Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368: DOI: /NEJMoa

2 SUPPLEMENTAL INFORMATION NEUTRINO PRINCIPAL INVESTIGATORS 4 FISSION PRINCIPAL INVESTIGATORS.. 4 SUPPLEMENTARY METHODS STUDY DESIGN Eligibility Criteria for NEUTRINO 6 Eligibility Criteria for FISSION. 10 DEFINITION OF VIROLOGIC FAILURE FOR BOTH STUDIES STATISTICAL METHODS NEUTRINO. 14 FISSION.. 14 Multivariate Analysis SUPPLEMENTARY EFFICACY STUDY DISPOSITION Figure S1. Patient Disposition in NEUTRINO Figure S2. Patient Disposition in FISSION Table S1. Reasons for Screen Failures in NEUTRINO (n=128 of 456 screened) Table S2. Reasons for Screen Failures in FISSION (n=139 of 666 screened) ANALYSES OF FACTORS ASSOCIATED WITH SVR12 IN NEUTRINO Table S3. SVR12 by Subgroup in NEUTRINO: Full Analysis Set Table S4. Univariate Analysis of Factors Associated With SVR12 in NEUTRINO Table S5: Multivariate Logistic Regression of Factors Associated With SVR12 in NEUTRINO ANALYSES OF FACTORS ASSOCIATED WITH SVR12 IN FISSION Table S6. SVR12 by Subgroup in FISSION: Full Analysis Set Figure S3. SVR Difference Between SOF and PEG in Stratification Subgroups: FISSION Table S7. Univariate Analysis of Factors Associated With SVR12 in FISSION: Full Analysis Set Table S8. Multivariate Logistic Regression in Assessing Factors Associated With SVR12 in SOF + RBV Patients in FISSION: Full Analysis Set Page 2

3 RESISTANCE IN NEUTRINO AND FISSION NEUTRINO. 27 FISSION SUPPLEMENTARY SAFETY Table S9. All Treatment-Emergent Adverse Events in NEUTRINO Table S10. All Treatment-Emergent Adverse Events in FISSION Figure S4. Treatment-Emergent Adverse Events by System-Organ Class in NEUTRINO Figure S5. Treatment-Emergent Adverse Events by System-Organ Class in FISSION 46 Table S11. Adverse Events Leading to Discontinuation in NEUTRINO 47 Table S12. Serious Adverse Events NEUTRINO 47 Figure S6. Proportional Differences in Treatment-Emergent AEs Occurring in 10% of Patients in SOF + RBV and PEG + RBV Treatment Groups in FISSION Table S13. Adverse Events Leading to Permanent Discontinuation of Both Study Drugs in FISSION Table S14. Serious Adverse Events in FISSION Table S15. Adverse Events by Cirrhosis Status in NEUTRINO Table S16. Adverse Events by Cirrhosis Status in FISSION Figure S7. Hematology Values During Treatment in NEUTRINO Figure S8. Hematology Values During Treatment in FISSION Figure S9. Treatment-Emergent Hematologic Abnormalities by Grade in NEUTRINO Figure S10. Treatment-Emergent Hematologic Abnormalities by Grade in FISSION. 58 Table S17. Patients With Post-baseline Hemoglobin <10 g/dl and <8.5 g/dl by Cirrhosis Status in NEUTRINO Table S18. Patients with Post-Baseline Hemoglobin <10 g/dl and <8.5 g/dl by Cirrhosis Status in FISSION

4 NEUTRINO PRINCIPAL INVESTIGATORS United States Nezam H. Afdhal, Avanish Aggarwal, Leslie Bank, Kimberly Beavers, Nicholaos C. Bellos, Michael T. Bennett, Christopher Christensen, James Cooper, Israel Crespo, Mitchell Davis, Robin Henry Dretler, Richard Elion, Robert Emslie, Kyle Etzkorn, Gregory Everson, Bradley Freilich, Michael Galambos, Joseph Galati, Stuart C. Gordon, Tarek Hassanein, David Hassman, Trevor Hawkins, Robert Herring, Jr., Federico Hinestrosa, Ira M. Jacobson, Kris V. Kowdley, Marcelo Kugelmas, Jay Lalezari, Eric Lawitz, Claudia T. Martorell, Anthony Mills, Giuseppe Morelli, Ronald G. Nahass, Lisa Nyberg, Keyur Patel, Ponni Perumalswami, Gary Poleynard, David Pound, Bruce S. Rashbaum, K. Rajender Reddy, Maribel Rodriguez-Torres, Peter J. Ruane, Vinod K. Rustgi, Michael Ryan, Michael Saag, Eugene R. Schiff, Thomas Sepe, Aasim Sheikh, Mitchell L. Shiffman, Coleman Smith, Mark Sulkowski, Karen T. Tashima, William J. Towner, David Wyles, Ziad Younes FISSION PRINCIPAL INVESTIGATORS Australia Peter Angus, Wendy Cheng, Geoffrey Farrell, Alice Lee, Barbara Leggett, Graeme Macdonald, Gerry McQuillan, Lindsay Mollison, Stuart Roberts, David Shaw, William Sievert, Simone Strasser, Katherine Stuart, Amany Zekry Canada Jeffrey Axler, Magdy Elkhashab, Alnoor Ramji, Morris Sherman, Saya Victor Feinman Italy Alessandra Mangia The Netherlands H.W. Reesink New Zealand Ed Gane, Katherine Grimwade, Michael Shultz, Nigel Stace, Catherine Stedman, Frank Weilert Sweden Ola Weiland, Rune Wejstal 4

5 United States George Abraham, Gary Abrams, Nezam Afdhal, Avanish Aggarwal, Kimberly Beavers, Michael Bennett, David Bernstein, Israel Crespo, Gary Davis, Mitchell Davis, Douglas Dieterich, Pedram Enayati, Kyle Etzhorn, Franco Felizarta, Joseph Galati, Rheem Ghalib, Alexandra Gibas, Robert Gish, Norman Gitlin, Eliot Godofsky, Stuart Gordon, Sinikka Green, Tarek Hassanein, Trevor Hawkins, Robert Herring, Federico Hinestrosa, Ira Jacobson, Donald Jensen, Zeid Kayali, Kris Kowdley, Marcelo Kugelmas, Jay Lalezari, Eric Lawitz, Benedict Maliakkal, Paul Manos, Claudia Martorell, Omar Massoud, Gary Matusow, Andrew Muir, Ronald Nahass, Tuan Nguyen, Gary Poleynard, David Pound, Mordechai Rabinovitz, Natarajan Ravendhran, Robert Reindollar, Maribel Rodriguez-Torres, Lorenzo Rossaro, Peter Ruane, Vinod Rustgi, Michael Ryan, John Santoro, Eugene Schiff, Paul Schleinitz, Thomas Sepe, Aasim Sheikh, Kenneth Sherman, Lawrence Stein, Gyongyi Szabo, Boris Yoffe, Ziad Younes 5

6 SUPPLEMENTARY METHODS STUDY DESIGN Eligibility Criteria for NEUTRINO Inclusion Criteria Subjects were to meet all of the following inclusion criteria to be eligible for participation in this study: 1. Willing and able to provide written informed consent 2. Male or female aged 18 years 3. Confirmation of chronic hepatitis C virus (HCV) infection documented by either: a) A positive anti-hcv antibody test, positive HCV RNA, or positive HCV genotyping test 6 months prior to the Baseline/Day 1 visit; or b) A liver biopsy performed prior to the Baseline/Day 1 visit with evidence of chronic HCV infection. 4. Infection with chronic genotype 1, 4, 5, or 6 HCV infection as determined at Screening 5. HCV RNA 10 4 IU/mL at Screening 6. Cirrhosis determination a) Cirrhosis is defined as any one of the following: Liver biopsy showing cirrhosis Fibroscan (in countries where locally approved) showing cirrhosis or results >12.5 kpa A FibroTest score of >0.75 and an aspartate aminotransferase (AST):platelet ratio index (APRI) of >2 during Screening b) Absence of cirrhosis is defined as any one of the following: Liver biopsy within 2 years of Screening showing absence of cirrhosis Fibroscan (in countries where locally approved) with a result of 12.5 kpa within 6 months of Baseline/Day 1 A FibroTest score of 0.48 and APRI of 1 during Screening In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required. Liver biopsy results supersede the results obtained by Fibroscan or FibroTest. 6

7 7. Liver imaging within 6 months of Baseline/Day 1 to exclude hepatocellular carcinoma is required in patients with cirrhosis. 8. HCV treatment naïve: defined as no prior treatment with interferon or ribavirin (RBV) 9. Body mass index (BMI) 18 kg/m Screening electrocardiogram (ECG) without clinically significant abnormalities 11. Subjects must have the following laboratory parameters at screening: a) Alanine aminotransferase (ALT) 10 x the upper limit of normal (ULN) b) AST 10 x ULN c) Hemoglobin (Hgb) 12 g/dl for male, 11 g/dl for female subjects d) White blood cell count 2500/µL e) Absolute neutrophil count 1500/µL (or 1000/µL if considered a physiologic variant in a subject of African descent) f) Platelets 90,000/µL g) International Normalized Ratio 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting International Normalized Ratio h) Albumin 3 g/dl i) Direct bilirubin 1.5 x ULN j) Thyroid-stimulating hormone (TSH) ULN k) HgbA1c 10% l) Creatinine clearance 60 ml/min, as calculated by the Cockcroft-Gault equation 12. Subject has not been treated with any investigational drug or device within 30 days of Screening visit 13. A female subject is eligible to enter the study if it is confirmed that she is: a) Not pregnant or nursing; b) Of nonchildbearing potential (ie, women who have had a hysterectomy, have both ovaries removed or medically documented ovarian failure, or are postmenopausal women >50 years of age with cessation [for 12 months] of previously occurring menses); or c) Of childbearing potential (ie, women who have not had a hysterectomy, both ovaries removed, or medically documented ovarian failure). Women aged 50 years with amenorrhea will be considered to be of childbearing potential. These women must have a 7

8 negative serum pregnancy test at Screening and a negative urine pregnancy test on the Baseline/Day 1 visit prior to enrollment, and agree to one of the following from 3 weeks prior to Baseline/Day 1 until 6 months after the last dose of RBV: Complete abstinence from intercourse Consistent and correct use of 1 of the following methods of birth control, in addition to a male partner who correctly uses a condom, from the date of screening until 6 months after the last dose of RBV: Implants of levonorgestrel Injectable progesterone Any intrauterine device with a documented failure rate <1% per year Oral contraceptives (either combined or progesterone only) Female barrier method: cervical cap or diaphragm with spermicidal agent Contraceptive vaginal ring Transdermal contraceptive patch Tubal sterilization Vasectomy in male partner 14. All male study participants must agree to consistently and correctly use a condom while their female partner agrees to use 1 of the methods of birth control listed above from the date of Screening until 7 months after their last dose of RBV 15. Male subjects must agree to refrain from sperm donation for 7 months after the last dose of RBV 16. Subjects must be of generally good health as determined by the Investigator 17. Subjects must be able to comply with the dosing instructions for study drug administration and to complete the study schedule of assessments Exclusion Criteria Subjects who meet any of the following exclusion criteria are not to be enrolled in this study: 1. Prior treatment for HCV with an interferon or RBV 2. Prior exposure to a direct-acting antiviral targeting the HCV NS5B polymerase 3. Pregnant or nursing female, or male with pregnant female partner 8

9 4. Chronic liver disease of a non-hcv etiology (eg, hemochromatosis, Wilson s disease, α1 antitrypsin deficiency, cholangitis) 5. Infection with hepatitis B virus (HBV) or HIV 6. Contraindications for pegylated interferon (PEG) or RBV therapy 7. Pre-existing significant psychiatric conditions including severe depression, severe bipolar disorder, and schizophrenia. Other psychiatric disorders are permitted if the condition is well controlled with a stable treatment regimen for 1 year from Screening 8. Presence of autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, psoriasis of greater than mild severity) 9. Severe chronic obstructive pulmonary disease (eg, forced expiratory volume in 1 second 50% predicted value) 10. History of significant cardiac disease (including myocardial infarction based on ECG and/or clinical history) 11. History of clinically significant retinal disease 12. History of clinically significant hemoglobinopathy (eg, sickle cell disease, thalassemia) 13. History of malignancy diagnosed or treated within 5 years (recent localized treatment of squamous or noninvasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to Screening). Subjects under evaluation for malignancy are not eligible 14. Chronic use of systemically administered immunosuppressive agents (eg, prednisone equivalent >10 mg/d) 15. Clinically relevant drug or alcohol abuse within 12 months of Screening. A positive drug screen will exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the Investigator 16. History of solid organ transplantation 17. Current or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, or variceal hemorrhage) 18. History of clinically significant illness or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with protocol 19. History of a gastrointestinal disorder (or postoperative condition) that could interfere with absorption of study drug 9

10 20. History of porphyria 21. Excessive alcohol ingestion, defined as >3 glasses/d (1 glass is equivalent to beer 284 ml, wine 125 ml, or distilled spirits 25 ml for females and >4 glasses/d for males) 22. History of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy 23. Donation or loss of >400 ml of blood within 2 months prior to Baseline/Day Use of any prohibited concomitant medications within 28 days of the Baseline/Day 1 visit 25. Known hypersensitivity to PEG, RBV, the study investigational medicinal product, the metabolites, or formulation excipients Eligibility Criteria for FISSION Inclusion Criteria 1. Males or females aged 18 years, or the legal age of consent, whichever is older, at Screening. Subjects or their heterosexual partner(s) must either be of nonchildbearing potential or use effective contraception from 2 weeks before the initiation of therapy until 6 months (or the duration recommended locally for RBV if longer) after the last dose of study medication. Nonchildbearing potential (ie, physiologically incapable of becoming pregnant) is defined as including any female or male who: a) Has had a hysterectomy; b) Has had a bilateral oophorectomy (ovariectomy); c) Is postmenopausal (a demonstration of a total cessation of menses for 1 year; FSH will be performed to confirm postmenopausal status); d) Has had a bilateral tubal ligation or fallopian tube inserts; e) Has had a vasectomy; or f) Is a sterile male or female. Effective contraception is defined as using at least two of the following at least one of which must be a barrier method: a) Use of an intrauterine device b) Use of an oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 10

11 c) Use of a barrier method: a male or female condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicidal foam/gel/film/cream/suppository 2. Chronic genotype 2 or 3 HCV infection documented by 1 measurement of serum HCV RNA 10,000 IU/mL measured during Screening and 1 of the following: a) A positive anti-hcv antibody, HCV RNA, or HCV genotype test 6 months prior to Baseline/Day 1 visit, together with positive HCV RNA test and anti-hcv antibody at the time of Screening b) A positive HCV RNA test and anti-hcv antibody test at the time of Screening, together with either a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of chronic HCV, such as the presence of fibrosis) 3. Patients with Childs A cirrhosis may be included (up to 20% of patients randomized). Cirrhosis is defined as any one of the following: a) Any biopsy (or transient elastography, where locally approved) showing cirrhosis b) Where approved by the local ethics committee, transient elastography performed during Screening with a result of >12.5 kpa c) A FibroSure score of >0.75 and APRI of >2 performed during Screening Absence of cirrhosis is defined as one of the following: a) A liver biopsy performed within 24 calendar months of Day 1 showing absence of cirrhosis b) Where approved by the local regulatory agency, transient elastography performed within 12 calendar months preceding Day 1 with a result of 12.5 kpa c) A FibroSure score of 0.48 and APRI of 1 performed during Screening In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required. 4. Subjects must be naïve to all HCV antiviral treatments, including but not limited to immunomodulatory and nucleoside/tide treatments for chronic HCV infection. 5. BMI of 18 kg/m 2 6. Otherwise suitable for participation as determined by the medical history, physical examination, ECG, and clinical laboratory measurements performed at Screening 11

12 7. Able to effectively communicate with the Investigator and other center personnel; willing to give written informed consent and comply with the study restrictions and requirements Exclusion Criteria 1. Positive test at Screening for hepatitis B surface antigen, anti-hepatitis B core antigen immunoglobulin-m antibody, or anti-hiv antibody 2. History of any other clinically significant chronic liver disease (eg, hemochromatosis, autoimmune hepatitis, Wilson s disease, α1-antitrypsin deficiency, alcoholic liver disease, and toxin exposures) 3. History of consistent decompensated liver disease, including ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, and hepatopulmonary syndrome, among others 4. History or current evidence of psychiatric illness, immunologic disorder, hemoglobinopathy, pulmonary disease (including pneumonia or pneumonitis), cardiac disease, seizure disorder or anticonvulsant use, poorly controlled diabetes, cancer, or history of malignancy, which in the opinion of the Investigator makes the patient unsuitable for the study. Chronic medical conditions, especially if treated with medications (such as hypertension), must be stable at the time of Screening. No new therapies should be started prior to the study that may confound the assessment of study drug safety 5. Clinical signs and symptoms of acute pancreatitis with elevated lipase 6. Clinically significant ECG findings at Screening, Screening corrected QT interval 450 ms (noncirrhotic) or 500 ms (cirrhotic), or personal or family history of Torsades de pointes 7. History of major organ transplantation with an existing functional graft 8. Active substance abuse, which in the opinion of the Investigator would make the candidate inappropriate for participation in this study 9. History of uncontrolled thyroid disease or abnormal TSH levels (<0.8 x LLN or >1.2 x ULN) at Screening (subjects will be eligible with an abnormal TSH if the T3 and T4 are within normal limits) 10. Abnormal hematologic and biochemical parameters, including: a) Neutrophil count <1500 cells/mm 3 (or <1250 cells/mm 3 for African-American/black subjects or cirrhotic patients) 12

13 b) Hgb <11 g/dl in females or <12 g/dl in males c) Platelet count 90,000 cells/mm 3 (noncirrhotic) or 75,000 cells/mm 3 (cirrhotic) d) Creatinine 1.5 x ULN e) Estimated glomerular filtration rate, calculated by the Chronic Kidney Disease- Epidemiology Collaboration equation, <60 ml/min/1.73 m 2 f) ALT or AST 10 x ULN g) Total bilirubin 1.5 x ULN (except patients with Gilbert s syndrome) h) Albumin 3.2 g/dl 11. Donation or loss of >400 ml of blood within 2 months prior to first dose administration 12. History of clinically significant drug allergy to nucleoside/nucleotide analogs 13. History of having received any systemic antineoplastic or radiation therapy within 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study 14. Subjects receiving oral or intravenous strong p-glycoprotein inhibitors (including cyclosporine, quinidine, dronedarone, itraconazole, verapamil, or ritonavir) within 28 days of dosing 15. Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to first dose administration 16. Pregnant/breastfeeding women or males whose partners are currently pregnant 17. Poor venous access making the patient unable to complete the required laboratory testing schedule DEFINITION OF VIROLOGIC FAILURE FOR BOTH STUDIES Virologic failure is defined as confirmed HCV RNA LLOQ after 2 consecutive HCV RNA <LLOQ, confirmed >1 log 10 increase in HCV RNA from on-treatment nadir, HCV RNA levels persistently LLOQ after 8 weeks of treatment, or HCV RNA LLOQ during the post-treatment period having achieved HCV RNA <LLOQ at end of treatment. 13

14 STATISTICAL METHODS NEUTRINO The hypothesis was that patients treated with SOF + PEG and RBV for 12 weeks would have a rate of sustained virologic response at 12 weeks (SVR12) after treatment >60%. The primary efficacy endpoint is HCV RNA < lower limit of quantification 12 weeks after cessation of therapy in the full analysis set population. Any subject with missing data due to premature discontinuation of the study medication will be considered a failure at the time points on or following the date of discontinuation. The primary endpoint will be tested using a two-sided onesample binomial test to determine if a 60% rate can be ruled out at the 0.05 significance level. A sample size of 300 subjects will provide 90% power to detect a 9% improvement in SVR12 rate from 60% to 69% using a two-sided one-sample binomial test at the 0.05 significance level. The basis for this 60% SVR null rate is derived from: 1) a historical SVR rate of ~65% calculated from the telaprevir (ADVANCE study) and boceprevir (SPRINT2 study) data after adjusting for the expected proportion of subjects with cirrhosis (~20%) in this study; and 2) a 5% trade-off in efficacy exchanged for an expected improved safety profile and shorter duration of treatment. The weighted average of the telaprevir and boceprevir data is estimated to be ~70% in noncirrhotic subjects and 44% in cirrhotic subjects. The SVR rate for the historical control in this study (ie, a patient population of 80% noncirrhotics and 20% cirrhotics) is then calculated to be ~65% (ie, % %). As noted above, the 60% null SVR rate is obtained after allowing for a 5% trade-off in efficacy exchanged for an expected improved safety profile and shorter treatment duration. FISSION Noninferiority will be demonstrated (or null hypothesis will be rejected) if the lower bound of the 95% confidence interval for the stratum-adjusted difference in proportions (SOF + RBV minus PEG + RBV) for SVR12 is > -15%. If noninferiority is demonstrated, the P value for a Cochran-Mantel-Haenszel test stratified by HCV genotype, screening HCV RNA, and cirrhosis status will be calculated to test for superiority of SOF + RBV over PEG + RBV. Superiority will be demonstrated if the two-sided P value is <0.05. Based on the selected noninferiority margin of 15%, a sample size of 250 per arm provided greater than 95% power at the 2.5% significance level (ie, by using one-sided 97.5% confidence intervals to assess noninferiority), assuming the 14

15 rate of SVR was 75% in the control arm and 75% in the SOF arm. A sample size of 250 per arm provided at least 90% power to detect a 12% difference between groups for SVR using a twosided chi-square test at the 0.05 significance level, and assuming an SVR rate of 75% in the control arm. Multivariate Analysis Multivariate logistic-regression (prespecified exploratory) analyses were performed for patients who took sofosbuvir and ribavirin to study which variables were associated with higher rates of SVR. A stepwise procedure was used to identify independent predictors of SVR (with P = 0.10 as the threshold level for variables to be entered into and P = 0.05 for those to be retained in the final model). All baseline clinical/demographic factors delineated in the univariate logistic regression model in Tables S4 and S7 were candidate variables for inclusion in the multivariate model using the stepwise procedure described above. 15

16 SUPPLEMENTARY EFFICACY STUDY DISPOSITION Figure S1. Patient Disposition in NEUTRINO 327 were enrolled and received study drugs 7 discontinued treatment 5 due to AEs 1 consent withdrawn 1 incarceration 320 completed treatment 2 never entered follow-up 1 had early out-of-window follow-up Wk 4 visit 324 returned for Wk 4 post-treatment visit SVR4 in 301/327 (92%) 301 achieved SVR4 and returned for Wk 12 post-treatment visit SVR12 in 295/327 (90%) Total Subjects screened, n 456 Screen failure subjects who were not randomized, n 128 Subjects enrolled, n 328 Subjects enrolled but never treated, n 1 Subjects in safety analysis set, n 327 Subjects in full analysis set, n 327 Study treatment status, n (%) Completed study treatment 320 (98) Discontinued study treatment 7 (2) Reason for premature discontinuation of study treatment, n (%) AE 5 (2) Protocol violation 1 (<1) Subject withdrew consent 1 (<1) AE, adverse event; SVR4/12, sustained virologic response at Week 4/12. 16

17 Figure S2. Patient Disposition in FISSION 527 underwent randomization 263 were assigned to SOF + RBV for 12 wk 256 received assigned treatment 7 were not treated 3 GT 1 patients were excluded from FAS 11 discontinued treatment 3 due to AEs 1 due to viral failure 2 were lost to follow-up 1 death 1 consent withdrawn 3 other 245 completed treatment 7 never entered follow-up 5 lost to follow-up 1 death 1 consent withdrawn 246/253 returned for Wk 4 post-treatment visit SVR4 in 187/253 (74%) 7 discontinued study 4 consent withdrawn 2 start other HCV treatment 1 lost to follow-up 264 were assigned to PEG + RBV for 24 wk 243 received assigned treatment 21 were not treated 54 discontinued treatment 26 due to AEs 17 due to viral failure 5 lost to follow-up 2 consent withdrawn 4 other 189 completed treatment 10 never entered follow-up 7 lost to follow-up 3 consent withdrawn 233 with Wk 4 posttreatment assessment SVR4 in 181/243 (74%) 8 discontinued study 5 viral failure 1 consent withdrawn 1 lost to follow-up 1 death 239/253 returned for Wk 12 posttreatment visit SVR12 in 170/253 (67%) 225/243 returned for Wk 12 posttreatment visit SVR12 in 162/243 (67%) SOF + RBV PEG + RBV Total Subjects screened, n 666 Subjects rescreened, n 11 Screen failure subjects who were not randomized, n 139 Subjects randomized, n Subjects randomized but never treated, n Subjects in safety analysis set, n Subjects in full analysis set, n Subjects in per-protocol analysis set, n Study treatment status, n (%) Completed 245 (96) 189 (78) 434 (87) Discontinued 11 (4) 54 (22) 65 (13) AEs, adverse events; FAS, full-analysis set; GT, genotype; HCV, hepatitis C virus; PEG, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir. 17

18 Table S1. Reasons for Screen Failures in NEUTRINO (n=128 of 456 screened) Screen failure patients who did not meet criteria Inclusion criteria 50 Lab parameters at screening: ALT 10xULN, AST 10xULN, Hgb 12 g/dl (M) & 11 g/dl (F), WBC 2500/uL, ANC 50 ( 49.0%) 1500/uL, Platelets 90000/uL, INR 1.5, Albumin 3 g/dl, Direct bilirubin 1.5xULN 17 Infection with chronic genotype 1, 4, 5, or 6 HCV infection as determined at screening 7 HCV RNA 10 4 IU/mL at screening 7 Cirrhosis determination at screening 2 Confirmation of chronic HCV infection 1 Willing and able to provide written informed consent 1 Liver imaging within 6 months of Baseline/Day 1 in patients with cirrhosis 1 HCV treatment naive; defined as no prior treatment with IFN or RBV 1 Screening ECG without clinically significant abnormalities 1 Subject must be of generally good health as determined by the Investigator Exclusion criteria 12 Clinically-relevant drug or alcohol abuse within 12 months of screening 3 Pre-existing significant psychiatric condition(s) including severe depression, sever bipolar disorder, and 3 (2.9%) schizophrenia 3 History of clinically-significant illness or any other major medical disorder that may interfere with subject 3 (2.9%) treatment, assessment, or compliance with the protocol 2 Prior treatment for HCV with an interferon or RBV 2 Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) 1 Contraindications for PEG or RBV therapy 1 Presence of autoimmune disorders 1 History of significant cardiac disease 1 History of malignancy diagnosed or treated within 5 years 1 History of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy Screen failure patients who did meet criteria Reason 18 Subject withdrew consent 4 Study enrollment closed 2 Lost to follow-up 1 Adverse event 1 Investigators discretion 18

19 Table S2. Reasons for Screen Failures in FISSION (n=139 of 666 screened) Screen failure patients who did not meet criteria Inclusion criteria 51 Chronic Genotype 2 or 3 HCV-infection documented by at least one measurement of serum HCV RNA 10,000 IU/mL measured during Screening and at least one of two positive HCV tests 15 Able to effectively communicate with the Investigator and other center personnel. Willing to give written informed consent and comply with the study requirements 11 History or current disease that makes the patient unsuitable for the study. If treated with medications, must be stable at screening. No new therapies 8 Patients with Childs A cirrhosis may be included (up to 20% of patients randomized). In the absence of a definitive diagnosis of cirrhosis, a liver biopsy is required 7 Otherwise suitable for participation as determined by the medical history, physical examination, ECG, and clinical laboratory measurements performed at Screening 6 Positive test at Screening for HBsAg, anti-hbc IgM Ab, or anti-hiv Ab 3 Clinically significant ECG findings at screening, screening QTc 450 ms (non-cirrhotic) or 500 ms (cirrhotic), or a personal or family history of Torsades de pointes 2 18-year old at Screening. Patients/their heterosexual partner(s) must be of nonchildbearing potential or use contraception from 2 weeks before therapy to 6 months after therapy 2 A history of consistent decompensated liver disease 1 History of any other clinically significant chronic liver disease 1 Clinical signs and symptoms of acute pancreatitis with elevated lipase Exclusion criteria 29 Abnormal hematological and/or biochemical parameters 7 History of uncontrolled thyroid disease or abnormal TSH levels (<0.8 x LLN or >1.2 x ULN [eligible if T3 and T4 w/in normal]) at Screening 3 Active substance abuse which, in the opinion of the investigator, would make the candidate inappropriate for participation in this study 3 Poor venous access making the patient unable to complete the required laboratory testing schedule 2 Pregnant/Breastfeeding women or males whose partners are currently pregnant Screen failure patients who did meet criteria Reason 3 Screen failure patients who met eligibility criteria 19

20 ANALYSES OF FACTORS ASSOCIATED WITH SVR12 IN NEUTRINO Table S3. SVR12 by Subgroup in NEUTRINO: Full Analysis Set Subgroup, n (%) SOF + PEG + RBV (N = 327) Overall 295/327 (90.2) Age at baseline Sex Race <50 yr 104/110 (94.5) 95% CI 88.5, yr 191/217 (88.0) 95% CI 82.9, 92.0 Male 184/209 (88.0) 95% CI 82.9, 92.1 Female 111/118 (94.1) 95% CI 88.2, 97.6 Black 47/54 (87.0) 95% CI 75.1, 94.6 Nonblack 248/273 (90.8) Ethnicity 95% CI 86.8, 94.0 Hispanic/Latino 42/46 (91.3) 95% CI 79.2, 97.6 Not Hispanic/Latino 253/281 (90.0) Cirrhosis 95% CI 85.9, 93.3 No 252/273 (92.3) 95% CI 88.5, 95.2 Yes 43/54 (79.6) HCV GT 95% CI 66.5, 89.4 GT 1 (1a, 1b, 1a/b) 261/292 (89.4) 95% CI 85.3, 92.7 GT 1a 206/225 (91.6) 95% CI 87.1, 94.8 GT 1b 54/66 (81.8) 20

21 95% CI 70.4, 90.2 GT 4, 5, 6 34/35 (97.1) 95% CI 85.1, 99.9 Baseline HCV RNA <6 log 10 IU/mL 68/71 (95.8) 95% CI 88.1, log 10 IU/mL 227/256 (88.7) 95% CI 84.1, 92.3 Baseline BMI <30 kg/m 2 184/198 (92.9) 95% CI 88.4, kg/m 2 111/129 (86.0) 95% CI 78.8, 91.5 Baseline ALT IL28B 1.5 x ULN 145/161 (90.1) 95% CI 84.4, 94.2 >1.5 x ULN 150/166 (90.4) 95% CI 84.8, 94.4 CC 93/95 (97.9) 95% CI 92.6, 99.7 Non-CC 202/232 (87.1) 95% CI 82.1, 91.1 Hepatitis C virus (HCV) RNA analyzed using Roche TaqMan V 2.0 assay for use with High Pure system with limit of quantitation 25 IU/mL. If cirrhosis status was missing, then cirrhosis = No for purposes of analysis unless cirrhosis was documented postbaseline. A missing sustained virologic response at Week 12 (SVR12) value was imputed as a success if it was bracketed by values that were termed successes (ie, <lower limit of quantitation [LLOQ] target not detected or <LLOQ detected ); otherwise, the missing SVR12 value was imputed as a failure. The exact 95% confidence interval (CI) for the proportion was based on the Clopper-Pearson method. ALT, alanine transaminase; BMI, body mass index; GT, genotype; PEG, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir; ULN, upper limit of normal. 21

22 Table S4. Univariate Analysis of Factors Associated With SVR12 in NEUTRINO Variable Odds Ratio Confidence Limit P Value Age: < vs 50 yr (0.941, 5.916) Sex: female vs male (0.902, 5.146) Race: black vs non-black (0.277, 1.655) 0.39 Ethnicity: Hispanic or Latino vs non-hispanic or Latino (0.388, 3.482) 0.79 Cirrhosis: no vs yes (1.383, 6.819) Baseline HCV: < vs 6 log 10 IU/mL (0.855, 9.794) Baseline HCV RNA (IU/mL): < vs 800, (0.853, ) IL28 category: CC vs non-cc (1.616, ) HCV genotype: 1a vs other (0.041, 2.461) HCV genotype: 1b vs other (0.016, 1.064) Baseline BMI: < vs 30 kg/m (1.02, 4.454) Baseline ALT: vs >1.5 x ULN (0.466, 2.005) 0.93 Adherence rate: < vs (0.286, 1.406) 0.26 Baseline GGT (0.993, 1) RBV exposure, mg/kg/d (1.107, 1.557) ALT, alanine transaminase; BMI, body mass index; GGT, γ-glutamyltransferase; HCV, hepatitis C virus; RBV, ribavirin; SVR12, sustained virologic response at Week 12; ULN, upper limit of normal. Table S5. Multivariate Logistic Regression of Factors Associated With SVR12 in NEUTRINO Variable Odds Ratio Confidence Limit P Value Cirrhosis: no vs yes (1.662, 9.265) IL28B: CC vs non-cc (1.815, ) RBV exposure, mg/kg/d (1.153, 1.662) RBV, ribavirin; SVR12, sustained virologic response at Week

23 ANALYSES OF FACTORS ASSOCIATED WITH SVR12 IN FISSION Table S6. SVR12 by Subgroup in FISSION: Full Analysis Set Subgroup SOF + RBV (n = 253) PEG + RBV (n = 243) SOF + RBV vs PEG + RBV/ Prop Diff (95% CI) Overall 170/253 (67.2%) 162/243 (66.7%) 0.3% (-7.5%, 8.0%) Age at baseline Sex Race <50 yr 80/126 (63.5%) 86/118 (72.9%) -9.4% (-21.1%, 2.4%) 95% CI 54.4%, 71.9% 63.9%, 80.7% 50 yr 90/127 (70.9%) 76/125 (60.8%) 10.1% (-1.7%, 21.8%) 95% CI 62.1%, 78.6% 51.7%, 69.4% Male 103/168 (61.3%) 96/156 (61.5%) -0.2% (-10.9%, 10.4%) 95% CI 53.5%, 68.7% 53.4%, 69.2% Female 67/85 (78.8%) 66/87 (75.9%) 3.0% (-9.8%, 15.7%) 95% CI 68.6%, 86.9% 65.5%, 84.4% Black 9/12 (75.0%) 2/5 (40.0%) 35.0% (-17.8%, 76.6%) 95% CI 42.8%, 94.5% 5.3%, 85.3% Nonblack 161/241 (66.8%) 160/238 (67.2%) -0.4% (-9.0%, 8.0%) Ethnicity 95% CI 60.5%, 72.7% 60.9%, 73.2% Hispanic/Latino 29/40 (72.5%) 20/31 (64.5%) 8.0% (-14.2%, 30.5%) 95% CI 56.1%, 85.4% 45.4%, 80.8% Not Hispanic/Latino 141/213 (66.2%) 142/212 (67.0%) -0.8% (-10.0%, 8.3%) Cirrhosis 95% CI 59.4%, 72.5% 60.2%, 73.3% No 147/204 (72.1%) 143/193 (74.1%) -2.0% (-10.8%, 6.8%) 95% CI 65.4%, 78.1% 67.3%, 80.1% Yes 23/49 (46.9%) 19/50 (38.0%) 8.9% (-11.0%, 28.3%) HCV GT 95% CI 32.5%, 61.7% 24.7%, 52.8% GT 2 68/70 (97.1%) 52/67 (77.6%) 19.5% (8.4%, 31.5%) 95% CI 90.1%, 99.7% 65.8%, 86.9% GT 3 102/183 (55.7%) 110/176 (62.5%) -6.8% (-17.1%, 3.5%) 95% CI 48.2%, 63.1% 54.9%, 69.7% Baseline HCV RNA <6 log 10 IU/mL 80/107 (74.8%) 71/106 (67.0%) 7.8% (-4.6%, 20.0%) 95% CI 65.4%, 82.7% 57.2%, 75.8% 6 log 10 IU/mL 90/146 (61.6%) 91/137 (66.4%) -4.8% (-16.1%, 6.5%) 95% CI 53.2%, 69.6% 57.9%, 74.3% 23

24 Table S6. SVR12 by Subgroup in FISSION: Full Analysis Set (continued) Subgroup Baseline BMI SOF + RBV (n = 253) PEG + RBV (n = 243) SOF + RBV vs PEG + RBV/ Prop Diff (95% CI) <30 kg/m 2 120/176 (68.2%) 117/172 (68.0%) 0.2% (-9.7%, 10.1%) 95% CI 60.8%, 75.0% 60.5%, 74.9% 30 kg/m 2 50/77 (64.9%) 45/71 (63.4%) 1.6% (-14.3%, 17.1%) Region 95% CI 53.2%, 75.5% 51.1%, 74.5% Non-US 48/91 (52.7%) 58/92 (63.0%) -10.3% (-24.5%, 4.3%) 95% CI 42.0%, 63.3% 52.3%, 72.9% US 122/162 (75.3%) 104/151 (68.9%) 6.4% (-3.6%, 16.4%) 95% CI 67.9%, 81.7% 60.8%, 76.2% Baseline ALT IL28B 1.5 x ULN 82/116 (70.7%) 70/97 (72.2%) -1.5% (-13.7%, 11.0%) 95% CI 61.5%, 78.8% 62.1%, 80.8% >1.5 x ULN 88/137 (64.2%) 92/146 (63.0%) 1.2% (-10.1%, 12.7%) 95% CI 55.6%, 72.2% 54.6%, 70.8% CC 74/106 (69.8%) 82/106 (77.4%) -7.5% (-19.5%, 4.4%) 95% CI 60.1%, 78.3% 68.2%, 84.9% Non-CC 96/145 (66.2%) 79/136 (58.1%) 8.1% (-3.5%, 19.5%) 95% CI 57.9%, 73.8% 49.3%, 66.5% Study drug completer Yes 169/242 (69.8%) 147/189 (77.8%) -7.9% (-16.2%, 0.5%) 95% CI 63.6%, 75.5% 71.2%, 83.5% No 1/11 (9.1%) 15/54 (27.8%) -18.7% (-36.2%, 15.4%) 95% CI 0.2%, 41.3% 16.5%, 41.6% Hepatitis C virus (HCV) RNA analyzed using Roche TaqMan V 2.0 assay for use with High Pure system with limit of quantitation 25 IU/mL. If cirrhosis status was missing, then cirrhosis = No for purposes of analysis unless cirrhosis was documented postbaseline. A missing sustained virologic response at Week 12 (SVR12) value was imputed as a success if it was bracketed by values that were termed successes (ie, <lower limit of quantitation [LLOQ] target not detected or <LLOQ detected ); otherwise, the missing SVR12 value was imputed as a failure. The exact 95% confidence interval (CI) for the proportion within treatment group and subgroup was based on the Clopper- Pearson method. For the overall result, difference in proportions and associated 95% CI were calculated based on stratum-adjusted Mantel-Haenszel proportions. For subgroups, the 95% CI on the difference was based on the exact method (standardized statistic and inverting two 1-sided tests). ALT, alanine transaminase; BMI, body mass index; GT, genotype; PEG, pegylated interferon; Prop Diff, proportional difference; RBV, ribavirin; SOF, sofosbuvir; ULN, upper limit of normal. 24

25 Figure S3. SVR Difference Between SOF+RBV and PEG+RBV in Stratification Subgroups: FISSION Note: for the overall result, differences in proportions and associated 95% CI were calculated based on stratum-adjusted Mantel-Haenszel proportions. Relative to the vertical line at 0, differences on the right favor SOF + RBV and differences on the left favor PEG + RBV. For each stratum, the 95% CI on the difference was based on the exact method (standardized statistic and inverting two 1-sided tests). 25

26 Table S7. Univariate Analysis of Factors Associated With SVR12 in FISSION: Full Analysis Set Variable Odds Ratio 95% Confidence Limit 2-Sided P Value Age: < vs 50 yr (0.422, 1.211) 0.21 Sex: female vs male (1.282, 4.306) Race: black vs non-black (0.393, 5.657) 0.56 Ethnicity: Hispanic or Latino vs non-hispanic or Latino (0.636, 2.849) 0.44 Cirrhosis: no vs yes (1.538, 5.522) Baseline HCV RNA: < vs 6 log 10 IU/mL (1.064, 3.192) Baseline HCV RNA (IU/mL): < vs 800, (0.816, 2.461) 0.22 IL28B: CC vs non-cc (0.652, 1.892) 0.70 HCV genotype: 2 vs (6.422, ) <0.001 Baseline BMI: < vs 30 kg/m (0.657, 2.037) 0.61 Baseline ALT: vs >1.5 x ULN (0.790, 2.284) 0.28 Adherence to both drugs: < vs 80% (0.317, 1.449) 0.32 HOMA-IR: vs > (0.634, 1.897) 0.74 RBV exposure, mg/kg/d (1.027, 1.300) ALT, alanine transaminase; BMI, body mass index; HCV, hepatitis C virus; HOMA-IR, Homeostasis Model of Assessment Insulin Resistance; RBV, ribavirin; ULN, upper limit of normal. Table S8. Multivariate Logistic Regression in Assessing Factors Associated With SVR12 in SOF + RBV Patients in FISSION: Full Analysis Set Variable Odds Ratio 95% Confidence Limit 2-Sided P value HCV genotype: 2 vs (9.539, ) < Cirrhosis: no vs yes (1.377, 6.257) Baseline HCV RNA: < vs 6 log 10 IU/mL (1.237, 4.368) RBV exposure, mg/kg/d (1.088, 1.455) Note: for univariate and multivariate analysis, subjects with cirrhosis = missing were assumed to have cirrhosis = no ; Homeostasis Model of Assessment Insulin Resistance (HOMA-IR) = missing assumed to have HOMA-IR 2; and IL28B category = missing assumed to have IL28B CC. HCV, hepatitis C virus; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response at Week

27 RESISTANCE IN NEUTRINO AND FISSION NEUTRINO No patient in NEUTRINO experienced on-treatment virologic failure; all 28 patients with virologic failure relapsed after stopping treatment. Deep sequence data were successfully obtained from all 28 patients. No previously identified SOF or RBV-associated mutations in nonstructural protein 5B (NS5B) were detected by deep sequencing in any of these patients. Two NS5B substitutions were observed in >2 patients, but were not associated with change in susceptibility to SOF, IFN, and RBV. No reduction in susceptibility to SOF, interferon, or RBV was observed among patient samples containing substitutions, indicating that NS5B amino acid changes observed at relapse did not reduce the viral sensitivity to SOF, IFN, or RBV. FISSION Seventy-four patients in the SOF+RBV arm relapsed after stopping treatment. Deep sequencing results were obtained from all 74 of these patients. Full-length NS5B was successfully sequenced in 70 and a short fragment covering amino acid residue 282 was generated and deep sequenced for the remaining 4 patients. No SOF-associated mutation in NS5B (S282T) was detected. No reduction in susceptibility to SOF or RBV was observed among patient samples containing substitutions, indicating that NS5B amino acid changes observed at relapse did not reduce the viral sensitivity to SOF or RBV. 27

28 SUPPLEMENTARY SAFETY Table S9. All Treatment-Emergent Adverse Events in NEUTRINO 28

29 Table S9. All Treatment-Emergent Adverse Events in NEUTRINO (Continued) 29

30 Table S9. All Treatment-Emergent Adverse Events in NEUTRINO (Continued) 30

31 Table S9. All Treatment-Emergent Adverse Events in NEUTRINO (Continued) 31

32 Table S9. All Treatment-Emergent Adverse Events in NEUTRINO (Continued) 32

33 Table S9. All Treatment-Emergent Adverse Events in NEUTRINO (Continued) 33

34 Table S9. All Treatment-Emergent Adverse Events in NEUTRINO (Continued) 34

35 Table S9. All Treatment-Emergent Adverse Events in NEUTRINO (Continued) 35

36 Table S10. All Treatment-Emergent Adverse Events in FISSION 36

37 Table S10. All Treatment-Emergent Adverse Events in FISSION (Continued) 37

38 Table S10. All Treatment-Emergent Adverse Events in FISSION (Continued) 38

39 Table S10. All Treatment-Emergent Adverse Events in FISSION (Continued) 39

40 Table S10. All Treatment-Emergent Adverse Events in FISSION (Continued) 40

41 Table S10. All Treatment-Emergent Adverse Events in Fission (Continued) 41

42 Table S10. All Treatment-Emergent Adverse Events in Fission (Continued) 42

43 Table S10. All Treatment-Emergent Adverse Events in Fission (Continued) 43

44 Table S10. All Treatment-Emergent Adverse Events in Fission (Continued) 44

45 Table S10. All Treatment-Emergent Adverse Events in Fission (Continued) 45

46 Figure S4. Treatment-Emergent Adverse Events by System-Organ Class in NEUTRINO Blood disorders Gastrointestinal disorders General disorders 1 2 3/4 Grade SOF + PEG + RBV Infections Metabolism and nutrition disorders Musculoskeletal disorders Nervous system disorders Psychiatric disorders Respiratory disorders Skin disorders Patients (%) Figure S5. Treatment-Emergent Adverse Events by System-Organ Class in FISSION Blood disorders Gastrointestinal disorders General disorders 1 2 3/4 Grade SOF + RBV PEG + RBV Infections Metabolism and nutrition disorders Musculoskeletal disorders Nervous system disorders Psychiatric disorders Respiratory disorders Skin disorders Patients (%) 46

47 Table S11. Adverse Events Leading to Discontinuation in NEUTRINO, n (%)* Event SOF + PEG + RBV (N = 327) Overall 8 (2.4) Anemia 2 (0.6) Blood creatinine increased 1 (0.3) Dermatitis 1 (0.3) Hemoglobin abnormal 1 (0.3) Hemolytic anemia 1 (0.3) Neutropenia 1 (0.3) Vision blurred 1 (0.3) *No. (%) of subjects experiencing any adverse event leading to permanent discontinuation from any of the study drugs by preferred term. PEG, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir. Table S12. Serious Adverse Events in NEUTRINO, n (%) Event SOF + PEG + RBV (N = 327) Patients experiencing any serious AE 4 (1.2) Abdominal pain 1 (0.3) Anemia 1 (0.3) Cryoglobulinemia 1 (0.3) Laryngeal cancer 1 (0.3) Leukopenia 1 (0.3) Noncardiac chest pain 1 (0.3) Pyrexia 1 (0.3) Spinal compression fracture 1 (0.3) PEG, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir. 47

48 Figure S6. Proportional Differences in Treatment-Emergent AEs Occurring in 10% of Patients in SOF + RBV and PEG + RBV Treatment Groups in FISSION AE Proportional Difference (95% CI*) P Value Fatigue <.0001 Headache <.0001 Nausea.0057 Insomnia <.0001 Rash.0052 Diarrhea.0075 Irritability.0328 Decreased appetite.0001 Myalgia.0060 Pruritus.0009 Dizziness.3360 Flu-like symptoms <.0001 Arthralgia.0016 Chills <.0001 Anemia.1739 Depression.0013 Pyrexia <.0001 Pain <.0001 Neutropenia < SOF+RBV Better PEG+RBV Better *95% confidence interval (CI) on difference (pegylated interferon [PEG] + ribavirin [RBV] minus sofosbuvir [SOF] + RBV) in 2 binomial proportions based on the standardized statistic and inverting two 1-sided tests. P value from 2-sided Fisher s Exact Test AE, adverse event. 48

49 Table S13. Adverse Events Leading to Permanent Discontinuation of Both Study Drugs in FISSION, n (%)* Event SOF + RBV (n = 256) PEG + RBV (n = 243) Overall 3 (1.2) 26 (10.7) Fatigue 0 5 (2.1) Depression 1 (0.4) 4 (1.6) Anemia 0 3 (1.2) Insomnia 0 3 (1.2) Nausea 0 3 (1.2) Alanine aminotransferase increased 0 2 (0.8) Anxiety 0 2 (0.8) Hemoglobin decreased 0 2 (0.8) Irritability 0 2 (0.8) Loss of consciousness 0 2 (0.8) Pain 0 2 (0.8) Platelet count decreased 0 2 (0.8) Abnormal dreams 1 (0.4) 0 Agitation 1 (0.4) 0 Anger 0 1 (0.4) Apathy 1 (0.4) 0 Arthralgia 0 1 (0.4) Arthropathy 0 1 (0.4) Aspartate aminotransferase increased 0 1 (0.4) Asthenia 0 1 (0.4) Blood alkaline phosphatase increased 0 1 (0.4) Blood creatine phosphokinase increased 1 (0.4) 0 *No. (%) of subjects experiencing any adverse event leading to permanent discontinuation from any of the study drugs by preferred term. PEG, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir. 49

50 Table S13. Adverse Events Leading to Permanent Discontinuation of Both Study Drugs in FISSION, n (%)* (continued) Event SOF + RBV (n = 256) PEG + RBV (n = 243) Chest pain 1 (0.4) 0 Decreased appetite 1 (0.4) 0 Feeling abnormal 0 1 (0.4) Malaise 0 1 (0.4) Mood altered 0 1 (0.4) Mood swings 0 1 (0.4) Myalgia 0 1 (0.4) Peripheral neuropathy 0 1 (0.4) Neutropenia 0 1 (0.4) Neutrophil count decreased 0 1 (0.4) Oropharyngeal discomfort 0 1 (0.4) Pain of skin 0 1 (0.4) Palpitations 0 1 (0.4) Retinal exudates 0 1 (0.4) Retinal hemorrhage 0 1 (0.4) Skin burning sensation 0 1 (0.4) Skin reaction 0 1 (0.4) Tachycardia 0 1 (0.4) Weight decreased 1 (0.4) 0 White blood cell count decreased 0 1 (0.4) *No. (%) of subjects experiencing any adverse event leading to permanent discontinuation from any of the study drugs by preferred term. PEG, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir. 50

51 Table S14. Serious Adverse Events in FISSION, n (%) Event, n (%) SOF + RBV (n = 256) PEG + RBV (n = 243) Patients experiencing any serious AE 7 (2.7) 3 (1.2) Allergy to arthropod sting 1 (0.4) 0 Anemia 1 (0.4) 0 Atrioventricular block 0 1 (0.4) Breast cancer in situ 0 1 (0.4) Cellulitis 1 (0.4) 0 Chest pain 1 (0.4) 0 Chronic obstructive pulmonary disease 1 (0.4) 0 Clavicle fracture 0 1 (0.4) Infection 0 1 (0.4) Chronic osteomyelitis 1 (0.4) 0 Pneumothorax 0 1 (0.4) Rib fracture 0 1 (0.4) Toxicity to various agents 1 (0.4) 0 Urinary tract infection 1 (0.4) 0 PEG, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir. 51

52 Table S15. Adverse Events by Cirrhosis Status in NEUTRINO Event, n (%) SOF + PEG + RBV Cirrhotic (n = 54) SOF + PEG + RBV Noncirrhotic (n = 273) Any AE 51 (94) 259 (95) Grade 3 9 (17) 39 (14) Grade 2 36 (67) 158 (58) Treatment-related AE 51 (94) 253 (93) Grade 3 8 (15) 34 (13) Grade 2 31 (57) 144 (53) Serious AE 1 (2) 3 (1) Treatment-related serious AE 0 2 (0.7) AE leading to permanent discontinuation of any of the study drugs 1 (2) 7 (3) AE leading to permanent discontinuation from SOF 1 (2) 4 (2) AE leading to modification/interruption of study drug 24 (44) 85 (31) Death 0 0 If cirrhosis status was missing, then cirrhosis = no, for purposes of analysis unless cirrhosis was documented post-baseline. Data included to last dose date of study regimen + 30 days. Percentages calculated based on no. of subjects (cirrhotics and noncirrhotics) in the safety analysis set for SOF + PEG + RBV. AE, adverse event; PEG, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir. 52

53 Table S16. Adverse Events by Cirrhosis Status in FISSION Event, n (%) SOF + RBV Cirrhotic (n = 50) SOF + RBV Noncirrhotic (n = 206) Any AE 41 (82) 179 (87) Grade 3 6 (12) 12 (6) Grade 2 18 (36) 85 (41) Treatment-related AE 33 (66) 150 (73) Grade 3 1 (2) 7 (3) Grade 2 14 (28) 60 (29) Serious AE 2 (4) 5 (2) Treatment-related serious AE 0 1 (0.5) AE leading to permanent discontinuation from any study drug 1 (2) 2 (1) AE leading to permanent discontinuation from both study drugs in regimen 1 (2) 2 (1) AE leading to modification/interruption of study drug 2 (4) 23 (11) Death 0 1 (0.5) If cirrhosis status was missing, then cirrhosis = no, for purposes of analysis unless cirrhosis was documented post-baseline. Data included to last dose date of study regimen + 30 days. Percentages calculated based on no. of subjects (cirrhotics and noncirrhotics) in the safety analysis set for SOF + RBV. AE, adverse event; RBV, ribavirin; SOF, sofosbuvir. 53