Interferon Side Effects and The Future of Interferon Sparing Regimens Todd Wills, MD ETAC Infectious Disease Specialist HEPATITIS C TREATMENT EXPANSION INITIATIVE MULTISITE CONFERENCE CALL FEBRUARY 15, 2012
Managing Adverse Effects: PegIFN PegIFN Depression Decreased WBC and platelets Influenzalike symptoms Dry, itchy skin GI upset Hair loss Insomnia Injection-site reactions Surveillance/Treatment Assess mood prior to treatment and during treatment Ask about mood, sleep, suicidal thoughts Consider SSRI to treat baseline or new depression Ask mental health services to follow high-risk patients during HCV treatment Monitor CBC frequently Ask about symptoms of infection or bleeding Reduce dose of interferon Acetaminophen Hydration Reduce dose of interferon Moisturizing lotion Antihistamines Antiemetics Dietary supplements Appetite stimulants Encouragement Diphenhydramine or other sleep aid Alternate injection sites; stomach and thighs are good places to inject Inject at 45-90 degree angle to skin Warm interferon in hand prior to injecting
Management of Neutropenia Primary strategy is peginterferon dose reduction Permanent discontinuation rarely necessary, but temporary discontinuation necessary for: ANC < 400 cells/mm 3 Active bacterial infection AND ANC < 500 cell/mm 3 Permanent discontinuation for neutropenia which is refractory to peginterferon dose reduction and filgrastim (G-CSF)
Use of Filgrastim (G-CSF) For ANC <500 cells/mm 3 Neutropenia which dose not respond to level 1 peginterferon dose reduction G-CSF 300 mcg SC once or twice weekly Monitor ANC at least 1-2X weekly Redose based on response G-CSF may need dosed 2-3x/week in some cases to maintain ANC >500 cells/mm 3 Hold G-CSF for ANC > 750 cells/mm 3
Level 1 Dose Reductions Indications peg-interferon alfa-2a dose Peg-interferon alfa-2b dose Monitoring Moderate to severe depression *ANC <500 cells/mm 3 Platelet count <40,000 but >25,000 135 mcg weekly 1.0 mcg/kg weekly Clinical/laboratory evaluation at least every 2 weeks until stabilized Level 2 Dose Reductions Indications peg-interferon alfa-2a dose Peg-interferon alfa-2b dose Monitoring severe depression *ANC <500 cells/mm 3 not responding to level 1 reduction Platelet count <40,000 but >25,000 not responding to level 1 reduction 90 mcg weekly 0.5 mcg/kg weekly Clinical/laboratory monitoring at least every 2 weeks until stabilized NOTE: When the clinical parameter stabilizes after dose reduction, the peg-interferon dose should remain at the decreased level for the duration of therapy. *The use of filgrastim (G-CSF) when the ANC falls below 500 cells/mm3 may limit the need for further interferon dose reductions and makes the need for therapy discontinuation unlikely Stopping Therapy Neutropenia refractory to dose reduction AND filgrastim (rare) Platelet count below 25,000 therapy should not be restarted Active suicidal ideation or rapid development of severe depression Adapted from Florida Caribbean HIV/HCV Pocketcard
The evolving biochemical profile of thyroid hormones in IFN-induced thyroiditis. Tran H et al. QJM 2009;102:117-122
Additional Patient Populations With Need Contraindication or poor tolerance to pegifn or RBV Safety and efficacy of boceprevir and telaprevir not yet established in certain special populations Organ transplant recipients Patients with end-stage liver disease Patients with HIV and/or HBV coinfection Pediatric patients PIs not recommended in patients with decompensated cirrhosis or moderate to severe hepatic impairment Though pegifn/rbv effective for genotypes 2/3, better options desired, ideally IFN free Boceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011.
What Are the Key Elements of an Ideal HCV Regimen? Simple Regimen Short duration, simple, straightforward stopping rules Easy Dosing Once daily, low pill burden All Oral PegIFN/RBV replaced with alternate backbone with low chance of resistance Pan-Genotypic Regimen can be used across all genotypes Highly Effective High efficacy in traditionally challenging populations (ie, nulls, cirrhosis) Safe and Tolerable Few or easily manageable adverse effects From Clinical Care Options: Stefan Zeuzem, MD
Evolution of HCV Therapy 2001 2011 Beyond PegIFN/RBV Protease inhibitor Nucleos(t)ide polymerase inhibitor Nonnucleoside polymerase inhibitor NS5A inhibitor Host targeting agent From Clinical Care Options: Stefan Zeuzem, MD
Daclatasvir + Asunaprevir ± PegIFN/RBV in Previous PegIFN/RBV NS5A inhibitor daclatasvir (BMS-790052) 60 mg QD + NS3 protease inhibitor asunaprevir (BMS-650032) 200 mg BID* for 24 wks [1] All patients had genotype 1b HCV High SVR rates, as in previous US study that evaluated combination with, without pegifn/rbv [2] Null Responders SVR24 (%) 100 80 60 40 Daclatasvir + asunaprevir Daclatasvir + asunaprevir + PegIFN/RBV AASLD 2011: Japan Study (N = 10) [1] 90 US Study [2] 36 90 *Started at 600 mg BID but reduced due to elevated transaminases in separate study. 20 n/n = 0 9/10 N/A 4/11 9/10 1. Chayama K, et al. AASLD 2011. Abstract LB-4. 2. Lok A, et al. EASL 2011. Abstract 1356.
Ongoing Research Evaluates Potential for All-Oral Therapy Several all-oral regimens under investigation Protease inhibitor NS5A inhibitor Nucleos(t)ide analogue polymerase inhibitor Nonnucleoside polymerase inhibitor Drug 1 Drug 2 Drug 3 RBV BI 201335 BI 207127 N/A ± PSI-7977 PSI-938 N/A ± ABT-450/ RTV ABT-333 or ABT-072 N/A PSI-7977 Daclatasvir N/A ± GS-9256 Tegobuvir N/A ± GS-9451 GS-5885 ± Tegobuvir ± Asunaprevir Daclatasvir BMS-791325 N/A All-oral regimens of single drug + RBV also under investigation. + SVR (%) IFN-free regimens shown to be highly effective in GT2/3 [1] Nucleotide analogue PSI-7977 + RBV for 12 wks 100 80 60 40 20 0 PegIFN included for 0, 4, 8, or 12 wks 100 100 100 100 PSI-7977 + 0 wks PegIFN (IFN-free) PSI-7977 + 4 wks PegIFN PSI-7977 + 8 wks PegIFN PSI-7977 + 12 wks PegIFN 1. Gane EJ, et al. AASLD 2011. Abstract 34.
SOUND-C2 Interim Analysis: BI 201335 + BI 207127 RBV in GT1 Tx-Naive Patients NS3/4A protease inhibitor BI 201335 and nonnucleoside polymerase inhibitor BI 207127 ± RBV Preliminary SVR12 analysis: high response rates in arm with BI 201335 120 mg QD + BI 207127 600 mg TID + RBV for 16 wks (n = 81) Patients (%) 100 80 60 40 20 70 0 ETR SVR12 Relapse n/n = 65/81 48/81 12/81 Zeuzem S, et al. AASLD 2011. Abstract LB-15. 86 43 69 23 10 Genotype 1a Genotype 1b
Current Phase III Trials Telaprevir in GT1 IL28B CC patients TVR BID + TVR BID + TMC435 in GT1 patients TMC435 + TMC435 + Daclatasvir in GT1/4 patients Daclatasvir + Daclatasvir + PSI-7977 across genotypes PSI-7977 + R Telaprevir + VX-222 + in GT1 QUAD BI 201335 in GT1 patients BI 201335 + BI 201335 + BI 201335 +