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HCV resistance
- Clinical point of view
Daniel Beer
PZB Aachen AREVIR-Meeting - Cologne 05.05.2017 t = 25min
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HCV resistance - Clinical point of view Daniel Beer PZB Aachen - - PowerPoint PPT Presentation
HCV resistance - Clinical point of view Daniel Beer PZB Aachen - - PowerPoint PPT Presentation
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,
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http://www.malteser-krankenhaus-stcarolus.de/medizin-und-pflege/anaesthesie-und-intensivmedizin/intensivmedizin.html
Antibiotic treatment Meropenem + Vancomycine
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https://www.miamed.de/amboss/antibiotika-mosaik
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EASL - guidelines 2016 (excerpt)
https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf
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Upcoming
http://www.natap.org/2016/AASLD/AASLD_34.htm http://www.natap.org/2016/images/111516/111516-9/HCV2.gif
…should we do it the „anaesthesiological way“?
VOX
NS3/4A PI
VEL
NS5A inhibitor
SOF
Nucleotide polymerase inhibitor
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https://www.miamed.de/amboss/antibiotika-mosaik
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EASL - guidelines 2016
https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf
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EASL - guidelines 2016
https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf
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EASL - guidelines 2016
https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf
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Reasons to not do it the „anaesthesiological way“
cost-effectiveness shorter duration of treatment reduced pill-burden therapeutic success
- ptions for further treatment after treatment-failure
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Case 1 – resistance testing in genotype 1a
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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
Case 1 – ID 58346
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Points of interest
genotype fibosis/ cirrhosis pretreatment viral load comorbidities potential interactions
- economic
reasons duration of treatment adherence
Decision
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Case 1 – ID 58346
https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf
12 wk treatment SOF/LDV 3D GZR/EBR expenses interactions easy application effectiveness /
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Case 1 – ID 58346
https://www.easl.eu/medias/cpg/HCV2016/English-report.pdf
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Resistance analysis in genotype 1a
Zeuzem S, Ann Int. Med. 2015, 163, 1-13; http://www.hcv-trials.com/showStudy.asp?Study=10
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Resistance analysis in genotype 1a
Zeuzem S, Ann Int. Med. 2015, 163, 1-13; http://www.hcv-trials.com/showStudy.asp?Study=10
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Case 1 – ID 58346
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208261Orig1s000lbl.pdf
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Case 1 – ID 58346
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Decision: treatment with GZR/EBR for 12 weeks
Case 1 – ID 58346
Cost calculation: 12wk SOF/LDV ~53.000€ 12wk GZR/EBR ~35.000€ difference ~18.000€ vs. Resistance analysis ~260€
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Case 2 – resistance testing in retreatment-setting
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Case 2 - ID 20098
gender male age 52 years height 182 cm weight 88 Kg
- rigin
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
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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
Case 2 - ID 20098
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05.04.2004 PEG-IFN 180µg + RBV 1200mg → Non-responder ↓ Progression of fibrosis ↓ 11.01.2007 PEG-IFN 360µg + RBV 1400mg → Non-responder
Case 2 - ID 20098
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
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Resistance analysis week 4 (retrospective) R155I
Case 2 - ID 20098
HCV- RNA (IE/ml) Resistance analysis week 8 V36M + R155K
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Persistence of RAS
Loss of detectable RAS in patients with earlier RAS when failing to treatment with TVR + PegIFN/RBV
Sullivan J, et al. EASL 2011. Abstract 8.
Months after treatment failure
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2014 …two years later…
Case 2 - ID 20098 HCV RNA = 2.2 Mio IU/ml
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Therapeutic options in 2016 ?
Case 2 - ID 20098 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
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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
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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
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HCV resistance analysis 16.01.2017
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Future options
http://www.natap.org/2016/AASLD/AASLD_34.htm http://www.natap.org/2016/images/111516/111516-9/HCV2.gif
VOX
NS3/4A PI
VEL
NS5A inhibitor
SOF
Nucleotide polymerase inhibitor
2018 (?) autumn 2017 autumn 2017
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Future options
Poordad F., MAGELLAN-I, EASL 2017
G/P in GT 1 or 4 patients with DAA failure
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Future options
SVR12 by baseline RASs, %
20 40 60 80 100
98 96 97 100 94 Any RASs NS3 only NS5A only NS3 + NS5A No RASs 43 208 9 127 72
%
- Two patients had S282T at baseline, both achieved SVR12
- None of the patients who relapsed had treatment-emergent RASs
N=
POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6
Bourlière M. AASLD 2016, Abs. 194
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Future options
RASs 46/49 94%
3/49 No RASS 12/43 28%
RASs 31/43 72%
No RASs 18/43 42%
RASs 25/43 58%
No RASs 14/49 29%
RASs 35/49 71% PREVALENCE
NS5A NS3
16 Weeks + RBV 16 Weeks + RBV 24 Weeks 24 Weeks
46 46 3 3 35 35 14 14 31 31 12 12 25 25 18 18
GZR/RZR/UPR – C-SURGE Impact of Baseline NS5A or NS3 RASs on SVR12
Wedemeyer H., C-SURGE 1, EASL 2017
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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.
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…thanks for your attention!
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Zeuzem S, Ann Int. Med. 2015, 163, 1-13; http://slides.hcvonline.org/uploads/179/cedge_treatment_nave.pdf
Resistance analysis in genotype 1a
C-EDGE TN: GZR/EBR in GT 1,4 and 6
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Wedemeyer H., C-SURGE 1, EASL 2017
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Wedemeyer H., C-SURGE 1, EASL 2017
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Stuart KR, POLARIS 1-4, EASL 2017
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Stuart KR, POLARIS 1-4, EASL 2017