1. Hepatitis C TREATMENT 2012
Lisa Townshend-Bulson, MSN, FNP-C
Alaska Native Tribal Health Consortium

2. 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

3. 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

4. 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

5. 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

6. Do Not Treat
 Clinically decompensated cirrhosis
ascites variceal bleeding
coagulopathy encephalopathy
 Kidney,liver, heart or other solid-organ
transplant
 When contraindications to
peginterferon, ribavirin and protease
inhibitors exist (see later slides)

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

8. IL28B and Hepatitis C
 CC= Good response
 TT = Poor response
 CT = Intermediate response (heterozygous)
IL-28b in AN/AIs in
Alaska
8% CC
40% CT
52% TT

9. Percentage of treatment induced SVR
by genotypes of rs12979860
DL Ge et al. Nature, 461, 399-401, 2009.

10. 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

11. Vitamin D Levels in
AN/AIs with Hepatitis C in Alaska
27%
<30
>30
223 tested
73%

12. 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)

13. History of Hepatitis C
Treatment SVR
100
90
80 75 75
70
62
60
G1 SVR %
50
44
G 2/3 SVR %
40
30 29
30
20
9
10
0
Interferon α 1992-1998 Inf α/Rib 1998-2002 PegInf/Rib 2002-2011 PegInf/Rib/PI 2011…

15. 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%

16. 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

17. 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)

18. 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

19. Hepatitis C Treatment 2012
Genotype 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
 24weeks
 68%-79% SVR
Other Genotypes (4,5,6)
 Peginterferon
and ribavirin for 48 weeks
 Underrepresented in U.S.

20. 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

21. 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)

22. 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

23. 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

24. 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

25. 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

27. 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)

28. Peginterferon & Ribavirin
Side Effects
≥ 20% ≥ 10% ≥ 5%
Depression Anxiety Thyroid problems
Fatigue Pain Abdominal pain
Nausea/Vomiting Diarrhea Dry mouth
Fever Lymphopenia Dyspepsia
Insomnia Anemia Thrombocytopenia
Dizziness Weakness Dyspnea on exertion
Headache Weight Loss Memory impairment
Neutropenia Inability to concentrate Mood alteration
Anorexia Dyspnea Back pain
Myalgia Cough Rash
Arthralgia Pruritis Increase in sweating
Alopecia Dermatitis Eczema
Rigors Dry skin Blurred vision
Injection site reaction

29. Baseline Lab Parameters
Before Treatment
Mono-infection HIV Coinfection
 Plt ≥ 90,000 cells/mm3  Plt ≥ 70,000 cells/mm3
or 75,000 cirrhosis  ANC ≥ 1500 cells/mm3
 ANC ≥ 1500 cells/mm3  CD4 count ≥ 200
 Cr ≤ 1.5 ULN cells/mm3
 TSH and T4 WNL  Cr ≤ 1.5 ULN
 Hgb ≥ 12g/dL  TSH and T4 WNL
women, 13g/dL men  Hgb ≥ 11g/dL
women, 12g/dL men

30. 1st Generation Protease Inhibitors
for 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

32. 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

33. 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

35. Drug Contraindications with
Telaprevir or Boceprevir
 Atorvastatin, lovastatin, simvastatin
 Alfuzosin
 Rifampin
 Cisapride
 Ergot derivatives
 Midazolam (oral), triazolam
 PDE5 Inhibitors (PAH doses)
 Pimozide
 St. John’s wort

36. Potential Significant Drug Interactions
Telaprevir, Boceprevir *
Antiarrhythmics ↑ Tenofovir ↑
Antifungals ↑ Cyclosporine ↑
Anticonvulsants ↑ or ↓ Sirolimus ↑
-Mycin antibiotics ↑ Tacrolimus ↑
Colchicine ↓ Salmeterol ↑
Alprazolam ↑ Fluticasone ↑
Zolpidem ↓ Budesonide ↑
Ca++ channel blockers ↑ Methadone ↓
Corticosteroids ↑ PDE5 Inhibitors for ED ↑
Bosentan ↑ Rifabutin ↑
Escitalopram ↓ Warfarin ↑ or ↓
Buprenorphine/naloxone ↑
* Not all inclusive. Check individual drug interactions before starting treatment.

37. 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.

38. Terms
Relapser – 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

39. Comparison Boceprevir Telaprevir PegInf/Rib
# of pills 17-18/day 11-12/day 5-6 Rib/day
(4 Bocep TID) (2 Telap TID w/fat)
How to take? With food q8h With 20g fat q8h BID with food
New Side Effects Anemia requiring Rash, GI SEs, N/A
EPO, Dysgeusia Anemia
How long on this 24-44 weeks 12 weeks 48 weeks
med?
Tx Length incl. 28, 36 or 48 24 or 48 weeks 48 weeks
PegInf/Rib weeks
SVR in Tx Naive 63-66% 79% 38%
SVR in Relapsers 70-75% 86% 22%
SVR in Partial 40-52% 59% 7%
Responders
SVR in Null Not studied 32% 5%
Responders
SVR in Advanced 41-52% 62% 10-38%
Fibrosis
Total Cost 31,680-$58,080 $59,080 $20,000-40,000

40. Fatty Foods for Absorption
of Telaprevir
 ½ cup trail mix  15 dark chocolate
 2 ounces of cheese covered almonds
 ¾ cup regular ice  2 T peanut butter
cream  35 almonds/peanuts
 1 container Total  ½ cup Agutuk
Classic Fage (berries, seal
 Fruit yogurt and 1 oz oil, shortening, sugar)
coconut  5 ½ oz cooked king
 2 oz potato chips salmon
 ½ c or 4oz avocado  1 ½ Tablespoon seal oil
 3 oz smoked hooligan

41. Ribavirin Dose Modification
Algorithm for Telaprevir
≥10 g/dl Continue at current dose
Test Hgb
<10 g/dl Reduce dose to 600mg/d
Weeks <8.5 g/dl Discontinue RBV
0-2-4-8-12*
Hgb < 12
Reduce
Test Hgb >2g/dL drop in g/dL after 4 D/C
RBV to
Hgb during wks at RBV
600mg/d
any 4 wk tx pd reduced
dose
*More frequent monitoring may be clinically appropriate
Source: Vertex Incivek® Treatment Management Guide

42. 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

43. 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, 24
Boceprevir – Weeks 8, 12, 24

44. 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)

45. Boceprevir Treatment Algorithm
Boceprevir Treatment Duration
Lead-in: Wk 8 Wk 24 Triple therapy: Peg/RBV Total
Peg/RBV RNA RNA Peg/RBV/BOC Duration
Treatment- 4 wks Neg Neg 24 wks - 28 wks
naïve 4 wks Pos Neg 32 wks 12 wks 48 wks
Prior Relapser 4 wks Neg Neg 32 wks - 36 wks
or 4 wks Pos Neg 32 wks 12 wks 48 wks
Partial
Responder
Cirrhotics 4 wks Neg 44 wks 48 wks
Null responder No data
Peg = Peginterferon RBV = Ribavirin BOC = Boceprevir
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.

46. Telaprevir Treatment Algorithm
Telaprevir Treatment Duration
Wk 4 Wk 12 Wk 24 Triple therapy: Peg/Rib Total
RNA RNA RNA Peg/Rib/TPR Duration
Treatment- Neg Neg Neg 12 wks 12 wks 24 wks
naïve or Prior Pos Pos 12 wks 36 wks 48 wks
Relapser
Prior Partial Neg/Pos Neg/Pos Neg 12 wks 36 wks 48 wks
Responder or
Null Responder
Cirrhosis Neg/Pos Neg/Pos Neg 12 wks 36 wks 48 wks
Peg = Peginterferon RBV = Ribavirin TPR = Telaprevir
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.

47. 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

49. “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

50. New Drugs for HCV
Class Drug Potency Resistance Active Active
Examples Barrier Genotype 1 Genotype 2 &3
1st Gen PI Telaprevir Mod. Lowest Yes No
(NS3/4A) Boceprevir high
2nd Gen PI Simeprevir High Low Yes Low/moderate
Asunaprevir
GS 9256
MK 5172
ACH 2684
Nucleotide GS 7977 High High Yes Yes
Inhibitors
Polymerase Tegobuvir High Low Yes Yes
Inh/NS5B ABT-072
NS5A Daclatasvir High Intermediate Yes ?
Protease
Inhibitors
Cyclophilin Alisporivir Yes
Inhibitors

51. Future Treatment with
Direct Acting Antivirals (DAAs)
 Interferon-free
 Fewer side effects
 More drug options
 Tailored treatment
 Less frequent administration (QD or BID)
 Fewer pills (Combining drugs)

52. Thank You!
 My contact info:
 ltownshend@anthc.org
 907-729-1573
 ANTHC Hepatitis Website
 http://www.anthctoday.org/community/hep
/providerinformation.html