The document summarizes research on hepatitis C virus (HCV) resistance to treatments. It discusses three key points:
1. HCV can develop resistance to interferon-alpha and ribavirin treatment, as well as direct-acting antivirals (DAAs). Resistance is caused by genetic mutations in the virus.
2. Certain genetic variants of the host, particularly near the IL28B gene, influence treatment response by affecting interferon signaling and HCV kinetics.
3. New DAAs target various stages of the HCV life cycle including the NS3/4A protease, NS5B polymerase, and NS5A protein. While some DAAs have a low barrier to resistance,
This downloadable slideset summarizes key studies selected by Andrew J. Muir, MD, David R. Nelson, MD, and Norah Terrault, MD, MPH, regarding the use of investigational agents for treating hepatitis C presented at the 2015 Annual Meeting of the European Association for the Study of the Liver.
Format: Microsoft PowerPoint (.ppt)
File size: 1.99 MB
Clinical Impact of New Data From AASLD 2015hivlifeinfo
In this downloadable slideset, David R. Nelson, MD, and Norah Terrault, MD, MPH, review key HCV studies presented at the 2015 Annual Meeting of the European Association for the Study of the Liver.
Format: Microsoft PowerPoint (.ppt)
File size: 2.19 MB
Date posted: 12/2/2015
This downloadable slideset summarizes key studies selected by Andrew J. Muir, MD, David R. Nelson, MD, and Norah Terrault, MD, MPH, regarding the use of investigational agents for treating hepatitis C presented at the 2015 Annual Meeting of the European Association for the Study of the Liver.
Format: Microsoft PowerPoint (.ppt)
File size: 1.99 MB
Clinical Impact of New Data From AASLD 2015hivlifeinfo
In this downloadable slideset, David R. Nelson, MD, and Norah Terrault, MD, MPH, review key HCV studies presented at the 2015 Annual Meeting of the European Association for the Study of the Liver.
Format: Microsoft PowerPoint (.ppt)
File size: 2.19 MB
Date posted: 12/2/2015
Πέτρος Καραγιάννης
Καθηγητής Μικροβιολογίας / Μοριακής Ιολογίας, Ιατρική Σχολή, Πανεπιστήμιο Λευκωσίας.
Νέες Εξελίξεις στη Θεραπεία της Χρόνιας Ηπατίτιδας Γ
David Wyles, M.D., of the UC San Diego AntiViral Research Center, presents "HCV in 2015: New Medication Approvals and Innovative Studies...Including a One-Shot Cure?" at AIDS Clinical Rounds
HIV Alert- Novel Strategies and Agents for HIV Management.2016hivlifeinfo
In this downloadable slideset, Daniel R. Kuritzkes, MD, and Paul E. Sax, MD, review potential future HIV treatment strategies—including long-acting ART, dual-therapy regimens, and investigational agents—and discuss where these strategies might fit into the current therapeutic landscape.
Format: Microsoft PowerPoint (.ppt)
File size: 926 KB
Date posted: 6/21/2016
ARVs are included in the drugs with narrow therapeutic index. It's important for every doctors and health care workers to understand mechanism of ARV resistance. Video file is available in the following link: http://www.youtube.com/watch?v=TvNOmwRh0I0&feature=player_detailpage
Patients with acute hepatitis C virus (HCV) infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). Because spontaneous resolution is common, no definitive timing of therapy initiation can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.
Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). These guidelines are constantly being updated. For more information, see HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C.
The guidelines propose that because all patients cannot receive treatment immediately upon the approval of new agents, priority should be given to those with the most urgent need.
The recommendations include the following :
Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and those with severe extraheptic hepatitis are to be given the highest priority for treatment
Based on available resources, patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications should be given high priority for treatment
Treatment decisions should balance the anticipated reduction in transmission versus the likelihood of reinfection in patients whose risk of HCV transmission is high and in whom HCV treatment may result in a reduction in transmission (eg, men who have high-risk sex with men, active injection drug users, incarcerated persons, and those on hemodialysis)
Πέτρος Καραγιάννης
Καθηγητής Μικροβιολογίας / Μοριακής Ιολογίας, Ιατρική Σχολή, Πανεπιστήμιο Λευκωσίας.
Νέες Εξελίξεις στη Θεραπεία της Χρόνιας Ηπατίτιδας Γ
David Wyles, M.D., of the UC San Diego AntiViral Research Center, presents "HCV in 2015: New Medication Approvals and Innovative Studies...Including a One-Shot Cure?" at AIDS Clinical Rounds
HIV Alert- Novel Strategies and Agents for HIV Management.2016hivlifeinfo
In this downloadable slideset, Daniel R. Kuritzkes, MD, and Paul E. Sax, MD, review potential future HIV treatment strategies—including long-acting ART, dual-therapy regimens, and investigational agents—and discuss where these strategies might fit into the current therapeutic landscape.
Format: Microsoft PowerPoint (.ppt)
File size: 926 KB
Date posted: 6/21/2016
ARVs are included in the drugs with narrow therapeutic index. It's important for every doctors and health care workers to understand mechanism of ARV resistance. Video file is available in the following link: http://www.youtube.com/watch?v=TvNOmwRh0I0&feature=player_detailpage
Patients with acute hepatitis C virus (HCV) infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). Because spontaneous resolution is common, no definitive timing of therapy initiation can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.
Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). These guidelines are constantly being updated. For more information, see HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C.
The guidelines propose that because all patients cannot receive treatment immediately upon the approval of new agents, priority should be given to those with the most urgent need.
The recommendations include the following :
Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and those with severe extraheptic hepatitis are to be given the highest priority for treatment
Based on available resources, patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications should be given high priority for treatment
Treatment decisions should balance the anticipated reduction in transmission versus the likelihood of reinfection in patients whose risk of HCV transmission is high and in whom HCV treatment may result in a reduction in transmission (eg, men who have high-risk sex with men, active injection drug users, incarcerated persons, and those on hemodialysis)
La disponibilidad de un sistema de multiplicación del virus de la hepatitis C (VHC) infeccioso en cultivos celulares está permitiendo investigar nuevos factores de respuesta a tratamientos antivíricos en condiciones controladas. Se presentará evidencia de que el fitness vírico puede ser un factor de multiresistencia a inhibidores y quese pueden obtener eficientes reducciones de carga viral empleando diseños secuenciales de administración de inhibidores que incluyan ribavirina. Se discutirán posibilidades de aplicación clínica.
A slideshow for my collegues in hospitals on 2014 Oct 15th.
This presentation is about a case who developed resistance to lamivudine, an anti-HBV agent, during treatment. We discussed about how resistance develop, how to interpret resistance result, and how to optimize the therapy in lamivudine-resistant settings. Time to stop anti-viral agents is also discussed.
Chemical Modifications that Enable Silencing, Expressing and Editing Nucleic Acids for Therapeutic Applications
Extensive chemical modification is the key to success in Antisense, RNAi and now potentially for Genome and mRNA Therapeutic Editing. I will review how the toolbox of backbone, sugar, base and terminal modifications has been deployed throughout the field of RNA therapeutics, and how these modifications affect mechanism, nuclease stability, specificity and delivery. I will also describe the major methods deployed in gene silencing, mRNA Therapeutics™, and Therapeutic Editing™ of mRNA and genomes, including my early work on antisense gapmers, self-delivering siRNA and mRNA editing by nucleobase modification. Lastly, I will describe how chemically modified oligonucleotides have been used without a requirement for programmable nucleases.
Douglas Richman, MD
Distinguished Professor of Pathology and Medicine (Active Emeritus)
Director, The HIV Institute
Co-Director, San Diego Center for AIDS Research
Florence Seeley Riford Chair in AIDS Research (Emeritus)
VA San Diego Healthcare System and University of California San Diego
David Haas, MD, professor at Vanderbilt University School of Medicine, presents "Pharmacogenomics of HIV therapy" for AIDS Clinical Rounds at UC San Diego
Современное лечение и профилактика ВИЧ : передовые стратегии лечения у пациен...hivlifeinfo
Стратегии смены АРТ у пациентов с вирусной супрессией, включая смену АРТ при резистентности, рекомендации по инъекционным препаратам длительного действия , смена АРТ до или во время беременности
HIV Alert:Новые стратегии и агенты в лечении ВИЧ/Novel Strategies and Agents ...hivlifeinfo
HIV Alert-Новые стратегии и агенты в лечении ВИЧ/Novel Strategies and Agents for HIV Management.2017
In this downloadable slideset, Daniel R. Kuritzkes, MD, and Paul E. Sax, MD, review potential future HIV treatment strategies—including dual-therapy regimens, long-acting ART, and investigational agents—and discuss where these might fit into the current therapeutic landscape.
Format: Microsoft PowerPoint (.ppt)
File size: 570 KB
Date posted: 9/27/2017
Presentación realizada por Piedad Arazo Garcés, en el curso de la Jornada Pacientes y Salud: “Foros en el CIBA”. Novedades terapéuticas e importancia del paciente informado, el 12 de noviembre de 2014.
Falcon stands out as a top-tier P2P Invoice Discounting platform in India, bridging esteemed blue-chip companies and eager investors. Our goal is to transform the investment landscape in India by establishing a comprehensive destination for borrowers and investors with diverse profiles and needs, all while minimizing risk. What sets Falcon apart is the elimination of intermediaries such as commercial banks and depository institutions, allowing investors to enjoy higher yields.
Premium MEAN Stack Development Solutions for Modern BusinessesSynapseIndia
Stay ahead of the curve with our premium MEAN Stack Development Solutions. Our expert developers utilize MongoDB, Express.js, AngularJS, and Node.js to create modern and responsive web applications. Trust us for cutting-edge solutions that drive your business growth and success.
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Improving profitability for small businessBen Wann
In this comprehensive presentation, we will explore strategies and practical tips for enhancing profitability in small businesses. Tailored to meet the unique challenges faced by small enterprises, this session covers various aspects that directly impact the bottom line. Attendees will learn how to optimize operational efficiency, manage expenses, and increase revenue through innovative marketing and customer engagement techniques.
B2B payments are rapidly changing. Find out the 5 key questions you need to be asking yourself to be sure you are mastering B2B payments today. Learn more at www.BlueSnap.com.
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RMD24 | Debunking the non-endemic revenue myth Marvin Vacquier Droop | First ...BBPMedia1
Marvin neemt je in deze presentatie mee in de voordelen van non-endemic advertising op retail media netwerken. Hij brengt ook de uitdagingen in beeld die de markt op dit moment heeft op het gebied van retail media voor niet-leveranciers.
Retail media wordt gezien als het nieuwe advertising-medium en ook mediabureaus richten massaal retail media-afdelingen op. Merken die niet in de betreffende winkel liggen staan ook nog niet in de rij om op de retail media netwerken te adverteren. Marvin belicht de uitdagingen die er zijn om echt aansluiting te vinden op die markt van non-endemic advertising.
"𝑩𝑬𝑮𝑼𝑵 𝑾𝑰𝑻𝑯 𝑻𝑱 𝑰𝑺 𝑯𝑨𝑳𝑭 𝑫𝑶𝑵𝑬"
𝐓𝐉 𝐂𝐨𝐦𝐬 (𝐓𝐉 𝐂𝐨𝐦𝐦𝐮𝐧𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬) is a professional event agency that includes experts in the event-organizing market in Vietnam, Korea, and ASEAN countries. We provide unlimited types of events from Music concerts, Fan meetings, and Culture festivals to Corporate events, Internal company events, Golf tournaments, MICE events, and Exhibitions.
𝐓𝐉 𝐂𝐨𝐦𝐬 provides unlimited package services including such as Event organizing, Event planning, Event production, Manpower, PR marketing, Design 2D/3D, VIP protocols, Interpreter agency, etc.
Sports events - Golf competitions/billiards competitions/company sports events: dynamic and challenging
⭐ 𝐅𝐞𝐚𝐭𝐮𝐫𝐞𝐝 𝐩𝐫𝐨𝐣𝐞𝐜𝐭𝐬:
➢ 2024 BAEKHYUN [Lonsdaleite] IN HO CHI MINH
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➢CHILDREN ART EXHIBITION 2024: BEYOND BARRIERS
➢ WOW K-Music Festival 2023
➢ Winner [CROSS] Tour in HCM
➢ Super Show 9 in HCM with Super Junior
➢ HCMC - Gyeongsangbuk-do Culture and Tourism Festival
➢ Korean Vietnam Partnership - Fair with LG
➢ Korean President visits Samsung Electronics R&D Center
➢ Vietnam Food Expo with Lotte Wellfood
"𝐄𝐯𝐞𝐫𝐲 𝐞𝐯𝐞𝐧𝐭 𝐢𝐬 𝐚 𝐬𝐭𝐨𝐫𝐲, 𝐚 𝐬𝐩𝐞𝐜𝐢𝐚𝐥 𝐣𝐨𝐮𝐫𝐧𝐞𝐲. 𝐖𝐞 𝐚𝐥𝐰𝐚𝐲𝐬 𝐛𝐞𝐥𝐢𝐞𝐯𝐞 𝐭𝐡𝐚𝐭 𝐬𝐡𝐨𝐫𝐭𝐥𝐲 𝐲𝐨𝐮 𝐰𝐢𝐥𝐥 𝐛𝐞 𝐚 𝐩𝐚𝐫𝐭 𝐨𝐟 𝐨𝐮𝐫 𝐬𝐭𝐨𝐫𝐢𝐞𝐬."
Recruiting in the Digital Age: A Social Media MasterclassLuanWise
In this masterclass, presented at the Global HR Summit on 5th June 2024, Luan Wise explored the essential features of social media platforms that support talent acquisition, including LinkedIn, Facebook, Instagram, X (formerly Twitter) and TikTok.
The world of search engine optimization (SEO) is buzzing with discussions after Google confirmed that around 2,500 leaked internal documents related to its Search feature are indeed authentic. The revelation has sparked significant concerns within the SEO community. The leaked documents were initially reported by SEO experts Rand Fishkin and Mike King, igniting widespread analysis and discourse. For More Info:- https://news.arihantwebtech.com/search-disrupted-googles-leaked-documents-rock-the-seo-world/
3.0 Project 2_ Developing My Brand Identity Kit.pptxtanyjahb
A personal brand exploration presentation summarizes an individual's unique qualities and goals, covering strengths, values, passions, and target audience. It helps individuals understand what makes them stand out, their desired image, and how they aim to achieve it.
Enterprise Excellence is Inclusive Excellence.pdfKaiNexus
Enterprise excellence and inclusive excellence are closely linked, and real-world challenges have shown that both are essential to the success of any organization. To achieve enterprise excellence, organizations must focus on improving their operations and processes while creating an inclusive environment that engages everyone. In this interactive session, the facilitator will highlight commonly established business practices and how they limit our ability to engage everyone every day. More importantly, though, participants will likely gain increased awareness of what we can do differently to maximize enterprise excellence through deliberate inclusion.
What is Enterprise Excellence?
Enterprise Excellence is a holistic approach that's aimed at achieving world-class performance across all aspects of the organization.
What might I learn?
A way to engage all in creating Inclusive Excellence. Lessons from the US military and their parallels to the story of Harry Potter. How belt systems and CI teams can destroy inclusive practices. How leadership language invites people to the party. There are three things leaders can do to engage everyone every day: maximizing psychological safety to create environments where folks learn, contribute, and challenge the status quo.
Who might benefit? Anyone and everyone leading folks from the shop floor to top floor.
Dr. William Harvey is a seasoned Operations Leader with extensive experience in chemical processing, manufacturing, and operations management. At Michelman, he currently oversees multiple sites, leading teams in strategic planning and coaching/practicing continuous improvement. William is set to start his eighth year of teaching at the University of Cincinnati where he teaches marketing, finance, and management. William holds various certifications in change management, quality, leadership, operational excellence, team building, and DiSC, among others.
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As an Army veteran dedicated to lifelong learning, I bring a disciplined, strategic mindset to my pursuits. I am constantly expanding my knowledge to innovate and lead effectively. My journey is driven by a commitment to excellence, and to make a meaningful impact in the world.
Company Valuation webinar series - Tuesday, 4 June 2024FelixPerez547899
This session provided an update as to the latest valuation data in the UK and then delved into a discussion on the upcoming election and the impacts on valuation. We finished, as always with a Q&A
Company Valuation webinar series - Tuesday, 4 June 2024
Pawlotsky jm résist tt hcv 2014
1. Hépatite C: Résistance
aux Traitements
Prof. Jean-Michel Pawlotsky
CNR des Hépatites B, C et delta
Laboratoire de Virologie & INSERM U635
Hôpital Henri Mondor
Université Paris XII
Créteil
2. HCV Resistance
• IFN--ribavirin treatment failure
• HCV resistance to DAAs
• Treatment Failure with the combination
of Peg-IFN, ribavirin and a DAA
• HCV Resistance in All-oral,
IFN-free regimens
5. Genome-Wide Association
Studies (GWAS)
A population with
distinct clinical
phenotypes
> 3 billion nucleotides
> 10 million SNPs
GWAS chip
> 500,000 ‘tag’ SNPs
> 90% coverage of
common genetic
variation
Bioinformatics to
process data and
associate
genotype with
phenotype
SNP association
6. SNP and SVR in the IDEAL Trial
IL28B
(Ge et al, Nature, 2009;461:399-401)
7. Sustained virological response (%)
SVR in the IDEAL Trial According
to SNP rs12979860 (genotype 1)
100%
80%
60%
40%
20%
0%
(Ge et al., Nature 2009;461:399-401)
TT
N=186
CT
N=559
CC
N=392
9. Viral Kinetics According to
to SNP rs12979860
Mean HCV RNA Decrease
(Log10 IU/mL)
0
-1.0
-2.0
-3.0
TT
CT
-4.0
p < 0.001
-5.0
CC
-6.0
0
2
4
12
Weeks
(Thompson et al., Gastroenterology 2010:139;120-9)
10. VK on High-Dose Peg-IFN
According to IL28B Genotype
Weeks of therapy
0
4
8
12
16
20
24
HCV RNA reduction (Log10 IU/mL)
0
-1
NS
P=0.045
-2
P=0.021
TT
-3
-4
CT
P=0.004
-5
-6
(Chevaliez S, et al., Gastroenterology 2011;141:119-127)
P=0.0005
11. SVR Predictors
Odds Ratio
95% CI
p-value
rs12979860 CC vs non-CC
5.2
4.1
6.7
<0.0001
HCV RNA ≤ 600,000 IU/mL
3.1
2.3
4.1
<0.0001
Caucasian vs African American
2.8
2.0
4.0
<0.0001
Hispanic vs African American
2.1
1.3
3.6
0.004
METAVIR score ≤F2
2.7
1.8
4.0
<0.0001
Fasting blood sugar < 5.6 mmol/L
1.7
1.3
2.2
<0.0001
(Thompson et al., Gastroenterology 2010;139:1181-9)
12. Summary
• In patients infected with HCV genotype
1, the rs12979860 genotype:
• Is strongly associated with the SVR
• Explains 60% of the ethnic influence on SVR
• Influences HCV kinetics on therapy
• Is probably a marker of patient cell “resistance“
to the effect of IFN- through mechanisms that
remain to be elucidated
13. Incidence of Peg-IFN-Ribavirin
Treatment Failures
60
58%
54%
PEG-IFN-α2a+ribavirin (Fried et al)
48%
PEG-IFN-α2a+ribavirin (Hadziyannis et al)
PEG-IFN-α2b+ribavirin (Manns et al)
45
30
24%
16%
15
18%
2%
0
Genotype 1
Genotypes 2/3
(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
18. Summary
• HCV resistance to IFN- antiviral effect
exists
• Its molecular mechanisms are unknown
and probably complex
• It accounts for only a small part of IFN-based treatment failures
43. Nucleoside/Nucleotide Analogue
Inhibitors of HCV RdRp
Phase
Dose
Duration
Median/mean log
HCV RNA level
reduction
Sofosbuvir (Gilead)
III
400 mg qd
3 days
-3.7
VX-135 (ALS-2200, Vertex)
II
200 mg qd
7 days
-4.5
Mericitabine (Roche)
II
1500 mg bid
14 days
-2.7
Drug
44. HCV Resistance to 2’-C-Methyl
Nucleoside Inhibitors
2’C-Me-ATP in the catalytic site
(Migliaccio et al., J Biol Chem 2003;278:49164-70)
45. Sofosbuvir Resistance
• Sofosbuvir binds to the highly conserved catalytic
site of the HCV RdRp
• S282T
• Is the only known aa substitution conferring phenotypic
resistance to sofosbuvir
• Is associated with low-level resistance (<20-fold) in vitro
• Results in a severe reduction of replication capacity in vitro
and in vivo
• No S282T variants found at baseline by population
sequencing (n=1992) or deep sequencing (n=576)
(Gilead, data on file)
47. Non-Nucleoside Inhibitors
of HCV RdRp (NNIs)
Phase
Dose
Duration
Median/mean log
HCV RNA reduction
Tegobuvir (Gilead)
II
40 mg bid
8 days
-1.4
Setrobuvir (Roche)
II
800 mg bid
3 days
-2.9
Deleobuvir (BI207127, BI)
II
800 mg q8h
3 days
-3.1
ABT-333 (AbbVie)
III
600 mg bid
2 days
-1.5
ABT-072 (AbbVie)
III
600 mg qd
3 days
-1.6
Lomibuvir (VX-222,
Vertex)
II
750 mg bid
3 days
-3.7
GS-9669 (Gilead)
II
500 mg qd
3 days
-3.1
BMS-791325 (BMS)
II
?
?
?
TMC647055 (Janssen)
Ib
1000 mg bid
6 days
-3.4
Drug
48. Non-Nucleoside Inhibitors (NNI)
Thumb I
Deleobuvir (BI207127)
BMS-791325
TMC647055
Palm I
Setrobuvir
ABT-333
ABT-072
A
B
C
D
Thumb II
Filibuvir
Lomibuvir (VX-222)
GS-9669
Palm II
Tegobuvir
49. HCV NNI Resistance Mutations
95
142
Thumb
A
C
495
499
496
423
419
411
96
451
448
316
365
201
Palm
D
(courtesy of Isabel Najera, Roche)
176
414
482
B
282
Fingers
50. NS5A Protein
Required for HCV RNA
replication
NS5A Dimer
Domain III
Domain II
Domain I
Cytosol
Required for HCV viral
particle assembly
ER membrane
ER lumen
May be involved in the
release of HCV particles
51. NS5A Inhibitors
Phase
Dose
Duration
Median/mean log
HCV RNA reduction
Daclatasvir (BMS)
III
10 mg qd
1 day
-3.2
Ledipasvir (GS-5885, Gilead)
III
30 mg qd
3 days
-3.3
PPI-461 (Presidio)
II
100 mg qd
3 days
-3.7
PPI-668 (Presidio)
II
240 mg qd
3 days
-3.7
ACH-2928 (Achillion)
II
60 mg qd
3 days
-3.7
ABT-267 (AbbVie)
III
200 mg qd
3 days
-3.1
GSK2336805 (GSK)
II
60 mg qd
1 day
-3.0
BMS824393 (BMS)
II
50 mg qd
3 days
-3.9
Samatasvir (IDX719, Idenix)
II
50 mg qd
3 days
-3.7
MK-8742 (2nd-gen, Merck)
Ib
50 mg qd
5 days
-4.1
ACH-3102 (2nd-gen, Achillion)
Ib
50 mg qd
1 day
-3.8
GS-5816 (2nd-gen, Gilead)
Ib
50 mg qd
3 days
-4.0
Drug
52. NS5A Inhibitor Resistance
Effect of NS5A Domain I Mutations on
Replication and Daclatasvir Potency
Mutation
Fold Resistance
Replication Level, %a
Wild-type
1
100
F28S
7735
125 49
L31M
141
83 37
C92R
98
10 8
Y93H
749
NS5A Dimer, Domain I
81 21
Means standard deviations from transient-transfection assays with
luciferase reporter replicon.
Primary and secondary mutation sites
(Fridell et al., Hepatology 2011;54:1924; Aghemo & De Francesco Hepatology 2013;58:428)
61. Treatment Failures on Triple
Combination with a DAA
• Due to an inadequate response to PegIFN and ribavirin
• Results in uncontrolled outgrowth of
resistant HCV variants selected by the
protease inhibitor
(Pawlotsky JM. Hepatology 2011;53:1742-51)
62. SVR According to Lead-in
(SPRINT-2, non-black)
100
% of patients with SVR
90
82%
82%
80
70
60
<1 log HCV RNA
decrease
50
39%
40
30
≥1 log HCV RNA
decrease
29%
20
10
0
BOC/RGT
(Poordad et al., N Engl J Med 2011;364:1185-206)
BOC/PR48
64. Probability of TelaprevirResistant Variant Detection
1.0
0.9
Median time to wild-type by population
sequencing =7 months (95% CI: 5-8)
0.8
Probability
0.7
0.6
median
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
Time after treatment failure (months)
(Sullivan et al., EASL 2011)
18
66. Practical Recommendations
• Prior to therapy:
• All patients should be considered as harboring minor viral
populations that are resistant to telaprevir and boceprevir
• There is no indication for resistance testing at baseline
67. Practical Recommendations
• In case of treatment failure:
• Protease inhibitor-resistant viral populations have been
enriched in every patient treated with telaprevir or
boceprevir who did not clear infection
• There is no indication for resistance testing during and
after therapy, as the result will have no impact on treatment
decisions
• Resistance testing is required in clinical trials and global
surveillance studies (research setting)
69. P + R + Simeprevir-QUEST-1/2
Phase III, Treatment-naive, Gen 1
Simeprevir + PR
(RGT 12+12)
100
90
SVR24 rate (%)
80
Placebo + PR
81%
80%
70
60
50%
50%
50
40
30
20
10
0
N=264
N=130
QUEST-1
(Jacobson et al., EASL 2013; Manns et al., EASL 2013)
N=257
N=134
QUEST-2
70. P + R + Simeprevir-QUEST-1/2
Role of HCV subtype and Q80K substitution
*Q80K prevalence in 1500 clinical specimens sent to an US commercial lab
• GT 1a: 32.5%
• GT 1b: 0.1%
(Jacobson et al., AASLD 2013; Choe et al., AASLD 2013; FDA AVDAC, Oct 24, 2013)
71. Summary of Simeprevir
Resistance Data
• Baseline Q80K polymorphism
• Present in 41% of patients with genotype 1a infection
• Associated with lower SVR12 rate in QUEST-1
• Selection of NS3 protease substitutions in >90%
of patients without SVR
• Genotype 1a: R155K alone, with mutations at positions 80
and/or 168;
• Genotype 1b: most common substitutions: D168V,
Q80R+D168E
(Jacobson et al., EASL 2013; Manns et al., EASL 2013)
73. P + R + Sofosbuvir-NEUTRINO
Phase III, 12 weeks, Gen 1-4-5-6,
Treatment-naive
100
96%
100%
90%
89%
N=327
N=292
N=28
N=7
TOTAL
Genotype 1
(89%)
Genotype 4
(9%)
Genotype 5, 6
(2%)
90
SVR12 rate (%)
80
70
60
50
40
30
20
10
0
(Lawitz et al., N Engl J Med 2013;368:1878-87)
74. Sofosbuvir Resistance in
Phase III Trials
• S282T identified as primary mutation in
all replicon genotypes (1–6)
• No genotypic or phenotypic resistance to
sofosbuvir observed
• L159F identified in 3% of relapse patients
with no phenotypic shift
92. Conclusions
• In the real life, 5-15% of patients receiving alloral, IFN-free regimens may fail to eradicate
HCV
• In most cases, treatment failures will be
associated with/due to multidrug resistant
viruses
• Retreatment strategies will need to be well
defined in this patients