Disclosures Research Grant support to UCSF from Advanced HCV - - PDF document

12/8/17 1

Advanced HCV management

Annie Luetkemeyer, MD Division of HIV, ID and Global Medicine ZSFG, UCSF

Disclosures

• Research Grant support to UCSF from
• AbbVie
• Gilead
• Merck
• Proteus
• NIH

Overview

• Renal failure
• Acute HCV
• Retreatment
• Resistance testing
• Decompensated cirrhotics
• HCV treatment for children and pregnant

women

Renal failure

12/8/17 2 HCV can worsen renal failure (and vice versa)

Tran AASLD 2017

• Glecaprevir/pibrentasvir

– Duration as per non-cirrhotic prescribing recommendations

• Grazoprevir/Elbasvir x12 weeks

– C-Surfer trial did not give RBV (N=111, 52% GT1a) (Roth Lancet 2015)

VA evaluation of GLE/PIB in CKD

Kramer AASLD 2017

What if patient can’t take HCV PI?

12/8/17 3

SOF in renal failure

• SOF not approved for use at CrCl<30 due to

increased metabolite

• Small studies of simprevir + SOF (regular or ½ dose)

– Overall high SVR, generally well tolerated

• Target: SOF + RBV, SIM, PEG

– Similar cure rates – HOWEVER, worse anemia (RBV), progression of renal dz (? causality)

Saxena Liver Int 2016

< 30 30-45 45-60 >60

Sofosbuvir-based regimens in ESRD

• Number of small studies demonstrating safety and efficacy
• f SOF-based regimens in CKD

– 18 GT1 patients with GFR < 30 but not on dialysis, 12 weeks SOF/LDV without

RBV

Lawitz E, et al. AASLD 2017. Abstract 1587.

• NO clinically

meaningful change in eGFR

Sofosbuvir-based regimens in ESRD

• Number of small studies demonstrating safety and efficacy
• f SOF-based regimens in CKD

– 18 GT1 patients with GFR < 30 but not on dialysis, 12 weeks SOF/LDV without

RBV

Lawitz E, et al. AASLD 2017. Abstract 1587.

• NO clinically

meaningful change in eGFR

Take Home: Stick with approved regimens when feasible but SOF- based regimens are an alternative, particularly if can avoid RBV

Acute HCV Considerations

• No indication for HCV PEP
• Consider monitoring for

spontaneous clearance

• Consider early treatment :

– HCV transmission prevention – Reduce risk of clinical complications (ex: already cirrhotic) – Concern for LTFU in 3-6 months

• IF HCV RNA <LLOD, repeat

at least 12 weeks later to confirm clearance

Adapted from EACS Guidelines version 9.0, www.eacsguidelines.org

12/8/17 4

SWIFT-C

Naggie #196 AASLD 2017

• 100% SVR with 8 weeks of SOF/LDV in HIV(+) men with acute

HCV

• Acute HCV defined as < 24 of week of infection or reinfection after clearance,

new HCV RNA+ and

• ALT > 5x ULN if previously normal within 12 months
• ALT>10X ULN if no ALT baseline
• Documentation of new HCV Ab(+) or RNA (+) w/in past 6 months

Or treat the same as chronic HCV- now have 8 week option

Shortened Regimens? Treating DAA failures

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First steps after NS5a failure

2016 Message:

• Identify any patient related issues that

contributed to failure: poor adherence, treatment interruption, drug-drug interactions, intolerance

• Resistance testing:

– At least NS5a & consider NS3a/4 ( HCV PI) – Low utility to test for NS5b (nucleotide) resistance

First steps after NS5a failure

2016 Message:

• Identify any patient related issues that

contributed to failure: poor adherence, treatment interruption, drug-drug interactions, intolerance

• Resistance testing:

– At least NS5a & consider NS3a/4 ( HCV PI) – Low utility to test for NS5b (nucleotide) resistance

Principles of treating DAA failures

• Type of prior treatment important, i.e. NS5a or

NS3 alone, vs NS5a & NS3 together (EBR/GRZ or GLE/PIB)

• PEG/RBV +/- SOF failures treated as treatment

naïve, except for GT3 treated with GLE/PIB

• Ribavirin & treatment extension to 24 weeks

generally unnecessary

• Resistance testing generally unnecessary

Improved resistance profile of “Next Generation” NS5As

Wang C. AAC 2012. Wang C. AAC 2014. Cheng G, et al. EASL 2012. Abstract 1172. Zhao Y, et al. EASL 2012. Abstract A845. Yang G, et al. EASL 2013. Abstract 1199. Ng T, et al. CROI 2014. Abstract 639. Asante-Appiah E, et al. AASLD 2014. Abstract 1979. Ng T. THU-305 EASL 2017.Lawitz E. AAC 2016.

Fold Change Genotype 1a Genotype 1b GT3a M28T Q30R L31M/V Y93H/N L31V Y93H Y93H Ledipasvir 20x > 100x > 100x/ > 100x > 1000x/ > 10,000 > 100x N/A Ombitasvir > 1000x > 100x < 3x > 10,000x/ > 10,000x < 10x 20x N/A > 100x Daclatasvir > 100x > 1000x > 100x/ > 1000x > 1,000x/ > 10,000x < 10x 20x >1000x Elbasvir 20x > 100x > 10x > 1000x/ > 1000x < 10x > 100x N/A > 100x Velpatasvir < 10x < 3x 20x/50x > 100x/ > 1000x < 3x < 3x >100x Pibrentasvir < 3x < 3x < 3x 7x/7x < 3x < 3x <3x Ruzasvir < 10x < 10x < 10x < 10x < 10x < 10x

12/8/17 6

SOF/VEL/VOX

• Has become mainstay for retreatment of NS5a

failure as well as other DAA failures

• Vosevi Package insert

Triple DAA therapy for re-treatment

SVR12: 96% GT1a; 100% GT1b; 95% GT3

POLARIS-1 (n=263)

NS5A experienced 46% cirrhosis

POLARIS-4 (n=182)

NO NS5A exposure 46% cirrhosis 97% SVR vs 90% SOF/VEL No cirrhosis Cirrhosis SOF/VEL/VOX: 98% GT1a; 96% GT1b; 94% GT3 Bourliere M. NEJM 2017. 96 99 93 20 40 60 80 100 All No Cirrhosis Cirrhosis SOF/VEL: 89% GT1a; 95% GT1b; 85% GT3

Regimen: SOF/VEL/VOX for 12 weeks

4/101 GT1a non-SVR 2 LTFU 1 relapse 1 BT (non-compliance)

No impact of pre-treatment RASs

Sarrazin C. et al. #THU-248 EASL 2017.

POLARIS-1 POLARIS-4 No impact by genotype or VEL and VOX specific RASs

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Non-NS5a, treatment experienced, +/- cirrhosis GT3 Cirrhotic, Treatment naïve or experienced (non-DAA failures)

Zeuzem AASLD 2016, Bourliere NEJM 2017, Foster NEJM 2016

GLE/PIB for retreatment

• Magellan-1: DAA experienced with or without

cirrhosis, GT1 and 4 only, GLE/PIB x 12 or 16 weeks

Poodad EASL 2017 Poordad EASL 2017 Mavyret package insert

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• PRS= Prior PEG/RBV +/- SOF
• Essentially the same as treatment naïve except for GT3

patients- extend to 16 weeks

Mavyret package insert Krishnan AASLD 2017

C-ISLE

Foster 2017 EASL

• Treatment experienced, cirrhotic GT3 patients
• ELB/GRZ/SOF with or w/o RBV

SOF/VEL/VOX & GLE/PIB failures??

12/8/17 9

GLE/PIB failures

Pilot-Matias T. SAT-204. EASL 2017.

• In 2256 Phase 2/3 participants, < 1% developed viral resistance
• BUT, when patients DO fail, the patterns are complex with

substantial resistance

Lack of additional RAS selection in failures

Sarrazin C. et al. #THU-248 EASL 2017. Bourliere AASLD 2007

All POLARIS-1 relapses also had cirrhosis POLARIS-1 Deferred treatment

SOF/VEL/VOX & GLE/PIB failures

• Consider resistance testing of NS3 and NS5a
• No data (yet) to guide retreatment

Consider:

• GLE/PIB failures-> SOF/VEL/VOX +/- RBV or

GLE/PIB/SOF (data forthcoming from Magellan- 3)

• SOF/VEL/VOX failures-> SOF/VEL/VOX x 24

weeks + RBV

• Expert consultation

Drug resistance testing

12/8/17 10 When (if ever) is drug resistance testing indicated in 2017?

Scenario Action GT1a, EBR/GRZ planned

• NS5a RAS testing
• If EBR RAS present, extend

treatment to 16 week with RBV GT3, cirrhotic, SOF/VEL planned

• NS5a RAS testing
• If Y93H present, consider

adding RBV SOF/VEL/VOX or GLE/PIB failure

• ?NS5a and NS3 RAS testing to

help guide therapy

Decompensated Cirrhosis

HCV cure reduces death in decompensated cirrhosis

• Always best to proceed in consultation with

hepatologist and transplant team, if applicable

• Stabilize medical condition before treating
• Avoid HCV protease inhibitors – levels can be

markedly elevated

– This includes Glecaprevir/Pibrenstasvir and Sofosbuvir/Velpatasvir/Voxilaprevir

• Include low dose Ribavirin if possible

– 600 mg , titrate up as tolerated

DAA Genotype Considerations SOF/LDV/RBV x 12 weeks GT 1, 4 Extend therapy to 24 weeks if cannot include RBV SOF/VEL/RBV x 12 weeks GT 1-6 DCV/SOF/RBV x 12 weeks GT 1-4

12/8/17 11 Decompensated Cirrhotics: Retreatment after NS5a and/or SOF failure

Pregnancy & Children HCV in pregnancy

• Risk of transmission ≈ 5%

– Higher in HIV(+) women

• Vaginal delivery ok, but should avoid fetal

scalp monitors and forceps delivery

• Breastfeeding not a risk for transmission, but

nursing with bloody/cracked nipples not recommended

• No approved treatment during pregnancy

– Treat HCV before seeking pregnancy if possible

• PK study of SOF/LDV x 12 weeks started at 24

weeks gestation ongoing (NCT02683005)

HCV in children

• Rate of fibrosis progression in children is low
• Generally recommended to wait to treat until age 12
• SOF/LDV approved for ≥ 12 years
• GLE/PIB and SOF/VEL still only for ≥ 18 years
• DAA’s under evaluation for treatment of children ages 3-

11

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Conclusions

• Good options for renal failure,

decompensated cirrhotics, and NS5a failures

• Drug resistance testing increasingly

unnecessary

• We need data to inform safe and effective

HCV treatment in pregnant women, children and adolescents.

Thank you ! Additional slides

GT Wks No Cirrhosis Compensated Cirrhosis eGFR < 30 mL/min 1 8 GLE/PIB

• GLE/PIB‡

12 GZR/EBR,* SOF/LDV,† SOF/VEL GLE/PIB, GZR/EBR,* SOF/LDV, SOF/VEL GZR/EBR 2 8 GLE/PIB

• GLE/PIB‡

12 SOF/VEL GLE/PIB, SOF/VEL

• 3

8 GLE/PIB

• GLE/PIB‡

12 SOF/VEL GLE/PIB, SOF/VEL§

• 4

8 GLE/PIB

• GLE/PIB‡

12 GZR/EBR, SOF/LDV, SOF/VEL, GLE/PIB, GZR/EBR, SOF/LDV, SOF/VEL GZR/EBR 5, 6 8 GLE/PIB

• GLE/PIB‡

12 SOF/LDV, SOF/VEL GLE/PIB, SOF/LDV, SOF/VEL

• *If GT1a with BL NS5A RASs for EBR, 12 wks not recommended; can increase duration to 16 wks with RBV (alternative).

†Some data to support 8 wks, but 8 wks not recommended in HIV/HCV coinfection. ‡If also cirrhotic, increase duration to 12 wks. §If BL Y93H RAS present, add RBV or consider SOF/VEL/VOX.

AASLD/IDSA GUIDELINES 9/17 www.hcvguidelines.org

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GT Wks NS3 + PegIFN/RBV Experience Non-NS5A, SOF- Containing Experience NS5A Experience 1 12 GLE/PIB, SOF/LDV,* SOF/VEL GLE/PIB, SOF/VEL,† SOF/VEL/VOX‡ SOF/VEL/VOX 2 12 GLE/PIB, SOF/VEL 3 12 SOF/VEL/VOX§ SOF/VEL/VOX§ SOF/VEL/VOX§ 4-6 12 SOF/VEL/VOX SOF/VEL/VOX SOF/VEL/VOX

*Not recommended if also cirrhotic. †For genotype 1b only. ‡For genotype 1a only. §If also cirrhotic with prior NS5A failure, add RBV.

DAA experienced

2017 Dvory-Sobol AASLD