update on hepatitis c: new drugs, nuts, bolts, …5/1/17 1 update on hepatitis c: new drugs, nuts,...

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Update on Hepatitis C: New Drugs, Nuts, Bolts, Odds & Ends

Anthony Dalpiaz, PharmD Clinical Pharmacist, Gastroenterology and Hepatology

University of Utah Health

•  No conflicts of interest to disclose.

•  Off-label uses: Brief review of new agents for hepatitis C that may be FDA-approved in 2017. – Voxilaprevir/velpatasivir/sofosbuvir – Glecaprevir/pibrentasvir

Disclosure

At the conclusion of this ac3vity, par3cipants should be able to successfully… 1. List common adverse reac3ons associated with newer treatments for hepa33s C 2. Compare drug-‐drug interac3on risk profiles for available treatments of hepa33s C 3. Assess a pa3ent’s response to treatment of hepa33s C

Learning Objectives: Pharmacists C3FACTSYOU SHOULD KNOW ABOUT

HEPATITISCHepatitis C is aleading cause of liver cancer.

Millions of Americans have hepatitis C, but most don’t know it.

Treatments can eliminate the hepatitis C virus.

Talk to your doctor about getting tested.

It could save your life.

www.cdc.gov/knowmorehepatitis TM

Publication No. 221238

Know More Hepa33s. Centers for Disease Control and Preven3on Web site. Available at: hNps://www.cdc.gov/knowmorehepa33s/. Accessed February 25, 2017.

Know More Hepa33s. Centers for Disease Control and Preven3on Web site. Available at: hNps://www.cdc.gov/knowmorehepa33s/. Accessed February 25, 2017.

•  RNA virus (formerly non-‐A, non-‐B hepa33s) • Most common cause of liver disease •  2.7-‐3.9 million in the US1

•  ~70% born 1945-‐19642 • Minimal symptoms (fa3gue) • Most with chronic HCV not successfully treated •  No vaccine available

Hepatitis C (HCV)

1.  Viral Hepatitis – Hepatitis C Information. Centers for Disease Control and

Prevention Web site. Available at: http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm. Accessed February 25, 2017.

2.  Armstrong GL, et al. Ann Intern Med. 2006;144:705-‐714.

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HCV Genotypes

Zein NN, et al. Ann Intern Med. 1996;125:634-‐639.

21%

•  6 HCV genotypes •  Genotypic prevalence varies

by geography •  Genotype 1 is the most common

in the US •  GT1a = 73% •  GT1b = 27%

US Genotypes

Natural History of HCV Infection

Chen SL, Morgan TR. Int J Med Sci. 2006;3:47-‐52.

*20%-‐30% of individuals are symptoma3c. HCC=hepatocellular carcinoma.

Acute Infec4on* Chronic Infec4on 75%-‐85%

Clearance of HCV RNA 15%-‐25%

HCC 1%-‐4% per

year

Decompensated Cirrhosis

30% at 10 years 5-‐yr survival rate 50%

Cirrhosis 20%-‐30%

20 years

Benefits of Achieving Cure

↓ Cirrhosis ↓ Decompensation

↓ HCC ↓ Transplantation

↓ All-cause mortality Improved QoL

Malignancy Diabetes

CVD Renal

Neurocognitive

Cure: Sustained Virologic Response (SVR)

Improved clinical outcomes[1,2]

Slide credit: clinicaloptions.com 1. Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19.

2. Negro F, et al. Gastroenterology. 2015;149:1345-1360. 3. George SL, et al. Hepatology. 2009;49:729-738.

Hepatic Extrahepatic

Decreased transmission[1]

What Defines HCV Cure?

•  In one study, of those pa3ents who reached SVR, 99% had undetectable levels of HCV RNA more than 4 years afer treatment end3

1. US Department of Health and Human Services, Center for Drug Evalua3on and Research. Draf Guidance for Industry. Chronic Hepa33s C Virus Infec3on: Developing Direct-‐Ac3ng An3viral Drugs for Treatment. October 2013.

2. AASLD, IDSA, IAS-‐USA. Recommenda3ons for tes3ng, managing, and trea3ng hepa33s C. hNp://www.hcvguidelines.org. Accessed February 25, 2017. 3. Swain MG et al. Gastroenterology. 2010;139(5):1593-‐1601.

Cure, also known as sustained virologic response (SVR), is defined as no detectable HCV in the blood at 12 or more weeks afer therapy is complete1,2

I

Cure or sustained virologic response for HCV therapy is defined as?

A.  A nega3ve HCV DNA 24 weeks afer completed treatment B.  A nega3ve HCV RNA 12 weeks afer completed treatment C.  A nega3ve HCV RNA at 4 weeks and end of treatment D.  Normalized liver injury tests 12 weeks afer completed treatment

Question

SVR

(%)

IFN 6 Mos

PegIFN/ RBV

12 Mos

IFN 12 Mos

IFN/RBV 12 Mos

PegIFN 12 Mos

2001 1998

2011 Standard Interferon

Ribavirin

Peginterferon

1991

PegIFN/ RBV + DAA

IFN/RBV 6 Mos

6 16

34 42 39

55 70+

0

20

40

60

80

100

DAA + RBV ± PegIFN

90+ 2013

All–Oral DAA± RBV

Current 95+

All-Oral Therapy

Direct-Acting Antivirals

Slide credit: clinicaloptions.com

Rx and SVR through the years….

Telaprevir Boceprevir

Simeprevir Sofosbuvir

LDV+SOF PrOD PrO DCV+SOF

See References

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Elbasvir + Grazoprevir (GT 1 and 4 pts) Velpatasvir + Sofosbuvir (pan-‐genotypic)

Therapeu4c op4ons for HCV approved in 2016

pibrentasvir + glecaprevir voxilaprevir + velpatasvir + sofosbuvir

Possible new therapeu4c op4ons for HCV in 2017…

•  Ribavirin (RBV)

•  Direct-Acting Antivirals (DAAs) •  NS3/4 Serine Protease Inhibitor •  NS5B RNA-‐Dependent Nucleo3de Polymerase Inhibitor •  NS5A Inhibitor

Mechanism of Action of Drugs to Treat HCV Ribavirin: mechanism

NATURE 2005; 436 (7053): 967

©!!""#!Nature Publishing Group!

!

INSIGHT REVIEW NATURE|Vol 436|18 August 2005

970

ing therapy have been measured using peripheral blood only, whichmight or might not reflect T-cell responses occurring in the liver67.Compartmentalization of relevant HCV responses in the liver mightpartly account for the discrepant results and the lack of clear correlationbetween responses to IFN therapy and T-cell responses to HCV anti-gens. Alternatively, the immunomodulatory effects of IFN-! might beless important than its antiviral effects in treating hepatitis C.

RibavirinInitially synthesized as a guanosine analogue in 1970, ribavirin wasimmediately recognized to possess activity against several RNA andDNA viruses. Ribavirin was first approved for use in humans as a treat-ment for severe respiratory syncytial virus (RSV) infection in children.Its broad antiviral activity led to trials of ribavirin monotherapy for thenewly discovered HCV in the early 1990s. Ribavirin monotherapy wasassociated with improvements in serum aminotransferase levels in atleast half of patients, but viral levels did not change and patients did notclear HCV even with prolonged treatment68,69. Surprisingly, the additionof ribavirin to IFN-! therapy led to marked improvements in SVR rates,increasing the proportion of patients who cleared the virus and alsodecreasing the relapse rate4. Ribavirin was subsequently approved for usein chronic hepatitis C, but only as a combination therapy with IFN-!.

Pawlotsky et al.70 recently reassessed the effects of ribavirinmonotherapy on early viral kinetics. Ribavirin led to a small, early,transient reduction in HCV viraemia in a proportion of patients.When used in combination, ribavirin had no effect on the first andsecond phases of viral kinetics but did reduce the rebound in viral lev-els seen before the second dose of IFN. These effects correlated withribavirin concentration and elimination half-life. Corroborating theimportance of dose, Lindahl et al.71 showed that, if high doses of rib-avirin were used to achieve concentrations of 15 "M, high rates of SVR(90%) could be achieved even in patients with genotype-1 infectionand high viral load. Not surprisingly, toxicity was also greater. Thesestudies illustrate the need to develop ribavirin-like agents that are bet-ter tolerated. How ribavirin augments the response rate to IFN is notknown, but multiple mechanisms have been proposed, each with someexperimental support (Fig. 3).

Direct inhibition of HCV replicationAs a guanosine analogue, ribavirin is phosphorylated intracellularly to

form the monophosphate (RMP), diphosphate (RDP) and triphos-phate (RTP). The misincorporation of RTP by RNA polymerasescould lead to early chain termination and inhibition of replication.Indeed, RTP has been shown to be a weak inhibitor of many viral poly-merases, including that of bovine diarrhoeal virus, a virus closelyrelated to HCV72. Using an HCV RNA-dependent RNA-polymeraseassay, Maag et al.73 showed that RTP was incorporated into nascentviral RNA opposite cytosine or uridine, resulting in a significant blockto RNA elongation. This inhibitory effect was present for polymerasesfrom all six HCV genotypes but required fairly high concentrations(50–150 "M) compared with the concentrations achieved in clinicaluse (10 "M). Thus, although ribavirin might have a small direct effecton HCV-RNA replication through polymerase inhibition, this isunlikely to be its major mechanism of action against hepatitis C.

Inosine-monophosphate-dehydrogenase inhibitionIntracellularly, RMP is a competitive inhibitor of inosine monophos-phate dehydrogenase (IMPDH), which leads to depletion of the GTPnecessary for viral RNA synthesis. In the replicon system, ribavirin andother IMPDH inhibitors (mycophenolic acid and VX-497) partlyinhibit HCV replication. The addition of excess guanosine abolishesthe activity of both mycophenolic acid and VX-497 but only partlyreverses the effects of ribavirin72. These findings are consistent with theminimal effects of ribavirin monotherapy on serum levels of HCVRNA and indicate that IMPDH inhibition and GTP depletion mightcontribute to, but are unlikely to be the major determinants of, theeffects of ribavirin therapy in hepatitis C.

Mutagenesis and error catastropheHCV circulates in serum as many quasispecies (virions with minorgenomic differences). Quasispecies diversity is caused by the high fre-quency of mutations that occur during viral replication owing to the poorfidelity and lack of proofreading activity of the HCV RNA polymerase.Crotty et al.74,75 introduced the concept that ribavirin acts as a viral muta-gen, causing a higher frequency of mutations and pushing viruses towardthe threshold of ‘error catastrophe’. Several findings in vitro and in vivosupport this explanation for the effects of ribavirin in hepatitis C.

In the replicon system, although ribavirin has little effect on levelsof HCV replication, it significantly reduces the efficiency with whichprogeny subgenomic replicons transfect new cells29,76, an indirect

TH1

IFN-γ, TNF-α

Ribavirin

Ribavirin

Hepatocyte

Immunomodulation

RMP RDP RTP

IMP

GMP

GTP

IMPDH

(–)

Inhibition of IMPDH

Replication

HCV RNA RdRp

(–)

RNAmutagen

Inhibition of HCV RdRp RNA mutagenesis

Defective HCVparticles

HCV RNA

es transporter

a

b c d

TH2

CTL

Figure 3 | Proposed mechanisms by which ribavirin could act in HCVinfection. These include a, immunomodulation promoting TH1 over TH2phenotype, b, IMPDH inhibition leading to GTP depletion, c, direct

inhibition of HCV RNA polymerase and d, mutagenesis resulting inreduced virion infectivity. IMPDH, inosine monophosphate dehydrogenase;TH, T helper cell. TNF, tumour necrosis factor.

HCV life cycle

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor binding and endocytosis

Fusion and uncoating

Transport and release

(+) RNA

Translation and polyprotein processing RNA replication

Virion assembly

Membranous web

ER lumen

LD

LD ER lumen

LD

Direct-‐Ac4ng An4viral Agents (DAAs) in HCV

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor binding and endocytosis

Fusion and uncoating

Transport and release

(+) RNA

Translation and polyprotein processing RNA replication

Virion assembly

Membranous web

ER lumen

LD

LD ER lumen

LD

NS3/4 protease inhibitors NS5B polymerase inhibitors

Nucleoside/nucleotide Nonnucleoside

NS5A inhibitors

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•  Combina3on of Direct-‐Ac3ng An3virals (DAAs) +/-‐ Ribavirin (RBV) o NS3/4 + NS5B +/-‐ RBV o NS5B + NS5A +/-‐ RBV o NS5A + NS3/4 +/-‐ RBV o NS3/4 + NS5B + NS5A +/-‐ RBV

•  Dura3on o Range of 8 to 24 weeks o Usually 12 weeks o Extended dura3on 16 to 24 weeks

Ribavirin = reduced relapse Extended treatment dura3on = reduced relapse

What makes up a HCV regimen? FDA-‐Approved Regimens for HCV Infec3on Regimen* Component Classes Approved

Genotypes Simeprevir + sofosbuvir (SMV/SOF) NS3/4 Protease inhibitor + NS5B inhibitor 1 Grazoprevir/elbasvir (GZR/EBR) NS3/4 Protease inhibitor + NS5A inhibitor 1, 4 Paritaprevir/ritonavir/Ombitasvir (PrO) NS3/4 Protease inhibitor + NS5A inhibitor 4 Paritaprevir/ritonavir/Ombitasvir + dasabuvir (PrOD)

NS3/4 Protease inhibitor + NS5A inhibitor + NS5B inhibitor 1

Sofosbuvir + daclatasvir (SOF/DCV) NS5B inhibitor + NS5A inhibitor 1, 3 Sofosbuvir/ledipasvir (SOF/LDV) NS5B inhibitor + NS5A inhibitor 1, 4, 5, 6 Sofosbuvir/velpatasvir (SOF/VEL) NS5B inhibitor + NS5A inhibitor 1, 2, 3, 4, 5, 6

References: product labeling. Slide credit: clinicaloptions.com

*All regimens: +/-‐ Ribavirin depending on specific factors

FDA-‐Approved Regimens for HCV, by Genotype Genotype Regimen* Component Classes

1 Simeprevir + sofosbuvir (SMV/SOF) NS3/4 Protease inhibitor + NS5B inhibitor Grazoprevir/elbasvir (GZR/EBR) NS3/4 Protease inhibitor + NS5A inhibitor Paritaprevir/ritonavir/Ombitasvir + dasabuvir (PrOD)

NS3/4 Protease inhibitor + NS5A inhibitor + NS5B inhibitor

Sofosbuvir + daclatasvir (SOF/DCV) NS5B inhibitor + NS5A inhibitor Sofosbuvir/ledipasvir (SOF/LDV) NS5B inhibitor + NS5A inhibitor Sofosbuvir/velpatasvir (SOF/VEL) NS5B inhibitor + NS5A inhibitor

References Product Labeling Slide credit: clinicaloptions.com


SVR, Genotype 1, naïve

97 100 96 96 95 99

0 10 20 30 40 50 60 70 80 90 100

SVR, naïve

SMV+SOF PrOD+/-‐RBV LDV+SOF DCV+SOF GZR+EBR VEL+SOF

PEARL III PEARL IV OPTIMIST-‐1 ION-‐3 ASTRAL-‐1 ALLY-‐2 C-‐EDGE

1a 92% 1b 98%

1a 97% 1b 100%

SVR (%

)

See References

FDA-‐Approved Regimens for HCV, by Genotype Genotype Regimen* Component Classes

2 Sofosbuvir + Ribavirin NS5B inhibitor + ribavirin Sofosbuvir/velpatasvir (SOF/VEL) NS5B inhibitor + NS5A inhibitor



Genotype Regimen* Component Classes 3 Sofosbuvir + Ribavirin NS5B inhibitor + ribavirin

Sofosbuvir + daclatasvir (SOF/DCV) NS5B inhibitor + NS5A inhibitor Sofosbuvir/velpatasvir (SOF/VEL) NS5B inhibitor + NS5A inhibitor


94 99

0 10 20 30 40 50 60 70 80 90

100

SVR, naïve

SVR %

SOF+RBV VEL+SOF

ASTRAL-‐2

Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infec3on. N Engl J Med. 2015 Dec 31;373(27):2608-‐17.

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84

96 97

0 10 20 30 40 50 60 70 80 90

100

SVR, naïve

SOF+RBV DCV+SOF VEL+SOF

VALENCE ALLY-‐3 ASTRAL-‐3

SVR (%

)

See References

FDA-‐Approved Regimens for HCV, by Genotype Genotype Regimen Component Classes

4 Grazoprevir/elbasvir (GZR/EBR) NS3/4 Protease inhibitor + NS5A inhibitor Paritaprevir/ritonavir/Ombitasvir (PrO) NS3/4 Protease inhibitor + NS5A inhibitor Sofosbuvir/ledipasvir (SOF/LDV) NS5B inhibitor + NS5A inhibitor Sofosbuvir/velpatasvir (SOF/VEL) NS5B inhibitor + NS5A inhibitor


Genotype Regimen Component Classes 5, 6 Sofosbuvir/ledipasvir (SOF/LDV) NS5B inhibitor + NS5A inhibitor

Sofosbuvir/velpatasvir (SOF/VEL) NS5B inhibitor + NS5A inhibitor



100 100 100

0 10 20 30 40 50 60 70 80 90

100

SVR, naïve

PrO+RBV LDV+SOF GZR+EBR VEL+SOF

NIAID SYNERGY ION-‐4 PEARL-‐1 C-‐EDGE TN ASTRAL-‐1

SVR (%

)

See References

SVR, Genotype 5 & 6, naïve

95 96 96 100

0 10 20 30 40 50 60 70 80 90

100

SVR, naïve

LDV+SOF-‐5 VEL+SOF-‐5 LDV+SOF-‐6 VEL+SOF-‐6

ASTRAL-‐1 ASTRAL-‐1 ELECTRON-‐2 LDV/SOF GT5 Study Study 1119

SVR (%

)

See References

All FDA-approved regimens are effective Multiple drug combinations, multiple durations Variables to consider •  Pa3ent characteris3cs •  Concomitant medical issues •  Drug-‐Drug Interac3ons (DDIs) •  Poten3al Toxicity •  Efficacy •  Resistance Associated Subs3tu3ons (RAS), aka Resistance Associated Variants (RAVs)

•  Cost vs Formulary

How do you select a DAA regimen for HCV?

hNp://hcvguidelines.org/ AASLD & IDSA •  Refer to latest HCV guidelines for most up to date recommenda3ons

•  Refer to latest HCV guidelines for the BEST combina3on and dura3on for the individual pa3ent

Selection of DAAs for HCV

AASLD, IDSA, IAS-‐USA. Recommenda3ons for tes3ng, managing, and trea3ng hepa33s C. Available at: hNp://www.hcvguidelines.org. Accessed February 25, 2017.

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hNp://hcvguidelines.org/ •  Genotype •  Level of fibrosis •  Treatment experience •  Unique pa3ent popula3ons

o Decompensated cirrhosis o Post liver transplant o Renal insufficiency o HIV/HCV co-‐infec3on

HCV Guidance: Recommenda4ons for Tes4ng, Managing, and Trea4ng Hepa44s C


•  Genotype: GT3 •  Renal insufficiency • Warnings/Precau3ons of DAAs

•  Cirrhosis, Decompensated cirrhosis •  DDIs •  Reac3va3on of HBV

•  Resistance Associated Subs3tu3ons

HCV treatment challenges

SVR, Genotype 3 – cirrhosis + treatment experienced

62

88 89 96

0 10 20 30 40 50 60 70 80 90

100

SVR, tx exp

SOF+RBV DCV+SOF+RBV VEL+SOF VEL+SOF+RBV

VALENCE ALLY-‐3+ ASTRAL-‐3 Pianko, et al POLARIS-‐4

VOX+VEL+SOF

97

SVR (%

)

HCV treatment challenges: Genotype 3

voxilaprevir + velpatasvir + sofosbuvir

See References SURVEYOR-‐II, Part 3: glecaprevir/pibrentasvir

Slide credit: clinicaloptions.com Wyles DL, et al. AASLD 2016. Abstract 113. Reproduced with permission.

Tx Wks Cirrhosis

Tx Experienced

100

80

60

40

20

0

SV

R12

(%)

91 96 98 96

12 - +

16 - +

12 + -

16 + +

20/22 21/22 39/40 45/47 n/N =

HCV treatment challenges: Genotype 3 SVR, Genotype 3 – cirrhosis + treatment experienced

pibrentasvir + glecaprevir (NS5A inhibitor + NS3/4 inhibitor) voxilaprevir + velpatasvir + sofosbuvir (NS3/4 inhibitor + NS5A inhibitor + NS5B inhibitor)

IMPROVED SVR IN HARD TO TREAT PATIENTS (GT3, CIRRHOSIS) PANGENOTYPIC

Possible new therapeu4c op4ons in 2017 for HCV… HCV treatment challenges: Renal disease

96 94

0 10 20 30 40 50 60 70 80 90 100

SVR

PrOD+/-‐RBV GZR+EBR

RUBY-‐I C-‐SURFER ESRD

§ SMV, LDV, DCV, VEL hepa3cally metabolized

§ Limited data w/ SOF in pts GFR <30

§ Recommended: PrOD/PrO +/-‐ RBV OR GZR+EBR +/-‐ RBV

§ Cau3on w/ RBV à ANEMIA

SVR, Genotype 1, renal


SVR (%

)

glecaprevir + pibrentasvir

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HCV Treatment Challenges DAAs and Warnings/Precau3ons

•  Hepa3c Decompensa3on and Hepa3c Failure in Pa3ents with Decompensated Cirrhosis + NS3/4 Protease Inhibitors

•  DDIs, significant – Risk of reduced therapeu3c effect due to concomitant inducers of CYP and transporters

– Amiodarone – Other significant DDIs

•  Reac3va3on of hepa33s B (HBV)

•  Cirrhosis, compensated (Childs Class A) §  +/-‐ RBV VS Extended treatment dura3on

•  Cirrhosis, decompensated (Childs Class B/C) §  Avoid SMV, GZR+EBR, PrOD, & PrO regimens §  Recommended: VEL+SOF, LDV+SOF or DCV+SOF §  +/-‐ RBV VS Extended treatment dura3on

HCV treatment challenges: Cirrhosis

Protease inhibitor containing regimens are not recommended due to risk of rapidly progressive liver failure and death


Hepa3c Decompensa3on and Hepa3c Failure in Pa3ents with Decompensated Cirrhosis + NS3/4 Protease Inhibitors

•  DDIs, significant (www.hep-‐druginterac3ons.org/) – Risk of reduced therapeu3c effect due to concomitant inducers of CYP and transporters •  St John’s Wort •  rifampin • phenobarbital, carbamazepine, phenytoin (others)

– Amiodarone: serious symptoma3c bradycardia – Other significant DDIs

HCV treatment challenges: DDIs

HEP Drug Interac3ons. HEP Drug Interac3on Checker. Available at: hNp://hep-‐druginterac3ons.org. Accessed February 25, 2017.

•  Other significant DDIs (www.hep-‐druginterac3ons.org/) – Herbals/supplements – Enzyme/transporter à inhibitors

§ Sta3ns § HIV an3-‐retrovirals

– PPIs/H2RAs/antacids

HCV treatment challenges: DDIs, significant


•  Other significant DDIs (www.hep-‐druginterac3ons.org/) – Enzyme/transporter à inhibitors

§ Sta3ns o Atorvasta8n: avoid with PrOD/PrO; max 20mg/day with GZR/EBR; max 40mg/day with SMV

o Fluvasta8n, Lovasta8n, Pitavasta8n, Simvasta8n: avoid with PrOD/PrO

o Pravasta8n: max 40mg/day with PrOD/PrO o Rosuvasta8n: avoid with LDV; max 10mg/day with SMV, VEL, PrOD/PrO, GZR/EBR

HCV treatment challenges: DDIs, significant


DAAs and DDIs: CYP, transporters Drug Substrate Inhibitor Simeprevir 3A4 1A2, 3A4 (intestinal), Pgp,

OATP1B1/3 Velpatasvir Pgp, BCRP, 2B6, 2C8, 3A4 Pgp, BCRP, OATP1B1/3, OATP2B1

Sofosbuvir Pgp, BCRP Ledipasvir Pgp, BCRP Pgp, BCRP Ombitasvir Pgp, BCRP UGT1A1 Paritaprevir 3A4, Pgp, BCRP,

OATP1B1/3OATP1B1/3, BCRP, UGT1A1

Dasabuvir 2C8, Pgp, BCRP UGT1A1, BCRP Ritonavir 3A4, Pgp 3A4, BCRP, 2C8, 2D6 Daclatasvir 3A Pgp, OATP1B1/3, BCRP Elbasvir 3A, Pgp Pgp (weak), BCRP Grazoprevir 3A, Pgp, OATP1B1/3 3A (weak), BCRP HEP Drug Interac3ons. HEP Drug Interac3on Checker. Available at: hNp://hep-‐druginterac3ons.org. Accessed February 25, 2017.

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•  pH dependent absorp3on: Ledipasvir, Velpatasvir •  Increased pH = decreased AUC PPIs

o  Ledipasvir: Simultaneously w/ equivalent omeprazole 20mg once daily o  Velpatasvir: Not recommended. If medically necessary, administer w/ food 4 hours prior to equivalent omeprazole 20mg once daily

H2RA o  Simultaneously w/ OR 12 hrs apart (max equivalent famo3dine 40mg twice daily)

Antacids o  Separate 4 hrs

DAAs and DDIs: pH

www.harvoni.com www.epclusainfo.com

of clinical characteristics following the matching proce-dures. Overall, the propensity score yielded PPI andnon-PPI cohorts that were well balanced. However,among PPI recipients there were more patientsobserved at academic practices (57.6% vs. 49.4%) andthose with decompensated cirrhosis (4.5% vs. 1.3%).After propensity score matching, SVR12 rates were nodifferent as a function of PPI use, irrespective of treat-ment duration. In the matched cohort, patients receiv-ing daily PPI (n 5 410) experienced SVR12 97.8%(96.4-99.2) of the time whereas those receiving PPItwice-daily (n 5 34) experienced an SVR12 rate of91.1% (81.5-100.0). Patients not taking PPI (n 5443) experienced SVR 97.2% (95.7-98.7). of the time.Multiple logistic regressions were performed to ascer-

tain the effect of PPI use on SVR in cohorts matchedbased on propensity scores for any PPI use (see Table2). Results of the adjusted regression analyses aredetailed in Table 3. Among patients matched on theirpropensity to receive any PPI, neither PPI use overallnor high-dose or twice-daily PPI was associated withSVR12. Sensitivity analyses were performed by restrict-ing the matched cohort to patients with cirrhosis andPPI users who refilled their PPI prescriptions through-out treatment (Table 3). When restricted to patientswith cirrhosis, it appears that twice-daily PPI use maybe associated with lower SVR12 rates (odds ratio [OR],

0.11; 95% CI, 0.02-0.59), albeit with P 5 0.05. A sepa-rate sensitivity analysis was performed by matching thecohort using a propensity score conditioned on high-dose PPI use instead of any daily PPI use. After match-ing based on the propensity to receive high-dose PPIuse, there were no significant effects on SVR12 fromany PPI use, high-dose PPI use, or twice-daily PPI use,with respective SVR12 rates of 98.7% (95% CI, 97.5-100), 100% (95% CI, 100-100), and 97.8% (95% CI,93.6-100). After multivariable regression, no significantdifferences in SVR12 rates were detected.

DiscussionWe sought to determine the effect of PPI therapy

on LDV/SOF effectiveness given the biological plausi-bility—decreased absorption of ledipasvir at highergastric pH—and the decreased SVR rate attributed toPPI therapy in a report from the HCV-TARGET.This study of 1,979 patients from a real-world cohortwith chronic HCV treated with LDV/SOF clarifiesthe relationship between PPI and SVR. First, we showthat PPI usage overall is not associated with SVR, irre-spective of treatment duration. Second, we demon-strate an unadjusted association between twice-dailyPPI use and decreased SVR that is no longer signifi-cant after adjustment for propensity to receive PPIs.These data extend the prior literature on the real-

world outcomes of HCV with highly effective DAAsin multiple ways. First, the SVR rates observed in this

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

FIG. 2. Predictors of SVR: univariate associations. The dottedline indicates the overall sustained virological response rate(97.9%) in the per-protocol analysis.

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

TABLE 2. Clinical Characteristics of the Propensity-Matched Cohorts

PPI(n 5 444)

No PPI(n 5 443) P Value

Male sex (n, %) 254 (57.2) 273 (61.6) 0.18Age (mean 6 SD) 60.1 (8.5) 60.0 (9.8) 0.09BMI mean (median IQR) 28.2 (25-32.1) 27.5 (24.2-31.4) 0.37Caucasian (n, %) 373 (84.0) 353 (79.6) 0.09Treatment na€ıve (n, %) 229 (51.5) 244 (55.0) 0.30Diabetes (n, %) 84 (20.1) 67 (16.5) 0.17HIV (n, %) 22 (4.9) 26 (5.8) 0.55HBV (n, %) 4 (0.9) 3 (0.7) 0.18Posttransplant (n, %) 24 (5.4) 13 (2.9) 0.07Platelets <100K (n, %) 83 (18.6) 82 (18.5) 0.94Cirrhosis (n, %) 180 (40.5) 155 (35.0) 0.09Decompensated (n, %) 17 (4.5) 5 (1.3) 0.009Academic practice (n, %) 256 (57.6) 219 (49.4) 0.018-week regimen (n, %) 41 (9.2) 41 (9.2) 1.012-week regimen (n, %) 294 (66.2) 294 (66.3)24-week regimen (n, %) 109 (24.5) 108 (24.3)

Patients were matched 1:1 based on a propensity score condi-tioned on the receipt of PPIs.Abbreviation: K, thousand.

HEPATOLOGY, Vol. 00, No. 00, 2016 TAPPER ET AL.

5

Simultaneously w/ once daily PPI

LDV/SOF + PPI

Hepatology 2016 Dec; 64(6): 1893-‐1899.

www.harvoni.com

VEL/SOF + PPI: Avoid if possible

2

In the absence of a large clinical dataset for the use of SOF/VEL with PPI, a more cautious approach may be warranted. The Agency and the applicant have reached the following agreements:

• Allow coadministration of omeprazole with SOF/VEL only when it is medically necessary.o In ASTRAL 3, VEL AUC exposures were 30% lower in relapsers compared to

non-relapsers. Thus, even this degree of decrease in VEL AUC may be problematic.

o Since SOF/VEL is administered under fed conditions and omeprazole should be administered under fasted conditions (based on recommendations in the omeprazole label), there is concern over the practicality of dosing in the real world when a patient needs to consider the dose of omeprazole to take (20 mg), time of day to take two different drugs (SOF/VEL 4 hours before omeprazole), and prandial condition of each drug administration. In considering the worst case scenario, there were significant decreases in exposure for both SOF and VEL that could impact efficacy for patients with any HCV genotype.

• SOF/VEL should not be used with other PPIs, because the use of SOF/VEL with other proton pump inhibitors has not been studied.

• SOF/VEL should be administered with food and taken 4 hours before omeprazole 20 mg, because the impact of omeprazole on VEL is relatively less as compared to when omeprazole is administered 2 hours ahead of SOF/VEL as shown in the following table. There is 33% and 28% reduction on VEL Cmax and AUC, respectively, as compared to that when SOF/VEL is administered under fasted conditions without omeprazole. Because administration of SOF/VEL with a high-fat/high-calorie or a moderate-fat/moderate-calorie meal resulted in a 21% and 34% increase in VEL AUC, and SOF/VEL can be given with or without food, for patients who take SOF/VEL under fed conditions, the true effect of omeprazole on VEL exposures could actually be more.

Therefore, use of omeprazole or other PPIs with SOF/VEL is not recommended unless medically necessary.

Drug Interactions: Changes in Pharmacokinetic Parameters for Velpatasvir in the Presence of Omeprazole

Mean Ratio (90% CI) of Velpatasvir PK With/Without Coadministered Drug

No Effect=1.00Dose of

Omeprazole(mg)

SOF Dose(mg)a

VEL Dose(mg)a N Cmax AUC

20 once daily 2 hours prior to

SOF/VEL

400 single dose fed

100 single dose fed 40 0.52 (0.43, 0.64) 0.62 (0.51, 0.75)

20 once daily 4 hours after SOF/VEL

400 single dose fed

100 single dose fed 38 0.67 (0.58, 0.78) 0.74 (0.63, 0.86)

a SOF/VEL was administered under fasted conditions in the reference arms.

Reference ID: 3947635

(b) (4)

ê38%

ê26%

hNps://www.accessdata.fda.gov/drugsawda_docs/nda/2016/208341Orig1s000ClinPharmR.pdf

True or False: Velpatasvir should be administered simultaneously with omeprazole 40mg po once daily.

Question

HCV Treatment Challenges DAAs and Warnings/Precau3ons

•  Reac3va3on of hepa33s B (HBV) – Reported cases of acute eleva3on of liver injury tests – Resulted in deaths, transplant, hospitaliza3ons, and DAA discon3nua3ons

– Occurs within week 4 to 8 – Screen for baseline HBV status (an3-‐HBs, HBsAg, an3-‐HBc total, DNA?)

•  If all (-‐) à Vaccinate •  If any (+) à Treat HBV (if indicated) and monitor livery injury tests monthly

– Monitor


NS5A: Presence of baseline polymorphisms at amino acid posi3ons 28, 30, 31, or 93 •  Genotype 1a: GRZ+EBR

o  (+) RAS: add RBV, 16 wks dura3on o  (-‐) RAS: no RBV, 12 wks dura3on

NS5A: Presence of baseline polymorphisms at amino acid posi3on Y93 •  Genotype 3, cirrhosis OR treatment experienced: VEL+SOF (probably DCV+SOF)

o  (+) RAS: add RBV o  (-‐) RAS: no RBV needed

HCV treatment challenges: RAS (baseline)


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Drug/Regimen

Headache Fa4gue Nausea Loose stools

OTHER

SOF+RBV 24-‐30% 30-‐38% 13-‐22% 9-‐12% Pruritus 11-‐27%, Insomnia 15-‐16%

SMV+SOF 17-‐23% 16-‐32% 13-‐14% 6-‐16% Photosensi3vity and rash 12-‐16%

PrOD/PrO 7% 8-‐9% Pruritus 5-‐7%, rash 7%, insomnia 5%, asthenia 4-‐25%

GZR+EBR 7-‐10% 7-‐11% 5% 5% Insomnia 5%

LDV+SOF 11-‐17% 13-‐18% 6-‐9% 3-‐7% Insomnia 3-‐6%

VEL+SOF 22% 15% 9% Asthenia 5%, insomnia 5%

DCV+SOF 8-‐14% 14-‐15% 8-‐9% 5-‐7%

DAAs and tolerability ADRs generally mild (w/o RBV)

The most commonly reported side effect with grazoprevir + elbasvir therapy is? A.  Pruritus B.  Hemoly3c anemia C.  Fa3gue D.  Photosensi3vity

Question

•  Adherence o  Taking correctly o  Missed doses o  Refill history

•  Safety o  Side effects o  Laboratory Assessment

ü CBC, creatinine, and hepatic function at 4 wks and if clinically indicated ü hepatic function more frequently with GZR+EBR or PrOD/PrO ü CBC every 2 to 4 wks with RBV

•  Efficacy o  Assess HCV PCR periodically (week 4 and 12 wks post treatment) o  Goal is SVR (cure)

DAAs: Monitoring and follow-up


•  Adherence o  Take correctly, same time each day o  Do not miss doses o  Refills on time o  Avoid supplements, herbals, etc o  Adhere to instructions with pH altering medications

•  Safety o  Drug-drug interactions o  Side effects are usually mild (if any) o  Reassurance!! o  Labs are important

•  Efficacy o  Cure will be assessed 12 weeks after treatment completed o  Yes HCV can be cured

Pharmacist involvement in HCV therapy

•  Medication access –  Refills –  Copay cards, patient assistance, PAN Foundation (https://panfoundation.org/) –  If hospitalized… take HCV medications to the hospital

•  Encourage HCV screening in high-risk population •  Motivate patients to seek treatment, high rate of cure •  Immunize!!

–  Hepatitis A, Hepatitis B –  Pneumococcal –  Influenza

Pharmacist involvement in HCV therapy

Helpful online HCV references: •  hNp://www.hep-‐druginterac3ons.org •  hNp://www.hepa33sc.uw.edu •  hNps://www.clinicalop3ons.com/Hepa33s.aspx •  hNp://www.cdc.gov/hepa33s/HCV/HCVfaq.htm •  hNp://www.hcvguidelines.org

Questions?

Update on Hepatitis C: New Drugs, Nuts, Bolts, Odds & Ends

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References: Rx and SVR through the years…. Manns MP, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347:975-982. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. Ferenci P, et al. N Engl J Med. 2014;370:1983-1992. Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Kwo P, et al. EASL 2015. Abstract LB14. Zeuzem S, et al. Ann Intern Med. 2015;163:1-13. Feld JJ, et al. N Engl J Med. 2015;373:2599-2607. Foster GR, et al. N Engl J Med. 2015;373:2608-2617.

•  OPTIMIST-‐1: Kwo P, Gitlin N, Nahass R, et al. Simeprevir Plus Sofosbuvir (12 and 8 Weeks) in HCV Genotype 1-‐Infected Pa3ents Without Cirrhosis: OPTIMIST-‐1, a Phase 3, Randomized Study. Hepatology. 2016 Jan 22.

•  PEARL-‐III: Ferenci P, Bernstein D, Lalezari J, et al. ABT-‐450/r-‐ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-‐92.

•  PEARL-‐IV: Ferenci P, Bernstein D, Lalezari J, et al. ABT-‐450/r-‐ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-‐92.

•  ION-‐3: Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879-‐88.

•  ALLY-‐2: Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in pa3ents coinfected with HIV-‐1. N Engl J Med. 2015;373:714-‐25.

•  C-‐EDGE TN: Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-‐Elbasvir Combina3on Therapy for Treatment-‐Naive Cirrho3c and Noncirrho3c Pa3ents With Chronic Hepa33s C Virus Genotype 1, 4, or 6 Infec3on: A Randomized Trial. Ann Intern Med. 2015;163:1-‐13.

•  ASTRAL-‐1: Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infec3on. N Engl J Med. 2015;373:2599-‐607.

References: SVR, Genotype 1, naive

•  VALENCE: Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014 May 22;370(21):1993-‐2001.

•  ALLY-‐3: Nelson DR, Cooper JN, Lalezari JP, et al. All-‐oral 12-‐week treatment with daclatasvir plus sofosbuvir in pa3ents with hepa33s C virus genotype 3 infec3on: ALLY-‐3 phase III study. Hepatology. 2015 Apr;61(4):1127-‐35.

•  ASTRAL-‐3: Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infec3on. N Engl J Med. 2015 Dec 31;373(27):2608-‐17.

References: SVR, Genotype 3, naïve •  PEARL-‐1: Hézode C, Asselah T, Reddy KR, et al. Ombitasvir plus paritaprevir plus

ritonavir with or without ribavirin in treatment-‐naive and treatment-‐experienced pa3ents with genotype 4 chronic hepa33s C virus infec3on (PEARL-‐I): a randomised, open-‐label trial. Lancet. 2015;385:2502-‐9.

•  NIAID SYNERGY (genotype 4): Kohli A, Kapoor R, Sims Z, et al. Ledipasvir and Sofosbuvir for Hepa33s C Genotype 4: A Proof of Concept Phase 2a Cohort Study. The Lancet Infec8ous diseases. 2015;15(9):1049-‐1054.

•  ION-‐4: Naggie S, Cooper C, Saag M, et al. Ledipasvir and Sofosbuvir for HCV in Pa3ents Coinfected with HIV-‐1. The New England journal of medicine. 2015;373(8):705-‐713.

•  C-‐EDGE TN: Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-‐Elbasvir Combina3on Therapy for Treatment-‐Naive Cirrho3c and Noncirrho3c Pa3ents With Chronic Hepa33s C Virus Genotype 1, 4, or 6 Infec3on: A Randomized Trial. Ann Intern Med. 2015;163:1-‐13.


References: SVR, Genotype 4, naïve

•  LDV GT5 Study: Abergel A, Asselah T, Me3vier S, Kersey K, Jiang D, Mo H, Pang PS, Samuel D, Loustaud-‐Raz V. Ledipasvir-‐sofosbuvir in pa3ents with hepa33s C virus genotype 5 infec3on: an open-‐label, mul3centre, single-‐arm, phase 2 study. Lancet Infect Dis. 2016 Apr;16(4):459-‐64.


•  ELECTRON-‐2: Gane EJ, Hyland RH, An D, Svarovskaia E, Pang PS, Brainard D, Stedman CA. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in pa3ents with HCV genotype 3 or 6 infec3on. Gastroenterology. 2015 Nov;149(6):1454-‐1461.

References: SVR, Genotype 5 & 6, naïve

•  VALENCE: Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014 May 22;370(21):1993-‐2001.

•  ALLY-‐3+: Leroy V, Angus P, Bronowicki JP, Dore GJ, et al. Daclatasvir, sofosbuvir, and ribavirin for hepa33s C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-‐3+). Hepatology. 2016 May;63(5):1430-‐41.

•  ASTRAL-‐3: Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infec3on. N Engl J Med. 2015 Dec 31;373(27):2608-‐17.

•  Pianko S, Flamm SL, Shiffman ML, et al. Sofosbuvir Plus Velpatasvir Combina3on Therapy for Treatment-‐Experienced Pa3ents With Genotype 1 or 3 Hepa33s C Virus Infec3on: A Randomized Trial. Ann Intern Med. 2015 Dec 1;163(11):809-‐17.

•  POLARIS-‐4: Zeuzem S, et al. AASLD 2016. Abstract 109.

References: SVR, Genotype 3 – cirrhosis + treatment experienced

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•  RUBY-‐I: Pockros PJ, Reddy KR, Mantry PS, et al. Efficacy of Direct-‐Ac3ng An3viral Combina3on for Pa3ents With Hepa33s C Virus Genotype 1 Infec3on and Severe Renal Impairment or End-‐Stage Renal Disease. Gastroenterology. 2016 Jun;150(7):1590-‐8.

•  C-‐SURFER: Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-‐naive and treatment-‐experienced pa3ents with hepa33s C virus genotype 1 infec3on and stage 4-‐5 chronic kidney disease (the C-‐SURFER study): a combina3on phase 3 study. Lancet. 2015 Oct 17;386(10003):1537-‐45. Erratum in: Lancet. 2015 Nov 7;386(10006):1824.

References: HCV Renal disease

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