hepatitis c treatment in patient- specific populations yemm hepatitis... · ©2016 mfmer | slide-1...

©2016 MFMER | slide-1

Hepatitis C Treatment in Patient-Specific PopulationsKristyn E. Yemm, PharmDPGY1 Pharmacy ResidentPharmacy Grand RoundsMay 10, 2016


Presentation Objectives• Identify a guideline-based approach to select an

appropriate regimen in patients diagnosed with hepatitis C virus

• Discuss treatment options for hepatitis C virus in patients with renal dysfunction

• Review hepatitis C virus treatment strategies in compensated versus decompensated cirrhosis


Complications of Acute Hepatitis C Virus (HCV) Infection

AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed April 20, 2016.http://www.cdc.gov/hepatitis/C/cFAQ.htm#statistics. Accessed April 20, 2016.

N Engl J Med 2009; 361: 1279-90.

75-85% 60-70% 5-20% 20-40% 50%

Chronic Infection Chronic Liver Disease Cirrhosis Hepatorenal

Syndrome Mortality

Transplant


Which of the following should be considered prior to choosing a HCV therapeutic regimen?1. Genotype2. Degree of liver disease3. Cost/adherence4. Comorbidities5. Potential drug-drug interactions6. All of the above


Choosing a HCV Therapeutic Regimen

Liver stagingFibrosis Cirrhosis

Comorbidities

Potential drug interactions

Cost and adherence

Genotype1a, 1b, 2, 3, 4, 5, 6

AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed April 20, 2016.HCV: Hepatitis c virusAASLD-IDSA: American Association for the Study of Liver Disease - Infectious Disease Society of America


End Stage Renal Disease (ESRD) and Hemodialysis (HD) Treatment StrategiesPart 1: HCV Specific Populations


Accelerates the decline in kidney

dysfunction

Mortality

#1 Cause of post renal

transplant liver disease

J Viral Hepat 2012; 19: 601-07.Am J Transplant. 2005 Oct;5(10):2433-40.


Choosing a HCV Therapeutic Regimen for ESRD and HD

Kidney transplant candidacy

Benefits and risks of HCV therapy

Comorbidities

Life expectancy

Kidney Int Suppl. 2008 Apr;(109):S1-99.ESRD: End-stage renal diseaseHD: Hemodialysis


Historical Complications to Antiviral Treatment in ESRD/HD• Suboptimal treatment efficacy• Lack of evidence• Toxic accumulation of renal metabolites• Intolerable side effect profile

ESRD: End-stage renal diseaseHD: Hemodialysis


HCV Standard of Care in ESRD/HD Prior to February 2016

33

56

0

10

20

30

40

50

60

70

80

90

100

PEG-IFN PEG-IFN + RVN

Perc

enta

ge

SVR

Ann Intern Med. 2013;159:729-738.

30% Discontinued

Treatment

22% Discontinued

Treatment

PEG-IFN: Pegylated interferon RVN: RibavirinSVR: Sustained virologic response = undetectable HCV RNA (<15IU/mL) after completion of therapy


Side Effect Profile PEG-IFN

• Rash

• Flu-like symptoms

• HA/Fatigue

• Arthralgia/myalgia

• Paresthesias

• Dysgeusia

• Mood changes

• Cytopenias (Hgb, ANC, Plt)

RBV

• Rash

• HA/Fatigue

• Anorexia

• Depression

• Anemia

• Hyperuricemia


HCV Treatment Limitations in ESRD/HD

Renally Cleared Metabolites

• Sofosbuvir

• Ribavirin

Adverse Reactions

• Poorly tolerated• Pegylated interferon

• Life-threatening• Ribavirin

Ann Intern Med. 2013;159:729-738.


Patient Case CK is a 58yoM diagnosed with genotype 1a HCV

PMH: seasonal allergies, ESRD on HD M/W/F secondary to mixed cryoglobulinemia syndrome

SH: alcohol dependence

Medications:

-fluticasone 2 sprays in each nostril QD -vitamin D3 2000un po QD

-ferrous sulfate 325mg po QD -calcium acetate 667mg po TID

What HCV treatment options are available for the patient?


Updated Recommendations: ESRD/HDAfter February 2016

Genotype Regimen

1a, 1b, 4 elbasvir 50mg/grazoprevir 100mg(Zepatier®) for 12 weeks

2, 3, 5, 6 PEG-IFN and dose-adjusted RBV at 200mg daily for 48 weeks

*RBV should be discontinued if hemoglobin level declines by more than 2 g/dL despite the use of erythropoietin

ESRD: End-stage renal diseaseHD: HemodialysisPEG-IFN: Pegylated interferon RVN: Ribavirin

Lancet 2015; 386: 1537–45.Ann Intern Med. 2013;159:729-738.


Approval of Zepatier®

C-SURFER TrialDesign Phase 3, international, multicenter, double-blind study

Methods

Randomized 1:1Treatment: elbasvir 50mg/grazoprevir 100mg

(Zepatier®) once dailyControl: Placebo

Observational efficacy

Outcomes Non-randomized comparison of SVR at 12 weeks vs. historical control SVR12 of 45%

Safety Increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST)

Lancet 2015; 386: 1537–45.


C-SURFER Results99.1

94.3

0

10

20

30

40

50

60

70

80

90

100

Modified Full Analysis Full analysis

Perc

enta

ge SVR

Lancet 2015; 386: 1537–45.Modified Full Analysis: Immediate treatment of intensive pharmacokinetic groupFull Analysis: All patients who received at least one dose

0-4.4% Discontinued

Treatment

HeadacheNauseaFatigue

Side EffectsSide Effects


C-SURFER Trial Strengths and Limitations

Strengths

• 75% on Hemodialysis

• Historical SVR control

• Treatment naïve and failed treatment

• Potential to increase waitlist for kidney transplant candidacy

Limitations

• Small population

• 6% cirrhosis in population

• Lacking active comparator

• Unclear long term adverse effect profile

Lancet 2015; 386: 1537–45.


Zepatier® SVR Comparison to Previous Standard of Care

99

56

33

0

10

20

30

40

50

60

70

80

90

100

Zepatier® PEG-IFN + RBV PEG-IFN

Perc

enta

ge

SVR

Lancet 2015; 386: 1537–45.Modified Full Analysis: Immediate Treatment of Intensive Pharmacokinetic Group

43%

incr

ease

66%

incr

ease


Which HCV treatment regimen would be most appropriate for CK?1. Sofosbuvir containing regimen2. PEG-IFN monotherapy for 48 weeks3. PEG-IFN + dose adjusted RBV for 48 weeks4. Zepatier® once daily for 12 weeks


Compensated versus Decompensated Cirrhosis Treatment StrategiesPart 2: HCV Specific Populations


Progression of Liver Dysfunction

• Progressive hepatic fibrosis

Child Turcotte Pugh Class AChild Turcotte Pugh Class A

CTP: Child Turcotte PughSBP: Spontaneous bacterial peritonitis

Child, CG, III, Turcotte, JG. Surgery and Portal Hypertension. In: The Liver and portal hypertension, Child, CG III (Eds), WB Saunders, Philadelphia 1964. p.50.

• Variceal hemorrhage

• Ascites• SBP• HE• HCC• Hepatorenal

syndrome

Child Turcotte Pugh Class B/CChild Turcotte

Pugh Class B/C

HCC: Hepatocellular carcinomaHE: Hepatic encephalopathy

Decompensated Cirrhosis


Patient Case Revisited CK is a 58yoM diagnosed with genotype 1a HCV

PMH: seasonal allergies, ESRD on HD M/W/F secondary to mixed cryoglobulinemia syndrome

SH: alcohol dependence

***CK now has compensated liver disease due to his persistent alcohol consumption***

Medications:

-fluticasone 2 sprays in each nostril QD -vitamin D3 2000un po QD

-ferrous sulfate 325mg po QD -calcium acetate 667mg po TID

What HCV treatment options are available for the patient?


0102030405060708090

100

PEG-IFN + RBV PEG-IFN + RBV +PI

IFN Sparing IFN Free

Sustained Virologic Response (%)

All values percentage of sustained virologic responsePI: Protease inhibitorIFN Sparing: Combination with polymerase inhibitor

Lancet 2015; 385: 1124-35.

2001Timeline

40-50

> 90

50-60

80-91

2011 2014 2015


Key Viral Replication Targets in Genotype 1• NS3/4A protease inhibitors

• Simeprevir• Paritaprevir• Boceprevir• Telaprevir• Grazoprevir

• NS5A protein inhibitors viral replication/assembly

• Ledipasvir• Ombitasvir• Elbasvir

• NS5B polymerase inhibitors• Sofosbuvir (prodrug)• Dasabuvir• Ribavirin

• Immunomodulators• PEG-IFN• Ribavirin

• Ritonavir is a potent CYP3A inhibitor

• Increases peak and trough plasma drug concentrations of paritaprevir

Lancet 2015; 385: 1124-35.


MOA ImmunomodulatorsPEG-IFN• Bind to specific receptors on the

surface of human cells

• Inhibition of virus replication in virus-infected cells

• Suppression of cell proliferation

• Enhancement of the phagocytic activity of macrophages

RBV• Inhibits the initiation and

elongation of RNA fragments resulting in inhibition of viral protein synthesis


Historical Complications to Antiviral Treatment Selection in Liver Dysfunction• Suboptimal treatment efficacy • Intolerable side effect profile• Treatment duration• Numerous drug-drug interactions• High pill burden with frequent dosing• PEG-IFN based regimens can worsen

decompensated cirrhosis


Compensated Cirrhosis: Treatment Naïve 1st Line Therapies

Genotype 1a

• Zepatier® 50mg/100mg*

• ledipasvir 90mg/sofosbuvir 400mg (Harvoni®)*

Genotype 1b

• Zepatier® 50mg/100mg*

• Harvoni® 90mg/400mg*

• paritaprevir 150mg/ritonavir 100mg/ombitasvir 25mg + BID dasabuvir 250mg (Viekira Pak®)*

*Treatment duration 12 weeksAASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed April 20, 2016.


Compensated Cirrhosis: Treatment Naïve 1st Line Therapies SVR12

0

10

20

30

40

50

60

70

80

90

100

Zepatier® Harvoni® Viekira Pak®

SVR

Lancet 385(9973):1087-97.N Engl J Med. 2014a;370(20):1889-1898.

N Engl J Med 2014;370:1973-1982.PHAST Patient Monthly, Dec 2014-Aug 2015, Extracted Oct 2015.

92-99 97-9989-95

HeadacheNauseaFatigue

HeadacheWeakness

Fatigue

HeadacheInsomniaFatigue

Side Effects Side EffectsSide Effects


Which of the following would be the best treatment option for CK now that he suffers from compensated liver disease?1. Harvoni® for 12 weeks2. Viekira Pak® for 12 weeks3. Zepatier® for 12 weeks4. None of the above are appropriate treatment

regimens


Decompensated CirrhosisGenotype 1 or 4

RBV Eligible

Harvoni® + low dose RBV*

Daclatasvir 60mg +

sofosbuvir 400mg + low dose RBV*

Daclatasvir 60mg +

sofosbuvir 400mg for 24

weeks

Harvoni® for 24 weeks

Failed prior sofosbuvir treatment

Harvoni® + low dose RBV for 24 weeks

Yes No

Gastroenterology 2015;149:649–659.Gastroenterology. 2015b;149(3):649-59.

Lancet Infect Dis. 2015;15(4):397-404.Lawitz E, et al. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). April 22-26, 2015b; Vienna, Austria.

*Treatment duration 12 weeks

Low dose RBV = 600mg starting dose of RBV, increase as tolerated

Yes


Decompensated Cirrhosis First and Second Line Therapies SVR

8783

71

0

10

20

30

40

50

60

70

80

90

100

Harvoni® + low doseRBV*

Daclatasvir/sofosbuvir+ low dose RBV*

Harvoni® for 24wks

SVR

Gastroenterology 2015;149:649–659.Gastroenterology. 2015b;149(3):649-59.

Lancet Infect Dis. 2015;15(4):397-404.Lawitz E, et al. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). April 22-26, 2015b; Vienna, Austria.



Zepatier® and Harvoni® are preferred and first line treatment options in compensated and decompensated liver disease (T/F)• True• False


Choosing a HCV Therapeutic Regimen

Liver stagingFibrosis Cirrhosis

Comorbidities

Potential drug interactions

Cost and adherence

Genotype1a, 1b, 2, 3, 4, 5, 6

AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed April 20, 2016.


HCV Genotype 1: Current Treatment Options of Choice in Special Populations• ESRD/HD

• Zepatier®*

• Compensated liver disease

• Zepatier®* • Harvoni®*

• Decompensated liver disease

• Harvoni® + low dose RBV*

• IFN-free regimens are currently preferred

• Higher SVR• Tolerable side effect

profiles• Significantly reduced

duration of treatment



Questions?Kristyn E. Yemm, [email protected]


Dose Adjustments for PEG-IFN and RBV • For patients with eGFR 15 to 29 mL/min per 1.73 m2:

• PEG-IFN-2a SQ 135 mcg per week• PEG-IFN-alfa2b SQ 1 mcg/kg per week• RBV po 200 mg per day

• For patients with eGFR <15 mL/min per 1.73 m2 or on dialysis:

• PEG-IFN-2a SQ 135 mcg per week• PEG-IFN-alfa2b SQ 1 mcg/kg per week• RBV po 200 mg weekly with an increase as

tolerated to a maximum of every other day


HCV-associated vasculitis or glomerulonephritis as primary cause of ESRD• Immunosuppressant doses (delay DAA Tx 1-4 months)

• PEG-IFN• 135mcg weekly• 1-1.5mcg/kg weekly

• Rituximab – vasculitis/skin ulcers/peripheral neuropathy/glomerulonephritis• 375mg/m2

• 1 month prior to antiviral• RBV

• 800-1200mg daily

• Duration up to 72 weeks (if non-responders showing clinical improvement) • Up to 48 weeks for HCV genotypes 2 or 3• 72 weeks for HCV genotypes 1 or 4)

• Apheresis/steroids• GC (1–10 mg/kg) or as pulse therapy, low-dose GC therapy may improve IFN Tx

Ann Intern Med. 2013;159:729-738.Autoimmun Rev. 2011 Jun;10(8):444-54.

Blood. 2010;116(3):326.


Indications that Warrant DAA Therapy (Patients who will benefit in the short term)• Advanced fibrosis or cirrhosis• Renal transplant candidates• Mixed cryoglobulinemic vasculitis / HCV-related

glomerulonephritis• Genotypes 1, 4• Timing

• If need urgent immunosuppressant therapy, delay DAA


Antiviral Metabolism Studied in severe ESRD/HD?

Sofosbuvir Renal Increased drug exposure, anemia, worsening renal, half-dose +

simeprevir SVR91, minor events

Ombitasvir-paritaprevir-ritonavir plus dasabuvir

(PrOD)

Liver Increased AUC (?clinical relevance)

Simeprevir Liver Safety not studiedLedipasvir Biliary Only fixed dose combo with

sofosbuvir, safety not studied

Daclatasvir Liver, minor renal Only fixed dose combo with sofosbuvir, safety not studied

PEG-IFN Renal Decreased CL, increased t ½, increased AUC

Ribavirin Renal Plasma concentrations correspond with hemolytic anemia SE, not

removed by HD


Renal Impairment Dosing Spectrum• eGFR >50 mL/min per 1.73 m2 - Regimen selection is the

same as that for patients without renal impairment

• eGFR 30 to 50 mL/min per 1.73 m2 - Regimen selection is the same as that for patients without renal impairment

• eGFR < 30 mL/min per 1.73 m2 or on dialysis - Zepatier, do not recommend sofosbuvir-containing regimen due to renal metabolism

• Hepatorenal syndrome (I or II) - not candidates for HCV antiviral therapy due to portal hypertension/decompensated liver disease

• Post kidney transplant - IFN is contraindicated• increased risk of acute rejection of the allograft



Trial Genotype RegimenPrimary

Outcome (SVR)

Remarks

C-EDGE 1a (50%)1b (41%) ELB 50mg/GRP 100mg* 1a = 92%

1b = 99%

Presence of baseline NS5A RAVs reduced SVR to 58%

ION-1 1LER 90mg/SFB 400mg +/-

RBV12 vs. 24 weeks

12 wk: 97-99%

No difference in SVR:

Length of treatment, +/-

RBV, HCV genotype 1

subtypeELB: elbasvirGRP: grazoprevir LER: ledipasvirSFB: sofosbuvir

RBV: ribavirin*Treatment duration 12 weeks N Engl J Med. 2014a;370(20):1889-1898.




Outcome (SVR)

Remarks

TURQUOISE-II 1aPrOD + RBV

12 vs. 24 weeks

12 wk: 89%24 wk: 95%

Difference between

groups was driven by pts

who failed PEG-

IFN/RBV

ELB: elbasvirGRP: grazoprevir LER: ledipasvirSFB: sofosbuvir

RBV: ribavirinPrOD: paritaprevir/ritonavir /ombitasvir/dasabuvir*Treatment duration 12 weeks

N Engl J Med 2014;370:1973-1982.PHAST Patient Monthly, Dec 2014-Aug 2015, Extracted Oct 2015.

October 2015 WARNINGPrOD and PrO are contraindicated in CTP class B or C


Decompensated Cirrhosis: Treatment Naïve 1st Line Therapies Primary Literature


Outcome (SVR)

Note

ION-1 1LER/SFB +/-

RBV12 vs. 24 weeks

12 wk: 97-99%

No difference in SVR in cirrhosis vs. non-

cirrhosis:Length of treatment,

+/- RBV, HCV genotype 1 subtype

SOLAR-1 14

LER/SFB + RBV

12 vs. 24 weeks

*12 wk: 87%*24 wk: 89%

MELD and CTP scores decreased

from baseline

N Engl J Med. 2014a;370(20):1889-1898.Gastroenterology. 2015b;149(3):649-59.


RBV: ribavirin*After excluding transplant during the studyMELD: Model For End Stage Liver DiseaseCTP: Child-Turcotte-Pugh


Decompensated Cirrhosis: Treatment Experienced 1st Line Therapies Primary Literature

Trial Genotype Regimen Primary Outcome (SVR) Note

SOLAR-2 14

LER/SFB + RBV 12 vs. 24 weeks

*12 wk: 87%*24 wk: 89%

MELD and CTP scores

decreased from baseline

Bourliere et al. 1

LER/SFB + RBV 12 weeks

12 week PBO phase

12 wk: 96%24 wk (+ PBO): 97%

Most common adverse events:

asthenia, headache, pruritus but

frequency was low in both

groups


RBV: ribavirin*After excluding transplant during the studyMELD: Model For End Stage Liver DiseaseCTP: Child-Turcotte-Pugh

Gastroenterology. 2015b;149(3):649-59.Lancet Infect Dis. 2015;15(4):397-404.


Average Wholesale Price (AWP)• Harvoni® $37800.00 for 28 tabs• Zepatier® $21840.00 for 28 tabs• Ribavirin® $496.02 for 50 capsules• Sofosbuvir $33600.00 for 28 tabs• Viekira® $33327.60 for 112 tabs• Daklinza® $25200.00 for 28 tabs• PEG-IFN alfa 2a $4533.65 for 4x135mcg


Cost (AWP)• ESRD/HD treatment costs:

• $65,520 for 12 week course of Zepatier®

• PEG-IFN alfa 2a + QOD RBV for 48 weeks • ($54,403.8 + $1666.63 = $56,070.43)

• Compensated cirrhosis treatment costs:• $65,520 for 12 week course of Zepatier®

• $113,400 for 12 week course of Harvoni®• $24,995.7 for a 12 week course of Viekira®

Cost of liver transplant ~$577,100Cost of kidney transplant ~$262,900

http://www.transplantliving.org. (UNOS) Accessed May 2016.


Cost (AWP)-Continued• Decompensated cirrhosis

treatment costs:• Harvoni® + daily RBV for

12 week course • ($113,400 + $833.32 =

$114,233.31)• Sofosbuvir + Daklinza® +

daily RBV for 12 week course

• ($100,800 + $75,600 + $833.32 =$177,233.32)

• Failed sofobuvir-Tx:

• Harvoni® + daily RBV for 24 week course

• ($226,800 + $1666.64 =$228,466.64)

• RBV in-eligible:

• $226,800 for 24 week course of Harvoni®

• $352,800 for 24 week course of sofosbuvir + Daklinza®

hepatitis c treatment in patient- specific populations yemm hepatitis... · ©2016 mfmer | slide-1...

Documents