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Hepatitis C Infection: Pharmacotherapy Update

Autumn Bagwell, PharmD, BCPS, AAHIVPInfectious Diseases Clinical Pharmacist

Vanderbilt Specialty Pharmacy

Disclosures I have no financial disclosures.

Objectives Describe and apply appropriate screening

criteria for HCV

Describe the general biology and life cycle of HCV

Distinguish pharmacologic characteristics between HCV Direct Acting Antiviral classes

Describe treatment strategies for patients with HCV infection

Recognize common drug interactions with direct-acting antivirals (DAA)

Outline HCV epidemiology and biology HCV Treatment Considerations Currently Available Direct Acting Antivirals

(DAA) DAA medication interactions Current HCV treatment regimens Special Populations

HCV Epidemiology 170 million infections worldwide 3.2 to 5.2 million infections in the US

Webster D et al. The Lancet. 2015// Davis GL et al. Gastroenterology 2010.

Presenter
Presentation Notes
-Based on NHANES and expanded NHANES criteria -For every new symptomatic acute HCV case reported, there is an estimated 3.3 cases of asymptomatic acute HCV actually occur. -Number of new annual HCV infections has been relatively stable at approximately 17,000 per year in the past decade Peak incidence between 1970 and 1990 (IVDU and blood transfusion) Peak prevalence around 2001 Peak cirrhosis around 2020 Peak HCC around 2020 or slightly before Peak decompensated cirrhosis shortly after 2020

HCV and Mortality in the USA

Ly KN et al. Ann Int Med 2012. // Ly KN et al. Clin Infect Dis 2016.

Presenter
Presentation Notes
Mortality related to HCV has surpassed HIV (~15,000 compared to ~13,000 in 2007)

Courtesy of Dana Jackson, Tennessee Department of Health.

HCV Risk Factors

Daw M et al. Hepatitis C Virus: Molecular Pathways and Treatments, 2014.

Presenter
Presentation Notes
Risk behaviors Injection-drug use (current or ever, including those who injected once) Intranasal illicit drug use Risk exposures Long-term hemodialysis (ever) Getting a tattoo in an unregulated setting Healthcare, emergency medical, and public safety workers after needlesticks, sharps, or mucosal exposures to HCV-infected blood Children born to HCV-infected women Prior recipients of transfusions or organ transplants, including persons who: Were notified that they received blood from a donor who later tested positive for HCV infection Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992 Received clotting factor concentrates produced before 1987 Persons who were ever incarcerated  Other HIV infection Unexplained chronic liver disease and/or chronic hepatitis including elevated alanine aminotransferase levels Solid organ donors (deceased and living)

HCV Screening One-time HCV testing recommended for

persons born 1945-1965

AASLD/IDSA HCV Treatment Guidelines 2016.

Risk behaviors• Injection-drug use

(current or ever)• Intranasal illicit drug

use

Risk exposure• Long-term

hemodialysis (ever)• Getting a tattoo in an

unregulated setting• Healthcare workers• Children born to

HCV-infected women• Prior recipients of

transfusions or organ transplants

• Ever incarcerated

Other• HIV infection• Unexplained chronic

liver disease• Solid organ donors

Presenter
Presentation Notes
-Annual screening for persons who inject drugs and HIV-positive MSM unprotected sex -Anti-HCV test is recommended. If positive confirm with sensitive HCV RNA test.

HCV Diagnosis HCV Antibody Tests for exposure Near 100% sensitivity once >6 months after

infection HCV RNA Polymerase Chain Reaction

(PCR) Tests for active infection Helps determine treatment duration

HCV Genotype Defines treatment options Adds prognostic info

AASLD/IDSA Guidelines

HCV Infection Single-stranded RNA virus of the Flaviviridae family Predominantly infects liver cells Six major genotypes, further classified to subtypes US: genotypes 1a and 1b most common

Most patients are asymptomatic and undiagnosed

Extrahepatic manifestations:

Deming P. Chapter 26. Viral Hepatitis. Pharmacotherapy

• Cryoglobulinemia• B-cell non-Hodgkin’s

lymphoma• Sjogren’s syndrome• Glomerulonephritis• Arthritis

• Corneal ulcers• Thyroid disease• Neuropathies• Porphyria cutanea tarda• Insulin resistance• Chronic fatigue

Presenter
Presentation Notes
-lack of a proofreading polymerase and enabling frequent viral mutations no latent reservoir -US followed by 2 and 3 -Symptoms occur 7 weeks after infection , with a range from 3 to 12 weeks. <20% of patients will have symptoms 1/3 of adults will experience some mild nonspecific symptoms: fatigue, anorexia, weakness, jaundice, abdominal pain, or dark urine. -Many patients are screened due to elevated LFTs -Cryo: deposition of immune complexes that causes vasculitis

Natural History of HCV Cirrhosis may take >20 years to

develop in the absence of comorbidities

Factors Impacting Rate of Progression of Fibrosis: Older age Male sex HIV or HBV co-infection Metabolic factors Use of alcohol Genotype 3 infection

www.cdc.gov/hepatitis/HCV

Outline HCV epidemiology and biology HCV Treatment Considerations Currently Available Direct Acting Antivirals

(DAA) DAA medication interactions Current HCV treatment regimens Special Populations

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

Presenter
Presentation Notes
-No longer “high priority to treat” category -Sustained virologic rate (SVR) is considered a virologic cure, defined as continued absence of detectable hcv rna at least 12 weeks after completing therapy- <1% chance of still having the virus -Results of a cure: improved AST, ALT, reduced liver fibrosis, improved portal HTN, splenomegaly, and other clinical manifestations of advanced liver disease, quality of life (physical, emotional, and social health) -Benefits of early treatment: 15-year survival rate improved

Primary Factors when Selecting HCV Treatment1. Genotype2. Degree of fibrosis I.e. Non-cirrhotic vs. cirrhotic

3. Treatment history I.e. Treatment naïve vs. treatment experienced Recommendations may differ depending on

what therapies were used previously (i.e. PEG-IFN vs. DAA-based therapy)

Slide modified courtesy of . Cody Chastain, MD

Secondary Factors when Selecting HCV Treatment Efficacy Relatively equal among recommended regimens

Safety Side effect profile Including need for PEG-IFN or RBV

Drug-drug interactions Access Cost Formulary restrictions

Slide modified courtesy of . Cody Chastain, MD

Released January 29, 2014Last updated July 6th, 2016

Available at www.hcvguidelines.org

www.hcvguidelines.org

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

Presenter
Presentation Notes
-No longer “high priority to treat” category -Sustained virologic rate (SVR) is considered a virologic cure, defined as continued absence of detectable hcv rna at least 12 weeks after completing therapy- <1% chance of still having the virus -Results of a cure: improved AST, ALT, reduced liver fibrosis, improved portal HTN, splenomegaly, and other clinical manifestations of advanced liver disease, quality of life (physical, emotional, and social health) -Benefits of early treatment: 15-year survival rate improved

Benefits of Treatment

Van der Meer AJ et al. JAMA 2012.

Presenter
Presentation Notes
From HCV Guidance: “Numerous studies have demonstrated that hepatitis C therapy and the achievement of an SVR in this population results in dramatic decreases in hepatic decompensation events, hepatocellular carcinoma, and liver-related mortality. (Morgan, 2013); (van der Meer, 2012); (Backus, 2011); (Dienstag, 2011); (Berenguer, 2009); (Mira, 2013) In the HALT-C study, patients with advanced fibrosis secondary to HCV infection who achieved an SVR, compared with patients with similarly advanced liver fibrosis who did not achieve an SVR, had a decreased need for liver transplantation (hazard ratio [HR], .17, 95% confidence interval [CI], .06–.46), development of liver-related morbidity and mortality (HR, .15, 95% CI, .06–.38) and hepatocellular carcinoma (HR, .19, 95% CI, .04–.80).”

Treatment Response in DAA Era

0102030405060708090

100HCV Mono-infection SVR

Modified slide courtesy of Susanna Naggie, MD and Cody Chastain, MD.

Presenter
Presentation Notes
This is a figure representing the various treatment options of HCV over the past 2 decades. As you can see we see a nice increase in SVR rates from pegIFN/RBV to triple therapy with a first wave PI and PR from about 40 to 70% and predicting from publically released data of IFN sparing regimens approximately 90% cure rates in treatment naïve patients. It is exactly this expectation that drives much of our current clinical decision making in HCV therapy.

Outline HCV epidemiology and biology HCV Treatment Considerations Currently Available Direct Acting

Antivirals (DAA) DAA medication interactions Current HCV treatment regimens

HCV Treatment Timeline

• Peg-IFN

• RBV

Pre-2011

• Peg-IFN• RBV• Telaprevir

(Incevik®)• Boceprevir

(Victrelis®)

July 2011 • Peg-IFN• RBV• Telaprevir• Boceprevir• Simeprevir

(Olysio®)• Sofosbuvir

(Sovaldi®)

Nov-Dec 2013

• Peg-IFN• RBV• Telaprevir• Boceprevir• Simeprevir• Sofosbuvir• (Harvoni®) ledipasvir, sofosbuvir

• (Viekira Pak®): parataprevir, ombitasvir, dasabuvir

Oct-Dec 2014

• Peg-IFN• RBV• Boceprevir• Simeprevir• Sofosbuvir• Ledipasvir• Parataprevir• Ombitasvir• Dasabuvir• Daclatasvir

(Daklinza®)

July 2015

• Peg-IFN• RBV• Simeprevir• Sofosbuvir• Ledipasvir• Parataprevir• Ombitasvir• Dasabuvir• Daclatasvir • (Zepatier®):

elbasvir, grazoprevir

• (Epclusa®): velpatasvir, Sofosbuvir

Jan-June 2016

HCV Replication Complex

Morales, J. M. & Fabrizi, F. (2015) Hepatitis C and its impact on renal transplantationNat. Rev. Nephrol. doi:10.1038/nrneph.2015.5

Presenter
Presentation Notes
-lack of a proofreading polymerase and enabling frequent viral mutations 1 polyprotein 10 proteins, 4 structural (C, E1, E2, p7) and 6 nonstructural (NS2, NS3, NS4A, NS4B, NS5A, NS5B)

HCV Therapies by ClassNonspecific Antivirals

• Pegylated interferon-alfa• Ribavirin

NS5B Polymerase Inhibitors (-buvir)

• Sofosbuvir • Dasabuvir

NS3/4A Protease Inhibitors (-previr)

• Telaprevir• Boceprevir• Simeprevir• Paritaprevir• Grazoprevir• Glecaprevir

NS5A Inhibitors (-asvir)

• Ledipasvir • Ombitasvir• Daclatasvir • Elbasvir • Velpatasvir • Pibrentasvir

Presenter
Presentation Notes
NS5B inhibitors cause chain termination of the RNA virus Phosphorylation of NS5A catalyzes the process of RNA replication and viral assembly.

NS3/4A Protease Inhibitors -previr Single tablet regimen Simeprevir (Olysio®)

Combination tablet regimens Paritaprevir (Viekira Pak®)(Viekira XR®)

(Technivie®) Grazoprevir (Zepatier®) Glecaprevir

Simeprevir (SMV; Olysio®) FDA approved on 11/22/13 Indication in combination with sofosbuvir: Genotype 1 and 4 Compensated cirrhosis HIV/HCV coinfection

Dosing: 1 capsule (150mg) daily with food No renal dose adjustment

Reesink HW et al. YGAST 2010. // Moreno C et al. J Hepatol 2012.http://www.hepatitisc.uw.edu

Presenter
Presentation Notes
Drug levels substantially increased in patients with moderate to severe liver dysfunction -2nd gen PI due to enhanced binding affinity -Approved in 2011 with PEGIFN/RBV, approved in 2014 with SOF Once daily with food -Baseline Q80k for 1a -Prego C -Rash, Photosensitivity most common in the first 4 weeks usually

Simeprevir Adverse effects: Rash, pruritus, nausea, photosensitivity, headache,

fatigue, diarrhea, dizziness

Warnings/Precautions Not recommended in moderate or severe hepatic

impairment (Child-Turcotte Pugh (CTP) Class B/C) Sulfonamide moiety

Negatively impacted by GT 1a NS3/4A protease polymorphisms (Q80K) Baseline HCV resistance testing is recommended

Reesink HW et al. YGAST 2010. // Moreno C et al. J Hepatol 2012.http://www.hepatitisc.uw.edu

Presenter
Presentation Notes
Drug levels substantially increased in patients with moderate to severe liver dysfunction -2nd gen PI due to enhanced binding affinity -Approved in 2011 with PEGIFN/RBV, approved in 2014 with SOF Once daily with food -Baseline Q80k for 1a -Prego C -Rash, Photosensitivity most common in the first 4 weeks usually

Simeprevir Drug Interactions

Avoid strong CYP3A4 inhibitors Avoid strong CYP3A4 inducers Contraindicated HIV medications All HIV protease inhibitors Non-Nucleoside Reverse Transcriptase

Inhibitors: efavirenz, etravirine, nevirapine Rosuvastatin: max dose 10mg

Bagwell. Curr Treat Opt Infect Dis 2016

Presenter
Presentation Notes
Not inhibitor of hepatic 3A4

NS5B Polymerase Inhibitors -buvir Single tablet regimen Sofosbuvir (Sovaldi®)

Combination tablet regimens Dasabuvir (Viekira Pak®) (Viekira XR®)

Sofosbuvir (SOF; Sovaldi®) FDA approved on 12/6/13 Coformulated with: Ledipasvir (Harvoni®) Velpatasvir (Epclusa®)

Indication (as Sovaldi® with ribavirin): Genotypes 1-6

Dosing: 1 tablet (400mg) daily with or without food

Lawitz E et al. Lancet Inf Dis 2013. // http://www.hepatitisc.uw.edu

Presenter
Presentation Notes
S282T L159F E341D -Prego B -p-gp inducers: rifampin, St Johns wort

Sofosbuvir Adverse effects: (all ≤10%) Fatigue, headache

Warnings/Precautions: Not recommended with severe renal

impairment (GFR <30 ml/min/1.73m2) Drug interactions: Substrate of P-gp and BCRP Contraindicated with amiodarone

Bagwell. Curr Treat Opt Infect Dis 2016

Presenter
Presentation Notes
S282T L159F E341D -Prego B -p-gp inducers: rifampin, St Johns wort

NS5A Protein Inhibitors -asvir Single tablet regimen Daclatasvir (Daklinza®)

Combination tablet regimens Ombitasvir (Viekira Pak®)(Viekira XR®)

(Technivie®) Ledipasvir (Harvoni®) Velpatasvir (Epclusa®) Elbasvir (Zepatier®) Pibrentasvir

Daclatasvir (DCV; Daklinza®)

FDA approved on 7/24/15 Indication (in combination with sofosbuvir): Genotypes 1 and 3 Compensated cirrhosis Decompensated cirrhosis Transplant recipients

http://www.hepatitisc.uw.edu

Presenter
Presentation Notes
-inhibits viral assempbly

Daclatasvir

Dosing: 1 tablet daily with or without food Typically 60mg daily Dose modification required: 30mg with strong CYP3A4 inhibitors 90mg with moderate CYP3A4 inducers Contraindicated with strong CYP3A inducers

No dose adjustment for renal impairment However, used with sofosbuvir which should be

avoided in CrCl <30ml/min

http://www.hepatitisc.uw.edu

Presenter
Presentation Notes
-inhibits viral assempbly

Ledipasvir/Sofosbuvir (LDV/SOF; Harvoni®) FDA approved on 10/10/14

Indications: Genotypes 1, 4, 5, 6 Liver transplant patients with or without

compensated cirrhosis (GT 1, 4) Decompensated cirrhosis (GT 1) HIV/HCV coinfection

Dosing: LDV 90mg/SOF 400mg tablet daily with or without food

Lawitz E et al. Journal of Hepatology 2012. // http://www.hepatitisc.uw.edu

Ledipasvir/Sofosbuvir Adverse effects: Fatigue, headache, nausea

Warnings/Precautions: Not recommended with severe renal

impairment (GFR <30 ml/min/1.73m2) Drug interactions: Acid reducing agents*** Contraindicated with amiodarone

Bagwell. Curr Treat Opt Infect Dis 2016

FDA approval 2014, 2015, 2016 Paritaprevir (PTV) Class: NS3/4A protease inhibitor coformulated

with ritonavir (RTV or /r) Ombitasvir (OBV) Class: NS5A replication complex inhibitor

Dasabuvir (DBV) Class: NS5B RNA non-nucleoside polymerase

inhibitor

Ombitasvir (OBV)/Paritaprevir (PTV)/ Ritonavir (RTV) +/- Dasabuvir (DBV) (Viekira Pak®, Viekira XR ®, Technivie®)

Bagwell. Curr Treat Opt Infect Dis 2016https://www.hepmag.com/article/abbvies-viekira-pak-works-just-hepatitis-c-drug-resistancehttps://www.hepmag.com/article/fda-approves-oncedaily-hepatitis-c-regimen-viekira-xr

Indications: Genotype 1

RBV used for HCV GT 1A Liver transplant recipients with ≤F2 fibrosis HIV/HCV coinfection OBV/PTVr/DBV: Genotype 4

Dosing: Viekira Pak: 3 tablets in the morning and 1 tablet

in the evening Viekira XR: 3 tablets once daily Technivie: 2 tablets daily with food With food No dose adjustment with renal dysfunction

Ombitasvir (OBV)/Paritaprevir (PTV)/ Ritonavir (RTV) +/- Dasabuvir (DBV)

Bagwell. Curr Treat Opt Infect Dis 2016

Ombitasvir (OBV)/Paritaprevir (PTV)/ Ritonavir (RTV) +/-Dasabuvir (DBV)

Adverse effects: Fatigue, nausea, pruritus, insomnia, asthenia,

skin reactions Warnings/Precautions: Not recommended in moderate/severe hepatic

impairment (CTP Class B/C) Drug Interactions Avoid concomitant ethinyl estradiol therapy Contraindicated with many drugs due to strong

CYP3A inhibition by ritonavir

Bagwell. Curr Treat Opt Infect Dis 2016

Presenter
Presentation Notes
ALT elevation in first 4 weeks- especially in combo with

Elbasvir/Grazoprevir(EBV/GZP; Zepatier®) FDA approved on 1/28/16 Class Elbasvir

NS5A replication complex inhibitor Grazoprevir

NS3/4A protease inhibitor Indications: Genotypes 1 and 4 Renal impairment including those on hemodialysis (HD) HIV/HCV coinfection

Dosing: 1 tablet (EBV 50MG/GZR 100mg) daily with or without food No dose adjustment for renal dysfunction

Requires baseline NS5A resistance testing in genotype 1a

http://www.hepatitisc.uw.eduhttp://www.multivu.com/players/English/7672251-merck-zepatier-fda-approval

Presenter
Presentation Notes
-Baseline polymorphs= 12%

Elbasvir/Grazoprevir Adverse effects: Fatigue, headache, nausea

Warnings/Precautions Not recommended in moderate/severe hepatic

impairment (CTP Class B/C) ALT elevations: Monitor at week 8 of treatment

Drug Interactions: Contraindicated HIV medications All HIV protease inhibitors Non-Nucleoside Reverse Transcriptase Inhibitors:

efavirenz, etravirine, nevirapine Rosuvastatin: do not exceed 10mg

http://www.hepatitisc.uw.edu/

Presenter
Presentation Notes
ALT at week 12 as well for patients taking 16 weeks

Velpatasvir/Sofosbuvir (VEL/SOF; Epclusa®) FDA approved on 6/28/16 Indications: FDA approved for genotypes 1 and 4 with and

without compensated cirrhosis Decompensated cirrhosis (with RBV)

Dosing: 1 tablet (VEL 100mg/SOF 400mg) daily with or without food

http://www.hepatitisc.uw.edu

Presenter
Presentation Notes
-Baseline polymorphs= 12%

Velpatasvir/Sofosbuvir Adverse Effects Common: Headache, fatigue Less common: rash, depression

Warnings/Precautions: Serious symptomatic bradycardia with amiodarone Not recommended with severe renal impairment

(GFR <30 ml/min/1.73m2)

Drug interactions Contraindicated with amiodarone Acid-reducing agents***

http://www.hepatitisc.uw.edu

Presenter
Presentation Notes
-Baseline polymorphs= 12%

Ribavirin FDA approved in 1998 Purine nucleoside analog, complete

mechanism of action unknown FDA approved for GT1-6 Dosing: Weight-based dose adjustment ≥75kg: 1200mg daily <75kg: 1000mg daily

Renal dose adjustment Creatinine Clearance ≤30ml/min: 200mg daily

Take with food

http://www.hepatitisc.uw.edu

Presenter
Presentation Notes
-MOA: augment host T cells clearance of HCV, inhibit host enzyme inosine monophosphate dehydrogenase, hinibits HCV replication, induction of RNA virus mutagenesis

Ribavirin Adverse effects: Hemolytic anemia (black box warning (BBW)),

photosensitivity, pancreatitis, retinopathy, insomnia, fatigue, rash, pruritis

Warnings/Precautions: Teratogenicity up to 6 months following

treatment (BBW) Anemia Hepatic Failure Sensitivity

Drug interactions: Other drugs contributing anemia didanosine

Ribavirin Package Insert

Presenter
Presentation Notes
-MOA: augment host T cells clearance of HCV, inhibit host enzyme inosine monophosphate dehydrogenase, hinibits HCV replication, induction of RNA virus mutagenesis

HCV DAA Monitoring 4 weeks and as indicated CBC Creatinine Calculated GFR Hepatic function panel HCV RNA

If HCV RNA is detectable at week 4, repeat in 2 weeks Zepatier® (EBR/GZR): hepatic function panel at 8 weeks 12 weeks (or end of treatment) HCV RNA

12 weeks after treatment (SVR12) HCV RNA

HBV DNA levels for patients HBsAg + during and after HCV treatment

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

Presenter
Presentation Notes
-10-fold increase in ALT at week 4 should prompt d/c of therapy -Any increase in ALT less than 10-fold at week4 with weakness, nausea, vomiting, jaundice, or increased bili, alk phos, INR should prompt d/c -Asymptomatic ALT increase less than 10-fold should be monitored at week 6 and 8 -If HCV increased at 6 weeks greather than 10-fold, d/c treatment -No official rec to extend or stop therapy if it remains positive, but low -Zepatier: 1% of subjects had AALT >5x ULN at or after week 8

Financial SupportMedication Copay Card* Patient Assistance

Program (for uninsured or underinsured)

Sovaldi™ Yes ($5/month) Support Path™

Olysio™ Yes ($5/month) Janssen Prescription Assistance™

Ribavirin Yes ($5/month - for brand name Moderiba™ only)

AbbVie Patient Assistance Foundation™

Viekira Pak™ Yes ($5) Proceed™

Technivie™ Yes ($5) Proceed™

Daklinza™ Yes ($0 - up to $5000/month)

BMS CONNECT™

Zepatier™ Yes ($5) Merck Access Program™

Epclusa™ Yes ($5) SupportPath™

*Copay Cards are only available to those without government-funded insurance

Grant Funding Grant Patient Cost Information Eligibility

Patient AccessNetwork Foundation (PANF)

$0 https://pharmacyportal.panfoundation.org/Home.aspx

Contact: 1-866-316-7263

-Max of $30,000/year-Reside in US-Income below 400% or 500% FPL-Any insurance

Patient Advocate Foundation (PAF)

$0 https://www.copays.org/diseases/hepatitis-c

Contact: 1-866-512-3861

-Max of $25,000/year-Reside in US-Income below 400% FPL-Any insurance

Chronic Disease Fund (CDF)

Based on poverty percentage-up to $50

http://www.mygooddays.org/for-patients/patient-assistance/

Contact:1-972-608-7141

-Max of $30,000/year-Reside in US-Any insurance, must pay at least 50% of copay-Income below 500% FPL

HealthwellFoundation

$5/fill https://www.healthwellfoundation.org/fund/hepatitis-c/

Contact: 1-800-675-8416

-Max of $30,000/year-Reside in US-Any insurance-Income below 500% FPL

Other Access Resources National Viral Hepatitis Roundtable NVHR.org/hepatitis-c-treatment-acces

Hepatitis C New Drug Research http://hepatitiscnewdrugresearch.com/hcv-drugs-

financial-support.html American Liver Foundation http://hepc.liverfoundation.org/resources/what-if-i-

need-financial-assistance-to-pay-for-treatment/ Life Beyond Hepatitis C http://www.lifebeyondhepatitisc.com/medical-

information/financial-assistance/

Outline HCV epidemiology and biology HCV Treatment Considerations Currently Available Direct Acting Antivirals

(DAA) DAA medication interactions Current HCV treatment regimens Special Populations

HCV Medication Interactions

HEP Drug Interactions

http://hep-druginteractions.org/

HCV Medication Interactions

Acid-reducing agents Anticonvulsants Amiodarone, digoxin Azole antifungals Statins

AASLD/IDSA Guidelines

Outline HCV epidemiology and biology HCV Treatment Considerations Currently Available Direct Acting Antivirals

(DAA) DAA medication interactions Current HCV treatment regimens Special Populations

HCV GT 1a, Treatment Naïve Fibrosis Recommended Treatment Treatment Duration

F0-F3 (Non-cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™)

12 weeks

EBR/GZP (Zepatier™) 12 weeks*LDV/SOF (Harvoni™) 12 weeks**PrOD (Viekira Pak/XR™) + RBV 12 weeks

SOF (Sovaldi™) + SMV (Olysio™)

12 weeks

SOF/VEL (Epclusa™) 12 weeks

* - If no NS5A resistance-associated variants detected. ** - Consider 8 weeks in select patients.

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 1a, Treatment NaïveFibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™)

12 weeks

EBR/GZP (Zepatier™) 12 weeks*LDV/SOF (Harvoni™) 12 weeks**PrOD (Viekira Pak/XR™) + RBV 12 weeksSOF (Sovaldi™) + SMV (Olysio™)

12 weeks

SOF/VEL (Epclusa™) 12 weeksF4 (Cirrhotic)

EBR/GZP (Zepatier™) 12 weeks*LDV/SOF (Harvoni™) 12 weeksSOF/VEL (Epclusa™) 12 weeks

* - If no NS5A resistance-associated variants detected. ** - Consider 8 weeks in select patients.

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 1a, P/R Treatment ExperiencedFibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™)

12 weeks

EBR/GZP (Zepatier™) 12 weeks*LDV/SOF (Harvoni™) 12 weeksPrOD (Viekira Pak/XR™) + RBV 12 weeksSOF (Sovaldi™) + SMV (Olysio™)

12 weeks

SOF/VEL (Epclusa™) 12 weeksF4 (Cirrhotic)

EBR/GZP (Zepatier™) 12 weeks*LDV/SOF (Harvoni™) + RBV 12 weeksSOF/VEL (Epclusa™) 12 weeks

* - If no NS5A resistance-associated variants detected.

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 1b, Treatment NaïveFibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™)

12 weeks

EBR/GZP (Zepatier™) 12 weeksLDV/SOF (Harvoni™) 12 weeks*PrOD (Viekira Pak/XR™) 12 weeksSOF (Sovaldi™) + SMV (Olysio™)

12 weeks

SOF/VEL (Epclusa™) 12 weeks

* - Consider 8 weeks in select patients.

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 1b, Treatment NaïveFibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™)

12 weeks

EBR/GZP (Zepatier™) 12 weeksLDV/SOF (Harvoni™) 12 weeks*PrOD (Viekira Pak/XR™) 12 weeksSOF (Sovaldi™) + SMV (Olysio™)

12 weeks

SOF/VEL (Epclusa™) 12 weeksF4 (Cirrhotic)

EBR/GZP (Zepatier™) 12 weeksLDV/SOF (Harvoni™) 12 weeksPrOD (Viekira Pak/XR™) 12 weeksSOF/VEL (Epclusa™) 12 weeks

* - Consider 8 weeks in select patients.

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 1b, P/R Treatment ExperiencedFibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™)

12 weeks

EBR/GZP (Zepatier™) 12 weeksLDV/SOF (Harvoni™) 12 weeksPrOD (Viekira Pak/XR™) 12 weeksSOF (Sovaldi™) + SMV (Olysio™)

12 weeks

SOF/VEL (Epclusa™) 12 weeksF4 (Cirrhotic)

EBR/GZP (Zepatier™) 12 weeksLDV/SOF (Harvoni™) + RBV 12 weeksPrOD (Viekira Pak/XR™) 12 weeksSOF/VEL (Epclusa™) 12 weeks

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 2: Treatment Naïve

Fibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

SOF/VEL (Epclusa™) 12 weeksAlternative:SOF (Sovaldi™) + DCV(Daklinza™)

12 weeks

F4 (Cirrhotic)

SOF/VEL (Epclusa™) 12 weeksAlternative:SOF (Sovaldi™) + DCV(Daklinza™)

16-24 weeks

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 2: P/R Treatment Experienced

Fibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

SOF/VEL (Epclusa™) 12 weeksAlternative:SOF (Sovaldi™) + DCV(Daklinza™)

12 weeks

F4 (Cirrhotic)

SOF/VEL (Epclusa™) 12 weeksAlternative:SOF (Sovaldi™) + DCV(Daklinza™)

16-24 weeks

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 3: Treatment Naïve

Fibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™)

12 weeks

SOF/VEL (Epclusa™) 12 weeksF4 (Cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™) +/- RBV

24 weeks

SOF/VEL (Epclusa™) 12 weeks

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 3: P/R Treatment Experienced

Fibrosis Recommended Treatment Treatment DurationF0-F3 (Non-cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™)

12 weeks

SOF/VEL (Epclusa™) 12 weeksF4 (Cirrhotic)

DCV (Daklinza™) + SOF (Sovaldi™) + RBV

24 weeks

SOF/VEL (Epclusa™) + RBV 12 weeks

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 4: Treatment Naïve

Fibrosis Recommended Treatment Treatment DurationF0-F4 EBR/GZP (Zepatier™) 12 weeks

LDV/SOF (Harvoni™) 12 weeksPrO (Technivie™) + RBV 12 weeksSOF/VEL (Epclusa™) 12 weeks

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 4: Treatment Experienced

Fibrosis Recommended Treatment Treatment DurationF0-F4 EBV/GZR (Zepatier™)

Previous relapse on Peg-IFN/RBV

12 weeks

EBV/GZR (Zepatier™) + RBVPrior on-treatment virologicfailure

16 weeks

LDV/SOF (Harvoni™) 12 weeksPrO (Technivie™) + RBV 12 weeksSOF/VEL (Epclusa™) 12 weeks

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV GT 5, 6: Treatment Naïve or Experienced

Fibrosis Recommended Treatment Treatment DurationF0-F4 LDV/SOF (Harvoni™) 12 weeks

SOF/VEL (Epclusa™) 12 weeks

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

HCV Pipeline Focus on difficult-to-treat populations Genotype 3 cirrhosis Decompensated cirrhosis End stage renal disease

Shorter duration of treatment Pan-genotypic

https://www.hepmag.com/article/2016-hepatitis-c-treatment-research-pipeline

Outline HCV epidemiology and biology HCV Treatment Considerations Currently Available Direct Acting Antivirals

(DAA) DAA medication interactions Current HCV treatment regimens Special Populations

HIV/HCV Coinfection

Same regimens as used for HCV monoinfection Efficacy similar between HCV monoinfection and

HIV/HCV coinfection populations HIV antiretroviral therapy (ART) should not be

interrupted Special attention to drug-drug interactions Avoid “double dosing” RTV when using RTV-boosted

DAA therapy (i.e. paritaprevir) Adjust DCV dose based on concomitant ART Monitor impact of DAA and ART on TDF

Slide adapted from Cody Chastain, MD.

Renal Impairment and HCV Mild to moderate impairment: CrCl 30- 80ml/min No dose adjustment necessary to currently approved

Direct Acting Antivirals (DAA) Severe impairment: CrCl <30ml/min Considerations for sofosbuvir-containing regimens and

ribavirin Treatment options in clinical practice may differ between

patients with severe renal impairment (CrCl 10-30 ml/min) and those with CKD stage 5 / end stage renal disease (although not differentiated in HCV Guidelines).

AASLD/IDSA HCV Guidelines. www.hcvguidelines.com.

Retreatment of DAA Failures Strongly consider referral to expert HCV treater Treatment approach depends on: Prior DAA regimen Duration of prior DAA regimen Stage of liver disease Prior adherence Drug-drug interactions Baseline and/or acquired resistance-associated

variants (RAVs) Anticipated DAA approvals

Slide adapted from Cody Chastain, MD.

Decompensated Cirrhosis Refer to experienced hepatology and HCV provider,

ideally in at a liver transplant center Avoid HCV therapies that are contraindicated in

decompensated cirrhosis: IFN Telaprevir Boceprevir Simeprevir Paritaprevir/ritonavir/Ombitasvir + Dasabuvir Elbasvir/Grazoprevir

Treatment may impact transplant eligibility and status

Slide adapted from Cody Chastain, MD.

Education and Counseling Transmission Natural history Alcohol and substance use abstinence HAV and HBV vaccination

Available resources Centers for Disease Control American Liver Foundation Veterans Affairs

Brau N. Clin Infect Dis 2013.

HCV Prevention and Screening

No available vaccine Use universal precautions, avoid high-risk

sexual behavior, and avoid IVDU Poor outcomes related to chronic HCV

infection may be reduced by abstaining from alcohol and hepatotoxic medications

Summary HCV treatment has transformed over the past several

years. High efficacy therapies with limited side effects are

available for all genotypes. Select HCV treatment is based on primary (genotype,

stage, treatment experience) and secondary factors. Strongly consider referral of special patient

populations to an expert Though costly, the price of HCV treatment should not

limit prescribing of these medications.

Questions?

Autumn Bagwell, PharmD, BCPS, AAHIVPAutumn.D.Bagwell@vanderbilt.edu

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