1. Newly Approved Hepatitis C Virus Drugs: Approach to Initial Therapy
Kristen M. Marks, MD
Assistant Professor
Weill Cornell Medical College
New York, New York

2. Financial Relationships With Commercial Entities
Dr Marks was awarded research grants, paid to her institution, from Bristol-Myers Squibb, Gilead Sciences, Inc, and Merck. (Updated 10/16/17)

3. Learning Objectives
After attending this presentation, learners will be able to:
Describe regimens recommended for initial treatment of HCV infection
Recognize when to do testing for HCV resistance
Identify the advantages and limitations of newly approved HCV treatment regimens

4. IDSA/AASLD EASL www.hcvguidelines.org
guidelines/detail/easl-recommendations-on-treatment-of-hepatitis-c-2016

5. Newer strategy for HCV therapy: Direct acting antivirals target life cycle
---PREVIR
Protease inhibitors
e.g. telaprevir, boceprevir, faldaprevir, simeprevir, danoprevir, asunaprevir, paritaprevir, grazoprevir, voxilaprevir, glecaprevir
---BUVIR
Polymerase inhibitors
Nucleos(t)ide analogs: e.g. tegobuvir, sofosbuvir,
Non-nucs: e.g. deleobuvir, dasabuvir
---ASVIR
NS5A inhibitors
e.g. daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir, pibrentasvir
In 2011, HCV treatment moved into a new era with the approval of the first direct acting antivirals, or DAAs. These agents target the steps of the HCV life cycle. Those of you familiar with HIV will recognize several of these drug classes: there are protease inhibitors, polymerase inhibitors (both nucleoside analogs and non-nucs allosteric polymerase inhibitors). There is also a unique class, NS5A inhibitors which also block HCV replication. Highlighted in red is my simple method of remembering them. ADD 5

6. Currently used combinations of DAA classes
NUC-SPARING HIV
Toxicity
Resistance
Renal insufficiency
Drug-drug interactions
Affordability
+/- RBV
NUC + PI
+/- RBV
NUC +
NS5A
+/- RBV
NUC + PI +
NS5A PI +
NS5A PI +
NS5A +
nonNuc
+/- RBV
NUC-SPARING HCV
Renal insufficiency
Drug-drug interactions
Duration
Affordability/Access
Toxicity
Resistance

7. Minimum to Know Pre-Treatment
HCV genotype/subtype
HCV resistance (sometimes)
Stage of fibrosis
Cirrhosis - yes/no
If yes, decompensated? (e.g., ascites, encephalopathy, etc)
If yes, don’t use PIs!
Method?
Liver biopsy
Transient elastography
Laboratory biomarkers
Imaging
Prior HCV treatment?
Response?
DAA used?
Medications
To check for drug interactions
Comorbidities
Renal function
HIV status
Patient preference
Child-bearing potential of patient/partner
Ribavirin is a teratogen
HIV/Hepatitis C helpline

8. Approved Drug Regimens for Initial Treatment
+/-
RBV
+/-
PEG
RBV
PTV/r
RBV
RBV
SMV
LDV
DAC
OMV
GZR
VEL
GLE
+/-
SOF
SOF
SOF
SOF
SOF
DAS
EBV
SOF
PBV
Interferon
PegIFN
Ribavirin
ribavirin
+/-ribavirin
Nucs
sofosbuvir
Protease
inhibitors
simeprevir
Paritaprevir
/ritonavir
grazoprevir
velpatasvir
glecaprevir
NS5A
ledipasvir
daclatasvir
ombitasvir
elbasvir
pibrentasvir
Non-Nucs
dasabuvir G1 X G2 G3 G4

9. G1b Initial Treatment Recommended Regimens
G1b vs G1a:
G1b Initial Treatment Recommended Regimens
IDSA/AASLD
NO CIRRHOSIS:
Elbasvir/grazoprevir x 12 w
Glecaprevir/pibrentasvir x 8 w
Ledipasvir/sofosbuvir x 8* or 12 w
Sofosbuvir/velpatasvir x 12 w
Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w
Simeprevir x sofosbuvir 12w
Daclatasvir + sofosbuvir x 12w
*8 wk not recommended for Black patients or HIV-infected
CIRRHOSIS:
Elbasvir/grazoprevir x 12 w
Glecaprevir/pibrentasvir x 12 w
Ledipasvir/sofosbuvir x 12 w
Sofosbuvir/velpatasvir x 12 w
Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w*
(BOLDED are regimens approved since last year!)

10. G1a Initial Treatment Recommended Regimens
IDSA/AASLD
CIRRHOSIS:
Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance
Glecaprevir/pibrentasvir x 12 w
Ledipasvir/sofosbuvir x 12 w
Sofosbuvir/velpatasvir x 12 w
NO CIRRHOSIS:
Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance
Glecaprevir/pibrentasvir x 8 w
Ledipasvir/sofosbuvir x 8* or 12 w
Sofosbuvir/velpatasvir x 12 w
Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w
Simeprevir x sofosbuvir 12w
Daclatasvir + sofosbuvir x 12w
*8 wk not recommended for Black patients or HIV-infected
(BOLDED are regimens approved since last year!)

11. Pangenotypic Glecaprevir/pibrentasvir
DAA combo naive (TN, PEG/RBV, SOF) & special pops
Co-formulated – 3 pills once daily
Pangenotypic
Next generation
Active vs NS3 RAS at 80, 155, 168 and NS5A RAS at 28, Q30, 31, 93
A30K associated with failure in GT3 infection
Negligible renal excretion
Contains a protease inhibitor
Has interaction with acid suppressing meds but ?clinically significant
ENDURANCE (Phase 3)
GT 1 no cirrhosis (8 vs 12W)
GT 2 no cirrhosis (12W)
GT 3 no cirrhosis (8 and 12W)
GT 4-6 (12W)
EXPEDITION (Phase 3)
GT 1, 2, 4-6 cirrhosis
GT 1-6 HIV
GT 1-6 Renal impairment
SURVEYOR (Phase 2)
GT 2, 4-6 no cirrhosis 8 weeks
GT 3 cirrhosis/TE 12 vs 16 W
Co-formulated – 3 pills once daily
Pangenotypic
Next generation
Active vs NS3 RAS at 80, 155, 168 and NS5A RAS at 28, Q30, 31, 93
A30K associated with failure in GT3 infection
Negligible renal excretion
Contains a protease inhibitor
Has interaction with acid suppressing meds
G/P Slides courtesy of S. Naggie

12. Glecaprevir/pibrentasvir: No Cirrhosis
8 (N=828) vs 12 (N=1076) weeks
TN and TE
PEG, RBV, SOF
No DAA otherwise
Relapse <1%
Tx emergent RAS
GT3 with more relapse albeit low number
Puoti et al. EASL 2017

13. Glecaprevir/pibrentasvir: Cirrhosis
12 weeks in N=146
Compensated cirrhosis
TN or TE (25%) with IFN, P/R or SOF+P/R
GT1a 33%, GT1b 27%, GT2 23%, GT4 11%, GT5 1%, GT6 5%
1 relapse- GT1a
EXPEDITION-1
Forns et al. EASL 2017

14. Sofosbuvir/velpatasvir x 12 wks in HIV/HCV G1-6, Naïve + Rx-exp
18% cirrhosis
12% NS5a RAVs
Of 2 relapses:
1 rx-exp, 0 cirrhosis, 0 baseline RAVS
Renal fxn looked unchanged in pts on boosted TDF
Wyles, EASL, 2016

15. POLARIS-2: 8-Wk SOF/VEL/Voxilaprevir vs
POLARIS-2: 8-Wk SOF/VEL/Voxilaprevir vs. 12-Wk SOF/VEL Not Non-inferior for DAA-naïve
SOF/VEL/VOX 8 wks
SOF/VEL 12 wks
8-wk SOF/VEL/VOX did not meet criteria for noninferiority vs 12-wk SOF/VEL
Treatment difference: -3.4% (95% CI: -6.2% to -0.6%) 98 98 99 97 97 97
100 99 97 98 94
100
100
100 95
100 93 92 92 80
SVR12 (%) 60 40 20
476/ 501
432/ 440
217/ 233
228/
232
155/
169
170/
172
61/ 63
57/ 59
61/ 63
53/ 53
91/ 92
86/ 89
58/ 63
56/ 57
17/ 18
30/ 30 9/ 9 2/ 2
n/N =
AE, adverse event; D/c, discontinued; GT, genotype; HCV, hepatitis C virus; LTFU, lost to follow-up; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VOX, voxilaprevir.
Overall
GT1
GT1a
GT1b
GT2
GT3
GT4
GT5
GT6
Unknown
Relapse, n
LTFU, n
D/c for AE, n 21 4 3 4 1 16 2 14 1 2 1 2 1 2 1 2 3 1 1
Slide credit: clinicaloptions.com
Jacobson IM, et al. Gastroenterology
Jacobson IM, et al. Gastroenterology

16. HCVguidlines.org accessed 9/29/17

17. Glecaprevir/pibrentasvir: HIV
GT 1-6
Primarily an 8 week study
12 weeks in 16 patients with cirrhosis
TN or TE (19%) with IFN, P/R or SOF+P/R
VBT on treatment – GT3 with cirrhosis
mITT
136/ /15
Rockstroh et al. EASL 2017

18. RAS Testing prior to Treatment
NS5A RASs are relatively common (10-15%)
Significance of NS5A RASs may depend on the RAV, the genotype, the regimen used and whether prior NS5A treatment
In initial treatment, use resistance testing prior to:
Treatment with grazoprevir/elbasvir for 1a
Treatment of G3 with sofosbuvir/velpatasvir if cirrhosis

19. Elbasvir/grazoprevir x12w Results
Overall study 95% SVR
144/157 (92%) G1a, 129/131 (99%) G1b, 18/18 G4, 8/10 G6
68/70 (97%) with cirrhosis
Baseline NS5A RASs & SVR
Ann Intern Med. 2015;163(1):1-13

20. v (Slide to be updated later this month with guidelines release)
HCVguidlines.org accessed 9/29/17

21. Glecaprevir/pibrentasvir: Renal Impairment
GT 1-6 for 12 weeks
Stage 4 or 5 CKD
GFR<30 including HD
82% on HD
TN or TE (42%) with IFN, P/R or SOF+P/R
Including compensated cirrhosis (19%)
GT1a 22%, GT1b 28%, GT2 16%, GT3 11%, GT4 19%, GT5 1, GT6 11
EXPEDITION-4
Gane et al. EASL 2017

22. Drug-Drug Interactions with DAAS
Acid-reducing drugs
Anti-epileptics
Antiretrovirals
Amiodarone
Lipid-lowering drugs

23. Guidelines Recommendation about use of LDV or VEL with TDF
SOF/LDV + TDF CrCl < 60 mL/min: AVOID CrCl > 60: MONITOR SOF/LDV + TDF + cobi- or ritonavir-boosted PI Any CrCl: AVOID if possible, Consider TAF
SOF/VEL + TDF
CrCl < 60 mL/min: AVOID
CrCl > 60: MONITOR
SOF/VEL + TDF + cobi- or ritonavir-boosted PI
CrCl > 60: MONITOR or consider TAF
HCVguidlines.org accessed 9/29/17

24. G4 INITIAL TREATMENT RECOMMENDED REGIMENS
IDSA/AASLD
NO CIRRHOSIS:
Elbasvir/grazoprevir x 12 w
Glecaprevir/pibrentasvir x 8 w
Ledipasvir/sofosbuvir x 12 w
Sofosbuvir/velpatasvir x 12 w
Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w
CIRRHOSIS:
Elbasvir/grazoprevir x 12 w
Glecaprevir/pibrentasvir x 12 w
Ledipasvir/sofosbuvir x 12 w
Sofosbuvir/velpatasvir x 12 w
Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w*
(BOLDED are regimens approved since last year!)

25. IDSA/AASLD/IAS–USA G2 INITIAL TREATMENT RECOMMENDED REGIMENS
NO CIRRHOSIS:
Glecaprevir/pibrentasvir x 8 w
Sofosbuvir/velpatasvir x 12 wks
CIRRHOSIS:
Glecaprevir/pibrentasvir x 12 w
Sofosbuvir/velpatasvir x 12 wks

26. IDSA/AASLD/IAS–USA G3 INITIAL TREATMENT RECOMMENDED REGIMENS
NO CIRRHOSIS:
Glecaprevir/pibrentasvir x 8 w
Sofosbuvir/velpatasvir x 12 w
Sofosbuvir + daclatasvir x 12w
CIRRHOSIS:
Glecaprevir/pibrentasvir x 12 w
Sofosbuvir/velpatasvir x 12 w*
Sofosbuvir + daclatasvir +/-RBV x 24w*
*RAV testing for Y93H and add RBV if present or use sofosbuvir/velpatasvir/voxilaprevir

27. Sofosbuvir + Daclatasvir for G3 (ALLY-3)
Nelson, Hepatology :

28. Glecaprevir/pibrentasvir in GT3 Treatment-naïve without Cirrhosis
Non-inferiority
12W vs DAC/SOF X12W
12W vs 8W
Viral Failure 3% G/P
4 in 12W (3 relapse, 1 VBT)
1 in DAC/SOF
6 in 8W (5 relapse, 1 VBT)
BL Y93H: 5/5 SVR
BL dual NS3/NS5A
71-86% SVR
Tx emergent RAS
50% failures with A30K BL
A30K+Y93 (69-fold R)
ENDURANCE-3
SURVEYOR-II – G3 with Cirrhosis
48 patients received G/P +/- RBV x 12 w = 100% SVR
Foster et al. EASL 2017

29. Glecaprevir/pibrentasvir in GT3 Treatment-naïve without Cirrhosis – A30K effect?
Non-inferiority
12W vs DAC/SOF X12W
12W vs 8W
Viral Failure 3% G/P
4 in 12W (3 relapse, 1 VBT)
1 in DAC/SOF
6 in 8W (5 relapse, 1 VBT)
Tx emergent RAS
50% failures with A30K BL
6% patients overall had a BL A30K
ENDURANCE-3
SURVEYOR-II – G3 with Cirrhosis
48 patients received G/P +/- RBV x 12 w = 100% SVR
Foster et al. EASL Krishnan et al. EASL 2017

30. Sofosbuvir/velpatasvir x 12 wks for G3 (ASTRAL-2)
Most of this 3% w/ failure had cirrhosis
Foster, NEJM, 2015, hcvguidelines.org

31. Treatment Experienced
POLARIS-3: SVR12 Rates With 8-Wk SOF/VEL/Voxilaprevir for DAA-naive Cirrhotic GT3
SOF/VEL/VOX 8 wks SOF/VEL 12 wks 96 96 97 96 99 91 95 95
100
100
100 80 60
SVR12 (%) 40 20
106/ 110
105/ 109
72/ 75
76/ 77
34/ 35
29/ 32
80/ 84
76/ 80
23/ 23
23/ 23
n/N =
Overall
Treatment Naive
Treatment Experienced
No BL RASs
Any BL RASs
BL, baseline; GT, genotype; RAS, resistance associated substitution; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VF, virologic failure; VOX, voxilaprevir.
Both regimens: P < .001 for superiority vs prespecified 83% goal
Overall VF: SOF/VEL/VOX, n = 2 relapses; SOF/VEL, n = 1 each for relapse and on-treatment failure
No treatment-emergent RASs in SOF/VEL/VOX arm; Y93H in both VFs in SOF/VEL arm
Jacobson IM, et al. Gastroenterology. 2017
Slide credit: clinicaloptions.com

32. Initial Treatment Algorithm
HCV genotype/subtype & resistance
HIV status
Cirrhosis - yes/no - duration
If yes, decompensated? (e.g., ascites, encephalopathy, etc)
If yes, don’t use PIs!
Renal function
Avoid Sof if CrCl <30
Medications
Address drug interactions
Ribavirin is a teratogen
Patient preference (8 or 12 w, # pills, packaging)
Our case patient
1b, no need for resistance testing, start with 4 recommended regimens
HIV neg
Cirrhosis – yes
No 8 wk regimens
Compensated so ok to use Pis
CrCl <30, no regimens w/ sofosbuvir, so 2 remaining regimens
Medications: PPI qd
Elbasvir/grazoprevir – no interaction
Glecaprevir/pibrentasvir (limit dose)
Pills and packaging
Elbasvir/grazoprevir – 1 pill/d
Glecaprevir/pibrentasvir 3 pills/d
(WHAT PAYER COVERS)

33. Summary : Is this as good as it gets?
Remarkable advances in terms of HCV treatment tolerability & efficacy
Advances in G2, G3, ESRD
SVRs for HIV/HCV now mirror monoinfection
Still drug interaction issues, but valuable resources to help manage
RAV testing prior to initial treatment if:
G1a and planned grazoprevir/elbasvir
G3 & cirrhosis and planned sofosbuvir/velpatasvir
Successful treatment prevents cirrhosis, end stage liver disease, and hepatocellular cancer
Post SVR – continue liver disease management/HCC screening, monitor HBV reactivation, and consider HCV screening if ongoing risk

34. THANK YOU Resources HCVguidelines.org nynjaetc.org
THANK YOU