Preparing for Direct Acting Antivirals (DAAs) in PracticeNew Paradigms in the Management of HCV...

Preparing for Direct Acting Antivirals (DAAs) in Practice—New Paradigms in

the Management of HCV

Sherilyn C. Brinkley, MSN, CRNPNurse Practitioner/Program Manager

Infectious Disease Department

Johns Hopkins University

Baltimore, Maryland

HCV Genotype 1HCV Genotype 1

Peginterferon, weekly

Ribavirin, weight-based, daily

Boceprevir or telaprevir, thrice

daily

Duration variable based on regimen used and on-treatment viral kinetics

HCV Genotypes 2 and 3HCV Genotypes 2 and 311


Ribavirin, 800 mg, daily

Duration 24 weeks

HCV Genotypes 4HCV Genotypes 411


Ribavirin, weight-based, daily

Duration 48 weeks

HCV Standard of Care 2011

Ghany MG, et al. Hepatology. 2009;49:1335-1374.Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Preparing for Anti-HCV Therapy

Case Study—Carmen

• Carmen is a 59-year-old female from Puerto Rico diagnosed with chronic HCV in 1999 after moving to the United States and starting job as medical assistant– Previously evaluated and treated by a

gastroenterologist but fell out of care in 2004– Reports taking peginterferon and ribavirin for

48 weeks leading to an undetectable viral load followed by relapse

• She heard about new anti-HCV drugs with shorter duration and wants more information

Who Is a Candidate for Anti-HCV Treatment with DAAs?

• Adults with chronic HCV genotype-1 infection• Treatment-naive or prior relapsers or

nonresponders• If cirrhotic, should be compensated• Ability to adhere to dosing (peginterferon,

ribavirin, and protease inhibitor) and monitoring schedule

The protease inhibitor is never used as monotherapy

Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

Who Is NOT a Treatment Candidate?• Contraindications to peginterferon/ribavirin apply • Planning for pregnancy or unwilling to use adequate

contraception• Coadministration of contraindicated drugs

– Highly dependent on CYP3A for clearance– Strongly induce CYP3A

• Special populations where safety and efficacy not established– Organ transplant– End-stage liver disease– Coinfected with HIV or HBV– Pediatrics

Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

What Are Key Components of HCV Evaluation?

• Basic lab tests– HCV RNA by PCR, genotype, complete metabolic

panel, prothrombin time/international normalized ratio, thyroid stimulating hormone, pregnancy test

• Liver histology assessment (as needed)– Liver biopsy– Fibrosis markers

• Comorbid disease status• Gauge patient motivation to take anti-HCV

therapy

Carmen’s Laboratory FindingsTest Result Reference Range

Hemoglobin (g/dL) 13.1 12–16.0 g/dL

Platelets (/mm3) 160,000 150,000–400,000

ALT (U/L) 88 ALT (U/L)

Bilirubin, total (mg/dL) 0.7 <1.0

Albumin (g/dL) 4.2 3.5–5.5

Creatinine (mg/dL) 1.1 0.6–1.2

International Normalized Ratio 1.0 1.0–1.2

HCV RNA 1.8 x 109 IU/mL

HCV genotype 1a

Body mass index 29

Liver biopsy Metavir grade 2 inflammationStage 3 bridging fibrosis

Carmen’s Comorbidities and Current Medications

• Comorbidities– Hypertension– Coronary artery disease– Hyperlipidemia– Insomnia

• Current medications – Simvastatin– Aspirin– Trazodone– Atenolol

How Do You Prepare Patients for Therapy?

• Educate about treatment regimens and potential side effects

• Discuss adherence to medications, administration schedule, food requirements, monitoring schedule

• Explain variable treatment durations and futility rules

• Review current medications, herbal products, and supplements for drug interactions

• Counsel regarding pregnancy risk and contraception

How Do You Prepare Your Practice Setting for Integration of DAAs?

• Ensure adequate appointment time for patient counseling

• Limit number of patients starting treatment each week to avoid clinic volume overload

• Use treatment initiation checklist• Use pocket guides for drug interactions,

response-guided therapy, and futility rules• Delegate tasks to others when appropriate

– Prior authorizations– Medication administration teaching– Specialty pharmacy services

Carmen’s Follow-Up Appointment

• Carmen presents to clinic to review labs and biopsy results

• Decision is made to treat with peginterferon, ribavirin, and a protease inhibitor

• Next steps– Discuss side effects and lessons learned from prior

therapy– Review current medication list for drug-drug

interactions and discuss plan for changes– Consult patient’s cardiologist regarding clearance for

treatment and an alternative lipid-lowering agent

Treatment Goals and Challenges

Why Treat Chronic HCV?

• Sustained virologic response (SVR) is achievable

• SVR is associated with gradual regression of fibrosis

• SVR is associated with lower risk of liver failure and hepatocellular carcinoma

Pearlman BL, et al. Clin Infect Dis. 2011;52:889-900.Pearlman BL, et al. Clin Infect Dis. 2011;52:889-900.

What Are the Benefits of Using DAAs?

• Higher SVR rates observed across all patient groups1-4

– Previously untreated, relapsers, partial and null responders

• Response-guided therapy allows for 24- or 28-week duration for most treatment-naive patients with rapid response5,6

1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 3. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 4. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 5. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 6. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 3. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 4. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 5. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 6. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

Boceprevir

SPRINT-21 Naive

RESPOND-22 Nonresponders

1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Sherman KE, et al. 61st AASLD; October 29-November 2, 2010; Boston, Mass. Abstract LB-2. 5. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

Protease Inhibitor Phase III Clinical Trials

Telaprevir

ADVANCE3 Naive

ILLUMINATE4 Naive

REALIZE5 Nonresponders

SPRINT-2—Boceprevir in Treatment-Naive Genotype-1 Patients

Abbreviations: B, boceprevir 800 mg TID; P, peginterferon -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy; TW, treatment week.Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

Two cohorts: 1, nonblack; 2, black.Two cohorts: 1, nonblack; 2, black.

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

SPRINT-2—SVR by Cohort and Treatment Arm

RESPOND-2—Boceprevir in Genotype-1 Prior Nonresponders

Abbreviations: B, boceprevir 800 mg TID; P, peginterferon -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy; TW, treatment week.Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

RESPOND-2—SVR by Prior Response

Abbreviations: B, boceprevir 800 mg TID; P, peginterferon -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

ADVANCE—Telaprevir in Treatment-Naive Genotype-1 Patients

Abbreviations: eRVR, extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12); P, peginterferon -2a 180 µg/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 750 mg q8h.Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

ADVANCE—SVR Rates

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416

REALIZE—Telaprevir in Genotype-1 Prior Nonresponders

Abbreviations: P, peginterferon -2a 180 µg/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 750 mg q8h.Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

REALIZE—SVR by Prior Response

Abbreviations: LI, lead-in; P, peginterferon -2a 180 µg/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 750 mg q8h. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

What Are the Challenges of Triple Combination Therapy?

• Increased complexity– Protease inhibitor dosed every 8 hours– Food requirements– High pill burden

• More adverse effects• Frequent lab monitoring and clinic visits• Emergence of resistance-associated variants

if SVR not achieved• Increased cost

Using Response-Guided Therapy

How Does Response-Guided Therapy Impact Treatment

Duration?

• Both boceprevir and telaprevir use a response-guided therapy approach

• Allows on-treatment virologic response to dictate treatment duration among noncirrhotics

• Early response is the goal and may allow for a shorter duration of therapy

Boceprevir—Response-Guided Therapy

HCV RNA Results

Treatment-Naive Patients

Previous Partial Responders and

Relapsers

Undetectable HCV RNA at weeks 8 and 24

Complete triple therapy at week 28

Complete triple therapy at week 36

Detectable HCV RNA at week 8

Continue triple therapy through week 36, then administer peginterferon/ribavirin only through week 48

For all patients: peginterferon/ribavirin only weeks 1 through 4, then add boceprevir

Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

Boceprevir—Additional Duration Instruction

• Response-guided therapy was not studied in patients who did not achieve early virologic response (<2-log drop in HCV RNA by week 12) during prior therapy– These patients should receive 4 weeks of peginterferon/ribavirin

followed by 44 weeks of triple therapy

• For treatment-naive patients who have a poor response (<1-log drop in HCV RNA) to peginterferon/ribavirin after the 4-week lead-in phase, consider extending boceprevir in combination with peginterferon/ribavirin through week 48

Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

Telaprevir—Response-Guided Therapy

HCV RNA Results

Treatment-Naive Patients

and Prior Relapsers

Prior Partial and Null Responders

Undetectable HCV RNA at weeks 4 and 12

Continue triple therapy through week 12, then

administer peginterferon/ribavirin only

through week 24



through week 48

Detectable HCV RNA at weeks 4 and/or 12



through week 48

For all patients: telaprevir, peginterferon, and ribavirin start on day 1

Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

Should Response-Guided Therapy Be Used in Cirrhotics?

• Boceprevir1

– Patients with compensated cirrhosis should receive 4 weeks of peginterferon alfa and ribavirin followed by 44 weeks of triple therapy

• Telaprevir2

– Treatment-naive patients with cirrhosis who have undetectable HCV-RNA at weeks 4 and 12 of telaprevir combination treatment may benefit from an additional 36 weeks of peginterferon/ribavirin (48 weeks total)

1. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 2. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.1. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 2. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

What If a Patient Has a Poor Virologic Response?

• Futility (stopping) rules are guidelines that require discontinuation of treatment medications at specific time points in the event of inadequate response

• Stopping rules for futility – Decrease drug exposure – Minimize emergence of resistance– Lower cost

Boceprevir—Futility (Stopping) Rules

Week HCV RNA Result

Action

12 ≥100 IU/mL Stop all 3 medications

24 Detectable Stop all 3 medications

Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

Telaprevir—Futility (Stopping) Rules

Week HCV RNA Result

Action

4 >1000 IU/mL Stop all 3 medications

12 >1000 IU/mL Stop all 3 medications

24 Detectable Stop peginterferon/ribavirin (telaprevir already stopped

at week 12)

Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

What Are the Implications of Inadequate Virologic Response?

• HCV has rapid viral dynamics and high mutation rate1

• Baseline resistance mutations exist – 7% of population in boceprevir trials2

– 5% of population in telaprevir trials3

– Some achieve SVR regardless2,3 • Majority of patients with protease inhibitor treatment

failure are left with resistant variants2,3

• Predominant strain returns to wild type in majority within 2 years4,5

• Cross resistance with other protease inhibitors anticipated1

• Long-term clinical impact unknown

1. Kieffer TL, et al. J Antimicrob Chemother. 2010;65:202-212. 2. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 3. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011. 4. Vierling JM, et al. 46th EASL; April 14-18, 2010; Berlin, Germany. Abstract 2016. 5. Sullivan JC, et al. 47th EASL; March 30-April 3, 2011; Barcelona, Spain. Abstract 8.

1. Kieffer TL, et al. J Antimicrob Chemother. 2010;65:202-212. 2. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 3. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011. 4. Vierling JM, et al. 46th EASL; April 14-18, 2010; Berlin, Germany. Abstract 2016. 5. Sullivan JC, et al. 47th EASL; March 30-April 3, 2011; Barcelona, Spain. Abstract 8.

Safety Considerations with DAAs

Are There Drugs to Avoid with Protease Inhibitors?

• Boceprevir and telaprevir are inhibitors of CYP3A1,2

• Use of boceprevir or telaprevir with drugs/herbs metabolized by CYP3A may lead to1,2

– Altered drug concentrations– Loss of therapeutic activity– Adverse events from toxicity

• Refer to lists of contraindicated drugs and drugs to use with caution in FDA-approved product package inserts1,2

• Use drug-drug interaction pocket guide and refer to drug interaction websites– http://www.hep-druginteractions.org/

• Review patient medication/supplement list at each patient interaction


Are There Additional Contraceptive Requirements with DAAs?

• Ribavirin may cause birth defects and fetal death

• Negative pregnancy test prior to therapy and monthly

• 2 forms of contraception during therapy and for 6 months posttherapy– Systemic hormonal contraception should not be relied

upon as effective method during protease inhibitor use• Decreased ethinyl estradiol concentrations

– Use 2 effective nonhormonal methods of contraception (barrier methods or nonhormonal IUD)

Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

What Are the Most Common Side Effects with Protease Inhibitors?

• Boceprevir (≥35% of subjects)1

– Fatigue, anemia, nausea, headache, dysgeusia

• Telaprevir (≥5% higher than in controls)2

– Rash, pruritus, anemia, nausea, hemorrhoids, diarrhea, anorectal discomfort, dysgeusia, fatigue, vomiting, anal pruritus


Anemia Management Is a Mainstay of Anti-HCV Therapy

• Increased anemia with boceprevir and telaprevir• Hematologic parameters at baseline and

treatment weeks 2, 4, 8, 12, and periodically after–typically every 4 weeks–or more frequently as clinically indicated

• Utilize anemia management tools employed with peginterferon and ribavirin– Ribavirin dose reduction– Erythropoietin– Never dose reduce protease inhibitor

Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

Adherence Equals Safety

Adherence with medication regimen is critical but only part of the story

Adherence with…

Medication regimen

Lab schedule

Clinic appointment schedule

Drug interactions schedule

Contraception

Carmen’s Pretreatment Counseling

• Select medication dosing schedule every 7−9 hours for protease inhibitor

• Customize written daily schedule for taking ribavirin and protease inhibitor with detailed food requirements

• Reinforce adherence with doses, labs, and clinic visits• Instruct to not take new medications, supplements, or

herbals without provider clearance• Emphasize to never discontinue or dose reduce the

protease inhibitor• Review side effects of protease inhibitor, peginterferon,

and ribavirin

Carmen’s Pretreatment Counseling

• Discuss and document contraceptive plan – Postmenopausal– Vasectomy

• Review response-guided therapy and potential treatment durations

• Explain rationale for futility rules• Review clinic/provider contact information • Provide lab requisitions, lab schedule, next

appointment reminder• Demonstrate peginterferon injection

Carmen Begins Triple Therapy

• She leaves with lab orders for end of treatment weeks 2 and 4

• She has a follow-up visit scheduled in 2 weeks• She will begin treatment the next day after

breakfast – 1st telaprevir and ribavirin doses at 7:00 am – 1st peginterferon dose planned for 6:00 pm

• She remembers the flu-like symptoms with peginterferon from prior therapy and plans to premedicate with ibuprofen

• She will enlist the support of her family

Summary

• DAAs improve SVR rates among all genotype-1 patient groups

• Triple therapy utilizes response-guided therapy and potential for shortened treatment duration

• Anti-HCV treatment is increasingly complex with drug-drug interactions, increased pill burden and dosing frequency, risk of protease inhibitor resistance, and more side effects

• Pretreatment education requires adequate time and detail to prepare patients for treatment success

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Preparing for Direct Acting Antivirals (DAAs) in PracticeNew Paradigms in the Management of HCV...

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