Transcript Strategic Applications of HCV Guidelines: Putting Protease

Jeff Allen, MD, FAAFP
Chief of Health Programs, FBOP
Michelle Williams, PharmD
Lieutenant, USPHS
Hepatitis/HIV Program Manager, FBOP
Newton Kendig, MD
RADM, Assistant Surgeon General, USPHS
Assistant Director Health Services Division, FBOP
“We do not have any relevant financial
relationships with any commercial interests.”
At the end of this presentation, participants will be able to:

Discuss the Federal Bureau of Prisons Guidelines for the
treatment of HCV with protease inhibitors.

Describe barriers to effective HCV treatment in the
correctional setting.

Outline key decisions needed to implement an effective HCV
treatment program in the correctional setting.
 HCV
identified late 1980’s.
• 3.2 million Americans with chronic infx.
• Genotypes identified 1994 – 1,2,3, (4,5,6-less common)
 Genotype 1 most common in US (⅔ to ¾ of cases)
 Natural
history
• 1/5 resolve spontaneously
• 3/5 develop chronic infx but no sequelae
• 1/5 with chronic infx develop cirrhosis / complications
 More die from HCV now than from HIV (15,000 + / yr)
 ½ of HCC deaths (@9K / yr) from HCV
 Most common reason for liver transplant
 Direct medical costs > $6.7 billion (2010-2019)
 1991 – IFN
• < 10% SVR
 1998 – IFN
alfa approved
alfa + RBV approved
 2001 - PegIFN introduced
• Significant improvement in SVR rates combined with
RBV
• SVR for genotype 2 or 3=70-80%; for genotype 1 = 4050%.
• Less effective in high viral loads, African Americans,
cirrhosis, HIV or HBV co-infx, IL28B genotype C/T or
T/T, prior treatment failures.
 FDA approved May 2011
• Boceprevir (VictrelisTM) and Telaprevir (IncivekTM)
• AASLD published updated guideline November 2011
• BOP Guideline issued March 2012
 Mechanism of action:
• Direct Acting Antiviral Agent inhibits HCV viral
replication
• Binds to protease enzyme and inhibits cleavage into
mature viral forms
• Similar mechanism to HIV protease inhibitors but
different spectrum of antiviral activity and NOT
interchangeable.
Treatment
of chronic HCV, genotype 1
- Not approved for tx of other HCV genotypes
In
combination with pegIFN + RBV
- Not approved for monotherapy
Treatment
naïve or prior tx failures with
pegIFN/RBV
- Relapse, partial or null response.
- Re-tx of null responders not studied with BOC
- SVR rates for prior null responders < 30% to
40%

SVR rates ↑ 20 to 40% compared to pegIFN + RBV!
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
Overall (70-80%)
Treatment naïve (67-75%)
African-American (62%)
Advanced fibrosis (62%)
High viral load (74%)
Relapser (69 -88%)
Partial responder (40-59%)
Null responder (23-38% with telaprevir based tx)
HCV Protease Inhibitor Trials
• Boceprevir – SPRINT 1/2; RESPOND 2
• Telaprevir – ADVANCE, ILLUMINATE, PROVE 1/2; REALIZE
 Viral
Resistance
• IFN / RBV do not produce resistance.
• Viral mutations → Resistance to HCV PIs
• Treatment failure = viral resistance.
 80% to 90% correlation.
• Non-adherence → viral resistance.
• Viral resistance appears to be class effect
- Cannot switch from one HCV PI to another for tx failure.
 Complex
Medication Regimens / Decision
Points
• Duration of treatment determined by 4 variables
 HCV treatment history
- Tx naïve vs. relapser vs. partial responder vs. null responder
 Fibrosis stage
- Compensated cirrhosis treated for 48 weeks
 Which HCV PI is prescribed
- Tx algorithm is different for each HCV PI
 Response to treatment
- a.k.a. Response Guided Therapy (RGT)

28 wks (total)
• 4 weeks pegIFN+ RBV (DT) followed by 24 weeks of BOC +
pegIFN + RBV (TT)
• If tx naïve & RNA undetectable (-) at 8 & 24 wks

36 weeks (total)
• 4 wks DT + 32 wks TT
• If prior relapser / partial responder & RNA (-) at 8 & 24 wks

48 wks (total)
•
•
•
•

4 wks DT + 32 wks TT + 12 wks DT
If tx naïve, prior relapser or partial responder AND
RNA (+) after week 8 but (-) after TW 24
If & RNA (+) at 8 but (-) at 24 wks
48 wks (total) – 4 wks DT + 44 wks TT
• If compensated cirrhosis
 Stop
all HCV meds if HCV RNA is
• ≥ 100 IU/ml at 12 wks or
• detectable (+) at 24 wks or
• ↑ by > 1 log10 above treatment nadir
*a.k.a. – “Futility Rules”

First 12 weeks
• Triple Therapy with TVR + pegIFN + RBV
 TVR dose = 750 mg (two 375 mg tabs) PO q 8 hr (+/- 1hr)
 Each dose must be taken with 20 gm fat snack
 pegIFN + RBV, standard dosing.
• D/C all meds if RNA > 1,000 IU/ml at 4 or 12 weeks or > 1 log
increase from treatment nadir

Continue pegIFN + RBV for 24 or 48 weeks (total)
• 24 wks total if
 Tx naïve or relapser AND
 RNA undetectable at 4 & 12wks.
• 48 wks total if
 Treatment naïve or relapser AND
 HCV RNA (+) but ≤ 1,000 at 4 and 12 wks & undetectable at 24 wks
 Compensated cirrhosis or prior partial responder AND
 HCV RNA ≤ 1,000 at 4 and 12 wks & undetectable at 24 wks
• D/C all meds if HCV RNA is
• > 1000 IU/ml at 4 or 12 weeks or
• Detectable at 24 weeks or
• Increased by > 1 log 10 above treatment nadir.
*a.k.a. – “Futility Rules”
 Medication
side effects
• PegIFN and RBV side effects
• Boceprevir (BOC)
 Anemia
 Dysgeusia
• Telaprevir (TVR)
 Anemia
 Rash / Pruritus
 GI / anorectal
 Dysgeusia
 Hyperuricemia
 Cost
(FSS or FSR)
• Boceprevir + pegIFN/RBV (PR)
 PR 28 / BOC 24 = $23,000
 PR 36 / BOC 32 = $30,400
 PR 48 / BOC 32 = $32,500
 PR 48 / BOC 44 = $41,537
• Telaprevir + PR
 TPV 12 / PR 24 = $39,400
 TPV 12 / PR 48 = $43,700
 HCV
Genotype 1 with ≥ stage 2 fibrosis on liver
biopsy
• Prioritize higher stages of fibrosis, e.g. stages 3 & 4
• Consider / discuss deferring tx for lower stages of fibrosis,
e.g. stage 2 – newer agents likely in 2 to 5 yrs.
• No contraindications /exclusions.
• Highly motivated and compliant.
 Continuity of care for new intakes on triple tx.
• With appropriate assessment following intake.
 Prior null responders to DT considered on case-
by-case basis.
 Comorbid medical conditions
• Cardiovascular or metabolic conditions
 E.g. known coronary heart disease, DM, hyperlipidemia, or hyperuricemia/gout
 Telaprevir requires 20 gm fat snack 3x/day and increases uric acid levels;
• Anorectal conditions
 E.g. hemorrhoids, proctitis, diarrhea
 increased incidence of anorectal symptoms with telaprevir
• Dermatologic conditions
 E.g. eczema, psoriasis
 Increased incidence of rash with telaprevir.
 Lower fibrosis score
• E.g. stage 2/4 – more likely to meet criteria for shorter course of therapy
• BOC is cheaper / more cost effective with shorter treatment durations.
 Medication
contraindications (CI) with telaprevir
• e.g. atorvastatin is CI with telaprevir but “use with caution” in BOC.
 Short
Course of BOC not indicated
• Compensated cirrhosis or prior treatment failures with
pegIFN/RBV
 Prior null responders not studied in BOC trials.
• Simpler TVR regimen could improve adherence;
• Cost advantage with BOC is lost with longer BOC tx course.
 Medication
contraindications with BOC
• e.g. carbamazepine, phenobarbital, and phenytoin are CI
with BOC but labeled as “use with caution” with TVR.

Borderline acceptable hemoglobin levels
• Hgb decreased but not at contraindicated levels
 BOC studies used ESAs (erythropoietin stimulating agents) in up to
50% of cases whereas TVR studies did not use ESAs and
discontinuation rates were similar).
 HCV
PIs must be taken q 8 hr (+/- 1 hr) with food
• Continue BID pill line for RBV and weekly pegIFN injx as
per current local procedures.
• Dispense weekly supply of HCV PI
 Inmate must return empty bottles / blisters each wk.
 Remote fill – requested 1 week prior.
• Treating clinician sends e-mail request for supplemental
feeding (3 times / day) to FSA.
 TVR – 20 gm fat snack (3 TBSP peanut butter or 2 slices cheese
with bread or crackers)
 BOC – taken with a meal or light snack, per policy.
Sample Lab
Planner
which can
autopopulate
dates due for
labs based on
treatment
start date
 HCV
RNA schedule
• Baseline, end of tx, & 24 wks after ETR
• BOC – treatment weeks 4, 8, 12, 24
• TVR – treatment wks 4, 12, 24
 Report
interpretation
• Futility: > 1000 IU/ml wk 4 or wk 12 (TVR); or ≥ 100
IU/ml wk 12 (BOC).
• Detectable vs. Undetectable
 Timely
drawing and result reporting is
essential
 Transfer issues
• Place medical hold on patients during treatment to
prevent treatment interruptions.
 Patient
education is essential
• Treatment regimen and adherence
• Side effects
• Medication interactions / pregnancy issues
• Option to postpone therapy if stage 2 fibrosis
• Cannot transfer or release during treatment
• Have patient sign Hep C tx consent form
 Utilizing
a multidisciplinary team helps navigate
the complexities of HCV treatment
 BOP
is utilizing Regional HCV Clinical Pharmacist
Consultants to work in conjunction with health
services staff at the local level to provide guidance
on the new HCV protease inhibitors and optimize
patient outcomes, while promoting cost
efficiencies.
 Non-formulary requests approved for tx – 153
• 92 for boceprevir
• 61 for telaprevir
 130 started on treatment; 98 active on tx; 17
completed tx (16 with ETR, 1 relapse)
 28 d/c’d; 8 due to virologic failure; 10 due to
patient non-compliance or refusal; 10 due to
hematologic factors (anemia, neutropenia,
thrombocytopenia) despite INF/RBV dose
adjustment
 Too early to assess overall efficacy
 ETRs:
BOC – 10/TVR – 11
 Virologic failures: BOC – 6/TVR – 5
 Discontinuance: BOC – 17/TVR - 13
• Hematologic - BOC – 8/TVR - 4
 Patient education / informed consent is critical
 Tracking snack intake is important
 Telaprevir requires uric acid monitoring
 Lack of timely laboratory monitoring can be
dangerous for the patient and costly when
treatment fails
 Major side effects noted: anemia, neutropenia,
and rash
 Quality control is absolutely critical as there are
multiple ways of making mistakes in treatment
regimen / monitoring.
Treatment is very expensive – ensure guidelines and
administrative controls are in place
Treatment is extraordinarily complicated – consolidate
treatment centers where feasible, implement
algorithms/monitoring tools, and adopt quality control
measures
Await newer treatment options to include simpler,
possible all oral regimens in the future
Anticipate more personalized approach to treatment
based on genetic host factors