Managing Hepatitis C: a Case-based Approach December 9, 2016 Bryn - - PDF document

12/9/16 1

Managing Hepatitis C:

a Case-based Approach

December 9, 2016 Bryn A Boslett, MD

Disclosures

• None

Outline

• Pre-treatment evaluation
• Impact of illicit drug use
• Newest regimens and how they work
• Management of concomitant medications
• How to monitor your patient during and after therapy

Case 1

• 36M with well-controlled HIV, chronic HCV, and intermittent IV

heroin abuse. His HCV has never been treated.

• He states that he’s been clean for 8 months
• Patient wonders, “Can I qualify for one of those fancy new

hepatitis treatments that I keep hearing about?”

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Question 1

What studies are necessary in pre-treatment assessment for a patient with HCV? A) Hepatitis C genotype B) Hepatitis C resistance testing C) FibroScan (transient elastography) D) All of the above

Effect of HCV genotype

• Worldwide, genotypes 1 – 6
• Predicts response to HCV therapy
• May predict progression of disease (eg, GT 3 à steatohepatitis)
• In the US:
• GT 1a and 1b (70%)
• GT 2 and 3 (30%)
• GT 4 (1%)

Messina JP . Hepatology. 2015 Jan;61(1):77-87.

US Distribution of HCV Genotypes

Genotype 1 Genotype 2 Genotype 3 Genotype 4

GT3 GT1 GT2

Fibrosis Evaluation

• Physical Exam: palmar erythema,

telangectasia, splenomegaly, etc

• Non-invasive markers:
• AST, ALT, INR, albumin, platelets
• FIB-4, APRI, FibroSure/FibroTest
• Transient elastography

(Fibroscan)

• Imaging: Ultrasound for HCC,

splenomegaly, nodularity, etc

• Biopsy: rarely needed

APRI = x 100 AST ÷ AST (Upper limit of normal) Platelet count (10⁹ /L)

Further discussion of liver disease evaluation: Marion Peters, MD 9:50 – 10:30 am (Next talk!)

Back to our patient

• HCV viral load ~ 5 million, genotype 1b
• HAV immune, HBV non-immune (sAb, core Ab and sAg neg) à
• HIV RNA <40, ND
• Cr 0.80 (GFR >60)
• AST 55, ALT 90
• Hgb 14, Platelets 180
• APRI: 0.64, FIB-4: 1.9 à Fibrosis stage 2 (non-cirrhotic)

APRI = x 100 AST ÷ AST (Upper limit of normal) Platelet count (10⁹ /L)

VACCINATE!!!

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Question 2

Before initiating HCV therapy for the patient, what other information is needed? A) Current antiretroviral therapy B) Psych evaluation C) Evaluation for varices D) At least three months of negative urine tox screens

Review of Medications List

• Antiretroviral therapy may need to be adjusted
• Least interactions: TDF/FTC (Truvada), TAF/FTC (Descovy),

ABC/3TC (Epzicom), rilpivirine, raltegravir, dolutegravir

• Other NNRTIs, PIs also OK for certain regimens
• Others with potential drug interactions:

antacids, anticonvulants, antiarrhythmics, statins

Workshop on HCV pharmacology: Parya Saberi, PharmD, MAS Pharmacology for All HCV Clinicians Breakout Session B, 4:10 – 4:55 pm

People who inject drugs (PWID)

• Estimated that 60% of HCV cases in the US exist in current or

former PWID

• Approx 30,000 new HCV infections related to IVDU in 2013 –

80% of all new cases that year

• Growing HCV epidemic in persons age <30 years
• Surveillance data from four states (Kentucky, Tennessee, Virginia, West

Virginia) showed 364% increase in the number of cases of acute HCV infection from 2006 to 2012 among persons aged ≤30 years.

• Similar trends in other states, concurrent with rise in opiate abuse

Litwin AH, et al. Clin Infect Dis. 2005;40:S339-S345.; Grebely J, et al. Clin Infect Dis. 2013;57:1014-1020; CDC. MMWR. 2012;61:1-43; SAMHSA. National Survey on Drug Use and Health Report. September 4, 2014.; CDC. MMWR. 2015:64:1-7. CDC.MMWR. 2015:64:1-7.

Incidence of acute HCV, age <30

Non-urban Urban

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Real-life data for PWID

• 121 HCV+ patients accessing primary care from a federally-

qualified health center (FQHC) in the Bronx, NY in 2014-2015

• 46/121 patients (52%) were PWID
• HCV care coordinator on-site for scheduling, reminder calls,

education, prior authorizations

Norton BL, et al. #585. CROI 2016

Ready…set…

• Your patient is motivated to start HCV therapy
• Abacavir/Lamivudine/Dolutegravir (Triumeq) for ART
• Methadone maintenance therapy

But what to start???

Guidelines Help

• http://www.hcvguidelines.org
• Management guidelines from IDSA and AASLD
• http://www.hep-druginteractions.org
• Free downloadable app
• www.hcvadvocate.org
• Great patient information

DAA Mechanisms of Action

NS5b Inhibitors

à Target viral RNA polymerase à “-buvir” NS5b Nucleotide Sofosbuvir NS5b Non-nucleotide Dasabuvir

NS5a Inhibitors

à Target viral assembly and release à “-asvir” Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir

Protease inhibitors

à Target viral protease à “-previr” Simeprevir Paritaprevir Grazoprevir

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Available regimens

NS3 protease inhibitors NS5A inhibitors NS5B nucleos(t)ide polymerase inhibitors NS5B Non- nucleoside polymerase inhibitors

Grazoprevir Paritaprevir Simeprevir Velpatasvir Elbasvir Daclatasvir Ombitasvir Ledipasvir Sofosbuvir Sofosbuvir Sofosbuvir Sofosbuvir Dasabuvir Red box: Combo pill or pack

Best options

Genotype 1, treatment naïve, +/- cirrhosis Regimen Dose Duration Elbasvir/Grazoprevir (Zepatier) +/- RBV* 1 tab daily EBR (50mg)/GZR (100mg) 12 -16* wks Ledipasvir/Sofosbuvir (Harvoni) 1 tab daily LDV (90mg)/SOF (400mg) 12 wks Velpatasvir/Sofosbuvir (Epclusa) 1 tab daily VEL (100mg)/SOF (400mg) 12 wks

http://www.hcvguidelines.org/

*16 wks + RBV needed in GT 1a with NS5A RAS

Question 3

What additional steps need to happen before this regimen (elbasvir/grazoprevir) is started? A) Change needs to be made to ART B) Change needs to be made to methadone therapy C) Resistance testing should be sent D) No additional steps – we’re ready!

Gt 1b, treatment naïve, non-cirrhotic, ABC/3TC/DTG (Triumeq)

Elbasvir (EBR)/Grazoprevir (GRZ)

PROs

• Approved for GT 1 and 4
• Can be used in renal failure,

incl HD (C-Surfer)

• Single pill
• Activity against resistance-

associated substitutions (RAS) with 1st gen PI

• Lower cost ($54,600)

CONs

• GT1a: If NS5A resistance,

needs ribavirin and 16 wks

• Cannot use with PI-based

regimens, cobicistat or EFV

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C-EDGE: SVR12 Results by Genotype

Zeuzem, et al. Ann Intern Med. 2015 Jul 7;163(1):1-13

95 92 99 100

20 40 60 80 100

All GT1a GT1b GT4

Patients with SVR12 (%)

Genotype

299/316 144/157 129/131 18/18 Overall SVR12 results includes the 10 patients with GT 6, 8 of whom achieved SVR12.

ELB/GRZ in treatment naive

22% compensated cirrhotics

• High HCV RNA + baseline

NS5a resistance predicts lower SVR for GT 1a only

• For GT 1a, must perform

baseline resistance testing prior to use!

• If NS5A resistance present,

must extend therapy to 16 weeks and add ribavirin

Zeuzem, et al. Ann Intern Med. 2015 Jul 7;163(1):1-13. Kwo, et al. J Hepatol. 2015 Apr;62, Supplement 2:S674–5.

ELB/GRZ failures: resistance impacts GT 1a

Baseline HCV RNA Baseline NS5A Resistance <800K IU/mL >800K IU/mL YES NO

C-EDGE CO-INFECTION: SVR12 Results by Genotype

Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27.

93 93 93 93

20 40 60 80 100

All GT1a GT1b GT4

Patients with SVR12 (%)

Genotype

203/218 134/144 41/44 26/28 Overall SVR12 results includes the 2 patients with GT 6, who both achieved SVR12.

ELB/GRZ in HIV co-infection

35% compensated cirrhotics

ELB/GRZ in patients on opiate agonists

• 92% SVR in C-EDGE CO-STAR

trial of PWID

• High adherence despite 60% of

patients with Utox+ during the study

• Methadone and

buprenorphine do not appear to significantly interact with ELB/GRZ

Dore AIM 2016

>80% >90% >95% % Adherence

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ELB/GRZ + ART interactions

HIV Drug Class Medication Interaction

HIV protease inhibitors Atazanavir/r ↑ ELB/GRZ, ATV Darunavir/r HIV NNRTI Rilpvirine Compatible Efavirenz ↓ ELB/GRZ, EFV Etravirine No data Integrase inhibitors Dolutegravir Compatible Raltegravir Elvitegravir/cobi ↑ ELB/GRZ CCR5 Inhibitors Maraviroc No data HIV NRTIs ABC, TAF, 3TC/FTC Compatible TDF Compatible

Elbasvir/Grazoprevir Summary

Genotype NS5A resistance Ribavirin Duration 1a No No 12 weeks 1a Yes Yes 16 weeks 1b N/A No 12 weeks 1b N/A No 12 weeks 4 N/A No 12 weeks Treatment naïve or experienced*, including compensated cirrhosis

*If prior PI failure (telaprevir, boceprevir, simeprevir), need to add RBV

Take Home Points from Case 1

• Pre-treatment: genotype, fibrosis assessment (ultrasound,

serologic markers +/- transient elastography), accurate medication list, check HAV/HBV status and vaccinate!

• Recent or active IVDU not a contraindication to HCV

therapy, and opiate agonists compatible with all regimens

• Elbasvir/Grazoprevir (ELB/GRZ) - Zepatier
• Can be used in ESRD
• Compensated cirrhosis does not affect regimen
• GT1a: need to check NS5A resistance, may need to add

ribavirin and extend course

• Contraindicated with PIs, cobicistat, NNRTIs except

rilpivirine

Case 2

• 72M with well-controlled HIV, chronic HCV genotype 1a with

compensated cirrhosis, hypertension and peptic ulcer disease

• Failed interferon + ribavirin + telaprevir in 2012 (relapsed)
• Cr 1.2 (eGFR 55), Hgb 11.0
• HAV immune and HBV sAb pos, core Ab pos, sAg neg
• He is willing to try HCV Rx again – ”Second time’s a charm?”

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Best options

Genotype 1, treatment experienced, +/- cirrhosis Regimen Dose Duration

Elbasvir/Grazoprevir (Zepatier) +/- RBV* 1 tab daily EBR (50mg)/GZR (100mg) 12 - 16* wks Ledipasvir/Sofosbuvir (Harvoni) +/- RBV‡ 1 tab daily LDV (90mg)/SOF (400mg) 12 - 24‡ wks Velpatasvir/Sofosbuvir (Epclusa) 1 tab daily VEL (100mg)/SOF (400mg) 12 wks

http://www.hcvguidelines.org/

*16 wks needed in all GT 1a with NS5A RAVs; if prior PI failure, add RBV

‡ Compensated cirrhotics: 12 wks if RBV added, or 24 wks without RBV

Back to our patient

• He was switched to TAF/FTC/ELV/cobi (Genvoya) for

ART this year, and happy with it

• Other medications: HCTZ, omeprazole, iron

supplement

• You plan on starting velpatasvir/sofosbuvir (Epclusa)

Question 4

Before initiating VEL/SOF for the patient, what may need to be changed or adjusted? A) Hydrochlorothiazide B) Iron supplement C) TAF/FTC/ELV/cobi (Genvoya) D) Omeprazole E) Nothing – these are all compatible with this regimen

Velpatasvir (VEL)/Sofosbuvir (SOF)

PROs

• Pan-genotypic and approved

for GT 1 - 6

• Single pill
• Activity against NS3/4 (PI) and

NS5A resistance-associated substitutions (RAS) CONs

• SOF not recommended for

GFR<30 or ESRD

• Cannot use with EFV or ETR,

caution TDF (but TAF is Ok!)

• Co-administration with PPIs is

not recommended

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ASTRAL 1 ,2, 3, 5 trials

ASTRAL 1: All genotypes except GT3, treatment naïve and experienced, cirrhotic and non-cirrhotic

• VEL/SOF x 12 wks vs placebo

ASTRAL 2 and 3: GT2 or GT3 only

• ASTRAL 2: VEL/SOF vs SOF + RBV x 12 wks
• ASTRAL 3: VEL/SOF x 12 wks vs SOF + RBV x 24 wks

ASTRAL 5: GT 1-4, HIV coinfection Primary end points: SVR12 (cure) and discontinuations due to adverse effects

Feld, JJ. N Engl J Med. 2015 Dec 31;373(27):2599-607.; Foster, GR. N Engl J Med. 2015a Dec 31;373(27):2608-17.; Wyles D, EASL 2016, Abs. PS104, J Hepatol 2016;64:S188

ASTRAL results

SVR12 (%) by Genotype ASTRAL 1 - 3 ASTRAL 5 HIV Coinfection 24% compensated cirrhotics

ASTRAL-1: Impact of baseline resistance

Feld JJ, NEJM 2015

Patients with baseline NS5A RAS Patients without baseline NS5A RAS

VEL/SOF + ART interactions

HIV Drug Class Medication Interaction

HIV protease inhibitors Atazanavir/r Concern for ↑Tenofovir levels* Darunavir/r HIV NNRTI Rilpvirine Compatible Efavirenz Contraindicated - ↓ VEL levels Etravirine No data Integrase inhibitors Dolutegravir Compatible Raltegravir Elvitegravir/cobi Compatible CCR5 Inhibitors Maraviroc No data HIV NRTIs ABC, TAF, 3TC/FTC Compatible TDF Concern for ↑Tenofovir levels

*Only of concern when co-administered with TDF

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Other VEL/SOF interactions

• Acid-suppressing therapies:
• PPIs: If needed, omeprazole 20 mg (or equivalent) with

food, 4 hours prior to VEL/SOF

• H2 blockers: Famotidine 40 mg (or equivalent) can be given

simultaneously with VEL/SOF, or staggered by 12 hours

• No problem: methadone, immunosuppressants, most statins,
• ral contraception, anticoagulants, SSRIs, diuretics

Take Home Points from Case 2

• Velpatasvir/Sofosbuvir (VEL/SOF) - Epclusa
• First DAA approved for GT 1 – 6
• Resistance (RAS) testing typically unnecessary
• Compensated cirrhosis does not affect regimen for Gt 1
• Avoid in GFR<30
• Contraindicated with efavirenz, caution with TDF, no

data with etravirine

Case 3

• 50F with HIV and chronic HCV genotype 3, no cirrhosis
• Previously failed interferon and ribavirin in 2004 (relapsed)
• Cr 0.80 (GFR >60), Hgb 14, normal LFTs and INR
• HAV/HBV immune (sAb pos, core Ab neg, sAg neg)

Question 5

What should you tell her about HCV therapy for genotype 3 ? A) All regimens for genotype 3 require baseline resistance testing B) All regimens for genotype 3 require ribavirin (RBV) C) Cirrhosis and prior treatment can significantly impact SVR D) HIV infection impacts genotype 3 more than other genotypes E) All of the above

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Best options

• Genotype 3, treatment naïve or experienced, +/- cirrhosis

Regimens Dose Duration Velpatasvir/Sofosbuvir (Epclusa) +/- RBV 1 tab daily VEL (100mg)/SOF (400mg) 12-24 wks Sofosbuvir + Daclatasvir (Sovaldi + Daklinza) +/- RBV 1 tab daily SOF (400mg) + DCV (60mg)* 12-24 wks

*DCV dose ↑ to 90mg with EFV, ETR or NVP; or ↓ to 30mg with ATV/r or cobi regimen

ASTRAL 3

VEL/SOF x 12 wks versus SOF + RBV x 24 wks

20 40 60 80 100 120

Non-cirrhotic Cirrhotic Non-cirrhotic Cirrhotic

VEL/SOF SOF + RBV

98 90 93 73 91 71 89 58

Treatment Naïve Treatment Experienced

Foster, GR. N Engl J Med. 2015a Dec 31;373(27):2608-17.

Foster NEJM 2016

ASTRAL-3: baseline resistance had an impact in GT3

Patients with baseline NS5A RAS Patients without baseline NS5A RAS

If Y93H, SVR was 84%

Resistance testing in GT3

• AASLD/IDSA Guidelines
• RAS testing for cirrhotic OR treatment experienced GT3

with addition of RBV if Y93H

• If cirrhotic AND treatment experienced GT3, add RBV no

matter what

• EASL:
• If available, RAS testing for treatment experienced and/or

cirrhosis -> if Y93H mutation, add RBV to 12 weeks VEL/SOF

• If no RAS testing available, add RBV to 12 weeks VEL/SOF

for treatment experienced or cirrhosis.

• If cannot take RBV, then 24 weeks VEL/SOF

http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection http://www.easl.eu/medias/cpg/HCV2016/English-report.pdf

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Velpatasvir/Sofosbuvir Summary

Genotype Cirrhosis or Tx Experience* NS5A testing Ribavirin Duration 1, 2, 4-6 N/A No No 12 wks 3 No No No 12 wks Yes Yes If Y93H+ 12-24** wks

http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection http://www.easl.eu/medias/cpg/HCV2016/English-report.pdf

*PEG/RBV experience. If SOF or NS5a failures, see guidelines **If cannot take RBV, then 24 weeks SOF/VEL

Monitoring on therapy

• Monitor CBC, LFT, BUN/Cr, HCV RNA at week 4, repeat PRN
• More frequent in challenging patients: cirrhotics, CKD, anemia on

RBV, patients on regimens that will boost TDF, etc

• After therapy, HCV RNA check at week 12 for SVR
• For cirrhotics, remember to continue HCC screening!

Summary

• Well tolerated, effective regimens available NOW for

majority of HIV/HCV patients

• Genotype, fibrosis stage inform therapy choices
• Harder to treat populations need longer therapy +/-

ribavirin

• Cirrhotic patients and prior treatment failures
• Most notable in Gt3
• Continue to monitor and educate patients on re-infection
• Genotypes 2 & 4:
• IDSA and AASLD guidelines
• Additional workshops on HCV later today!

Acknowledgements

SFGH

• Annie Luetkemeyer
• Meg Newman
• Diane Havlir
• Monica Gandhi
• Parya Saberi
• Val Robb
• Dan Berrner
• Monika Roy
• Lillian Brown
• Cait Koss

UCSF

• Joanne Engel
• Malcolm John
• Brian Schwartz
• Cristina Gruta
• Julienne Rafael
• Allan Paschke
• Parousha Zand
• Roland Zepf
• Jeff McKinney

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Guidelines Help

• http://www.hcvguidelines.org
• Management guidelines from IDSA and AASLD
• http://www.hep-druginteractions.org
• Free downloadable app
• www.hcvadvocate.org
• Great patient information