9/30/2016 HCV Treatment Peri-Transplant: Update Nothing to Disclose Eliana Agudelo, PA-C Physician Assistant Viral Hepatitis Clinic, UCSF Medical Center Stephanie Straley, PA-C Physician Assistant Viral Hepatitis Clinic, UCSF Medical Center HCV TREATMENT PERI-TRANSPLANT A Brief History of Hepatitis C Medications Objectives 1989 Hepatitis C virus identified 1997 Interferon (alfa -2a, -2b, -alfacon-1) 1998 Interferon + ribavirin � Review of the current HCV treatment options peri-transplant 2001 Peginterferon alfa-2b (PegIntron) � Review of current Direct Acting Antivirals (DAAs) 2002 Peginterferon alfa-2a (Pegasys) 2002 Peginterferon + ribavirin � Review of HCV treatment efficacy data in the post-transplant 2011 Boceprevir (Victrelis, discontinued 2015) patient 2011 Telaprevir (Incivek, discontinued 2014) � Review of HCV treatment special considerations in the post- 2013 Simeprevir (Olysio) transplant patient 2013 Sofosbuvir (Sovaldi) 2014 Sofosbuvir/ledipasvir (Harvoni) � Review of HCV treatment efficacy data in the pre-transplant 2014 Ombitasvir/paritaprevir/ritonavir+dasabuvir patient (ViekiraPak) � Review of HCV treatment special considerations in the pre- 2015 Daclatasvir (Daklinza) transplant patient 2015 Ombitasvir/paritaprevir/ritonavir (Technivie) 2016 Grazoprevir/elbasvir (Zepatier) 2016 Sofosbuvir/velpatasvir (Epclusa) HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT 1
9/30/2016 Multi-targeted Approach for Treatment: Evolution of Chronic Hepatitis C Approved Protease, Polymerase and NS5A Treatment and SVR Rates That Are Inhibitors Achieved 5’ UTR 3’ UTR 9.6 kb RNA region region Discovery Polyprotein NS3/4 Protease of Hep C C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Inhibitors IFN- α 2b PEG-IFN +RBV α 2b+RBV Polyprotein Processing NS5B IFN- α 2a Polymerase PEG-IFN C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Inhibitor α 2a+RBV IFN- α 2b IFN- α con Core Envelope Protease Serine Helicase Serine RNA-dependent Glycoproteins Ledipasvir Protease Protease RNA polymerase NS5A Cofactor Ombitasvir Inhibitors Daclatasvir Elbasvir NS3-4A Velpatasvir NS5B Simeprevir protease polymerase Paritaprevir inhibitors inhibitors Grazoprevir Asunaprevir 2011 2013 2014 1992 1997 2001 2002 1989 1991 1998 non- nucleoside analogs nucleoside analogs SVR 16% 35% 44% 70% ≥ 90% *Agents are investigational Sofosbuvir Dasabuvir Beclabuvir in the United States SVR: sustained virologic response = cure Adapted from McGovern B, Abu Dayyeh B, and Chung HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT RT. Hepatology . 2008; 48:1700-12 Hepatitis C Treatment: How to Keep the Names Straight Common Adverse Effects Ribavirin Simeprevir Elbasvir/Graz Sofosbuvir + Ombitasvir / oprevir Ledipasvir / Paritaprevir Daclatasvir/ Ritonavir Look at the end of the drug’s name: Velpatasvir ±Dasabuvir Hemolysis Fatigue Fatigue Ledipasvir: Fatigue • PREvir = PRotEase inhibitor (hemolytic Nausea Headache Fatigue Nausea anemia) * Headache Nausea Headache Pruritus ‒ Simeprevir, paritaprevir, grazoprevir Elevated Rash Diarrhea Nausea Insomnia indirect • Asvir = NS5A inhibitor Photosensitivity Elevated ALT Asthenia bilirubin Daclatasvir: Elevated Elevated Elevated ALT Rash Fatigue ‒ Ledipasvir, daclatasvir, ombitasvir, elbasvir, bilirubin bilirubin Elevated Nausea Headache bilirubin velpatasvir Insomnia Irritability Velpatasvir • BUvir = NS5B nUcleotide/nUcleotide inhibitor Teratogenic Fatigue ‒ Sofosbuvir, dasabuvir Headache Nausea * Potentially dose limiting. Asthenia HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT 2
9/30/2016 Opportunities to Treat HCV: Natural History of HCV Post-Liver Transplant Post-Liver Transplant Saxena V et al. Clin Liver Dis 2015 D Joshi et al. Nat Rev Gas Hep , 2014 HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT Biggins SW et al. Infect Dis Clin N Am 2006 Treatment Data Post-Transplant Drug-drug interactions with IS Summary Therapeutic options Study Regimen SVR12 Comment DAA Cyclosporine Tacrolimus • More anemia w/ RBV w/o 88% SOF +SMV ± RBV HCV- SVR benefit in SIM/SOF group Healthy Healthy Adjustment Adjustment • Decreased efficacy in TARGET volunteers volunteers SOF/LDV ± RBV 93 -100% decomp Sofosbuvir Not significant Not required No change Not required SOF/LDV + • Less efficacy with CTP B SOLAR-1 93 – 100% RBV and C Not Simeprevir AUC ↑ 19% recommended AUC ↑ 17% Not required SOF + DAC + • NS5A RAVs universal if fail ALLY-1 94% RBV • No decomps Ledipasvir Velpatasvir No change Not required No change Not required ANRS SOF + DAC ± • No benefit from RBV Daclatasvir 93 – 100% CULPIT RBV • No decomps Paritaprevir Ombitasvir AUC ↑ 72% ↓ 20% ↓ a 0.5/wk CORAL-I 3D + RBV 98-100% • F0-F2 (24 weeks) Dasabuvir Elbasvir - TREATING POST-TRANSPLANT HAS HIGH EFFICACY! grazoprevir No change Not required No change Not required JUST REMEMBER CNI AND PI INTERACTIONS. HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT 3
9/30/2016 Risk of Immune Graft Dysfunction Drug Interactions: DAAs and IS with HCV Treatment NS5a inhibitors (--asvir) are known to inhibit P- The risk of developing acute and chronic rejection was a high with glycoprotein and mTOR-inhibitors are substrates to P- interferon (immune-modulator). glycoproteins Treatment with DAA therapies have been clinically associated with immune graft dysfunction • Theoretically one would expect the plasma levels of mTOR- • Transplant recipients treated with DAA regimens exhibit increased inhibitor to increase, but by what magnitude there is no metabolism of IS. published data. • It is postulated that the rapid hepatic recovery after viral clearance • Clinically, this has been observed. leads to improved drug metabolism. • No clinical actionable dose adjustments/ recommendations • This observation suggests that attention needs to be given to IS regarding co-administration of m-TOR inhibitors (e.g. management on treatment and maintenance of target levels be sirolimus, everolimus) and available DAAs closely monitored to avoid rejection episodes as patients clear HCV. . HCV TREATMENT PERI-TRANSPLANT HCV TREATMENT PERI-TRANSPLANT Coadministration of Harvoni and pH-Based Interactions: Acid-Reducing Agents Epclusa with acid- reducing agents Perpetrator Object AUC, % C max , % Ledipasvir and velpatasvir solubility decreases as pH increases. Drugs that increase gastric SOF SOF/VEL (fasted) ↔ ↔ simultaneous with GS-331007 pH are expected to decrease the concentration of ledipasvir and velpatasvir. ↔ ↔ FAM 40mg VEL ↔ ↔ SOF ↓ 23 SOF/VEL (fasted) ↔ 12 h after GS-331007 It is recommended to separate antacid and HARVONI or ↔ ↔ Antacids a FAM 40mg VEL EPCLUSA administration by 4 hours ↔ ↔ SOF ↓ 29 ↓ 34 SOF/VEL (fasted) simultaneous with GS-331007 ↔ ↔ H 2 -receptor antagonists may be administered OME 20mg VEL ↓ 37 ↓ 37 simultaneously with or 12 hours apart from HARVONI or H 2 -receptor SOF ↓ 44 ↓ 45 SOF/VEL (fasted) EPCLUSA at a dose that does not exceed doses comparable to antagonists b 12 h after GS-331007 ↔ ↔ famotidine 40 mg twice daily OME 20mg VEL ↓ 56 ↓ 57 SOF ↓ 16 SOF/VEL (fed) ↔ 2 h after GS-331007 Proton-pump inhibitor doses comparable to omeprazole ↔ ↔ OME 20mg VEL ↓ 37 ↓ 48 20 mg or lower can be administered simultaneously with SOF ↓ 21 SOF/VEL (fed) ↔ HARVONI under fasted conditions 4 h before GS-331007 ↔ ↔ OME 20mg Coadministration of omeprazole or other proton-pump VEL ↓ 26 ↓ 33 Proton-pump SOF ↓ 30 inhibitors is not recommended with EPCLUSA SOF/VEL (fed) ↔ inhibitors c 4 h before GS-331007 ↔ ↔ • If it is considered medically necessary to coadminister, OME 40mg VEL ↓ 53 ↓ 56 EPCLUSA should be administered with food and taken FAM=famotidine; OME=omeprazole 4 hours before omeprazole 20 mg. Use with other Administration of SOF/VEL with FAM 40 mg simultaneously or staggered by 12 hours resulted in no clinically � proton-pump inhibitors has not been studied relevant change in SOF/VEL PK SOF/VEL exposures are lower when co-administered with a PPI under fasting conditions � a Eg, aluminum and magnesium hydroxide. HCV TREATMENT PERI-TRANSPLANT Mogalian, EASL, 2016, Presentation # FRI-168; Mogalian E, HCV TREATMENT PERI-TRANSPLANT b Eg, famotidine. et al., ASCPT 201, PI050 c Eg, omeprazole. 4
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