Hepatitis C TREATMENT 2012

Lisa Townshend-Bulson, MSN, FNP-CAlaska Native Tribal Health Consortium

Objectives Define Sustained Virologic Response (SVR)

Identify candidates for hepatitis C treatment

Differentiate appropriate treatment by genotype

Identify factors associated with treatment response

Recognize common side effects of treatment

Recognize key drug interactions with telaprevir and boceprevir

Discuss future treatment of hepatitis C

Why Treat HCV? Sustained Virologic Response (SVR) =

Undetectable HCV RNA 6 months after completing treatment

SVR is considered a cure (Swain, Gastroenterology Nov 2010; 139(5):1593-601.)

Risk of developing decompensated cirrhosis is greatly reduced and

Regression of cirrhosis can occur (Mallet Ann Int Med 2008;149:399-403)

Risk of hepatocellular carcinoma (HCC) in those with cirrhosis reduced

Consider Treatment Now

Patients with bridging fibrosis or cirrhosis on liver biopsy

Patients with HCV and HIV coinfection (early and mild disease)

Patients with acute hepatitis C who do not clear virus spontaneously

Patients with mild disease

Not urgent

If circumstances are right and no contraindications

Candidates for HCV Treatment

Persons who are motivated to get better

Genotype 1 after biopsy (recommended, not req’d)

Genotype 2 & 3 without biopsy

Persons not interested in getting pregnant/fathering a

child in next 12-24 months

Rehabilitated alcoholics/drug abusers: 6-month abstinence

from alcohol & drugs before treatment

AUDIT-C Alcohol Screening Tool

Random drug screening

Persons not depressed or depression well-controlled

PHQ-9/Prime-MD Depression Screening Tool

Do Not Treat

Clinically decompensated cirrhosisascites variceal bleedingcoagulopathy encephalopathy

Kidney, liver, heart or other solid-organ transplant

When contraindications to peginterferon, ribavirin and protease inhibitors exist (see later slides)

Factors Affecting Treatment Response Genotype Viral load Age Fibrosis stage Insulin resistance Steatosis IL28B genotype Vitamin D level Coffee Consumption

IL28B and Hepatitis C CC= Good response TT = Poor response CT = Intermediate response

(heterozygous)

40%

52%

8%

IL-28b in AN/AIs in Alaska

CC

CT

TT

DL Ge et al. Nature, 461, 399-401, 2009.

Percentage of treatment induced SVR by genotypes of rs12979860

Vitamin D Levels and HCV 197 HCV genotype 1 patients receiving

IFN-RBV therapy; 49 healthy controls matched by age and sex

25 (OH) D levels significantly lower in HCV persons (25) vs. controls (43); p<0.001)

Low levels significantly associated with: Female sex, increased liver inflammation, increased liver fibrosis and decreased SVR

Hepatology 2010;51:1158-67

Vitamin D Levels in AN/AIs with Hepatitis C in Alaska

73%

27%

<30>30

223 tested

Coffee Consumption and HCV

HALT-C trial serial liver biopsies q2 years Coffee consumption > 3 cups/day

associated with: Significantly reduced fibrosis (Hepatology

2009;50:1360-9) Significantly better response to Peg

IFN+RBV (Freedman et al, Gastroenterology 2011; 140(7): 1961-1969)

Quantity of coffee consumption associated with decreased risk of HCC(Hepatology 2008; 48:129-36)

History of Hepatitis C Treatment SVR

Interferon α 1992-1998

Inf α/Rib 1998-2002

PegInf/Rib 2002-2011

PegInf/Rib/PI 2011…

0

10

20

30

40

50

60

70

80

90

100

9

29

44

75

30

62

75

G1 SVR %

G 2/3 SVR %

Genotype 1 Peginterferon/Ribavirin Treatment Response Rates by Ethnicity

Asian: ~60%+

Caucasian: ~50%

Hispanic: ~30%

African American: ~10%-20%

Alaska Native/American Indian Persons (AI/AN): 32-46%

AN/AI Treatment Outcomes Peg-IFN/RBV through 2011

SVR in those who

Genotype Treated Discontinued Failed Relapsed SVR* completed tx 1 43 20 (47%) 10 3 10 (23%) 10/23

(43%)

2 37 7 (19%) 3 3 26 *(70%) 24/30 (80%)

3 20 7 (35%) 1 2 10 (50%) 10/13 (77%)

Total 100 34 (34%) 14 8 46 (46%) 46/66 (70)%

*Includes pts who discontinued tx and still achieved SVR

S Livingston et al, ANTHC, Circumpolar Health Conference Abstract 2012

How Often Do Persons Complete Treatment

Peginterferon/ribavirin clinical trials: Dropout rates 10-15%

VA study: Dropout rate 77.5% 134,934 patients with HCV, 16,043 treated (12%)

10,641 with 1 year data: 2,394 completed treatment (22.5%)

Only 1 in 56 patients with known HCV finish treatment

(AA Butt et al. Liver Int. 2010 Aug;30(7):1082)

Difficulties in Treating HCV

Many patients have medical or psychiatric contraindications Prospective study done at ANMC

40% of patients are treatment candidates 60% are not treatment candidates

(S Livingston et al. Int J Circumpolar Health 2012, 71:18445)

As long as treatment includes interferon, HCV infection will be difficult to treat

Hepatitis C Treatment 2012Genotype 1

Peginterferon, ribavirin AND a protease inhibitor (telaprevir or boceprevir) 24-48 weeks – depends on response, stage of liver

disease, history of treatment response SVR (Details in later slide) – Boceprevir and Telaprevir -

Not apples to apples comparison

Genotypes 2 & 3 Peginterferon and ribavirin only 24 weeks 68%-79% SVR

Other Genotypes (4,5,6) Peginterferon and ribavirin for 48 weeks Underrepresented in U.S.

Pre-treatment Screening

Medical/psychiatric history for contraindications

Review ALL medications

EKG (men over 40 & women over 50)

Stress test (all patients with hx of cardiac disease)

Dilated retinal exam recommended

Pre-treatment labs, including HCV RNA, genotype, CBC, PT, CMP, AFP, TSH, uric acid, and pregnancy testing for females of childbearing age.

Consider biopsy - Genotype 1

Follow Up During Treatment Monitor closely for side effects & tolerability Genotypes 2 & 3, labs at weeks 0 (Start), 1, 2

and 4, then monthly after that unless: Significant anemia Thrombocytopenia Neutropenia

Adjust medication doses (refer to prescribing information) Hgb < 10 (Ribavirin) Platelets < 50 (Peginterferon) ANC < 0.5 (Peginterferon)

HCV Treatment Medications:

Peginterferon (PegInf) Pegylated interferon

Polyethylene glycol added to interferon Extends half-life of interferon Provides a more constant level in the blood

Given weekly, subcutaneously Pharmacodynamics:

Immunomodulation Increases T cell activity Stimulates B cells for increased antibody

response

Contraindications to Peginterferon

Known hypersensitivity reactions to alpha interferons Autoimmune hepatitis Hepatic decompensation (Child-Pugh > 6 mono-infection,

≥ 6 for HIV coinfection) Women who are pregnant and men whose female

partners are pregnant Cardiac disease Severe pulmonary disease Bone marrow suppression Autoimmune disorders incl. RA, thyroid disease,

uncontrolled DM, ulcerative colitis

Use Extreme Caution

Severe depression & serious psychiatric conditions Bipolar depression/Mania Psychosis/Hallucinations Suicidal ideation and past attempts Homicidal ideation or history

Active substance or alcohol abuse Patients who can’t practice birth control

HCV Treatment Medications:Ribavirin (RBV) Oral antiviral agent Does not cause a reduction in serum HCV

RNA when used alone Enhances the virologic response to

interferon Prevents breakthrough and reduces relapse

rates Important not to miss doses Reduce dose in adverse event rather than

stop dose, if possible

Contraindications to Ribavirin

Anemia (Hgb <11, Hct <33%)

Renal disease (CrCl < 50)

Unstable coronary artery or cerebrovascular disease

Pregnancy, those contemplating pregnancy (men & women), breastfeeding

Inability to practice birth control (men & women)

Didanosine use (lactic acidosis, hepatic failure)

Peginterferon & Ribavirin Side Effects

Baseline Lab Parameters Before Treatment

Mono-infection Plt ≥ 90,000 cells/mm3

or 75,000 cirrhosis ANC ≥ 1500

cells/mm3

Cr ≤ 1.5 ULN TSH and T4 WNL Hgb ≥ 12g/dL women,

13g/dL men

HIV Coinfection Plt ≥ 70,000 cells/mm3

ANC ≥ 1500 cells/mm3

CD4 count ≥ 200 cells/mm3

Cr ≤ 1.5 ULN TSH and T4 WNL Hgb ≥ 11g/dL women,

12g/dL men

1st Generation Protease Inhibitorsfor Genotype 1-New Std of Care

1st two drugs, telaprevir and boceprevir

approved 2011

Telaprevir – Incivek®

Boceprevir – Victrelis®

Must be used with peginterferon and ribavirin

Cannot be used alone

May shorten treatment to 24-28 weeks

Protease Inhibitors (PI)Mechanism of Action

NS3/4A protease is necessary for cleavage of the HCV encoded polyprotein into mature proteins

Inhibits HCV NS3/4A protease

This inhibits viral replication in HCV-infected host cells

The Down Side Increased side effects

Telepavir: Rash (moderate/severe in 56%) , anemia (36%), GI Side Effects (29%)

Boceprevir: Severe anemia requiring drug modification in 39% (EPO)

Many drug interactions including non-prescription meds

Can develop resistance. Must follow futility (stopping) rules

Drug Contraindications withTelaprevir or Boceprevir

Atorvastatin, lovastatin, simvastatin

Alfuzosin

Rifampin

Cisapride

Ergot derivatives

Midazolam (oral), triazolam

PDE5 Inhibitors (PAH doses)

Pimozide

St. John’s wort

Potential Significant Drug Interactions Telaprevir, Boceprevir *

Antiarrhythmics ↑Antifungals ↑Anticonvulsants ↑ or ↓-Mycin antibiotics ↑Colchicine ↓Alprazolam ↑Zolpidem ↓Ca++ channel blockers ↑Corticosteroids ↑Bosentan ↑Escitalopram ↓Buprenorphine/naloxone ↑

Tenofovir ↑Cyclosporine ↑Sirolimus ↑Tacrolimus ↑Salmeterol ↑Fluticasone ↑Budesonide ↑Methadone ↓PDE5 Inhibitors for ED ↑ Rifabutin ↑Warfarin ↑ or ↓

* Not all inclusive. Check individual drug interactions before starting treatment.

Hepatitis C and HIV Coinfection Treatment

Treatment unchanged genotypes 2 through 6

Provisional guidance for genotype 1 and PIs: boceprevir and telaprevir*

No shortened treatment with PIs

More drug interactions

Consult specialist

*Thomas, D. et al. CID 2012(54): 979-983.

TermsRelapser – HCV RNA undetectable at end

of treatment (EOT) with PegInf/RBV but detectable 24 weeks after treatment

Partial Responder – Greater than 2 log drop at week 12 but not achieving undetectable RNA by week 24 of a prior course of therapy with PegInf/RBV

Null Responder – Less than 2 log reduction in HCV RNA at week 12 of prior course of therapy with PegInf/RBV

Comparison Boceprevir Telaprevir PegInf/Rib

# of pills 17-18/day(4 Bocep TID)

11-12/day(2 Telap TID w/fat)

5-6 Rib/day

How to take? With food q8h With 20g fat q8h BID with food

New Side Effects Anemia requiring EPO,

Dysgeusia

Rash, GI SEs, Anemia

N/A

How long on this med?

24-44 weeks 12 weeks 48 weeks

Tx Length incl. PegInf/Rib

28, 36 or 48 weeks

24 or 48 weeks 48 weeks

SVR in Tx Naive 63-66% 79% 38%

SVR in Relapsers 70-75% 86% 22%

SVR in Partial Responders

40-52% 59% 7%

SVR in Null Responders

Not studied 32% 5%

SVR in Advanced Fibrosis

41-52% 62% 10-38%

Total Cost 31,680-$58,080 $59,080 $20,000-40,000

Fatty Foods for Absorption of Telaprevir

½ cup trail mix 2 ounces of cheese ¾ cup regular ice

cream 1 container Total

Classic Fage Fruit yogurt and 1 oz

coconut 2 oz potato chips ½ c or 4oz avocado

15 dark chocolate covered almonds

2 T peanut butter 35 almonds/peanuts ½ cup Agutuk (berries,

seal oil, shortening, sugar)

5 ½ oz cooked king salmon

1 ½ Tablespoon seal oil 3 oz smoked hooligan

Ribavirin Dose Modification Algorithm for Telaprevir

Test Hgb ≥10 g/dl Weeks0-2-4-8-12*

Test Hgb <10 g/dl <8.5 g/dl

Reduce dose to 600mg/d

Continue at current dose

Discontinue RBV

>2g/dL drop in Hgb during any 4 wk tx pd

Reduce RBV to

600mg/d

Hgb < 12 g/dL after 4

wks at reduced

dose

D/C RBV

*More frequent monitoring may be clinically appropriate

Source: Vertex Incivek® Treatment Management Guide

Financial Resources for HCV Treatment

Boceprevir (and Pegintron®) www.Merck-CARES.com 1-866-939-4372

Telaprevir www.VertexGPS.com 1-855-837-8394

Peginterferon alfa 2a (Pegasys®) www.genentechaccesssolutions.com 1-800-530-3083

Response Guided Therapy (RGT) The opportunity to shorten treatment

duration based on HCV RNA decline at specific timepoints during treatment

Key RGT HCV RNA Timepoints:Telaprevir - Weeks 4, 12, 24Boceprevir – Weeks 8, 12, 24

Interpreting HCV RNA Results Virus must be “not detected” or

“undetectable” to be considered negative for genotype 1 RGT

<43 or <25 IU/ml – Unclear Result should specify:

Detected/Below Level of Quantification (Still detected – Not negative)

Not Detected/Below Level of Detection (Negative result – Proceed with RGT)

Harrington, P., Wen Zeng, L. Naeger. Hepatology, 2012 (online 10/1011)

Boceprevir Treatment AlgorithmBoceprevir Treatment Duration

Lead-in:Peg/RBV

Wk 8 RNA

Wk 24 RNA

Triple therapy:

Peg/RBV/BOC

Peg/RBV

Total Duratio

n

Treatment-naïve

4 wks4 wks

NegPos

NegNeg

24 wks32 wks

-12 wks

28 wks48 wks

Prior Relapser orPartial Responder

4 wks4 wks

NegPos

NegNeg

32 wks32 wks

-12 wks

36 wks48 wks

Cirrhotics 4 wks Neg 44 wks 48 wks

Null responder

No data

STOPPING RULES/TREATMENT FUTILITY: If HCV RNA ≥100 IU/mL at wk 12, or detectable at any level at wk 24, discontinue all treatment. It isn’t working.

Peg = Peginterferon RBV = Ribavirin BOC = Boceprevir

Telaprevir Treatment Duration

Wk 4 RNA

Wk 12 RNA

Wk 24RNA

Triple therapy:

Peg/Rib/TPR

Peg/Rib Total Duratio

n

Treatment-naïve or Prior Relapser

NegPos

NegPos

Neg 12 wks12 wks

12 wks36 wks

24 wks48 wks

Prior Partial Responder or Null Responder

Neg/Pos Neg/Pos Neg 12 wks 36 wks 48 wks

Cirrhosis Neg/Pos Neg/Pos Neg 12 wks 36 wks 48 wks

STOPPING RULES/TREATMENT FUTILITY: If >1000 IU/mL at wks 4 or 12, or detectable at any level at wk 24, discontinue all treatment. It isn’t working.

Telaprevir Treatment Algorithm

Peg = Peginterferon RBV = Ribavirin TPR = Telaprevir

PI Treatment Caution HCV/HIV - provisional guidance HCV/HBV Coinfection – not studied Children – not studied Patients over 65 - not studied sufficiently

(35 subjects in telaprevir study >65 yrs) Cirrhotics – limited study ESRD or patients on hemodialysis – not

studied Solid Organ Transplantation – not studied

“Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning”

-Winston Churchill

New Drugs for HCVClass Drug

ExamplesPotency Resistance

BarrierActiveGenotype 1

ActiveGenotype 2 &3

1st Gen PI (NS3/4A)

TelaprevirBoceprevir

Mod. high

Lowest Yes No

2nd Gen PI SimeprevirAsunaprevirGS 9256MK 5172ACH 2684

High Low Yes Low/moderate

Nucleotide Inhibitors

GS 7977 High High Yes Yes

Polymerase Inh/NS5B

TegobuvirABT-072

High Low Yes Yes

NS5A Protease Inhibitors

Daclatasvir High Intermediate Yes ?

Cyclophilin Inhibitors

Alisporivir Yes

Future Treatment withDirect Acting Antivirals (DAAs)

Interferon-free

Fewer side effects

More drug options

Tailored treatment

Less frequent administration (QD or BID)

Fewer pills (Combining drugs)

Thank You!

My contact info: ltownshend@anthc.org 907-729-1573

ANTHC Hepatitis Website http://www.anthctoday.org/community/hep/

providerinformation.html