  Genotype 2/3: less common, may be slightly

more difficult to treat

 Genotype 4: Africa, Middle East, Europe  Genotype 5: South Africa  Genotype 6: Asia

 Subtypes a/b/c or mixed

 Subtypes may also be predictive of response HCV Genotypes in the United States

Treatment Decisions: Liver Disease Staging

 Does the patient have cirrhosis?  If yes, compensated or decompensated?  Biopsy: “gold standard” but invasive, generally avoided

in favor of less invasive techniques

 Imaging: Ultrasound/MRI, Fibroscan elastograpy  Labs: LFTs, INR, SCr, CBC, FibroSure  Symptoms of decompensation?  Scoring/grading systems

 FIB-4/APRI, CTP  MELD

Predictive of response to treatment: the worse the cirrhosis, the harder to treat

Pretreatment Assessment: Predictors of Response

 Response depends on both host and viral factors:

 Viral: genotype/subtype, mutations, HCV RNA level  Host: fibrosis/cirrhosis, treatment history, BMI, adherence

 BE3A score: Newer validated scoring tool: to predict potential benefits of

DAA therapy in those with decompensated cirrhosis

 One point for each of the following:

 BMI <25 kg/m2  No Hepatic Encephalopathy  No Ascites  Serum Albumin >3.5 g/dL  ALT >60 IU/mL

 Score of 4-5 = 75% chance of reduction from CTP B or C to CTP A with DAA

therapy

Treatment Decisions: Treatment History

 The majority of patients are treatment naïve

 Historically only treated the sickest of patients with IFN, often

treatment was avoided altogether due to adverse effects and poor success rate

 Good news: better prognosis if treatment naïve

 Previous treatment failure may indicate that HCV is more

difficult to treat

 Treatment decisions become more complicated

AASLD/IDSA Guidance: First-Line Treatments for HCV (Tx Naïve)

AASLD/IDSA. HCV guidelines. September 2017.

HCV GT Regimen Duration, Wks No Cirrhosis Compensated Cirrhosis 1 GLE/PIB GZR/EBR* SOF/LDV SOF/VEL 8 12 8 or 12† 12 12 12 12 12 2 or 3 GLE/PIB SOF/VEL 8 12 12 12‡ 4 GLE/PIB SOF/VEL GZR/EBR SOF/LDV 8 12 12 12 12 12 12 12 5 or 6 GLE/PIB SOF/LDV SOF/VEL 8 12 12 12 12 12

Only four DAA combo therapies specified as first- line per guidelines

*If GT1a, use only if no baseline NS5A elbasvir RAVs detected.

†If nonblack, no HIV, and HCV

RNA < 6 million IU/mL, 8-wk duration recommended.

‡For GT3, if Y93H RAV

detected, add RBV or consider SOF/VEL/ VOX.

AASLD/IDSA Guidance: First-Line Pangenotypic Regimens

Setting SOF/VEL GLE/PIB

Treatment naive GT1-6 ▪ No cirrhosis or compensated cirrhosis: 12 wks GT1-6 ▪ No cirrhosis: 8 wks ▪ Compensated cirrhosis: 12 wks IFN/RBV experienced GT1-6 ▪ No cirrhosis or compensated cirrhosis: 12 wks GT1, 2, 4, 5, 6 ▪ No cirrhosis: 8 wks ▪ Compensated cirrhosis: 12 wks GT3 ▪ No cirrhosis or compensated cirrhosis: 16 wks

SOF/VEL/VOX: also pan- genotypic, but not first- line

AASLD/IDSA. HCV guidelines. September 2017.

First-Line Pangenotypic Regimens: SOF/VEL & GLE/PIB

Variable SOF/VEL (Epclusa) GLE/PIB (Mavyret) Treatment duration: no cirrhosis 12 weeks 8 weeks Treatment duration: cirrhosis 12 weeks 12 weeks Pill total 1 pill daily 3 pills daily Administration With or without food With food Renal disease Avoid in eGFR <30 ml/min No restriction for renal impairment or dialysis Use in decompensated liver disease Can be used (with RBV) Contraindicated Cost ~$26,000/month ~$13,000/month

Newer Data: Can We Reduce Duration of Therapy?

 Treatment-naive patients with chronic HCV infection (GT1-6) and

compensated cirrhosis treated with glecaprevir (GLE)/pibrentasvir (PIB) for 8 weeks versus the currently recommended 12 weeks:

 SVR12: 98%  Proof-of-concept study: response-guided therapy based off of viral

load reduction throughout treatment

 GT 1-6 with compensated liver disease and treatment naïve (or IFN

experienced) treated with DAA regimens (Epclusa, Zepatier, Harvoni, Mavyret) (n=22)

 Viral loads at baseline, day 2, week 1, week 2 and week 4 after start of

treatment

 Mathematical modeling at week 2 and week 4 to project time to cure and

individualize treatment duration

 Resulted in reductions in duration to 6-10 weeks versus usual 12 weeks  SVR12 results: 15/16 patients had achieved SVR

Treatment Decisions

 For most patients, treatment decisions have become fairly

straightforward

• 1. Look at the following to determine best treatment options:

 Genotype  Treatment history  Stage of liver disease

• 2. Use pretreatment assessment to further guide therapy:

 Labs (SCr, CBC, LFTs)  Adherence  Cost/insurance coverage  Drug interactions

 Conducive to management by a non-specialist

Rates of Cure with Non-Specialist Treatment



2017 study of treatment outcomes with specialist versus nonspecialist treatment of HCV with ledipasvir/sofosbuvir (Harvoni) X 8- 24 weeks (n=600) in 13 urban FQHCs



All providers viewed underwent 3-hour training session



Results: overall SVR12 = 87.1%, with no significant difference in SVR rates or safety

• utcomes between provider types



Specialists: 84.8%



PCPs: 87.6%



NPs: 90.4%



Rate of adherence: 86.6%



Those who did not achieve SVR (n=84):



54% lost to follow up



42% had viral relapse

Kattakuzhy S, et al. Ann Intern Med. 2017;167(5):311-318. Baseline Demographic and Clinical Characteristics Overall (n=600) NPs (n=150) PCPs (n=160) Specialists (n=290) Mean age (SD), years 58.7 (6.9) 58.2 (7.6) 59.0 (6.3) 58.8 (6.7) Men 69% 72% 72% 67% Black 96% 93% 100% 96% HIV- coinfection 23% 15% 28% 24% Cirrhosis 20% 19% 18% 22% Recreational drug use

Current = 15% Never = 40% Previous = 45% Current = 10% Never = 42% Previous = 48% Current = 14% Never = 38% Previous = 48% Current = 20% Never = 39% Previous = 41%

Housing

Temporary = 9% Homeless = 7%

Temporary = 10%

Homeless = 3% Temporary = 8% Homeless = 8% Temporary = 9% Homeless = 9%

Getting Patients to SVR: Starting Treatment

 New medication education

 Hepatitis C general education  Importance of adherence

 If >2 doses missed in a row, may need to restart treatment

 Instructions for administration  Adverse effects  Drug-drug interactions  Assessment of immunization history  Hep A & Hep B immunizations  Pneumococcal vaccine for cirrhotic patients

Treatment Monitoring & Follow-up

 Follow up:

 Adverse effects – infrequent and mild with DAAs  Labs: CBC, SCr, LFTs, HBV DNA if coinfected

 May not be necessary during treatment for some, others

require closer monitoring

 Adherence  Viral response – post-treatment for SVR12

 Usually see marked decrease at week 4, may even be

undetectable (will still finish full course of treatment)

Indications for Specialist Referral

(And/Or Closer Monitoring, Multidisciplinary Treatment)

 Major drug-drug interactions  Prior treatment failure  Chronic kidney disease (eGFR <30ml/min)  Current IVDU or EtOH use disorder (substance use treatment)  HCV genotype 3 (especially if cirrhosis)  Decompensated liver disease  Hepatocellular carcinoma  HBV surface antigen positive  HIV co-infection

Special Populations: Management of Drug-Drug Interactions

 Can be challenging to identify

 Lack of data, studies on healthy subjects and usually one DDI at a time

 Common drugs that interact with hepatitis C direct-acting antivirals

 Acid reducing agents (PPIs, H2RAs and antacids)

 Major interactions with ledipasvir and velpatasvir requiring lots of patient education,

change/dose reduction in acid reducing regimen or change to alternative DAA (EBR/GZR or GLE/PIB)

 Statins – increased serum concentrations, monitor for myalgias  Beta-blockers  Calcium-channel blockers  Digoxin  Antiepileptic medications – monitor levels  HIV medications - careful choice of regimens  CYP3A4/Pg-p interactions (St. John’s Wort, rifampin, grapefruit, ketoconazole) Increased serum concentrations, monitor for ADRs

Common DDIs with DAAs

Concomitant Medication GLE/PIB SOF/VEL DCV LDV SOF EBR/GZR SOF/VEL/VOX Acid-reducing agents X X X Amiodarone X X X X X Anticonvulsants X X X X X X X Azole antifungals X X Calcium channel blockers X X Cyclosporine X Digoxin X X X X X Ethinyl estradiol–containing products X Glucocorticoids X X Herbals, St John’s wort, milk thistle X X X X X X X Statins X X X X X Macrolide antimicrobials X† X

AASLD/IDSA. HCV guidance. September 2017. FDA GLE/PIB. FDA SOF/VEL/VOX.

• Requires careful screening for drug interactions to ensure safety and efficacy of

therapy, and looking at individual DDI to determine best course of action

 Recommended drug interaction checker:  University of Liverpool – Hep Drug Interaction

 http://www.hep-druginteractions.org/checker

Special Populations: Prior Treatment Failure

 Previous treatment failure – what now?

 First question: is it a failure or a reinfection?  Important to know why/how they failed: Null responder vs. relapse vs.

intolerance?

 What treatment? IFN + RBV? Or DAA?

 If IFN-based treatment failure, not necessarily a need to refer to specialist

 Is advanced cirrhosis a contributor to treatment failure?  Is there resistance? (RAV testing)

 New drugs with low failure rates → few failures to study and

determine best course of treatment

Resistance-Associated Variants (RAVs): DAA Characteristics

Class Antiviral Potency Resistance Barrier Prevalence of significant baseline RAVs Persistence of RAVs FDA-Approved Medication NS3 Protease Inhibitors High Low/Moderate Rare 1-3% Low, will disappear within 6-12 months Simeprevir Paritaprevir Grazoprevir Glecaprevir Voxilaprevir NS5A Inhibitors High Very Low Common ~10% (Y93H results in >1000->10,000 fold change in resistance) High, will persist >2 years Ledipasvir Ombitasvir Daclatasvir **Elbasvir** Velpatasvir Pibrentasvir NS5B Nucleoside/tide Moderate High VERY rare <1% Low Sofosbuvir NS5B Non- nucleoside/tide Moderate Moderate Rare 1-3% Low Dasabuvir

Source: Dietz J, et al. PLoS One. 2015; 10(8): e0134395.

Special Populations: Management of Drug Resistance

 Resistance testing is directed at NS5A polymorphisms  Specific recommendations based on:

 Genotype: typically only considered in GT1a and GT3  Treatment history: more likely to be recommended in those who are

treatment-experienced, although can be considered in treatment-naïve in some instances

 Presence of cirrhosis: if cirrhosis, stronger recommendations for

screening

 Choice of drug: elbasvir, ledipasvir, velpatasvir, daclatasvir are most

likely to have resistance

 Which polymorphism: Y93H is most important, and better guidance for

either adding ribavirin or a protease inhibitor and length of treatment

Special Populations: Management of Drug Resistance

 Newer data for management of treatment failures:  AASLD 2018: Glecaprevir/pibrentasvir for 16 weeks in GT1

patients (+/- cirrhosis) with previous virologic failure on NS5A inhibitor + sofosbuvir +/- ribavirin (RBV)

 Overall SVR12 = 95% for those treated with GLE/PIB alone for

16 weeks (94% in noncirrhotic, 97% in cirrhotic)

 No treatment failure in GT1b patients treated for either 12 or 16

weeks

 Addition of ribavirin resulted in increased adverse effects

without improved efficacy

Special Populations: Management of Drug Resistance

 SOF/VEL/VOX (Vosevi) X 12

weeks resulted in SVR12 in 97% of patients with baseline NS5A and/or NS3A RAVs and prior treatment failure

 95% SVR12 in those with Y93

polymorphism in NS5A

 New treatment-selected drug

resistance in those who failed treatment in <1% of patients

Sarrazin C, et al. Hepatology. 2018;69(6):1221-1230.

Special Populations: Chronic Kidney Disease

 Major comorbidity in those with chronic HCV infection  Interplay between HCV infection and renal disease:

 Hemodialysis is a risk factor for HCV infection (longer duration = greater risk)  Extrahepatic manifestations of chronic HCV may result in kidney disease  HCV may increase risk of renal cell carcinoma and accelerate decline in renal

function

 Drug-related issues:

 Avoid sofosbuvir in severe impairment (eGFR <30ml/min) or dialysis  Ribavirin in select patients → dose adjusted and patients closely monitored

 AASLD-IDSA Guidelines:

 Mild to moderate CKD: any DAA regimen is ok  Severe CKD (stage 4-5): GLE/PIB or GZR/ELB

Special Populations: Persons Who Inject Drugs (PWIDs)

 Current IV drug users account for up to 70% of new

HCV infections in the US

 20-30% become infected within first 2 years of use, 50% within

first 5 years  Guidelines recommend testing and harm reduction

measures, in addition to linkage care for substance abuse and mental health comorbidities

 Combined opioid substitution therapy + needle/syringe

programs can reduce HCV incidence by up to 80%

MacArthur GJ, et al. Int J Drug Policy. 2014;25:34-52.

Special Populations: Persons Who Inject Drugs (PWIDs)

 High rates of SVR (>90-95%) with DAA treatment observed in clinical trials

for those who undergo treatment

96% 89% 87% 95% 90% 86% 93% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Norton 2017 (n=46) Hull 2016 (n=100) Powis 2017 (n=69) Litwin 2017 (n=150) Sulkowski 2017 (n=98) Maznaya 2017 (n=1126) Dore 2017 (n=201)

SVR12 Rates Among Current/Former PWID

Special Populations: Persons Who Inject Drugs (PWIDs)

 ANCHOR study: colocation of buprenorphine treatment with

HCV treatment with SOF/VEL in Washington DC (n=97)

 SOF/VEL X 12 weeks plus buprenorphine started between 0-24

weeks of SOF/VEL initiation

 Demographics: Majority male (75%) and black (93%), 51% with

unstable housing, 57% reporting daily IVDU

 Primary endpoints:

 Adherence: 94% received at least 8 weeks of treatment, 89% received all

12 weeks of treatment

 48% finished within 7 days after anticipated end of treatment (few missed

doses)

 SVR12 rate: 90% of 58 patients who made it to week 24 visit achieved SVR  Risk behaviors: significant decrease from start through week 24 (assessed

at week 4 (p=0.003), week 12 (p=0.001), week 24 (p=0.003)

Kattakuzhy S, et al. Hepatology. 2018;68(S1). doi: 10.1002/hep.30256.

Special Populations: Persons Who Inject Drugs (PWIDs)

 Evidence shows that there are

high rates of continued IV drug use, but consensus promotes

HCV treatment as a harm- reduction strategy

 Reinfection risk remains,

but reinfection is not inevitable

Rossi C, et al. Hepatology. 2018;69(5):1007-1014.

Cumulative incidence curves for reinfection, by injection drug use history

Special Populations: Persons Who Inject Drugs (PWIDs)

 DAA treatment should be paired with other

interventions and treatment paradigms:

 Access to care for other medical conditions, mental

health, social needs

 Medication-assisted therapy (methadone, buprenorphine)  Reducing reinfection risk (needle exchanges, education)  Individual-level treatment of injecting partners  Access to retreatment without stigma or discrimination  Preventative strategies for common coinfections (HBV

vaccination, HIV prep)

 Community-level approach to address outbreaks?

Special Populations: Persons Who Inject Drugs (PWIDs)

 Comprehensiveness of harm-reduction laws

assessed by:

 Authorization of syringe exchanges  Exemption of needles or syringes from the

definition of drug paraphernalia

 Decriminalization of possession and

distribution of syringes or needles for participants of a legally authorized syringe service program

 Avoidance of criminal prosecution for

possession of drug paraphernalia by disclosing possession of a needle or sharp

• bject to an arresting officer

 Allowance for the retail sale of syringes

without a prescription to persons who inject drugs

Campbell CA, et al. MMWR Morb Mortal Wkl Rep. 2017;66:465-469.

Special Populations: Pregnancy

 More younger people with

HCV infection = more women of reproductive age

 Wisconsin Medicaid Data

2011-2015: Rate of HCV infection increased 93% in pregnant women

 Low rate of HCV testing

in HCV-exposed infants (34%)

 2017 data: Up to 4% of

pregnant women in US infected with HCV

0.5 1 1.5 2 2.5 3 Reported cases/100,000 population Year 0-19 yrs 20-29 yrs 30-39 yrs 40-49 yrs Incidence of Acute HCV By Age Group: CDC Surveillance Data 2001-2016

Special Populations: Pregnancy

 Recommendations:

 May 2018 update to AASLD/IDSA Guidance: all

pregnant women should be tested for HCV infection at initiation of prenatal care

Treat HCV infections prior to pregnancy if possible Per guidelines, treatment during pregnancy not

recommended due to lack of data

 Children born to HCV-infected women should be

tested at or after 18 months of age

Hepatitis C Treatment Cascade:

Gaps in Current Practice

Hepatitis C – Traditional Screening and Treatment

Diagnosis

• Antibody testing, then later follow-up HCV RNA if positive
• Referral to specialist for further workup

Evaluation

• Viral load, genotyping, testing for RAVs
• Assessment of liver damage (biopsy?)
• Evaluate if patient is candidate for treatment based on comorbidities

Treatment

• Specialist monitoring treatment
• Frequent lab follow up, monitoring DDIs, ADRs, etc
• Often poorly tolerated

HCV Treatment Cascade:

Gaps in Current Practice

Yehia BR, et al. PLoS One. 2014;9:e101554.

How do we improve screening and diagnosis?

• Increase f/u testing and chain of

communication/response

• Rapid diagnostic tests
• Standard protocols w/ ED, PCPs

(DAAs only help here)

HCV Screening Recommendations

Population CDC AASLD USPSTF NIH

Born in the US between 1945-1965

X X X X

Any injection of illicit drugs (IVDU/PWID)

X X X X

Received blood transfusion or organ transplant before 1992

X X X X

Chronic hemodialysis

X X X X

Evidence of liver disease

X X X

HIV infection

X X X

HCW after exposure

X X X

Received an unregulated tattoo

X

Children born to HCV+ women

X X X

Incarceration

X X

Intranasal drug use (cocaine)

X X

HCV Screening: Point-Of-Care Assays

 A final diagnosis of active HCV infection has traditionally required multiple

visits, with opportunity for loss to follow up at each point along the way

 WHO: critical lack of effective, practical and affordable tools for point-of-

care diagnosis of chronic HCV infection

 FIND/WHO High-Priority Target Product Profile – consensus meeting 2015

 Guidance for product profile for manufacturers  Focus on impact in low- and middle-income countries  Desired profile:

 Portable and simple to operate with fast results  Sensitive & specific, ideally quantitative results  Capacity/throughput: ideally multiple at a time  Battery operated, little to no maintenance/calibration  Operating temp/humidity/altitude: 5-40C/90% humidity/3000m  Cost: <$15 per test, <$20,000 per instrument

Point-Of-Care Assays: HCV Antibody Testing

 HCV-antibody testing: widely available, can help address some issues to

access-– BUT requires confirmatory RNA testing for diagnosis

 OraQuick: noninvasive option for HCV antibody testing using oral fluids, >90%

sensitivity and specificity



Whole blood or fingerstick options provide higher sensitivity/specificity (95-100%)

 Walgreens study (2017): 45 pharmacies in 9 US cities provided HCV antibody

screening one day per week with 1) a subsequent follow up via phone from HCV specialist with initial results and 2) another 21-28 day follow up after initial call



8% of participants were HCV-antibody positive (103/1296)



88% were contacted by HCV specialist with results (91/103)



62% were reached at days 21-28 (56/103)



Of those contacted, 52% (29/56) had received follow up HCV RNA testing

Point-Of-Care Assays: HCV RNA

 Cepheid Xpert HCV Viral Load Assay – initially

introduced in 2017, fingerstick assay released September 2018

 Disadvantages: requires electrical power supply, toxic

reagents requiring special handling precautions and disposal by incineration, requires electrical outlet

 Genedrive plc: portable handheld device that allows

screening of serum samples for HCV RNA

 Advantages: battery operated, 30 microliter sample size

(pin prick testing), no toxic reagents  Cost ~$5000/instrument, $30-40/test  Bottom line: rapid, simple, accurate, affordable

and portable with potential to improve screening and diagnosis worldwide

Hepatitis C – New Screening and Treatment Paradigms

Diagnosis

• POCT
• Reflex testing (if Ab positive, then automatic follow up HCV RNA test)
• HCV RNA test at point-of-care

Evaluation

• Pangenotypic regimens → no need for genotyping (maybe)
• Simplified screening/tools to determine degree of liver disease
• Scoring tools: APRI/FIB-4, elastography

Treatment

• Non-specialist treatment for most (potential for pharmacist CPA)
• Easy regimens: once daily X 8-12 weeks, no IFN, rare need for RBV
• Well tolerated, minimal DDI
• Less monitoring (maybe no on-treatment monitoring in non-cirrhotic patients)

HCV Treatment Cascade:

Gaps in Current Practice

Yehia BR, et al. PLoS One. 2014;9:e101554.

How do we improve linkage to care?

• Immediate referral or screening within

care facility

• Peer navigators/other support
• PCP treatment versus specialist for most
• Improved treatment access, including

treatment for those who have historically been excluded

Treatment Access:

2017 National Viral Hepatitis Roundtable Report



Montana Fibrosis Restrictions: requires severe liver damage (F3 or greater)



Requires fibrosis staging



If cirrhotic, requires Child Pugh Grade



Required labs:

 HCV genotype 

HCV RNA viral load



FiboSure/FibroTest or liver biopsy report



CMP

 CBC 

Liver panel



INR

Treatment Access:

2017 National Viral Hepatitis Roundtable Report

 Montana Prescriber

Restrictions: requires HCV medications to be prescribed by a gastroenterologist, hepatologist, or ID physician

 PA process streamlined in 2016

to use one form regardless of medication choice

 Preferred drug list 2018:

 Preferred: Mavyret  Non-preferred: Daklinza,

Epclusa, Harvoni, Zepatier, Vosevi

Treatment Access:

2017 National Viral Hepatitis Roundtable Report



Montana Sobriety Restrictions: requires beneficiaries not to have a history of alcohol or other substance abuse for at least six months prior to the approval for HCV treatment



Patient must sign “Patient Readiness Criteria” on the prior authorization form

 Provider and patient

acknowledge compliance to medications and prior scheduled appointments and labs



If concurrent mental health condition, must be compliant



If untreated mental health condition, MH consult is required before treatment can begin

NHVR/Harvard Law School: Center for Health Law and Policy Innovation

F

NHVR/Harvard Law School: Center for Health Law and Policy Innovation

Why No HCV Vaccine??

 Challenges: multiple genotypes, mechanisms of immune

response/failure to clear the virus are not fully understood

 Prevention of primary infection:

 Different vaccine targets: (neutralizing antibodies, priming protective T

cells)

 Preventative vaccine trial in uninfected IVDU completed in mid-2018, results

pending  Preventing reinfection for those who have achieved cure:

 If initial infection didn’t result in appropriate immune response and

clearance, how do we prevent it the second time around?

 Potential T cell impairment– broaden T cell response to achieve more robust

response if re-exposed to the virus  Therapeutic vaccine trial: completion in 2020

The Pharmacist’s Role in Hepatitis C Management

 Large role in patient education

 Compliance/adherence  Screening recommendations  HCV risk factors/transmission  Lifestyle modifications

 Drug interactions – including

supplements/OTCs

 Immunizations  Improving access – cost/patient

assistance programs

 Harm-reduction strategies

The Pharmacist’s Role in Hepatitis C Management

 Provider education  Ensuring continuity of treatment at transitions of care through

medication reconciliation

 Identifying/managing issues with HCV treatment during acute

hospitalization with knowledge of drug-drug interactions and ADRs

 Potential for pharmacists to serve as agents for screening with

point-of-care testing

 Roles in determining appropriate therapy, collaborative practice

agreements and clinical services to screen and manage patients’ treatment

The Good News:

Hepatitis C is now:

 Preventable  Education  Public health initiatives  Continued safety practices to prevent bloodborne

transmission

 Harm-reduction strategies  Curable  Widespread screening and linkage to care  Early treatment prior to advanced cirrhosis  New and improved drugs + decreasing cost

New emphasis on screening and non-specialist treatment present multiple opportunities for pharmacists to be key players HCV treatment

Useful HCV Resources:

 HCV Advocate: great for patient information resources

 www.hcvadvocate.org

 University of Washington Hepatitis C Online: CE, in-depth course modules,

clinical calculators

 https://www.hepatitisc.uw.edu/

 Liverpool interaction checker

 http://www.hep-druginteractions.org/checker

 AASLD/IDSA Guidelines

 https://www.hcvguidelines.org/

Post-Assessment Questions

• 1. True/false: New direct-acting antiviral combinations are

highly effective against all hepatitis C genotypes.

• 2. True/false: Current data suggests that HCV treatment

provided by a specialist is superior to treatment provided by a non-specialist provider for the majority of those with chronic HCV infection.

Post-Assessment Questions

• 1. True/false: New direct-acting antiviral combinations are

highly effective against all hepatitis C genotypes.

• 2. True/false: Current data suggests that HCV treatment

provided by a specialist is superior to treatment provided by a non-specialist provider for the majority of those with chronic HCV infection.

QUESTIONS?