Supplementary AppendixSupplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Foster GR, Afdhal

Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. DOI: 10.1056/NEJMoa1512612

1

Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about

their work.

Supplement to: Graham Foster, Nezam Afdhal, Stuart K. Roberts, et al. Sofosbuvir and

Velpatasvir for HCV Genotype 2 and 3 Infection

2

Table of contents

ASTRAL-2 Study Investigators 3

ASTRAL-3 Study Investigators 4

Table S1. ASTRAL-2: Reasons for screen failure 5

Table S2. ASTRAL-3: Reasons for screen failure 6

Figure S1. Patient disposition: ASTRAL-2 7

Figure S2. Patient disposition: ASTRAL-3 8

Table S3. SVR12 in patient subgroups of ASTRAL-3 9

Table S4. Characteristics of patients receiving SOF-VEL in ASTRAL-3 who did not achieve SVR 11

Figure S3. Rates of SVR12 by baseline resistance-associated variants in ASTRAL-3 12

Table S5. Serious adverse events in ASTRAL-2 13

Table S6. Serious adverse events in ASTRAL-3 14

3

ASTRAL-2 Study Investigators

United States

Nezam Afdhal, Ritu Agarwal, M. Tarek Al-Assi, Michael Bennett, David Bernstein, Raj

Bhandari, Norbert Bräu, Stuart Cohen, Mitchell Davis, Adrian Di Bisceglie, Kyle Etzkorn,

Gregory Everson, Jeffrey Fessel, Steven Flamm, Reem Ghalib, Norm Gitlin, Elliot Godofsky,

Stuart Gordon, William Harlan, Trevor Hawkins, Robert Herring, Federico Hinestrosa, Ira

Jacobson, Eric Lawitz, Anne Luetkemeyer, Giuseppe Morelli, Timothy Morgan, Anders Nyberg,

Neville Pimstone, David Pound, Nancy Reau, Rajender Reddy, Maribel Rodriguez-Torres,

Sergio Rotjer, Peter Ruane, Vinod Rustgi, Michael Ryan, Arun Sanyal, Eugene Schiff, Thomas

Sepe, Obaid Shaikh, Aasim Sheikh, Mitchell Shiffman, Mark Sulkowski, Paul Thuluvath, Myron

Tong, William Towner, Tram Tran, Kimberly Workowski, David Wyles, Ziad Younes

4

ASTRAL-3 Study Investigators

Australia

Wendy Cheng, Greg Dore, Barbara Leggett, Lindsay Mollison, Stephen Pianko, Stuart Roberts,

Simone Strasser, Alexander Thompson,

Canada

Brian Conway, Curtis Cooper, Jordan Feld, Stephen Shafran, Mark Swain, Bernard Willems,

Eric Yoshida

France

Armand Abergel, Laurent Alric, Tarik Asselah, Marc Bourlière, Victor De Ledinghen,

Christophe Hézode, Véronique Loustaud-Ratti, Philippe Mathurin, Stanislas Pol, Didier Samuel,

Fabien Zoulim

Germany

Keikawus Arastéh, Thomas Berg, Guido Gerken, Tobias Goeser, Norbert Gruener, Michael

Manns, Stefan Mauss, Jorg Petersen, Stefan Zeuzem

Italy

Alessandra Mangia, Francesco Mazzotta

New Zealand

Edward Gane, Catherine Stedman

United Kingdom

Kosh Agarwal, Richard Aspinall, Ashley Brown, Jane Collier, Matthew Cramp, Daniel Forton,

Graham Foster, Ray Fox, William Rosenberg, Stephen Ryder, Andrew Ustianowski

United States

Nezam Afdhal, Michael Bennett, Norbert Bräu, Stuart Cohen, Mitchell Davis, Kyle Etzkorn,

Gregory Everson, Steven Flamm, Stuart Gordon, Federico Hinestrosa, Ira Jacobson, Eric Lawitz,

Giuseppe Morelli, Keyur Patel, David Pound, K. Rajender Reddy, Maribel Rodriguez-Torres,

Michael Ryan, Eugene Schiff, Obaid Shaikh, Aasim Sheikh, Mitchell Shiffman, Mark

Sulkowski, William Towner, Tram Tran, Ziad Younes

5

Table S1. Reasons for screen failure: ASTRAL-2

6

Table S2. Reasons for screen failure: ASTRAL-3

7

Figure S1. Patient disposition: ASTRAL-2

317 screened

269 randomized

135 randomized to receive sofosbuvir-velpatasvir

134 randomized to receive sofosbuvir-ribavirin

134 began treatment 132 began treatment

133 completed treatment

134 assessed for efficacy



1 discontinued treatment due to adverse event 1 discontinued treatment: LTFU

48 were not randomized 45 did not meet eligibility criteria 1 withdrew consent 1 were lost to follow-up 1 outside visit window

1 did not begin treatment 2 did not begin treatment

8

Figure S2. Patient disposition: ASTRAL-3

652 screened

558 randomized

278 randomized to receive sofosbuvir-velpatasvir

280 randomized to receive sofosbuvir-ribavirin

277 began treatment 275 began treatment





2 discontinued treatment 1 due to lack of efficacy 1 non-adherence

21 discontinued treatment: 9 adverse event 4 lost to follow-up 3 withdrew consent 2 death

2 non-compliance with study drug 1 lack of efficacy

94 were not randomized 87 did not meet eligibility criteria 6 withdrew consent 1 study enrolment was closed

1 did not begin treatment 5 did not begin treatment

9

Table S3. SVR12 in patient subgroups of ASTRAL-3

10

Table S3. SVR12 in patient subgroups of ASTRAL-3 (continued)

*One patient with HCV genotype 3 had previously received telaprevir with pegylated interferon and ribavirin.

*

(

11

Table S4. Characteristics of patients receiving sofosbuvir-velpatasvir who relapsed in ASTRAL-3

Age Sex Race BMI Geno-type

Cirrhosis IL28B HCV RNA

Timing of VF

HCV treatment history

Resistance-associated variants

NS5A NS5B

BL FU wk 12 BL FU wk12

53 F White 23.7 3a Yes CC 6.9 FU wk 4 Naive Y93H (15.2%) Y93H (>99%) None None

58 M White 24.6 3a Yes CC 6.3 FU wk 12 Experienced None Y93H (>99%) None None

61 M White 25.2 3a Yes CT 6.0 FU wk 12 Naïve Y93H (>99%) Y93H (>99%) None None

61 M White 21.7 3a No TT 5.5 FU wk 4 Experienced None Y93H (>99%) None None

50 M White 28.7 3a No CT 6.5 FU wk 4 Naïve Y93H (>99%) Y93H (>99%) None None

56 M White 26.7 3a Yes TT 6.1 FU wk 4 Experienced None Y93H (>99%) None None

45 M White 30.6 3 No CC 6.9 FU wk 4 Experienced Y93H (2.8%) Y93H (>99%) None None

46 M White 23.9 3a Yes CT 6.1 FU wk 4 Experienced A30K (>99%) A30K (>99%) Y93H (97.2%)

None None

57 M White 26.8 3a Yes CT 6.3 FU wk 4 Naïve None Y93H (>99%) None None

56 M White 28.1 3a Yes CT 6.3 FU wk 4 Experienced None Y93H (>99%) None None

39 M White 22.4 3a No CC 6.6 FU wk 12 Experienced None GT1a reinfection

F denotes female; M male; BMI body mass index; VF virologic failure; BL baseline; FU follow-up.

12

Figure S3. Rates of sustained virologic response by baseline NS5A resistance-associated

variants (1% cutoff) in ASTRAL-3

Legend: Figures show rates of SVR12 in patients with and without NS5A resistance-associated

variants at baseline. Figure S3A shows results in patients with any NS5A resistance-associated

variant. Figure S3B shows results in patients with the Y93H NS5A resistance-associated variant

at baseline.

Figure S3A. Overall

Figure S3B. By the Y93H NS5A resistance-associated variant (1% cutoff)

13

Table S5. Serious adverse events in ASTRAL-2

14

Table S6. Serious adverse events in ASTRAL-3

Supplementary AppendixSupplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Foster GR, Afdhal

Documents