HCV resistance - Clinical point of view Daniel Beer PZB Aachen AREVIR-Meeting - Cologne 05.05.2017 t = 25min www.pzb.de
Disclosures Within the last 2 years I received lecture fees and/or sponsoring by the following companies Abbvie, BMS, Gilead, Hexal, Janssen, MSD, ViiV www.pzb.de
Antibiotic treatment Meropenem + Vancomycine http://www.malteser-krankenhaus-stcarolus.de/medizin-und-pflege/anaesthesie-und-intensivmedizin/intensivmedizin.html www.pzb.de
https://www.miamed.de/amboss/antibiotika-mosaik www.pzb.de
EASL - guidelines 2016 (excerpt) https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf www.pzb.de
Upcoming SOF VEL VOX Nucleotide NS5A NS3/4A polymerase inhibitor PI inhibitor …should we do it the „anaesthesiological way“? http://www.natap.org/2016/AASLD/AASLD_34.htm http://www.natap.org/2016/images/111516/111516-9/HCV2.gif www.pzb.de
https://www.miamed.de/amboss/antibiotika-mosaik www.pzb.de
EASL - guidelines 2016 https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf www.pzb.de
EASL - guidelines 2016 https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf www.pzb.de
EASL - guidelines 2016 https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf www.pzb.de
Reasons to not do it the „anaesthesiological way“ cost-effectiveness shorter duration of treatment reduced pill-burden therapeutic success options for further treatment after treatment-failure www.pzb.de
Case 1 – resistance testing in genotype 1a www.pzb.de
Case 1 – ID 58346 Patient M., V. male, 30 years old, caucasian (RUS) GT 1a, diagnosed in 2008 former IVDU F0-fibrosis (FibroScan 6,8 kPa) VL 835.000 IE/ml (abbott) normal transaminases Treatment history: IFN + RBV in 2010, Relapse Substitution: Buprenorphine 4mg drugs: occasionally heroine inhalative www.pzb.de
Points of interest genotype fibosis/ adherence cirrhosis duration of Decision pretreatment treatment oeconomic viral load reasons potential comorbidities interactions www.pzb.de
Case 1 – ID 58346 12 wk treatment SOF/LDV 3D GZR/EBR expenses interactions easy application / effectiveness https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf www.pzb.de
Case 1 – ID 58346 https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf www.pzb.de
Resistance analysis in genotype 1a Zeuzem S, Ann Int. Med. 2015, 163, 1-13; http://www.hcv-trials.com/showStudy.asp?Study=10 www.pzb.de
Resistance analysis in genotype 1a Zeuzem S, Ann Int. Med. 2015, 163, 1-13; http://www.hcv-trials.com/showStudy.asp?Study=10 www.pzb.de
Case 1 – ID 58346 https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208261Orig1s000lbl.pdf www.pzb.de
Case 1 – ID 58346 www.pzb.de
Case 1 – ID 58346 Decision: treatment with GZR/EBR for 12 weeks Cost calculation: 12wk SOF/LDV ~53.000€ 12wk GZR/EBR ~35.000€ difference ~18.000€ vs. Resistance analysis ~260€ www.pzb.de
Case 2 – resistance testing in retreatment-setting www.pzb.de
Case 2 - ID 20098 gender male age 52 years height 182 cm weight 88 Kg origin Italy time of infection unknown first consultation at PZB 01/2001 reason for consultation HIV-infection firstly diagnosed HIV 02/2001 firstly diagnosed HBV 02/2001 firstly diagnosed HCV 07/2001 www.pzb.de
Case 2 - ID 20098 HIV 02/2001 stomatitis due to candida (CD4=242 / 9,7%) 02/2001 initiation of ART: AZT+3TC+SQV/r 12/2001 AZT+3TC+TDF (failure of pre-treatment) 03/2007 AZT+TDF/FTC (simplification) 09/2009 TDF/FTC + RAL (lipodystrophy) HBV HBV-DNA consistently below detection HCV 21.08.2003 HCV-VL: 1,14 Mio IU/ml HCV genotype: 1a IL28B: T/T Liverbiopsy 09/2003: chron. fibros. Inflammation and steatosis, no cirrhosis 05.04.2004 GPT 114 ↑ / PLT 163.000 patient asks for IFN-treatment www.pzb.de
Case 2 - ID 20098 05.04.2004 PEG- IFN 180µg + RBV 1200mg → Non -responder ↓ Progression of fibrosis ↓ 11.01.2007 PEG- IFN 360µg + RBV 1400mg → Non -responder 09.05.2012 HCV VL: 6,0 Mio IU/ml / GPT=114 ↑ / PLT=103.000 FibroScan 26,5 kPa = F4 22.05.2012 RBV 1200 mg (Lead in 4 weeks) 19.06.2012 RBV 1200mg + Telaprevir 2250mg + PEG-IFN 180µg www.pzb.de
Case 2 - ID 20098 HCV- RNA (IE/ml) Resistance analysis week 8 V36M + R155K Resistance analysis week 4 (retrospective) R155I www.pzb.de
Persistence of RAS Loss of detectable RAS in patients with earlier RAS when failing to treatment with TVR + PegIFN/RBV Months after treatment failure Sullivan J, et al. EASL 2011. Abstract 8. www.pzb.de
Case 2 - ID 20098 2014 …two years later… HCV RNA = 2.2 Mio IU/ml www.pzb.de
Case 2 - ID 20098 Therapeutic options in 2016 ? genotype 1a HCV RNA = 387.440 IU/ml liver-cirrhosis CHILD-Pugh A 2 x PEG-IFN + RBV – failure 1 x PEG-IFN + RBV + Telaprevir – failure NS3 RAS: Q80K + R155G ART: TDF/FTC + RAL (VL bld) Co-medication: Omeprazol, Nitrendipin, Citalopram, Ramipril www.pzb.de
Therapeutic options 2016 ? Treatment recommendations for retreatment of HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C who failed to achieve an SVR on prior antiviral therapy containing one or several DAA(s). Potential drug-drug-interactions with co-medication http://www.easl.eu/research/our-contributions/clinical-practice-guidelines/detail/easl-recommendations-on-treatment-of-hepatitis-c-2016 http://www.hep-druginteractions.org www.pzb.de
Therapeutic approach no. 4 06.12.16 SOF/LDV + RBV (planned 12 weeks) 15.12.16 multiple side effects discontinuation of RBV (allergic reaction) 09.01.17 discontinuation of SOF/LDV by the patient 16.01.17 HCV-PCR = 2214 IU/ml www.pzb.de
HCV resistance analysis 16.01.2017 www.pzb.de
Future options autumn 2017 SOF VEL VOX Nucleotide NS5A NS3/4A polymerase inhibitor autumn 2017 PI inhibitor 2018 (?) http://www.natap.org/2016/AASLD/AASLD_34.htm http://www.natap.org/2016/images/111516/111516-9/HCV2.gif www.pzb.de
Future options G/P in GT 1 or 4 patients with DAA failure Poordad F., MAGELLAN-I, EASL 2017 www.pzb.de
Future options POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6 % 100 98 97 96 94 100 80 60 40 20 43 208 9 127 72 N= 0 No RASs Any RASs NS3 only NS5A only NS3 + NS5A SVR 12 by baseline RASs, % Two patients had S282T at baseline, both achieved SVR 12 None of the patients who relapsed had treatment-emergent RASs Bourlière M. AASLD 2016, Abs. 194 www.pzb.de
Future options GZR/RZR/UPR – C-SURGE Impact of Baseline NS5A or NS3 RASs on SVR12 NS5A NS3 16 Weeks + RBV 16 Weeks + RBV 24 Weeks 24 Weeks No No RASs No RASs RASs RASs RASS RASs PREVALENCE RASs 25/43 12/43 31/43 46/49 35/49 3/49 18/43 14/49 28% 42% 58% 29% 72% 94% 71% 12 3 46 18 31 25 14 35 12 31 3 46 18 25 14 35 Wedemeyer H., C-SURGE 1, EASL 2017 www.pzb.de
Conclusion We could do it the „anaesthesiological way“. We should not do it the „anaesthesiological way“ by routine. Even in genotype 1a-infection and especially in re-treatment after DAA-failure, HCV-resistance analysis can give useful information. Use of „future options“ will be driven mainly by label and oeconomic issues. www.pzb.de
…thanks for your attention! www.pzb.de
www.pzb.de
Resistance analysis in genotype 1a C-EDGE TN: GZR/EBR in GT 1,4 and 6 Zeuzem S, Ann Int. Med. 2015, 163, 1-13; http://slides.hcvonline.org/uploads/179/cedge_treatment_nave.pdf www.pzb.de
Wedemeyer H., C-SURGE 1, EASL 2017 www.pzb.de
Wedemeyer H., C-SURGE 1, EASL 2017 www.pzb.de
Stuart KR, POLARIS 1-4, EASL 2017 www.pzb.de
Stuart KR, POLARIS 1-4, EASL 2017 www.pzb.de
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