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)
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
26.
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
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
31.
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
34.
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
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
48.
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)
Unlike most other viruses, we can get rid of hepatitis C through treatment. Not only that, a whole cascade of good things can happen from treatment.Liver is a very forgiving organ if not pushed too far. You get regeneration of healthy liver cells following HCV tx. This in turn reduces the risk of HCC.First and foremost, if patient achieves a sustained…. It is a virologic cure.<1% have HCV RNA in serum, PBMC or liver tissue on long-term f/u
Prioritize: Those with bridging fib/cirrhosis, don’t have time on their side to wait for better, easier drugs to come along.HIV – More likely to die from liver disease. There is a 2-fold increase in risk of cirrhosis in HIV coinfection. However, you’d like to have the CD4 count up to at least 350, so you want to start HIV therapy first.Mild disease – easiest to treat.
This is a blood test that looks for a change/polymorphism on chromosome 19 and can tell whether a patient is likely to respond to interferon-based therapy.Associated with 2 fold difference in response to Peg IFN/RBV treatment – with CC genotype responding the best, TT the worst and CT a little better than TT.In Alaska, I’ve tested 63 patients for IL-28b. So far,…
1137 patients studied. This shows IL28b and treatment response in different ethnic groups. TT responds the worst among all ethnic groups.
This study looked at vitamin D levels in hepatitis C patients on treatmentFindings were that lower Vit D levels were associated with…
Of the 223 AN/AI patients tested, 73% had sub-optimal levels of vitamin D.
So, if no other health contraindications, drink coffee.Add reference
Starting in 1992, there was plain Interferon alfa, and response rates were 9% for genotype 1 and 30% for genotypes 2/3.Then ribavirin came along in 1998 and response rate increasedto 29% G1, 62% G2/3In 2002 came the start of pegylated interferon tx along with ribavirin…
When I think of these early years of treatment, I can relate to this cartoon which says…
Here are genotype 1 treatment response rates for peg/rib by ethnicity. This data was pulled from a number of peer-reviewed journal articles.
Data since 2002. SVR – intent-to-treat response rates not very good, completed tx response much better. Since I started looking into this when I began tx’g patients at ANTHC in 2007, I have worked on preventing discontinuation of tx through increased teaching, increased follow up especially in the 1st month, weekly phone call follow up, and using a side effects inventory to hone in on what’s bothering them.
This is a VA study, that showed that 77.5% of their patients quit treatment.
With the current medications which I am going to discuss in more detail, you cannot treat someone with significant heart disease, uncontrolled thyroid disease, rheumatoid arthritis, significant depression, unresolved addiction issues and those who are pregnant/contemplating pregnancy.Add reference
Genotype 1 tx with protease inhibitor and peg/rib requires more frequent monitoring for anemias.ANC = Absolute neutrophil count or estimate: WBCs x PMNs (aka PMLs or granulocytes) x .01
Be alert to these red flags before treating a patient with any of these issues
I put this cartoon here because I get patients who look up tx on the internet and assume that everyone gets the new protease inhibitors: telaprevir or boceprevir and I have to tell the genotype 2 or 3 patient, you don’t need telap or boceprevir and that’s good news – but they don’t want to take just ribavirin.
A little lower starting counts acceptable for coinfection treatment
This is what a protease inhibtor does…next slide
Significant anemia seen. Check CBC every 1-2 weeks while on telaprevir.
The side effects of current genotype 1 treatment are no joke.
Alfuzosin – for BPH. Midazolam (versed), Triazolam – halcion, pimozide (Tourette’s)Atorvastatin, lovastatin and simvastatin were only statins studied in clinical trials but recommendations are to avoid all statins.
Not all inclusive. Major ones noted here. Check drug interactions prior to starting patient on tx.Combination with drugs that are highly dependent on CYP50 (CYP3A4/5) pathway. Salmeterol (Advair, Serevent). Fluticasone (Flovent). Budesonide (Pulmicort). Buprenorphine/naloxone (Suboxone).
Progression of liver disease is more rapid in HIV/HCV coinfection with a 2-fold increased risk of cirrhosis.If you are going to treat HCV, start anti-retroviral therapy first. Give enough time to work out the side effects from that, before starting HCV tx.Provisional guidance means not FDA approved.
Now if you are going to put someone on any of these drugs, you need to know whether they have had previous treatment and how they responded.These terms are used in next several slides. 2 log – taking two 0s off count. So if they started out at 1 million, it went down to 10,000 or below
Add in the cost of erythropoeitin if needed: $400 to 2000/weekly injection. Telaprevir will assist pts making < $100k/ and Boceprevir for $89,400/family of 4. Most major insurances will cover the drugs but you need to check first if you’re not sure. Get pre-approval.
A special requirement withtelaprevir – it needs to be taken with 20g of fat 3x/day. You may want to talk to your nutritionist for sample traditional Native American foods containing 20g of fat.
Telaprevir now recommends this algorithm for ribavirin dose reduction when anemia occurs. When Hgb gets below 10,…There currently aren’t any recommendations for growth factors but if Hgb continues to drop despite ribavirin dose reduction, you need to consider adding erythropoeitin
You want to know that your lab uses a sensitive real-time PCR assay with Limit of Detection of 10-15 IU/ml must be used for monitoring HCV RNA during telaprevir/boceprevirtx. Roche COBAS TaqMan HCV Test v2.0, Abbott Real Time HCV Test are approved.
Cirrhosis:
This is an old slide that showed in 2008, bocep and telap were in clinical trials, they’ve now made it to market. Several of the phase 2 drugs have moved on to phase 3, although some of these went to the research drug graveyard because of side effects
The Holy Grail of hepatitis C treatment is all oral medications and once daily treatment. We’re not there yet. May get there in the next 5 years.