1. Clinical Impact of New Data From Boston 2016*
CCO Independent Conference Coverage* of the 2016 American Association for the Study of Liver Diseases November 11-15, 2016; Boston, Massachusetts
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This activity is supported by independent educational grants from AbbVie, Gilead Sciences, and Merck

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3. Faculty
Ira M. Jacobson, MD Chair, Department of Medicine Mount Sinai Beth Israel Professor of Medicine and Vice-Chair Department of Medicine Icahn School of Medicine at Mount Sinai New York, New York Stefan Zeuzem, MD Professor of Medicine Chief, Department of Medicine I JW Goethe University Hospital Frankfurt, Germany
This slide lists the faculty who were involved in the production of these slides.

4. Disclosures
Ira M. Jacobson, MD, has disclosed that that he has served as a consultant or on advisory boards for AbbVie, Achillion, Bristol- Myers Squibb, Gilead Sciences, Intercept, Janssen, Merck, and Trek; has served on speaker bureaus for AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Janssen; and has received funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Intercept, Janssen, and Merck. Stefan Zeuzem, MD, has disclosed that he has served as a consultant or on advisory boards for Abbott, AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Idenix, Janssen, Merck, Novartis, Roche, Santaris, and Vertex and has served on speaker bureaus for Boehringer Ingelheim, Bristol- Myers Squibb, Gilead Sciences, Merck, and Roche.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

5. HCV Treatment: Investigational Regimens
HCV, hepatitis C virus.
Ira M. Jacobson, MD:
In this Expert Analysis, Stefan Zeuzem, MD, and I discuss new clinical data that affect the management of patients with liver disease. We review more than 20 of the most influential studies presented at the 2016 Hepatology meeting in Boston, with topics ranging from investigational regimens for hepatitis C virus (HCV) infection and real-world HCV treatment with approved agents to hepatitis B virus (HBV) monitoring and reactivation and emerging therapeutic options for nonalcoholic steatohepatitis (NASH).

6. Summary of Approved Direct-Acting Antivirals Discussed in This Slideset
Drug
Abbreviation
Class
Grazoprevir
GZR
NS3/4A protease inhibitor
Paritaprevir
PTV
Simeprevir
SMV
Daclatasvir
DCV
NS5A inhibitor
Elbasvir
EBR
Ledipasvir
LDV
Ombitasvir
OBV
Velpatasvir
VEL
Sofosbuvir
SOF
NS5B nucleotide polymerase inhibitor
Dasabuvir
DSV
NS5B nonnucleoside polymerase inhibitor
Slide credit: clinicaloptions.com

7. Summary of Investigational Direct-Acting Antivirals Discussed in This Slideset
Drug
Abbreviation
Class
Glecaprevir (formerly ABT-493)
GLE
NS3/4A protease inhibitor
Voxilaprevir
VOX
Pibrentasvir (formerly ABT-530)
PIB
NS5A inhibitor
Ruzasvir (formerly MK-8408)
RZR
MK-3682 --
NS5B polymerase nucleotide inhibitor
Slide credit: clinicaloptions.com

8. Overview of Investigational DAA Studies Discussed in This Slideset
SOF/VEL/VOX
Study Population
Comparator
POLARIS-1[1]
12 wks for NS5A inhibitor experienced GT1-6 HCV
PBO
POLARIS-2[2]
8 wks for DAA-naive GT1-6 HCV
SOF/VEL
POLARIS-3[3]
8 wks for cirrhotic GT3 HCV
POLARIS-4[4]
12 wks for DAA-experienced (no NS5A inhibitors) GT1-6 HCV
GLE/PIB
ENDURANCE-1[5]
8 or 12 wks for noncirrhotic pts with GT1 HCV
ENDURANCE-2[6]
12 wks for noncirrhotic pts with GT2 HCV
ENDURANCE-4[7]
12 wks for noncirrhotic pts with GT4-6 HCV
None
SURVEYOR-II/3[8]
12 or 16 wks for pts with GT3 HCV ± tx exp ± cirrhosis
EXPEDITION-IV[9]
12 wks for pts with GT1-6 HCV and stage 4/5 CKD
MK-3682/GZR/RZR
C-CREST Part B[10]
8/12/16 wks ± RBV for GT1-3 HCV ± tx exp ± cirrhosis
C-CREST Part C[11]
16 wks + RBV for 8-wk MK-3682/GZR/(RZR or EBR) failures
C-SURGE[12]
16 or 24 wks ± RBV for GT1 HCV pts relapsing on DAAs
CKD, chronic kidney disease; DAA, direct-acting antiviral; EBR, elbasvir; exp, experienced; GLE, glecaprevir; GT, genotype; GZR, grazoprevir; HCV, hepatitis C virus; PIB, pibrentasvir; PBO, placebo; RBV, ribavirin; RZR, ruzasvir; SOF, sofosbuvir; tx, treatment; VEL, velpatasvir; VOX, voxilaprevir.
Stefan Zeuzem, MD:
We start with this overview of ongoing or recently completed investigational direct-acting antiviral (DAA) studies. In total, there are 4 POLARIS trials of the investigational triple therapy comprising sofosbuvir (SOF)/velpatasvir (VEL) plus the pan-genotypic protease inhibitor voxilaprevir (VOX). Two of the trials investigate patients with previous exposure to a DAA regimen, either including NS5A inhibitors (POLARIS-1) or excluding them (POLARIS-4).
Across all POLARIS studies, cirrhosis was defined in one of 3 ways: by histology (METAVIR F4 or Ishak 5-6 on biopsy), by FibroScan (> 12.5 kPa), or by a combination of the FibroTest (> 0.75) and the APRI score (> 2).
References for slide:
1. Bourlière M, et al. AASLD Abstract 194.
2. Jacobson IM, et al. AASLD Abstract LB12.
3. Foster GR, et al. AASLD Abstract 258.
4. Zeuzem S, et al. AASLD Abstract 109.
5. Zeuzem S, et al. AASLD Abstract 253.
6. Kowdley KV, et al. AASLD Abstract 73.
7. Asselah T, et al. AASLD Abstract 114.
8. Wyles DL, et al. AASLD Abstract Gane EJ, et al. AASLD Abstract LB11.
10. Lawitz E, et al. AASLD Abstract 110.
11. Serfaty L, et al. AASLD Abstract 112.
12. Wyles DL, et al. AASLD Abstract 193.
Slide credit: clinicaloptions.com
References in slidenotes.

9. POLARIS-1: SOF/VEL/VOX for 12 Wks After NS5A Failure in GT1-6 HCV
Randomized, double-blind, placebo-controlled phase III trial
Stratified by
cirrhotic vs noncirrhotic
Wk 12
SOF/VEL/VOX
400/100/100 mg PO QD
(n = 263)
DAA-experienced pts
with GT1-6 HCV and NS5A inhibitor
experience*
(N = 415)
Subsequently
received
deferred
SOF/VEL/VOX
Placebo PO QD
(n = 152)
*Pts with GT1 HCV at screening equally randomized between arms; pts with GT2-6 HCV assigned to active treatment arm.
APRI, aspartate aminotransferase to platelet patio index; DAA, direct-acting antiviral; DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PO, orally; QD, once daily; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
Stefan Zeuzem, MD:
POLARIS-1 is an international, double-blind, placebo-controlled phase III trial in 415 DAA-experienced patients with previous NS5A inhibitor failure.[1] Patients were predominantly white (81%) and male (77%). Only those infected with genotype 1 HCV at screening were randomized equally to receive either daily oral triple therapy with SOF/VEL/VOX or placebo for 12 weeks. Patients infected with genotype 2-6 HCV automatically received SOF/VEL/VOX, except 2 individuals with genotype 6 who received placebo. In total, 63% of patients received active treatment. One half of these SOF/VEL/VOX recipients had previously been treated with ledipasvir (LDV); other previous agents included daclatasvir, ombitasvir, and various others. Stratification occurred by cirrhosis status. Overall, 41% of patients were cirrhotic, although the incidence of cirrhosis was numerically higher in the active treatment arm (46% vs 34% for placebo).
For more information about this study, go to
Previous NS5A treatment in SOF/VEL/VOX group (n = 263)
LDV, 51%; DCV, 27%; OBV, 11%; other, 13%
Cirrhosis definition for POLARIS studies: METAVIR F4 or Ishak 5-6 on biopsy, or FibroTest > APRI > 2, or FibroScan > 12.5 kPa
Slide credit: clinicaloptions.com
Bourlière M, et al. AASLD Abstract 194.

10. POLARIS-1: SVR12 Rates With 12-Wk SOF/VEL/VOX in Previous NS5A Failure
SVR12, % (n/N)
SOF/VEL/VOX
Overall
96 (253/263)
Cirrhosis status
No cirrhosis
99 (140/142)
Cirrhosis
93 (113/121)
Baseline RAVs
None
98 (42/43)
Any
96 (199/208)
SVR12, % (n/N)
SOF/VEL/VOX
Genotype 1a
96 (97/101) 1b
100 (45/45) 2
100 (5/5) 3
95 (74/78) 4
91 (20/22) 5
100 (1/1) 6
100 (6/6)
GT, genotype; RAV, resistance associated variant; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VOX, voxilaprevir.
Stefan Zeuzem, MD:
The overall sustained virologic response (SVR) at 12 weeks posttreatment in patients receiving triple therapy was 96%; 99% of noncirrhotic vs 93% of cirrhotic patients achieved SVR12. All 7 virologic failures occurred in cirrhotic patients. However, baseline resistance associated variants (RAVs) did not affect response, as 96% of patients with RAVs vs 98% of patients without RAVs achieved SVR12. Furthermore, no relapsing patient demonstrated a treatment-emergent RAV. Across all genotypes, no major differences in efficacy arose. Thus, 12-week SOF/VEL/VOX appears to be a pan-genotypic option that successfully treats patients for whom previous DAA regimens including an NS5A inhibitor have failed.
Ira M. Jacobson, MD:
Yes, we are going to take significant steps forward in our ability to treat the few DAA failures we currently see. Second-generation regimens such as SOF/VEL/VOX appear to offer something better than what we can accomplish with retreatment using another first-generation regimen.
The observation about cirrhosis is very important. Even with current effective DAAs, cirrhosis still affects efficacy, albeit in a small number of patients. These results with SOF/VEL/VOX make me question whether additional measures will be required when retreating DAA-experienced patients with cirrhosis with this combination, if we can identify predictors of failure. Will adding ribavirin (RBV) or extending treatment duration to 16 weeks be warranted?
A small difference in efficacy also remains between genotype 1a and 1b where 96% vs 100% of patients achieved SVR12, respectively.
Current American Association for the Study of Liver Diseases (AASLD)/Infectious Disease Society of America (IDSA) guidelines for patients with previous DAA failure recommend RAV testing before retreatment in some scenarios.[2] Because of data from trials such as POLARIS-1 showing that RAVs do not substantially influence outcome, RAV testing before salvage SOF/VEL/VOX appears unneeded.
Yes, I agree. Second-generation regimens do not seem to be influenced by baseline RAVs, and after failure of these regimens, treatment-emergent RAVs appear to be far less common than with first-generation regimens.
7 virologic failures; all cirrhotic pts (GT1a, n = 2; GT3, n = 4; GT4, n = 1)
Slide credit: clinicaloptions.com
Bourlière M, et al. AASLD Abstract 194.

11. POLARIS-2: 8-Wk SOF/VEL/VOX vs 12-Wk SOF/VEL for DAA-Naive GT1-6 Pts
Randomized, open-label, active-controlled phase III trial
Stratified by HCV genotype, cirrhosis (yes vs no), and prior IFN (experienced vs naive)
Wk 8
Wk 12
SOF/VEL/VOX 400/100/100 mg PO QD (n = 501)
DAA-naive pts with GT1-6 HCV with or without compensated cirrhosis and/or IFN experience
(N = 941)
SOF/VEL 400/100 mg PO QD (n = 440)
DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; IFN, interferon; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VOX, voxilaprevir.
Ira M. Jacobson, MD:
It was my privilege to present this next study in Boston. POLARIS-2 is an international, open-label, active-controlled phase III trial comparing 8 weeks of the investigational triple therapy SOF/VEL/VOX vs 12 weeks of the US Food and Drug Administration (FDA)–approved dual therapy SOF/VEL[3] in 941 DAA-naive genotypes 1-6 patients.[4] Only patients infected with genotype 1-4 HCV were randomized between study arms. To explore the investigational triple-drug regimen in less common genotypes, all individuals with genotype 5/6 HCV infection were allocated to the SOF/VEL/VOX arm. A few patients with genotype 6 HCV infection were originally misidentified as having genotype 1 and received SOF/VEL.
Previous interferon exposure was permitted, cirrhotics were included across all genotypes except for genotype 3, and patients were stratified by genotype, cirrhosis status, and interferon experience. The primary endpoint was SVR12, with noninferiority evaluated at a predetermined margin of 5%.
For more information about this study, go to
*Treatment allocation randomized in pts with GT1-4 HCV; pts with GT5-6 HCV allocated to SOF/VEL/VOX arm; cirrhotic pts with GT3 HCV infection enrolled in POLARIS-3.
Slide credit: clinicaloptions.com
Jacobson IM, et al. AASLD Abstract LB12.

12. POLARIS-2: SVR12 Rates With 8-Wk SOF/VEL/VOX vs 12-Wk SOF/VEL
8 wks SOF/VEL/VOX did not meet criteria for noninferiority vs 12 wks SOF/VEL
Treatment difference: -3.4% (95% CI: -6.2% to -0.6%)
SOF/VEL/VOX 8 wks
SOF/VEL 12 wks
n/N =
Overall
Noncirrhotic
Cirrhotic
Relapse, n
LTFU, n
D/c for AE, n 21 4 3 1 14 2 7
SVR12 (%)
100 80 60 40 20 95 98 96 91 99
476/501
432/440
394/411
349/356
82/90
83/84
AE, adverse event; D/c, discontinued; LTFU, lost to follow-up; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VOX, voxilaprevir.
Ira M. Jacobson, MD:
Overall, patients assigned to both treatment arms did extremely well, with SVR rates of 95% and 98% for the 8-week and 12-week regimens, respectively. Underneath the bar graph, however, we see a clinically meaningful greater number of relapses or virologic failures in the 8-week SOF/VEL/VOX group. Because of this difference, the 8-week regimen failed to meet its primary noninferiority endpoint vs 12-week SOF/VEL, as established in the protocol. The SVR difference was greater in cirrhotics than in noncirrhotics, but the elevated relapse rate for 8-week SOF/VEL/VOX underpinned the reduced efficacy in both comparisons. It is therefore difficult to conclude whether the 8-week regimen will be best for noncirrhotics and whether the 12-week regimen should be reserved for cirrhotics.
Stefan Zeuzem, MD:
Yes, it is unclear whether these investigational drug combinations will give us viable 8-week treatment options. It appears that, in noncirrhotic patients, 8 weeks is a very feasible approach with certain new combinations, but that the cirrhotic patient population really requires the longer treatment duration of at least 12 weeks.
An important variable to consider is the confidence of the provider (eg, hepatologist vs nonspecialist) in identifying liver cirrhosis and making a subsequent recommendation for an appropriate treatment length. Noninvasive markers are either not available to many HCV-treating practitioners or are not 100% reliable and accurate, as in the case of biochemical markers. If we allow the reduced treatment duration of 8 weeks in noncirrhotic patients, cirrhotics may be misidentified and therefore undertreated if less experienced colleagues underestimate the fibrosis stage in some of their patients. This should be investigated in real-world studies to determine whether the benefits of mandating shorter treatment for some patients outweigh the benefits of having a unified recommendation of 12 weeks for all patients, which may simplify management across practitioner experience levels.
Specific to POLARIS-2, this discussion raises the question if SOF/VEL/VOX could serve as a viable 8-week regimen for noncirrhotics. At this time, I think that the difference in number of relapses, despite the similarities in topline SVR rates, may make the use of the 8-week regimen prohibitive, even for the noncirrhotics.
Jacobson IM, et al. AASLD Abstract LB12. Reproduced with permission.
Slide credit: clinicaloptions.com

13. POLARIS-2: Efficacy by HCV GT With 8-Wk SOF/VEL/VOX vs 12-Wk SOF/VEL
SOF/VEL/VOX 8 wks
SOF/VEL 12 wks 98 98 99 97 97 97
100 99 97 92 98 94
100
100
100 95
100 93 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.
Ira M. Jacobson, MD:
Here, the SVR rates from POLARIS-2 are stratified by HCV genotype. Patients infected with genotype 1a HCV and treated with 8-week SOF/VEL/VOX had lower SVR rates than those treated with 12-week SOF/VEL (92% vs 99%, respectively). A resistance analysis showed that patients receiving SOF/VEL/VOX with vs without baseline RAVs exhibited lower SVR rates (93% vs 97%, respectively), and this was more true of the baseline NS3 RAVs than the NS5A RAVs. This observation of lower SVR rates in genotype 1a HCV remains unexplained and will require future mechanistic explanation.
In summary, the difference in SVR rates between the 8-week and 12-week treatment arms in this study was driven largely, if not entirely, by the genotype 1a population. To me, the POLARIS-2 results provide evidence against treating DAA-naive patients with this triple regimen of SOF/VEL/VOX. Based on SVR rates, one could argue this applies to genotype 1a only, but many clinicians may draw this conclusion across all genotypes, given the absence of superiority vs SOF/VEL for 12 weeks, plus the occasional gastrointestinal adverse event (AE) and potential for drug–drug interactions that accompany the addition of a third drug, particularly an NS3/4A protease inhibitor.
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
Jacobson I, et al. AASLD Abstract LB12. Reproduced with permission.
Slide credit: clinicaloptions.com

14. POLARIS-3: 8-Wk SOF/VEL/VOX vs 12-Wk SOF/VEL for Cirrhotic, DAA Naive GT3
Randomized, open-label, active-controlled phase III trial
Stratified by prior IFN (experienced vs naive)
Wk 8
Wk 12
SOF/VEL/VOX 400/100/100 mg PO QD (n = 110)
Patients with
GT3 HCV infection
and cirrhosis with or without prior IFN experience
(N = 219)
SOF/VEL 400/100 mg PO QD (n = 109)
DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; IFN, interferon; PO, orally; QD, once daily; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VOX, voxilaprevir.
Ira M. Jacobson, MD:
POLARIS-3 is an international, open-label, active-controlled phase III study of DAA-naive patients with genotype 3 HCV infection and cirrhosis (N = 219),[5] a patient group that has represented the major ongoing challenge with DAA therapy. This study includes the same regimens and treatment durations as in POLARIS-2.[4] At baseline, nearly one third of the patients were interferon experienced. The primary endpoint was SVR12, and prespecified efficacy analysis dictated a superiority performance goal of 83% for each regimen.
For more information about this study, go to
IFN experience in 29% to 32% of pts
Slide credit: clinicaloptions.com
Foster GR, et al. AASLD Abstract 258.

15. POLARIS-3: SVR12 Rates With 8-Wk SOF/VEL/VOX for Cirrhotic GT3 Pts
SOF/VEL/VOX 8 wks SOF/VEL 12 wks 97 96 96 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 RAVs
Any BL RAVs
BL, baseline; GT, genotype; RAV, resistance associated variant; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VF, virologic failure; VOX, voxilaprevir.
Ira M. Jacobson, MD:
The SVR rates overall were very high, particularly for this challenging population at 96% in each of the 2 treatment arms. Each arm included 4 treatment failures, 2 of these per arm were virologic failures and 2 were nonvirologic failures. Thus, there was absolutely no difference in efficacy between groups.
SVR results were equally good for treatment-naive patients in both arms, but interferon-experienced patients receiving SOF/VEL had lower efficacy than those receiving SOF/VEL/VOX (91% vs 97%, respectively). Baseline RAVs did not affect SVR, and although no treatment-emergent RAVs occurred in the 2 relapsed patients receiving SOF/VEL/VOX, sequencing analysis revealed treatment-emergent Y93H in both virologic failures in the SOF/VEL arm. This underscores a difference in the virology of failure between this triple regimen and even a very potent dual regimen.
Stefan Zeuzem, MD:
AASLD/IDSA guidelines recommend SOF/VEL in combination with RBV for treatment-experienced, cirrhotic patients infected with genotype 3 HCV.[2] If RBV had been added to SOF/VEL in this study, I wonder if the SVR may have increased to higher than 91% in this patient group, bringing the efficacy of this dual therapy closer to that of the triple therapy with SOF/VEL/VOX.
This reduced SOF/VEL response rate in treatment-experienced, cirrhotic patients infected with genotype 3 HCV is very similar to the 89% SVR12 rate previously published for this population with SOF/VEL treatment in the phase III ASTRAL-3 study.[6] Collectively, these data suggest that this subpopulation may benefit from more aggressive treatment, whether it be the use of a triple regimen, extended treatment duration, or addition of RBV.
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 RAVs in SOF/VEL/VOX arm; Y93H in both virologic failures in SOF/VEL arm
Slide credit: clinicaloptions.com
Foster GR, et al. AASLD Abstract 258. Reproduced with permission.

16. POLARIS-4: SOF/VEL/VOX for DAA-Exp’d, NS5A Inhibitor-Naive GT1-6 HCV
Randomized, open-label, active-controlled phase III trial
Stratified by HCV genotype, cirrhosis (yes vs no)
Wk 12
SOF/VEL/VOX
400/100/100 mg PO QD
(n = 182)
DAA-experienced pts
with GT1-6 HCV* and no NS5A inhibitor
experience with or without cirrhosis
(N = 333)
SOF/VEL 400/100 mg PO QD (n = 151)
*Pts with GT1-3 HCV randomized 1:1 between arms. Pts with GT4-6 HCV assigned to SOF/VEL/VOX.
DAA, direct-acting antiviral; Exp’d, experienced; GT, genotype; HCV, hepatitis C virus; RAV, resistance associated variant; SMV, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
Stefan Zeuzem, MD:
POLARIS-4 is an international, open-label, active-controlled phase III trial comparing 12 weeks of SOF/VEL/VOX with 12 weeks of SOF/VEL in 333 patients infected with genotype 1-6 HCV, with or without cirrhosis.[7] Similar to POLARIS-1,[1] patients in this study were DAA experienced, but unlike POLARIS-1, they had no previous NS5A inhibitor experience. Most patients were previously treated with SOF (69%), SOF plus simeprevir (11%), or another NS5B/NS3 inhibitor combination (14%). Approximately 2% of patients were pretreated with other agents, including investigational drugs from phase II/III trials.
Patients with genotype 4-6 HCV infection were assigned to receive triple therapy with SOF/VEL/VOX, and only genotype 1-3 HCV patients were randomized 1:1 between the 2 treatment arms. The primary endpoint was SVR12, with independent performance goals of 85% for each regimen.
For more information about this study, go to
Prior HCV treatment
SOF, 69%; other NS5B inhibitor, 4%
SOF + SMV, 11%; other NS5B/NS3 inhibitor combinations, 14%
Other, 2%
Slide credit: clinicaloptions.com
Zeuzem S, et al. AASLD Abstract 109.

17. POLARIS-4: Efficacy of SOF/VEL/VOX for DAA-Exp’d, NS5A Inhibitor Naive HCV Pts
SOF/VEL/VOX 12 wks SOF/VEL 12 wks 97 98 96
100 94 94 89 90
100 90 86 80 60
SVR12 (%) 40 20
177/
182
136/
151
96/ 98
77/ 82
81/ 84
59/ 69
84/ 89
67/ 75
83/ 83
63/ 70
n/N =
Overall
Noncirrhotic
Cirrhotic
No RAVs
Any RAVs
DAA, direct-acting antiviral; Exp’d, experienced; HCV, hepatitis C virus; LTFU, lost to follow-up; RAV, resistance associated variant; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VOX, voxilaprevir.
Stefan Zeuzem, MD:
The data show overall SVR rates greater than 90%, with a trend for better response with the triple therapy over the dual therapy across subgroups. In fact, only SOF/VEL/VOX met its prespecified superiority goal of 85% (P < .001). SOF/VEL failed to demonstrate superiority vs prespecified 85% rate (P = .092). Both regimens performed better in noncirrhotic patients than in cirrhotic patients. Of most importance, we see here again that the presence or absence of RAVS does not affect the achievement of SVR, making the necessity of RAV testing less important when these newer regimens are used.
Ira M. Jacobson, MD:
These results are fascinating. Other than patients with genotype 3 HCV infection, particularly those with cirrhosis, these are the lowest SVR rates that we have seen with SOF/VEL.
More than two thirds of patients in POLARIS-4 were previously treated with regimens containing SOF, a drug with a high barrier to resistance. Although it is an extremely potent drug, foundational to many of the regimens currently in use, these results suggest that SOF failure may predispose patients to failure again if SOF is added to VEL alone as opposed to VEL plus VOX. This underscores that unknown factors—such as absorption, bioavailability within the cell, or other unknown factors—may play a role in determining an individual’s response to SOF. In other words, adding the third DAA may have made a difference because of whatever factors are being reflected by the previous failure to SOF therapy. Overall, POLARIS-4 establishes a preference for the triple vs the double regimen in these DAA-experienced, NS5A inhibitor–naive genotype 1-6 HCV–infected patients.
SOF/VEL/VOX: P < .001 for superiority vs prespecified 85% goal; SOF/VEL: P = .092
Overall, reduced SVR12 rate for SOF/VEL driven by increased number of relapses
SOF/VEL/VOX (n = 182): 1 relapse, 1 death, 3 LTFU
SOF/VEL (n = 151): 14 relapses, 1 breakthrough
Slide credit: clinicaloptions.com
Zeuzem S, et al. AASLD Abstract 109. Reproduced with permission.

18. POLARIS Studies: Safety
Outcome, %
POLARIS-1[1]
POLARIS-2[2]
SOF/VEL/VOX
(n = 263)
PBO
(n = 152)
(n = 501)
SOF/VEL
(n = 440)
Any AE 78 70 72 69
Grade 3/4 AE 2 3 1
Serious AE 5
Serious TRAE
D/c for AE
< 1
Death
AE in > 10% of pts
Headache 25 17 27 23
Fatigue 21 20
Diarrhea 18 13 7
Nausea 14 8 16 9
Grade 3/4 lab abnormality 4
AE, adverse event; D/c, discontinued; NR, not reported; PBO, placebo; SOF, sofosbuvir; TRAE, treatment-related adverse event; VEL, velpatasvir; VOX, voxilaprevir.
References for slide:
1. Bourlière M, et al. AASLD Abstract 194.
2. Jacobson IM, et al. AASLD Abstract LB12.
Stefan Zeuzem, MD:
The SOF/VEL/VOX regimen is overall very safe. Rates of serious AEs or discontinuations for AEs in the POLARIS studies were very low, with no differences observed between the triple therapy or dual therapy and placebo. However, among AEs that occurred in more than 10% of patients, 2 gastrointestinal-associated AEs arose more frequently with triple therapy across all 4 POLARIS trials. Addition of VOX seemed to induce slightly higher rates of nausea and diarrhea. Typically, the diarrhea was mild, at a frequency not exceeding 3-4 bowel movements per day.
Ira M. Jacobson, MD:
This elevated incidence of nausea and diarrhea with SOF/VEL/VOX vs SOF/VEL or placebo is not prohibitive by any means. Drug-related AEs almost never led to discontinuation of SOF/VEL/VOX in any of the studies of this regimen. Furthermore, these AEs are readily managed and will likely play a relatively minor role during treatment selection in the future.
Slide credit: clinicaloptions.com
References in slidenotes.

19. POLARIS Studies: Safety
Outcome, %
POLARIS-3[1]
POLARIS-4[2]
SOF/VEL/VOX
(n = 110)
SOF/VEL
(n = 109)
(n = 182)
(n = 151)
Any AE 75 74 77
Grade 3/4 AE 3 4 1
Serious AE 2
Serious TRAE
D/c for AE
< 1
Death
< 1*
< 1†
AE in > 10% of pts
Headache 25 29 27 28
Fatigue 24
Diarrhea 15 5 20
Nausea 21 9 12 8
Grade 3/4 lab abnormality 13 6 7
AE, adverse event; D/c, discontinued; SOF, sofosbuvir; TRAE, treatment-related adverse event; VEL, velpatasvir; VOX, voxilaprevir.
References for slide:
Foster GR, et al. AASLD Abstract 258.
Zeuzem S, et al. AASLD Abstract 109.
*Death from hypertension deemed unrelated to treatment. †Death from illicit drug overdose.
Slide credit: clinicaloptions.com
References in slidenotes.

20. ENDURANCE-1, 2, 4: GLE/PIB for Treatment of GT1, 2, 4, 5, 6 HCV
Wk 8
Wk 12
ENDURANCE-1: randomized, open-label phase III trial[1]
Noncirrhotic pts with GT1 HCV
with or without
IFN experience or HIV coinfection
(N = 703)
GLE/PIB* (n = 351)
GLE/PIB* (n = 352)
ENDURANCE-2: randomized, double-blind, placebo-controlled phase III trial[2]
Noncirrhotic pts with GT2 HCV
with or without
IFN experience
(N = 302)
GLE/PIB* (n = 202)
Placebo (n = 100)
GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; IFN, interferon; PIB, pibrentasvir; QD, once daily.
Stefan Zeuzem, MD:
The large series of phase III ENDURANCE studies evaluated the efficacy and safety of glecaprevir (GLE)/pibrentasvir (PIB) in noncirrhotic HCV-infected patients who were treatment experienced or naive and coinfected or not coinfected with HIV.
Based on the results of these studies, GLE/PIB has been submitted to the FDA as a potential pan-genotypic 8-week regimen for patients without cirrhosis and has been granted breakthrough status as a potential rescue therapy for DAA-experienced patients with genotype 1 HCV infection.
ENDURANCE-1 is a multicenter, randomized, open-label study comparing 8 weeks and 12 weeks of GLE/PIB in genotype 1 HCV–infected patients (N = 703).[8]  
ENDURANCE-2 is a randomized, double-blind, placebo-controlled study comparing 12 weeks of GLE/PIB with placebo in genotype 2 HCV–infected patients (N = 302).[9]
ENDURANCE-4 is an open-label, single-arm study of 12-week GLE/PIB in patients infected with the more rare genotypes of HCV: 4, 5, and 6 (N = 121).[10]
ENDURANCE-3 data for genotype 3 HCV–infected patients are still pending and were not presented in Boston.[11]
For more information about ENDURANCE-1, go to:
ENDURANCE-4: open-label, single-arm phase III trial[3]
Noncirrhotic pts with GT4-6 HCV
with or without IFN experience
(N = 121)
GLE/PIB* (N = 121)
*Dosing: GLE/PIB given as 3 coformulated 100/40 mg tablets QD for a total dose of 300/120 mg.
Slide credit: clinicaloptions.com
References in slidenotes.

21. ENDURANCE Studies: Key Baseline Demographics
Characteristic, %
ENDURANCE-1[1]
ENDURANCE-2[2]
ENDURANCE-4[3]
GLE/PIB 8 Wks
(n = 351)
GLE/PIB 12 Wks
(n = 352)
GLE/PIB
12 Wks (n = 202)
PBO
12 Wks
(n = 100)
12 Wks (N = 121)
Fibrosis stage
F0-F1 85 76 86 F2 6 7 9 F3 8 15
Treatment experienced* 38 30 29 32
HIV coinfected 4 5 NA
GLE, glecaprevir; IFN, interferon; NA, not applicable; PBO, placebo; pegIFN, peginterferon; PIB, pibrentasvir; RBV, ribavirin; SOF, sofosbuvir.
Stefan Zeuzem, MD:
Across treatment arms in the ENDURANCE-1, 2, and 4 trials, most patients (76% to 86%) were at a fibrosis stage of 0 or 1. Fewer than 10% had F2 fibrosis, and 6% to 15% had F3 fibrosis. Approximately one third of all patients were treatment experienced, and in ENDURANCE-1, only 5% of patients were coinfected with HIV.
Ira M. Jacobson, MD:
I initially found this fibrosis distribution surprising. In my practice, the predominant stage is F2, followed by F1, which raised the question of whether more F2 and F3 fibrotics should have been included in the studies. Given the high SVR rates that will next be discussed, my concerns have been attenuated dramatically.
*Pts could have treatment experience with IFN or pegIFN ± RBV or SOF + RBV ± pegIFN.
1. Zeuzem S, et al. AASLD Abstract 253.
2. Kowdley KV, et al. AASLD Abstract 73.
3. Asselah T, et al. AASLD Abstract 114.
Slide credit: clinicaloptions.com

22. ENDURANCE Studies: Efficacy of GLE/PIB for Treating GT1, 2, 4, 5, 6 HCV
Outcome
ENDURANCE-1[1]
(GT1)
ENDURANCE-2[2]
(GT2)
ENDURANCE-4[3]
(GT4-6)
GLE/PIB 8 Wks
GLE/PIB 12 Wks
GLE/PIB
12 Wks
SVR12, % (n/N)
99.1* (332/335)
99.7* (331/332)
99† (195/196)
99‡
(120/121)
Relapse/ on-treatment failure, n 1§
GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat; PIB, pibrentasvir; SOF, sofosbuvir.
Stefan Zeuzem, MD:
This slide summarizes the SVR rates of all 3 ENDURANCE studies, which were uniformly at or greater than 99%. These data suggest that noncirrhotic patients infected with genotype 1, 2, 4, 5 or 6 HCV can be safely treated with GLE/PIB, sometimes for just 8 weeks, without compromising SVR rates. Of the 4 patients who did not achieve SVR in ENDURANCE-1, 1 patient experienced on-treatment virologic failure, 1 patient discontinued on Day 2 because of noncompliance, and 2 patients had missing SVR12 data.[8] No virologic failures were observed in the ENDURANCE-2 or 4 studies.[9,10]
Ira M. Jacobson, MD:
Over the years, when I have contemplated the enticing potential of 8-week regimens, I have adamantly maintained that shorter regimens should be considered only if we do not sacrifice SVR. Given the ENDURANCE data, there is no question that clinicians can feel comfortable with the 8-week GLE/PIB regimen in noncirrhotic patients with genotype 1 HCV infection.
It is interesting that a decision was made not to study the other genotypes for 8 weeks. For now at least, we would anticipate using the regimen for 12 weeks in genotypes 2, 4, 5, and 6.
*ITT-PS analysis: included all pts receiving ≥ 1 dose of study drug; excluded pts with HIV coinfection or SOF experience. †ITT analysis: excluded pts with SOF experience. ‡ITT analysis. §On-treatment virologic failure at Day 29 in pt with GT1a HCV.
1. Zeuzem S, et al. AASLD Abstract Kowdley KV, et al. AASLD Abstract Asselah T, et al. AASLD Abstract 114.
Slide credit: clinicaloptions.com

23. SURVEYOR-II, Part 3: GLE/PIB for Pts With GT3 HCV ± Cirrhosis
Partially randomized, open-label phase II trial (N = 131)
Wk 12
Wk 16
GLE/PIB* (n = 22)
Treatment-experienced, noncirrhotic
pts with GT3 HCV
GLE/PIB* (n = 22)
Treatment-naive
pts with GT3 HCV and compensated cirrhosis
GLE/PIB* (n = 40)
GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon; PIB, pibrentasvir; QD, once daily; RBV, ribavirin; SOF, sofosbuvir.
Ira M. Jacobson, MD:
SURVEYOR-II, Part 3 is an open-label phase II trial of 12 weeks or 16 weeks of GLE/PIB in 131 genotype 3 HCV–infected patients with treatment experience, cirrhosis, or both.[12] Previous treatment experience consisted of interferon, peginterferon with or without RBV, or SOF and RBV with or without peginterferon. Only treatment-experienced, noncirrhotic patients were randomized. Cirrhotic patients received 12 weeks of therapy if they were treatment naive and 16 weeks if they were treatment experienced, owing to previous studies showing higher failures in such patients.
For more information about this study, go to
Treatment-experienced
pts with GT3 HCV and compensated cirrhosis
GLE/PIB* (n = 47)
Prior treatment experience consisted of IFN or pegIFN ± RBV or SOF + RBV ± pegIFN
*Dosing: GLE/PIB given as 3 coformulated 100/40 mg tablets QD for a total dose of 300/120 mg.
Slide credit: clinicaloptions.com
Wyles DL, et al. AASLD Abstract 113.

24. SURVEYOR-II, Part 3: SVR12 Rates With GLE/PIB for Pts With GT3 HCV ± Cirrhosis96 98 96
100 91 80 60
SVR12 (%) 40 20
n/N =
20/22
21/22
39/40
45/47
GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; LTFU, lost to follow-up; PIB, pibrentasvir; SVR, sustained virologic response; Tx, treatment.
Ira M. Jacobson, MD:
Two of 22 noncirrhotic, treatment-experienced patients receiving 12-week therapy relapsed, resulting in an SVR12 of 91%. With an extended 16-week course of GLE/PIB in similar patients, only 1 relapse occurred, giving an SVR12 of 96%. However, given the small size of this study, it is difficult to say whether that is a real difference conferred by the extra 4 weeks of GLE/PIB.
In cirrhotic patients treated with GLE/PIB for 12 weeks or 16 weeks, SVR12 rates were ≥ 96% regardless of treatment experience. Even though response rates seem to climb from left to right on this slide, no definitive conclusions can be drawn, except to say that GLE/PIB appears very promising for genotype 3 patients, and that some patients likely need extra help in the form of an extra 4 weeks of therapy.
Stefan Zeuzem, MD:
The numbers here are still very small, and it is difficult to say whether 1 or 2 patients with breakthrough or relapse are meaningful or simply due to chance.
What is potentially confusing about this study is the different treatment durations and populations. In practice, improperly assigning a patient to a certain treatment duration can reduce the chance of SVR or increase the cost of treatment. The more variable the treatment durations are, the better the guidelines and guidance for the treating physicians must be.
Tx Wks Cirrhosis Tx Experienced Breakthrough Relapse
LTFU
12 - + 2
16 - + 1
12 + - 1
16 + + 1
Slide credit: clinicaloptions.com
Wyles DL, et al. AASLD Abstract 113. Reproduced with permission.

25. EXPEDITION-IV: GLE/PIB for Pts With GT1-6 HCV and Renal Impairment
Open-label, single-arm phase III trial
Wk 12
GT1-6 HCV pts
with stage 4 or 5 CKD
with compensated cirrhosis or without cirrhosis
and with or without treatment experience†
(N = 104)
GLE/PIB* (N = 104)
At baseline, 82% on hemodialysis; 19% cirrhotic; 42% treatment experienced
SVR12 rate of 98% (ITT; n/N = 102‡/104)
CKD, chronic kidney disease; d/c, discontinued; GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; IFN, interferon; ITT, intent to treat; LTFU, lost to follow-up; pegIFN, peginterferon; PIB, pibrentasvir; QD, once daily; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response.
Stefan Zeuzem, MD:
Patients with renal impairment have limited options with current HCV therapies. GLE/PIB is therefore of major interest for patients with significant kidney insufficiency receiving hemodialysis.
EXPEDITION-IV is an open-label, single-arm phase III study of 12-week GLE/PIB in 104 patients with genotype 1-6 HCV infection and stage 4/5 chronic kidney disease.[13] At baseline, 82% of patients were receiving hemodialysis, 19% were cirrhotic, and 42% were treatment experienced. The intent-to-treat SVR12 rate is impressive at 98%, with no virologic failures. Of importance, the regimen was safe and well tolerated with no drug-related serious AEs or alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations greater than grade 1.
Ira M. Jacobson, MD:
In 2015, when an overall SVR rate of 99% was reported in a per protocol analysis of the phase III C-SURFER study (N = 224) of grazoprevir (GZR) and elbasvir (EBR), it dramatically improved treatment options for HCV-infected patients with renal impairment, including those receiving hemodialysis.[14]
Ombitasvir/paritaprevir/ritonavir with or without dasabuvir has also shown efficacy in the much smaller RUBY-I[15] (N = 20) and RUBY-II[16] (N = 18) studies for this renal population, albeit with data that are far less robust.
The GLE/PIB results presented here are extremely impressive; this pan-genotypic regimen will likely be a good option with enough data to be widely embraced for patients with renal disease.
For more information about this study, go to
*Dosing: GLE/PIB given as 3 coformulated 100/40-mg tablets QD for a total dose of 300/120 mg.
†Prior treatment experience consisted of IFN or pegIFN ± RBV or SOF + RBV ± pegIFN.
‡1 pt d/c, 1 pt LTFU in ITT analysis of SVR12.
Slide credit: clinicaloptions.com
Gane EJ, et al. AASLD Abstract LB11.

26. GLE/PIB Studies: Safety
Outcome, %
ENDURANCE-1[1]
ENDURANCE-2[2]
ENDURANCE-4[3]
GLE/PIB 8 Wks
(n = 351)
GLE/PIB 12 Wks
(n = 352)
GLE/PIB
12 Wks (n = 202)
PBO
12 Wks
(n = 100)
12 Wks (n = 121)
Any AE 62 66 65 58 69
D/c for AE
< 1 2
Serious AE 1
Death
AE in ≥ 10% of pts
Fatigue 9 12 11 10 17
Headache 19 18 21
AST grade ≥ 3*
ALT grade ≥ 3*
Total bilirubin grade 3†
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; D/c, discontinued; GLE, glecaprevir; PBO, placebo; PIB, pibrentasvir; ULN, upper limit of normal.
Stefan Zeuzem, MD:
The safety and tolerability of GLE/PIB were extraordinarily reassuring. For example, in ENDURANCE-2 the numbers of reported AEs in the treatment arm were not substantially different from those in the placebo arm.[9] No dramatic elevations in fatigue, headache, and pruritus or other skin reactions were noted. In fact, across all GLE/PIB studies, very few patients discontinued for AEs.
There is always a potential concern for increases in aminotransferases with potent protease inhibitors, which may be associated with a concomitant increase in bilirubin, indicating potential hepatic toxicity. These GLE/PIB data from ENDURANCE are very reassuring, as there were very few grade 3 or higher increases of aminotransferases.
In the SURVEYOR-II study, there was a 5% incidence of AST elevation with GLE/PIB, but this reflects only 1 patient because only 22 patients were enrolled overall.[12] Similarly, only 2 patients make up the 9% with ALT elevation in that study. Furthermore, no more than 2% of patients exhibited grade 3 or higher increases in bilirubin. Thus, these GLE/PIB trials have not indicated any relevant hepatic toxicity.
Ira M. Jacobson, MD:
I agree. These data are in keeping with the excellent AE profile of this regimen, and no signal of any extra concern emerged.
*> 5 times ULN. †3-10 times ULN.
1. Zeuzem S, et al. AASLD Abstract Kowdley KV, et al. AASLD Abstract Asselah T, et al. AASLD Abstract 114.
Slide credit: clinicaloptions.com

27. GLE/PIB Studies: Safety
Outcome, %
SURVEYOR-II, Part 3[1]
EXPEDITION-IV[2]
Tx-Exp Noncirr
G/P 12 Wks
(n = 22)
G/P 16 Wks
Tx-Naive Cirrhotic
G/P 12 Wks (n = 40)
Tx-Exp Cirrhotic
(n = 47)
Pts With Renal Impairment
G/P 12 Wks (n = 104)
Any AE 55 77 80 72 71
D/c for AE 4
Serious AE‡ 5 3 7 24
Death NR 1
AE in ≥ 10% of pts
Fatigue 18 13 34 14
Headache 23 25 12
Pruritus NA 20
AST grade ≥ 3*
ALT grade ≥ 3* 9
Total bilirubin grade ≥ 3† 2
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; D/c, discontinued; GLE/G, glecaprevir; NA, not applicable; Noncirr, noncirrhotic; PBO, placebo; PIB/P, pibrentasvir; Tx, treatment; ULN, upper limit of normal.
*> 5-20 times ULN. †> 3-10 times ULN. ‡No serious drug-related AEs.
1. Wyles DL, et al. AASLD Abstract Gane EJ, et al. AASLD Abstract LB11.
Slide credit: clinicaloptions.com

28. C-CREST 1 & 2: MK-3682/GZR/RZR ± RBV for Treating Pts With GT1-3 HCV
Part B: randomized, open-label phase II trials
Wk 8
Wk 12
Wk 16
MK-3682/GZR/RZR
(n = 173: GT1, n = 88; GT2, n = 32; GT3, n = 53)
MK-3682/GZR/RZR + RBV
(n = 81: GT2, n = 31; GT3, n = 50)
Patients with GT1-3 HCV,
HCV RNA ≥ 10,000 IU/mL,
with or without compensated
cirrhosis
(N = 664)
MK-3682/GZR/RZR
(n = 213: GT1, n = 88; GT2, n = 46; GT3, n = 79)
MK-3682/GZR/RZR + RBV
(n = 96: GT2, n = 16; GT3, n = 80)
MK-3682/GZR/RZR
(n = 76: GT2, n = 26; GT3, n = 50)
GT, genotype; GZR, grazoprevir; HCV, hepatitis C virus; QD, once daily; pegIFN, peginterferon; RBV, ribavirin; RZR, ruzasvir.
Ira M. Jacobson, MD:
The next regimen to discuss consists of the investigational NS5B polymerase nucleotide inhibitor MK-3682, the NS3/4A protease inhibitor GZR, and the newer NS5A inhibitor ruzasvir (RZR) (previously MK-8408). This triple combination provides excellent coverage against the broad array of RAVs variants that are associated with first-generation members of the NS5A class.
C-CREST-1 and 2, Part B, is an exploratory, randomized, open-label phase II trial of 8-week, 12-week, or 16-week MK-3682/GZR/RZR with or without RBV in genotype 1-3 HCV–infected patients (N = 664).[17] Distribution of genotypes across the different treatment arms was not even. For instance, genotype 1 patients received only either 8 weeks or 12 weeks of the RBV-free regimen, as this population had been extensively studied earlier in this development program. At baseline, 35% to 43% of patients per arm had compensated cirrhosis, and 44% of the genotype 3 patients had previous peginterferon and RBV experience.
For more information about this study, go to
MK-3682/GZR/RZR + RBV
(GT3, n = 25)
Dosing: MK-3682/GZR/RZR dosed as two 225/50/30-mg tablets QD. Pts with GT3 HCV could be treatment naive or have failed on pegIFN/RBV; all others treatment naive. Cirrhosis definition in notes.
Baseline: 35% to 43% cirrhotic; 44% of GT3 pts had prior pegIFN/RBV
Slide credit: clinicaloptions.com
Lawitz E, et al. AASLD Abstract 110.

29. C-CREST 1 & 2: Efficacy of MK-3682/ GZR/RZR ± RBV for Pts With GT1-3 HCV
Full Analysis Set
8 wks
12 wks
16 wks 93 98 98
100 97
100 95 97 96
100 86 80 60
SVR12 (%) 40 20
39/ 42
47/ 48
45/ 46
40/ 40
54/ 63
60/ 62
26/ 26
98/ 103
155/ 159
72/ 75
n/N =
GT1a
GT1b
GT2
GT3
Relapse (n) 2 1 7 4 3 2
GT, genotype; GZR, grazoprevir; HCV, hepatitis C virus; RAV, resistance associated variant; RBV, ribavirin; RZR, ruzasvir; SVR, sustained virologic response; tx, treatment.
Ira M. Jacobson, MD:
Here, response rates are aggregated by genotype across the 3 treatment durations of MK-3682/GZR/RZR with or without RBV. The presence or absence of RBV is not separated out for this analysis, as its use did not affect SVR12 rates. The blue bars, representing 8-week treatment, demonstrate the lowest SVR rates for each of the included genotypes, with the biggest deficit occurring in genotype 2 patients.
When comparing genotype 1 HCV subtypes, the SVR rates seem approximately equivalent between 8 weeks and 12 weeks for genotype 1b patients (98% vs 100%, respectively) but numerically lower for the shorter duration in genotype 1a (93% vs 98%, respectively). This is, however, only a difference between 1 and 2 relapses, making a definitive conclusion difficult. Of interest, the genotype 3 patients did equally well across the board with SVR12 rates of 95% to 97%. This shows promise for perhaps even a short-duration regimen in genotype 3 and testifies to the coverage provided by RZR.
At the bottom of this slide, a selected RAV analysis evaluates the impact of baseline L31M in genotype 2 or Y93H in genotype 3 on SVR achievement with 8 weeks or 12 weeks of MK-3682/GZR/RZR. Presence of the L31M RAV clearly lowers the SVR12 rate during 8-week treatment (80% vs 94% when absent). However, SVR was unaffected by this substitution with 12 weeks of therapy, reinforcing the concept that the impact of resistant RAVs on outcomes may be dependent on the duration of treatment. Overall, genotype 3 patients with the Y93H RAV demonstrated reduced efficacy compared with those lacking this substitution (50% vs 98% with 8-week treatment, 71% vs 99% with 12-week treatment). This seems like a clear signal that the Y93H RAV negatively affects response, albeit in a very small number of patients here. Because of the reduced sample size, it is difficult to say whether the 12-week regimen offered an advantage, but this population may likely require a longer duration of therapy to attain response. One would like to know how many of the Y93H failures did or did not receive RBV.
Stefan Zeuzem, MD:
The Y93H story is interesting. In vitro, RZR demonstrates more potent antiviral activity and a higher genetic barrier to resistance than other NS5A inhibitors, but the assays typically explore EC90 values in genotype 1, not genotype 3, replicons.[18,19] Patients enrolled in C-CREST with genotype 3 HCV infection and the Y93H RAV seemed to perform poorly. This emphasizes the need for in vitro data on RZR using genotype 3 backbones.
Moreover, it is a bit surprising that the other 2 components of the regimen, MK-3682 and GZR, did not mitigate the effect of Y93H. In the future, more information on the relative activity of GZR in genotype 3, as well as the antiviral efficacy of MK-3682 compared with SOF, would be advantageous.
Presence of cirrhosis, use of ribavirin, prior tx experience did not impact SVR12 rates
SVR12 by Baseline RAV Presence, % (n/N)
GT2 HCV
GT3 HCV
No L31M
L31M
No Y93H
Y93H
8 wks
94 (31/33)
80 (20/25)
98 (95/97)
50 (2/4)
12 wks
100 (23/23)
100 (28/28)
99 (147/148)
71 (5/7)
Slide credit: clinicaloptions.com
Lawitz E, et al. AASLD Abstract 110. Reproduced with permission.

30. C-CREST 1 & 2: Retreatment With MK-3682/GZR/RZR for 8-Wk Failures
Part C: open-label phase II trial retreating pts with GT1-3 HCV who failed 8 wks of treatment with MK-3682/ GZR/RZR or MK-3682/GZR/EBR during Part A of C-CREST 1 & 2 (n = 24)
Pts retreated with MK-3682/GZR/RZR + RBV for 16 wks
Outcome
GT1 HCV
GT2 HCV
GT3 HCV
SVR12, % (n/N)
100 (2/2)
93 (13/14)
100 (8/8)
Relapsed, n
Discontinued, n 1
EBR, elbasvir; GT, genotype; GZR, grazoprevir; HCV, hepatitis C virus; RBV, ribavirin; RZR, ruzasvir; SVR, sustained virologic response.
Stefan Zeuzem, MD:
Part C of C-CREST-1 and 2 was an open-label phase II trial that retreated 24 genotype 1-3 HCV–infected patients who had failed 8 weeks of treatment with either MK-3682/GZR/RZR or MK-3682/GZR/EBR during Part A.[20] Patients were retreated with 16 weeks of MK-3682/GZR/RZR plus RBV, and 23 of 24 patients were cured with this rescue option. The overall message here is that even though patients were exposed to at least 2 of the 3 salvage regimen components for 8 weeks, the MK-3682/GZR/RZR regimen could still overcome failure when the duration was doubled for retreatment. The contribution of RBV addition could not be explored, given the small number of patients. Because these patients had failed such potent triple therapy, it made sense to add RBV and treat for longer, rather than exploring whether RBV was needed.
Ira M. Jacobson, MD:
I agree that it was prudent to use RBV in this case, as 20 of 24 patients had NS5A RAVs at the time of retreatment. I wonder, however, if 16-week RBV-free retreatment might have performed just as well.
I am reminded of the single-arm, prospective phase II study by Lawitz and colleagues[21] where patients were treated with 24 weeks of LDV/SOF after failure on 8-week or 12-week LDF/SOF-based therapy (Capsule Summary). [Coder, please link to: Patients previously failing an 8-week regimen achieved 80% SVR12 whereas those on previous 12-week regimens reached only 46% SVR12. During a resistance analysis of the study population, it was discovered that all patients without baseline NS5A RAVs had previously received 8 weeks of therapy. This was invoked as an explanation for why the 24-week retreatment regimen was more successful in this subgroup.
The Lawitz and colleagues study clearly showed that the existence of RAVs did matter, especially in those harboring Y93H/N or L31M, where SVR12 rates were reduced to 33% and 80%, respectively.
Yes, but if it continues to be true that treatment-emergent RAVs are relatively uncommon with these newer triple-therapy or second-generation regimens, the relative benefits of RBV use vs duration of treatment will need to be elucidated.
Slide credit: clinicaloptions.com
Serfaty L, et al. AASLD Abstract 112.

31. C-SURGE: MK-3682/GZR/RZR for GT1 HCV Pts Who Relapsed on DAA Therapy
Randomized, open-label phase II trial (interim analysis)
Stratified by GT1 subtype (1a vs 1b) and cirrhosis (yes vs no)
Wk 16
Wk 24
MK-3682/GZR/RZR + RBV
(n = 45)
Pts with GT1 HCV (HCV RNA ≥ 10,000 IU/mL) and relapse after SOF/LDV ± RBV or GZR/EBR ± RBV
(N = 94)
MK-3682/GZR/RZR
(n = 49)
Baseline characteristics:
Previous failing regimen: LDV/SOF wks, 61%; LDV/SOF 8 wks, 15%; GZR/EBR 12 wks, 24%
NS5A RAVs, 84%; NS3 RAVs, 65%
DAA, direct-acting antiviral; EBR, elbasvir; GT, genotype; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; RAV, resistance associated variant; RBV, ribavirin; RZR, ruzasvir; SOF, sofosbuvir.
Stefan Zeuzem, MD:
C-SURGE is an open-label phase II study exploring the MK-3682/GZR/RZR regimen in genotype 1 HCV–infected patients who relapsed after previous SOF/LDV or GZR/EBR, each with or without RBV.[22] Most patients had detectable RAVs in NS5A (84%) or NS3 (65%), and 42% were cirrhotic. Patients were randomized to receive this triple therapy either with RBV for 16 weeks or without RBV for 24 weeks. Results discussed here are from the interim analysis (N = 94).
For more information about this study, go to
Dosing: MK-3682/GZR/RZR two 225/50/30-mg tablets once daily; weight-based RBV ( mg/day).
Trial included compensated cirrhotic and noncirrhotic pts; cirrhosis definition in slidenotes.
Slide credit: clinicaloptions.com
Wyles DL, et al. AASLD Abstract 193.

32. C-SURGE: SVR8 Rates With MK-3682/GZR/RZR for DAA Relapses98
100 98
100 91 92
16 wks + RBV
24 wks without RBV
100 80 60
Percent of Pts With HCV RNA
< 15 IU/mL 40 20
n/N =
DAA, direct-acting antiviral; GZR, grazoprevir; RAV, resistance associated variant; RBV, ribavirin; RZR, ruzasvir; SVR, sustained virologic response; TW, treatment week.
Stefan Zeuzem, MD:
SVR8 rates were ≥ 98% for both treatment arms. With these data, we are unable to answer the question posed by Dr. Jacobson where he challenged the need for RBV with a 16-week treatment duration. We only have the answer here that treating for as long as 24 weeks does not require the use of RBV in this population.
Ira M. Jacobson, MD:
It remains to be seen how important shortening the duration of therapy is to clinicians and patients. These results do have to be interpreted in the context of other studies that are demonstrating extremely high SVR rates with 12 weeks of RBV-free therapy (eg, POLARIS-1[1]). Even if all of the C-SURGE patients go on to achieve SVR12, and these data are duplicated in a larger study, clinicians may still opt for a shorter treatment duration at the cost of rare but potential virologic failure.
40/44
45/49
43/44
38/38
43/44
30/30
TW4
SVR4
SVR8
No impact of NS5A or NS3 RAVs on SVR4, including Y93 RAVs
4% of pts had ≥ 3 NS5A RAVs; 55% had dual NS5A and NS3 RAVs
Slide credit: clinicaloptions.com
Wyles DL, et al. AASLD Abstract 193. Reproduced with permission.

33. MK-3682/GZR/RZR Studies: Safety
Outcome, %
C-CREST 1 & 2 Part B[1]
MK-3682/GZR/RZR
C-SURGE[2]
No RBV
(n = 462)
+ RBV
(n = 202)
+ RBV, 16 Wks (n = 44)
24 Wks
(n = 49)
Any AE 69 86 91 80
Drug-related AE 36 67 75 47
D/c for AE
< 1 3
Serious AE 2 8
Death
< 1*
AE in > 10% of pts
Fatigue 15 29 48 24
Headache 19 27 14 12
Nausea 11 NA
Diarrhea 7 10
Pruritus
Rash 4
AE, adverse event; D/c, discontinued; GZR, grazoprevir; NA, not applicable; RBV, ribavirin; RZR, ruzasvir.
Stefan Zeuzem, MD:
The safety for this triple therapy comprising MK-3682, GZR, and RZR looks very promising. When included in this regimen, RBV is the biggest driver of drug-related AEs. We can conclude this, as the typical AEs known to arise because of RBV occur. Comparing the rates of AEs between regimens of different durations can be complicated, so it is reassuring that, here, 24-week RBV-free treatment is not necessarily associated with AEs much higher than those reported for the 16-week RBV-containing regimen. Because the safety analysis reports single events of the patient, what remains missing is the duration of each reported AE.
Ira M. Jacobson, MD:
I agree. I would also make a specific point about the rarity of late ALT or AST elevations above 5 times the upper limit of normal. Because clinical trials of GZR/EBR showed ALT elevations in approximately 1% of patients, current prescribing information for this regimen recommends liver test monitoring at treatment Weeks 8 and 12.[23] In C-CREST-1 and 2, Part B, ALT elevations were also reported in 1% of patients, whereas in C-SURGE, no ALT elevations were reported, although the sample size was much smaller.
*Deemed unrelated to study drug.
1. Lawitz E, et al. AASLD Abstract 110.
2. Wyles DL, et al. AASLD Abstract 193.
Slide credit: clinicaloptions.com

34. MK-3682/GZR/RZR Studies: Safety
Outcome, %
C-CREST 1 & 2 Part B[1]
MK-3682/GZR/RZR
C-SURGE[2]
No RBV
(n = 462)
+ RBV
(n = 202)
+ RBV, 16 Wks (n = 44)
24 Wks
(n = 49)
Hemoglobin < 10 g/dL
< 1 3 9
Total bilirubin > 5 x baseline
< 1* 3* 0†
Late ALT/AST > 5 x ULN 1
Creatinine grade 1 ( x ULN) NR
Creatinine grade 2 ( x ULN) 2
*Total bilirubin. †Direct bilirubin.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GZR, grazoprevir; NR, not reported; RBV, ribavirin; RZR, ruzasvir; ULN, upper limit of normal.
1. Lawitz E, et al. AASLD Abstract 110.
2. Wyles DL, et al. AASLD Abstract 193.
Slide credit: clinicaloptions.com

35. HCV Treatment: Real-World Studies With Approved Therapies
HCV, hepatitis C virus.

36. Real-World HCV Treatment in the US VA Healthcare System
Analysis of real-world SVR for pts with GT1-4 HCV treated with SOF + RBV ± pegIFN, SOF/LDV, or OBV/PTV/RTV + DSV (N = 17,487)[1] 96 95 95
100 93 93 90 80 60
SVR (%) 40 20
n =
13,974
1975
1556
135
D, dasabuvir; DSV, dasabuvir; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; O, ombitasvir; OBV, ombitasvir; pegIFN, peginterferon; P, paritaprevir; PTV, paritaprevir; RBV, ribavirin; R, ritonavir; RTV, ritonavir; SOF, sofosbuvir; SVR, sustained virologic response; VA, Veterans Affairs.
Ira M. Jacobson, MD:
In our field, real-world studies based on large multicenter databases, or sometimes even large single-center databases, have become an important tool to evaluate how closely the results of regimens in the postmarketing era match previous results achieved in clinical trials. They also permit us to look at some of the nuances of therapy such as treatment duration, which may not have been compared as robustly in the trial setting.
The US Veterans Affairs (VA) healthcare system offers an ideal opportunity to take advantage of a very large and well-managed national database to evaluate HCV treatment. In this setting, real-world SVR rates were analyzed in 17,487 genotype 1-4 HCV–infected patients treated with SOF/LDV (65%), ombitasvir/paritaprevir/ritonavir plus dasabuvir (18%), or SOF plus RBV with or without peginterferon (17%) across 167 medical centers.[24] Of note, dasabuvir remains the only commercially available nonnucleoside NS5B polymerase inhibitor for hepatitis C to date.[25] Overall, 93% of patients with genotype 1 HCV infection attained SVR. Although not quite as high perhaps as in many of the pivotal trials, this response rate is good and expected for a real-world setting.
SVR rates between the 8-week and 12-week treatment durations of LDV/SOF were compared in genotype 1 patients and found to be equivalent (95% and 96%, respectively). These 3531 patients were treatment naive and noncirrhotic with baseline HCV RNA < 6 million IU/mL, a description that characterizes a very typical patient in the United States.
The uniform SVR rates observed here are important; I was initially skeptical of 8-week LDV/SOF based on retrospective analysis of a single trial, the ION-3 study.[26] Many of the real-world studies since then, however, including this one now, confirm that clinicians can be comfortable with the 8-week regimen for genotype 1 HCV–infected, treatment-naive, noncirrhotic patients with HCV RNA < 6 million IU/mL.
Stefan Zeuzem, MD:
Another real-world cohort run by the German Liver Foundation also compared the 8-week and 12-week LDV/SOF durations and revealed identical SVR results.[27] Thus, multiple cohorts do support the assumption that 8 weeks of treatment are not in any way inferior to 12 weeks.
Although an increasing number of real-world studies support the efficacy of the 8-week regimen, the September 2016 update of AASLD/IDSA guidance recommends that 8-week LDV/SOF should not be given to patients who are black or coinfected with HIV or who have the CT or TT IL28B polymorphism.[2] This latter recommendation is surprising, as the IL28B genotype assay is no longer frequently used, but in my practice, the restriction for black and HIV-coinfected patients is something to which I would likely adhere, and I would prefer 12 weeks in those patients.
In this VA analysis, independent predictors of treatment failure were identified, but the data did not evaluate at the topline level whether subsets of patients (eg, black patients) experienced slight decrements in SVR with 8 weeks of therapy.
Another major lesson gleaned from this real-world VA study emerged from the comparison of LDV/SOF and ombitasvir/paritaprevir/ritonavir plus dasabuvir in genotype 1 HCV–infected patients. The SVR rates were 93% and 95%, respectively, and no significant difference was found when investigators ran propensity score adjusted models that corrected for baseline factors such as prevalence of cirrhosis. Thus, no advantage of one regimen over the other was identified in genotype 1 HCV infection.
The 135 patients with genotype 4 HCV infection, which responds to almost any of the commercially available regimens, achieved 90% SVR. Additional analyses of genotypes 2 and 3 showed somewhat low SVR rates (86% and 75%, respectively), but patients were not using newer regimens such as VEL or daclatasvir combined with SOF. These data are, therefore, less important and not shown on this slide.
The second VA healthcare study mentioned on this slide demonstrates how extremely ambitious and aggressive the VA has recently been in treating their HCV-infected population.[28] Indeed, in 2015, they treated as many patients as they had for the previous 15 years combined. That is amazing. This dramatic increase in treated patients occurred because of drugs with improved antiviral efficacy and the availability of funding. In fact, if treatment rates remain elevated, it is projected that HCV can be eradicated in all infected patients insured by this VA system within the next 2-3 years. These data show that, in certain groups or organizations, elimination of HCV infection is indeed possible.
GT1
8 wks
12 wks
SOF/LDV
O/P/R + D
GT4
GT1, SOF/LDV
GT1
Analysis of HCV treatment in VA healthcare system (N = 107,079)[2]
Dramatic increases in HCV treatment in vs ( , 1989 to treatments/yr; 2014, 9180 treatments; 2015, 31,028 treatments)
Related to improved antiviral efficacy and availability of funding
1. Ioannou GN, et al. AASLD Abstract 21. Reproduced with permission.
2. Moon AM, et al. AASLD Abstract 227.
Slide credit: clinicaloptions.com

37. Real-World HCV Retreatment Efficacy for DAA Failures
Analysis of retreatment data in German database
Previous DAA Regimen Failure
Retreatment Regimens
SVR12, % (n/N)
GT1: SMV + SOF ± RBV
Overall
93 (28/30)
LDV/SOF ± RBV 12/24 wks
92 (24/26)
OBV/PTV/RTV + DSV ± RBV 12/24 wks
100 (4/4)
GT1: DCV or LDV + SOF ± RBV
84 (26/31)
SMV + SOF ± RBV 12/24 wks
90 (19/21)
OBV/PTV/RTV + DSV ± RBV 12 wks
83 (5/6)
50 (2/4)
GT1: OBV/PTV/RTV + DSV ± RBV
100 (7/7)
100 (5/5)
SMV ± LDV + SOF + RBV 24 wks
100 (2/2)
GT3: SOF + RBV
78 (18/23)
DCV + SOF ± RBV 12/24 wks
77 (17/22)
LDV/SOF + RBV 24 wks
100 (1/1)
DAA, direct-acting antiviral; DCV, daclatasvir; DSV, dasabuvir; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response.
Stefan Zeuzem, MD:
This next study describes real-world HCV retreatment after DAA failure.[29] By way of background, Drs. Johannes Vermehren and Christoph Sarrazin built up a program that enabled any physician to send samples for RAV testing to our laboratory in Frankfurt, Germany. This service was heavily used by colleagues in, and even outside of, Europe. We often recommended a retreatment regimen based on the results of the RAV testing, and most physicians adopted our recommendations to treat those patients. This slide stratifies patients by genotype, previous DAA failure, and retreatment regimen to examine SVR12 outcome. Overall, the recommendations borne from RAV testing were very successful.
The debate going forward will be whether to perform RAV testing after DAA failure and treat using carefully selected dual DAA combinations based on those results or to forego RAV testing and instead retreat with one of the triple DAA combinations. This choice is likely most dependent on the availability of reliable RAV testing, but it will be interesting to determine if both strategies are equally successful. This will probably never be explored in a randomized, controlled trial, but rather in real-world registries. Until then, we have here an example of how retreatment can be managed based on RAV testing.
Ira M. Jacobson, MD:
This study supports a central theme that there are regimens available that may salvage patients for whom a first-line DAA regimen has failed. As Dr. Zeuzem mentioned, the best retreatment regimen may be identified using information from RAV testing. In fact, the AASLD/IDSA guidance recommends such a strategy in patients for whom DAA therapy with the protease and NS5A inhibitor classes has failed.[2] With high SVR12 rates, these data clearly show that RAV-based retreatment approaches can work quite well.
What is lacking in this study is a breakdown of the patients by RBV use. Despite the smaller number in each resultant denominator, it remains possible that a signal for better or worse outcome could result.
After DAA failure, the AASLD/IDSA guidance also recommends waiting on retreatment in noncirrhotics or those without urgent need for retreatment.[2] I see no reason to deviate from that recommendation, no matter how high the SVR rates were in this study. I recently saw a patient who had failed LDV/SOF and had never cleared virus while on treatment despite insistence that he had adhered to therapy. Because the patient had F0/1 fibrosis on elastography and a mild fibrosis score on noninvasive testing, I was very comfortable telling him that we should wait until a new, proven salvage regimen such as a triple therapy, or an alternative double therapy, became available.
Slide credit: clinicaloptions.com
Vermehren J, et al. AASLD Abstract 894.

38. ASCEND: HCV Treatment Efficacy and Adherence by Provider Type
Nonrandomized phase IV trial of HCV-infected pts in Washington, DC (N = 600)
Pts mostly male (69%), black (96%), GT1a (72%), and treatment naive (82%)
20% of pts had compensated cirrhosis, 23% had HCV/HIV coinfection
All providers received uniform 3-hr training
No difference in SVR12 by provider type, cirrhosis status
Adherence to all treatment visits by cirrhotic pts lower for specialists (61%) vs PCPs (56%) and NPs (75%) (P = .04)
100 89 86 83 86 80
GT, genotype; HCV, hepatitis C virus; ITT, intent to treat; NP, nurse practitioner; PCP, primary care provider; SVR, sustained virologic response.
Ira M. Jacobson, MD:
To achieve HCV elimination, some argue that expending the pool of HCV providers will be necessary. The ASCEND study was a nonrandomized phase IV trial of LDV/SOF in 600 HCV-infected patients in Washington, DC,[30] and was designed to compare SVR rates across 3 provider types: nurse practitioners, primary care physicians, and specialist physicians. All providers received uniform, 3-hour training, although it can be inferred that specialists might have had more antecedent experience in HCV treatment.
Patients were mostly male (69%), black (96%), and treatment naive (82%) and had genotype 1a HCV infection (72%). Overall, 20% had compensated cirrhosis, and 23% were coinfected with HIV.
No difference in achievement of SVR12 was noted according to provider type or cirrhosis status. This observation regarding cirrhosis status underscores the idea that no matter how challenging the patient type, nurse practitioners and primary care physicians were equally effective as specialists at providing care that lead to viral clearance.
It may be sobering to note that, in cirrhotic patients, adherence to all treatment visits was lower with the specialist physician providers than with the primary care physician providers or nurse practitioners. Knowing the factors that might have led to this would be interesting, such as time spent with patients or the patients’ familiarity with their primary care providers.
Given the anticipated large number of patients yet to be identified that will require treatment, these results provide an opportunity to expand the pool of HCV providers, especially when staffing opportunities arise in a center where the limited availability of specialists might be delaying care for patients eager to be treated.
Stefan Zeuzem, MD:
Although this was an interesting approach of comparing different treatment providers, I have a slightly more critical approach to this study.
First, this may not apply to all centers, as the care of patients by nurse practitioners is unique to some countries such as the United States.
Moreover, enrolled patients were uncomplicated in their care needs (eg, only genotype 1, no retreatment or decompensated cirrhosis).
Finally, SVR rates only ranged between 83% and 89%, which is suboptimal, as other real-world datasets with LDV/SOF, such as HCV-TARGET and TRIO, had SVR rates > 94%.[31] I wonder if race may be a factor here: In the current analysis most patients were black (96%), and other real-world studies of LDV/SOF have suggested that race may be a predictor of SVR.[32] 60
ITT SVR12 (%) 40 20
135/ 151
138/ 160
240/ 289
513/ 600
n/N = NP
Primary MD
Specialist MD
Overall
Slide credit: clinicaloptions.com
Emmanuel B, et al. AASLD Abstract 22. Reproduced with permission.

39. HBV Studies
HBV, hepatitis B virus.

40. HBV Reactivation in Pts Receiving DAAs: Postmarketing Cases Reported to FDA
Case reports of HBV reactivation in pts receiving DAAs
Reactivation: increase in HBV DNA or seroconversion to HBsAg positive
29 confirmed cases in ~ 3 yrs (November 2013 to October 2016)
Pts from Japan (n = 19), US (n = 5), other (n = 5)
Most cases occurred within 4-8 wks of initiation
2 deaths, 1 transplant, 6 hospitalizations, 10 DAA discontinuations
HBV Reactivation (N = 29)
31%
(n = 9)
38%
(n = 11)
21%
(n = 6)
10%
(n = 3)
HBV at Baseline
DAA, direct-acting antiviral; FDA, US Food and Drug Administration; GT, genotype; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
Stefan Zeuzem, MD:
HBV reactivation was examined in the postmarketing setting in patients receiving approved, second-generation HCV DAAs.[33] Study investigators queried the FDA’s Adverse Event Reporting System database and found 29 HBV reactivation cases temporally related to DAA initiation between November 2013 and October 2016, a period of approximately 3 years. Reactivation typically occurred within 4-8 weeks of HCV therapy initiation, and most patients were from Japan (66%), although equal minorities derived from either the United States or other countries (17% each). It is likely that these 29 case reports came from countries that altogether have treated several hundred thousand HCV-infected patients with previous HBV infection, which makes the frequency of HBV reactivation during HCV DAA therapy quite rare.
As this was a series of case reports, there was no control group, although a beneficial control group to add would have been HBV-monoinfected patients; the rates of HBV flare and/or reactivation could have been compared, as these events can spontaneously occur quite easily due to other factors such as initiation of immunotherapy or chemotherapy.
In these 29 cases of reactivation, 2 patients died, 1 received a liver transplantation, 6 were hospitalized, and 10 discontinued their DAAs.
Because of this report, the FDA appended a boxed warning regarding HBV reactivation risk to HCV DAA labeling in October 2016.[34] The warning recommends that all patients should be screened for HBV infection before initiation of HCV DAA therapy and that patients with previous HBV infection should be monitored for signs of possible HBV reactivation following initiation of HCV DAA therapy.
At my institution, we have treated more than 1000 patients with DAAs, and we have not seen a single case of HBV reactivation. There have also even been dedicated trials for HBV/HCV-coinfected patients including a study by Gane and colleagues[35] that demonstrated small increases in aminotransferases, but no patient developed liver failure. Thus, HBV reactivation cases are quite rare and must be examined carefully, each individually.
Ira M. Jacobson, MD:
In my personal polling of large audiences, very few providers have seen HBV reactivation during DAA treatment. Nevertheless, given the cases identified here, the presentation of these data, both as a safety warning and for academic purposes, seems justified.
Based on these results, future phase II/III HCV treatment trials will not enroll patients if they are anti-HBc positive or hepatitis B surface antigen (HBsAg) negative. In the past, only HBsAg-negative patients were excluded. To exclude patients who are anti-HBc positive is moving away from a large, real-world population. Exclusion of these patients disallows trials from being reflective of the real population where these trials are needed, and I personally oppose this approach.
Yes, I agree completely. Other factors besides HCV DAA therapy are more likely contributing to HBV reactivation overall. Nevertheless, now that we know about these small case report datasets, they must be considered.
I want to highlight the HBsAg-negative, anti-HBc–positive patients, which are troubling because there are few data on how to manage such patients. In this report, they accounted for only 3 of the documented HBV reactivations, shown in yellow in the pie chart. During the presentation of this study in Boston, it was revealed that one of those 3 patients was receiving rituximab, which could account for the observed reactivation event.
For more information about this study, go to
Not reported, uninterpretable, or undetectable HBV DNA w/o HBsAg status
Detectable HBV DNA
HBsAg+, undetectable HBV DNA
HBsAg-, undetectable HBV DNA
Slide credit: clinicaloptions.com
Bersoff-Matcha SJ, et al. AASLD Abstract LB17.

41. HBV Testing and Monitoring During HCV DAA Therapy: AASLD/IDSA Guidance
Test all pts initiating HCV therapy for HBsAg, anti-HBc, and anti-HBs
No HBV markers: VACCINATE (this is not new)
HBV markers present:
HBsAg positive
HBsAg negative;
anti-HBc positive
(± anti-HBs)
HBV DNA detectable
HBV DNA low or
undetectable
“Insufficient data to provide
recommendations”
HBV DNA meets criteria for treatment in AASLD HBV
guidelines
AASLD, American Association for the Study of Liver Diseases; DAA, direct-acting antiviral; HBc, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IDSA, Infectious Diseases Society of America.
Ira M. Jacobson, MD:
So how should we approach the prospect of HBV reactivation during HCV DAA therapy? I developed this algorithm slide based largely on AASLD/IDSA recommendations.[2] First, all HCV-infected patients initiating therapy should be tested for HBsAg, anti-HBc, and anti-HBs. This has been standard practice for a long time—mostly to determine whether the patient is coinfected with hepatitis B—as there are often shared risk factors in these patients, but also to know if the patient is seronegative (and therefore requires vaccination).
If a patient is HBsAg positive and HBV DNA is detectable and warrants therapy (ie, > 2000 IU/mL if hepatitis B e antigen (HBeAg) negative or > 20,000 IU/mL if HBeAg positive),[36] treatment of HBV is recommended. If HBsAg is positive but the HBV DNA level is low or undetectable, monitoring for reactivation is recommended, as is eventual HBV treatment if the HBV DNA levels rise to meet the aforementioned criteria. During HCV treatment and for a short time after completing HCV treatment, I would argue for also treating HBV in any HBsAg-positive patient, regardless of HBV DNA level, even if undetectable.
Stefan Zeuzem, MD:
In my practice, my approach is to test for HBsAg and anti-HBc in a patient with HCV infection initiating DAA therapy. Only if that patient later has an increase in aminotransferases, I test for HBV DNA, which is a standard procedure in our clinics.
For HBsAg-negative, anti-HBc–positive patients, regardless of the presence or absence of surface antibody, current AASLD/IDSA guidelines state that insufficient data exist to provide recommendations for HBV testing and monitoring.[2] However, some patients with rituximab-induced HBV reactivation are negative for anti-HBs and are therefore unprotected. For HBsAg-negative, anti-HBc–positive patients, it is important to monitor for unexpected ALT elevations or perhaps even the failure of ALT to normalize during HCV therapy. This latter event is not rare and is usually attributable to other issues such as concomitant steatosis. However, if ALT is rising, be mindful of the remote possibility of HBV reactivation, and test for it by assessing HBV DNA and HBsAg.
I fully agree with this chart because it reflects what all international hepatitis B guidelines are recommending, and it is based on well-documented data and guidance. I am concerned that the boxed warning gives the impression that something new has occurred, which is not the case. We should manage patients as outlined here; when treating patients with any kind of viral disease, coinfection is always possible and must be taken into consideration.
Monitor for reactivation; treat if HBV DNA level meets AASLD HBV guideline treatment
criteria
Treat with HBV drug
AASLD/IDSA. HCV guidance. September Graphic created by Ira M. Jacobson, MD.
Slide credit: clinicaloptions.com

42. GS-108/110: Changes in BMD With TAF vs TDF in HBV Pts
Randomized, double-blind, active-controlled phase III studies in which pts with chronic HBV infection* treated with first-line TAF 25 mg QD (n = 866) or first-line TDF 300 mg QD (n = 432)[1]
Noninferior efficacy between groups previously shown[2,3]
TDF also associated with significantly decreased hip and spine BMD at Wks 24 and 48 vs TAF (P < .001 for all comparisons)
Mean Change in BMD at Wk 72, %
TAF
TDF
P Value
Hip
-0.29
-2.43
< .001
Spine
-0.60
-2.52
ALT, alanine aminotransferase; BMD, bone mineral density; HBV, hepatitis B virus; QD, once daily; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
Ira M. Jacobson, MD:
GS-108 and GS-110 were randomized, double-blind, active-controlled phase III studies in 1298 patients with chronic HBV infection comparing the effects of first-line tenofovir alafenamide (TAF) 25 mg/day vs first-line tenofovir disoproxil fumarate (TDF) 300 mg/day on bone mineral density (BMD).[37] Previous studies in these groups demonstrated that TAF was noninferior to TDF in terms of virologic efficacy.[38,39]
TAF is dosed at 25 mg/day, lower than the typical 300-mg/day dose of TDF, because of a different carrier molecule that delivers higher concentrations of drug to the liver. This results in less systemic exposure and has the potential to limit kidney and bone AEs.
In the presentation from Boston, mean changes in both hip and spine BMD at Week 72 statistically favored TAF. Other recent studies have shown a decrease in bone density with TDF of approximately 2% in HBV-infected patients.[40] This is consistent with the 2% to 3% decrease observed in the current study and in earlier trials in HIV, where most of that decrease occurred in the first year.[41] This seems to be true for spine BMD decline with TDF, as the rate somewhat plateaus after 24 weeks, whereas hip BMD decline with TDF appears steady over the full 72 weeks.[47]
Although these studies demonstrate a difference in drug-associated decreases of BMD between HBV-infected TAF and TDF recipients, the clinical significance of these changes is not yet clear. This may be an important consideration in drug selection for hepatitis B patients who are significantly osteopenic and certainly for those who are osteoporotic.
Now that TAF is approved for chronic HBV infection in the United States,[42] clinicians must also consider what approach to take for their patients currently receiving TDF, based on the results of studies such as GS-108/110 that have favored first-line TAF over TDF in terms of renal and bone markers.[38,39] Will these data also apply to patients who are switched from TDF to TAF?
In my view, every patient with HBV infection currently receiving TDF should be made aware of this new option, given its advantages in terms of bone and kidney signals. For my patients, I am inclined to offer the switch to TAF if the patient is agreeable and there are no significant cost implications for the patient. Switching may be particularly advantageous in patients with or at risk for osteopenia or borderline renal function.
Stefan Zeuzem, MD:
It is important to note that economic considerations will likely vary per country, particularly when TDF becomes a generic option. This will be a factor to consider when contemplating a switch to TAF.
I would also highlight that the standard deviations on BMD changes in GS-108/110 are quite large. This means that some patients receiving TDF had virtually no change whatsoever in their bone metabolism, whereas other patients had changes that were far more clinically significant.
These data must also be examined in the context of antiviral efficacy with TAF vs TDF. Overall, in phase III trials efficacy looked identical,[38,39] but subgroups should be examined.
I agree that antiviral efficacy would have to be the same for one to contemplate a switch. In patients who do switch, it will be very important to determine if any virologic breakthroughs occur after switching. To be clinically significant, these virologic changes would need to be more than just detectable but less than the lower limit of quantifiable. That type of viral blip is seen even in patients very well controlled on long-term TDF or entecavir.
*HBV DNA ≥ 20,000 IU/mL, ALT > 60/38 U/L (male/female).
1. Seto WK, et al. AASLD Abstract 67.
2. Buti M, et al. Lancet Gastroenterol Hepatol. 2016;1:
3. Chan HLY, et al. Lancet Gastroenterol Hepatol. 2016;1:
Slide credit: clinicaloptions.com

43. GS-1059: TLR-7 Agonist GS-9620 for Pts With Suppressed Chronic HBV Infection
Randomized, double-blind, placebo-controlled phase II trial analyzing the immunomodulatory effects of GS-9620
Pts with chronic HBeAg-negative GTD HBV infection suppressed with nucleos(t)ide analogue for ≥ 3 yrs were randomized to 12 wks GS , 2, or 4 mg PO QW (N = 26) or placebo; all pts continued nucleos(t)ide analogue
Key results:
At Wk 24, no pts treated with GS-9620 had HBsAg change > 0.5 log10; no pts lost HBsAg
Improvements in specific T-cell responses observed with GS-9620 (eg, IFN-γ and IL-2 production)
GTD, genotype D; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IFN, interferon; IL, interleukin; PO, orally; QW, once weekly.
Stefan Zeuzem, MD:
We will now discuss 2 investigational immunologic approaches to managing HBV that were presented at this meeting. The first, GS-1059, is a small, randomized, double-blind, placebo-controlled phase II study of the TLR-7 agonist GS-9620 in 26 patients with chronic HBV infection suppressed on nucleos(t)ide analogue for 3 or more years.[43,44]
Patients received 1 mg, 2 mg, or 4 mg of oral GS-9620 or placebo weekly for the first 12 weeks, both in combination with their nucleos(t)ide analogue treatment. All patients then received their nucleos(t)ide analogue alone for an additional 12 weeks. The primary endpoint was mean change in HBsAg from baseline to Week 24. Unfortunately, at Week 24, no patient met the primary endpoint, which was an HBsAg change of more than one-half log, and no patient lost HBsAg.
Although there were observable cellular responses, with improvements in interferon-γ and interleukin-2 production by T-cells, these may not be the right efficacy parameters.
Ira M. Jacobson, MD:
The current goal of HBV therapy is to induce functional cure, which involves at least HBsAg clearance. Although this agent did improve T-cell responses, I agree it is discouraging that it was unable to demonstrate any change in HBsAg titer.
Nevertheless, immunologic approaches certainly have a mechanistic basis of validity in HBV therapy. After all, interferon is thought to act both through immunomodulatory effects and antiviral effects, and it remains a first-line treatment option for chronic hepatitis B.[36]
Boni C, et al. AASLD Abstract 13.
ClinicalTrials.gov. NCT
Slide credit: clinicaloptions.com

44. Median (Q1, Q3) ΔHBsAɑ From Baseline (log10 IU/mL)
GS-4774, a Heat-Inactivated, Yeast-Based T-Cell Vaccine for Pts With Chronic HBV
Randomized phase II study assessing the GS-4774 vaccine* + TDF in pts with chronic HBV who were not on antivirals (HBV DNA ≥ 2000 IU/mL) (N = 195)
Through Wk 48, HBsAg changes similar between GS TDF and TDF alone groups; no pts lost HBsAg
Changes in HBsAg
0.2
TDF
TDF + 2 YU GS-4774
TDF + 10 YU GS-4774
TDF + 40 YU GS-4774
0.1
Median (Q1, Q3) ΔHBsAɑ From Baseline (log10 IU/mL)
-0.1
-0.2
-0.3
HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate; YU, yeast units.
Ira M. Jacobson, MD:
This next randomized phase II study examined another immunologic approach with an agent called GS-4774.[45] This heat-inactivated, yeast-based T-cell vaccine contains core, surface, and X proteins and was administered at 3 different doses with TDF. A control group of TDF administration alone was also included.
An analogous yeast-based vaccine was first evaluated for HCV several years ago, with a goal of inducing dendritic cell and subsequent T-cell activation.[46] That system was unsuccessful in HCV but is now being studied in HBV.
In the current study, over 48 weeks, there were no changes in HBsAg across the different regimens. Moreover, there were also no significant differences in achievement of HBV DNA undetectability (< 20 IU/mL) at Weeks 24 and 48. These results are disappointing
Stefan Zeuzem, MD:
As Dr. Jacobson just pointed out, an immunomodulating, immunostimulating agent is needed for this field, but nothing beyond interferon has shown efficacy. Much work is in progress, but no breakthrough is yet visible with the toll-like receptor (TLR) agonists or therapeutic vaccines.
-0.4
-0.5 4 12 20 28 36 48
Study Wk
At Wks 24 and 48, similar rates of pts in GS TDF and TDF alone groups with HBV DNA < 20 IU/mL
*Includes HBV core, surface, and X proteins.
Slide credit: clinicaloptions.com
Janssen HL, et al. AASLD Abstract 231. Reproduced with permission.

45. NASH: Investigational Therapeutics
NASH, nonalcoholic steatohepatitis.

46. Selonsertib ± Simtuzumab for Pts With NASH and F2/F3 Fibrosis
Randomized, open-label, active-controlled phase II trial[1]
Wk 24
Stratification by
diabetes
Selonsertib 18 mg PO QD
(n = 22)
Selonsertib (formerly GS-4997): ASK1 inhibitor
ASK1:Ser/Thr kinase that activates p38 and JUN kinases, stimulating apoptotic, fibrinogenic, and inflammatory pathways[2]
Simtuzumab: monocolonal Ab to LOXL2, an enzyme in the ECM that promotes collagen crosslinking[3]
Also studied in other fibrotic diseases, including myelofibrosis
Selonsertib 6 mg PO QD
(n = 20)
Pts with
biopsy-proven NASH
with NAS ≥ 5 and
F2/F3 fibrosis
(N = 72)
Selonsertib 18 mg PO QD +
Simtuzumab 125 mg SC QW
(n = 10)
ECM, extracellular matrix; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis; PO, orally, QD, once daily; SC, subcutaneous.
Ira M. Jacobson, MD:
Statistically, the most common liver disease in the United States is fatty liver disease, which presents in its most severe form as NASH. Management of NASH is much more complicated than treatment of viral hepatitis where viral clearance is the goal.
Stefan Zeuzem, MD:
The first NASH study we will review is a randomized, open-label, active-controlled phase II study in 72 patients with biopsy-proven NASH (nonalcoholic fatty liver disease activity score [NAS] ≥ 5) and F2/F3 fibrosis.[47]
Patients received one of 2 investigational NASH medications, selonsertib (an ASK1 inhibitor that stimulates apoptotic, fibrinogenic, and inflammatory pathways),[48] or simtuzumab (a monoclonal antibody to LOXL2),[49] or a combination of both. Different doses were also tested, resulting in a total of 5 arms.
As background, it was hoped that simtuzumab, which is also being studied in other liver diseases, might have an independent antifibrotic effect in NASH because of its inhibitory effect on collagen cross-linking, and that selonsertib might have both antiinflammatory and antifibrotic effects.
The results indicated that simtuzumab had no clear effect on outcomes, resulting in essentially 3 comparisons for the final analysis:
Selonsertib 18 mg with or without simtuzumab
Selonsertib 6 mg with or without simtuzumab
Simtuzumab monotherapy, which was considered a control arm
For more information about this study, go to
Selonsertib 6 mg PO QD +
Simtuzumab 125 mg SQ QW
(n = 10)
Simtuzumab 125 mg SC QW
(n = 10)
Slide credit: clinicaloptions.com
References in slidenotes.

47. Selonsertib ± Simtuzumab for Pts With NASH: Key Findings
Wk 24 Outcome, n/N (%)
SEL 18 mg
± SIM†
SEL 6 mg ± SIM†
SIM
Fibrosis improvement*
13/30 (43)
8/27 (30)
2/10 (20)
Fibrosis improvement without NASH worsening*
11/30 (37)
Progression to cirrhosis*
1/30 (3)
2/27 (7)
≥ 2-point reduction in NAS*
7/31 (23)
5/27 (19)
NASH resolution*‡
0/31 (0)
1/27 (4)
0/10 (0)
Grade 3/4 AE
3/32 (9)
1/10 (10)
Serious AE
2/30 (7)
Discontinuation for AE
2/32 (6)
Death
AE, adverse event; BL, baseline; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis; SEL, selonsertib; SIM, simtuzumab.
Stefan Zeuzem, MD:
The focus, then, is on the effect of selonsertib. Fibrosis improved in 13 of 30 (43%) patients receiving the higher 18-mg dose of selonsertib. This occurred without NASH worsening in 11 (37%) of those patients. Only 1 patient (3%) receiving higher-dose selonsertib progressed to cirrhosis compared with 2 (7%) receiving lower-dose selonsertib and 2 (20%) receiving simtuzumab monotherapy.
Thus, although there were no improvements in NASH-related outcomes (resolution of NASH or improvement in the NAS by at least 2 points), the fibrosis outcomes were convincing enough to trigger larger, phase III trials of selonsertib in patients with NASH and advanced fibrosis.
SEL may have potential role as antifibrotic
*For pts with evaluable liver biopsies at BL and Wk 24. †Results grouped by SEL dose based on combination tx and monotherapy achieving similar outcomes. ‡Defined as reduction in grade of ballooning to 0 and inflammation to 0 or 1.
Slide credit: clinicaloptions.com
Loomba R, et al. AASLD Abstract LB3.

48. CENTAUR: Cenicriviroc for Pts With NASH and F1-3 Fibrosis
Randomized, double-blind, placebo-controlled phase II trial
Cenicriviroc: dual C-C chemokine receptor (CCR) type 2/5 antagonist
CCR2/5 expressed on Kupfer and other proinflammatory cells; promote inflammation, hepatic stellate cell activation, and liver fibrosis in response to liver fat accumulation[2]
CCR5 antagonists have been explored for HIV therapy; CCR5 a coreceptor necessary for cellular entry of certain HIV strains[3]
Stratified by
NAS (4 vs ≥ 5) and fibrosis stage (≤ 2 vs > 2)
Mo 12
Primary Endpoint
Mo 24
NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis; PO, orally; QD, once daily.
Ira M. Jacobson, MD:
The second study, CENTAUR, is a randomized, double-blind, placebo-controlled phase II study of cenicriviroc in 289 patients with NASH (NAS ≥ 4) and F1-3 fibrosis.[50]
Cenicriviroc is a dual chemokine receptor antagonist, inhibiting both CCR2 and CCR5. This mechanism of action also has relevance in the HIV field, as CCR5 antagonists have been explored because of CCR5’s role as a coreceptor necessary for cellular entry of certain HIV strains.[51] CCR2/5 antagonism was hoped to have antiinflammatory and antifibrotic effects here, based on its expression pattern on Kupfer and other proinflammatory cells.[52]
Patients were stratified by NAS and fibrosis stage and randomized 1:1 to active treatment or placebo. Patients in the cenicriviroc arm received study drug for 24 months, and those in the placebo arm were randomized again at 12 months to either remain on placebo or cross over to active cenicriviroc treatment. The primary endpoint was improvement in NAS by at least 2 points without fibrosis worsening.
For more information about this study, go to
Cenicriviroc 150 mg PO QD
(n = 145)
Pts with NASH, NAS ≥ 4, F1-3
(N = 289)
After 1 yr, placebo pts randomized to cenicriviroc 150 mg PO QD or placebo
Placebo PO QD
(n = 144)
Slide credit: clinicaloptions.com
References in slidenotes.

49. CENTAUR: Key Efficacy and Safety Findings
Outcome at Yr 1, n (%)
Cenicriviroc
(n = 145)
Placebo
(n = 144)
P Value
Improvement in NAS by ≥ 2 points* and no fibrosis worsening†
23 (16)
27 (19)
.519
Complete NASH resolution and no fibrosis worsening
11 (8)
8 (6)
.494
Improvement in fibrosis stage of ≥ 1 and no NASH worsening
29 (20)
15 (10)
.023
Grade 3/4 AE
38 (26)‡
37 (26) NR
Serious AE
16 (11)‡
10 (7)
Causing d/c
1 (< 1)‡
2 (1)
Death --
AE, adverse event; d/c, discontinuation; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis; NR, not reported.
Stefan Zeuzem, MD:
The primary study endpoint was not met: Improvement in the NAS by at least 2 points without fibrosis worsening was equivalent between the active treatment and placebo groups. Complete NASH resolution without fibrosis worsening was also equivalent between arms.
However, similar to the selonsertib study just discussed, more promising antifibrotic effects emerged. For the endpoint of improvement in fibrosis stage by at least 1 point without worsening of NASH, cenicriviroc was superior to placebo.
The AE profile appeared acceptable, with similar rates of grade 3/4 and serious AEs between arms and very few discontinuations overall.
These fibrosis and safety data were convincing enough to trigger larger phase III trials of this agent in NASH patients.
Thus, as was true for selonsertib, the main potential for cenicriviroc going forward in NASH may be as an antifibrotic rather than as an agent that induces regression of NASH or the inflammation associated with it. It is reasonable to hope that future trials of this agent may uncover more about its effects on NASH, inflammation, and fibrosis regression.
*With ≥ 1 point reduction in lobular inflammation or hepatocellular ballooning. †Primary endpoint. ‡Cenicriviroc safety population, n = 144.
Cenicriviroc may have potential role as antifibrotic
Slide credit: clinicaloptions.com
Sanyal AJ, et al. AASLD Abstract LB1.

50. NAFLD and Alcohol

51. Moderate vs No Alcohol Use: Moderate Use Associated With Less Severe NAFLD
General population: modest drinkers (n = 12,384) had 32% lower odds of NAFLD vs nondrinkers (n = 30,791)[1]
OR: 0.68 (95% CI: ; P < 10-5)
Modest drinking defined as < 40 g alcohol/day
NAFLD population: modest drinkers (n = 331) had lower odds of NASH diagnosis vs nondrinkers (n = 251)[2]
OR: 0.56 (95% CI: ; P = .002)
Modest drinking defined as ≤ 2 drinks/day, no binge drinking
NAFLD, nonalcoholic fatty liver disease.
1. Sookoian S, et al. Gut. 2014;63:
2. Dunn W, et al. J Hepatol. 2012;57:
Slide credit: clinicaloptions.com

52. Moderate vs No Alcohol Use: Does Moderate Use Help or Harm NAFLD?
Prospective analysis of histological changes in paired liver biopsies (mean 47 mos apart) from pts with biopsy-proven NAFLD (N = 304)
Excluded more than modest alcohol use (> 2 drinks per day), former drinkers
Change in Histology
Nondrinker (n = 117)
Modest Drinker (n = 168)
P Value
Mean Difference
Steatosis
Hepatocyte ballooning
Lobular inflammation
Fibrosis stage
-0.49
-0.24
-0.25
0.06
-0.30
-0.16
-0.26
0.08
.04
.43
.86
.85
Resolution of NASH (%) 21 13
.13
NAFLD, nonalcoholic fatty liver disease.
Slide credit: clinicaloptions.com
Ajmera VH, et al. AASLD Abstract 31.

53. Cross-Sectional Study: Multivariate Analysis
Prospective, multicenter study of pts in Sweden with biopsy-proven NAFLD (N = 120)
Increasing self-reported alcohol consumption* associated with lower fibrosis stage
Adjusted OR: (95% CI: ; P = .017)
Potential biomarker of heavy drinking† associated with higher fibrosis stage
Adjusted OR: (95% CI: ; P = .047)
NAFLD, nonalcoholic fatty liver disease.
*Up to maximum of 13 drinks/wk. †Phosphatidyl ethanol ≥ 0.3 μmol/L.
Slide credit: clinicaloptions.com
Hagström H, et al. AASLD Abstract 36.

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