1. 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

2. “We do not have any relevant financial relationships with any commercial interests.”

3. 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.

4.  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)

5.  1991 – IFN alfa approved < 10% SVR  1998 – IFN 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 = 40- 50%. Less effective in high viral loads, African Americans, cirrhosis, HIV or HBV co-infx, IL28B genotype C/T or T/T, prior treatment failures.

6.  FDA approved May 2011 Boceprevir (Victrelis TM ) and Telaprevir (Incivek TM ) 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.

7.  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%

8.  SVR rates ↑ 20 to 40% compared to pegIFN + RBV! 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

9.  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.

10.  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)

12.  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

13.  Stop all HCV meds if HCV RNA is ≥ 100 IU/ml at 12 wks or detectable (+) at 24 wks or ↑ by > 1 log 10 above treatment nadir *a.k.a. – “Futility Rules”

16.  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

17. 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”

19.  Medication side effects PegIFN and RBV side effects Boceprevir (BOC)  Anemia  Dysgeusia Telaprevir (TVR)  Anemia  Rash / Pruritus  GI / anorectal  Dysgeusia  Hyperuricemia

20.  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

21.  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.

22.  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.

23.  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).

24.  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.

26. Sample Lab Planner which can auto- populate dates due for labs based on treatment start date

27.  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

28.  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

29.  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.

30.  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

31.  ETRs: BOC – 10/TVR – 11  Virologic failures: BOC – 6/TVR – 5  Discontinuance: BOC – 17/TVR - 13 Hematologic - BOC – 8/TVR - 4

32.  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.

33. 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

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