1. HCV Treatment Options in 2017/2018: What’s Here and What’s Coming Soon
Supported by educational grants from AbbVie; Bristol-Myers Squibb; Gilead Sciences; Janssen Therapeutics; Merck & Co., Inc; and ViiV Healthcare.

2. About These Slides
Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients
When using our slides, please retain the source attribution:
These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details
Slide credit: clinicaloptions.com
Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

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 Norah Terrault, MD, MPH Professor of Medicine and Surgery Director, Viral Hepatitis Center Division of Gastroenterology University of California, San Francisco San Francisco, California

4. Disclosures
Ira M. Jacobson, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Intercept, Merck, and Trek; fees for non-CME/CE services received directly from a commercial interest or their agent (eg, speaker bureau) from Gilead Sciences, Intercept, and Merck; and funds for research support from Genfit, Gilead Sciences, and Merck. Norah Terrault, MD, MPH, has disclosed that she has received consulting fees from Biotest, Gilead Sciences, Merck, and Mylan Pharmaceuticals and funds for research support from AbbVie, Biotest, Bristol-Myers Squibb, Gilead Sciences, and Merck.

5. Where HCV Therapy Stands Now
Interferon is gone in the US; ribavirin not quite
SVR in > 95% of pts
“Difficult-to-cure” populations no longer difficult
Black race
HIV coinfection
Persons who inject drugs (PWID)
Genotype 3 remains more challenging (but not by much)
Emergent issues and controversies:
HBV reactivation
Cost and access issues persist but improving
Cirrhosis
Older age
Renal failure and kidney transplant
Liver transplant
DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; SVR, sustained virologic response.
So where do we stand with HCV therapy today? Interferon is gone—in the United States, at least—and ribavirin is on its way out but still persists for now as part of some regimens. We now can say to patients that their SVR rates are greater than 95% across a broad array of patient profiles. But so called difficult-to-treat populations that we had in the interferon era are no longer difficult. And what we’ve seen is a shift from the interferon era where genotype 1 was the difficult-to-treat HCV type; now we see genotype 3 as perhaps the more challenging genotype for us to deal with but not by much. There’s been a few emergent issues and controversies over the last year, specifically related to HBV reactivation and HCC recurrence after DAA therapy. And really I think across the United States, although it does vary by state, cost and access issues persist but are I think improving.
HCC recurrence after DAA therapy

6. Approved DAAs From Multiple Classes: Basis of 2016 Combination HCV Regimens
Structural Domain
Nonstructural Domain
Core E1 E2
NS2
NS3 4A
NS4B
NS5A
NS5B
5’UTR P7
3’UTR
Polymerase
Protease
Ribavirin (RBV)
NS3 Protease Inhibitors
NS5A Replication Complex Inhibitors
NS5B NUC Inhibitors
NS5B Non-NUC Inhibitors
DAA, direct-acting antiviral.
So here are the approved DAAs from the various drug classes that we have available. So we have 3 NS3 protease inhibitors that are approved: grazoprevir, paritaprevir (which is ritonavir boosted), and simeprevir. And this year we’re anticipating 2 additional protease inhibitors to be approved as part of combination regimens—voxilaprevir and glecaprevir. In terms of NS5A inhibitors, we have 5 already approved NS5A inhibitors: daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir. And we’re anticipating 1 new NS5A inhibitor be approved this year, pibrentasvir. In the NS5B polymerase inhibitor category, we really have 1 nucleoside and 1 nonnucleoside drug; sofosbuvir is the nucleoside and dasabuvir the nonnucleoside. And as you know, we combine 2 or more of these classes together to achieve high rates of SVR and to minimize the chance for resistance. And you’ll see that ribavirin is still on the list because we, in fact, use ribavirin in certain situations where we’re really trying to amplify the responses of the DAA combinations.
Grazoprevir (GZR)
Paritaprevir/Ritonavir
(PTV/RTV)
Simeprevir (SMV)
Voxilaprevir (VOX)*
Glecaprevir (GLE)*
Daclatasvir (DCV)
Elbasvir (EBR)
Ledipasvir (LDV)
Ombitasvir (OBV)
Velpatasvir (VEL)
Pibrentasvir (PIB)*
Sofosbuvir
(SOF)
Dasabuvir
(DSV)
*Possible approval in 2017.
Slide credit: clinicaloptions.com

7. Treatment Options for Genotype 1
So I’m going to go through the current AASLD/IDSA guidance regarding HCV treatment. The guidance document—for those of you that have not been using this document—is really is incredible because it’s updated in real time and represents sort of the most current information about who you should treat and how you should treat. And the guidance is set out by genotype; and then within that, it looks at those with cirrhosis and those without. And then, those that are treatment naive and those that are treatment experienced.

8. Recommended Regimens (All 12 Wks Except as Noted)
Recommended for GT1 Treatment-Naive or IFN-Experienced Pts Without Cirrhosis
HCV GT
Recommended Regimens (All 12 Wks Except as Noted) 1a
LDV/SOF (8 wks if tx naive, nonblack, no HIV, and HCV RNA < 6 million IU/mL)
SOF/VEL
DCV + SOF
SMV + SOF
EBR/GZR*
OBV/PTV/RTV/DSV extended release + RBV or OBV/PTV/RTV + DSV BID + RBV 1b
EBR/GZR
OBV/PTV/RTV/DSV extended release or OBV/PTV/RTV + DSV BID
BID, twice daily; DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GT, genotype; GZR, grazoprevir; IFN, interferon; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir; VEL, velpatasvir.
These are the recommendations for genotype 1 treatment-naive or interferon-experienced populations without cirrhosis. So you’ll see here that one thing about genotype 1 is that the recommendations differ by subtype—1a vs 1b. In general, 1b easier to treat. So recommendations tend to be a little bit more involved for genotype 1a. Genotype 1 is the one genotype for which we have the most choices right now—we have 6 different therapies that are available—and it’s also the one genotype for which we have an 8-week approved regimen with ledipasvir/sofosbuvir recommended in treatment-naive patients only who are nonblack, without HIV, without cirrhosis, and have a viral load that’s less than 6 million IU/mL. All of the other regimens that are recommended are 12 weeks in duration. Most of the regimens are without ribavirin with the exception of the ombitasvir/paritaprevir/dasabuvir combination, which in genotype 1a is with ribavirin. You’ll also notice that there is an asterisk beside the elbasvir/grazoprevir regimen in the 1a patient, indicating that there’s a nuance to using this drug in 1a patients. And the specific thing is that we have to actually test for resistance associated variants. So in individuals in whom you’re going to treat with elbasvir/grazoprevir, the recommendation is to test them for NS5A resistance associated substitutions or RASs. And if they have specific RASs at position 28, 30, 31, or 93, then the recommendation in the guidance document is that for elbasvir/grazoprevir, they need to get 16 weeks of treatment and need to have ribavirin added.
*Only if no baseline NS5A elbasvir RASs detected.
Slide credit: clinicaloptions.com
AASLD/IDSA. HCV guidance. April 2017.

9. Recommended Regimens (All 12 Wks)
Recommended for GT1 Treatment-Naive or IFN-Experienced Pts With Compensated Cirrhosis
HCV GT
Recommended Regimens (All 12 Wks)
Treatment Naive
IFN/RBV Experienced 1a
EBR/GZR*
LDV/SOF
SOF/VEL
LDV/SOF + RBV 1b
EBR/GZR
OBV/PTV/RTV/DSV ER
OBV/PTV/RTV+ DSV BID
BID, twice daily; DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; ER, extended release; GT, genotype; GZR, grazoprevir; IFN, interferon; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir; VEL, velpatasvir.
Now if we shift to the cirrhotic patient—and it’s important to make the distinction between a patient with compensated vs decompensated cirrhosis—but for the patient with compensated Child-Pugh A disease, again we have different recommendations for genotype 1a vs 1b. You’ll also notice that there are fewer recommendations under the compensated cirrhotic than when we looked at the noncirrhotic populations. But we have several good options available for patients with either genotype 1a or 1b. And the other differentiation that you’ll see here is that we now are looking at things separately in treatment-naive vs interferon-experienced patients. Largely the treatments are the same, but the exception is that in an interferon-experienced patient who has cirrhosis if you’re going to use ledipasvir/sofosbuvir, you need to add ribavirin. Otherwise the treatment regimens are the same in the treatment-naive and the interferon-experienced populations. And the need for baseline NS5A resistance testing for patients with genotype 1a HCV infection who will be treated with elbasvir/grazoprevir holds for patients with compensated cirrhosis as discussed for noncirrhotic patients on the previous slide.
*Only if no baseline NS5A elbasvir RASs detected.
Slide credit: clinicaloptions.com
AASLD/IDSA. HCV guidance. April 2017.

10. Adjust EBR/GZR Duration Based on Baseline NS5A RASs in GT1a
C-EDGE Treatment Naive: 12 Wks of Elbasvir/Grazoprevir 99 92 99
100 58 80 60
SVR12 (%) 40 20
n/N =
144/157
133/135
11/19
129/131
BL, baseline; EBR, elbasvir; GT, genotype; GZR, grazoprevir; RAS, resistance associated substitutions; RBV, ribavirin; SVR, sustained virologic response.
And the rationale behind that recommendation is from this study, the C-EDGE study, in which patients were all treated with elbasvir/grazoprevir without ribavirin. You can see that overall the SVR rate is excellent at 92%. But if you break them down by patients who had baseline RASs vs those who did not, there’s a very distinct difference. Those that have the baseline RASs had an SVR rate of only 58% vs those without, which is 99%. And other studies have shown that if you add ribavirin to that group of patients and extend the treatment to 16 weeks, then the SVR rates, again, are back up to the 95% range. So that’s the data that led to that specific recommendation. It’s the only drug combination for which in genotype 1a you need to do baseline resistance testing.
All
No BL NS5A RASs
BL NS5A RASs
All
GT1a
GT1b
If NS5A RASs in GT1a, treat with EBR/GZR + RBV for 16 wks (alternative) No baseline RAS testing needed in GT1b pts
Zeuzem Z, et al. Ann Intern Med. 2015;163: Kwo P, et al. J Hepatol. 2015;62(suppl 2):S674-S675.
Slide credit: clinicaloptions.com

11. TRIO, HCV-TARGET, VA: Real-World Efficacy of EBR/GZR
Analyses of SVR12 rates in HCV- infected pts using specialty pharmacies and providers in real- world cohorts
US TRIO Network[1]
US and international clinical practices[2]
US Veterans Affairs Healthcare System[3]
HCV-TARGET[2]
TRIO[1]
VA[3] 60 20
SVR12 (%)
100 40 80 97
97*
97†
245/
253
135/
139
2190/
2257
n/N =
EBR, elbasvir; GZR, grazoprevir; SVR, sustained virologic response.
And this is some real-world data that’s been recently presented to just show that this combination, when it’s used both with and without, ribavirin has excellent SVR rates across a broad array of populations. These are real-world data from TRIO, which is specialty pharmacies; HCV-TARGET, which is a US/international clinical practices consortium; and then the VA. And you can see the VA has actually a very large experience with more than 2000 patients treated, SVR rates of 97%. So that’s genotype 1 in short.
*For pts missing SVR12 outcome, data replaced with SVR4 outcome. †For pts missing SVR12 outcome, data replaced with HCV RNA test results obtained during posttreatment Wks 4-12.
1. Bacon B, et al. EASL Abstract THU Pearlman BL, et al. EASL Abstract THU-237.
3. Kramer JR, et al. EASL Abstract PS-095.
Slide credit: clinicaloptions.com

12. Resistance Considerations
Which classes are prone to resistance?
Protease, NS5A, and nonnucleotide NS5B inhibitors
Barrier to PI and NS5A resistance
Higher for GT1b vs GT1a
Most pts with failure of current DAAs have emergent resistance-associated substitutions (RASs)
NS5A RASs persist much longer than PI RASs
15% of pts have baseline NS5A RASs with variable effects on GT1a response
Second-generation drugs designed to cover RASs
DAA, direct-acting antiviral; GT, genotype.
Slide credit: clinicaloptions.com

13. Treatment Options for Genotype 3
Now we’re going to shift to genotype 3.

14. Recommended for Treatment-Naive Pts With Genotype 3 HCV
Cirrhosis?
RAS Test?
RAS Test Result
Recommended regimens No
Don’t test -
DCV + SOF 12 wks
SOF/VEL 12 wks
Yes
Test
No Y93
DCV + SOF ± RBV 24 wks
Y93
DCV + SOF + RBV 24 wks
SOF/VEL + RBV 12 wks
DCV, daclatasvir; RAS, resistance-associated substitution; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir.
So the first you’ll see, as we look through this, is that there’s fewer treatment options. Instead of having 6 drugs to choose from, now really the recommended therapies are of 2: daclatasvir plus sofosbuvir or sofosbuvir/velpatasvir. Now we’re going to look at it first by treatment naive, and here we’re doing the breakdown with cirrhosis or without cirrhosis. So this is another scenario where baseline resistance testing may be needed. So I just explained that in the genotype 1a patient in which you’re going to use elbasvir/grazoprevir you need to do baseline resistance testing. But also in genotype 3 patients, there’s a subset in which we need to do baseline resistance testing in the NS5A region for the Y93, in particular. And it’s because that resistance associated variant has also been associated with reduced rates of SVR. And whenever we see reduced rates of SVR, our go-to is to add ribavirin. So, as you see here, treatment-naive patients that have cirrhosis, it’s recommended you test them to see if they have the Y93 RAS. And if they have the RAS present, then you would treat them with ribavirin and extend the treatment in the case of daclatasvir and sofosbuvir to 24 weeks and, if you’re using SOF/velpatasvir, to 12 weeks. So the addition here is to add ribavirin when the Y93 is present. If the Y93 is not present, then you don’t need to add the ribavirin.
Slide credit: clinicaloptions.com
AASLD/IDSA. HCV guidance. April 2017.

15. Recommended for PegIFN/RBV-Experienced Pts With Genotype 3 HCV
Cirrhosis?
RAS Test?
RAS Test Result
Recommended regimens No
Test
No Y93
DCV + SOF 12 wks
SOF/VEL 12 wks
Y93
DCV + SOF + RBV 12 wks
SOF/VEL + RBV 12 wks
Yes
Don’t test -
EBR/GZR + SOF 12 wks
DCV, daclatasvir; EBR, elbasvir; GZR, grazoprevir; pegIFN, peginterferon; RAS, resistance-associated substitution; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir.
Similarly, in the treatment-experienced population with genotype 3, again you’ll see that there’s a need to do RAS testing. Here you’re doing it in a patient without cirrhosis. And here the testing, again, if they have the Y93, you’re going to add ribavirin to the mix. And the reason you’re not doing the testing in the cirrhotic patient who’s treatment experienced is because those individuals are recommended to get ribavirin with sofosbuvir/velpatasvir anyway. So there’s no need to test because you’re going to routinely give them ribavirin. But the other thing to point out on this slide is there was a very new addition in the most recent guidance document of using elbasvir/grazoprevir plus sofosbuvir for the treatment-experienced genotype 3 patient who has cirrhosis. And that was based on a study that was done that showed that this is an effective regimen in this population. So that was a new addition. So we now have some new strategies to treat that genotype 3 population, especially the cirrhotic, the treatment experienced.
Slide credit: clinicaloptions.com
AASLD/IDSA. HCV guidance. April 2017.

16. Need for RBV Based on Baseline Y93 RAS in GT3 With Cirrhosis or Previous PegIFN/RBV
Based on very low SVR12 rates in these groups when treated without RBV
For pts with both cirrhosis and previous pegIFN/RBV, RBV required regardless of Y93 status (unless using EBR/GZR + SOF)
These recommendations are pending further data on optimal regimen[1]
GT3 Study and Population
SVR12, %
No Y93H
Y93H
ALLY-3: DCV + SOF for 12 Wks[2]
Overall
92 (n = 162)
54 (n = 13)
No cirrhosis
98 (n = 128)
67 (n = 9)
Cirrhosis
71 (n = 34)
25 (n = 4)
ASTRAL-3: SOF/VEL for 12 Wks[3]
97 (n = 249)
84 (n = 25)
DCV, daclatasvir; EBR, elbasvir; GT, genotype; GZR, grazoprevir; pegIFN, peginterferon; RAS, resistance-associated substitution; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir.
So just to point out a little bit of the data about why that Y93 RAS is so important, and why when we see that RAS present in our genotype 3 patients, we add ribavirin. And that’s true in patients with genotype 3 with cirrhosis or who’ve been previously treated. So looking down at the table, these are results where they divided the SVR rates by patients who had the Y93 and who did not. So the no Y93 is shown on the left-hand column, and the with Y93 is shown on the right. And you can see that when you’re using daclatasvir plus sofosbuvir for 12 weeks, or if you’re using sofosbuvir/velpatasvir for 12 weeks, there’s a significant reduction in the SVR rates when the Y93 is present. And for this reason, it’s recommended that those individuals have ribavirin added.
1. AASLD/IDSA. HCV guidance. April Nelson DR, et al. Hepatology. 2015;61: Foster GR, et al. N Engl J Med. 2015;373:
Slide credit: clinicaloptions.com

17. Treatment Options for Genotypes 2, 4, 5, 6
So now onto treatment of genotypes 2, 4, 5, and 6.

18. Recommended Regimens for Treatment-Naive Pts With GT 2, 4, 5, 6 HCV
All regimens 12 wks
HCV GT
No Cirrhosis
Compensated Cirrhosis 2
SOF/VEL
SAME 4
OBV/PTV/RTV + RBV
EBR/GZR
LDV/SOF
5 or 6
EBR, elbasvir; GT, genotype; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SOF, sofosbuvir; VEL, velpatasvir.
Again, these are a little bit simpler, I think, in the sense that the cirrhotic patients and the noncirrhotic patients are treated quite similarly across these genotypes, especially in the treatment-naive group. So here looking at genotype 2, we have only 1 treatment that is recommended for both cirrhotics and noncirrhotics, sofosbuvir/velpatasvir. For genotype 4, we have 4 options available. Keep in mind that genotype 4, if you’re going to use ombitasvir/paritaprevir/ritonavir, there’s no dasabuvir needed here, but ribavirin is added. And then for genotypes 5 and 6, we have sofosbuvir/velpatasvir and ledipasvir/sofosbuvir—so, again, no differences with vs without compensated cirrhosis if they’re treatment naive.
Slide credit: clinicaloptions.com
AASLD/IDSA. HCV guidance. April 2017.

19. Compensated Cirrhosis
Recommended Regimens for PegIFN/RBV-Experienced Pts With GT2, 4, 5, 6 HCV
All regimens 12 wks unless noted otherwise
HCV GT
No Cirrhosis
Compensated Cirrhosis 2
SOF/VEL
SAME 4
OBV/PTV/RTV + RBV
EBR/GZR*
LDV/SOF
LDV/SOF + RBV
5 or 6
EBR, elbasvir; GT, genotype; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PegIFN, peginterferon; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SOF, sofosbuvir; VEL, velpatasvir.
Now if you shift to looking at patients who are treatment experienced with prior peginterferon/ribavirin, you can see here that, again, generally the cirrhosis and the compensated cirrhosis are treated the same across the genotypes, but the one exception similar to what we saw with genotype 1 is that if you have a patient who has compensated cirrhosis and is peginterferon/ribavirin experienced with genotype 4 and you’re going to use ledipasvir/sofosbuvir, you would add ribavirin, but otherwise the treatment regimens are very similar between the interferon-experienced and the treatment-naive patients.
*Previous relapse only; pts with previous virologic nonresponse or breakthrough should be treated with 16 wks with addition of RBV.
Slide credit: clinicaloptions.com
AASLD/IDSA. HCV guidance. April 2017.

20. Late-Phase Investigational HCV Regimens by Drug Classes
NS5B Polymerase Nucleotide Inhibitor (. . . buvir)
NS3/4A Protease Inhibitor
(. . . previr)
NS5A Inhibitor (. . . asvir)
Sofosbuvir/velpatasvir/voxilaprevir
SOF
VOX
VEL
Glecaprevir/pibrentasvir --
GLE
PIB
Grazoprevir/ruzasvir/uprifosbuvir
UPR
GZR
RZR
AL odalasvir + simeprevir
AL-335
SMV
ODV
I’m going to shift now to looking at the new drugs that are coming. And normally when we give these talks, the drugs are very far away and we’re sort of looking way into the future, but in this case, at least 2 of the combinations under investigation are anticipated to be approved very soon, in the next several months, certainly this year. The first of those combinations is sofosbuvir/velpatasvir/voxilaprevir, which is a triple-drug combination including each of the drug classes—the NS5B inhibitor, the protease inhibitor, and the NS5A inhibitor.
And the second combination anticipated soon is glecaprevir/pibrentasvir, which is a dual-combination therapy of a protease inhibitor and an NS5A inhibitor. And then you’ll see that we also have 2 other triplets that are being evaluated and are well along in drug development, and each of those other combinations include a drug from each of the drug classes. So I’m going to show you data on each of these combinations as we go through them.
Slide credit: clinicaloptions.com

21. 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.
First of all, I’ll focus on the SOF/VEL/VOX combination which is the new triplet, and there are many studies—they all have the POLARIS name associated with them—and I’m going to show you 2 of the studies, POLARIS-2 and POLARIS-3. In POLARIS-2, the study sought to compare 8 weeks of SOF/VEL/VOX vs 12 weeks of SOF/VEL in treatment-naive patients with genotypes 1 through 6 HCV infection.
So one of the key things about all of the new drugs that are being developed is that they’re pan-genotypic, so they’re being used across all genotypes, and there’s definitely an effort to move towards shorter duration therapy. So instead of most of our regimens right now are 12 weeks, and most of the new drug combinations that are coming forward, they’re trying to move toward an 8-week regimen so that a greater proportion of our patients could be treated for shorter durations.
So that’s sort of the layout for this randomized trial in which they looked at the triplet for 8 weeks vs SOF/VEL for 12 weeks. These were all treatment-naive again, all genotypes represented. They included cirrhotics and they included patients who’d been previously treated with interferon.
*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. Gastroenterology. 2017;[Epub ahead of print].

22. POLARIS-2: SVR12 Rates With 8-Wk SOF/VEL/VOX vs 12-Wk SOF/VEL
8-wk SOF/VEL/VOX did not meet criteria for noninferiority vs 12-wk SOF/VEL
Treatment difference: -3.4% (95% CI: -6.2% to -0.6%)
14/21 pts with relapse to SOF/VEL/VOX 8 wks had GT1a
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
SOF/VEL/VOX 8 wks
SOF/VEL 12 wks
AE, adverse event; D/c, discontinued; LTFU, lost to follow-up; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VOX, voxilaprevir.
And so what you can see here in the overall results is that the 8-week regimen didn’t meet the criteria for noninferiority. So what they were trying to do in this study is to establish that the triplet for 8 weeks was as good—meaning noninferior—as the SOF/VEL for 12 weeks, and it didn’t meet that endpoint. You can see that the blue bars are a little bit lower than the orange bars across the overall noncirrhotic and cirrhotic. Now what’s not shown here is that most of the differential in terms of the responses between the 8-week SOF/VEL/VOX vs 12-week SOF/VEL were quite comparable across the genotypes, with the exception of genotype 1a, but nonetheless this study failed to meet the noninferiority endpoint.
Slide credit: clinicaloptions.com
Jacobson IM, et al. Gastroenterology. 2017;[Epub ahead of print].

23. 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
IFN experience in 29% to 32% of pts
Stratified by prior IFN (experienced vs naive)
Wk 8
Wk 12
SOF/VEL/VOX 400/100/100 mg PO QD (n = 110)
Pts 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.
The POLARIS-3 trial focused on the genotype 3 patients. And since genotype 3 is a little bit more challenging for us to treat, in this instance what they were looking at is, again, the SOF/VEL/VOX combination for 8 weeks vs what is currently one of our approved therapies, SOF/VEL for 12 weeks. Again, what’s unique about this is they only studied cirrhotic patients which are more difficult to treat, they could be with or without prior interferon experience; about a third of the patients had prior experience.
Slide credit: clinicaloptions.com
Jacobson IM, et al. Gastroenterology. 2017;[Epub ahead of print].

24. POLARIS-3: SVR12 Rates With 8-Wk SOF/VEL/VOX for Cirrhotic GT3 Pts
SOF/VEL/VOX 8 wks SOF/VEL 12 wks 96 96 97 96 99 91 95 95
100
100
100 80 60
SVR12 (%) 40 20
106/ 110
105/ 109
72/ 75
76/ 77
34/ 35
29/ 32
80/ 84
76/ 80
23/ 23
23/ 23
n/N =
Overall
Treatment Naive
Treatment Experienced
No BL RASs
Any BL RASs
SVR rates similar between treatment arms, and both regimens superior to prespecified historic SVR rate of 83% (P < .001 for each arm)
Overall VF: SOF/VEL/VOX, n = 2 relapses; SOF/VEL, n = 1 each for relapse and on- treatment failure
No treatment-emergent RASs in SOF/VEL/VOX arm; Y93H in both VFs in SOF/VEL arm
BL, baseline; GT, genotype; RAS, resistance associated substitution; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VF, virologic failure; VOX, voxilaprevir.
And in this setting, you can see that both the 8-week SOF/VEL/VOX and the 12-week SOF/VEL regimens were shown to be superior to a prespecified historical SVR rate of 83%. So this looks like an attractive option for genotype 3 patients with cirrhosis, and remember, this is including both patients with and without prior interferon experience. There was 1 case of relapse and 1 case of on-treatment failure in the SOF/VEL arm and 2 cases of relapse among the patients treated with SOF/VEL/VOX. Importantly, those 2 individuals that had a relapse with SOF/VEL/VOX did not have any treatment-emergent RASs. That’s quite unique because normally when we have patients experience failure of a DAA combination, usually after we assess them post-DAA therapy they have emergence of resistance. But in this setting of SOF/VEL/VOX, even though they had relapse in 2 patients, they didn’t have any evidence of treatment-emergent RASs.
Slide credit: clinicaloptions.com
Jacobson IM, et al. Gastroenterology. 2017;[Epub ahead of print].

25. POLARIS-2, -3: Safety of SOF/VEL/VOX for 8 Wks
Outcome, %
POLARIS-2
POLARIS-3
SOF/VEL/VOX 8 Wks (n = 501)
SOF/VEL 12 Wks
(n = 440)
SOF/VEL/VOX 8 Wks (n = 110)
(n = 109)
Any AE 72 69 75 74
Serious AE 3 2
D/c for AE
< 1 1
Death
AE in > 10% of pts
Headache 27 23 25 29
Fatigue 21 20 28
Diarrhea 18 7 15 5
Nausea 16 9
AE, adverse event; D/c, discontinued; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
In terms of the safety profile—and here it’s being compared to SOF/VEL—it’s a very well-tolerated triplet, but you’ll see that what stands out potentially is being side effects that are unique to the SOF/VEL/VOX combination is diarrhea and nausea. You can see that they were in slightly higher proportions than in the SOF/VEL group.
Slide credit: clinicaloptions.com
Jacobson IM, et al. Gastroenterology. 2017;[Epub ahead of print].

26. POLARIS-2, -3: Pooled Analysis of BL RAS Effect on SOF/VEL/VOX in DAA-Naive Pts
606 DAA-naive pts treated with 8-wk SOF/VEL/VOX in POLARIS-2 and -3
RASs assessed by deep sequencing (15% assay cutoff)
VOX-specific and VEL-specific RASs had no impact on SVR
No emergent RASs in 22/23 pts who relapsed after 8 wks of SOF/VEL/VOX
98% SVR12
304/311
94% SVR12
257/273
19% NS3 112/584
53% No RASs 311/584
24% NS5A 140/584
BL, baseline; DAA, direct-acting antiviral; RAS, resistance associated substitution; SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir; VOX, voxilaprevir.
And this is just a summary of the POLARIS-2 and -3 data looking at the effect of the baseline RASs. So you remember that currently with genotype 3, we’re very concerned about individuals who might have the Y93 RAS at baseline, that this variant is influencing the responses to current therapies. So here they’re looking at 606 treatment-naive patients who were treated with the 8 weeks of SOF/VEL/VOX in the study, and what they’re showing in the blue is that 98% of patients without any baseline RASs achieved SVR. And then on the right in the orange are the patients that had baseline RASs, including 24% who had NS5A RASs, which would include, for example, the Y93 resistance associated substitution. You can see that the group with baseline RASs achieved very good SVR rates at 94%. And, in fact, they found that none of the VOX-specific or VEL-specific RASs had any impact on the SVR rates in this group of patients, so it seems like a very attractive treatment combination for individuals who may have baseline RASs.
4% NS3+NS5A 21/584
Slide credit: clinicaloptions.com
Wyles D, et al. EASL Abstract THU-257.

27. ENDURANCE Studies: Glecaprevir/Pibrentasvir in Noncirrhotic Patients
Now I’m going to move to glecaprevir/pibrentasvir in noncirrhotic patients.

28. 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]
GLE/PIB* (n = 351)
Noncirrhotic pts with GT1 HCV with or
without IFN experience or HIV coinfection
(N = 703; 38% tx-experienced†)
GLE/PIB* (n = 352)
ENDURANCE-2: randomized, double-blind, placebo-controlled phase III trial[2]
GLE/PIB* (n = 202)
Noncirrhotic pts with GT2 HCV
with or without IFN experience
(N = 302; 29% to 30% tx-experienced†)
Placebo (n = 100)
GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon; PIB, pibrentasvir; QD, once daily; RBV, ribavirin.
References:
1. Zeuzem S, et al. AASLD Abstract 253.
2. Kowdley KV, et al. AASLD Abstract 73.
3. Asselah T, et al. AASLD Abstract 114.
This is the ENDURANCE-1, -2, and -4, and, again, it’s across all the genotypes except 3. So 3 was evaluated separately. They’re looking at, again, 8 weeks and 12-week regimens, they’re looking at noncirrhotic patients, and ENDURANCE-1 is genotype 1, ENDURANCE-2 is genotype 2, and ENDURANCE-4 is genotypes 4 through 6. Again, in this group, they could be treatment experienced, and about one third of the patients in all groups were treatment experienced.
ENDURANCE-4: open-label, single-arm phase III trial[3]
Noncirrhotic pts with GT4-6 HCV with or without IFN experience
(N = 121; 32% tx-experienced†)
GLE/PIB* (N = 121)
*Dosing: GLE/PIB given as 3 coformulated 100/40-mg tablets QD for a total dose of 300/120 mg.
†Treatment experience permitted: IFN or pegIFN ± RBV or SOF + RBV ± pegIFN.
Slide credit: clinicaloptions.com
References in slidenotes.

29. ENDURANCE-1, -2, -4 Studies: Efficacy of GLE/PIB for Treating GT1, 2, 4, 5, 6 HCV
99.1*
99.7*
99†
99‡
100 80 60
1 case of on-treatment virologic failure at Day 29 in pt with GT1a HCV infection
SVR12 (%) 40 20
332/
335
331/
332
195/
196
120/
121
n/N =
8 Wks
12 Wks
12 Wks
12 Wks
GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat; ITT-PS, intent to treat excluding HIV coinfection and previous sofosbuvir; PIB, pibrentasvir; SOF, sofosbuvir; SVR, sustained virologic response.
So here you can see the SVR rates are excellent in both the 8-week as well as the 12-week group, and in ENDURANCE-1 that’s the genotype 1 and also very high rates of SVR for 12 weeks in the ENDURANCE-2, which is genotype 2, and ENDURANCE-4, which is the genotypes 4 through 6. There was 1 case of on-treatment virologic failure in one of the patients who had genotype 1a, but overall a very high rate of SVR, as you can see.
ENDURANCE-1 (GT1)[1]
ENDURANCE-2 (GT2)[2]
ENDURANCE-4 (GT4-6)[3]
*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.
1. Zeuzem S, et al. AASLD Abstract Kowdley KV, et al. AASLD Abstract Asselah T, et al. AASLD Abstract 114.
Slide credit: clinicaloptions.com

30. ENDURANCE-1, -2, -4 Studies: Safety of GLE/PIB for Treating GT1, 2, 4, 5, 6 HCV
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; GT, genotype; PBO, placebo; PIB, pibrentasvir; ULN, upper limit of normal.
Looking at the safety profile for this drug, really, again, very low rates of adverse events, as was shown in the prior study with SOF/VEL/VOX; these are very well-tolerated drugs. Here, the most noteworthy AEs were fatigue and headache, which is common in most of the DAA combinations, and they looked specifically here at any evidence for hepatotoxicity related to AST/ALT elevations and total bilirubin, and you can see that it was, in fact, extremely rare—so a very safe combination.
*> 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

31. SURVEYOR 2, Part 4: 8 Wks GLE/PIB For Pts With GT 2, 4, 5, 6 HCV Without Cirrhosis
99% SVR12 rate with 8-wk regimen in DAA-naive pts with GT2 HCV – noninferior to 95% historical control (SOF + RBV for 12 wks)
ITT
mITT 99 98
100
194/
196
140/
142
43/ 43 2/ 2 9/ 9 97 98 93
100 90
100
100 80 80 60 60
SVR12 (%)
SVR12 (%) 40 40
DAA, direct-acting antiviral; D/C, discontinued; GLE, glecaprevir; GT, genotype; ITT, intent-to-treat; mITT, modified ITT; PIB, pibrentasvir; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response.
Now there’s another study, the SURVEYOR 2 in which 8 weeks of glecaprevir /pibrentasvir was used in patients, again, with genotypes 2 4, 5, and 6; this is, again, 8-week regimen. So remember that they’d looked at the 8-week regimen in the genotype 1 and then looked at genotypes 2, 4, 5, and 6 for 12 weeks, now we’re looking at 8-week data. And you can see that the SVR rates in this—it’s a smaller study for some of the genotypes—but across the genotypes, especially genotypes 2, 3, and 6 where we have fairly good numbers of patients—only 2 genotype 5 patients—but across the board very good SVR rates ranging from 90 to 100, but most of them over the 95% range that we’ve come to expect. 20 20
196/
203
142/
145
43/ 46
n/N =
2/2
9/10
n/N =
All 2 3
GT2 2 1
GT4 1 2
GT5
GT6 1
All
GT2
GT4
GT5
GT6
Relapse
D/C
No SVR12 data
Slide credit: clinicaloptions.com
Hassanein TI, et al. AASLD Abstract LB-15.

32. ENDURANCE-3: Glecaprevir/Pibrentasvir in GT3 HCV Without Cirrhosis
Most pts had history of IDU (63% to 66%)
8-wk GLE/PIB
12-wk GLE/PIB
12-wk DCV + SOF
Noninferior
Noninferior 97 95 95
100
No serious AEs deemed related to study drug
No clinically relevant ALT increases, 1 isolated bilirubin increase (G/P 8 wks), 1 isolated neutrophil count decrease (G/P 12 wks) 80 60
SVR12 by ITT (%) 40 20
149/ 157
222/ 223
111/ 115
AE, adverse event; ALT, alanine aminotransferase; d/c, discontinuation; DCV, daclatasvir; GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; IDU, injection drug use; ITT, intent-to-treat; LTFU, lost to follow-up; PIB, pibrentasvir; SOF, sofosbuvir; SVR, sustained virologic response.
And then, finally, because those studies excluded genotype 3 HCV infection, now we focus on the patients with genotype 3 HCV. This is ENDURANCE-3, and, again, we’re looking at variable treatment durations, 8 and 12 of the glecaprevir/pibrentasvir, and now comparing it to 12 weeks of daclatasvir plus sofosbuvir, which is one of the therapies that currently is approved for genotype 3. And you’ll see here that they showed noninferiority of 8 vs 12 weeks of glecaprevir/pibrentasvir and between the 12 weeks of glecaprevir/pibrentasvir and the 12 weeks of daclatasvir plus sofosbuvir. And, again, very low rates of relapse, although there was a slightly higher number of relapsers in the group that received 8 weeks, but overall SVR rates, again, 95% and higher. This study was specifically in noncirrhotic patients.
n/N =
Failure, n (%)
Breakthrough Relapse
AE-related d/c
LTFU
1 (1)
5 (3)
2 (1)
1 (< 1)
3 (1)
4 (2)*
1 (1)
2 (2)
*2 other failures due to consent withdrawal and noncompliance.
Slide credit: clinicaloptions.com
Foster GR, et al. EASL Abstract GS-007.

33. EXPEDITION-1: Glecaprevir/Pibrentasvir in GT1, 2, 4, 5, or 6 HCV and Compensated Cirrhosis
Tx-naive and tx-exp’d pts enrolled[1,2]
1 relapse in pt with GT1a HCV with new NS5A mutations (Q30R, H58D)
No AE-related discontinuations or DAA- related serious AEs[1,2]
1 death deemed unrelated to study drug
Rare grade 3 laboratory abnormalities
In EXPEDITION-2,[3] 98% SVR12 rate with GLE/PIB for 8 or 12 wks (without vs with cirrhosis) in HCV/HIV-coinfected pts
100 80 60 40 20
SVR12 (%)
All Pts 1
145/ 146
89/ 90
31/ 31
7/ 7 99
2/ 2 2 4 5 6
Genotype
n/N =
16/ 16
AE,[1,2] n (%)
Pts (N = 146)
Any AE
101 (69)
Any serious AE
11 (8)
AEs occurring in ≥ 10% of pts
Fatigue
Headache
Pruritus
28 (19)
20 (14)
14 (10)
HCC
2 (1)
AE, adverse event; DAA, direct-acting antiviral; GLE, glecaprevir; GT, genotype; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; PIB, pibrentasvir; SVR, sustained virologic response.
So now to shift to patients with compensated cirrhosis. Here we’re looking at, again, all genotypes except for genotype 3. They’re treatment-naive and -experienced patient populations, and they were treated for 12 weeks with glecaprevir/pibrentasvir. And you can see that although the numbers of genotypes—again, 5 and 6—may be small, but nonetheless across all of the genotypes, there is a very good rate of sustained virological response, from a 99% overall, and many of the subgroups at 100%. There was a relapse in 1 patient—again, it’s a genotype 1a patient—and that patient had new NS5A mutations, the Q80R and H58D. Overall, like in the noncirrhotic population, this was found to be a very well-tolerated regimen, and again, the main AEs were headache and fatigue but excellent regimen in this population of patients with cirrhosis.
The final group that is worth mentioning is—they’ve also studied this combination of glecaprevir/pibrentasvir in patients who have HIV coinfection and looked at it in patients with and without cirrhosis and looking at the 8- vs 12-week regimen, and overall, the SVR rate in that group of patients was also very good at 98%.
1. Forns X, et al. EASL Abstract GS ClinicalTrials.gov. NCT
3. Rockstroh J, et al. EASL Abstract LBP-522.
Slide credit: clinicaloptions.com

34. MAGELLAN-2: Glecaprevir/Pibrentasvir for 12 Wks in GT1-6 HCV With Liver or Renal Transplant
Liver/kidney transplant: 80%/20%
1 relapse in pt with GT3a HCV; 1 pt LTFU
No deaths during study, 1 pt with transplant rejection (unrelated to DAA)
Outcome, %
GLE/PIB (N = 100)
Any AE 85
Serious AE
DAA related 8 2
D/c for AE 1
AEs in ≥ 10% of pts
Headache
Fatigue
Nausea
Pruritus 22 12
Grade ≥ 3 abnormality
AST
ALT
Total bilirubin
CrCl 98 99
100 80 60
SVR12 (%)
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CrCl, creatinine clearance; DAA, direct-acting antiviral; D/c, discontinued; GLE, glecaprevir; GT, genotype; HCV, hepatitis C virus; ITT, intent-to-treat; mITT, modified ITT; LTFU, lost to follow-up; PIB, pibrentasvir; SVR, sustained virologic response.
One of the unique populations that’s been studied with the glecaprevir/pibrentasvir combination is liver transplant and kidney transplant recipients, and this is, I think, an important advance, as well, to have something to offer our transplant patients. We have several good drug combinations now, but this one looks like it’s potentially another one, genotypes 1 through 6 looked at. You can see that the overall rate of SVR is excellent with just 12 weeks of treatment. And why this drug combination is particularly interesting is that this is the first study that actually has looked at treating posttransplant patients with DAA therapy that doesn’t include ribavirin. All of the other currently approved regimens require us to use ribavirin, so this is an important advance potentially for treating that patient population because it’ll be a ribavirin-free regimen. And, again, this was shown to be very well tolerated. 40 20
98/ 100
98/ 99
n/N =
ITT
mITT
Slide credit: clinicaloptions.com
Reau N, et al. EASL Abstract LBO-03.

35. C-CREST 1 & 2: GZR/RZR/UPR ± RBV for Treating Pts With GT1-4, 6 HCV
Part B: randomized, open-label phase II trials
Wk 8
Wk 12
Wk 16
GZR/RZR/UPR
(n = 180: GT1, n = 88; GT2, n = 32; GT3, n = 53; GT4, n = 7)
GZR/RZR/UPR + RBV
(n = 81: GT2, n = 31; GT3, n = 50)
Patients with GT1-4, 6 HCV,
HCV RNA ≥ 10,000 IU/mL,
with or without compensated
cirrhosis
(N = 675)
GZR/RZR/UPR
(n = 217: GT1, n = 88; GT2, n = 46; GT3, n = 79; GT6, n = 4)
GZR/RZR/UPR + RBV
(n = 96: GT2, n = 16; GT3, n = 80)
GZR/RZR/UPR
(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; UPR, uprifosbuvir.
Now a few slides on the combinations that are a little bit farther behind in terms of their development—but not far behind. So this is the C-CREST study that involves grazoprevir/ruzasvir/uprifosbuvir, with or without ribavirin, in patients who have genotype 1 through 4 and 6; so they didn’t have any genotype 5, which are hard to come by. And you can see in this program they’re looking at, again, always looking at trying to shorten treatment, so 8 weeks. They also looked at 12 and also looked at 16 weeks. So with and without ribavirin, and these were all individuals with or without compensated cirrhosis.
GZR/RZR/UPR + RBV
(GT3, n = 25)
Dosing: GZR/RZR/UPR dosed as two 50/30/225-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. EASL Abstract THU-285.

36. C-CREST 1 & 2: Efficacy of GZR/RZR/UPR ± RBV for Pts With GT1-4, 6 HCV
Full Analysis Set
8 wks
12 wks
16 wks 96
100 93 97
100
100 90 86 93 96 96 80
100% SVR12 rates in 7 pts with GT4 (treated for 8 wks) and 4 pts with GT6 (treated for 12 wks) HCV infection 60
SVR24 (%) 40 20
39/ 42
43/ 48
44/ 46
40/ 40
54/ 63
60/ 62
26/ 26
96/ 103
153/ 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; RAS, resistance associated substitution; RBV, ribavirin; RZR, ruzasvir; SVR, sustained virologic response; tx, treatment; UPR, uprifosbuvir.
So just to give you a flavor of the results that are coming through, so, again, genotype 1a and 1b, the 8 vs 12 weeks looks really very encouraging and quite comparable. You can see with genotype 2 the 8 week seems to be less favorable for genotype 2, but 12 and 16 weeks achieve SVR rates over 95%. And then when you get to genotype 3, basically across the board—8, 12, and 16 weeks—that are all 93% or higher. So this represents yet another triplet for us to look forward to.
Presence of cirrhosis, use of ribavirin, prior tx experience did not impact SVR12 rates
SVR12 by Baseline RAS Presence, % (n/N)
GT2 HCV
GT3 HCV
No L31M
L31M
No Y93H
Y93H
8 wks
94 (31/33)
81 (21/26)
98 (95/97)
50 (2/4)
12 wks
100 (28/28)
100 (31/31)
99 (147/148)
71 (5/7)
Slide credit: clinicaloptions.com
Lawitz E, et al. EASL Abstract THU-285.

37. AL-335 800 mg QD + ODV 50 mg QOD + SMV 75 mg QD
AL ODV ± SMV for ≤ 12 Wks in Treatment-Naive Pts With GT1/3 HCV ± Cirrhosis
Randomized, open-label phase IIa trial; treatment-naive patients with GT1/3 HCV infection with or without cirrhosis
Wk 6
Wk 8
SVR12*
AL mg QD + ODV 50 mg QD + SMV 100 mg QD (n = 20)
100%
GT1
AL mg QD + ODV 50 mg QOD
(n = 25)
84%
AL mg QD + ODV 50 mg QOD + SMV 75 mg QD (n = 20)
100%
GT, genotype; ODV, odalasvir; QD, once daily; QOD, every other day; SMV, simeprevir; SVR, sustained virologic response.
And then, finally, the other drug combination in development is AL-335 plus odalasvir with or without simeprevir. This study looked at genotypes 1 and 3 which are the predominant genotypes, of course, in the population. These are treatment-naive patient populations, again, with or without cirrhosis. This is a very ambitious program because they’re looking at 6 weeks as well as 8 weeks in terms of a treatment duration, so, again, trying to shorten that treatment duration. These are relatively small preliminary studies with about patients per group. And you can see that the SVR rates for the genotype 1 patients who had the triplet was 100% in these 20 patients; without the simeprevir, that decreased for the genotype 1 patients. And then you can see that certainly shortening the therapy in this small study looked somewhat encouraging, so that’s an interesting alley to see if we’re going to get to a 6-week regimen. But obviously for genotype 3, you can see that this is a regimen that probably is going to have to be tweaked; it’s only 5 patients, but needs some more work.
GT1
AL mg QD + ODV 50 mg QOD + SMV 75 mg QD
(n = 20)
100%
AL mg QD + ODV 50 mg QOD + SMV 75 mg QD (n = 5)
GT3 0%
*All pts with SVR12 also achieved SVR24.
Slide credit: clinicaloptions.com
Gane E, et al. EASL Abstract PS-153.

38. Do DAAs Increase the Risk of de Novo or Recurrent HCC?
DAA, direct-acting antiviral; HCC, hepatocellular carcinoma.
So that’s kind of gives a flavor of what’s coming immediately and then a little bit further down the pike. And I’m going to end on 2 other issues, and that’s to look at how DAAs that we are currently using might be affecting the risk of additional complications and, in particular, the issue of HCC and then the HBV reactivation.
There was a very provocative paper that was published about a year ago now that suggested that patients who were treated with DAAs may have higher rates of HCC. Since that initial publication, there’s been, I think, more robust datasets that have been looked at, and I’m going to just share with you some of that subsequent data.

39. High Rate of HCC Recurrence With DAAs
Retrospective study of pts with history of HCC before starting DAA
Recurrence in Pts With Previous HCC Complete Response
Among pts starting DAAs ≤ 4 mos after CR, 4 pts (20%) died
Deaths occurred in Mos 9, 10, 15, 16 after starting DAA
10 pts had second HCC recurrence or progression
100 80
Pts With HCC Recurrence After DAA (%)
Endpoint
Pts With Recurrence (n = 24)*
Median time from DAA start to first recurrence, mos (IQR)
3.5 (2-7.6)
Median time from first to second recurrence/progression, mos (IQR)
Within 6 mos of first recurrence, n/n (%)
Death, n (%)
6.0 ( )
6/20 (30)
5 (20.8) 60
45.0
35.3 40
31.2 20
n/N = / / /20
All Pts
Confirmed Radiologic Assessment
Starting DAA ≤ 4 Mos After CR
CR, complete response; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma.
*Pts from cohort with confirmed radiologic assessment, no confounding factors.
Slide credit: clinicaloptions.com
Reig M, et al. EASL Abstract PS-031.

40. HCC Occurrence or Recurrence Equivalent in Pts With SVR to DAAs vs IFN
Meta-analysis and meta-regression analysis of 41 studies (N = 13,875)
HCC occurrence in cirrhotic pts who achieved SVR with DAAs or IFN
HCC recurrence in pts who had had curative treatment for liver cancer
HCC and Risk Factor
Adjusted RR (95% CI)
P Value
HCC occurrence
Average follow-up
0.77 ( )
.03
Average age
1.06 ( )
.08
Treatment (DAA vs IFN)
0.75 ( )
.62
HCC recurrence
0.79 ( )
.19
1.11 ( )
.14
0.62 ( )
.56
DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; IFN.
This is a meta-analysis that was done looking at 41 studies. These are patients that were treated with either DAAs or with interferon therapy and looking at the patient’s risk of HCC after they achieve SVR. And basically what the study shows is that regardless of whether you got interferon-based therapy or you got a DAA-based therapy, if your HCV is treated and cured, your rate for cancer goes down. So this was very, I think, compelling data to say that we get a benefit in treating our patients in terms of their HCC risk, and there does not appear to be a difference in the ability to reduce that risk of cancer whether you were treated with interferon-based therapy vs DAAs.
Slide credit: clinicaloptions.com
Dore G, et al. EASL Abstract PS-160.

41. De Novo HCC in HCV-Infected Pts Treated With Oral DAAs
Italian pts with HCV and advanced liver disease treated with DAAs and monitored January June 2016
N = 3075
Mean follow-up after starting DAA therapy: days
41 pts developed HCC
HCC incidence analyzed by multivariate Cox regression (forward stepwise selection)
CP A
Cirrhosis F3
Stage of Liver Disease
CP B
Interim Analysis of SVR12 60 20
SVR12 (%)
100 40 80
97.2
92.7
80.0
CP, Child-Pugh; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma.
But we’ve come to understand that de novo HCC still occurs after HCV has been cured, and I think the message is that it’s really important that we continue to do surveillance afterwards. This is a study that looked at patients who’ve been treated with DAAs and then followed to see if they got cancer, and they looked at what factors were associated with getting de novo cancer post-HCV cure.
Slide credit: clinicaloptions.com
Romano A, et al. AASLD Abstract 19.

42. De Novo HCC in HCV-Infected Pts Treated With Oral DAAs
Subgroup
HCC Incidence in Cirrhotic Pts, % per Pt-Yr
P Value
Child-Pugh score A/B
1.64/2.92
.58
DAA regimen
SOF + RBV
LDV/SOF ± RBV
SMV + SOF ± RBV
DCV + SOF ± RBV
OBV/PTV/RTV + DSV ± RBV
3.32
1.45
1.35
1.12
1.88
.90
APRI score < 2.5/≥ 2.5
1.52/3.27
.02
SVR12 no/yes
8.38/1.55
.001
APRI, Aspartate aminotransferase to Platelet Ratio Index; DAA, direct-acting antiviral; DCV, daclatasvir; DSV, dasabuvir; HCC, hepatocellular carcinoma; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response.
And you can see that there’s a trend towards the more severe disease may be a factor, but certainly the drug regimens didn’t have anything to do with it. And the most important thing is that if you achieved SVR, your rate was much lower than if you didn’t achieve SVR.
Slide credit: clinicaloptions.com
Romano A, et al. AASLD Abstract 19.

43. De Novo HCC in HCV-Infected Pts Treated With Oral DAAs
Subgroup
HCC Incidence in Cirrhotic Pts, % per Pt-Yr
P Value
Child-Pugh score A/B
1.64/2.92
.58
DAA regimen
SOF + RBV
LDV/SOF ± RBV
SMV + SOF ± RBV
DCV + SOF ± RBV
OBV/PTV/RTV + DSV ± RBV
3.32
1.45
1.35
1.12
1.88
.90
APRI score < 2.5/≥ 2.5
1.52/3.27
.02
SVR12 no/yes
8.38/1.55
.001
Cirrhotic pts with HCV treated with DAAs are not at increased risk of developing HCC compared with untreated pts
APRI, Aspartate aminotransferase to Platelet Ratio Index; DAA, direct-acting antiviral; DCV, daclatasvir; DSV, dasabuvir; HCC, hepatocellular carcinoma; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response.
These data reinforce the benefit of DAA therapy in terms of reducing HCC risk—that is sort of the take-home message—but also on the other hand, to make sure we know who’s cirrhotic so that they can continue to get surveillance after they’ve achieved cure because the risk doesn’t go to zero.
Slide credit: clinicaloptions.com
Romano A, et al. AASLD Abstract 19.

44. HBV Reactivation During HCV DAA Therapy
DAA, direct-acting antiviral.

45. HBV Reactivation in Pts Receiving HCV DAAs
Case reports of HBV reactivation in pts treated with SMV + SOF ± RBV,[1,2] DCV + ASV,[3,4] and LDV/SOF[5]
Possibly due to loss of host immune response to HBV[6]
29 confirmed cases of HBV reactivation in HCV DAA recipients in ~ 3 yrs (November 2013 to October 2016)[7]
Most cases occurred within 4-8 wks of HCV DAA initiation
October 2016 FDA issued boxed warning
ASV, asunaprevir; DAA, direct-acting antiviral; DCV, daclatasvir; FDA, US Food and Drug Administration; LDV, ledipasvir; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir.
There were case reports of HBV reactivating in patients who were treated with SMV plus SOF with or without ribavirin, daclatasvir plus asunaprevir, and ledipasvir/sofosbuvir. And there was this concept that if you cure someone of hep C and you sort of take away something that’s generating an immune response, that, in fact, you may set the patient up to have an alteration in their host immune response to HBV and get reactivation. And the number of cases coming forward to the FDA was so impressive that, in October of 2016, they actually issued a specific boxed warning about the use of HCV DAAs and monitoring for HBV recurrence.
1. Collins JM, et al. Clin Infect Dis. 2015;61: Ende AR, et al. J Med Case Rep. 2015;9: Hayashi K, et al. Clin J Gastroenterol. 2016;9: Takayama H, et al. Hepatol Res. 2016;46: De Monte A, et al. J Clin Virol. 2016;78: Balagopal A, et al. Clin Infect Dis. 2015;61: Bersoff-Matcha SJ, et al. AASLD Abstract LB-17.
Slide credit: clinicaloptions.com

46. HBV Testing/Monitoring During HCV DAA Therapy
Test all pts initiating HCV therapy for HBsAg, anti-HBc, and anti-HBs
Vaccinate if no HBV markers; follow flow chart below if HBV markers present
HBsAg positive
HBsAg negative;
anti-HBc positive
(± anti-HBs)
HBV DNA detectable
Low or HBV DNA undetectable
HBV DNA meets criteria for treatment in AASLD HBV
guidelines
Monitor for reactivation; treat if HBV DNA level meets AASLD HBV guideline treatment
criteria
“Insufficient data to provide
recommendations”
(Consider HBV
reactivation if clinical symptoms or ALT rise)
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.
So the AASLD/IDSA guidance has specific recommendations, as shown in this diagram. First, it’s recommended that all patients who are initiating HCV treatment need to be tested for hep B: test for hepatitis B surface antigen, anti-HBc, and anti-HBs. If they have no markers, then you should use that opportunity to vaccinate for HBV. If they’re hepatitis B surface antigen positive, then you should test them for HBV DNA. If the HBV DNA is detectable and they meet the usual criteria for treatment of hepatitis B, then they should be treated. And if they have a low level of HBV DNA that doesn’t meet criteria for treatment of their hepatitis B, then you should monitor those individuals for reactivation during the course of their HCV treatment and then treat the HBV if they should meet the guidelines for HBV treatment.
And then for the patient who is hepatitis B surface antigen negative but anti-HBc positive—so has prior HBV exposure—with our without the presence of hepatitis B surface antibody, the guidance document says there are insufficient data to make a recommendation, but just to be aware that this is another group in which there is a need for more data to determine if there is a significant risk for HBV reactivation. But the group to be most aware of is the hepatitis B surface antigen–positive group.
Treat with HBV drug
Slide credit: clinicaloptions.com
AASLD/IDSA. HCV Guidance. April Graphic adapted from Ira M. Jacobson, MD.

47. Conclusions
Multiple current regimens highly effective and safe across genotypes; confirmed in “real-world” studies
GLE/PIB appears poised to be an 8-wk pangenotypic regimen for DAA-naive noncirrhotic pts
Short duration SOF/VEL/VOX not superior to current regimens for DAA-naive pts; likely to find niche in pts with previous DAA failure
GZR/RZR/UPR a promising pangenotypic regimen; phase III trial results awaited
Controversy persists re: HCC recurrence after DAA-induced SVR
Little evidence for spike in de novo HCC after SVR
HBV reactivation very rare in anti-HBc–positive pts; precautions in HBsAg-positive pts especially with HBV viremia
DAA, direct-acting antiviral; GLE, glecaprevir; GT, genotype; HBc, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PIB, pibrentasvir; RZR, ruzasvir; SOF, sofosbuvir; SVR, sustained virologic response; UPR, uprifosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
So just to conclude, where we’ve been and where we are and where we’re going. Multiple current regimens highly effective and safe across genotypes, and although I didn’t show you a lot of real-world data, there are a lot of real-world data that confirm that when you take these drugs that have been shown to produce very good results in clinical trial and then use them in clinical practice, that we get very comparable results. I showed you some of the data around the drugs that are coming out or we anticipate this year, one of them glecaprevir/pibrentasvir. And this appears to be poised to be an 8-week pan-genotypic regimen for our DAA-naive noncirrhotic patients, so I think pretty exciting times where we’ll be able to offer a broad array of patients 8 weeks.
And then the short duration of SOF/VEL/VOX, although not superior to the current regimens for DAA-naive patients, is likely going to find its niche in patients who have been previous DAA treated and have failed, sort of a rescue therapy, it seems to have very high efficacy in that group of patients. And then we have other pan-genotypic regimens that look very promising, and you can anticipate that phase III trial results will be coming forth with those new regimens more in late 2017 and in 2018.
And then I highlighted the controversy around HCC. To me it’s less of a controversy, I think it’s more a recognition that HCC is still an issue even after SVR that we have to be monitoring for. I think there’s little evidence that the DAAs themselves have any influence specifically on the risk of HCC; I think it’s really get cure, you reduce risk, but then you still have risk that remains and you have to monitor.
And then HBV reactivation is very rare in anti-HBc–positive patients—that’s been shown and that’s why there’s not a specific recommendation about doing any monitoring in that group. But remember that the hepatitis B surface antigen–positive patient can potentially reactivate in the context of HCV DAA therapy, so you need to monitor their HBV viremia to determine if you need to treat.

48. Go Online for More CCO Coverage of Viral Hepatitis!
Multimedia modules featuring case-based expert roundtable discussions of key HCV management issues Downloadable slidesets on other important HCV topics, including strategies for managing patients who have experienced HCV DAA failure
clinicaloptions.com/hepatitis