Jorge L. Herrera, MD, MACG HCV – Retreatment of DAA Failures JORGE L. HERRERA M.D., MACG UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE, MOBILE, AL DAA Drug Classes NS3/4 (protease) inhibitors ◦ Telaprevir, boceprevir, simeprevir, paritaprevir ◦ Coming soon: grazoprevir NS5a Inhibitors ◦ Ledipasvir, dasabuvir, Daclatasvir ◦ Coming soon: Elbasvir, velpatasvir NS5b (polymerase) ◦ Sofosbuvir (nucleoside) ◦ Ombitasvir (non-nucleoside) In general: Resistance is shared among classes ◦ New generation drugs may overcome resistance within class Resistant mutants are sensitive to drugs from other classes ◦ Basis for multiple drug cocktails New generation drugs within a class may overcome existing resistance ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology Page 1 of 17
Transcript
Jorge L. Herrera, MD, MACG
HCV – Retreatment of DAA FailuresJORGE L. HERRERA M.D., MACG
UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE, MOBILE, AL
DAA Drug ClassesNS3/4 (protease) inhibitors◦ Telaprevir, boceprevir, simeprevir,
+ = very low barrier to resistance ++++++ = very high barrier to resistance
Schaefer EA, et al. Gastroenterology 2012;142:1340-1350
Determinants of barrier to resistanceNumber of mutations needed to become resistant◦ 1st Generation protease inhibitors◦ Genotype 1a – 1 mutation◦ Genotype 1b – 2+ mutations
Fitness of the resultant mutant◦ Nucleoside polymerase inhibitor-resistant mutant – very unfit◦ Protease inhibitor-resistant mutant – retain some fitness◦ Non-nucleoside polymerase inhibitor mutants – remain fit◦ NS5a – remain fit
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 2 of 17
Jorge L. Herrera, MD, MACG
Persistence of Resistance After Failure to Pr/O/DGenotype 1a patients
Persistence assessed 48 weeks after discontinuation of therapy
Resistance Mutation Percent Persisting at 48 wkNS3 9%
NS5b (non-nucleoside) 57%NS5a 96%
Krishnan P, et al. J Hepatol 2015;62:S220, Abstract O057
Informs decision-making process on how to re-treat prior failures
Resistant Variants are Selected During Therapy
XX
Sensitive (wild) virus Resistant virus
Baseline Antiviral TherapyResistant
variants expand
Pawlotsky JM. Clin Liv Dis 2003;7:45-66
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 3 of 17
Jorge L. Herrera, MD, MACG
Clinical Management of DAA Failures
Clinical Practice ScenariosFailedIFN + boceprevir, telaprevir or simeprevir
IFN + sofosbuvir + ribavirin
Sofosbuvir + ribavirin
Sofosbuvir + simeprevir
Sofosbuvir + ledipasvir
Paritaprevir + ombitasvir + dasabuvirLevel of Difficulty
+
-
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
G1 Prior Sofosbuvir Failures (no NS5a)PegIFN + sofosbuvir + ribavirin or sofosbuvir + ribavirin
Hcvguidelines.org accessed May 16, 2016
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 7 of 17
Jorge L. Herrera, MD, MACG
G1 Failures to Sofosbuvir + SimeprevirDefer therapy if possibleIf cirrhosis or urgent need for therapy:◦ Test for NS3 and NS5a resistance◦ If using a sofosbuvir based regimen with two drugs◦ Use ribavirin, treat for 24 weeks
◦ Best to use a sofosbuvir-based triple or quadruple DAA regimen
Failed 8-12 weeks, re-treated with 24 weeks of ledipasvir + sofosbuvir
Lawitz E, et al. J Hepatol 2015;62:S192, Abstract O005
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 10 of 17
Jorge L. Herrera, MD, MACG
Re-Treatment of LDV/SOF Failures – Effect of Baseline RAVs
NS5b variants (S282T) emerged during retreatment in 4/12 patients with virologicfailure
Lawitz E, et al. EASL 2015, Abstract O005
Re-Treatment of NS5a Containing Regimen FailuresData is very limitedPersistence of NS5a resistant polymorphism is likely◦ Particularly if prior treatment was >12 weeks
Co-existence of NS3 resistant polymorphisms affects choice of therapyPre-treatment resistance testing important
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 11 of 17
Jorge L. Herrera, MD, MACG
Treatment of Genotype 1 NS5a-Experienced Patients AASLD/IDSA Guidance
If mild liver disease◦ Defer treatment until data available
Cirrhosis or need for urgent therapy◦ Test for NS3 and NS5a resistance-associated variants (RAVs)
RAV Testing Result Retreatment Regimen Duration
No NS5a RAVs Ledipasvir/sofosbuvir + ribavirin 24 weeks
NS5a but no NS3 RAVs Simeprevir + sofosbuvir + ribavirin 24 weeks
NS5a and NS3 RAVs Refer to clinical trial
Testing for Resistance is Commercially AvailableResistance Panel Quest LabCorp
NS3 90924 550540
NS5a 92447 550325
NS5b 92204 550505
Currently, testing is only available for genotype 1
Controversies How accurate are these tests? How many mutations are too many?Which mutations do we need to pay attention to?
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 12 of 17
Jorge L. Herrera, MD, MACG
Mutations of Importance for NS5a experienced Patients
Paritaprevir/Ombitasvir/DasabuvirFailuresFew data availablePatients who have failed often have resistance to◦ NS3◦ NS5a◦ NS5b
Defer therapy if mild liver diseaseTest for resistance if therapy needed now◦ Design a sofosbuvir-based regimen
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
Page 16 of 17
Jorge L. Herrera, MD, MACG
Take Home Points1. Fortunately, the majority of treated patients are cured!
2. Get it right the first time!
3. For the second time around◦ Treatment is easy if failed a 1st generation PI◦ Options are good if failed sofosbuvir + ribavirin◦ Use pre-treatment RAVs testing for failures to◦ NS5a◦ Non-nucleoside NS5b
4. Refer to the HCV guidance document for latest updates
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
