Choosing the Right 1. Diagnosis screening 2. Staging of disease - - PDF document

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Choosing the Right Treatment Regimen

Hemant Shah MD MScCH HPTE Jordan Feld MD MPH

What is the role of primary care in HCV management?

• 1. Diagnosis – screening
• 2. Staging of disease
• 3. Preventing progression
• 4. Treatment!
• 5. Follow-up after treatment

Access to Treatment

• Access for all!
• No fibrosis restrictions
• Limited provider restrictions
• No sobriety restrictions
• All patients with chronic HCV are eligible for treatment
• Limited use codes – very easy!!
• HCV RNA positive x 2 more than 6 m apart (exclude spontaneous clearance)
• GI, ID or “provider experienced in HCV treatment”

The Lifecycle - Lots of Targets

Manns Nat Rev 2007

Protease Inhibitors Polymerase Inhibitors NS5A Inhibitors

Great options available

3’UTR 5’UTR Core E1 E2 NS2 NS3 NS5A NS5B P7 Ribavirin (RBV) Polymerase Daclatasvir (DCV) Elbasvir (EBR) Ledipasvir (LDV) Ombitasvir (OBV) Velpatasvir (VEL) Pibrentasvir (PIB)* Sofosbuvir (SOF) Dasabuvir (DSV) NS5B NUC Inhibitors (-buvir) NS5A Replication Complex Inhibitors (-asvir) NS5B Non-NUC Inhibitors (-buvir) Grazoprevir (GZR) Paritaprevir/Ritonavir (PTV/RTV) Simeprevir (SMV) Voxilaprevir (VOX)* Glecaprevir (GLE)* NS3 Protease Inhibitors (-previr) Protease Structural Domain 4A NS4B Nonstructural Domain NS5A

Treatment Regimens

• Genotype-specific

a) Elbasvir/grazoprevir (Zepatier) – G1, 4 b) Ledipasvir/sofosbuvir (Harvoni) – G1, (3), 4 c) Paritaprevir/r/Ombitasvir + dasabuvir (Holkira Pak) – G1b, (G1a) d) Sofosbuvir + Daclatasvir (Sovaldi + Daklinza) – G1, 3, 4

• Pan-genotypic

a) Sofosbuvir/velpatasvir (Epclusa) – G1-6 b) Glecaprevir/pibrentasvir (Maviret) – G1-6 c) Sofosbuvir/velpatasvir/voxilaprevir (Vosevi) – G1-6 (reserved for salvage therapy)

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Approved Regimens Approach to Treatment

Individualized

• Comprehensive assessment of

each patient

• Identifying best drug for patient

according to:

• Genotype
• Degree of fibrosis
• Past treatment history
• Other characteristics
• Work with all the drugs

Simplified

• Basic assessment of each patient
• Choose a pan-genotypic agent

according to:

• Genotype
• Decompensated cirrhosis yes/no
• Work with a couple of drugs

Individualized BUT simple approach to treatment

Regimen Genotype Duration (weeks) Pills per day 1a 1b 2 3 4 5 6 SOF/LDV (Harvoni) 8-12 1 ELB/GZV (Zepatier) (8)-12 1 SOF/VEL (Epclusa) 12 1 GLE/PIB* (Mavyret) 8 3 * Non-cirrhotic, no prior treatment 1. Confirm infection – RNA + genotype 2. Exclude cirrhosis – APRI < 0.7 3. Exclude drug interactions – www.hep-druginteractions.org 4. Start!

SOF/LDV (Harvoni) or SOF/VEL (Epclusa)

• Single Tablet Regimen
• Well tolerated
• Fatigue, headache common, occasionally severe
• Some patients complain more than expected
• SOF/LDV (not SOF/VEL)
• can shorten to 8 weeks if HCV RNA<6 M IU/ML
• DDIs – NS5A adds some
• Acid Suppression: Reduce absorption up to 80%!
• PPI – best to avoid (can co-administer)
• Antacid – 4 hrs apart
• H2RA – 12 hrs apart or together
• Seizure meds: All seizure meds except Kepra
• HBV/HIV - tenofovir – increase levels (renal toxicity)
• Cardiac: Digoxin – avoid

Crestor - increase risk of rhabdo – usually stop it

SOF/VEL/VOX (Vosevi)

• Single Tablet Regimen
• Well tolerated
• Fatigue, headache common, occasionally severe
• Additional side effect of mild diarrhea in about 15-20% of

patients

• Some patients complain more than expected
• Similar DDIs – NS5A adds some
• Acid Suppression: Reduce absorption up to 80%!
• Seizure meds: All seizure meds except Kepra
• HBV/HIV - tenofovir – increase levels (renal toxicity)
• Cardiac: Digoxin – avoid Crestor - increase risk of rhabdo –

usually stop it

• Because of Voxilaprevir, cannot use in decompensated

cirrhosis

Elbasvir/Grazoprevir (Zepatier)

• Single Tablet Regimen
• Well tolerated
• Fatigue, headache
• Cannot be used in decompensated cirrhosis
• Resistance an issue with G1a (not with G1b)
• If present  extend to 16 weeks and add RBV
• Either test everyone (guidelines) or Treat naïve/relapsers x 12w & non-

responders for 16 weeks with RBV (Label)

• DDIs – protease adds some
• No PPI issue
• Limited Amio issue
• Safe in renal failure including dialysis
• Look up the others…

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Pibrentasvir/Glecaprevir (Maviret)

• Three Tablets Taken all at once
• Well tolerated
• Fatigue, headache
• Cannot be used in decompensated cirrhosis
• No issues with resistance to date
• For non-cirrhotic patients – 8 weeks
• For cirrhotic patients – 12 weeks (8 week study looks promising)
• Can be used in some patients who have failed prior DAA therapy, but

not preferred

• DDIs – protease adds some
• No PPI issue
• Limited Amio issue
• Safe in renal failure including dialysis
• Look up the others…

Comparison of Pan-genotypic Regimens

SOF/VEL

• 1 pill per day
• 12 weeks for all
• DDI
• PPI
• Statins

GLE/PIB

• 3 pills per day
• 8 weeks – non-cirrhotic
• 12 weeks – cirrhotic (maybe 8

weeks??)

• DDI
• BCP
• Statins

When would I choose 1 first-line agent over the other?

• SOF/LDV (Harvoni)
• G1a especially if HCV RNA<6 M IU/mL (8 weeks)
• Decompensated cirrhosis (with RBV)
• SOF/VEL (Epclusa)
• Can’t think of any…maybe LDV resistance?
• EBV/GZV (Zepatier)
• G1b
• Chronic kidney disease (eGFR<45 and for sure <30)
• Cannot stop PPI
• GLE/PIB (Maviret)
• Chronic kidney disease (eGFR<45 and for sure <30)
• All non-cirrhotic patients can have 8 weeks of treatment, even if

high viral load

Genotypes in Canada

Centre for Disease Analysis 2014 What’s worth noting?

• Genotype 1 subtype
• Genotype 3 + cirrhosis

Why does G1 sub-type matter?

G1b – EASY to cure

• No need for resistance testing –

no effect

• No need for RBV
• Protease-based regimens highly

effective

G1a – Tougher to cure

• Protease-based regimens a

bit less effective

• Previously would
• ccasionally need ribavirin
• r resistance testing (not

anymore)

Genotype 3 is important

• 2nd most common

genotype globally – 10- 15% in the US (more among S. Asian immigrants)

• Associated with more

rapid progression of fibrosis and higher risk of HCC

• Sub-optimal responses to

DAAs with established cirrhosis

Nkontchou J Viral Hep 2011

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Pangenotypic regimen Example

99 98 99 100 100 97 100 20 40 60 80 100 SVR12 (%) 618 624 206 210 117 118 104 104 116 116 34 35 41 41 Total 1a 1b 2 4 5 6 Genotype

SOF + Velpatasvir (NS5A) x 12 wks in G1, 2, 4, 5, 6 – Naïve/Experienced +/- cirrhosis

Feld NEJM 2015, Foster NEJM 2015

1 relapse 2 lost to follow-up 1 withdrew consent 1 relapse 1 death

SVR12 (%) 100 80 60 40 97

191/ 197

91

73/ 80

G3: SOF/RBV x 24 vs SOF/VEL x 12

F0-3 F4

For G3 Cirrhosis, ADD Ribavirin

Esteban et al. 2018

Back to a Super Duper Simplified Approach **Assume refer decompensated to specialist

• G1, 2, 3*, 4, 5, 6
• SOF/VEL x 12 weeks
• GLE/PIB x 8 weeks
• G3 Cirrhosis:
• SOF/VEL/RBV x 12 weeks
• GLE/PIB x 12 weeks
• Treatment Failures:
• SOF/VEL/VOX x 12 weeks

If you treat 1000 patients this way…

Action Number of Patients Cured Not Cured Treat First Line 1000 950 50 Treat Second Line 50 45 5

TOTAL TREATMENTS ADMINISTERED: 1050 OVERALL CURE RATE: 99.5%

Treating HCV in Primary Care

• Therapy is getting MUCH easier
• Simpler regimens
• Fewer contraindications
• Minimal monitoring
• Support from hepatology/ID
• Project ECHO
• Preceptorships
• Patients prefer it!
• Patients prefer local treatment by HCPs they know!
• HIV a great model

Primary Care MDs Nurses Other care providers Project ECHO

• Linking PCPs to specialists
• Facilitates linkage to care
• Allows people to be treated by people

and in settings they know & trust

• 20’ didactic followed by cases

Now we cover more than HCV  HBV, fatty liver, alcohol, cirrhosis Monday 12 to 1:30 PM – free, CME credits!

That’s why we’re doing ECHO!

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Summary

• Hepatitis C treatment regimen selection is much easier than in the

past

• Simplified approach can utilized
• Few scenarios to be aware of (Decompensation, DDIs, G1 subtype, G3

cirrhosis)

• In the wheelhouse of primary care