Accepted Manuscript

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients
with Advanced Liver Disease

Michael Charlton, Gregory T. Everson, Steven L. Flamm, Princy Kumar, Charles

Landis, Robert S. Brown, Jr., Michael W. Fried, Norah A. Terrault, Jacqueline
G. O'Leary, Hugo E. Vargas, Alexander Kuo, Eugene Schiff, Mark S. Sulkowski,
Richard Gilroy, Kymberly D. Watt, Kimberly Brown, Paul Kwo, Surakit Pungpapong,
Kevin M. Korenblat, Andrew J. Muir, Lewis Teperman, Robert J. Fontana, Jill
Denning, Sarah Arterburn, Hadas Dvory-Sobol, Theo Brandt-Sarif, Phillip S. Pang,
John G. McHutchison, K. Rajender Reddy, Nezam Afdhal

PII: S0016-5085(15)00682-4
DOI: 10.1053/j.gastro.2015.05.010
Reference: YGAST 59781

To appear in: Gastroenterology

Accepted Date: 8 May 2015

Please cite this article as: Charlton M, Everson GT, Flamm SL, Kumar P, Landis C, Brown Jr RS, Fried
MW, Terrault NA, O'Leary JG, Vargas HE, Kuo A, Schiff E, Sulkowski MS, Gilroy R, Watt KD, Brown
K, Kwo P, Pungpapong S, Korenblat KM, Muir AJ, Teperman L, Fontana RJ, Denning J, Arterburn
S, Dvory-Sobol H, Brandt-Sarif T, Pang PS, McHutchison JG, Reddy KR, Afdhal N, for the SOLAR-1
Investigators, Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with
Advanced Liver Disease, Gastroenterology (2015), doi: 10.1053/j.gastro.2015.05.010.

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 ACCEPTED MANUSCRIPT

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in

Patients with Advanced Liver Disease

Short title: Ledipasvir and sofosbuvir in advanced liver disease

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Authors: Michael Charlton1*, Gregory T. Everson2, Steven L. Flamm3, Princy Kumar4, Charles

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Landis5, Robert S. Brown, Jr6, Michael W. Fried7, Norah A. Terrault8, Jacqueline G. O'Leary9,

Hugo E. Vargas10, Alexander Kuo11, Eugene Schiff12, Mark S. Sulkowski13, Richard Gilroy14,

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Kymberly D. Watt15, Kimberly Brown16, Paul Kwo17, Surakit Pungpapong18, Kevin M.

Korenblat19, Andrew J. Muir20, Lewis Teperman21, Robert J. Fontana22, Jill Denning23, Sarah

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Arterburn23, Hadas Dvory-Sobol23, Theo Brandt-Sarif23, Phillip S. Pang23, John G.
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McHutchison23, K. Rajender Reddy24, Nezam Afdhal25* for the SOLAR-1 Investigators
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Affiliations: 1Intermountain Medical Center, Salt Lake City, UT; 2University of Colorado

Denver, Aurora, CO; 3Northwestern Feinberg School of Medicine, Chicago, IL; 4Georgetown
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University, Washington, DC; 5University of Washington/Harborview Medical Center, Seattle,

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WA; 6Columbia University Medical Center/ New York Presbyterian, New York, NY;
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University of North Carolina at Chapel Hill / UNC School of Medicine, Chapel Hill, NC;
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University of California, San Francisco, CA; 9Baylor University Medical Center, Dallas, TX;
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Mayo Clinic Arizona, Phoenix, AZ; 11University of California, San Diego, CA; 12University of
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Miami, Miami, FL; 13Johns Hopkins University, Lutherville, MD; 14University of Kansas

Medical Center Research Institute, Kansas City, KS; 15Mayo Clinic, Rochester, MN; 16Henry

Ford Health System, Detroit, MI; 17Indiana University School of Medicine, Indianapolis, IN;
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Mayo Clinic Jacksonville, FL; 19Washington University, Saint Louis, MO; 20Duke University,

Durham, NC; 21New York University School of Medicine, New York, NY; 22University of

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Michigan, Ann Arbor, MI 23Gilead Sciences, Inc., Foster City, CA; 24University of Pennsylvania

School of Medicine, Philadelphia, PA; 25Beth Israel Deaconess Medical Center, Boston, MA

*Drs. Charlton and Afdhal contributed equally to this article.

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Corresponding authors: Michael Charlton, MD; Intermountain Medical Center, 5169 S

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Cottonwood St, Murray, UT 84107, USA; Telephone: (801) 507-3380; E-mail:

michael.charlton@imail.org and Nezam Afdhal, MD; Beth Israel Deaconess Medical Center,

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110 Francis St, Boston, MA 02215, USA; Telephone: (617) 632-1069; E-mail:

nafdhal@bidmc.harvard.edu.

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Trial registration details: NCT01938430 (ClinTrials.gov database)

The sponsor (Gilead Sciences) collected the data, monitored the study conduct, and performed
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the statistical analyses.

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Abbreviations: HCV, hepatitis C virus; SVR12, sustained virologic response at 12 weeks after
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the end of treatment; FCH, fibrosing cholestatic hepatitis; pTVR, post-transplant virologic

response; MELD, model for end-stage liver disease; CPT, Child Pugh Turcotte
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Contributors

MS, ES, KRR, GTE, AJM, JGM, RG, NA participated in the conception and design of the study;

PK, NT, MS, ES, KRR, SP, PSP, GTE, AJM,CL, PK, RG, NA, RF, JD, MC, RB, TB-S, SA, KB,

JO data acquisition; PK, NT, MS, KRR, PSP, GTE, AJM, JGM, CL, PK, RF, JD, MC, RB, TB-S

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SA NA interpretation; PK, NT, MS, ES, KRR, SP, PSP, GTE, AJM, JGM, CL, RG, RF, JD, MC,

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RB, TB-S JO, KB, NA, SA All authors critically revised draft versions of the report and

approved the final version for publication.

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Declaration of interests

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MC has received research support and grants from Gilead. GTE has received research support

and grants from AbbVie, BMS, Eisai, Gilead, Janssen, Merck, and Roche/Genentech; and has
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served on advisory boards for AbbVie, BMS, Gilead, Janssen, and Merck. PK has served as a

consultant for Janssen and ViiV Healthcare; and is a stock shareholder of GSK, Gilead, J&J,
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Merck, and Pfizer. CL has received research support and grants from AbbVie, BMS, and Gilead.
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RSB has received research support and grants from Gilead; and has served as a consultant for

Gilead. NAT has received research support and grants from Gilead. JGO has served as a
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consultant for AbbVie, Janssen, and Gilead; and was on the speakers’ bureau for AbbVie and

Gilead. HEV has received research support and grants from AbbVie, BMS, Eisai, Gilead, and
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Merck. AK has received research support and grants from Gilead; and has served as a consultant
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for AbbVie. ES has received research support and grants from Abbot, BMS, Beckman Coulter,

Conatus, Discovery Life Sciences, Gilead, MedMira, Merck, Orasure Technologies, Roche

Molecular, Janssen, and Siemens; has received personal fees from Acorda, Arrowhead, BMS,

Gilead, Merck, Janssen, Pfizer, and Salix; and has received non-financial support from Merck

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and Salix. MSS has received research support and grants from AbbVie, BMS, Gilead, Janssen,

and Merck; has served as a consultant for AbbVie, BMS, Gilead, Janssen, and Merck; has served

on an advisory board for Gilead; and has been involved with the NIH. RG has received research

support and grants from Gilead; and has received personal fees from AbbVie, Gilead, NPS, and

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Salix. KDW has served as a sponsor for Gilead. KB has received research support and grants

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from AbbVie, BMS, CDC Foundation, Gilead, Hyperion, Janssen, and Vertex; served as a

consultant for AbbVie, BMS, Gilead, Janssen, and Merck; was on the speakers’ bureau for

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AbbVie, CLDF, Gilead, HCV Viewpoints, and Simply Speaking; has served on advisory boards

for AJT Images, AST Past, CLDF, and CLD Journal; and was involved with Medscape. PK has

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received research support and grants from AbbVie, BMS, Conatus, Gilead, Janssen, Merck,
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Roche, and Vertex; has served as a consultant for Gilead; has served on advisory boards for

AbbVie, BMS, Gilead, Janssen, Merck, Novartis, and Vertex; and was on the speakers’ bureau
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for Merck and Vertex. SP has received research support and grants from BMS and Gilead. AJM
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has received research support and grants from Gilead; and has served on advisory boards for
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Gilead. RJF has received research support and grants from BMS, Gilead, Janssen, and Vertex.

KRR has received research support and grants from AbbVie, BMS, Genentech-Roche, Gilead,
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Janssen, Merck, and Vertex; has served as a consultant for AbbVie, BMS, Genentech-Roche,

Gilead, Idenix, Janssen, Merck, and Vertex; has served on advisory boards for CLDF and
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Novartis; and has received payment for development of educational presentations from ViralEd.
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NA has received research support and grants from AbbVie, BMS, and Gilead; has served on

advisory boards for Gilead; has served as a consultant for Gilead; and has received personal fees

from AbbVie, Achillion, BMS, Merck, Janssen, and SprinBank. JD, SA, TBS, PSP, and JGM are

employees of Gilead. SF, MWF, KMK, and LT have nothing to disclose.

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ABSTRACT

Background & Aims: There are no effective and safe treatments for chronic hepatitis C virus

(HCV) infection of patients who have advanced liver disease.

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Methods: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor

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ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with

HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic

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impairment who had not undergone liver transplantation. Cohort B enrolled patients who had

undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate,

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or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were
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randomly assigned (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing
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ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary endpoint was sustained

virologic response at 12 weeks after the end of treatment (SVR12).

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Results: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with

HCV genotype 4 infection. In cohort A (non-transplant), SVR12 was achieved by 86%–89% of

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patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients

without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic
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impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with
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fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar.

Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely

because of adverse events; 10 patients died, mainly from complications related to hepatic

decompensation.

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Conclusion: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced

high rates of SVR12 in patients with advanced liver disease, including those with decompensated

cirrhosis before and after liver transplantation.

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KEYWORDS: hepatitis C virus infection; decompensated cirrhosis, liver transplantation;

fibrosing cholestatic hepatitis

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(Funded by Gilead Sciences; ClinicalTrials.gov number NCT01938430)

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INTRODUCTION

Patients with chronic hepatitis C virus (HCV) infection and advanced liver disease—especially

those with decompensated cirrhosis—have a poor prognosis and limited treatment options.1,2

Liver failure and hepatocellular carcinoma related to HCV infection are the most common

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indications for liver transplantation in North America and Europe.3,4 In patients with detectable

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virus at the time of transplantation, recurrent HCV infection is universal and 30% of patients

have an aggressive clinical and histological course with increased morbidity, mortality, and graft

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loss.5-7 There is an urgent medical need for safe and effective treatments for patients with

advanced liver disease. To date, few clinical trials have included patients with decompensated

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liver disease and the effect of sustained virologic response on liver-related function and
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outcomes is not known.
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Sofosbuvir is a nucleotide analogue inhibitor approved for the treatment of HCV.8 In phase 2

trials, sofosbuvir plus ribavirin was used to treat patients both before and after liver
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transplantation, including those with compensated cirrhosis, with moderate efficacy after
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prolonged (24-48 weeks) administration .9,10 Sofosbuvir plus ribavirin has also been successfully

used in a subgroup of patients with decompensated cirrhosis in a compassionate use program,

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with similarly moderate efficacy.11 A fixed-dose combination of sofosbuvir with the HCV NS5A
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inhibitor ledipasvir has been recently approved in the United States and Europe for the treatment
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of chronic genotype 1 HCV infection.12 The safety and efficacy of ledipasvir-sofosbuvir among

patients with compensated cirrhosis has been established,13 but this combination has not been

previously evaluated in patients with more advanced liver disease. We conducted an open-label,

phase 2 study to determine the efficacy and safety of ledipasvir-sofosbuvir with ribavirin in

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patients with advanced liver disease, including patients who have undergone liver

transplantation.

METHODS

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Patients

Between September 6, 2013 and January 11, 2014, patients were enrolled at 29 clinical sites in

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the United States. Eligible patients were at least 18 years of age and chronically infected with

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genotype 1 or 4 HCV. Patients coinfected with HIV or hepatitis B virus or with prior exposure to

an NS5a inhibitor were not eligible for enrollment. Patients with any of the following laboratory

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abnormalities were also excluded from enrollment: hemoglobin <10 g/dL, platelets ≤30,000/
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mm3, ALT, AST, or alkaline phosphatase ≥10 times the upper limit of normal, total bilirubin

>10 mg/dL (except for the FCH cohort), serum creatinine >2.5 time the upper limit of normal
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and/or evidence of renal impairment (creatinine clearance <40 mL/min).

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Patients were enrolled in two Cohorts. Cohort A consisted of two groups of patients with
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advanced cirrhosis (Child-Pugh class B and C) due to chronic HCV infection who had not

undergone liver transplantation: group 1 enrolled patients with cirrhosis and moderate hepatic
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impairment (Child-Pugh class B) and group 2 enrolled patients with cirrhosis and severe hepatic

impairment (Child-Pugh class C). Cohort B consisted of five groups of patients, all of whom had
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previously undergone liver transplantation: Group 3 enrolled patients without cirrhosis, group 4
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enrolled patients with compensated cirrhosis and mild hepatic impairment (Child-Pugh class A),

group 5 enrolled patients with cirrhosis and moderate hepatic impairment (Child-Pugh class B),

group 6 enrolled patients with cirrhosis and severe hepatic impairment (Child-Pugh class C), and

group 7 enrolled patients with fibrosing cholestatic hepatitis (appendix).

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Study Design

In this open-label, phase 2 study, patients in each of the seven groups were randomized using a

computer-generated randomization sequence generated by Bracket (San Francisco, CA, USA)

and allocated by means of an interactive web response system in a 1:1 ratio to receive either 12

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or 24 weeks of treatment with ledipasvir 90 mg and sofosbuvir 400 mg in a fixed-dose

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combination tablet (ledipasvir-sofosbuvir) once daily plus ribavirin. For groups 3, 4, and 7,

ribavirin was administered orally twice daily, with the dose determined according to body weight

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(1000 mg daily in patients with a body weight of <75 kg, and 1200 mg daily in patients with a

body weight ≥75 kg). For groups 1, 2, 5, and 6, ribavirin was administered at a starting dose of

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600 mg in a divided daily dose. Provided that the starting dose was well tolerated, and that
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hemoglobin levels remained above 10 g/dL without hematologic growth factor support, the dose
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could be increased to a maximum of 1000 mg daily in patients with a body weight of <75 kg,

and 1200 mg daily in patients with a body weight ≥75 kg. For patients who could not tolerate the
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starting dose of 600 mg, the dose was reduced as necessary on the basis of hemoglobin levels or
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other ribavirin side effects.

Management of immunosuppression was not specified in the clinical protocol, but levels and
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resulting dose adjustments were recorded to assess whether the regimens required adjustment in
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correlation with resolution of HCV infection or due to drug interaction with study treatment.
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Study Assessments

Serum HCV RNA was measured using the Roche COBAS AmpliPrep/COBAS Taqman HCV

Test, v2.0 (HCV RNA PCR). HCV genotype and subtype was determined using the Siemens

VERSANT HCV Genotype INNO-LiPA 2.0 Assay, the TRUEGENE HCV 5’NC Genotyping

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Assay and NS5b sequencing, IL28B genotype was determined by polymerase chain reaction

(PCR) amplification of the single-nucleotide polymorphism rs12979860.

For analysis of viral resistance, we collected samples at baseline from all patients. The HCV

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NS5A and NS5B coding regions were amplified using standard reverse transcription polymerase

chain reaction technology. Variants present at more 1% of sequence reads are reported. For

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patients who had virologic failure, deep sequencing was performed for the HCV NS5A and

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NS5B coding regions with samples collected at the first virologic failure time point. Variants in

NS5A and NS5B coding regions present in at least 1% of the viral population were compared

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with the respective baseline sequence.
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End Points and Statistical Analysis

The primary efficacy end point was the rate of sustained virologic response, defined as the
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absence of quantifiable HCV RNA in serum (<15 IU per milliliter) at 12 weeks after the end of
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therapy (SVR12) among all patients who underwent randomization and received at least one
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dose of study drugs. The proportions of patients with SVR12 along with a two-sided 90%

confidence interval (using the Clopper-Pearson method) were calculated by group and treatment
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duration. We did not do a formal sample size calculation. The enrolment target of 50 patients for

all groups (except group 3,which had an enrolment target of 100 patients) was chosen to provide
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a reasonable estimate of SVR12 with appropriate 90% confidence intervals. The efficacy end
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point for patients who underwent liver transplantation while on study was the rate of post-

transplant virologic response (pTVR, defined as HCV RNA <15 IU per milliliter at 12 weeks

post-transplant) in all patients who have HCV RNA <15 IU per milliliter at their last observed

HCV RNA prior to transplantation. Six of these patients underwent liver transplantation with

HCV RNA <15 IU per milliliter prior to post-treatment week 12 and are not included in the

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efficacy analysis for Cohort A. The primary safety end point was the proportion of patients who

discontinued study treatment due to an adverse event. Secondary endpoints included

improvements in Child-Pugh class and Model for End-Stage Liver Disease (MELD) score during

treatment and follow-up. We used the Wilcoxon rank sum test to analyze the bilirubin and

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albumin data.

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Study Oversight

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The design of this study, which was in compliance with the principles of the Declaration of

Helsinki, Good Clinical Practice guidelines, and local regulatory requirements, was approved by

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the institutional review board or independent ethics committee at each participating site. The
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study was conducted according to the protocol by the sponsor (Gilead Sciences) in collaboration

with the academic investigators.

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Role of the Funding Source

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The sponsor collected the data, monitored the study conduct, and performed the statistical
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analyses. An independent data and safety monitoring committee reviewed the progress of the

study. The investigators, participating institutions, and sponsor agreed to maintain confidentiality
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of the data. All the authors had access to the data and assume responsibility for the integrity and

completeness of the data and analyses reported. The first draft of the manuscript was prepared by
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a professional writer who is an employee of Gilead Sciences and both corresponding authors,
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with input from all the authors.

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RESULTS

Patient Baseline Characteristics

Of the 417 patients screened, 337 were enrolled, 332 (99%) with HCV genotype 1 infection and

five (1%) with HCV genotype 4 infection (see Table S2 in the Supplementary Appendix). Only

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nine patients were enrolled in group 6 (patients with Child-Pugh class C liver disease who had

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undergone liver transplantation) and only six were enrolled in group 7 (patients with fibrosing

cholestatic hepatitis). The demographic and baseline clinical characteristics of the patients were

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generally balanced between the 12- and 24-week treatment arms in each of the seven patient

groups (Table 1).

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Seven patients in Cohort A underwent liver transplantation, four during study treatment and three

after completing study treatment (appendix).

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Efficacy
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Non-transplanted Patients with Decompensated Cirrhosis (Groups 1 and 2)

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Rates of sustained virologic response among patients with Child-Pugh class B disease who had

not undergone transplantation were similar regardless of treatment duration: 87% in those who
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received 12 weeks of treatment and 89% in those who received 24 weeks of treatment (Table 2).

Rates of sustained virologic response were also similar among patients with Child-Pugh class C
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decompensated disease who had not undergone transplantation regardless of treatment : 86% and
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87%in those who received 12 and 24 weeks of treatment, respectively.

In the majority of patients with Child-Pugh class B and C disease, MELD and CPT scores

between baseline and post-treatment week 4 (Figure 1 and Supplementary Figure S2). Patients

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with Child-Pugh class B disease had statistically significant improvements from baseline in total

bilirubin and albumin levels from baseline to post-treatment week 4 (appendix).

Post-Transplant Patients with No Cirrhosis or Compensated Cirrhosis (Groups 3 and 4)

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Among patients with no cirrhosis or compensated cirrhosis who had undergone liver

transplantation, rates of sustained virologic response ranged from 96% to 98%. Rates of response

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in these groups did not substantially vary by the presence or absence of cirrhosis or by treatment

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duration (Table 2).

Post-Transplant Patients with Decompensated Cirrhosis (Groups 5 and 6)

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Rates of sustained virologic response among patients with Child-Pugh class B disease who had
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undergone liver transplantation were similar regardless of treatment duration: 86% in those who

received 12 weeks of treatment and 88% in those who received 24 weeks of treatment. Patients
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with Child-Pugh class C disease who had undergone transplantation (group 6) had lower rates of
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sustained virologic response (60% and 75%, respectively, in patients receiving 12 and 24 weeks
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of treatment), but the small number of patients enrolled in this group (n=9) makes this result

difficult to interpret. As with non-transplanted patients, the majority of patients with both Child-
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Pugh class B and C disease who had undergone liver transplantation had MELD and CPT scores

that were improved at post-treatment week 4 over baseline levels (Figure 1 and Supplementary
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Figure S2).
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Fibrosing Cholestatic Hepatitis (Group 7)

All six patients with fibrosing cholestatic hepatitis achieved sustained viral response. These

patients also showed large decreases in total bilirubin by treatment weeks 2-4, accompanied by

suppression of HCV RNA (appendix).

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Patients with Genotype 4 HCV

Results for the five patients with genotype 4 HCV are included in the relevant groups above, but

we report them separately here. Three of the five (one each in Groups 1, 2, and 3) achieved

SVR12, one in Group 2 was lost to follow-up after achieving SVR4, and one in Group 5 died of

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complications relating to cirrhosis on day 75 of treatment (appendix).

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On-Study Liver Transplantation

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Seven patients in Cohort A underwent liver transplantation, four before the end of treatment and

three in the follow-up period before post-treatment week 12. Of the seven, six have achieved

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post-transplant virologic response. The seventh patient had undetectable HCV RNA at post-
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transplantation week 2 and died one day later of multi-organ failure and septic shock (appendix).

Post-transplantation Immunosuppression
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The most commonly used immunosuppressive agents among the 229 patients in Cohort B were
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tacrolimus in 174 patients (76%), mycophenolate mofetil, mycophenolate sodium, or

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mycophenolic acid in 82 patients (36%), and cyclosporine in 34 patients (15%) (appendix). One

patient experienced an increase in cyclosporine concentrations that the investigator attributed to

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an interaction with study treatment. However, increases in cyclosporine concentrations have also

been reported to be a result of an improvement of organ function. No other changes to

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immunosuppression were reported as due to drug interactions with the study treatment. Forty
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instances of adjustments to immunosuppression in 24 patients were attributed by the

Investigators to improvements in hepatic function following viral clearance.

Virologic Resistance

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Overall, NS5A and NS5B pretreatment resistance analysis was conducted for 311 and 309

patients with genotype 1 HCV infection, respectively. A total of 42 of 311 patients (14%) with

genotype 1 HCV infection had baseline NS5A resistance-associated variants (RAVs) that confer

reduced susceptibility to ledipasvir. Of these 42 patients, three (7%) relapsed. The rate of relapse

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among patients without baseline NS5A RAVs was 4% (10 of 269). None of the 25 patients with

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NS5A RAVs who received ledipasvir-sofosbuvir plus ribavirin for 24 weeks relapsed. At

virologic failure, 11 of 13 (85%) patients who relapsed were observed to have NS5A variants—

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M28T, Q30H/R, H58D, and Y93H/C. Neither S282T, the signature RAV associated with

resistance to sofosbuvir, nor other nucleotide inhibitor RAVs were observed at pretreatment or

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post-treatment in any of the patients with virologic failure.
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Safety
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Given that the study population consisted of patients with advanced liver disease, rates of

adverse events were high in all patient groups (Table 3). However, only 13 patients (4%)
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discontinued ledipasvir-sofosbuvir prematurely secondary to adverse events. The only adverse

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events that led to discontinuation in more than one patient were sepsis (n=2), acute renal failure

(n=2), dyspnea (n=2), and gastrointestinal hemorrhage (n=2). Seventy-seven patients (23%)
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experienced serious adverse events, the majority of which were associated with hepatic
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decompensation. A full list of serious adverse events is provided in Supplementary Table S7.
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Thirteen patients died during the study: four during treatment, six after discontinuing study

treatment, but within 30 days post-treatment, and three more than 30 days after the end of

treatment. The most common cause of death was septic shock accompanied by multi-organ

failure (appendix). None of the deaths were deemed treatment-related.

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Across all groups, the most common Grade 3 or 4 laboratory abnormalities were decreases in

hemoglobin and lymphocytes and increases in total bilirubin and glucose. Decreases in

hemoglobin levels and hyperbilirubinemia are known to be associated with ribavirin-induced

hemolysis.

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The most common Grade 3 or 4 laboratory abnormality for Cohort A was increases in total

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bilirubin followed by lymphopenia. For Cohort B patients, the most common Grade 3 or 4

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laboratory abnormalities were decreases in hemoglobin and lymphocytes. Elevations in serum

glucose were observed mostly among patients with elevated serum glucose at baseline. Across

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all groups, median creatinine values remained stable while on treatment.
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One hundred and thirty-two (39%) and 44 (13%) patients experienced hemoglobin values less

than 10 and 8.5, respectively. Fifty-one (15%) patients received at least one concomitant blood
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product or erythropoietin. The average daily dose of ribavirin in patients with decompensated
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cirrhosis (pre or post transplantation) was ~600 mg. The average daily dose of ribavirin in
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patients with no cirrhosis or compensated cirrhosis was ~1000 mg. The dose of ribavirin was

reduced in 43% (144/337) of patients and discontinued altogether in 18% (59/337) of patients.
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Discontinuation of ribavirin was more common in the 24-week groups and among patients with

worsening disease state (appendix).

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There were three reports of acute cellular rejection in post-transplant patients. None of the three
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were thought to be related to study treatment. Two reports were in group 3, one on day 169 of

treatment, which subsequently resolved, and one 91 days after the last dose of study drug, which

has not resolved. One patient in group 1 with acute cellular rejection had undergone

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transplantation during the study and had graft loss six days post-transplant. This patient was

retransplanted nine days later, and went on to achieve pTVR.

DISCUSSION

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In this first large-scale trial to evaluate the efficacy of all-oral DAA therapy in patients with

HCV genotype 1 and decompensated cirrhosis, and the first in post-transplant patients with

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cirrhosis, 12 or 24 weeks of treatment with ledipasvir-sofosbuvir and ribavirin resulted in high

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rates of response. Rates of sustained virologic response were over 85% in every group of patients

with Child-Pugh class B decompensated cirrhosis—in those who had and had not undergone

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liver transplantation, as well as those who were receiving 12 and 24 weeks of treatment. Similar
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response rates were observed in Child-Pugh class C patients who had not undergone liver

transplantation. Rates of response were numerically lower in liver transplant recipients with
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Child-Pugh class C disease, but the small sample size (n=9) make this a preliminary observation.

Our results also demonstrate that SVR12 in patients with decompensated cirrhosis is associated
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with early improvements in CPT and MELD scores, suggesting that eradication of the virus can
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rapidly improve hepatic function by attenuating the injury and inflammation due to HCV

replication. Similar effects have been described for suppression of hepatitis B virus in patients
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with decompensated disease.14,15 Long-term follow-up of patients with Child-Pugh class B and C
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disease who have achieved sustained virologic response is needed to determine possible long-
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term benefits, such as decreased demand for liver transplantation, reduced liver-related mortality

and hepatocellular carcinoma, as well as reversibility of clinical liver failure.

Our study included a small number of patients with fibrosing cholestatic hepatitis (FCH), an

uncommon complication of liver transplantation characterized by highly aggressive progression

of cholestasis and fibrosis. Until recently, there was no effective treatment for this frequently

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fatal condition. A number of recent case reports have shown that FCH can be successfully treated

with direct-acting antiviral therapy.16-19 Our results—all six patients with FCH treated with

ledipasvir-sofosbuvir plus ribavirin achieved sustained virologic response—provide further

encouraging evidence that FCH may now be a manageable complication of liver transplantation.

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Among patients in groups 3 and 4, which represented a broad spectrum of patients post-

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transplant, from mild histological disease to compensated cirrhosis, rates of sustained virologic

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response ranged from 96-98%. These rates are generally in keeping with those observed in the

ION-1 and ION-2 trials, in which patients who had not undergone liver transplantation received

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ledipasvir-sofosbuvir for 12 or 24 weeks with and without ribavirin.20,21 The CORAL-1, a study
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which evaluated the combination of ombitasvir-paritaprevir/ritonavir-dasabuvir plus ribavirin for

24 weeks in patients with mild histological recurrent HCV provided comparable efficacy for
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liver transplant recipients (fibrosis stages 0-2).22 However, the efficacy of this combination in

patients with more severe liver disease is unknown since CORAL-1 did not include patients with
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hepatic decompensation or more advanced stages of recurrence (fibrosis stage 3 and 4).
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An important attribute of ledipasvir-sofosbuvir is the lack of clinically relevant drug-drug

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interactions with CYP3A4 substrates such as calcineurin and mTOR inhibitors. Although

sofosbuvir and ledipasvir do not have significant direct effects on the metabolism of
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immunosuppressive agents,23 HCV infection itself is known to affect dosing requirements of

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calcineurin inhibitors. In addition, eradication of HCV is likely to reverse, at least in part, the

inhibitory effects of HCV proteins on adaptive immunity. For these reasons, we recommend

close monitoring of immunosuppression trough levels during and after treatment of HCV

infection.

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This study was designed to evaluate two durations of ledipasvir-sofosbuvir plus ribavirin. Since

patients in all treatment arms received the same combination, the importance of ribavirin in the

regimen cannot be determined. Although ribavirin dosing was reduced in many patients with

decompensated disease, there are not adequate data to determine whether relapse was associated

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with decreased ribavirin exposure. Patients with decompensated liver disease experience high

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frequencies of ribavirin hemotoxicity. For this reason, we used lower initial daily dosing in

patients with Child-Pugh class C cirrhosis. Whether higher doses of ribavirin would be

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associated with enhanced SVR rates in participants with Child-Pugh class C cirrhosis would be

an interesting subject of future studies.

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The benefits of treating patients prior to the onset of decompensation have been clearly

demonstrated, with several-fold decreases in the risk of death, need for liver transplantation and
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development of hepatocellular carcinoma.24,25 Whether similar benefits in outcomes will accrue

to patients with Child-Pugh class B and C cirrhosis who are cured of HCV infection remains to
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be seen. The optimal timing of treatment in patients with Child-Pugh class B and C cirrhosis
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among patients considering liver transplantation requires further investigation. Current treatment

decisions should be made in collaboration with the transplant center caring for the patient. In the
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post-transplant setting our results again suggest that treating prior to the development of
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decompensation results in a numerically higher SVR and patients will again have to be followed
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to determine potential for long-term benefits on graft survival and post-transplantation mortality.

In conclusion, our findings demonstrate that ledipasvir-sofosbuvir plus ribavirin for 12 weeks is

an effective treatment for a group of patients currently without effective treatment options—

those with advanced liver disease, including those with decompensated liver function before and

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after liver transplantation. Extending treatment to 24 weeks did not appear to be associated with

improved outcomes.

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SOLAR-1 study team members

Princy Kumar, Eugene Schiff, Nezam Afdhal, Robert S Brown, Michael Fried, Kris Kowdley,

Norah Terrault, Michael Charlton, Paul Kwo, Steve Flamm, John Lake, Greg Everson, Mark

Sulkowski, Michael Curry, Rajender Reddy, Lewis Teperman, Hugo Vargas, Surakit

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Pungpapong, Andrew Muir, Atif Zaman, Kimberly Brown, Charles Landis, Alexander Kuo,

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Robert Fontana, Jacqueline O'Leary, Richard Gilroy, Obaid Shaikh, Kevin Korenblat, Richard

Stravitz, Kymberly Watt, Narayanan Menon, James Bredfeldt, Carlos Romero-Marrero

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Acknowledgments

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Supported by Gilead Sciences.

Presented in part at the annual meeting of the American Association for the Study of Liver
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Diseases; Boston, MA; November 7-11, 2014.

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We thank the patients and their families, as well as the investigators and study-site personnel;
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Sherri Paxton and Ravi Grewal (Gilead Sciences) for contributions to the conduct of the study;

and David McNeel (Gilead Sciences) for providing editorial assistance.

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REFERENCES

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2013;12:232-238.

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3. Kim WR, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 Annual Data Report: liver. Am J
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4. Adam R, McMaster P, O'Grady JG, et al. Evolution of liver transplantation in Europe: report
of the European Liver Transplant Registry. Liver Transpl 2003;9:1231-1243.

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5. Charlton M, Ruppert K, Belle SH, et al. Long-term results and modeling to predict outcomes
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in recipients with HCV infection: results of the NIDDK liver transplantation database. Liver
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6. Berenguer M, Prieto M, Rayon JM, et al. Natural history of clinically compensated hepatitis C
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7. Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and
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survival after orthotopic liver transplantation. [see comments.]. Gastroenterology 2002;122:889-

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8. Sovaldi (sofosbuvir) tablets; US prescribing information. Foster City, CA:Gilead Sciences,

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9. Curry MP, Forns X, Chung RT, et al. Sofosbuvir and ribavirin prevent recurrence of HCV
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11. Forns X, Charlton M, Denning J, et al. Sofosbuvir compassionate use program for patients
with severe recurrent hepatitis C following liver transplantation. Hepatology 2015;61:1485-1494.

12. Harvoni (ledipasvir and sofosbuvir) tablets: US prescribing information. Foster City, CA:
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disease/harvoni/harvoni_pi.pdf ).

13. Bourlière M, Bronowicki J-P, de Ledinghen V, et al. Ledipasvir and sofosbuvir for 12 weeks

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with ribavirin or for 24 weeks alone in patients with genotype 1 HCV infection and cirrhosis in
whom prior protease inhibitor therapy failed (SIRIUS): a randomized, double-blind, phase 2

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trial. Lancet Infect Dis 201515:397-404.

14. Schiff E, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil for wait-listed and post-liver

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transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver
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Transpl 2007;13:349-360.

15. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant
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hepatitis B in pre- and post-liver transplantation patients. Hepatology 2003;38:1419-1427.

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16. Delabaudière C, Lavayssière L, Dörr G, et al. Successful treatment of fibrosing cholestatic

hepatitis with pegylated interferon, ribavirin and sofosbuvir after a combined kidney-liver
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transplantation. Transpl Int 2015;28:255-258.

17. Borentain P, Colson P, Dhiver C, et al. Successful treatment with sofosbuvir of fibrosing
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cholestatic hepatitis C after liver transplantation in HIV-HCV coinfected patient. Antivir Ther
2014 [epub]
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18. Kim B, Trivedi A, Thung SN, et al. Case report of successful treatment of fibrosing
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cholestatic hepatitis C with sofosbuvir and ribavirin after liver transplantation. Semin Liver Dis.
2014;34:108-112.

19. Al Nahdi N, Ford JA, Greanya ED, et al. First successful treatment of post-liver transplant
hepatitis C fibrosing cholestatic hepatitis with boceprevir, peginterferon and ribavirin in a pre-
transplant null responder. Ann Hepatol 2013;12:156-160.

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20. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1
infection. N Engl J Med 2014;370:1889-1898.

21. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated
HCV genotype 1 infection. N Engl J Med 2014;370:1483-1493.

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22. Kwo PY, Mantry PS, Coakley E, et al. An interferon-free antiviral regimen for HCV after
liver transplantation. N Engl J Med 2014;371:2375-2382.

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23. Trotter JF, Osborne JC, Heller M, et al. Effect of hepatitis C infection on tacrolimus doses

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and blood levels in liver transplantation recipients. Aliment Pharmacol Ther 2005;22:37-44.

24. Morgan TR, Ghany MG, Kim HY, et al. Outcome of sustained virological responders with

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histologically advanced chronic hepatitis C. Hepatology 2010;52:833-844.
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25. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical
outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med
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2007;147:677-684.

26. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and
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allocation of donor livers. Gastroenterology. 2003;124:91-96.

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FIGURE LEGEND

Figure 1. Patient Disposition during Trial

Figure 2. Change from Baseline to Post-treatment Week 4 in MELD Scores in Patients with

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Child-Pugh B and C Disease

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The figure shows change from baseline in Model for End-Stage Liver Disease (MELD) scores in

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patients in Groups 1, 2, 5, and 6. MELD is a scoring system for assessing the severity of chronic

liver disease and was designed to measure the urgency of the need for liver transplantation. The

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scores are calculated using the patient's values for serum bilirubin, serum creatinine, and the
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international normalized ratio for prothrombin time. The resulting scores range from 6 (the least

ill patients) to 40+ (gravely ill patients). Three-month mortality is 71% for patients with a score
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of 40 or more, 53% for those with a score of 30–39, 20% for those with a score of 20–29, 6% for

those with a score of 10-19, and 2% for those with a score of 9 or less.26 Each of the black bars
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represents an individual patient. Missing patient data for the post-treatment week 4 visit
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indicated in the figure.

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Table 1. Baseline demographic characteristics

Cohort A: Pre-transplantation Cohort B: Post-transplantation

Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7

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Characteristic CTP B CTP C No cirrhosis CTP A CTP B CTP C FCH
12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks
(n=30) (n=29) (n=23) (n=26) (n=55) (n=56) (n=26) (n=25) (n=26) (n=26) (n=5) (n=4) (n=4) (n=2)

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Median age, years (IQR) 60 (53, 58 (56, 58 (53, 59 (55, 59 (58, 58 (56, 60 (56, 61 (58, 61 (55, 61 58, 58 (58, 61 (60, 62 (59, 58 (52,
63) 62) 61) 62) 63) 61) 64) 65) 63) 65) 62) 62) 65) 64)

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Male, n (%) 22 (73) 18 (62) 14 (61) 18 (69) 45 (82) 46 (82) 19 (73) 22 (88) 22 (85) 23 (88) 5 (100) 4 (100) 4 (100) 2 (100)
Race, n (%)
White 29 (97) 26 (90) 21 (91) 24 (92) 50 (91) 49 (88) 21 (81) 20 (80) 21 (81) 24 (92) 4 (80) 4 (100) 4 (100) 2 (100)

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Black 1 (3) 3 (10) 2 (9) 1 (4) 4 (7) 4 (7) 3 (12) 4 (16) 5 (19) 2 (8) 1 (20) 0 0 0

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Other 0 0 0 1 (4) 1 (2) 3 (5) 2 (8) 1 (4) 0 0 0 0 0 0
†
HCV genotype

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1a 19 (63) 22 (76) 15 (65) 18 (69) 40 (73) 40 (71) 17 (65) 17 (68) 20 (77) 18 (69) 4 (80) 3 (75) 3 (75) 2 (100)
1b 10 (33) 7 (24) 6 (26) 8 (31) 14 (25) 16 (29) 9 (35) 8 (32) 6 (23) 7 (27) 1 (20) 1 (25) 1 (25) 0
4 1 (3) 0 2 (9) 0 1 (2) 0 0 0 0 1 (4) 0 0 0 0

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HCV RNA, log10 IU/mL±SD 5.9±0.7 5.8±0.8 5.6±0.6 5.8±0.7 6.5±0.6 6.4±0.9 6.2±0.8 6.7±0.3 6.3±0.6 6.2±0.7 6.4±0.4 6.3±0.4 6.5±1.2 7.1±0.9

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HCV RNA ≥800,000 IU/mL 16 (53) 18 (62) 9 (39) 11 (42) 45 (82) 46 (82) 19 (73) 25 (100) 20 (77) 17 (65) 4 (80) 4 (100) 3 (75) 2 (100)
IL28B genotype CC, n (%) 4 (13) 5 (17) 6 (26) 7 (27) 11 (20) 10 (18) 7 (27) 1 (4) 3 (12) 5 (19) 2 (40) 1 (25) 0 0
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Previously treated 22 (73) 19 (66) 11 (48) 18 (69) 39 (71) 48 (86) 22 (85) 24 (96) 22 (85) 22 (85) 4 (80) 4 (100) 4 (100) 1 (50)
Regimen received
Peg/Ribavirn 10 (45) 10 (53) 8 (73) 17 (94) 26 (67) 39 (81) 15 (68) 18 (75) 12 (55) 17 (77) 4 (100) 3 (75) 4 (100) 1 (100)
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PI + Peg/Ribavirin 9 (41) 9 (47) 2 (18) 0 9 (23) 5 (10) 3 (14) 4 (17) 8 (36) 4 (18) 0 1 (25) 0 0
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Other 3 (17) 0 1 (9) 1 (6) 4 (10) 4 (8) 4 (18) 2 (8) 2 (9) 1 (5) 0 0 0 0
Prior response
ǁ
Non-response 15 (68) 14 (74) 7 (64) 13 (72) 23 (59) 33 (69) 14 (64) 19 (79) 15 (68) 16 (73) 3 (75) 3 (75) 4 (100) 1 (100)
¶
Relapse/breakthrough 7 (32) 5 (26) 4 (36) 5 (28) 16 (41) 15 (31) 8 (36) 5 (21) 7 (32) 6 (27) 1 (25) 1 (25) 0 0
Median yrs since transplant -- -- -- -- 2.9 2.8 8.8 6.6 5.1 6.3 5.2 5.7 1.1 0.3
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Median eGFR, mL/min 98 (70, 81 (64, 77 (54, 78 (69, 61 (50, 71 (55, 59 (55, 68 (57, 68 (53, 56 (51, 67 (54, 62 (47, 90 (36, 69 (n=1)
(IQR) 108) 99) 90) 97) 75) 84) 67) 88) 77) 65) 67) 69) 92)
Median platelets, (IQR) 88 (61, 73 (63, 81 (51, 71 (53, 143 152 106 (75, 112 (88, 93 (73, 97 (66, 106 (63, 65 (54, 45 (42, 196 (182,
120) 91) 99) 79) (123, (108, 138) 168) 121) 97) 160) 93) 131) 210)
196) 206)

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Child-Turcotte-Pugh class
Class A (5-6) 0 1 (3) 0 0 -- -- 25 (96) 22 (88) 0 2 (8) 0 0 -- --

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Class B (7-9) 27 (90) 27 (93) 7 (30) 4 (15) -- -- 1 (4) 3 (12) 24 (92) 24 (92) 2 (40) 1 (25) -- --
Class C (10-12) 3 (10) 1 (3) 16 (70) 22 (85) -- -- 0 0 2 (8) 0 3 (60) 3 (75) -- --

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MELD score
<10 6 (20) 8 (28) 0 0 -- -- 15 (58) 13 (52) 8 (31) 5 (19) 1 (20) 0 -- --
10-15 21 (70) 16 (55) 16 (70) 13 (50) -- -- 10 (38) 10 (40) 14 (54) 19 (73) 3 (60) 2 (50) -- --

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16-20 3 (10) 5 (17) 7 (30) 12 (46) -- -- 1 (4) 2 (8) 2 (8) 2 (8) 1 (20) 1 (25) -- --

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21-25 0 0 0 1 (4) -- -- 0 0 2 (8) 0 0 1 (25) -- --

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Table 2. Response during and after treatment

Cohort A: Pre-transplantation Cohort B: Post-transplantation
Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7
Response CTP B CTP C No cirrhosis CTP A CTP B CTP C FCH

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12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks
(n=30) (n=29) (n=23) (n=26) (n=55) (n=56) (n=26) (n=25) (n=26) (n=26) (n=5) (n=4) (n=4) (n=2)

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HCV RNA <LLOQ on treatment

11/30 12/29 9/23 10/26 27/55 23/55 9/26 7/25 2/25 11/26 2/5 1/4 2/4
At week 2 0/2

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(37) (41) (39) (38) (49) (42) (35) (28) (8) (42) (40) (25) (50)

25/30 24/29 23/23 22/26 48/55 50/55 23/26 20/25 18/25 23/26 5/5 4/4 4/4 1/2
At week 4
(83) (83) (100) (85) (87) (91) (88) (80) (72) (88) (100) (100) (100) (50)

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30/30 29/29 22/22 25/26 53/55 55/55 25/25 25/25 25/25 26/26 5/5 4/4 4/4 1/2
At week 6

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(100) (100) (100) (96) (96) (100) (100) (100) (100) (100) (100) (100) (100) (50)

HCV RNA <LLOQ after treatment

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27/30 24/27 20/22* 22/23 53/55 55/56 25/26 25/25 23/26 24/26 5/5 3/4 4/4 2/2
At week 4 (SVR4)
(90) (89) (91) (96) (96) (98) (96) (100) (88) (92) (100) (75) (100) (100)

26/30 24/27 19/22 20/23 53/55 55/56 25/26 24/25 22/26 23/26 3/5 3/4 4/4 2/2
At week 12 (SVR12)

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(87) (89) (86) (87) (96) (98) (96) (96) (85) (88) (60) (75) (100) (100)

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90% CI 72-95 74-97 68-96 70-96 89-99 92-100 83-100 82-100 68-95 73-97 19-92 25-99 47-100 22-100

Virologic failure
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Breakthrough 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Relapse 3 1 1 2 2 0 0 0 1 0 2 1 0 0
*Patients transplanted with HCV RNA<LLOQ prior to the post-treatment visit window are excluded from analysis
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Table 3. Rates of Serious Adverse Events and Adverse Events Leading to Study Drug Discontinuation

Cohort A: Pre-transplantation Cohort B: Post-transplantation

CTP B CTP C No cirrhosis CTP A CTP B CTP C FCH

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Characteristic
12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks
(n=30) (n=29) (n=23) (n=26) (n=55) (n=56) (n=26) (n=25) (n=26) (n=26) (n=5) (n=4) (n=4) (n=2)

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Any adverse event 29 (97) 28 (97) 23 (100) 26 (100) 55 (100) 55 (98) 25 (96) 24 (96) 25 (96) 26 (100) 5 (100) 4 (100) 4 (100) 2 (100)
Serious adverse event 3 (10) 10 (34) 6 (26) 11 (42) 6 (11) 12 (21) 3 (12) 4 (16) 5 (19) 11 (42) 1 (20) 3 (75) 1 (25) 1 (50)

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D/c of LDV-SOF due to: 0 2 (7) 1 (4) 2 (8) 0 2 (4) 1 (4) 0 2 (8) 3 (12) 0 0 0 0
Sepsis 0 2 (7) 0 0 0 0 0 0 0 0 0 0 0 0
Gastric hemorrhage 0 1 (3) 0 0 0 0 0 0 1 (4) 0 0 0 0 0

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Acute renal failure 0 0 0 1 (4) 0 0 0 0 0 1 (4) 0 0 0 0

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ALT increased 0 0 0 0 0 1 (2) 0 0 0 0 0 0 0 0
AST increased 0 0 0 0 0 1 (2) 0 0 0 0 0 0 0 0
Aortic dissection 0 0 0 0 0 0 0 0 0 1 (4) 0 0 0 0

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Chest pain 0 0 0 0 0 0 0 0 1 (4) 0 0 0 0 0
Convulsion 0 0 0 0 0 0 0 0 0 1 (4) 0 0 0 0

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Diarrhea 0 0 0 0 0 0 0 0 1 (4) 0 0 0 0 0

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Dyspnea 0 0 0 0 0 1 (2) 1 (4) 0 0 0 0 0 0 0
Infection 0 0 1 (4) 0 0 0 0 0 0 0 0 0 0 0
Hepatic encephalopathy 0 0 0 1 (4) 0 0 0 0 0 0 0 0 0 0
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Hepatic hydrothorax 0 0 1 (4) 0 0 0 0 0 0 0 0 0 0 0
Hypotension 0 0 0 1 (4) 0 0 0 0 0 0 0 0 0 0
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Peritoneal hemorrhage 0 0 0 0 0 0 0 0 0 1 (4) 0 0 0 0

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Shock 0 0 0 0 0 0 0 0 0 1 (4) 0 0 0 0
Vomiting 0 0 0 0 0 0 0 0 1 (4) 0 0 0 0 0

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Figure 1. Patient Disposition

Pre-transplantation Post-transplantation

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CTP B CTP C No cirrhosis CTP A CTP B CTP C FCH

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N = 59 N = 49 N = 111 N = 51 N = 52 N=9 N=6

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30 assigned 29 assigned 23 assigned 26 assigned 55 assigned 56 assigned 26 assigned 25 assigned 26 assigned 26 assigned 6 assigned 4 assigned 4 assigned 3 assigned
to 12 weeks to 24 weeks to 12 weeks to 24 weeks to 12 weeks to 24 weeks to 12 weeks to 24 weeks to 12 weeks to 24 weeks to 12 weeks to 24 weeks to 12 weeks to 24 weeks

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of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF of LDV-SOF
+ RBV + RBV + RBV + RBV + RBV + RBV + RBV + RBV + RBV + RBV + RBV + RBV + RBV + RBV

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5 began 2 began
treatment treatment

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4 d/c 2 d/c 4 d/c 5 d/c 2 d/c 3 d/c 4 d/c 1 d/c
treatment treatment treatment treatment treatment treatment treatment treatment
2 due to AE 1 due to AE 2 due to AE 2 due to AE 1 due to AE 2 due to AE 2 due to AE due to

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2 had LT 1 had LT 1 had LT 1 w/d cons 1 died 1 Invest. 2 died protocol
1 died 1 LTFU decision violation
1 non-adh

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30 25 21 22 55 51 24 25 23 22
5 completed 3 completed 4 completed 2 completed
completed completed completed completed completed completed completed completed completed completed
treatment treatment treatment treatment
treatment treatment treatment treatment treatment treatment treatment treatment treatment treatment
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30 assessed 27 assessed 22 assessed 23 assessed 55 assessed 56 assessed 26 assessed 25 assessed 26 assessed 26 assessed 5 assessed 4 assessed 4 assessed 2 assessed
for efficacy for efficacy for efficacy for efficacy* for efficacy for efficacy for efficacy for efficacy for efficacy for efficacy for efficacy for efficacy for efficacy for efficacy

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Supplementary Appendix

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

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their work.

Supplement to:

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Michael Charlton, Gregory T. Everson, Steven L. Flamm, et al.

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Ledipasvir and sofosbuvir plus ribavirin for chronic hepatitis C virus infection in patients with

advanced liver disease (SOLAR-1): a multicenter, randomized, open-label, phase 2 study

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Table of Contents
Page

Criteria for determination of presence/absence of cirrhosis 3

Table 1. Child-Pugh Scoring System 4

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ILTS Criteria for Fibrosing Cholestatic Hepatitis 5

Table 2. Reasons for Screen Failure 6

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Table 3. Patients with HCV RNA <15 IU/mL While on Treatment by Visit 8

Table 4. Characteristics of patients who did not achieve SVR12

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Figure 1. Outcomes in Patients in Cohort A 12

Figure 2. Outcomes in Patients in Cohort B 12

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Figure 3. Change in CTP Score from Baseline to Post-treatment Week 4 13
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Figure 4. Change in MELD Score from Baseline to Post-treatment Week 12

Table 5. Change in Liver Function Labs from Baseline to Follow-up Week 4 14

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Figure 6. Bilirubin and HCV RNA in Patients with Fibrosing Cholestatic Hepatitis 18

Table 6. Outcomes in Patients in Cohort A Who Underwent Transplantation 18

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Table 7. Outcomes in Patients with Genotype 4 HCV 19

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Table 8. Immunosuppressive Regimens 20

Table 9. Serious Adverse Events 23

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Table 10. Treatment-emergent Deaths 31

Table 11. Ribavirin Dosing, Hemoglobin Levels, and Anti-anemic Therapy 32

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Criteria for Determination of the Presence/Absence of Cirrhosis

For the purposes of this trial, cirrhosis was defined as any one of the following:

• Liver biopsy showing cirrhosis

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• Fibroscan (in countries where locally approved) showing cirrhosis or results >12.5 kPa

• A FibroTest score of >0.75 AND an AST to platelet ratio index (APRI) of >2 performed

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during screening

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Absence of cirrhosis was defined as any one of the following:

• Liver biopsy within 2 years of Screening showing absence of cirrhosis

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• Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa within ≤6
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months of Baseline/Day1

• A FibroTest score of ≤0.48 AND APRI of ≤1 performed during Screening

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In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria,
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a liver biopsy was required; liver biopsy results superseded blood test results and were
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considered definitive.
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Table 1. Child-Pugh Scoring

The Child–Pugh scoring system uses five clinical measures of liver disease. Each measure is

assigned a score of 1 to 3 points, with 3 points indicating the most severe derangement. Scores

on the five measures are then summed to determine the overall severity of disease, with a sum of

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5 or 6 points indicating class A disease, 7 to 9 points class B, and 10 to 15 points class C, or the

RI
most severe disease. Patients with Child-Pugh class A disease have mild hepatic impairment

(compensated cirrhosis), patients with Child-Pugh class B disease have moderate hepatic

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impairment, and those with Child-Pugh class C disease have severe hepatic impairment. Patients

with both Child-Pugh class B and C disease have liver decompensated cirrhosis.

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Points
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1 2 3

Grade 1-2 Grade 3-4

Encephalopathy None
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(or precipitant-induced) (or chronic)

Mild/Moderate Severe
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Ascites None
(diuretic-responsive) (diuretic-refractory)

Bilirubin (mg/dL) <2 2-3 >3

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Albumin (g/dL) >3.5 2.8-3.5 <2.8

INR <1.7 1.7-2.3 >2.3

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Criteria for Diagnosis of Fibrosing Cholestatic Hepatitis

To be classed as having fibrosing cholestatic hepatitis, patients had to meet all the following

criteria of the International Liver Transplantation Society:*

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(1) longer than 1 month posttransplantation (usually 6 months)

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(2) serum bilirubin level greater than 6 mg/dL

(3) serum alkaline phosphatase and γ-glutamyltransferase levels greater than five times

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the upper limits of normal

(4) characteristic histological state with ballooning of hepatocytes predominantly in the

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perivenular zone (not necrosis or fallout), paucity of inflammation, and variable
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degrees of cholangiolar proliferation without bile duct loss

(5) very high serum HCV RNA levels

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(6) absence of surgical biliary complications (normal cholangiogram) and absence of

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evidence for hepatic artery thrombosis

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*Wiesner RH, Sorrell M, Villamil F, et al. Report of the first International Liver Transplantation Society Expert
Panel Consensus Conference on Liver Transplantation and Hepatitis C. Liver Transplant 2003;9(Suppl 3):S1-S9.
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Table 2. Reasons for Screen Failure

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Table 3A. Patients with HCV RNA <15 IU/mL While on Treatment by Visit: Cohort A

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Table 3B. Patients with HCV RNA <15 IU/mL While on Treatment by Visit: Cohort B, Group 3

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Table 3C. Patients with HCV RNA <15 IU/mL While on Treatment by Visit: Cohort B, Groups 4-6

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Table 3D. Patients with HCV RNA <15 IU/mL While on Treatment by Visit: Cohort B, Group 7

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Table 4. Characteristics of Patients Who Relapsed

Cohort Group Treatment Age Sex Race BMI Genotype IL28B HCV CPT MELD Timing of relapse
duration RNA

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A 1 12 weeks 61 M Black 34 1a TT 6.6 7 13 By post-treatment week 8

A 1 12 weeks 45 M White 28 1b CT 6.5 8 12 By post-treatment week 4

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A 1 12 weeks 61 M White 34 1b CT 6.0 10 13 By post-treatment week 8

A 1 24 weeks 59 M White 45 1a TT 6.4 7 11 By post-treatment week 4

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A 2 12 weeks 59 M White 34 1b CC 5.7 12 14 By post-treatment week 4

A 2 24 weeks 48 M Black 24 1a CT 6.8 9 17 By post-treatment week 12

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A 2 24 weeks 54 M White 34 1a CT 5.8 11 15 By post-treatment week 12

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B 3 12 weeks 63 M White 25 1a CT 6.3 5 13 By post-treatment week 4

B 3 12 weeks 66 M White 25 1a CC 6.1 5 8 By post-treatment week 4

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B 5 12 weeks 60 M White 35 1b CT 6.7 8 15 By post-treatment week 2

B 6 12 weeks 58 M White 39 1a CT 5.8 10 15 By post-treatment week 8

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B 6 12 weeks 57 M White 31 1a CC 6.3 11 17 By post-treatment week 8

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B 6 24 weeks 59 M White 24 1a CT 6.7 10 15 By post-treatment week 2
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Figure 2. Outcomes in Patients in Cohort A

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Figure 3. Outcomes in Patients in Cohort B

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Figure 4. Change in CTP Score from Baseline to Follow-up Week 4 in CPT B and C Patients

Pretransplant

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Missing FU-4: n=2 CPT B 12 wk; n=5 CPT B 24 wk; n=2 CPT C 12 wk; n=5 CPT C 24 wk
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Post-transplantation
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Missing FU-4: n=4 CPT B 12 wk; n=6 CPT B 24 wk; n=1 CPT C 12 wk; n=0 CPT C 24 wk

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Figure 5. Change in MELD Score from Baseline to Follow-up Week 12 in CPT B and C Patients

Pretransplant

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Post-transplantation
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Table 5A. Albumin, Total Bilirubin, Serum Creatinine, INR, and Platelet Count for Subjects
With Decompensated (CPT B and CPT C) Cirrhosis in Cohort A (Groups 1 and 2)
CPT B (Group 1) CPT C (Group 2)
LDV/SOF+RBV LDV/SOF+RBV LDV/SOF+RBV LDV/SOF+RBV
12 Week 24 Week 12 Week 24 Week
Median Median Median Median
N (Q1, Q3) N (Q1, Q3) N (Q1, Q3) N (Q1, Q3)

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Albumin (g/dL)
Baseline 30 2.9 (2.6, 3.2) 29 3.0 (2.8, 3.1) 23 2.6 (2.2, 2.8) 26 2.6 (2.2, 2.9)
Posttreatment Week 4 27 3.2 (2.9, 3.4) 26 3.4 (2.9, 3.5) 19 2.8 (2.5, 2.9) 19 3.0 (2.7, 3.4)

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Change From
Baseline to 27 0.2 (0.0, 0.5) 26 0.4 (0.2, 0.5) 19 0.1 (0.0, 0.2) 19 0.4 (0.1, 0.9)
Posttreatment Week 4
Total Bilirubin (mg/dL)

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Baseline 30 2.0 (1.6, 2.4) 29 1.4 (1.1, 1.9) 23 2.9 (1.7, 3.6) 26 3.8 (2.7, 4.6)
Posttreatment Week 4 27 1.6 (0.9, 2.1) 26 1.1 (0.9, 1.5) 19 1.9 (1.4, 2.3) 19 2.7 (1.6, 3.5)
Change From

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Baseline to 27 −0.4 (−1.0, 0.1) 26 −0.4 (−0.6, 0.1) 19 −1.0 (−1.5, −0.1) 19 −1.0 (−2.3, −0.4)
Posttreatment Week 4
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Serum Creatinine (mg/dL)
Baseline 30 0.77 (0.68, 0.93) 29 0.85 (0.76, 0.99) 23 0.99 (0.80, 1.14) 26 0.82 (0.73, 0.99)
Posttreatment Week 4 27 0.78 (0.64, 0.88) 26 0.85 (0.74, 0.98) 19 0.87 (0.63, 1.07) 19 0.90 (0.75, 1.21)
Change From
M

−0.03 0.02 −0.11

Baseline to 27 26 19 19 0.06 (−0.03, 0.19)
(−0.09, 0.07) (−0.03, 0.07) (−0.16, 0.00)
Posttreatment Week 4
INR
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Baseline 30 1.3 (1.2, 1.4) 29 1.3 (1.2, 1.4) 23 1.4 (1.2, 1.5) 26 1.4 (1.3, 1.5)
Posttreatment Week 4 27 1.2 (1.1, 1.3) 26 1.2 (1.1, 1.3) 19 1.3 (1.2, 1.4) 18 1.3 (1.2, 1.4)
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Change From
Baseline to 27 0.0 (−0.1, 0.0) 26 0.0 (−0.1, 0.0) 19 0.0 (0.0, 0.1) 18 0.0 (−0.2, 0.0)
Posttreatment Week 4
µL)
Platelet Count (× 103/µ
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Baseline 30 88 (61, 120) 29 73 (63, 91) 23 81 (51, 99) 26 71 (53, 79)

Posttreatment Week 4 25 77 (65, 109) 26 70 (51, 88) 19 82 (55, 109) 17 68 (56, 84)
Change From
C

Baseline to 25 −10 (−15, 2) 26 −7 (−19, 9) 19 1 (−14, 11) 17 −3 (−11, 7)

Posttreatment Week 4

Note: Baseline value was the last available value on or prior to first dose date of any study drug.
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Note: Data were included to last dose date of any study drug + 30 days.

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Table 5B. Albumin, Total Bilirubin, Serum Creatinine, INR, and Platelet Count for
Posttransplantation Subjects With Stage F0-F3 Fibrosis in Cohort B (Group 3)
Stage F0-F3 Fibrosis (Group 3)
LDV/SOF+RBV LDV/SOF+RBV
12 Weeks 24 Weeks
N Median (Q1, Q3) N Median (Q1, Q3)

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Albumin (g/dL)
Baseline 55 3.9 (3.5, 4.1) 56 3.8 (3.6, 4.1)
Posttreatment Week 4 43 4.0 (3.7, 4.2) 42 4.1 (3.9, 4.3)

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Change From Baseline to
43 0.1 (0.0, 0.4) 42 0.2 (0.0, 0.5)
Posttreatment Week 4
Total Bilirubin (mg/dL)

SC
Baseline 55 0.7 (0.5, 1.0) 56 0.7 (0.5, 1.0)
Posttreatment Week 4 43 0.5 (0.3, 0.7) 42 0.5 (0.4, 0.6)
Change From Baseline to
43 −0.2 (−0.3, −0.1) 42 −0.3 (−0.6, −0.1)
Posttreatment Week 4

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Serum Creatinine (mg/dL)
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Baseline 55 1.26 (1.04, 1.57) 56 1.09 (0.95, 1.39)
Posttreatment Week 4 43 1.31 (1.06, 1.43) 42 1.08 (0.96, 1.29)
Change From Baseline to
43 −0.03 (−0.11, 0.10) 42 0.03 (−0.02, 0.10)
Posttreatment Week 4
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INR
Baseline 55 1.0 (1.0, 1.1) 56 1.0 (1.0, 1.1)
Posttreatment Week 4 43 1.0 (1.0, 1.0) 42 1.0 (1.0, 1.0)
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Change From Baseline to

43 0.0 (0.0, 0.1) 42 0.0 (−0.1, 0.0)
Posttreatment Week 4
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µL)
Platelet Count (× 103/µ
Baseline 55 143 (123, 196) 56 152 (108, 206)
Posttreatment Week 4 41 151 (125, 191) 41 159 (124, 183)
EP

Change From Baseline to

41 7 (−9, 20) 41 9 (0, 23)
Posttreatment Week 4

Note: Baseline value was the last available value on or prior to first dose date of any study drug.
Note: Data were included to last dose date of any study drug + 30 days.
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Table 5C. Albumin, Total Bilirubin, Serum Creatinine, INR, and Platelet Count for Disposition of Posttransplantation Subjects With
Cirrhosis in Cohort B (Groups 4, 5, and 6)
CPT A (Group 4) CPT B (Group 5) CPT C (Group 6)

PT
LDV/SOF+ RBV LDV/SOF +RBV LDV/SOF +RBV LDV/SOF +RBV LDV/SOF +RBV LDV/SOF +RBV
12 Weeks 24 Weeks 12 Weeks 24 Weeks 12 Weeks 24 Weeks
(N = 26) (N = 25) (N = 26) (N = 26) (N = 5) (N = 4)
Median Median Median Median Median Median

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N N N N N N
(Q1, Q3) (Q1, Q3) (Q1, Q3) (Q1, Q3 (Q1, Q3 (Q1, Q3
Albumin (g/dL)

SC
Baseline 26 3.7 (3.4, 4.0) 25 3.5 (3.2, 3.9) 26 3.2 (2.7, 3.6) 26 3.3 (3.0, 3.6) 5 2.3 (2.0, 2.4) 4 2.5 (2.1, 2.7)
Posttreatment Week 4 19 3.9 (3.5, 4.2) 22 3.9 (3.7, 4.2) 18 3.5 (3.1, 4.1) 23 3.6 (3.4, 3.9) 4 2.6 (2.5, 2.6) 3 3.2 (2.1, 3.3)
Change From Baseline to
19 0.2 (0.0, 0.4) 22 0.3 (0.2, 0.4) 18 0.4 (0.1, 0.6) 23 0.5 (0.0, 0.6) 4 0.4 (0.2, 0.7) 3 0.5 (0.4, 0.7)

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Posttreatment Week 4
Total Bilirubin (mg/dL)

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Baseline 26 0.9 (0.6, 1.2) 25 0.8 (0.6, 1.2) 26 1.5 (0.8, 2.4) 26 1.1 (0.8, 1.6) 5 2.1 (1.1, 2.4) 4 2.2 (1.6, 3.0)
Posttreatment Week 4 19 0.7 (0.4, 1.0) 22 0.5 (0.3, 0.8) 18 0.7 (0.3, 1.2) 23 0.7 (0.4, 1.1) 4 1.4 (0.6, 4.2) 3 1.8 (0.5, 1.9)
Change From Baseline to −0.5 −0.4 −0.4
19 −0.2 (−0.5, 0.0) 22 −0.4 (−0.7, 0.0) 18 23 4 3 −1.6 (−2.0, 0.4)

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Posttreatment Week 4 (−1.2, −0.2) (−0.6, −0.1) (−2.1, −0.2)
Serum Creatinine (mg/dL)
1.19 0.97 1.12 1.35 1.14 1.47

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Baseline 26 25 26 26 5 4
(0.91, 1.45) (0.89, 1.26) (0.95, 1.29) (1.07, 1.51) (1.02, 1.21) (1.28, 1.90)
1.13 1.15 1.09 1.34 1.17 1.29

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Posttreatment Week 4 19 22 18 22 4 3
(0.99, 1.35) (0.89, 1.29) (0.88, 1.25) (1.17, 1.47) (1.11, 1.29) (1.15, 1.60)
Change From Baseline to 0.00 0.03 −0.06 −0.04 0.04 −0.03
19 22 18 22 4 3
Posttreatment Week 4 (−0.06, 0.06) (−0.04, 0.17) (−0.14, 0.08) (−0.17, 0.06) (0.01, 0.09) (−0.16, 0.04)
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INR
Baseline 26 1.1 (1.0, 1.1) 25 1.1 (1.0, 1.2) 26 1.2 (1.1, 1.3) 26 1.2 (1.1, 1.3) 5 1.2 (1.2, 1.3) 4 1.3 (1.2, 1.4)
Posttreatment Week 4 18 1.1 (1.1, 1.2) 22 1.1 (1.0, 1.1) 17 1.1 (1.0, 1.3) 21 1.1 (1.1, 1.2) 4 1.3 (1.2, 1.5) 3 1.1 (1.0, 1.2)
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Change From Baseline to

18 0.0 (0.0, 0.1) 22 0.0 (−0.1, 0.0) 17 0.0 (0.0, 0.1) 21 0.0 (−0.1, 0.0) 4 0.1 (−0.1, 0.2) 3 −0.1 (−0.3, 0.1)
Posttreatment Week 4
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µL)
Platelet Count (× 103/µ
Baseline 25 106 (75, 138) 25 112 (88, 168) 26 93 (73, 121) 26 97 (66, 125) 5 106 (63, 160) 3 65 (54, 93)
Posttreatment Week 4 17 83 (76, 126) 22 124 (91, 181) 18 94 (62, 107) 22 107 (74, 136) 4 127 (76, 167) 3 93 (69, 142)
Change From Baseline to
17 −1 (−5, 7) 22 4 (−14, 26) 18 4 (−13, 15) 22 12 (−13, 33 4 −9 (−20, 4) 2 46 (15, 77)
Posttreatment Week 4

Note: Baseline value was the last available value on or prior to first dose date of any study drug. Data were included to last dose date of any study drug + 30 days.

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Table 5D. Albumin, Total Bilirubin, Serum Creatinine, INR, and Platelet Count for
Posttransplantation Subjects with Fibrosing Cholestatic Hepatitis in Cohort B (Group 7)
Fibrosing Cholestatic Hepatitis (Group 7)
LDV/SOF+RBV LDV/SOF+RBV
12 Weeks 24 Weeks
N Median (Q1, Q3) N Median (Q1, Q3)

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Albumin (g/dL)
Baseline 4 2.7 (2.4, 3.2) 2 3.0 (2.7, 3.2)
Posttreatment Week 4 3 3.8 (3.7, 3.9) 1 4.3

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Change From Baseline to
3 1.3 (1.0, 1.5) 1 1.1
Posttreatment Week 4
Total Bilirubin (mg/dL)

SC
Baseline 4 5.0 (2.8, 9.3) 2 18.4 (8.6, 28.1)
Posttreatment Week 4 3 0.8 (0.7, 0.8) 1 0.4
Change From Baseline to
3 −3.1 (−5.3, −0.9) 1 −8.2
Posttreatment Week 4

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Serum Creatinine (mg/dL)
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Baseline 3 0.89 (0.84, 1.71) 1 1.00
Posttreatment Week 4 3 1.11 (0.95, 1.58) 1 1.05
Change From Baseline to
3 0.11 (−0.13, 0.22) 1 0.05
Posttreatment Week 4
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INR
Baseline 4 1.2 (1.1, 2.4) 2 1.1 (1.0, 1.2)
Posttreatment Week 4 3 1.1 (0.9, 1.1) 1 1.0
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Change From Baseline to

3 −0.1 (−0.2, 0.0) 1 0.0
Posttreatment Week 4
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µL)
Platelet Count (× 103/µ
Baseline 4 45 (42, 131) 2 196 (182, 210)
Posttreatment Week 4 3 62 (54, 106) 1 138
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Change From Baseline to

3 22 (9, 62) 1 −44
Posttreatment Week 4
Alkaline Phosphatase (U/L)
Baseline 4 213 (152, 317) 2 142 (114, 170)
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Posttreatment Week 4 3 153 (71, 199) 1 63

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Change From Baseline to

3 −88 (−49, 15) 1 −51
Posttreatment Week 4
GGT (U/L)
Baseline 4 371 (265, 628) 1 740
Posttreatment Week 4 3 126 (29, 254) 1 70
Change From Baseline to
3 −417 (−683, 20) 1 −670
Posttreatment Week 4

Note: Baseline value was the last available value on or prior to first dose date of any study drug.

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Figure 6. Bilirubin and HCV RNA in Patients with Fibrosing Cholestatic Hepatitis (Group 7)

Total bilirubin over time

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HCV RNA over time
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Table 6. Outcomes in Patients with Genotype 4 HCV

BL Timing of
Pt ID Group Duration Age Sex Race Outcome
MELD transplant

75247 1 12 weeks 68 F White 12 N/A SVR12

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75223 2 12 weeks 71 M White 13 N/A SVR12

75202 2 12 weeks 49 M White 19 N/A LTFU after achieving SVR4

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75388 3 12 weeks 55 F White N/A SVR12

Died on day 75 of treatment of

75527 5 24 weeks 61 M White 7
complications relating to cirrhosis

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Table 7. Patients in Cohort A Who Underwent Transplantation

Treatment BL
Age Sex Race Timing of transplant Outcome
group CPT

Child- 24 weeks 47 M White 9 Day 157 of treatment pTVR24

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Pugh B 24 weeks 69 M White 8 Day 138 of treatment pTVR24

12 weeks 59 M White 10 Day 21 of treatment Died 1 day after pTVR2

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12 weeks 50 M White 11 131 days after last dose SVR12 and pTVR24
Child-
24 weeks 58 F White 12 Day 91 of treatment pTVR24
Pugh C
24 weeks 57 M White 10 9 days after last dose pTVR24

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24 weeks 60 M White 11 9 days after last dose pTVR24

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Table 8A. Immunosuppressive Regimens in Cohort B, Group 3

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Table 8B. Immunosuppressive Regimens in Cohort B, Group 4, 5, and 6

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Table 8C. Immunosuppressive Regimens in Cohort B, Group 7

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Table 9. Serious Adverse Events

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Table 9. Serious Adverse Events (continued)

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Table 9. Serious Adverse Events (continued)

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Table 9. Serious Adverse Events (continued)

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Table 9. Serious Adverse Events (continued)

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Table 9. Serious Adverse Events (continued)

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Table 9. Serious Adverse Events (continued)

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Table 10. Treatment-Emergent Deaths

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Table 11. Hemoglobin Levels during Treatment, Ribavirin Dosing, and Anti-anemic Therapy
Cohort A: Pre-transplantation Cohort B: Post-transplantation
Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7
Characteristic CTP B CTP C No cirrhosis CTP A CTP B CTP C FCH

PT
12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks 12 wks 24 wks
(n=30) (n=29) (n=23) (n=26) (n=55) (n=56) (n=26) (n=25) (n=26) (n=26) (n=5) (n=4) (n=4) (n=2)
Post-baseline hemoglobin

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<10 g/dL, n (%) 5 (17) 8 (28) 6 (26) 7 (27) 26 (47) 21 (38) 13 (50) 9 (36) 10 (40) 18 (69) 4 (80) 3 (75) 1 (25) 1 (50)
<8.5 g/dL, n (%) 1 (3) 2 (7) 1 (4) 4 (15) 9 (16) 7 (13) 4 (15) 4 (16) 2 (8) 6 (23) 1 (20) 1 (25) 1 (25) 1 (50)

SC
Ribavirin dosing
Median daily dose, mg 698 (271, 600 (433, 600 (322, 600 (207, 936 (332, 1000 (260, 1000 991 (293, 600 (200, 600 (249, 552 (300, 462 (283, 845 (600, 674 (648,
(range) 1200) 1200) 1200) 1200) 1200) 1200) (571,1200) 1200) 1200) 1200) 600) 1120) 1200) 700)

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168 (6, 167 (2, 84 (31, 168 (8, 168 (32, 166 (16, 85 (42, 145 (25, 147 (124,
Median days, n (range) 85 (83, 88) 85 (5, 86) 84 (25, 90) 85 (4, 88) 84 (8, 85)
173) 174) 88) 172) 171) 171) 88) 174) 170)

AN
Discontinued RBV, n (%) 0 6 (21) 3 (13) 10 (38) 5 (9) 12 (21) 4 (15) 2 (8) 7 (27) 9 (35) 2 (40) 1 (25) 1 (25) 1 (50)
Reduced dose, n (%) 9 (30) 10 (34) 7 (30) 12 (46) 32 (58) 22 (39) 12 (46) 14 (56) 7 (27) 12 (46) 3 (60) 3 (75) 2 (50) 2 (100)

M
Anti-anemic therapy
Erythropoietin use, n (%) 0 0 1 (4) 2 (8) 9 (16) 5 (9) 2 (8) 3 (12) 3 (12) 5 (19) 1 (20) 2 (50) 0 1 (50)

D
Blood transfusion, n (%) 0 0 1 (4) 3 (12) 5 (9) 2 (4) 1 (4) 3 (12) 1 (4) 4 (15) 0 0 1 (25) 0

TE
C EP
AC

33