Conditions: HIV-1 Infection Hepatitis
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 44
Healthy volunteers: no

Brief summary:
Early identification of acute HCV infection is essential to prevent chronic infections and the long-term liver disease complications that may occur. Early identification and treatment of HCV during the acute phase can result in significantly higher response rates with shorter durations of therapy.

Pegylated-interferon alfa (PEG-IFN) was the typical treatment for HCV infection. Participants subcutaneously inject PEG-IFN where the average duration of treatment was approximately 20 weeks. With the advancement of direct-acting antivirals (DAAs), it was possible to see if a new DAA might be non-inferior compared to (PEG-IFN).

The study was designed to see if a fixed-dose combination tablet can replace the old HCV treatments by being more effective, safer and better tolerated in HIV-infected participants with new HCV infection. The study was a Phase I, open-label, two cohort clinical trial, in which 44 acutely HCV-infected HIV-1 positive participants were enrolled. Participants in each cohort were evaluated in two steps: on treatment (Step 1) and follow-up after discontinuing study treatment (Step 2). The cohorts were enrolled sequentially. Participants in Cohort 1 were enrolled and administered oral Sofosbuvir (SOF) in combination with weight-based ribavirin (RBV). Participants in Cohort 2 were enrolled and administered an oral fixed dose combination of Ledipasvir/Sofosbuvir (LDV/SOF).

Detailed description:
The first cohort opened with SOF/RBV treatment for 12 weeks and accrued 17 participants. All participants under Cohort 1 were to visit the clinical site at weeks 0, 1, 2, 4, 8, and 12 when on treatment (Step 1), then visit the clinical site again at 2, 4, 8, 12 and 24 weeks during follow-up after discontinuing study treatment (Step 2).

The second cohort opened for an 8-week treatment of LDV/SOF and included at least 27 subjects. All participants under Cohort 2 were to visit the clinical site at weeks 0, 1, 2, 4, and 8 when on treatment (Step 1), then visit the clinical site again at 2, 4, 8, 12 and 24 weeks during follow-up after discontinuing study treatment (Step 2).

Both cohorts were monitored for safety and HCV viral load response while the participants were on treatment.

The primary objective did not compare the cohorts together; instead, each study cohort was formally assessed for efficacy with sustained virologic response 12 weeks after treatment based on non-inferiority criteria compared to a historical SVR rate of 60% separately.

Arms:
arm 1: Participants in Cohort 1 were assigned Sofosbuvir (SOF)+weight-based ribavirin (RBV) for 12 weeks. Follow-up visits occurred through to 24 weeks after the end of treatment. arm 2: Participants in Cohort 2 were assigned Ledipasvir/Sofosbuvir for 8 weeks. Follow-up visits occurred through to 24 weeks after the end of treatment.

Interventions: intervention 1: Sofosbuvir intervention 2: Ribavirin intervention 3: Ledipasvir/Sofosbuvir
Intervention descriptions: intervention 1: Participants received one 400 mg tablet of sofosbuvir (SOF) orally every morning with food intervention 2: Participants received weight-based ribavirin RBV orally, 2 times a day, every morning and every evening, with food. Weight under 75 kg, 600 mg (3 tablets) morning and 400 mg (2 tablets) evening. Weight over 75 kg, 600 mg (3 tablets) morning and 600 mg (3 tablets) evening. The dose of RBV was based on subject's weight at entry. Changes in weight after entry did not require a change in dose. Doses were only changed for toxicity management. intervention 3: Participants received one daily fixed-dose combination tablet orally every morning of 90 mg of Ledipasvir (LDV) and 400 mg of SOF.

Protocol document:
Prot_002.pdf: 
 
 
 
A5327 
 
Sofosbuvir-Containing Regimens Without Interferon For 
Treatment of Acute HCV in HIV-1 Infected Individuals 
(SWIFT-C) 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
DA/DS ES # 11924 
 
This file contains the current ACTG A5327 protocol, which 
includes the following documents, presented in reverse 
chronological order: 
 
• Clarification Memorandum #1, dated 8 October 2015 
• Letter of Amendment #1, dated 10 October 2016 
• Clarification Memorandum #2, dated 1 November 2016 
• Protocol Version 2.0, dated 2 July 2015 


 
 
Clarification Memorandum #1 for: 
 
ACTG A5327 
Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute HCV 
in HIV-1 Infected Individuals (SWIFT-C)” 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 11924 
Clarification Memo Date: 8 October 2015 
 
 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your IRB; however, 
as always, you must follow your IRB's policies and procedures. If IRB review of 
clarification memos is required at your site, please submit this document for review. 
 
Each site should file a copy of this clarification memo with the protocol for reference. 
 
The protocol clarifications contained in this memo should be implemented immediately. 
These updates will be included in the next version of the A5327 protocol if it is amended 
at a future date. 
 
The following are clarifications (in bold font or strikethrough) to protocol A5327, Version 2.0, 
07/02/15: 
1. Section 6.3.5 is clarified as follows: 
Pregnancy Test 
For women with reproductive potential: a negative urine or serum β-HCG result by 
any US clinic or laboratory that has a CLIA certification or its equivalent, or is 
using a POC/CLIA-waived test, documenting a negative result will be required within 
48 hours prior to study entry and during study follow-up. The test should must 
have a sensitivity of at least 25 mIU/mL. 
 
Once a participant has enrolled with a negative documented serum pregnancy test 
and begins using 2 forms of contraception to prevent pregnancy, further testing per 
section 6.1 (during study drug dosing and in post treatment followup) can be urine 
testing. Urine test must have a sensitivity of at least 50 mIU/mL; if positive, must 
have immediate confirmation with serum b-HCG. 
 
2. The first paragraph in section 10.2, Pharmacology Study Design, is clarified as follows: 
 
Plasma and DBS will be obtained from all participants prior to initiation of SOF+RBV 
or LDV/SOF, at entry, weeks 1, 2, 4, 8, and 12 following SOF+RBV or LDV/SOF 
 
Clarification Memorandum #1 
Page 1 of 2 
8 October 2015 
ACTG A5327 Protocol Version 2.0 


 
 
initiation (weeks 8 and 12 only in those who receive 12 weeks of treatment), HCV VF 
Confirmation, and HIV-1 VF Confirmation, and premature discontinuation visits, and 
at weeks 2, 4, 8, and 12 post-treatment. Samples are collected prior to treatment 
initiation and after discontinuing treatment in the event there is a need to 
retrospectively evaluate the potential for ARV drug interactions or adherence, but 
these samples will not be analyzed a priori to limit costs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification Memorandum #1 
Page 2 of 2 
8 October 2015 
ACTG A5327 Protocol Version 2.0 


 
 
Letter of Amendment #1 for: 
 
ACTG A5327 
Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute HCV 
in HIV-1 Infected Individuals (SWIFT-C)” 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 11924 
Letter of Amendment Date: 10 October 2016 
 
 
The following information impacts the A5327 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This Letter of Amendment (LOA) must be approved by your 
IRB/EC before implementation. 
 
The following information also impacts the Sample Informed Consent. Your IRB/EC is 
responsible for determining the process of informing subjects of the contents of this LOA. 
 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit an 
LOA registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory 
Support Center. Sites will receive a registration notification for the LOA once the DAIDS 
PRO verifies that all required LOA registration documents have been received and are 
complete. An LOA registration notification from the DAIDS PRO is not required prior to 
implementing the LOA. A copy of the LOA registration notification, along with this letter and 
any IRB/EC correspondence, should be retained in the site’s regulatory files. 
 
The following are changes to A5327, Version 2.0, 07/02/15 (noted in strikethrough and bold 
font): 
 
The pregnancy risk summary information in the package insert for ledpasvir/sofosbuvir 
(Harvoni) states: 
No adequate human data are available to establish whether or not HARVONI® poses a risk to 
pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental 
outcomes was observed with the components of HARVONI® (ledipasvir or sofosbuvir) at 
exposures greater than those in humans at the recommended human dose (RHD). (Harvoni 
[package insert]. Foster City, CA: Gilead Sciences, Inc.; revised June 2016, section 8.1) 
 
The prior contraception requirement of 6 months after stopping the study drugs was mainly for 
the participants who enrolled in Cohort 1, which was under A5327 Version 1.0, and took 
ribavirin (RBV) as part of their study regimen. Since the participants in Cohort 2, which is under 
A5327 Version 2.0, are not taking RBV the 6-month contraception requirement does not apply. 
 
Letter of Amendment #1 
ACTG A5327 Protocol Version 2.0 
Page 1 of 2 
10 October 2016 


 
 
Therefore, the contraception requirement for Cohort 2 is changed to 30 days after the last dose 
for females and up to 90 days after the last dose for males as recommended by the 
manufacturer. 
 
1. The following changes are made in Step 1 Inclusion Criteria for Cohort 2, section 4.1.13: 
 
When participating in sexual activity that could lead to pregnancy, all participants must 
agree to use at least two reliable forms of contraception contraceptive simultaneously 
while receiving protocol-specified medications, and for 30 days 6 months after stopping 
the medications in female participants and 90 days after stopping medications in 
male participants. Such methods include: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Tubal ligation 
• 
Hormone-based contraceptive 
 
2. The following changes are made in the second paragraph of the ”Are there risks related to 
pregnancy” section of the Sample Informed Consent for Cohort 2: 
 
Because of the potential risk involved and due to the uncertainty of risk to the fetus, you 
and your partner must use at least two methods of birth control that you discuss with the 
study staff. You must continue to use both methods until for 30 days 6 months after 
stopping study drugs for women and 90 days after stopping study drugs for men. 
You must choose two or more of the birth control methods listed below: 
• 
A condom (male or female) with or without a spermicide 
• 
Diaphragm or cervical cap with spermicide 
• 
An intrauterine device (IUD) 
• 
Tubal ligation 
• 
Hormone-based contraceptives 
 
The information above will be incorporated into the next protocol version as necessary if the 
protocol is amended. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Letter of Amendment #1 
ACTG A5327 Protocol Version 2.0 
Page 2 of 2 
10 October 2016 


 
 
 
 
Clarification Memorandum #2 for: 
 
ACTG A5327 
Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute HCV 
in HIV-1 Infected Individuals (SWIFT-C)” 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
DAIDS ES # 11924 
Clarification Memo Date: 1 November 2016 
 
 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your IRB; however, 
as always, you must follow your IRB's policies and procedures. If IRB review of 
clarification memos is required at your site, please submit this document for review. 
 
Each site should file a copy of this clarification memo with the protocol for reference. 
 
The protocol clarifications contained in this memo should be implemented immediately. 
These updates will be included in the next version of the A5327 protocol if it is amended 
at a future date. 
 
The following are clarifications (in bold font or strikethrough) to protocol A5327, Version 2.0, 
07/02/15: 
1. Section 6.3.5 is clarified as follows: 
Pregnancy Test 
For women with reproductive potential: a negative urine or serum β-HCG result by 
any US clinic or laboratory that has a CLIA certification or its equivalent, or is 
using a POC/CLIA-waived test, documenting a negative result will be required within 
48 hours prior to study entry and during study follow-up. The test should must 
have a sensitivity of at least 25 mIU/mL. 
 
Once a participant has enrolled with a negative documented serum pregnancy test 
and begins using 2 forms of contraception to prevent pregnancy, further testing per 
section 6.1 (during study drug dosing and in post treatment followup) can be urine 
testing. Urine test must have a sensitivity of at least 50 mIU/mL; if positive, must 
have immediate confirmation with serum b-HCG. 
 
2. The first paragraph in section 10.2, Pharmacology Study Design, is clarified as follows: 
 
 
 
Clarification Memorandum #2 
ACTG A5327 Protocol Version 2.0 
Page 1 of 2 
1 November 2016 


 
 
Plasma and DBS will be obtained from all participants prior to initiation of SOF+RBV 
or LDV/SOF, at entry, weeks 1, 2, 4, 8, and 12 following SOF+RBV or LDV/SOF 
initiation (weeks 8 and 12 only in those who receive 12 weeks of treatment), HCV VF 
Confirmation, and HIV-1 VF Confirmation, and premature discontinuation visits, and 
at weeks 2, 4, 8, and 12 post-treatment. Samples are collected prior to treatment 
initiation and after discontinuing treatment in the event there is a need to 
retrospectively evaluate the potential for ARV drug interactions or adherence, but 
these samples will not be analyzed a priori to limit costs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification Memorandum #2 
ACTG A5327 Protocol Version 2.0 
Page 2 of 2 
1 November 2016 


 
 
A5327 
 
Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute HCV 
in HIV-1 Infected Individuals (SWIFT-C) 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
The National Institute of Allergy 
and Infectious Diseases 
 
 
Industry Support Provided by: 
Gilead Sciences, Inc. 
 
NON-IND 
 
 
The ACTG Hepatitis Transformative Science Group: 
Raymond Chung, MD, Chair 
Protocol Co-Chairs: 
Susanna Naggie, MD, MHS 
Raymond Chung, MD 
 
DAIDS Clinical Representative: 
Beverly Alston-Smith, MD 
 
Clinical Trials Specialist: 
Jhoanna C. Roa, MD 
 
 
 
 
Final Version 2.0 
July 2, 2015 
 
 
 
 
 
 
 
 
 


A5327 
Final Version 2.0 
07/02/15 
 
 
CONTENTS 
Page 
SITES PARTICIPATING IN THE STUDY .................................................................................... 4 
PROTOCOL TEAM ROSTER ..................................................................................................... 5 
STUDY MANAGEMENT ............................................................................................................. 8 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 10 
SCHEMA .................................................................................................................................. 12 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 14 
1.1 
Hypothesis ......................................................................................................... 14 
1.2 
Primary Objectives ............................................................................................. 14 
1.3 
Secondary Objectives ........................................................................................ 14 
2.0 
INTRODUCTION ........................................................................................................... 15 
2.1 
Background ........................................................................................................ 15 
2.2 
Rationale ........................................................................................................... 17 
2.3 
Rationale for Inclusion of Concomitant ARV Regimens ...................................... 47 
2.4 
Spontaneous Clearance of HCV ........................................................................ 48 
2.5 
Overall Risk/Benefit Assessment ....................................................................... 49 
2.6 
Adherence Measures ......................................................................................... 49 
3.0 
STUDY DESIGN ........................................................................................................... 49 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS................................................ 50 
4.1 
Step 1 Inclusion Criteria for Cohort 2 ............................................................... 50 
4.2 
Step 1 Exclusion Criteria for Cohort 2 .............................................................. 54 
4.3 
Step 2 Inclusion Criteria for Cohort 2 ............................................................... 55 
4.4 
Step 2 Exclusion Criteria for Cohort 2 .............................................................. 55 
4.5 
Study Enrollment Procedures ............................................................................ 56 
4.6 
Coenrollment Guidelines ................................................................................... 56 
5.0 
STUDY TREATMENT ................................................................................................... 57 
5.1 
Regimens, Administration, and Duration ........................................................... 57 
5.2 
Study Product Formulation ................................................................................ 58 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................. 59 
5.4 
Concomitant Medications .................................................................................. 59 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 61 
6.1 
Schedule of Events ............................................................................................ 61 
6.2 
Timing of Evaluations ......................................................................................... 68 
6.3 
Instructions for Evaluations ................................................................................ 70 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 77 
7.1 
Toxicity .............................................................................................................. 77 
7.2 
Pregnancy.......................................................................................................... 80 
7.3 
HCV Virologic Response-Based Stopping Criteria ............................................. 81 
7.4 
HIV-1 Treatment Failure ..................................................................................... 81 


A5327 
Final Version 2.0 
07/02/15 
 
CONTENTS (Cont’d) 
Page 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 82 
8.1 
Permanent Treatment Discontinuation .............................................................. 82 
8.2 
Premature Study Discontinuation ...................................................................... 82 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 83 
9.1 
General Design Issues ...................................................................................... 83 
9.2 
Outcome Measures ........................................................................................... 84 
9.3 
Randomization and Stratification ....................................................................... 85 
9.4 
Sample Size and Accrual .................................................................................. 85 
9.5 
Monitoring ......................................................................................................... 88 
9.6 
Analyses ........................................................................................................... 88 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 89 
10.1 
Pharmacology Objectives .................................................................................. 90 
10.2 
Pharmacology Study Design .............................................................................. 91 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis ............................... 91 
10.4 
Anticipated Outcomes ........................................................................................ 91 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 92 
11.1 
Records to Be Kept ............................................................................................ 92 
11.2 
Role of Data Management ................................................................................. 92 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 92 
11.4 
Expedited Adverse Event Reporting to DAIDS ................................................... 93 
12.0 
PARTICIPANTS ............................................................................................................ 94 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 94 
12.2 
Participant Confidentiality ................................................................................. 94 
12.3 
Study Discontinuation ........................................................................................ 94 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 94 
14.0 
BIOHAZARD CONTAINMENT....................................................................................... 94 
15.0 
REFERENCES .............................................................................................................. 96 
APPENDIX I: 
SCREENING FLOW CHART FOR ACUTE HCV INFECTION 
APPENDIX II: 
SAMPLE INFORMED CONSENT FOR COHORT 1 
APPENDIX III: SAMPLE INFORMED CONSENT FOR COHORT 2 


4 
A5327 
Final Version 2.0 
07/02/15 
 
 
SITES PARTICIPATING IN THE STUDY 
 
A5327/SWIFT-C is a multicenter study open only to US ACTG clinical research sites (CRSs). 


5 
A5327 
Final Version 2.0 
07/02/15 
 
PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Susanna Naggie, MD 
Duke University Medical Center 
Adult CRS 
Box 3850 
Durham, NC 27710 
Phone: 919-684-2584 
E-mail: susanna.naggie@duke.edu 
 
Raymond T. Chung, MD 
Gastroenterology Unit 
Massachusetts General Hospital ACTG 
CRS 
GRJ 724 
Boston, MA 02114 
Phone: 617-724-7562 
Fax: 
617-643-0446 
E-mail: rtchung@partners.org 
 
DAIDS Clinical Representative 
Beverly Alston-Smith, MD 
Complications and Co-Infections Research 
Branch, Division of AIDS 
NIAID, TRP, NIH 
5601 Fisher Lane, 9F50 
Rockville, MD 20852 
Phone: 301-435-3773 
Fax: 
301-480-4522 
E-mail: balston@niaid.nih.gov 
 
Clinical Trials Specialist 
Jhoanna C. Roa, MD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 George Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3196 
Fax: 
301-628-3302 
E-mail: jroa@s-3.com 
Statisticians 
Kimberly Hollabaugh, MS 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 549 
651Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-1352 
Fax: 
617-432-3163 
E-mail: hollabau@sdac.harvard.edu 
 
Michael Hughes, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
Building 2, Room 439A 
655 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-3161 
Fax: 
617-432-2832 
E-mail: mhughes@sdac.harvard.edu 
 
Data Manager 
Laura Weichmann, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 Ext. 7281 
Fax: 
716-834-8675 
E-mail: weichman@fstrf.org 
 
DAIDS Pharmacist 
Thucuma Sise, PharmD, BCPS 
Pharmaceutical Affairs Branch 
Division of AIDS, NIAID, NIH 
5601 Fishers Lane, 9A27 
Rockville, MD 20852 
Phone: 240-292-4848 
Fax: 
301-402-1506 
E-mail: sisetk@niaid.nih.gov 


6 
A5327 
Final Version 2.0 
07/02/15 
TEAM ROSTER (Cont'd) 
 
 
Pharmacologist 
Jennifer Kiser, PharmD 
Pharmaceutical Sciences 
University of Colorado Denver 
12850 E Montview Boulevard, C238 
Aurora, CO 80045 
Phone:   303-724-6131 
Fax:       303-724-6135 
E-mail: Jennifer.Kiser@ucdenver.edu 
 
Virologist 
Victoria Johnson, MD 
UAB Center for AIDS Research 
Birmingham School of Medicine 
University of Alabama 
THT 229 
1900 University Boulevard 
Birmingham, AL 35294 
Phone:   205-934-4472 
Fax:       205-975-7382 
E-mail: vjohnson@uab.edu 
Investigators (cont’d) 
Kristen Marks, MD 
Division of Infectious Diseases 
Weill Medical College 
New York Presbyterian Hospital (Cornell) 
525 East 68th Street 
F2437 
New York, NY 10021 
Phone: 212-746-4177 
Fax: 
212-746-8852 
E-mail: markskr@med.cornell.edu 
 
Marion Peters, MD 
Gastroenterology Division 
University of California, San Francisco 
AIDS CRS 
513 Parnassus Street, Room S-0537 
San Francisco, CA 94143-0538 
Phone: 415-502-0318 
Fax: 
415-476-0659 
E-mail: marion.peters@ucsf.edu 
 
Investigators 
Daniel Fierer, MD 
Division of Infectious Diseases 
Mount Sinai School of Medicine 
1 Gustave L. Levy Place 
Box 1009 
New York, NY 10029 
Phone: 212-824-7413 
Fax: 
212-824-2312 
E-mail: daniel.fierer@mssm.edu 
 
Field Representative 
Emily Cosimano, RN 
University of Rochester ACTG CRS 
P.O. Box 689 
601 Elmwood Avenue 
Rochester, NY 14642 
Phone: 585-276-5903 
Fax: 
585-473-5227 
E-mail: 
emily_cosimano@urmc.rochester.edu 
 
Arthur Y. Kim, MD 
Massachusetts General Hospital 
ACTG CRS 
Cox 5, 55 Fruit Street 
Boston, MA 02114 
Phone: 617-724-3230 
E-mail: akim1@partners.org 


7 
A5327 
Final Version 2.0 
07/02/15 
TEAM ROSTER (Cont'd) 
 
 
Laboratory Technologists 
Cheryl Jennings, BS 
Clinical Retrovirology Research Laboratory 
Northwestern University CRS 
1121 Jelke Building 
1750 West Harrison Street 
Chicago, IL 60612 
Phone: 312-942-5954 
Fax: 
312-942-6787 
E-mail: cheryl_jennings@rush.edu 
 
Sikhulile Moyo, BSc, MSc, MPH 
Botswana-Harvard-Gaborone 
Prevention/Treatment Trials CRS 
Botswana Harvard Partnership 
Boag BO 320 
Gaborone, 0000 
Botswana 
Phone: 267-390-2671 
Fax: 
267-390-1284 
E-mail: smoyo@bhp.org.bw 
Laboratory Data Managers 
Oswald Dadson, M.S. 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7238 
E-mail: dadson@fstrf.org 
 
Amanda Zadzilka, BS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7282 
Fax: 
716-833-0655 
E-mail: zadzilka@fstrf.org 
 
Community Scientific Subcommittee (CSS) 
Representative 
Aaron Laxton, BA 
5312 Northrup Ave. Rear 
St. Louis MO 63110 
Phone: 314-610-0999 
E-mail: aaronlaxton@gmail.com 
 
Industry Representatives 
Diana Brainard, MD 
Gilead Sciences 
300 Lakeside Drive 
Foster City, CA 94404 
Phone: 650-522-4761 
Cell: 
650-391-6035 
Fax: 
650-524-9127 
Email: 
Diana.Brainard@gilead.com 
 
James F. Rooney, MD 
Gilead Sciences 
333 Lakeside Drive 
Foster City CA 94404 
Phone: 650-522-5708 
E-mail: jim.rooney@gilead.com 


8 
A5327 
Final Version 2.0 
07/02/15 
 
 
STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.coreA5327@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to actg.coreA5327@fstrf.org. A 
response should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites should contact the Computer Support Group at the Data Management Center (DMC) as 
soon as possible to have the relevant personnel at the site added to the actg.protA5327 e-mail 
group. Include the protocol number in the e-mail subject line. 
 
• 
Send an e-mail message to actg.user.support@fstrf.org 
 
Clinical Management 
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol core team. Send an e-mail message to 
actg.coreA5327@fstrf.org (ATTN: Susanna Naggie and Raymond Chung). Include the protocol 
number, patient identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to virologic and pharmacologic laboratory tests, contact 
Victoria Johnson (virologist) and Jennifer Kiser (pharmacologist), respectively. Send an e-mail 
message to actg.coreA5327@fstrf.org. 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), 
the CRF schedule of events, registration, delinquencies, and other data management issues, 
contact the data manager. CRFs can be downloaded from the FSTRF website at www.fstrf.org. 
• 
For transfers, reference the Patient Transfer from Site to Site SOP 119, and contact Laura 
Weichmann directly. 
• 
For other questions, send an e-mail message to actg.coreA5327@fstrf.org (ATTN: Laura 
Weichmann). 
• 
Include the protocol number, PID, and a detailed question. 
 
Participant Registration 
For participant registration questions or problems and study identification number SID lists. 
• 
Send an e-mail message to rando.support@fstrf.org. Call the Statistical and Data Analysis 
Center (SDAC)/DMC Randomization Desk at 716-834-0900 x7301. 
 
Computer and Screen Problems 
Contact the SDAC/DMC programmers. 
• 
Send an e-mail message to actg.support@fstrf.org or call 716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist. Send an e- 
mail message to actg.coreA5327@fstrf.org (ATTN: Jhoanna Roa). 


9 
A5327 
Final Version 2.0 
07/02/15 
STUDY MANAGEMENT (Cont'd) 
 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGNCC@s-3.com (ATTN: Diane 
Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site 
(https://www.actgnetwork.org). 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707. 
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Thucuma Sise, protocol pharmacist, at 301-496-8213. 
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
Expedited Adverse Event (EAE) Reporting/Questions 
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710. 
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5327 team members. 
Send an e-mail to actg.coreA5327@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
3TC 
lamivudine 
ALT 
alanine aminotransferase (also SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase (also SGOT) 
ATV 
atazanavir 
AUC 
area under the curve 
AUCtau 
area under the plasma concentration versus time curve over the dosing interval 
BMI 
body mass index 
BOC 
boceprevir 
CAP 
College of American Pathologists 
CHC 
chronic hepatitis C 
CKD 
chronic kidney disease 
Cmax 
maximum observed concentration of drug 
CLIA 
Clinical Laboratory Improvement Amendments 
COBI 
cobicistat 
CrCl 
creatinine clearance 
CSA 
colony stimulating agents 
Ctau 
observed drug concentration at the end of the dosing interval (tau) 
d4T 
stavudine 
DAA 
direct acting antiviral 
DBS 
dried blood spots 
ddI 
didanosine 
DRV 
darunavir 
DTG 
dolutegravir 
ECG 
electrocardiogram 
EFV 
efavirenz 
Emax 
maximal effect 
EVG 
elvitegravir 
FDC 
fixed dose combination 
FTC 
emtricitabine 
GT 
genotype (viral) 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICH 
International Conference on Harmonisation 
IFN 
interferon 
IL28B 
IL28B gene 
ISGs 
IFN stimulated genes 
ITT 
intention-to-treat 
LLOQ 
lower limit of quantification 


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GLOSSARY OF PROTOCOL-SPECIFIC TERMS (Cont'd) 
 
 
LDV 
ledipasvir 
LDV/SOF ledipasvir/sofosbuvir 
Hg 
mercury 
PBMC 
peripheral blood mononuclear cell(s) 
PEG-INF pegylated interferon 
P-gp 
P-glycoprotein 
PI 
protease inhibitor 
POC 
point-of-care 
r 
low dose ritonavir (booster) 
RBV 
ribavirin 
RPV 
rilpivirine 
RTV 
ritonavir 
RVR 
rapid virologic response 
SOF 
Sofosbuvir, GS-7977 
SVR 
sustained virologic response 
TAF 
tenofovir alafenamide 
TFV 
tenofovir 
TDF 
tenofovir disoproxil fumarate 
TND 
target not detected 
TPV 
tipranavir 
TVR 
telaprevir 
t½ 
an estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate contant (λz) 
ULN 
upper limit of the normal range 
ZDV 
zidovudine 


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SCHEMA 
 
 
A5327 
Sofosbuvir-Containing Regimens without Interferon for Treatment of Acute HCV in HIV-1 
Infected Individuals (SWIFT-C) 
 
 
DESIGN 
SWIFT-C is a Phase I, open-label, two-cohort clinical trial, in which 
between 44 and 50 acutely HCV-infected HIV-1 positive participants will 
be enrolled and administered oral sofosbuvir (SOF) in combination with 
weight-based ribavirin (RBV, cohort 1) or ledipasvir (LDV, cohort 2). 
 
The study will investigate the safety and efficacy of two SOF- 
containing regimens and will assess if the addition of a second DAA 
allows for a shortened course of therapy. The study will open the first 
cohort with sofosbuvir plus ribavirin (SOF+RBV) for 12 weeks and 
with a planned accrual of at least 17 participants. The second cohort will 
open with ledipasvir/sofosbuvir (LDV/SOF) for an 8-week treatment. 
The second cohort will include at least 27 participants. Each cohort will 
occur in two steps: on treatment (Step 1) and followup (Step 2). See 
Figure 1. The cohorts will enroll sequentially. 
 
DURATION 
32-36 weeks (8-12 weeks on-treatment followed by 24 weeks of follow- 
up) 
 
SAMPLE SIZE 
A minimum of 44 participants will be enrolled in Cohort 1 and Cohort 2. 
 
Cohort 1: Minimum of 17 participants will be enrolled. 
Cohort 2: Minimum of 27 participants will be enrolled. 
If a participant is discontinued from study treatment for non-virologic 
reasons or is not evaluable for SVR12 while enrollment is ongoing to the 
same cohort, then an additional participant may be enrolled to that 
cohort to help ensure that an adequate number complete study treatment 
and are evaluable for SVR12, up to a maximum enrollment of 50 
participants. 
 
POPULATION 
HIV-1 coinfected individuals who have acute HCV infection or reinfection 
and have any genotype (Cohort 1) and genotype 1 or 4 (Cohort 2). 
 
REGIMEN 
Cohort 1: SOF 400mg once daily and weight-based RBV (1000 or 1200 
mg daily in two divided doses) 
 
Cohort 2: Daily fixed dose combination pill of LDV/SOF 
(90mg/400mg) 


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SCHEMA (Cont’d) 
 
 
 
 
 
 


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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
An interferon-sparing regimen of sofosbuvir (SOF) and ribavirin (RBV) and/or 
ledipasvir/sofosbuvir (LDV/SOF) can achieve sustained virologic response (SVR)12 
rates that are noninferior to the current standard of care assessed by historical control 
for the treatment of acute HCV in HIV-1/HCV co-infected individuals with an improved 
safety profile and a shorter length of treatment. 
 
1.2 
Primary Objectives 
 
1.2.1 To evaluate HCV treatment response to SOF and weight-based RBV (1000 or 
1200 mg daily in two divided doses) taken for 12 weeks and daily LDV/SOF 
taken for 8 weeks as assessed by SVR12, defined as HCV RNA undetectable 
[<lower of limit of quantification (LLOQ) target not detected (TND)] 12 weeks 
post-treatment in persons with existing HIV-1 infection who are acutely infected 
with any HCV genotype (Cohort 1) or Genotype 1 or 4 (Cohort 2). 
 
1.2.2 To evaluate the safety and tolerability of combination oral antiviral therapy with 
SOF and weight-based RBV taken for 12 weeks and daily LDV/SOF taken for 8 
weeks in persons with existing HIV-1 infection who are acutely infected with any 
HCV genotype (Cohort 1) or Genotype 1 or 4 (Cohort 2). 
 
1.3 
Secondary Objectives 
 
1.3.1 To evaluate the antiviral efficacy of SOF and weight-based RBV and LDV/SOF 
as measured by the proportion of participants with HCV RNA undetectable 
(<LLOQ TND) at weeks 1, 2, 4, 8, 12, and at 2 (SVR2), 4 (SVR4), 8 (SVR8), 12 
(SVR12), and 24 (SVR24) weeks post-treatment. 
 
1.3.2 To evaluate evidence of relapse, defined as HCV RNA undetectable (<LLOQ 
TND) at end-of-treatment but HCV RNA quantifiable (≥LLOQ) during followup. 
 
1.3.3 To assess the emergence of viral resistance to SOF and LDV when 
administered for acute HCV infection. 
 
1.3.4 To estimate RBV pharmacokinetics (PK) and evaluate covariates (including 
concomitant antiretroviral drugs) which may affect RBV PK. (Cohort 1 only) 
 
1.3.5 To assess the relationship of viral clearance and RBV PK (Cohort 1) with 
baseline predictors including genetic polymorphisms (eg, IL28B and ITPA), 
expression of key host immune response genes and proteins. 
 
1.3.6 To assess the effects of LDV on the PK of tenofovir (TFV) in persons on 
tenofovir disoproxil fumarate (TDF)-containing regimens. (Cohort 2 only) 


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1.3.7 To evaluate participants’ adherence by using several tools, including self-report, 
pill count, and drug concentrations. 
 
1.3.8 To evaluate the hypothesis that successful direct-acting antiviral (DAA)-based 
therapy alleviates type I interferon (IFN)-induced immune dysfunction during 
acute HCV infection. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Hepatitis C virus (HCV) infection affects more than 4 million persons and causes an 
estimated 12,000 deaths annually in the United States [Armstrong, 2006]. The projected 
burden to our society from chronic HCV infection from 2010 to 2019 has been estimated 
to exceed $10.7 billion in direct medical costs, $54.2 billion in premature mortality costs, 
and $21.3 billion in costs from morbidity due to disability [Wong, 2000]. The Centers for 
Disease Control and Prevention (CDC) estimate that there are close to 17,000 new 
cases of acute HCV per year, although only 700-800 are reported 
(www.cdc.gov/hepatitis/Statistics/index.htm), last accessed June 12, 2013]. Early 
identification of acute HCV infection is essential to prevent chronic infections and the 
long-term liver disease complications that may occur. Early identification and treatment 
of HCV during the acute phase can result in significantly higher response rates with 
shorter durations of therapy. This is true in HCV monoinfected and HIV/HCV coinfected 
individuals [Jaeckel, 2001; Corey, 2010; Matthews, 2009; Boesecke, 2011]. 
 
There is currently no accepted standard regimen for the management of acute HCV. 
Studies have included standard IFN monotherapy, pegylated interferon (PEG-IFN) 
monotherapy, and PEG-IFN in combination with RBV (both standard and weight-based 
dosing) [Jaeckel, 2001; Corey, 2010; Matthews, 2009; Boesecke, 2011]. A meta-analysis 
of HCV monoinfected participants with acute HCV infection (N=602) reported an overall 
SVR of 78%, which was significantly higher than those participants not receiving any 
therapy (55%, OR=3.08; 95% CI 1.8-4.8) [Corey, 2010]. A majority of participants were 
treated with PEG monotherapy with an average duration of therapy of 19.7 weeks. This 
analysis also reported that those participants who initiated treatment within the first 12 
weeks of diagnosis had the highest SVR rates. Across all studies included in the 
analysis, 44% of participants diagnosed with acute HCV (N=473) did not receive any 
therapy primarily due to participant deferment of therapy, contraindications to therapy, or 
spontaneous viral clearance prior to treatment initiation. In this meta-analysis, 
spontaneous clearance rates were higher than has been historically described and is 
likely because a majority of these participants were symptomatic and thus more likely 
to spontaneously clear. Jaundice on presentation has been previously associated with 
spontaneous clearance, a presentation more commonly seen in participants with the 
favorable IL28B CC genotype, a single nucleotide polymorphism associated with 
spontaneous clearance [Gerlach, 2003; Tillman, 2010]. Yet, approximately 50% of the 
participants did not resolve the infection and did not receive therapy. Furthermore, 
treatment responses in HIV-1/HCV coinfected participants have been lower than those 
reported in acute HCV monoinfection. The largest prospective study of acute HCV 


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treatment in HIV-infected individuals to date is from the European AIDS Treatment 
Network (NEAT), which included 36 participants and reported an SVR of 61% [Vogel, 
2006]. This study suggests that there is a need for improved regimens that will be more 
acceptable to participants and better tolerated than IFN. 
 
In the past two years, curative IFN-sparing regimens have been realized for both HCV 
genotype 1 and genotype 2/3 chronic infections and in both treatment-naïve and 
treatment-experienced participants. SOF, a nucleotide analogue of the HCV 
polymerase, was approved by the United States Food and Drug Administration 
(US FDA) in December 2013. The Phase 3 FISSION, FUSION, POSITRON, and 
VALENCE studies investigated SOF in treatment-naïve and -experienced participants 
with chronic HCV genotype 2/3 infection [Jacobson, 2013; Lawitz, 2013; Zeuzem, 2013]. 
In treatment-naïve and IFN-unable genotype 2 and 3 participants who received 12 
weeks of treatment, SVR12 rates were 93-97% and 56-61%, respectively. In treatment- 
experienced participants who received 12 and 16 weeks of therapy, SVR12 rates were 
86% and 94% in genotype 2 participants and 30% and 62% in genotype 3 
participants, respectively. In treatment-naïve and -experienced participants who 
received 24 weeks of treatment, SVR12 was 85%. The PHOTON-1 and 2 Phase 3 
studies investigated SOF with RBV for 12 weeks in genotype 2 treatment-naïve HIV-1 
co-infected participants and for 24 weeks in treatment-naïve genotype 3 and 
treatment-experienced genotype 2 or 3 HIV-1 coinfected participants. The studies 
also evaluated 24 weeks of SOF+RBV in genotype 1 treatment-naïve HIV-1 coinfected 
participants. A pooled analysis of the SVR12 results was recently presented at 
American Association for the Study of Liver Diseases Meeting in Boston, MA. SVR12 
was achieved by 81%, 89%, and 91% of genotype 1, 2, and 3 treatment-naïve 
participants, respectively [Rockstroh, 2014]. The ELECTRON study investigated the 
feasibility of using an IFN-free approach to the treatment of chronic genotype 1, 2, and 3 
infection in HIV negative participants [Gane, 2013]. The combination of SOF with RBV 
for 12 weeks resulted in 84% SVR12 in treatment-naïve genotype 1 participants. The 
SPARE trial investigated the combination of SOF with RBV for 24 weeks in treatment- 
naïve genotype 1 participants who had more difficult-to-treat baseline characteristics 
than in many registration trials, including 72-92% African-American race and up to 28% 
cirrhosis [Osinusi, 2013]. The largest trial of this IFN-free combination regimen reported 
SVR24 of 68% in this very difficult-to-treat patient population. 
 
The IFN and RBV-free fixed dose combination of LDV (an NS5A inhibitor) and SOF 
was approved for the treatment of chronic genotype 1 HCV infection in October 
2014 [Harvoni PI, 2015]. The Phase 3 ION studies (ION-1, 2, 3, 4) investigated the 
safety and efficacy of LDV/SOF in participants chronically infected with genotype 
1 and included treatment-naïve (ION-1 and ION-3) and -experienced (ION- 
2)/participants with cirrhosis (ION-1 and ION-2)/and participants with HIV co- 
infection (ION-4) [Harvoni PI, 2015; Naggie, CROI 2015 abstract LB152]. Overall 
SVR12 rates were high (>93%) across the Phase 3 program. Specifically, the ION-3 
study investigated 8 or 12 weeks of LDV/SOF in treatment-naïve participants. The 
8-week arm was non-inferior compared to the 12-week arm, although there were 
more relapses (5% vs. 1%, respectively). A subgroup analysis suggested that 
among participants with a baseline HCV RNA <6 million IU/mL, the SVR12 was 


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97% in the 8-week arm and 96% in the 12-week arm, suggesting specific patient 
populations may be able to achieve high SVR12 with just 8 weeks of LDV/SOF. 
 
To date over 5,000 HCV-infected participants have been dosed with SOF either in 
combination with PEG/RBV, RBV or alone as monotherapy and to date, no on-treatment 
viral breakthrough has occurred in any participant. However, approximately 230 
participants have experienced relapse after cessation of SOF-containing regimens 
[Gane, 2013; Jacobson, 2013; Lawitz, 2013]. Population sequencing identified only one 
participant (genotype (GT) 2b who had received SOF monotherapy) with the S282T 
mutation and this did confer decreased susceptibility to SOF. Deep sequencing did not 
identify this mutation in any other participant [Gane, 2013; Jacobson, 2013; Lawitz, 
2013]. Similarly, of over 1600 participants treated with LDV/SOF in the Phase 3 
program, no participant developed the S282T mutation. These results confirm that 
SOF has an exceptionally high barrier to resistance. Thus, SOF-containing regimens 
appear to be ideal for the treatment of acute HCV infection. Its broad efficacy across 
HCV genotypes, once daily dosing regimen, and minimal side effects profile could 
significantly increase uptake for treatment of acute HCV infection and provide similar, if 
not improved, efficacy over the current standard of care. The addition of LDV does 
increase the risk of developing resistance mutations at time of virologic failure. Of 
the over 1600 participants treated in the Phase 3 program, 1.8% had detected 
resistant variants in the NS5A region at the time of failure. Thus, with SOF as a 
backbone in this combination regimen, the risk of virologic failure is extremely 
low as is the risk of resistant variants [Harvoni PI, 2015]. 
 
The original study design of A5327 involved a 2-cohort clinical trial that planned to 
enroll participants sequentially using the same regimen of SOF+RBV with the 
potential to shorten the therapy from 12 to 8 weeks if a predetermined interim 
analysis found that SVR4 rates for the 12-week arm achieved non-inferiority as 
compared to a historic control. Due to the small sample size of cohort 1, the lower 
end of the non-inferiority margin would allow for only 3 virologic failures. Cohort 
1, which investigated SOF+RBV for 12 weeks, has reported 7 viral failures to date, 
all due to relapse after end of treatment. Although the prior study design would 
have continued to enroll participants on SOF+RBV for 12 weeks to improve the 
power to achieve non-inferiority, it was felt by the protocol team that this would 
have resulted in potentially unacceptable SVR rates and that significant 
advancements in HCV therapeutics since the initial design of the trial required 
implementation of more contemporary and effective therapies. Specifically, the 
availability of oral, DAA combination therapies would provide the possibility of 
higher efficacy and the same excellent safety. Thus, a protocol amendment was 
pursued to change the regimen for cohort 2 from SOF+RBV to LDV/SOF. Because 
of existing data demonstrating that 8 weeks of LDV/SOF is safe and effective in 
select chronically HCV infected participants, this was felt to be the ideal length of 
treatment for acute infection. 
 
2.2 
Rationale 
 
HIV infection treatment has improved with the widespread availability of antiretrovirals 
(ARVs) and the appearance of numerous drugs in the market over the past 15 years. 


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Currently, several ritonavir (RTV) (r)-boosted PIs in combination with other ARVs are 
recommended as options for first-line ARV therapy, and several are approved for and 
commonly used in treatment-experienced patients. While extremely effective for 
treatment of HIV, r-boosted PIs are substrates for and potent inhibitors of cytochrome 
P450 3A4 (CYP 3A4) enzymes; as a result, drug-drug interactions with these agents 
are frequent. Numerous PK studies and case reports provide evidence that r-boosted 
PIs are associated with a number of clinically relevant drug interactions as a result of 
PK changes related to either the PI or the concomitant medications. Other first-line 
ARV therapies include non-nucleoside reverse transcriptase inhibitors (NNRTI) and 
integrase inhibitors in combination with nucleoside or nucleotide reverse transcriptase 
inhibitors (NRTI). These non-nucleoside inhibitors, in particular efavirenz (EFV), are 
substrates and inducers of CYP-450 2B6 and 3A4. [Panel on ARV Guidelines for Adults 
and Adolescents 2012; Asboe, 2012] 
 
Thus far, HCV PIs are substrates and inhibitors of CYP3A4, and therefore have 
significant drug interactions with the ARV therapies [Seden, 2010]. Drug interactions 
with both TVR and BOC and ritonavir (RTV) boosted PIs, have been reported and in 
some cases have been contraindicated for combined use [Van Heeswiik, 2011; 
Hulskotte, 2012; Sulkowski, 2013d; Sulkowski, 2013e]. Drug interaction studies have 
also been reported between both drugs with EFV whereby exposures of both TVR and 
BOC are reduced [Van Heeswiik, 2011; Hulskotte, 2012; de Kanter, 2012; Sulkowski, 
2013d; Sulkowski, 2013e]. Thus, there is a tremendous need for direct-acting 
antivirals (DAAs) with reduced potential for drug interactions with ARV. 
 
SOF exhibits several attractive characteristics for combining with ARVs. SOF itself 
is a prodrug, requiring intracellular phosphorylation to a uridine triphosphate to exert 
antiviral effects. Multiple studies suggest a lack of involvement of SOF and its 
metabolites with the metabolic enzymes involved in xenobiotic transformation, and 
hence, demonstrate that metabolically based drug interactions with SOF are 
unlikely. In vitro assays indicate that SOF is a substrate but not an inhibitor of the 
drug transporters, P-gp and BCRP, and is not a substrate of OATP. SOF 
concentrations may be increased by drugs that inhibit these transporters (eg, 
cyclosporine), but concentrations of the primary circulating metabolite in plasma, 
GS-331007, are unaffected. Similarly, LDV is not an inhibitor or inducer of 
major drug metabolizing enzyme systems, and is unlikely to be a perpetrator 
of cytochrome P450 enzyme (CYP) or UGT1A1-mediated drug-drug 
interactions. LDV may be affected by transporter-related drug-drug 
interactions. LDV is a substrate for intestinal efflux transporters and is an 
inhibitor of the intestinal efflux transporters BCRP and Pgp. LDV is not a 
substrate for hepatic uptake transporters (OCT1, OATP1B1, and OATP1B3). 
LDV is an inhibitor of the hepatic transporters OATP1B1 and OATP1B3. In 
general, LDV has a low potential for drug interactions. 
 
HCV infection has been associated with early induction of a type I IFN program, which 
in turn results in successful spontaneous clearance by virtue of induction of an 
endogenous antiviral program, but with early chronicity appears to exert 
counterproductive effects that include T cell dysfunction/hypofunction/exhaustion. 
Exciting data support that abrogation of the type I program can restore dysfunctional 


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immunity and revert IFN stimulated genes (ISGs) to baseline in chronic infection 
(Wilson 2013; Teijaro 2013). With IFN-sparing regimens, the study team can now 
evaluate this hypothesis in early, acute infection and compare participants who 
successfully clear infection from those who do not. The study team will compare ISGs 
using customized Nanostring arrays from PBMCs prior to and at the end of treatment 
and followup and correlate with corresponding HCV specific functional assays (CD4 
proliferative and CD8 CTL assays) between sustained responders (expected to be 
about 85% of the group) and nonresponders/relapsers (expected to be about 15% of 
the group). The study team will also correlate with circulating IP-10, a type I IFN 
stimulated cytokine. To enhance the numbers of nonresponders and progressors to 
chronicity, the study team will also evaluate a unique cohort of 20 acutely HCV- 
infected participants with preexisting HIV infection whose serial PBMCs were 
collected as part of an ongoing MGH HCV immunology longitudinal repository and 
who progressed to chronic infection. Thus, the study team has the unique and ideal 
ability to assess whether early immune dysfunction can be abrogated with successful 
DAA therapy. The study team will also be able to analyze the ISG induction patterns 
at baseline prior to therapy as a function of IL28B genotype, since we hypothesize that 
a more elevated ISG induction pattern may be associated with less favorable IL28B 
genotype. These findings will have strong implications for recommendations for early 
treatment of acutely infected patients, since immune preservation may be reliant on it. 
 
SOF in combination with RBV has been shown to be safe and effective in 
patients with genotype 1-4 infections and the limited drug interaction profile and 
extremely limited risk of NS5B resistance makes this an ideal regimen for the 
treatment of acute hepatitis C in HIV/HCV co-infected persons. However, the 
recent approval of DAA combinations that are IFN- and RBV-free are also of 
great interest. The addition of other DAA into combination regimens may 
slightly increase the risk of drug interactions and resistance, but the 
exceptional safety and efficacy profiles makes these regimens preferred to a 12- 
week regimen of SOF+RBV. Moreover, data for some DAA combinations in 
chronic HCV support truncation of therapy in persons with favorable 
characteristics, including absence of cirrhosis and lower viral loads. Coupled 
with historic experience that shorter regimens of antiviral therapy can produce 
high rates of response in acute infection, there is strong rationale to investigate 
shorter courses of these DAA-based regimens in patients with acute HCV 
infection. 
 
2.2.1 Use of Sofosbuvir 
 
The efficacy of SOF was evaluated in seven Phase 3 trials in a total of 1724 
HCV mono-infected participants with genotypes 1 to 6 chronic hepatitis C 
(CHC) and 497 HIV/HCV co-infected participants with genotypes 1 to 4. Six 
of the trials investigated SOF in combination with RBV and included HCV 
mono-infected participants with genotype 2 or 3 infection and HIV/HCV co- 
infected participants with genotype 1 to 4 infection. Participants in these 
trials had compensated liver disease including cirrhosis. SOF was 
administered at a dose of 400 mg once daily and the RBV dose was weight- 
based 1000-1200 mg daily administered in two divided doses. 


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2.2.1.1 
Clinical Efficacy in Participants with Genotype 1 HCV infection and 
HIV Co-infection 
 
SOF was studied in an open-label clinical trial in North America 
and Puerto Rico evaluating the safety and efficacy of 12 or 24 
weeks of treatment with SOF+RBV in participants with genotype 1, 
2, or 3 CHC coinfected with HIV-1. Genotype 2 and 3 participants 
were either HCV treatment-naïve or treatment-experienced, 
whereas genotype 1 participants were all treatment-naïve. 
Participants received 400 mg SOF and weight-based RBV (1000 mg 
for participants weighing <75 kg or 1200 mg for participants 
weighing ≥75kg) daily for 12 or 24 weeks based on genotype and 
prior treatment history. Participants were either not on 
antiretroviral (ARV) therapy with a CD4+ cell count >500 cells/mm3 
or had virologically suppressed HIV-1 on ARV therapy with a CD4+ 
cell count >200 cells/mm3. Table 2-1 presents the available 
efficacy data 12 weeks post treatment for 210 of the 223 enrolled 
participants [Sulkowski, 2014]. 
 
Table 2-1: Response Rate in PHOTON-1 
 
HCV Genotype 1 
Treatment-Naive 
HCV Genotype 2/3 
Treatment-Naive 
HCV Genotype 2/3 
Treatment- 
Experienced 
SOF+RBV 24W 
N=114 
SOF+RBV 12W 
N=68 
SOF+RBV 24W 
N=28 
Overall SVR 
76% (87/114) 
75% (51/68) 
93% (26/28) 
On treatment failure 
1% (1/114) 
1% (1/68) 
0/28 
Relapse 
22% (25/113) 
18% (12/67) 
7% (2/28) 
Other 
1% (1/114) 
6% (4/68) 
0/28 
 
The SVR rate was 82% (74/90) in participants with genotype 1a 
infection and 54% (13/24) in participants with genotype 1b 
infection. SVR rates in participants with HCV genotype 1 infection 
were 80% (24/30) in participants with baseline IL28B C/C allele and 
75% (62/83) in participants with baseline IL28B non-C/C alleles 
[Sulkowski, 2014]. 
 
In the 223 enrolled participants, the CD4+ cell percentage did not 
change during treatment. Median CD4+ cell count decreases of 85 
cells/mm3 and 84 cells/mm3 were observed at the end of treatment 
with SOF+RBV for 12 or 24 weeks, respectively. HIV-1 rebound 
during SOF+RBV treatment occurred in 2 participants (0.9%) on 
ARV therapy. 


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2.2.1.2 
Clinical Efficacy in HCV Mono-infection 
 
In the SOF Phase 3 clinical program, the SOF+RBV treatment regimen 
for 12 or 16 weeks was evaluated in participants with genotype 2 or 3 
HCV infection and the SOF+PEG+RBV treatment regimen for 12 weeks 
was evaluated in participants with genotype 1, 4, 5, or 6 HCV infection. 
Across all relevant HCV genotypes and multiple patient populations, 
SOF, in combination with RBV with or without PEG demonstrated 
similar or superior efficacy to currently available treatment. 
 
All Phase 3 studies in participants with genotype 2 or 3 HCV infection 
demonstrated efficacy, achieving their primary endpoints in each study. 
Study P7977-1231 met its primary efficacy endpoint of noninferiority of 
treatment with SOF+RBV for 12 weeks compared with the current 
standard-of-care, PEG+RBV for 24 weeks (approximately 67% of 
participants achieving a SVR12 for both treatments). Study GS-US- 
334-0107 met its primary efficacy endpoint of superiority of treatment 
with SOF+RBV for 12 weeks compared with placebo (77.8% of 
participants achieved SVR12 in the SOF+RBV group versus 0% in the 
placebo group [p<0.001]). Study GS-US-334-0108 met its primary 
efficacy endpoint of superiority of treatment with SOF+RBV for both 12 
and 16 weeks compared with an historic control SVR12 rate of 25% 
(50.0% and 72.6% of participants achieved SVR12 in the SOF+RBV 
12 and 16 Week groups, respectively [p<0.001 for both groups]). As has 
been described previously for IFN-based treatment, response rates 
were higher in participants with genotype 2 HCV infection compared 
with participants with genotype 3 HCV infection. 
 
Study GS-US-334-0110 met its primary efficacy endpoint for superiority 
of SOF+PEG+RBV treatment for 12 weeks (90.2% of participants 
achieving a SVR12) compared with a predefined historic control SVR 
rate (60%; p<0.001). 
 
In a pooled analysis of 991 participants who received SOF in four 
Phase 3 trials (NEUTRINO, FISSION, POSITRON, and FUSION), 226 
participants qualified for resistance analysis due to virologic 
failure or early study drug discontinuation and having HCV RNA 
>1000 IU/mL. Post-baseline NS5B sequences were available for 
225 of the 226 participants, with deep sequencing data (assay 
cutoff of 1%) from 221 of these participants. The SOF-associated 
resistance substitution S282T was not detected in any of these 
participants by deep sequencing or population sequencing. 
However, an S282T substitution was detected in one genotype 2b 
participant who relapsed at Week 4 post-treatment after 12 weeks 
of SOF monotherapy in the Phase 2 trial P7977-0523 [ELECTRON]. 
The isolate from this participant displayed a mean 13.5-fold 
reduced susceptibility to SOF. For this participant, the S282T 
substitution was no longer detectable at Week 12 post-treatment 


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by next generation sequencing with an assay cut off of 1%. No 
other NS5B substitutions were identified to be associated with 
resistance to SOF by deep sequencing and phenotypic analyses 
[Sovaldi PI, 2015]. 
 
2.2.1.3 
Clinical Safety 
 
The primary safety data for this clinical safety section are derived from 
the 4 pivotal Phase 3 studies P7977-1231 (FISSION), GS-US-334-0107 
(POSITRON), GS-US-344-0108 (FUSION), and GS-US-334-0110 
(NEUTRINO), with supporting safety data from Phase 2 studies as 
appropriate. 
 
2.2.1.3.1 
Adverse Events 
 
Adverse events (AEs) comprised any events with onset 
dates on or after the date of the first dose of any study drug 
up to 30 days after the last dose of any study drug. 
 
2.2.1.3.2 
Overall Summary of Adverse Events 
 
Table 2-2 provides an overall summary of AEs reported in 
the 4 pivotal Phase 3 studies. The placebo group had the 
lowest proportion of AEs (77.5%) and the PEG+RBV group 
had the highest proportion of AEs (95.9%) compared with 
the SOF+RBV groups (approximately 88%). Similarly, the 
placebo group had the lowest (1.4%) and the PEG+RBV 
group had the highest (18.5%) proportion of Grade 3 or 4 
AEs compared with the SOF+RBV groups (4.1-7.2%). This 
trend was also observed for Grade 2 and higher AEs. The 
PEG+RBV group had the highest proportion of participants 
who had an AE that led to permanent discontinuation from 
any study drugs (11.9%) compared with all other groups. 
One death (cocaine and heroin overdose on Day 1 in the 
SOF+RBV 12 Week group) was reported. 


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Table 2-2: Overall Summary of Adverse Events in the Pivotal Phase 3 Studies 
(Safety Analysis Set) 
 
GS-US-334- 
0107 
(POSITRON) 
P7977-1231 
(FISSION) 
GS-US-334-0107 
(POSITRON) 
GS-US-334-0108 
(FUSION) 
GS-US-334- 
0108 
(FUSION) 
P7977-1231 
(FISSION) 
GS-US-334-0110 
(NEUTRINO) 
Placebo 
12 Weeks 
SOF+RBV 
12 Weeks 
SOF+RBV 
16 Weeks 
PEG+RBV 
24 Weeks 
SOF+PEG+RBV 
12 Weeks 
(N = 71) 
(N = 566) 
(N = 98) 
(N = 243) 
(N = 327) 
Number (%) of Subjects 
Experiencing Any: 
AE 
55 (77.5%) 
496 (87.6%) 
86 (87.8%) 
233 (95.9%) 
310 (94.8%) 
Grade 3 or 4 AE 
1 (1.4%) 
41 (7.2%) 
4 (4.1%) 
45 (18.5%) 
48 (14.7%) 
Grade 2 and Higher AE 
21 (29.6%) 
238 (42.0%) 
41 (41.8%) 
167 (68.7%) 
194 (59.3%) 
Treatment-Related AE 
40 (56.3%) 
408 (72.1%) 
75 (76.5%) 
228 (93.8%) 
304 (93.0%) 
Grade 3 or 4 Treatment- 
Related AE 
0 
15 (2.7%) 
2 (2.0%) 
39 (16.0%) 
42 (12.8%) 
Grade 2 and Higher 
Treatment-Related AE 
12 (16.9%) 
161 (28.4%) 
22 (22.4%) 
149 (61.3%) 
175 (53.5%) 
Any SAE 
2 (2.8%) 
22 (3.9%) 
3 (3.1%) 
3 (1.2%) 
4 (1.2%) 
Treatment-Related SAE 
0 
2 (0.4%) 
0 
0 
2 (0.6%) 
AE Leading to 
Permanent 
Discontinuation from 
Any of the Study Drugs 
3 (4.2%) 
9 (1.6%) 
0 
29 (11.9%) 
8 (2.4%) 
AE Leading to 
Permanent 
Discontinuation from 
SOF/SOF Placebo 
3 (4.2%) 
8 (1.4%) 
0 
N/A 
5 (1.5%) 
AE Leading to 
Modification or 
Interruption of Study 
Drug 
0 
63 (11.1%) 
7 (7.1%) 
65 (26.7%) 
109 (33.3%) 
Death 
0 
1 (0.2%) 
0 
0 
0 
Note: Data included to last dose date of study regimen (or active treatment in GS-US-334-0108) + 30 days. 
Note: Percentages were calculated based on the number of subjects in the safety analysis set. 
 
2.2.1.3.3 
Frequent Adverse Events 
 
Table 2-3 presents AEs that were reported in ≥10% of 
subjects in any treatment group across the 4 pivotal Phase 3 
studies. 


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Table 2-3: Adverse Events in ≥10% of Subjects in Any Group by Preferred Term in the Pivotal 
Phase 3 Studies (Safety Analysis Set) 
 
Preferred Term 
GS-US-334- 
0107 
(POSITRON) 
P7977-1231 
(FISSION) 
GS-US-334-0107 
(POSITRON) 
GS-US-334-0108 
(FUSION) 
GS-US-334- 
0108 
(FUSION) 
P7977-1231 
(FISSION) 
GS-US-334-0110 
(NEUTRINO) 
Placebo 
12 Weeks 
SOF+RBV 
12 Weeks 
SOF+RBV 
16 Weeks 
PEG+RBV 
24 Weeks 
SOF+PEG+RBV 
12 Weeks 
(N = 71) 
(N = 566) 
(N = 98) 
(N = 243) 
(N = 327) 
Number (%) of 
Subjects 
Experiencing 
Any AE: 
55 (77.5%) 
496 (87.6%) 
86 (87.8%) 
233 (95.9%) 
310 (94.8%) 
Fatigue 
17 (23.9%) 
229 (40.5%) 
46 (46.9%) 
134 (55.1%) 
192 (58.7%) 
Headache 
14 (19.7%) 
132 (23.3%) 
32 (32.7%) 
108 (44.4%) 
118 (36.1%) 
Nausea 
13 (18.3%) 
114 (20.1%) 
20 (20.4%) 
70 (28.8%) 
112 (34.3%) 
Insomnia 
3 (4.2%) 
91 (16.1%) 
28 (28.6%) 
70 (28.8%) 
81 (24.8%) 
Rash 
6 (8.5%) 
48 (8.5%) 
12 (12.2%) 
43 (17.7%) 
59 (18.0%) 
Pruritus 
6 (8.5%) 
53 (9.4%) 
7 (7.1%) 
42 (17.3%) 
54 (16.5%) 
Decreased 
Appetite 
7 (9.9%) 
33 (5.8%) 
5 (5.1%) 
44 (18.1%) 
58 (17.7%) 
Irritability 
1 (1.4%) 
58 (10.2%) 
11 (11.2%) 
40 (16.5%) 
42 (12.8%) 
Diarrhea 
4 (5.6%) 
57 (10.1%) 
6 (6.1%) 
42 (17.3%) 
38 (11.6%) 
Dizziness 
5 (7.0%) 
52 (9.2%) 
5 (5.1%) 
33 (13.6%) 
41 (12.5%) 
Arthralgia 
1 (1.4%) 
42 (7.4%) 
9 (9.2%) 
35 (14.4%) 
47 (14.4%) 
Anemia 
0 
58 (10.2%) 
4 (4.1%) 
28 (11.5%) 
68 (20.8%) 
Myalgia 
0 
35 (6.2%) 
9 (9.2%) 
40 (16.5%) 
45 (13.8%) 
Influenza Like 
Illness 
2 (2.8%) 
16 (2.8%) 
3 (3.1%) 
44 (18.1%) 
51 (15.6%) 
Cough 
2 (2.8%) 
39 (6.9%) 
13 (13.3%) 
21 (8.6%) 
34 (10.4%) 
Chills 
1 (1.4%) 
16 (2.8%) 
0 
43 (17.7%) 
54 (16.5%) 
Vomiting 
5 (7.0%) 
33 (5.8%) 
4 (4.1%) 
23 (9.5%) 
39 (11.9%) 
Pyrexia 
0 
19 (3.4%) 
3 (3.1%) 
33 (13.6%) 
58 (17.7%) 
Depression 
1 (1.4%) 
34 (6.0%) 
6 (6.1%) 
34 (14.0%) 
31 (9.5%) 
Dyspnea 
1 (1.4%) 
45 (8.0%) 
5 (5.1%) 
20 (8.2%) 
39 (11.9%) 
Pain 
2 (2.8%) 
17 (3.0%) 
5 (5.1%) 
30 (12.3%) 
33 (10.1%) 
Neutropenia 
0 
0 
0 
30 (12.3%) 
54 (16.5%) 
Note: Adverse events are mapped according to MedDRA Version 15.0. 
Note: Subjects are counted once for each system organ class (SOC), and once for each AE preferred term (PT). 
Note: Data included to last dose date of study regimen (or active treatment in GS-US-334-0108) + 30 days. 


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2.2.1.3.4 
Frequent Adverse Events During SOF+RBV Treatment 
 
The most frequently reported AEs in participants in the 
SOF+RBV 12 and 16 Week groups were fatigue (40.5%, 229 
participants and 46.9%, 46 participants, respectively), 
headache (23.3%, 132 participants and 32.7%, 32 
participants, respectively), insomnia (16.1%, 91 
participants and 28.6%, 28 participants, respectively), and 
nausea (20.1%, 114 participants and 20.4%, 20 
participants, respectively). Fatigue and nausea were 
reported at a comparable incidence in participants in the 
SOF+RBV 12 and 16 Week groups. The higher incidences 
of headache and insomnia in the 16-Week group were 
unlikely due to the longer treatment duration because 
beginning on or after Day 84 (ie, Week 12), there were only 
3 AEs of headache and no AEs of insomnia in this group. 
 
Similar percentages of participants in the SOF+RBV 12 and 
16-Week group experienced most of the AEs that occurred 
in ≥10% of participants. A higher incidence of cough was 
reported in the SOF+RBV 16-Week group compared with the 
12-Week group (13.3%, 13 participants and 6.9%, 39 
participants, respectively). The higher incidence of cough in 
the SOF+RBV 16-Week group was unlikely due to longer 
treatment duration because only 2 AEs of cough began on or 
after Day 84 (Week 12). 
 
The overall incidence of AEs was generally lower in the 
placebo group compared with the SOF+RBV 12-Week or 16- 
Week groups. Notably higher percentages of participants in 
the SOF+RBV 12 and 16 Week groups experienced AEs of 
fatigue, insomnia, anemia, dyspnea, irritability, cough, 
arthralgia, myalgia, and depression compared with the 
placebo group. 
 
With the exception of arthralgia, each of these AEs have 
been previously observed with RBV treatment. [Dusheiko, 
1996; McHutchison, 1998; Di Bisceglie, 1995; Brok, 2010; 
COPEGUS PI, 2013]. Cough has been reported when RBV 
was added to an HCV-treatment regimen, which may 
account for the increase in incidence of this AE in the 
SOF+RBV groups compared with placebo [Dusheiko, 1996; 
McHutchison, 1998]. 
 
In general, the overall incidence of AEs was highest in the 
PEG+RBV group compared with the placebo, SOF+RBV 12- 
Week, and SOF+RBV 16-Week groups. Most of the common 


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AEs reported in ≥10% of participants in the PEG+RBV 
group were reported for a smaller proportion of participants 
in the SOF+RBV 12-Week and 16-Week groups. These AEs 
included headache, nausea, rash, pruritus, decreased 
appetite, irritability, diarrhea, myalgia, dizziness, influenza- 
like illness, arthralgia, chills, depression, pyrexia, pain, and 
neutropenia; all of which have been reported previously with 
PEG+RBV treatment [PEGASYS PI, 2011; Dusheiko, 1996]. 
 
The incidence of fatigue, headache, and nausea was highest 
in the PEG-containing groups (PEG+RBV or 
SOF+PEG+RBV), which was consistent with the expected 
safety profile of PEG+RBV treatment [PEGASYS PI, 2011; 
Ribasphere PI, 2012]. The incidence of these AEs in the 
placebo group (18–24%) as well as the comparable 
incidence of rash, pruritus, decreased appetite, dizziness, 
and diarrhea between the placebo, SOF+RBV 12-Week, and 
SOF+RBV 16-Week groups, may also suggest a relatively 
high background rate of these AEs in HCV-infected 
participants. 
 
As would be expected with the administration of RBV, 
anemia was more commonly observed in the SOF+RBV 
groups than in the placebo group. Although the incidence of 
anemia was higher in the SOF+RBV 12-Week group than in 
the SOF+RBV 16-Week group (10.2%, 58 participants and 
4.1%, 4 participants, respectively), the rates of Grade 2-4 
anemia AEs were similar in both treatment groups (4.8%, 27 
participants and 3.1%, 3 participants, respectively). 
Furthermore, the mean reduction in hemoglobin at the end of 
treatment was similar in both treatment groups (-2.1 g/dL 
and -2.0 g/dL, respectively). 
 
The incidence of anemia AEs in the SOF+RBV groups was 
comparable to that observed in the PEG+RBV group (11.5%, 
28 participants) where the bone marrow suppressive 
effects of PEG offset the lower dose of RBV used in this 
regimen (800 mg). Anemia was managed through dose 
reductions as specified in the RBV labeling and study 
protocols, with <1% of participants receiving transfusion or 
erythropoietin. 
 
2.2.1.3.5 
Serious Adverse Events During SOF+RBV Treatment 
 
Few participants (≤4%) in all treatment groups in the 4 
pivotal Phase 3 studies experienced an SAE. 


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The incidence of SAEs was comparable between the 
SOF+RBV 12-Week and 16-Week groups (3.9%, 22 
participants and 3.1%, 3 participants, respectively. 
Malignant hepatic neoplasm (0.5%, 3 participants) and 
pyrexia and cellulitis (each 0.4%, 2 participants) were the 
only SAEs reported in ≥2 participants in the SOF+RBV 12- 
Week group. The reporting of hepatic neoplasm was not 
unexpected given that hepatocellular carcinoma (HCC) is a 
complication of cirrhosis [Naggie, 2010]. Participants 1055- 
7271 and 5586-1449, who developed malignant hepatic 
neoplasm, had cirrhosis in Studies GS-US-334-0107 and 
GS-US-334-0108, respectively. In Study GS-US-334-0108, 
Participant 1071-1492 who also developed malignant 
hepatic neoplasm, did not have cirrhosis based on the 
screening biopsy (score of F3), but this may have been 
unrepresentative sampling as a computer tomography scan 
done as part of this participant’s evaluation for HCC 
reported “Cirrhotic configuration of the liver with nodular 
contour irregularity.” 
 
No other individual SAEs in the SOF+RBV 12-Week group 
were reported in >1 participant, and there was no apparent 
clustering of SAEs observed within SOCs that had ≥5 
participants reporting SAEs. There was no apparent trend 
in the types of events reported or onset time observed. For 
the SOF+RBV 16-Week group, no individual SAE was 
reported by >1 participants. 
 
Treatment-related SAEs were reported in 2 participants 
(0.4%) in the SOF+RBV 12-Week group: anemia on Day 20 
in Participant 1073-310378 and peripheral edema and 
eczema on post-treatment Day 28 in Participant 2074-7398 
in Studies GS-US-334-0107 and GS-US-334-0108, 
respectively. 
 
Few participants experienced SAEs in the placebo (2.8%, 2 
participants) and PEG+RBV (1.2%, 3 participants) groups. 
No participants in these groups experienced a treatment- 
related SAE. 
 
Although the rates of SAEs were higher in the SOF+RBV 12- 
Week and 16-Week groups (3.9%, 22 participants and 
3.1%, 3 participants, respectively) than in other groups, the 
small difference was not considered to be clinically 
meaningful based on a review of the events. Furthermore, 
the incidence of SAEs was very low in the SOF+PEG+RBV 
group (1.2%, 4 participants). 


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2.2.1.3.6 
Deaths During SOF+RBV Treatment 
 
One death occurred among the 566 participants in the 
SOF+RBV 12-Week group. Participant 1276-310535 in 
Study P7977-1231 died due to cocaine and heroin 
intoxication (preferred term of “toxicity to various agents”) on 
Study Day 1. The participant was a 52-year-old white 
(Hispanic) male with a history of intravenous drug use and 
bipolar disorder. The death occurred on Study Day 1 and 
was considered unlikely to be related to study treatment. It is 
unknown whether the participant took any dose(s) of study 
drug because he was not observed taking his first dose in 
the study clinic, and study drugs were never recovered. 
 
Three nontreatment-emergent deaths occurred (during the 
study follow-up period but >30 days after last dose of study 
drug). In Study P7977-1231, Participant 1225-310184 in the 
PEG+RBV group died due to a brain neoplasm on post 
treatment Day 62 which started 41 days after study drug 
discontinuation. In Study GS-US-334-0107, Participant 
2074-7350 in 41 days after study drug discontinuation. In 
Study GS-US-334-0107, Participant 2074-7350 in the 
SOF+RBV group died of cardiogenic shock secondary to 
aortic stenosis 47 days after the last dose of study drug and 
Participant 5586-7322 in the SOF+RBV group died due to 
metastatic lung cancer 63 days after the last dose of study 
drug. None of the 3 nontreatment-emergent deaths was 
considered related to the study treatment. 
 
2.2.1.3.7 
Discontinuation of Treatment Regimen or Study Drug Dose 
Modification or Interruption Due to Adverse Events 
 
Adverse events that led to discontinuation, modification, or 
interruption of any treatment regimen for participants in the 
4 pivotal Phase 3 studies are described in this section. 
 
Table 2-4 summarizes AEs that led to permanent 
discontinuation from any study drug in a SOF-containing 
treatment regimen in the 4 pivotal Phase 3 studies. Anemia 
was the only AE reported by more than 1 participant treated 
with a SOF-containing regimen that led to discontinuation 
from treatment (SOF+RBV: n=1 [0.2%], SOF+PEG+RBV: 
n=2 [0.6%]). The anemia event in the participant receiving 
SOF+RBV led to discontinuation of RBV; the anemia events 
in the 2 participants receiving SOF+PEG+RBV led to 
discontinuation of all 3 study drugs. None of the 3 events of 
anemia were considered serious. 


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Table 2-4: Adverse Events Leading to Permanent Discontinuation from any Study Drug in a 
SOF-Containing Treatment Regimen Reported in ≥2 Subjects in the Pivotal Phase 3 Studies 
(Screened Subjects) 
 
GS-US-334- 
0107 
(POSITRON) 
P7977-1231 
(FISSION) 
GS-US-334-0107 
(POSITRON) 
GS-US-334-0108 
(FUSION) 
GS-US-334- 
0108 
(FUSION) 
P7977-1231 
(FISSION) 
GS-US-334- 
0110 
(NEUTRINO) 
Placebo 
12 Weeks 
SOF+RBV 
12 Weeks 
SOF+RBV 
16 Weeks 
PEG+RBV 
24 Weeks 
SOF+PEG+RBV 
12 Weeks 
(N = 71) 
(N = 566) 
(N = 98) 
(N = 243) 
(N = 327) 
Number (%) of 
Subjects 
Experiencing Any 
AE Leading to 
Permanent 
Discontinuation 
from Any Study 
Treatment 
3 (4.2%) 
8 (1.4%) 
0 
26 (10.7%) 
5 (1.5%) 
Anemia 
0 
1 (0.2%) 
0 
2 (0.8%) 
2 (0.6%) 
Note: Adverse events are mapped according to MedDRA Version 15.0. 
Note: Subjects are counted once for each system organ class (SOC), and once for each AE preferred term (PT). 
 
2.2.1.3.8 
Discontinuation of Treatment Regimen or Study Drug Dose 
Modification or Interruption Due to Adverse Events During 
SOF+RBV Treatment 
 
The lowest rates of discontinuation of SOF+RBV due to AEs 
were observed in the SOF+RBV 12-Week group (1.4%, 8 
participants) and SOF+RBV 16-Week group (0 
participants). In the SOF+RBV groups, there were no AEs 
leading to permanent discontinuation of SOF+RBV that 
occurred in more than 1 participant. 
 
In the placebo group, 3 participants (4.2%) had an AE that 
led to discontinuation of treatment regimen. The PEG+RBV 
group had the highest proportion of participants who had an 
AE that led to discontinuation from PEG+RBV (10.7%, 26 
participants), compared with all other groups (0–4.2%). 
 
Dose modification or interruption was allowed per study 
protocol for RBV or RBV placebo only; no dose modification 
of SOF was permitted. Anemia was the most commonly 
reported AE that led to study drug interruption or dose 
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(6.5%, 37 participants and 3.1%, 3 participants, 
respectively). 
 
Approximately a quarter (26.7%) of participants in the 
PEG+RBV group had an AE that led to study drug 
interruption or dose modification. The most commonly 
reported AEs that led to study drug interruption or dose 
modification were anemia, neutropenia (each 7.8%, 19 
participants), and thrombocytopenia (5.3%, 13 
participants). 
 
2.2.1.3.9 
Clinical Safety Conclusions 
 
Across clinical studies, SOF+PEG+RBV and SOF+RBV 
regimens were generally safe and well tolerated. Other than 
the expected AEs and laboratory abnormalities associated 
with RBV, the SOF+RBV for up to 16 weeks had a safety 
profile similar to that of placebo. Most AEs were mild to 
moderate. Severe and serious AEs were uncommon with 
SOF-based treatment and there were no consistent trends in 
type or timing of these events other than what would be 
expected with RBV with or without PEG. 
 
Across all groups in the pivotal Phase 3 studies (SOF+RBV 
12-Week, SOF+RBV 16-Week, SOF+PEG+RBV, 
PEG+RBV, and placebo), the 3 most frequently occurring 
AEs were fatigue, headache, and nausea. The incidence of 
these events was highest in the PEG-containing groups 
(PEG+RBV or SOF+PEG+RBV), which was consistent with 
the expected safety profile of PEG+RBV treatment 
[PEGASYS PI, 2011; Ribasphere PI, 2012]. Other than the 
expected AEs and laboratory abnormalities associated with 
RBV, the SOF+RBV 12 and 16 Week groups had a safety 
profile similar to the placebo group. No additional AEs than 
those in the expected safety profile for PEG+RBV or RBV 
were identified in the SOF+RBV or SOF+PEG+RBV groups. 
 
2.2.2 Ribavirin (RBV) 
 
RBV is a guanosine analogue that inhibits the in vitro replication of a wide range 
of RNA and DNA viruses [COPEGUS, Jan 2010 and March 2010]. RBV 
monotherapy has little or no effect on the replication of HCV but can result in 
normalization of serum ALT activity and improvement in liver histology. When 
combined with IFN or PEG therapy, RBV decreases substantially the relapse rate 
seen after cessation of IFN therapy [Poynard, 1998; McHutchison, 1998]. 
 
RBV is a known teratogen (FDA category X). Furthermore, RBV is known to 
accumulate intracellularly where it is cleared slowly, and is also excreted in 


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semen. Therefore, extreme care must be taken to avoid pregnancy during RBV 
therapy and for up to 6 months following completion of treatment. A 
comprehensive review of RBV is contained in the package insert/SmPC. 
 
2.2.3. Ledipasvir/sofosbuvir (LDV/SOF) 
 
LDV/SOF is an all-oral, once daily treatment regimen for chronic HCV 
infection. As such, it obviates the toxicity and tolerability issues, as well as 
the contraindications, associated with Peg-IFN and/or RBV. As of 21 March 
2014, 23 clinical studies have been initiated with LDV/SOF alone or in 
combination with RBV, including 344 healthy participants and 3504 
participants with chronic HCV infection. 
 
2.2.3.1 
Clinical Efficacy in Participants with Genotype 1 HCV infection and 
HIV Co-infection 
 
The efficacy data for LDV/SOF in Genotype 1 and 4 HCV infection 
is derived from the Phase 3 ION-4 study, which was a multicenter, 
open-label, single arm study of LDV/SOF for 12 weeks. The trial 
included HCV treatment-naïve and treatment-experienced (55%) 
participants and included 20% of participants with cirrhosis. 
Participants were required to be on ARVs and have evidence of 
HIV viral suppression. The allowable ARVs included tenofovir 
disoproxil fumarate (TDF) plus EFV, raltegravir (RAL), or rilpivirine 
(RPV). Overall the study population was 82% male, 34% self- 
reported black race, 24% IL28B CC genotype, and 98% GT1 (75% 
1a, 23% 1b, 8 genotype 4). The overall SVR12 was 96% (96% GT1 
and 100% GT4). Virologic failures included 10 participants with 
relapse after end of therapy and 2 participants with breakthrough 
due to nonadherence. One participant was lost to follow-up after 
achieving SVR4 although this participant did return for SVR24 
visit. There was one death for an unrelated event (infectious 
endocarditis in IDU). There was no difference in SVR12 for 
treatment-naïve (95%), treatment-experienced (97%), cirrhosis 
(94%), no cirrhosis (96%), treatment-experienced with cirrhosis 
(98%). In a multivariable analysis only self-reported black race was 
associated with a lower SVR12 (90%). This association of lower 
SVR12 and race was not observed in the mono-infected Phase 3 
program. Further investigations to explain this observation in ION- 
4, including population PK across race, ARV regimen, relapse and 
a candidate gene study of the CYP2B6 polymorphism, were 
negative. Deep sequencing was completed on all participants and 
NS5A resistant variants (RAV) were identified at baseline in 20% of 
participants; this did not associate with lower SVR12 (94% with 
RAVs at baseline vs 96% without). Ten of the 12 virologic failures 
in the study had RAV at failure, 4 of these were relapsers who had 
the RAVs at baseline. 


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2.2.3.2 
Clinical Efficacy in HCV Mono-infection 
 
The primary efficacy data for LDV/SOF in genotype 1 HCV infection 
in the clinical efficacy section is derived from 3 Phase 3 ION 
studies (GS-US-337-0102 [ION-1], GS-US-337-0109 [ION-2], and GS- 
US-337-0108 [ION-3]). Studies GS-US-337-0102 and GS-US-337- 
0109 evaluated treatment with LDV/SOF±RBV for 12 or 24 weeks in 
treatment-naive and treatment-experienced participants, 
respectively, who were infected with genotype 1 HCV. Both studies 
enrolled up to 20% of HCV-infected participants who had 
documented compensated cirrhosis. Study GS-US-337-0108 
evaluated LDV/SOF±RBV treatment for 8 weeks and LDV/SOF 
treatment for 12 weeks in noncirrhotic treatment-naive participants 
with genotype 1 HCV infection [Harvoni PI, 2015]. 
 
Additional data from Phase 2 studies that provide clinical efficacy 
information for retreatment of virologic failures to prior SOF-based 
regimens (Studies 13-I-0066 [SYNERGY] and GS-US-337-0118 
[LONESTAR]) are also presented. 
 
Efficacy data across the Phase 3 ION studies were not pooled or 
grouped with the exception of those for noncirrhotic treatment- 
naive participants from the LDV/SOF 12-week groups in Studies 
GS-US-337-0102 and GS-US-337-0108. These 2 studies had data for 
LDV/SOF 12-week groups pooled for purposes of subgroup 
analysis of noncirrhotic treatment-naive participants. With the 
exception of this 1 subset of participants, different participant 
populations were enrolled in each study. 
 
2.2.3.2.1 
Participant Disposition 
 
Of the 1952 participants who received at least 1 dose of 
study drug in the LDV/SOF Phase 3 ION studies, 98.1% 
completed their assigned study treatment, and 0.7% of 
participants discontinued study treatment due to an AE. 
Two participants discontinued treatment due to lack of 
efficacy, and, in both cases, PK data suggested study 
drug noncompliance (Studies GS-US-337-0102 and GS- 
US-337-0109). 
 
2.2.3.2.2 
Demographics and Baseline Disease Characteristics 
 
Overall, demographic characteristics were generally 
similar across all treatment groups in the LDV/SOF 
Phase 3 ION population; however, because Study GS- 
US-337-0102 enrolled 40.8% of participants in Europe, 
notable differences in demographics between the US 
and Europe compared with groups in Studies GS-US- 


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337-0109 and GS-US-337-0108 were observed for race 
and BMI as follows: in the US, a higher percentage of 
participants were black or African-American (19.5% US 
vs. 2.3% Europe) and had a BMI ≥30 kg/m2 (27.3% US vs. 
9.3% Europe). Overall, baseline disease characteristics 
were generally similar across all treatment groups. A 
total of 11.5% of participants had cirrhosis at screening: 
15.7% and 20.0% of participants had cirrhosis at 
screening in Studies GS-US-337-0102 and GS-US-337- 
0109, respectively. No participants had cirrhosis at 
screening in Study GS-US-337-0108. The majority of 
participants had genotype 1a (73.9%) or 1b (25.5%) HCV 
infection; 5 participants had genotype 1 (no subtype per 
the protocol-specified clinical assays) HCV infection, 2 
participants had genotype 4 HCV infection, and 5 
participants had no genotype determined by the 
protocol-specified clinical assays. The 7 participants 
who had either genotype 4 HCV infection or no genotype 
determined for their HCV infection were randomized in 
violation of the clinical study protocols [Harvoni PI, 
2015]. 
 
2.2.3.2.3 
Study GS-US-337-0102 (ION-1): Treatment-Naive 
Participants 
 
In Study GS-US-337-0102, both 12-week groups met the 
primary efficacy endpoint of an SVR12 rate that was 
superior to the historical control rate of 60% (p<0.001) 
and the prespecified interim criteria of SVR12 ≥90% in 
participants with and without cirrhosis separately. The 
SVR12 rates were 97.7% for the LDV/SOF 12-week group 
and 97.2% for the LDV/SOF+RBV 12-week group. 
 
Participants with and without cirrhosis achieved high 
rates of SVR12: SVR12 rates in participants with 
cirrhosis were 94.1% in the LDV/SOF 12-week group and 
100% in the LDV/SOF+RBV 12-week group; SVR12 rates 
in participants without cirrhosis were 98.3% in the 
LDV/SOF 12-week group and 96.7% in the 
LDV/SOF+RBV 12-week group. 
 
In the LDV/SOF 12-week group, only 1 participant 
relapsed and 4 participants did not have a post 
treatment Week 12 visit and were classified as failures. 
The participant who relapsed had IL28B TT alleles, 
cirrhosis, and the baseline NS5A resistance-associated 
variant (RAVs) L31M, and relapsed at the post treatment 
Week 4 visit; the participant had completed 12 weeks of 


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LDV/SOF without any dose interruptions. In the 
LDV/SOF+RBV 12-week group, no participants relapsed 
and 6 participants did not have a post treatment Week 
12 visit and were classified as failures. Across all 4 
treatment groups, 1 participant in the LDV/SOF 24-week 
group had on-treatment virologic failure at Week 8 
(breakthrough), associated with documented study drug 
noncompliance. 
 
Several host and viral factors that have been 
traditionally predictive of or associated with lower rates 
of SVR (eg, African-American race, cirrhosis, high BMI, 
genotype 1a, high viral load, non-CC IL28B allele) had 
no notable impact on SVR12 rates. The presence of 
baseline LDV-associated NS5A RAVs in 78 participants 
also had no notable impact on SVR12 rates. 
 
2.2.3.2.4 
Study GS-US-337-0108 (ION-3): Treatment-Naive 
Participants 
 
All treatment groups met the primary efficacy endpoint 
of an SVR12 rate that was statistically significantly 
higher (p<0.001) than the adjusted historical SVR null 
rate of 60%. The SVR12 rates were 94.0% for the 
LDV/SOF 8-week group, 93.1% for the LDV/SOF+RBV 8- 
week group, and 95.4% for the LDV/SOF 12-week group. 
 
The 8-week, RBV-free LDV/SOF regimen was noninferior 
to the 8-week RBV-containing regimen and the 12-week 
LDV/SOF regimen, as demonstrated by lower bound 
95.0% CI of −3.9% and lower bound 97.5% CI of −6.4%, 
respectively, based on the requirement that the lower 
bound of the CI of the difference between two treatment 
groups was greater than the prespecified noninferiority 
margin of −12%. 
 
The addition of RBV to an 8-week treatment course of 
LDV/SOF or extension of the LDV/SOF treatment 
duration from 8 to 12 weeks did not substantially 
increase the observed SVR12 rates. Relapse rates were 
similar in the 8-week treatment groups, but were lower 
in the LDV/SOF 12-week group. 
 
The overall virologic failure rate was low (LDV/SOF 8 
Weeks: 5.1%, LDV/SOF+RBV 8 Weeks: 4.2%, and 
LDV/SOF 12 Weeks: 1.4%). No resistance to SOF or LDV 
was detected in 21 and 7 of the 23 relapsed participants, 
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single-class LDV resistance in 16 (69.6%) of the relapse 
participants. The substitutions V321A and L159F in 
NS5B were each detected in 1 participant with genotype 
1a HCV infection at low levels at relapse. E237G, a 
conserved site substitution in NS5B, but distant from 
the active site, was detected in 2 genotype 1a 
participants at virologic failure. Eleven participants who 
achieved SVR4 did not achieve SVR12: 5 participants in 
the LDV/SOF 8-week group (3 relapsed, 1 lost to follow- 
up, and 1 withdrew consent); 4 participants in the 
LDV/SOF+RBV 8-week group (3 relapsed, 1 lost to 
follow-up) and 2 participants in the LDV/SOF 12-week 
group (2 participants had visits that had not occurred at 
time of data cut and were considered lost to followup). 
 
Prespecified analyses of subgroups indicated that the 
SVR12 rates across the 3 treatment groups were 
generally consistent with those observed in the overall 
population, with high SVR12 rates observed in most 
subgroups. 
 
For the 8-week treatment groups, exact univariate 
logistic regression analysis was used to assess the 
relationship between relapse and 10 prognostic factors 
(treatment with vs. without RBV, age, sex, race, 
ethnicity, HCV genotype 1 subtype, baseline HCV RNA 
viral load, BMI, IL28B alleles, and gamma-glutamyl 
transferase [GGT]). Among the 10 factors included in the 
analysis, 2 were found to be significant (p<0.05). These 
were male sex and having a baseline HCV RNA viral load 
≥800,000 IU/mL. Of note, the analysis showed that the 
absence of RBV in an 8-week regimen consisting of 
LDV/SOF was not a significant predictor of relapse. 
Additionally, several other host and viral factors that 
have traditionally been predictive of, or associated with, 
relapse (eg, age >65 years, black or African-American, 
Hispanic or Latino, high BMI, non-CC IL28B alleles) were 
not found be significant in this analysis. Subsequent 
exact multivariate regression analysis identified only 1 
factor, male sex, to be the most predictive of relapse, 
among the limited number of participants who relapsed. 
Although the SVR12 rate was numerically lower among 
male participants than female participants, the majority 
of male participants (92.6%, 225 of 243 participants) and 
female participants (98.9%, 178 of 180 participants) 
achieved SVR12 after 8 weeks of therapy. 


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ION-3 
ION-3 
ION-3 
ION-1 
ION-1 
LDV/SOF 
8-Week 
N=215 (%) 
LDV/SOF+ 
RBV 
8-Week 
N=216 (%) 
LDV/SOF 
12-Week 
N=216 (%) 
LDV/SOF 
12-Week 
N=214 (%) 
LDV/SOF+ 
RBV 
12-Week 
N=217 (%) 
Treatment-Naïve Total 
SVR12 
202/215 (94) 
201/216 (93) 
206/216 (95) 
209/214 (98) 
211/217 (97) 
95% CI 
89.9 - 96.7% 
88.8 – 96.1 
91.7 – 97.8 
94.6 – 99.2 
94.1 – 99.0 
P-value* 
<0.001 
<0.001 
<0.001 
<0.001 
<0.001 
Treatment-Naïve Noncirrhotic 
SVR12 
202/215 (94) 
201/216 (93) 
206/216 (95) 
177/180 (98) 
178/184 (97) 
95% CI 
89.9 – 96.7 
88.8 – 96.1 
91.7 – 97.8 
95.2 – 99.7 
93.0 – 98.8 
Treatment-Naïve Cirrhotic 
SVR12 
NA 
NA 
NA 
32/34 (94) 
33/33 (100) 
95% CI 
-- 
-- 
-- 
80.3 – 99.3 
89.4 - 100 
*Compared to historic control of 60% 
 
2.2.3.2.5 
Participants Retreated After Virologic Failure Final 
 
Participants who have failed either a SOF-containing 
regimen or a LDV/SOF-containing regimen have been 
retreated or will be retreated with LDV/SOF±RBV in the 
following studies: GS-US-337-0118 (LONESTAR), GS- 
US-337-0122 (ELECTRON-2), GS-US-337-1118, and an 
ongoing non-Gilead-sponsored study (Study 13-I-0066 
[SYNERGY]; IND 116585). Resistance and SVR data from 
20 participants, 1 from Study GS-US-337-0118 (final 
data) and 19 from Study GS-US-337-0122 (preliminary 
data), are currently available. Of these 20 retreatment 
participants, 11 had relapsed after treatment with a SOF- 
containing regimen and 9 had relapsed after treatment 
with a LDV/SOF-containing regimen. To date, all 
participants have achieved SVR12 following retreatment. 
 
2.2.3.2.6 
Clinical Efficacy Conclusions 
 
In the LDV/SOF Phase 3 clinical program, LDV/SOF±RBV 
treatment was evaluated for 12 or 24 weeks in treatment- 
naive and treatment-experienced participants in Studies 
GS-US-337-0102 and GS-US-337-0109, respectively, with 
genotype 1 HCV infection. Both studies enrolled up to 
20% HCV-infected participants who had documented 
compensated cirrhosis. Study GS-US-337-0108 
evaluated LDV/SOF±RBV treatment for 8 weeks and 
LDV/SOF treatment for 12 weeks in noncirrhotic 
treatment-naive participants with genotype 1 HCV 


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infection. Across all studies, LDV/SOF demonstrated a 
high degree of efficacy with point estimates for SVR12 
>93% in participants with genotype 1 HCV infection. 
 
Across the three Phase 3 studies, the addition of RBV to 
the LDV/SOF regimen did not substantially increase the 
SVR rate. When the SVR rates are considered, extending 
the duration of LDV/SOF treatment from 8 to 12 weeks in 
noncirrhotic treatment-naive participants in Study GS- 
US-337-0108 and 12 to 24 weeks in noncirrhotic or 
cirrhotic treatment-experienced participants in Study 
GS-US-337-0109 would not enhance the observed 
SVR12 rates for the majority of participants. 
Concordance analysis between SVR12 and SVR24 in 
treatment-naive and treatment-experienced participants 
receiving LDV/SOF for 12 or 24 weeks was 100% in the 
Phase 3 Studies GS-US-337-0102 and GS-US-337-0109. 
There was no clinically meaningful impact on SVR12 
rates or relapse when participants took LDV/SOF with or 
without food in any study. 
 
Comprehensive analyses showed that no genotypic or 
phenotypic resistance to either SOF or LDV was 
detected in 8 of 37 participants (22%) at virologic failure 
in the Phase 3 studies. Virologic failure was associated 
with single-class LDV phenotypic resistance in 29 of 37 
participants (78%). Low levels of V321A and L159F in 
NS5B, 2 substitutions previously identified to be SOF 
treatment-emergent substitutions with no phenotypic 
resistance to SOF, were detected in 1 participant with 
genotype 1a HCV infection at relapse by deep 
sequencing. In addition, E237G, a conserved site 
substitution in NS5B, but distant from the active site, 
was observed in 2 participants with genotype 1a HCV 
infection and 1 participant with genotype 1b infection at 
virologic failure. The clinical significance of these NS5B 
substitutions is unknown. No genotypic or phenotypic 
resistance to SOF was detected in the remaining 
participants. 
 
Overall, pre-existing baseline NS5A RAVs have a poor 
predictive value for virologic failure when participants 
are treated with a dual combination of SOF and LDV. 
Among all participants who had baseline NS5A RAVs, 
an SVR12 rate of 89.5% (34/38 participants) or 92.1% 
(82/89 participants) was observed among participants 
treated with LDV/SOF for 8 or 12 weeks, respectively. 
Nevertheless, among participants with baseline NS5A 


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RAVs, there were slight reductions in SVR12 observed, 
associated with NS5A RAVs expressing higher levels of 
LDV resistance within the treatment-experienced 
population. From a clinical perspective, the lack of a 
high predictive value between viral sequence and 
treatment outcome coupled with the observation that a 
large majority of participants with NS5A RAVs achieve 
SVR12 appears to preclude the clinical utility of baseline 
sequencing. 
 
2.2.3.3 
Clinical Safety 
 
The primary safety data for this clinical safety section are derived 
from the 3 Phase 3 LDV/SOF ION studies (GS-US-337-0102 [ION-1], 
GS-US-337-0109 [ION-2], GS-US-337-0108 [ION-3]) with supporting 
safety data from other studies as appropriate. The ION-4 safety 
analysis confirmed the clinical safety reported in the rest of the 
ION program. 
 
2.2.3.3.1 
Adverse Events 
 
Treatment-emergent AEs were any events with onset 
dates on or after the date of the first dose of any study 
drug up to 30 days after the last dose of any study drug. 
 
2.2.3.3.2 
Overall Summary of Adverse Events 
 
Table 2-5 presents an overall summary of AEs reported 
in the 3 Phase 3 ION studies. Of the participants in these 
studies, 79.1% had at least 1 AE and 4.7% had at least 1 
Grade 3 or 4 AE. In addition, 2.6% of participants had at 
least 1 SAE, with only 0.3% of participants experiencing 
a treatment-related SAE (Section 2.2.3.3.4). 
 
Overall, <1% of participants receiving LDV/SOF with or 
without RBV (0.7%) had an AE leading to 
discontinuation of LDV/SOF. The only AEs that led to 
discontinuation of LDV/SOF in >1 participant were 
palpitations and anxiety (2 participants each) (Section 
2.2.3.3.6). 
 
A higher proportion of participants in the RBV- 
containing (LDV/SOF+RBV) treatment groups (13.5%) 
had AEs leading to dose modification or interruption of 
any study drug than participants in the RBV-free 
(LDV/SOF) treatment groups (0.6%). 


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No treatment-emergent deaths were reported in the 
three Phase 3 studies. One nontreatment-emergent 
death was reported in a participant who had an SAE of 
hepatic failure secondary to HCV infection and alcohol 
use on post treatment Day 38. The participant died of 
liver failure on post treatment Day 121 (Section 
2.2.3.3.5). 
 
The difference in the AE profile of RBV-free (LDV/SOF) 
and RBV-containing (LDV/SOF+RBV) treatment groups 
was also evaluated. The percentage differences for the 
8-, 12-, or 24-week treatment durations and overall risk 
differences (adjusted for treatment duration based on 
Mantel-Haenszel proportions) were calculated for the AE 
brief summary and for AEs and treatment-related AEs 
that occurred in at least 5% of participants within any 
treatment group. The addition of RBV to the treatment 
regimen was associated with an increase in the total 
incidence of AEs for all treatment durations. Overall, 
when adjusted for treatment duration, the addition of 
RBV increased the risk of a participant experiencing any 
AE by 11.1%, the risk of a participant experiencing any 
treatment-related AE by 25.7%, and the risk of a 
participant experiencing any AE leading to modification 
or interruption of any study drug by 13.0%. For Grade 3 
or 4 AEs, Grade 3 or 4 treatment-related AEs, SAEs, 
treatment-related SAEs, AEs leading to permanent 
discontinuation of any study drug, AEs leading to 
permanent discontinuation of LDV/SOF, and AEs 
leading to interruption of LDV/SOF, the risk differences 
between the LDV/SOF and LDV/SOF+RBV treatment 
regimens were small (<5%). The majority of AEs 
attributable to the addition of RBV to LDV/SOF were 
Grade 1 to 2 in severity. 
 
The ION-4 reported 77% of participants with AEs, 4% 
with grade 3-4 (only 4 of the 14 were reported as related 
to the study regimen), 8 with severe AE (including 2 
diagnoses of hepatocellular carcinoma and 2 diagnoses 
of portal vein thrombosis). No participant discontinued 
treatment due to AE. Eleven percent of participants had 
a grade 3-4 laboratory abnormality but these were all 
transient and asymptomatic (elevated glucose in 
diabetic participants, elevated lipase and creatinine 
kinase). All participants maintained stable CD4 
throughout the study and no participant had confirmed 
HIV virologic rebound. Common AEs (≥ 5%) included 
headache (25%), fatigue (21%), diarrhea (11%), nausea 


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(10%), arthralgia (7%), and upper respiratory tract 
infection (5%). This is quite similar to Tables 2-5 and 2-6 
below. Due to the drug-drug interaction of LDV and TDF 
leading to increased serum TFV levels all participants 
had close renal monitoring at all study visits. There was 
no clinically or statistically significant increase in serum 
creatinine or decrease in creatinine clearance (CrCl) 
during the study. Four participants met the study 
protocol defined criteria of confirmed, treatment- 
emergent, renal insufficiency (creatinine ≥ 0.4 mg/dL). 
Two of these participants were simply monitored and in 
the absence of any evidence of tubular toxicity no 
changes were made in ARVs. One participant entered 
the study on RAL and had baseline CrCl of 
approximately 50 mL/min. With worsening CrCl but no 
evidence of tubular toxicity this participant had dose 
reduction of TDF as per package insert. The fourth 
participant also entered the study with evidence of 
chronic kidney disease (CKD) with CrCl of 
approximately 80 mL/min and baseline 4+ glucosuria 
and 2+ proteinuria. This participant had worsening renal 
function on study and due to the concern for tubular 
damage at baseline the decision was made to switch 
this participant off of TDF to RAL. The participant 
completed the study on EFV, RAL and lamivudine (3TC) 
without difficulty and achieved SVR12. 


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Table 2-5: Overall Summary of Adverse Events in LDV/SOF Phase 3 Safety Population 
 
Number (%) of Subjects 
Experiencing Any: 
ION-3 
LDV/SOF 
8 Week 
N=215 
RBV-Free 
Regimens 
(ION-1, 2, 3) 
Overall (N=1080) 
RBV-Containing 
Regimens 
(ION-1, 2, 3) 
Overall (N=872) 
AE 
145 (67%) 
800 (74%) 
745 (85%) 
Grade 3 or 4 AE 
2 (0.9%) 
46 (4.3%) 
45 (5.2%) 
Treatment-Related AE 
82 (38%) 
484 (44.8%) 
617 (70.8%) 
Grade 3 or 4 Treatment-Related AE 
0 
11 (1.0%) 
27 (3.1%) 
SAE 
4 (1.9%) 
34 (3.1%) 
17 (1.9%) 
Treatment-Related SAE 
0 
4 (0.4%) 
1 (0.1%) 
AE Leading to Permanent 
Discontinuation of Any Study Drug 
0 
6 (0.6%) 
11 (1.3%) 
AE Leading to Permanent 
Discontinuation of LDV/SOF 
0 
6 (0.6%) 
7 (0.8%) 
AE Leading to Modification or 
Interruption of Any Study Drug 
0 
6 (0.6%) 
118 (13.5%) 
AE Leading to Interruption of 
LDV/SOF 
0 
6 (0.6%) 
7 (0.8%) 
Treatment-Emergent Death 
0 
0 
0 
 
2.2.3.3.3 
Frequent Adverse Events Final 
 
Table 2-6 presents the AEs reported for at least 5% of 
subjects in any treatment group by preferred term in the 
three Phase 3 ION studies. Overall, the 3 most frequently 
reported AEs were fatigue (29.3%), headache (23.1%), 
and nausea (13.5%). All of these events were reported 
more commonly in participants receiving LDV/SOF+RBV 
compared with participants receiving LDV/SOF: fatigue 
(38.0% vs. 22.2%), headache (26.1% vs. 20.6%), and 
nausea (17.4% vs. 10.4%). 
 
The majority of AEs reported in at least 5% of 
participants occurred more commonly in participants 
receiving LDV/SOF+RBV compared with participants 
receiving LDV/SOF. Furthermore, irrespective of 
treatment duration (8 vs. 12 vs. 24 weeks), the AEs with 
a ≥5% risk difference were generally similar across the 3 
treatment durations (8 vs. 12 vs. 24 weeks). Therefore, a 
pooled analysis, which adjusted for treatment duration, 
was used to identify AEs occurring at ≥5% incidence in 
participants receiving LDV/SOF+RBV compared with 
participants receiving LDV/SOF. These AEs were 
fatigue, insomnia, anemia, nausea, dyspnea, irritability, 
cough, rash, pruritus, and headache. All of these events 


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were associated with the expected safety profile of RBV 
[Dusheiko, 1996; Ribasphere PI, 2012; COPEGUS PI, 
2013]. 
 
When evaluated at the system-organ-class level, 
numerically higher percentages (difference of >5%) of 
participants receiving LDV/SOF+RBV than participants 
receiving LDV/SOF experienced AEs within the following 
system organ classes: blood and lymphatic system 
disorders (10.7% vs. 1.5%); gastrointestinal disorders 
(39.6% vs. 30.6%); general disorders and administration 
site conditions (52.5% vs. 33.8%); infections and 
infestations (23.7% vs. 18.4%); nervous system 
disorders (36.9% vs. 27.8%); psychiatric disorders 
(29.6% vs. 16.2%); respiratory, thoracic, and mediastinal 
disorders (25.2% vs. 11.5%); and skin and subcutaneous 
tissue disorders (29.7% vs. 14.3%). No system organ 
class had an incidence of AEs higher (>5%) in 
participants receiving LDV/SOF compared with 
participants receiving LDV/SOF+RBV. 
 
Longer treatment duration (8 vs. 12 vs. 24 weeks) was 
associated with an increase in the total incidence of 
AEs, both in the LDV/SOF groups (67.4%, 72.4%, and 
81.3%, respectively) and LDV/SOF+RBV groups (76.4%, 
85.4%, and to 91.5%, respectively). 
 
When comparing the LDV/SOF groups by treatment 
duration, the differences in the incidence of any 
individual AE between 8 and 12 weeks of treatment or 
between 12 and 24 weeks of treatment were small (<5%); 
headache was the only AE with increased incidence of 
≥5% when the treatment durations increased from 8 to 
12 weeks. 
 
When comparing the LDV/SOF+RBV groups by 
treatment duration, most of the differences in the 
incidence of any individual AE between 8 and 12 weeks 
of treatment were small (<5%); insomnia, cough, 
asthenia, and dyspnea were exceptions with increased 
incidence of ≥5% when the treatment durations 
increased from 8 to 12 weeks. Similarly, the differences 
in the incidence of any individual AE between 12 and 24 
weeks of treatment were small (<5%), with the exception 
of headache, which had an increased incidence of ≥5% 
when the treatment duration increased from 12 to 24 
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Table 2-6: Adverse Events in at Least 5% of Subjects in Any Treatment Group by 
Preferred Term in the LDV/SOF Phase 3 Safety Population 
 
ION-3 
LDV/SOF 
8 Week 
N=215 
RBV-Free 
Regimens 
(ION-1, 2, 3) 
Overall (N=1080) 
RBV-Containing 
Regimens 
(ION-1, 2, 3) 
Overall (N=872) 
Number (%) of Subjects 
Experiencing Any AE: 
145 (67%) 
800 (74%) 
745 (85%) 
Fatigue 
45 (21%) 
240 (22.2%) 
331 (38%) 
Headache 
30 (14%) 
222 (20.6%) 
228 (26.1%) 
Nausea 
15 (7%) 
112 (10.4%) 
152 (17.4%) 
Insomnia 
11 (5.1%) 
82 (7.6%) 
155 (17.8%) 
Diarrhea 
15 (7%) 
88 (8.1%) 
67 (7.7%) 
Irritability 
3 (1.4%) 
46 (4.3%) 
95 (10.9%) 
Rash 
3 (1.4%) 
47 (4.4%) 
94 (10.8%) 
Arthralgia 
9 (4.2%) 
68 (6.3%) 
66 (7.6%) 
Cough 
3 (1.4%) 
42 (3.9%) 
90 (10.3%) 
Pruritis 
2 (0.9%) 
33 (3.1%) 
78 (8.9%) 
Dizziness 
6 (2.8%) 
47 (4.4%) 
61 (7%) 
Constipation 
9 (4.2%) 
53 (4.9%) 
42 (4.8%) 
Myalgia 
7 (3.3%) 
47 (4.4%) 
48 (5.5%) 
Asthenia 
1 (0.5%) 
38 (3.5%) 
56 (6.4%) 
Anemia 
2 (0.9%) 
5 (0.5%) 
84 (9.6%) 
Muscle Spasms 
3 (1.4%) 
28 (2.6%) 
57 (6.5%) 
Back Pain 
6 (2.8%) 
43 (4.0%) 
40 (4.6%) 
Dyspnea 
0 
12 (1.1%) 
69 (7.9%) 
Anxiety 
5 (2.3%) 
30 (2.8%) 
49 (5.6%) 
Nasopharyngitis 
3 (1.4%) 
38 (3.5%) 
41 (4.7%) 
Vomiting 
6 (2.8%) 
24 (2.2%) 
40 (4.6%) 
Dry Skin 
1 (0.5%) 
10 (0.9%) 
43 (4.9%) 
Dyspnea Exertional 
0 
6 (0.6%) 
35 (4%) 
 
2.2.3.3.4 
Serious Adverse Events in Phase 3 ION Studies 
 
Overall in the Phase 3 ION studies (GS-US-337-0102, GS- 
US-337-0109, and GS-US-337-0108), few participants 
(2.6%, 51 of 1952 participants) had any SAE. The only 
SAEs reported in >1 participant across all treatment 
groups were noncardiac chest pain (3 participants), and 
chest pain, colitis, gastroenteritis, hand fracture, 
hypertension, intervertebral disc protrusion, and 
pneumonia (2 participants each), suggesting that no 
trends in SAE type or onset time were observed. Only 5 


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participants (0.3%) had an SAE that was considered 
related to study drug by the investigator: anemia, 
development of factor VIII inhibitor, mesenteric vein 
thrombosis, salpingitis, and headache. These events are 
described below: 
1. A participant in the LDV/SOF+RBV 12-week group 
had 2 separate treatment-related SAEs of anemia; 
both events were Grade 3, led to interruption of the 
RBV dose, and resolved. 
2. A participant with cirrhosis in the LDV/SOF 24-week 
group had a treatment-related SAE of mesenteric 
vein thrombosis; this event was Grade 3, led to the 
interruption of the LDV/SOF dose, and resolved. 
3. A participant with a medical history of hemophilia A 
in the LDV/SOF 24-week group, who had received 
factor VIII supplementation prior to and during the 
study, had a treatment-related SAE of development 
of factor VIII inhibitor; this event was Grade 3, led to 
the discontinuation of LDV/SOF, and was ongoing at 
the time of the data cut. 
4. A participant in the LDV/SOF 24-week group had a 
treatment-related SAE of salpingitis; this event was 
Grade 3, did not lead to a dose change for LDV/SOF, 
and resolved. 
5. A participant in the LDV/SOF 24-week group had a 
treatment-related SAE of headache; this event was 
Grade 3, occurred on post treatment Day 6, and was 
ongoing at the time of the data cut. 
 
2.2.3.3.5 
Deaths: Participants in Phase 3 ION Studies 
 
One treatment-emergent death was reported in the 
LDV/SOF Phase 3 Safety Population. This participant 
was in the ION-4 trial and was discontinued from the 
study at week 4 due to hospitalization for severe 
staphylococcal aureus infective endocarditis resulting 
in multi-organ failure and death in a participant actively 
using intravenous drugs. 
 
One nontreatment-emergent death was reported in 
Study GS-US-337-0102. This participant, who had 
received LDV/SOF for 12 weeks and achieved SVR12, 
was reported to have died of hepatic failure on post 
treatment Day 121. This participant had an SAE of 
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use on post treatment Day 38; this event was 
considered not related to study drug by the investigator. 
 
2.2.3.3.6 
Discontinuations Due To Adverse Events: Participants 
in Phase 3 ION Studies 
 
Overall, the incidence of AEs leading to permanent 
discontinuation of any study drug was low across all 
treatment groups (0.9%, 17 of 1952 participants). 
Anemia, anxiety, fatigue, and rash were the only AEs 
leading to permanent discontinuation of any study drug 
in >1 participant (2 participants each); these were 
reported in the LDV/SOF+RBV treatment groups and are 
consistent with the expected safety profile of RBV 
[Dusheiko, 1996; Ribasphere PI, 2012; COPEGUS PI, 
2013]. 
 
All participants who discontinued LDV/SOF were 
required to discontinue the entire study treatment 
regimen (ie, for the RBV-containing [LDV/SOF+RBV] 
groups, RBV was also discontinued). Across treatment 
groups, palpitations and anxiety were the only AEs 
leading to discontinuation of LDV/SOF reported in >1 
participant (2 participants each). All of these events 
were Grade 1 or 2 in severity and resolved following the 
discontinuation of LDV/SOF. 
 
2.2.3.3.7 
Clinical Safety Conclusions 
 
The LDV/SOF Phase 3 clinical program compared the 
safety and tolerability of LDV/SOF with and without RBV 
for treatment durations of 8, 12, and 24 weeks. A total of 
1952 participants received at least 1 dose of study drug 
and 98.1% of these participants completed their 
assigned study treatment. 
 
Across the LDV/SOF Phase 3 Safety Population, 
treatment with LDV/SOF was generally safe and well 
tolerated. The incidence of AEs leading to permanent 
discontinuation of any study drug was low (0.9%) across 
all regimens, with no AEs leading to permanent 
discontinuation of any study drug that occurred in >1 
participant in the LDV/SOF treatment groups; the only 
AEs leading to permanent discontinuation of any study 
drug in >1 participant in the LDV/SOF+RBV treatment 
groups included AEs consistent with the expected 
safety profile of RBV (anemia, anxiety, fatigue, and rash 
[2 participants each]) [Dusheiko, 1996; Ribasphere PI, 


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2012; COPEGUS PI, 2013]. Across the LDV/SOF Phase 3 
Safety Population, the 3 most frequently occurring AEs 
were fatigue, headache, and nausea. A higher incidence 
of each event was reported in participants receiving 
LDV/SOF+RBV compared with participants receiving 
LDV/SOF: fatigue (38.0% vs. 22.2%), headache (26.1% 
vs. 20.6%), and nausea (17.4% vs. 10.4%). 
 
The addition of RBV to LDV/SOF increased the number 
of AEs experienced by participants. Overall, AEs were 
11.1% and treatment-related AEs were 25.7% more likely 
to occur in the RBV-containing (LDV/SOF+RBV) groups 
compared with the RBV-free (LDV/SOF) groups. In 
addition, the need for study drug modification or dose 
interruption due to any AE was 13.0% more frequent in 
the RBV-containing (LDV/SOF+RBV) groups compared 
with the RBV-free (LDV/SOF) groups. The specific AEs 
that increased in the presence of RBV were fatigue, 
insomnia, anemia, nausea, dyspnea, irritability, cough, 
rash, pruritus, and headache. 
 
For both RBV-free (LDV/SOF) and RBV-containing 
(LDV/SOF+RBV) regimens, increasing treatment 
duration from 8 to 12 weeks and from 12 to 24 weeks 
resulted in small but consistent increases in the 
incidence of AEs, but did not change the observed AE 
profile. 
 
No treatment-emergent deaths were reported in the 
LDV/SOF Phase 3 Safety Population and few 
participants (2.6%) had any SAE. The only SAEs 
reported in >1 participant across all treatment groups 
were noncardiac chest pain (3 participants), and chest 
pain, colitis, gastroenteritis, hand fracture, 
hypertension, intervertebral disc protrusion, and 
pneumonia (2 participants each), suggesting that no 
trends in SAE type or onset time were observed. Only 5 
participants (0.3%) had an SAE that was considered 
related to study drug by the investigator. 
 
Grade 4 laboratory abnormalities were reported in only 
1.0% of participants for both the RBV-free (LDV/SOF) 
and RBV-containing (LDV/SOF+RBV) groups. Grade 3 
laboratory abnormalities were reported in 5.4% of 
participants in the RBV-free (LDV/SOF) groups and 
11.4% of participants in the RBV-containing 
(LDV/SOF+RBV) groups. The increased incidence of 
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(LDV/SOF+RBV) groups compared with Grade 3 
laboratory abnormalities in the RBV-free (LDV/SOF) 
groups was driven largely by hemoglobin abnormalities. 
The addition of RBV to a LDV/SOF treatment regimen 
contributed substantially to the incidence of anemia that 
required dose modification or discontinuation 
(hemoglobin <10 g/dL). A small number of participants 
with changes in non-hematologic laboratory parameters 
met the criteria for Grade 3 and 4 laboratory 
abnormalities. The most common Grade 3 or 4 
chemistry laboratory abnormalities across all treatment 
groups were increased lipase (1.7%) and increased 
serum glucose (1.5%). In participants with Grade 3 or 4 
increased lipase, no case of Grade 3 or 4 increased 
lipase was associated with clinical signs or symptoms 
of pancreatitis. Only 1 case of pancreatitis occurred in 
the entire Phase 3 program; this event occurred post 
treatment in a participant with a history of chronic 
pancreatitis and was not associated with a Grade 3 or 4 
increased lipase. Among participants who experienced a 
Grade 3 or 4 increased serum glucose, all participants 
had a history of diabetes, were taking diabetes 
medication, or had glucose intolerance (denoted by 
HbA1c >6.0% at screening). 
 
2.3 
Rationale for Inclusion of Concomitant ARV Regimens 
 
SOF is a uridine nucleotide analogue. Nucleo(s)tide analogues have a low potential for 
drug interactions because they are primarily renally eliminated and not substrates, 
inhibitors, or inducers of the cytochrome P450 enzyme system. SOF has been 
coadministered with multiple ARVs (EFV/emtricitabine [FTC]/ TDF, atazanavir 
boosted with ritonavir [ATV/r], darunavir boosted with ritonavir [DRV/r], RAL or 
RPV) without evidence of clinically significant drug interactions [Sovaldi PI, 2015]. LDV 
has some interactions with antiretroviral agents. In healthy volunteers, TFV is 
increased 40% with FTC/RPV/TDF and 98% with EFV/FTC/TDF following 
administration of LDV/SOF (Study GS-US-337-0127). A reduction in LDV exposure 
of approximately 34% was observed with EFV/FTC/TDF. The ION-4 included EFV, 
RAL, or RPV in combination with TDF/FTC without evidence of clinically 
significant drug interactions. In fact in the ION-4 the mean TFV exposure (AUCtau) 
was lowest in participants on EFV (3600 ng*h/mL) and greatest in participants on 
RPV (4286 ng*h/mL) and the overall mean TFV exposure was lower in the ION-4 
population (3838 ng*h/mL) than in the healthy volunteer population (~4500 
ng*h/mL). In addition, LDV levels were not different across the ARV regimens in 
the ION-4, unlike in the healthy volunteer studies [Naggie, CROI 2015 abstract 
LB152]. TFV is increased with the addition of LDV/SOF in the setting of boosted 
HIV protease inhibitors (PIs), ATV/r and DRV/r. TFV concentrations are increased 
30-60% with the addition of LDV/SOF compared to the concentrations of TFV 
observed in participants taking ATV/r or DRV/r with TDF/FTC [German, CROI 2015 


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abstract 82]. The mechanism and clinical significance of the interaction is 
currently unknown, but additional monitoring for potential renal toxicity is 
warranted [Recommendations for Testing, Managing, and Treating Hepatitis C, 
2014] and will be performed in this study in participants taking this combination. 
Cobicistat (COBI) Cmin is increased 1.25-4.25 fold by LDV; however, the AUC 
change is 1.59 fold, which is not felt to be clinically meaningful. The package 
insert for the approval of LDV/SOF addressed these interactions of HIV PI/r and 
COBI with LDV and TDF differently, due to the general belief that participants on 
COBI regimens, such as elvitegravir (EVG)/COBI/TDF/FTC, would have other 
options for ARV switch, while participants on PI/r were less likely to have 
substituting options for ARVs. Studies with EVG/COBI/FTC/tenofovir alafenamide 
(TAF) and TDF/FTC/dolutegravir (DTG) are ongoing. 
 
All ARVs will be allowed in the study as part of a highly active combination regimen at 
the recommended dose of the marketed product with the exception of didanosine (ddI) 
and stavudine (d4T) due to risk of hepatotoxicity, zidovudine (ZDV) due to risk of 
additive anemia with RBV (RBV containing arms only), and tipranavir boosted with 
ritonavir (TPV/r) due to the predicted decrease in the concentrations of SOF when 
coadministered with TPV/r. The regimens containing TDF and COBI or ATV/r or 
DRV/r will be allowed in this study and participants will be monitored for renal 
toxicity. Plasma and intracellular samples will be obtained from all participants prior to 
initiating the study regimen, and throughout the course of treatment for assessments 
of potential drug interactions in participants exposed to LDV/SOF, TDF, and COBI, 
ATV/r or DRV/r should the need arise to investigate a potential interaction. 
 
2.4 
Spontaneous Clearance of HCV 
 
Reported rates of spontaneous clearance of HCV among HIV-1 infected individuals are 
highly variable due to small sample sizes and significant variance across study 
populations. On average it is reported that 5-40% of HIV-1 infected individuals acutely 
infected with HCV will spontaneously clear the infection [Danta, 2008; Gambotti, 2005; 
Gilleece, 2005; Serpaggi, 2006]. Multiple baseline factors have been reported as 
predictive of clearance including female sex, host genetic factors including the IL28B 
favorable genotype, and early favorable HCV-RNA kinetics [Thomas, 2000; Soriano, 
2008; Thomas 2009]. There are studies assessing viral kinetics in the early infection 
period and report ranges from 6%-48% of participants having detectable HCV RNA 12 
weeks after first clinical evidence of infection and go on to spontaneously clear the 
infection [Gerlach, 2003; Mosley, 2008; Vogel, 2010]. Indeed on rare occasions 
participants have been reported to spontaneously clear the infection after 12-13 months 
or even longer [Larghi, 2002; Spada, 2004]. Many of these are very small, single center 
studies; however, the bulk of studies suggest that the majority of participants with acute 
HCV infection who will spontaneously clear will do so during the first 12 weeks (90-94%) 
[Corey, 2010]. Thus, it is a minority (6-10%) of participants who may receive treatment 
unnecessarily. These data must be balanced with the evidence that suggests a delay in 
initiation of therapy for acute HCV decreases the chance of achieving a sustained 
virologic response (SVR). A meta-analysis of early treatment in 417 HCV monoinfected 
participants reported that those participants who delayed therapy >12 weeks (63-67%) 
from diagnosis had lower SVR than those treated at or within 12 weeks of diagnosis 


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(83%) [Corey, 2010]. While this is in part due to inclusion of those participants who 
would spontaneously clear, it is also proposed to be due to the earlier preservation of 
multispecific HCV-specific T cell responses, which is thought critical to the ability to 
prevent HCV viral persistence [Kamal, 2004]. 
 
2.5 
Overall Risk/Benefit Assessment 
 
No clinical safety issues specifically related to SOF or LDV/SOF have been identified to 
date in HCV monoinfected or HIV-1/HCV coinfected participants. 
 
The expected benefits to participants being treated with SOF+RBV or LDV/SOF is a 
rapid and durable eradication of HCV virus without the side effects associated with the 
use of PEG and a shortened treatment period. Potential risks include unforeseen safety 
issues and unknown implications of virologic failure due to the emergence of resistant 
virus which is thought to be very low. 
 
For the population of HIV-1/HCV coinfected participants, the potential benefit of 
achieving SVR with 8 to 12 weeks of an IFN-free regimen outweighs the risks 
associated with the possible development of previously unidentified safety issues or the 
emergence of quasispecies resistant to SOF or LDV. 
 
If high rates of SVR can be obtained with a shortened, IFN-free regimen, without 
frequent emergence of resistant HCV, the anticipated improvements in safety and 
tolerability would offer a favorable risk-benefit determination for individuals with acute 
HCV infection. 
 
2.6 
Adherence Measures 
 
The efficacy of SOF+RBV or LDV/SOF for the treatment of acute HCV may be 
influenced by participants’ adherence to the study medications. There is no perfect 
measure of adherence, but tools include pill counts, pharmacy refill records, self-report, 
directly observed therapy, measurement of drug concentrations, and electronic 
monitoring. This study will use a combination of these measures of adherence (see 
section 6.3.12). 
 
 
3.0 
STUDY DESIGN 
 
A5327/SWIFT-C is an open-label, two-cohort clinical trial, in which between 44 and 50 
acutely HCV (any genotype including mixed genotype infection) infected HIV-1 positive 
participants will be enrolled and administered oral SOF 400mg QD in combination with 
weight-based RBV (1000 or 1200 mg daily in two divided doses) or the daily fixed dose 
combination of LDV/SOF (90mg/400mg). 
 
The study will open the first cohort with treatment with SOF+RBV for 12 weeks and a 
planned accrual of at least 17 participants. Cohort 2 will enroll participants on 
LDV/SOF for an 8-week treatment course and a planned accrual of at least 27 
participants. The total time to complete all study visits is approximately 36 weeks for 


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participants treated with 12 weeks of therapy and 32 weeks for participants treated 
with 8 weeks of therapy. Both cohorts will be assessed for efficacy with SVR12 
based on noninferiority criteria compared to the study-defined historical SVR rate of 
60%.The SVR of 60% was chosen based on a summary of nine acute HCV treatment 
studies in HIV-1 coinfected participants identified in a recent report by the European 
AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus Panel [AIDS, 
2011]. In this summary, 96 (60%) of 159 participants treated with PEG/IFN combined 
with RBV achieved SVR24 (ie, the conventional definition of SVR evaluated at 24 weeks 
after stopping treatment). This was felt to be the best representation of a historical 
control for this small, evidence-generating study. If a participant is discontinued from 
study treatment for nonvirologic reasons or is not evaluable for SVR12 while enrollment 
is ongoing to the same cohort, then an additional participant may be enrolled to that 
cohort to help ensure that an adequate number of participants complete study 
treatment up to a maximum enrollment of 50 participants. Each cohort will occur in two 
steps: on-treatment (Step 1) and followup (Step 2). The cohorts will enroll sequentially. 
 
Potential participants who have met the enrollment definition for acute HCV will be 
consented and screened; however, they will not be eligible for study entry until an HCV 
RNA is confirmed to be detectable >12 weeks after first laboratory evidence of acute 
HCV (to confirm ongoing infection since a small percentage of participants will have 
spontaneously cleared virus). This confirmation may occur at screening if it is more than 
12 weeks from first laboratory evidence of infection. If the screening visit occurs less 
than 12 weeks from the first laboratory evidence of infection, then the participant will 
require a pre-entry study visit to confirm detectable HCV RNA at least 12 weeks from the 
first laboratory evidence of infection have passed (see Figure I-1 in Appendix I). It is 
optimal for this pre-entry visit to occur as close as possible to 12 weeks from first 
laboratory evidence of acute infection to ensure timely treatment. Potential participants 
who enter screening but who have an undetectable HCV RNA (<LLOQ target not 
detected [TND]) at the pre-entry visit (when required) will have exhibited evidence of 
possible spontaneous clearance and will not meet the entry criteria. 
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
Cohort 1 completed accrual under A5327 Version 1.0. The eligibility criteria that 
are specific for Cohort 1 only have been removed from sections 4.1 and 4.2. The 
eligibility criteria in sections 4.1 through 4.4 apply to Cohort 2. 
 
4.1 
Step 1 Inclusion Criteria for Cohort 2 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma 
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NOTE: The term “licensed” refers to a FDA-approved kit, which is required for all 
IND studies. 
 
WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should be confirmed by either another type of rapid assay or an 
E/CIA that is based on a different antigen preparation and/or different test 
principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 
RNA viral load. 
 
4.1.2 A documented confirmation of acute HCV infection within 6 months prior to 
A5327 entry or HCV reinfection as described below: 
 
Acute HCV infection will be defined as meeting one of the following criteria and 
exclusion of other causes of acute hepatitis: 
• 
New (<24 weeks prior to initial A5327 entry) ALT elevation to ≥5X upper limit 
of normal (ULN) OR >250 U/L in patients with documented normal ALT in 
the preceding 12 months or ≥10X ULN OR >500 U/L in patients with 
abnormal or no measured ALT baseline in the preceding 12 months with 
detectable HCV RNA excluding those with any prior positive anti-HCV. 
OR 
• 
Detectable HCV RNA with prior negative anti-HCV Ab or undetectable HCV 
RNA within the preceding 6 months. 
 
Acute HCV reinfection will be defined by documentation of clearance of prior 
infection (as evidenced by positive anti-HCV Ab) either spontaneously or after 
treatment with two negative HCV RNA a minimum of 6 months apart AND 
meeting one of the following criteria in addition to exclusion of other causes of 
acute hepatitis: 
• 
New (<24 weeks prior to initial A5327 entry) ALT elevation to ≥5X ULN OR 
>250 U/L in patients with documented normal ALT in the preceding 12 
months or ≥10X ULN OR >500 U/L in patients with abnormal or no 
measured ALT baseline in the preceding 12 months with detectable HCV 
RNA. 
OR 
• 
Positive HCV RNA with prior negative HCV RNA within the preceding 6 
months. 
 
4.1.3 HCV RNA confirmed to be detectable >12 weeks after first laboratory evidence of 
acute HCV and still within the <24 week from first laboratory evidence of acute 
HCV infection window. First laboratory evidence of infection is defined as date of 
first elevated liver enzymes or date of first serologic evidence of HCV 
seroconversion and/or viremia (whichever occurs first). 


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NOTE: If the screening visit occurs less than 12 weeks from the first laboratory 
evidence of infection, then the participant will require a pre-entry study 
visit to confirm detectable HCV RNA at least 12 weeks from the first 
laboratory evidence of infection have passed (see Figure I-1 in Appendix 
I). It is optimal for this pre-entry visit to occur as close as possible to 12 
weeks from first laboratory evidence to ensure timely treatment. Potential 
participants who enter screening but who have an undetectable HCV 
RNA (<LLOQ TND) at the pre-entry visit (when required) will have 
exhibited evidence of possible spontaneous clearance and will not meet 
the entry criteria. 
 
4.1.4 HCV genotype 1a, 1b, or 4 infection with source documentation from a 
CLIA-approved laboratory (or its equivalent). 
 
NOTE: Those with mixed 1a/b genotype will be classified as 1a. 
 
4.1.5 HIV-1 ARV therapy should fall into one of the following criteria: 
 
a) ARV untreated, for example due to (1) lack of indication per provider (CD4 T- 
cell count >500 cells/mm3) or (2) decision by provider and participant to 
defer ARV therapy during the study drug dosing period (8 or 12 weeks), or (3) 
elite controller (CD4+ >200 cells/mm3). 
OR 
b) On a stable, protocol-approved ARV regimen (the following ARVs are not 
allowed: ddI, d4T, and TPV/r) for >8 weeks prior to screening with a CD4 T- 
cell count >200 cells/mm3 and a documented plasma HIV-1 RNA level <50 
copies/mL or <LLOQ of local assay if LLOQ is >50 copies/mL by any 
laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) 
certification or its equivalent ≥ 8 weeks preceding the A5327 screening visit. 
HIV-1 RNA levels should be within 1 year of the screening visit. Screening 
HIV-1 RNA must be <50 copies/mL as measured by any local laboratory 
using an FDA-approved assay. 
 
4.1.6 Body mass index (BMI) ≥18 kg/m2 
 
4.1.7 Candidates must have the following laboratory parameters within 10-42 days 
prior to study entry: 
a) Hemoglobin ≥9 g/dL for male and female participants 
b) International normalized ratio (INR) ≤1.5 x ULN unless participant has 
known hemophilia or is stable on an anticoagulant regimen affecting INR 
c) Albumin ≥3 g/dL 
d) Creatinine clearance (CrCl) ≥60 mL/min, as calculated by the Cockcroft-Gault 
equation (refer to section 6.3.5 for calculator utility link) 
 
4.1.8 Screening electrocardiogram (ECG) without clinically significant abnormalities as 
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4.1.9 Willing and able to provide written informed consent. 
 
4.1.10 Men and women age ≥18 years. 
 
4.1.11 Female participants of reproductive potential (defined as women who have not 
been post-menopausal for at least 24 consecutive months, ie, who have had 
menses within the preceding 24 months, or women who have not undergone 
surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or 
bilateral salpingectomy) must have a negative serum or urine pregnancy test 
within 48 hours prior to study entry by any laboratory or clinic that has a CLIA 
certificate or its equivalent, or is using a point-of-care (POC)/CLIA-waived 
test. The serum, urine or POC pregnancy test must have a sensitivity of at 
least 25 mIU/mL. 
 
4.1.12 All participants must agree not to participate in a conception process (eg, active 
attempt to become pregnant or to impregnate, sperm donation, in vitro 
fertilization). 
 
NOTE: Female candidates who are pregnant or breastfeeding are not eligible. A 
male candidate who has a pregnant female partner is not eligible for the 
study. 
 
4.1.13 When participating in sexual activity that could lead to pregnancy, all 
participants must agree to use at least two reliable forms of contraceptive 
simultaneously while receiving protocol-specified medications, and for 6 months 
after stopping the medications. Such methods include: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Tubal ligation 
• 
Hormone-based contraceptive 
 
NOTE: Providers and participants should be advised that not all contraceptive 
choices listed above can prevent HIV transmission and that some may 
actually increase the risk of HIV acquisition. Study participants who are 
sexually active with HIV-1 negative or unknown HIV-1 serostatus 
partners should be advised that they need to consider effective 
strategies for reducing the risk of HIV transmission, as well as meeting 
the requirement for effective contraception during their participation in 
the study. Study participants should discuss contraceptive choices and 
HIV risk reduction methods with their health care provider. 
 
4.1.14 Participants who are not of reproductive potential (women who have been post- 
menopausal for at least 24 consecutive months or have undergone hysterectomy 
and/or bilateral oophorectomy or salpingectomy or men who have documented 
azoospermia or undergone vasectomy) are eligible without requiring the use of 


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contraceptives. Acceptable documentation of sterilization and menopause is 
specified below. 
 
Written or oral documentation communicated by clinician or clinician’s staff of 
one of the following: 
• 
Physician report/letter 
• 
Operative report or other source documentation in the patient record (a 
laboratory report of azoospermia is required to document successful 
vasectomy) 
• 
Discharge summary 
• 
Follicle stimulating hormone-release factor (FSH) measurement elevated into 
the menopausal range as established by the reporting laboratory. 
 
4.1.15 Intention to comply with the dosing instructions for study drug administration and 
able to complete the study schedule of assessments. 
 
4.2 
Step 1 Exclusion Criteria for Cohort 2 
 
4.2.1 Received investigational drug or device within 60 days prior to study entry. 
 
4.2.2 Any preceding attempt at HCV treatment during this acute HCV infection 
episode, ie, 24 weeks prior to entry. 
 
4.2.3 Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s 
disease, α1 antitrypsin deficiency, primary sclerosing cholangitis). 
 
4.2.4 Presence of active or acute AIDS-defining opportunistic infections within 30 days 
prior to study entry. 
 
NOTE: A list of AIDS-defining opportunistic infections as defined by the CDC, 
can be found in Appendix B of the following document: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm 
 
4.2.5 Active, serious infection (other than HIV-1 or HCV) requiring parenteral 
antibiotics, antivirals, or antifungals within 30 days prior to study entry. 
 
4.2.6 Infection with hepatitis B virus (HBV) defined as HBsAg positive. 
 
4.2.7 Evidence of acute hepatitis A infection defined as HAV IGM positive. 
 
4.2.8 Chronic use of systemically administered immunosuppressive agents (eg, 
prednisone equivalent >10 mg/day). 
 
4.2.9 History of solid organ transplantation. 
 
4.2.10 Current or prior history of clinical hepatic decompensation (eg, ascites, 
encephalopathy or variceal hemorrhage). 


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4.2.11 History of a gastrointestinal disorder (or post operative condition) that could 
interfere with the absorption of the study drug. 
 
4.2.12 History of significant or symptomatic pulmonary disease, cardiac disease, or 
porphyria. 
 
4.2.13 History of difficulty with blood collection and/or poor venous access for the 
purposes of phlebotomy. 
 
4.2.14 History of clinically significant illness or any other major medical disorder that 
may interfere with participant treatment, assessment, or compliance with study 
requirements, which may include active drug or alcohol use or dependence. 
 
4.2.15 Use of any prohibited concomitant medications within 30 days prior to study 
entry. 
 
4.2.16 Known hypersensitivity to SOF or LDV, the metabolites, or formulation excipients 
or any other contraindication to the use of SOF or LDV. 
 
4.2.17 Currently receiving TPV/r, ddI, d4T or amiodarone. 
 
4.2.18 Acute HIV infection defined as the phase immediately following infection during 
which anti-HIV antibodies are undetectable. 
 
NOTE: Participants with early infection, defined as within the first 6 months of 
infection and with a positive HIV antibody, should be discussed with the 
A5327 protocol core team. These participants may be considered for 
inclusion in the study on a case by case basis with the specific 
documented approval of the protocol chairs. 
 
4.2.19 Pregnancy or Breastfeeding 
 
4.3 
Step 2 Inclusion Criteria for Cohort 2 
 
4.3.1 Completion or premature discontinuation (including HCV VF) of Step 1 study 
treatment regimen. 
 
NOTE: See section 8.1 for premature treatment discontinuation. 
 
4.4 
Step 2 Exclusion Criteria for Cohort 2 
 
4.4.1 Premature study discontinuation. 
 
NOTE: See section 8.2 for premature study discontinuation. 


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4.5 
Study Enrollment Procedures 
 
Prior to implementation of this protocol, and any subsequent full version amendments, 
each site must have the protocol and the protocol consent form approved, as 
appropriate, by their local institutional review board (IRB) and any other applicable 
regulatory entity (RE). Upon receiving final approval, sites will submit all required 
protocol registration documents to the DAIDS Protocol Registration Office (DAIDS PRO) 
at the Regulatory Support Center (RSC). The DAIDS PRO will review the submitted 
protocol registration packet to ensure that all of the required documents have been 
received. 
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the 
DAIDS PRO, and sites will receive an Initial Registration Notification from the DAIDS 
PRO that indicates successful completion of the protocol registration process. A copy of 
the Initial Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB and any other applicable RE approvals for an amendment, sites 
should implement the amendment immediately. Sites are required to submit an 
amendment registration packet to the DAIDS PRO at the RSC. The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all the required 
documents have been received. Site-specific ICF WILL NOT be reviewed and approved 
by the DAIDS PRO, and sites will receive an Amendment Registration Notification when 
the DAIDS PRO receives a complete registration packet. A copy of the Amendment 
Registration Notification should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents 
required for initial and amendment registrations, refer to the current version of the 
DAIDS Protocol Registration Manual. 
 
Once a candidate for study entry has been identified, details will be carefully discussed 
with the participant. The participant will be asked to read and sign the approved 
protocol consent form. 
 
For participants from whom a signed informed consent has been obtained, an ACTG 
Screening Checklist must be entered through the Data Management Center (DMC) 
Subject Enrollment System. 
 
For participants from whom informed consent has been obtained, but who are deemed 
ineligible or who do not enroll into the initial protocol step, an ACTG Screening Failure 
Results form must be completed and keyed into the database. 
 
4.6 
Coenrollment Guidelines 
 
Sites are encouraged to coenroll participants in A5128, “Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses.” Coenrollment in A5128 does not require permission from the A5327 protocol 
chairs. 


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For specific questions and approval for coenrollment in other studies, sites should first 
check the A5327 protocol specific web page (PSWP) or contact the protocol chairs via e- 
mail as described in the Study Management section. 
 
 
5.0 
STUDY TREATMENT 
 
Study treatment is defined as sofosbuvir (SOF) in combination with weight based 
ribavirin (RBV) or the daily fixed dose combination (FDC) of ledipasvir/sofosbuvir 
(LDV/SOF). 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens 
 
Between 44 and 50 acutely HCV infected, HIV-1 positive participants will be 
enrolled in one of two successive cohorts (these cohorts will be enrolled 
sequentially). 
 
Cohort 1 (12-week treatment duration) 
At least 17 participants will receive: 
• 
SOF 400 mg, one tablet PO every morning with food. 
• 
Weight-based RBV PO BID, every morning and every evening, with food (see 
Table 4 for actual dose) 
 
Table 4 Weight-based RBV Dose 
 
Weight (kg) 
Morning Dose 
Evening Dose 
< 75 kg 
600 mg (3 tablets) 
400 mg (2 tablets) 
> 75 kg 
600 mg (3 tablets) 
600 mg (3 tablets) 
Total daily dose has been divided into two doses. The dose of RBV will be based on participant’s 
weight at entry. Changes in weight after entry do not require a change in dose. Doses will only be 
changed for toxicity management. 
 
Cohort 2 (8-week treatment duration) 
At least 27 participants will receive: 
• 
LDV/SOF (90/400 mg), one tablet PO every morning 
 
5.1.2 Administration 
 
5.1.2.1 
SOF+RBV regimen 
 
SOF should be taken with RBV. Participants should be instructed to 
take all doses of SOF and RBV with food. Study drug should be taken 
at the same times and maintain the same time intervals every day. 


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If a participant forgets to take the SOF at the correct time, it may be 
taken later in the day; however, no more than one 400 mg dose of SOF 
should be taken on any calendar day. The participant should resume 
the standing dosing schedule on the next day. Study medications 
should not be cut or split. If participants miss a dose of RBV, then they 
should take the missed dose as soon as possible with food during the 
same day. If an entire day has gone by, then the missed dose should 
be skipped, and the normal dosing schedule should be resumed. 
Participants should not double the next dose of either study drug in 
order to "make up" what had been missed. 
 
5.1.2.2 
LDV/SOF regimen 
 
FDC LDV/SOF tablets should be taken once daily and without 
regard to food. 
 
FDC LDV/SOF should be taken on a regular dosing schedule 
If a participant does not take a dose at the regular time, it should 
be taken as soon as they remember on the same day. The 
participant should resume the usual dosing schedule the next day. 
 
Participants should not take more than 1 tablet of FDC LDV/SOF in 
a day. 
 
5.1.3 Duration 
 
Study treatment may continue for a period of 8 to 12 weeks (as assigned at study 
entry). Study followup will be 24 weeks post treatment regardless of cohort. The 
study will be conducted for up to a total of 36 weeks. 
 
5.2 
Study Product Formulation 
 
5.2.1 Formulation 
 
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed 
with “GSI” on one side and “7977” on the other side. In addition to the active 
ingredient, SOF tablets contain the following inactive ingredients: mannitol, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinylalcohol, titanium dioxide, macrogol, talc, and 
yellow iron oxide. 
 
RBV 200 mg tablets are light pink to pink, round, bicovex, beveled, film-coated 
tablets debossed with the logo of “ZC19” on one side and plain on the other side. 
 
FDC LDV/SOF tablets are orange, diamond-shaped, film-coated tablets 
containing 400 mg of SOF and 90 mg of LDV. The tablets are debossed with 
“GSI” on one side and “7985” on the other side. The LDV/SOF FDC tablet 
contains the following inactive ingredients: lactose monohydrate, 


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copovidone, microcrystalline cellulose, croscarmellose sodium, colloidal 
silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, 
talc, polyethylene glycol, and FD&C yellow # 6 /sunset yellow FCF 
aluminum lake. 
 
5.2.2 Storage 
 
SOF bottles should be stored at a controlled room. Controlled room 
temperature is defined as 25°C (77°F); excursions are permitted between 
15°C and 30°C (59°F to 86°F). 
 
RBV tablets should be stored at 20°C - 25°C (68°F - 77°F). 
 
FDC LDV/SOF tablets should be stored at room temperature below 
30°C (86°F). FDC LDV/SOF may be dispensed only in the original 
container. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Gilead Sciences, Inc. will manufacture and supply SOF and FDC LDV/SOF for 
this study. Zydus will manufacture RBV. Study products will be available through 
the NIAID Clinical Research Products Management Center (CRPMC). The site 
pharmacist should obtain the study products for this protocol by following the 
instructions in the manual Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks in the section Study Product Management 
Responsibilities. 
 
ART will not be provided through the study. 
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products in US CRSs must be returned to the NIAID CRPMC (or as otherwise 
directed by the sponsor) after the study is completed or terminated. The 
procedures to be followed are in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks in the section Study Product 
Management Responsibilities. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 


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Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at: http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.4.1 Required Medications 
 
See inclusion criteria (section 4.1) for specifications about ART. Changes to 
ART must be discussed with the A5327 protocol core team during the study 
drug dosing period. 
 
5.4.2 Prohibited Medications 
 
For a list of prohibited medications, please refer to the A5327 PSWP. 
 
5.4.3 Colony Stimulating Agents 
 
Under no circumstances are potential participants to be treated with colony 
stimulating agents (CSA) during screening to elevate hematology laboratory 
parameters to facilitate entry into the study. CSAs, such as erythropoiesis 
stimulating agents or granulocyte colony-stimulating factor, will not be provided 
by the study. 


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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events 
 
6.1.1 Step 1 –Study Visits for 12-week Treatment (for Cohort 1) 
 
Evaluations 
Screening 
Pre-Entry 
(see 
section 
6.2.1) 
Entry 
(day 0) 
On-Treatment Study Visits 
HCV VF 
Confirmation 
HIV-1 VF 
Confirmation 
Prem. Tx/Study 
Disc 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Within 10-42 
days prior to 
entry 
See section 6.2.3 for visit windows 
HIV-1 Documentation 
X 
Medical History 
X 
Medication History 
X 
X 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X5 
X 
X 
12-lead ECG 
X 
Hematology and Chemistries 
X 
If needed 
X 
X 
X 
X 
X 
X 
X 
Calculated CrCl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel (fasting)1 
X 
(see section 
6.2.1) 
If 
needed 
X 
X 
X 
Coagulation Markers 
X 
If needed 
X 
X 
X 
Urinalysis 
X 
Pregnancy Test (see section 
6.3.5) 
X 
If needed 
X 
X 
X 
X 
X 
Serologies (see section 6.3.5) 
X 


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Evaluations 
Screening 
Pre-Entry 
(see 
section 
6.2.1) 
Entry 
(day 0) 
On-Treatment Study Visits 
HCV VF 
Confirmation 
HIV-1 VF 
Confirmation 
Prem. Tx/Study 
Disc 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Within 10-42 
days prior to 
entry 
See section 6.2.3 for visit windows 
Plasma HCV RNA 
(screening and pre-entry 
performed at local lab, see 
section 6.3.6) 
X 
X 
Plasma HCV RNA (real-time) 
X 
X 
X 
X 
X 
X 
X2 
X 
Plasma HCV Genotype Test 
(screening performed at local 
lab unless unavailable, see 
section 6.3.6) 
X 
Plasma HIV-1 RNA 
(real-time, see section 6.3.6) 
X 
X 
X 
X 
X3 
X 
Plasma HIV-1 RNA 
Resistance Testing 
(real-time genotyping, see 
section 7.4) 
X4 
Stored Serum and Plasma for 
HIV-1/HCV Studies 
(see section 6.3.6) 
X 
X 
X 
X 
X 
X 
X 
CD4+/CD8+ 
X 
X 
X 
X 
Stored Plasma and PBMC 
(see section 6.3.7) 
X 
X 
X 
X 
X 
X 
Additional Stored Samples 
(see section 6.3.8) 
X 
X 


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Evaluations 
Screening 
Pre-Entry 
(see 
section 
6.2.1) 
Entry 
(day 0) 
On-Treatment Study Visits 
HCV VF 
Confirmation 
HIV-1 VF 
Confirmation 
Prem. Tx/Study 
Disc 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Within 10-42 
days prior to 
entry 
See section 6.2.3 for visit windows 
PK Sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IL28B Genotype (see section 
6.3.10) 
X 
If needed 
ITPA Genotype (see section 
6.3.10) 
X 
Pregnancy Prevention 
Counseling 
X 
X 
X 
X 
Adherence Assessment (see 
section 6.3.12) 
X 
X 
X 
X 
X 
X 
Study Drug Dispensing 
X 
X 
X 
1 Although a fasting lipid panel is not required at screening, sites should make every effort to get participants to come to the clinic in a fasting state for the lipid panel at the 
designated study visits. 
2 An increase in plasma HCV RNA at any time point meeting HCV virologic-based treatment stopping criteria must be confirmed with repeat testing within 2 weeks. For 
more information please see section 7.3. 
3 HIV-1 viral breakthrough, as defined in section 7.4, should be confirmed with repeat testing as soon as possible, not to exceed 4 weeks. 
4 This specimen should be drawn at the time of HIV-1 treatment failure confirmation and shipped to the designated VSL. Please see section 7.4. 
5 The weight recorded at entry will be used as the weight for PK analysis and reported in the PK CRF for the weeks 1, 2, 4, and 8 visits and the HCV and HIV-1 
VF Confirmation visits. 


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6.1.2 Step 1 –Study Visits for 8-week Treatment (for Cohort 2) 
 
Evaluations 
Screening 
Pre-Entry 
(see 
section 
6.2.1) 
Entry 
(day 0) 
On-Treatment Study Visits 
HCV VF 
Confirmation 
HIV-1 VF 
Confirmation 
Prem. Tx/Study 
Disc 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Within 10-42 
days prior to 
entry 
See section 6.2.3 for visit 
windows 
HIV-1 Documentation 
X 
Medical History 
X 
Medication History 
X 
X 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X1 
X 
X 
12-lead ECG 
X 
Hematology and Chemistries 
X 
If needed 
X 
X 
X 
X 
X 
X 
Calculated CrCl 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel (fasting)2 
X 
(see section 
6.2.1) 
If 
needed 
X 
X 
X 
Coagulation Markers 
X 
If needed 
X 
X 
X 
Urinalysis 
X 
X3 
X3 
X3 
X3 
Pregnancy Test (see section 6.3.5) 
X 
If needed 
X 
X 
X 
X 
Serologies (see section 6.3.5) 
X 
Plasma HCV RNA (screening and 
pre-entry performed at local lab, see 
section 6.3.6) 
X 
X 
Plasma HCV RNA (real-time) 
X 
X 
X 
X 
X 
X4 
X 


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Evaluations 
Screening 
Pre-Entry 
(see 
section 
6.2.1) 
Entry 
(day 0) 
On-Treatment Study Visits 
HCV VF 
Confirmation 
HIV-1 VF 
Confirmation 
Prem. Tx/Study 
Disc 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Within 10-42 
days prior to 
entry 
See section 6.2.3 for visit 
windows 
Plasma HCV Genotype Test 
(screening performed at local lab 
unless unavailable, see section 
6.3.6) 
X 
Plasma HIV-1 RNA (real-time, see 
section 6.3.6) 
X 
X 
X 
X 
X5 
X 
Plasma HIV-1 Resistance Testing 
(real-time genotyping, see section 
7.4) 
X6 
Stored Serum and Plasma for HIV- 
1/HCV Studies (see section 6.3.6) 
X 
X 
X 
X 
X 
X 
CD4+/CD8+ 
X 
X 
X 
Stored Plasma and PBMC (see 
section 6.3.7) 
X 
X 
X 
X 
X 
X 
Additional Stored Samples (see 
section 6.3.8) 
X 
X 
PK Sampling 
X 
X 
X 
X 
X 
X 
X 
X 
IL28B Genotype (see section 6.3.10) 
X 
If 
needed 
ITPA Genotype (see section 6.3.10) 
X 
Pregnancy Prevention Counseling 
X 
X 
X 
X 
Adherence Assessment (see section 
6.3.12) 
X 
X 
X 
X 
X 


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Evaluations 
Screening 
Pre-Entry 
(see 
section 
6.2.1) 
Entry 
(day 0) 
On-Treatment Study Visits 
HCV VF 
Confirmation 
HIV-1 VF 
Confirmation 
Prem. Tx/Study 
Disc 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Within 10-42 
days prior to 
entry 
See section 6.2.3 for visit 
windows 
Study Drug Dispensing 
X7 
1 The weight recorded at entry will be used as the weight for PK analysis and reported in the PK CRF for the weeks 1, 2, and 4 visits and the HCV and HIV-1 VF 
Confirmation visits. 
2 Although a fasting lipid panel is not required at screening, sites should make every effort to get participants to come to the clinic in a fasting state for the lipid panel at the 
designated study visits. 
3 Urinalysis will be required at on treatment weeks 2, 4, and 8 for all participants on TDF as part of their HIV regimen. 
4 An increase in plasma HCV RNA at any time point meeting HCV virologic-based treatment stopping criteria must be confirmed with repeat testing within 2 weeks. For 
more information please see section 7.3. 
5 HIV-1 viral breakthrough, as defined in section 7.4, should be confirmed with repeat testing as soon as possible, not to exceed 4 weeks. 
6 This specimen should be drawn at the time of HIV-1 treatment failure confirmation and shipped to the designated VSL. Please see section 7.4. 
7 Dispense two bottles of study drug and ensure participant understands dosing instruction. 


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6.1.3 Step 2 –Post treatment Study Visits Following Last Dose of Study Treatment (Cohorts 1 and 2) 
 
Evaluations 
EOT 
Post Treatment (PTx) Period 
Prem 
Study 
Disc 
Date of last 
dose 
Wk 2 PTx 
Wk 4 PTx 
Wk 8 PTx 
Wk 12 PTx Wk 24 PTx 
See section 6.2.3 for visit windows 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
Hematology and Chemistries 
X 
X 
X3 
X3 
X4 
Calculated CrCl 
X5 
X5 
X5 
X5 
X5 
Lipid Panel (fasting)1 
X 
X 
Urinalysis 
X6 
X6 
X6 
X6 
Pregnancy Test (see section 6.3.5) 
X 
X 
X 
X 
X 
Serum HCV RNA2 (real-time) 
X 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA (real-time, see section 
6.3.6) 
X 
Stored Serum and Plasma for HIV-1/HCV 
Studies (see section 6.3.6) 
X 
X 
X 
X 
X 
X 
CD4+/CD8+ 
X 
X 
X 
Stored Plasma and PBMC (see section 6.3.7) 
X 
X 
X 
X 
X 
PK Sampling 
X 
X 
X 
X 
X 
Pregnancy Prevention Counseling 
X 
X 
X 
X 
X 
X 
1 Sites should make every effort to get participants to come to the clinic in a fasting state for the lipid panel at the designated study visits. 
2 A detectable HCV RNA after the end of treatment is virologic evidence of relapse which will require confirmation and should be performed in real time at the designated 
VSL as soon as possible but no later than 2 weeks. 
3 For Cohort 2 only: Creatinine required at post treatment weeks 8 and 12 for all participants on TDF as part of their HIV regimen. 
4 Cohort 1: Only required if study discontinuation occurs before week 4 PTx visit. Cohort 2: Required at study discontinuation. 
5 For Cohort 2 only: Calculated CrCl required at post treatment weeks 2, 4, 8, and 12 for all participants on TDF as part of their HIV regimen. 
6 For Cohort 2 only: Urinalysis required at post treatment weeks 2, 4, and 12 for all participants on TDF as part of their HIV regimen. 


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6.2 
Timing of Evaluations 
6.2.1 Screening and Pre-Entry Evaluations 
Screening 
Screening evaluations must occur prior to the participant starting any study 
medications, treatments, or interventions and, if possible, should be done in a 
fasting state (defined in section 6.3.5). Although fasting is not required for the 
screening visit, the site should make every effort to get the potential participant 
to come back to the clinic within 7 days of the originally scheduled screening visit 
for a fasting lipid panel. 
 
Screening evaluations to determine eligibility must be completed within 10-42 
days prior to entry unless otherwise specified. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database. 
 
Pre-Entry 
Pre-entry evaluations must occur at least 24 hours after screening evaluations 
have been completed, unless otherwise specified. 
 
The pre-entry visit will be required for those participants whose screening visit is 
less than 12 weeks from the first laboratory evidence of acute infection. 
 
NOTE: If the screening period is extended past 6 weeks (ie, more than 42 days) 
to meet the criterion for detectable HCV RNA >12 weeks from first 
laboratory evidence of acute infection, safety lab tests (hematology, 
chemistry, coagulation markers, pregnancy test) will need to be repeated 
at pre-entry with results available at the site so enrollment can occur. 
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur at least 24 hours after pre-entry (if required) 
evaluations have been completed and/or at least 10 days after screening, unless 
otherwise specified. 
 
Participant must begin treatment within 24 hours after registration. 
 
NOTE: Entry evaluations must be performed prior to dosing. Participant must 
be fasting (no food or drink, except water for taking prescription 
medications, for at least 8 hours). 
 
6.2.3 Post-Entry Evaluations 
 
All post-entry evaluations occur in reference to the date of study entry. 


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On-Treatment Evaluations 
Weeks 1 and 2 have a window of ±3 days. Weeks 4, 8, and 12 have a window of 
–7 days and +14 days. 
 
Post-Treatment Evaluations 
After the last dose of study drugs, the PTx study visits have the following 
windows: 
• 
Week 2 PTx: -5 days to +7 days 
• 
Weeks 4 and 8 PTx: -5 days to +21 days 
• 
Week 12 PTx: -5 days and +28 days 
• 
Week 24 PTx: -7 days and +28 days 
 
Study Completion Evaluations 
The week 24 PTx visit will be completed as the participant’s final study visit. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Registered Participants Who Do Not Start Study Treatment 
Participants who do not start study treatment will be taken off study with no 
further evaluations required. 
All CRFs must be completed and keyed for the period up to and including entry. 
HCV Virologic Failure 
Participants who permanently discontinue study treatment for HCV virologic 
failure (see details in section 7.3) will be followed on study/off treatment through 
the week 24 PTx visit. 
 
Premature Treatment Discontinuation Evaluations 
The protocol core team must be informed, as soon as possible, when a 
participant comes off study treatment due to an AE. Participants who 
permanently discontinue study treatment for toxicity or any other reason, and 
who have not met the HCV virologic failure criteria defined in section 7.3 will also 
follow the schedule in section 6.1.2. If applicable, additional or more frequent 
post-treatment toxicity followup may be determined by the site investigator. 
 
Participants who prematurely discontinue study treatment (ie, prior to 
completion of the last dose of SOF+RBV or LDV/SOF per the assigned dosing 
period) will complete the treatment discontinuation evaluations. Participants 
discontinuing study treatment prematurely will remain on study and complete PTx 
visits at 2, 4, 8, 12, and 24 weeks from the date on which the participant took 
the last dose of study treatment. 
 
NOTE: If SOF is discontinued, participants should discontinue RBV. 
Under no condition should the participant remain on RBV 
monotherapy. 


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For participants who discontinue the study treatment due to AEs or death, 
please document and record the following information on the CRFs: 
• 
All concomitant medications 
• 
Basis for determining that the AE was due to the study drug 
• 
Participant history of same AE or AEs similar to the one that resulted in 
discontinuation and when they occurred if known 
• 
Onset date of AE that led to discontinuation and actual date of 
discontinuation 
 
Pregnancy 
Pregnancy will result in immediate and permanent discontinuation of the study 
medications. Please see section 7.2 for detailed information regarding 
participant management. 
 
Premature Study Discontinuation Evaluations 
Participants who prematurely discontinue from the study will have the study 
discontinuation evaluations performed prior to being taken off the study. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
Web site for information about what must be included in the source document: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced 
ocappndx.pdf 
 
All stated evaluations are to be recorded on the CRF and keyed into the database 
unless otherwise specified. This includes events that meet the International Conference 
on Harmonisation (ICH) definitions for a serious adverse event: 
• 
Results in death 
• 
Life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect 
• 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the events listed above. 
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 1.0, December 2004 (Clarification, August 2009), which can be 
found on the DAIDS RSC Web site: http://rsc.tech- 
res.com/safetyandpharmacovigilance/. 


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6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the CRF. 
 
6.3.2 Medical History 
 
In addition to reporting all diagnoses within the past 30 days, the following 
diagnoses should be reported for all ACTG studies regardless of when the 
diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
 
In addition, the medical history must include all clinical events and diagnoses 
identified by Appendix 100 targeted for A5327. For current criteria, refer to the 
A5327 PSWP. 
 
Any allergies to any medications and their formulations must also be 
documented. 
 
6.3.3 Medication History 
 
A medication history must be present, including start and stop dates. Table 3 
below lists the medications that must be included in the history. 
 
Table 3: Medication History 
 
Medication Category 
Complete History or Timeframe 
HIV treatment 
Within 42 days prior to entry 
HCV treatment 
Complete history 
Prescription drugs for treatment of 
opportunistic infections 
Within 42 days prior to entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
Within 42 days prior to entry 
Other prescription drugs 
Within 42 days prior to entry 
Proton-pump inhibitors (Cohort 2 only) 
Within 42 days prior to entry 
Non-prescription drugs 
Within 42 days prior to entry 
Complementary and alternative therapies 
Within 42 days prior to entry 


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6.3.4 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination must be performed at screening and is to 
include at a minimum an examination of the head, neck and thyroid; eyes, ears, 
nose, throat, mouth and tongue; chest (excluding breasts); respiratory; 
cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; 
neurological. 
 
Targeted Physical Exam 
A targeted physical examination must be performed at entry and all subsequent 
visits. It should include vital signs (temperature, pulse, and respiratory rate, and 
resting blood pressure) and is to be driven by any previously identified or new 
signs or symptoms including diagnoses that the participant has experienced 
since the last visit. 
 
NOTE: Blood pressure will be measured following the current ACTG 
Standardization of Blood Pressure Measurement SOP. 
 
Height 
Record height at screening. 
 
Weight 
Record weight as indicated in section 6.1. 
NOTE: Weight should be done with inner clothing and without shoes. 
BMI 
BMI should be calculated using standard formula. 
 
12-Lead ECG 
An electrocardiogram (ECG) will be performed at screening. 
 
NOTE: Participant should rest in a supine position for ≥5 minutes prior to 
making a recording. The investigator (or qualified designee) should 
review the ECG traces recorded in real time for gross abnormalities.  
 
Signs and Symptoms 
At entry, all signs and symptoms, regardless of grade, that occurred within 42 
days prior to study entry must be recorded. Post-entry, only signs and symptoms 
Grade 2 must be recorded. Record all signs and symptoms that led to a change 
in treatment (excluding indications for RBV dose reduction), regardless of grade. 
 
Diagnoses 
Refer to section 6.3.2 for the diagnosis reporting requirements in the 
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At entry and thereafter, only the diagnoses identified as targeted for A5327 
should be reported. Refer to the A5327 PSWP. 
 
Concomitant Medications 
Record new or discontinued concomitant prescription and nonprescription 
medications taken since the last on treatment study visit and at the weeks 2, 4, 8, 
12, and 24 PTx visits. 
 
Start and stop dates of all prescription and all nonprescription medications will be 
recorded on the CRF. 
 
Study Treatment Modifications 
Record all study drug modifications, including initial doses, participant-initiated 
and/or protocol-mandated modifications, inadvertent and deliberate interruptions 
at each visit. Record any permanent discontinuation of treatment. 
 
6.3.5 Laboratory Evaluations 
 
At screening, pre-entry, and entry all laboratory values must be recorded. For 
post-entry assessments, record all Grade 2 laboratory values. All laboratory 
toxicities that led to a change in treatment (excluding indications for RBV dose 
reduction), regardless of grade, must be recorded. 
 
Fasting Instructions 
Fasting is defined as nothing to eat or drink except prescription medications and 
water for at least 8 hours. If participants are in a nonfasting state, they can have 
a fasting blood draw at the next scheduled study visit, as indicated in section 6.1. 
If nonfasting at the screening visit, the participant should return within 7 days for 
fasting blood draw. 
 
Hematology 
Hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), white 
blood cell count (WBC) with differential (absolute and percentage) including 
lymphocytes, monocytes, neutrophils, eosinophils, basophils, reticulocyte count, 
and MCV. 
 
Chemistries 
Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), albumin, alkaline phosphatase, creatinine, total bilirubin, direct 
bilirubin, glucose, lipase, potassium, thyroid-stimulating hormone, and sodium. 
At entry only, gamma-glutamyl transferase. 
Calculated CrCl 
Estimated each time that a creatinine level is determined during the on- 
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participants who are taking TDF as part of their HIV regimen (refer to 
section 7.1.2). 
 
To estimate calculated CrCl, use the following method of Cockcroft and Gault: 
• 
For men: [(140 - age in years) x (body weight in kg)] ÷ (serum creatinine in 
mg/dL x 72). 
• 
For women: use the same calculation as for men, then multiply the result by 
0.85. 
 
A calculator is available at the DMC Web site: 
https://www.fstrf.org/ACTG/ccc.html. 
 
Lipid Panel (fasting) 
Low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), 
total cholesterol (TC), and apolipoproteins B, E, and CIII (performed at the 
designated testing laboratory; see A5327 laboratory processing chart [LPC] 
for directions). 
 
Fasting lipid panel should only be performed at entry if not done at 
screening. 
 
Coagulation Markers 
INR, prothrombin time (PT), activated partial thromboplastin time (APTT). 
 
Urinalysis 
Appearance, blood, color, glucose, leukocyte esterase, pH, protein, urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal. 
 
Pregnancy Test 
For women with reproductive potential: a serum -HCG, urine or POC/CLIA- 
waived test documenting a negative result will be required within 48 hours prior 
to study entry. The test should have a sensitivity of at least 25 mIU/mL. 
 
Once a participant has enrolled with a negative documented serum pregnancy 
test and begins using 2 forms of contraception to prevent pregnancy, further 
testing per section 6.1 (during study drug dosing and in post treatment followup) 
can be urine testing. Urine test must have a sensitivity of at least 50 mIU/mL; if 
positive, must have immediate confirmation with serum -HCG. 
 
All females of reproductive potential will have a pregnancy test, as indicated in 
sections 6.1.1 and 6.1.2. In the event of a positive urine pregnancy result, 
participants will be instructed to stop study drugs immediately and return to the 
clinic as soon as possible for a serum pregnancy test. See section 7.2 for 
detailed information regarding study management. 


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Serologies 
HCV Ab, HAV IgM, and HbsAg will be done during screening with results 
available prior to study entry. 
 
If a historical HIV Ab test result (ie, used for HIV-1 infection documentation 
to meet inclusion criterion 4.1.1) is not available, an HIV Ab test will also be 
done at screening with the result available prior to study entry. 
 
6.3.6 Virologic Studies 
 
Plasma HCV RNA (screening and pre-entry) 
The screening and pre-entry HCV RNA result must be obtained by any FDA- 
approved test for quantifying HCV RNA at any local laboratory that has a CLIA 
certification or its equivalent. Screening HCV RNA must be obtained within 10-42 
days prior to study entry. 
 
The pre-entry HCV RNA will be obtained to confirm ongoing infection prior to 
study entry. 
 
Plasma HCV RNA (on-study evaluations) 
At the entry and post-entry visits, HCV RNA quantification will be performed at 
the designated testing laboratory as follows: 
 
Plasma HCV RNA real-time testing will be collected, processed, and shipped to 
the designated testing laboratory (see A5327 LPC for directions). These results 
will be reported within 2 weeks after specimen receipt. 
 
HCV Genotype 
At screening, the HCV genotype result will be obtained locally (real-time) from 
any laboratory that has a CLIA certification or its equivalent. ONLY IF IT IS NOT 
AVAILABLE LOCALLY should it be done (real-time) at the designated testing 
laboratory (see A5327 LPC). 
 
Plasma HIV-1 RNA 
A documented plasma HIV-1 RNA level must be noted within 10-42 days prior to 
study entry from any laboratory that has a CLIA certification or its equivalent. On- 
study HIV-1 RNA should be performed at the ACTG central laboratory. See the 
LPC for processing, shipping, and storage information. 
 
Participants on ART who later experience HIV-1 viral breakthrough while on HIV 
therapy should be managed as per section 7.4. 
 
Stored Serum and Plasma for HIV-1/HCV Studies 
Serum and plasma samples will be collected and stored for potential HCV and 
HIV sequencing and other virology studies. For processing and shipping 
instructions, refer to the A5327 LPC. 


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6.3.7 Immunologic Studies 
 
CD4+/CD8+ 
Screening CD4+/CD8+ testing may be done by any laboratory that possesses a 
CLIA certification or its equivalent. 
 
During the study, all laboratories must possess a CLIA certification or its 
equivalent and must be certified for protocol testing by the DAIDS Immunology 
Quality Assurance (IQA) Program. 
 
Stored Plasma and PBMC 
Stored plasma and PBMC will be collected, processed, and shipped to the 
designated immunology laboratory for testing of host ISGs proteins, and T cell 
immune responses will be evaluated (see A5327 LPC). Plasma will be used to 
assess protein levels of selected ISGs and PBMCs will be used to assess for 
CD4+/CD8+ T-cell responses and intracellular RNA expression of selected ISGs. 
 
DNA for host polymorphisms: DNA will be extracted from PBMC and stored for 
single nucleotide polymorphism (SNP) testing for key loci. 
 
6.3.8 Additional Stored Samples 
 
Stored plasma will be collected at the indicated visit (see section 6.1) for future 
testing and shipped according to the A5327 LPC. This additional blood will be 
collected from participants who consent to this collection; these samples will be 
used for future ACTG-approved research. 
 
6.3.9 PK Sampling 
 
For dried blood spots (DBS) and plasma for PK, please refer to section 10.2. 
 
6.3.10 IL-28B and ITPA Genotype 
 
Whole blood will be obtained and shipped batch to the designated immunology 
laboratory for testing of specific genetic variants; these samples will be analyzed 
for IL28B and ITPA genotype. IL28B and ITPA genotype will be determined by 
polymerase chain reaction (PCR) amplification by the designated immunology 
laboratory (see A5327 LPC). For processing and shipping instructions, refer to 
the A5327 LPC. 
 
IL28B genotype will be completed on all participants who consent to this 
collection regardless of whether the participant enrolls into the study. At entry, 
only collect the sample for IL28B genotype if it was not obtained during 
screening. 
 
The ITPA genotype will be performed only on participants who consent to this 
collection and are subsequently enrolled into the study. 


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6.3.11 Pregnancy Prevention Counseling 
 
Counseling on pregnancy prevention will be conducted as per site’s standard of 
care. 
 
6.3.12 Adherence Assessment 
 
This study will use a combination of three measures of adherence (1) the Adult 
ACTG 4-day recall, (2) pill count, and (3) measurement of RBV concentrations. 
 
Adherence questionnaire will be used to determine participant adherence to 
antiretroviral medications and study medications. 
 
Study drug and dosing diary will be reconciled at all on-treatment visits by the 
site staff/investigator in order to monitor the participant’s adherence with the 
study drug regimen. 
 
6.3.13 Study Drug Dispensing 
 
Participants must be instructed to bring back all bottles of study drugs in the 
original container at the post-entry study visits, as indicated in section 6.1. 
 
For Cohort 2 only: At the entry visit two bottles of study drug will be 
dispensed to participants (ie, 8 weeks supply of study drug). The site 
staff/investigator must confirm that participants understand the dosing 
instructions to ensure 8 weeks of continuous dosing. 
 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
Criteria for participant management, dose interruptions, dose adjustments and 
discontinuation, or changes in treatment will be described only for toxicities attributable 
to study drugs (ie, SOF and RBV or LDV/SOF). 
 
The grading system for drug toxicities is located in the DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, 
December 2004 (Clarification, August 2009), which can be found on the DAIDS RSC 
Web site: http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
NOTE: The team must be notified via e-mail within 72 hours regarding toxicities that 
result in a change in study regimen (actg.corea5327@fstrf.org). 
 
7.1 
Toxicity 
 
It is possible that some participants will experience transient or prolonged AEs during 
the trial. Some participants may need to adjust RBV dosing. To minimize the effects of 


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these dosing modifications on the eventual evaluation of the safety, tolerability, and 
activity of study treatment, the principles in the following sections will be used to 
determine the appropriate dose adjustment. 
 
Grades 1 and 2 AEs associated with SOF or RBV or LDV/SOF require no change in 
study treatment but close followup; with the exception that modifications of RBV dosing 
for Grades 1 and 2 anemia are provided in section 7.1.1. 
 
7.1.1 Management of Side Effects of RBV 
 
The most common AE of RBV therapy is anemia due to hemolysis. Anemia 
typically occurs within 1 to 2 weeks of initiating RBV therapy and usually resolves 
within 4 to 8 weeks of drug discontinuation or dose reduction. Indirect bilirubin 
elevation is commonly seen in those participants with anemia secondary to 
RBV-induced hemolysis. 
 
Another major side effect of RBV is its teratogenicity; it is therefore strongly 
recommended that pregnant women or breastfeeding women and men with 
pregnant sexual partners not receive RBV. Women who become pregnant on 
study and men on study whose partners become pregnant must discontinue 
study treatment and complete the discontinuation evaluations as indicated in 
section 7.2. 
 
RBV dosing in this study will be based on weight at study entry (see section 5.0). 
Dose reduction of RBV is the recommended management for ribavirin associated 
anemia and should be performed according to the product label. Information is 
summarized in Table 7-1. It is recommended that sites contact the protocol core 
team with questions regarding difficult anemia management and/or if it is felt 
ribavirin discontinuation is required. Participants may continue to take SOF if 
RBV is temporarily or permanently discontinued. 
 
Table 7-1. Suggested RBV Dose Reduction in the Event of Anemia 
 
Laboratory Values 
Reduce RBV Dose to 600 mg/day if: 
HOLD RBV if: 
Hemoglobin in participants 
with no cardiac disease 
<10 g/dL 
<8.0 g/dL 
Hemoglobin in participants 
with history of stable cardiac 
disease 
≥2 g/dL decrease in hemoglobin 
during any 4 week period treatment 
<10 g/dL despite 4 
weeks at reduced dose 
Symptomatic drop in hemoglobin to be managed at the discretion of the site investigator and 
can be discussed with the protocol chairs. 
 
Reintroduction of RBV 
If RBV is temporarily stopped due to anemia, the hemoglobin must be rechecked 
within 2 weeks and at 2-week intervals until stable. Once RBV has been withheld 
due to either a laboratory abnormality or clinical manifestation, an attempt may 


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be made to restart RBV at 600 mg daily in two divided doses and further increase 
the dose to 800 mg daily in two divided doses. However, it is not recommended 
that RBV be increased to the original assigned dose. Please refer to the table 
below for dosing intervals. 
 
Daily Dose 
Morning Dose 
Evening Dose 
600 mg 
400 mg (2 tablets) 
200 mg (1 tablet) 
800 mg 
400 mg (2 tablets) 
400 mg (2 tablets) 
 
 
NOTE 1: The half-life of RBV in patients with normal renal function is 290 hours. 
 
NOTE 2: The ranges of hemoglobin values used as criteria for triggering dose 
reduction of RBV do not correspond to those used to grade toxicities in 
the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Version 1.0, December 2004 (Clarification, August 
2009). Therefore, sites are expected to use A5327-specific criteria. 
 
7.1.2 Management of Side Effects of SOF or LDV/SOF 
 
To date, there has been no safety signal identified that is attributable to SOF or 
LDV/SOF when administered as part of a combination regimen. However if a 
SAE occurs, administration of SOF or LDV/SOF may be discontinued due to a 
clinical or laboratory event. TFV levels, when given with LDV/SOF, are 
anticipated to be similar to those achieved with boosted protease inhibitor 
(PI)-based regimens. For participants also on a RTV boosted HIV PI or a 
COBI-containing regimen there is potential for higher exposures. Thus, 
renal monitoring will be implemented during on-treatment and post 
treatment visits of the study for those participants taking TDF. Renal 
monitoring in Cohort 2 will include serum glucose, potassium, creatinine, 
and calculated creatinine clearance at screening, entry, every on-treatment 
visit, and at the post treatment weeks 2 and 4 visits and then followed by 
serum creatinine and calculated creatinine clearance at the post treatment 
weeks 8 and 12 visits. Urinalysis will be completed at entry, on-treatment 
weeks 2, 4, and 8, and post treatment weeks 2, 4, and 12. 
 
Protocol defined changes in renal function will include creatinine clearance 
<50 mL/min (confirmed within 5 days), increase in creatinine >0.4 mg/dL 
(confirmed within 2 weeks), and new 2+ proteinuria (confirmed within 2 
weeks). If any of these occur the site investigator should contact the 
protocol team immediately to discuss further management. No changes in 
LDV/SOF or the HIV regimen should occur without discussion with the 
protocol team. 
 
Dose reduction of SOF or LDV/SOF will not be allowed in the study. If SOF or 
LDV/SOF are stopped for toxicity, they should not be restarted. For participants 
receiving SOF+RBV for whom SOF has been stopped, RBV should also be 


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stopped and the participant should complete the treatment discontinuation visit. 
Under no condition should the participant remain on RBV monotherapy. 
 
All participants must complete the PTx week 2, 4, 8, 12, and 24 visits. For 
participants who have completed the treatment discontinuation visit, the PTx 
week 2, 4, 8, 12, and 24 visits will be scheduled from the date of the last dose of 
study treatment. 
 
Participants who meet any of the following laboratory criteria should stop 
treatment with SOF+RBV or LDV/SOF: 
• 
Confirmed elevation of ALT and/or AST >3 x values measured upon study 
entry 
• 
Confirmed direct bilirubin 3 x ULN and > 2.0 mg/dL 
• 
Any Grade 3 or greater rash associated with constitutional symptoms 
• 
Any Grade 4 event assessed as related to treatment with SOF or LDV/SOF 
 
7.2 
Pregnancy 
 
Pregnancy will result in immediate discontinuation of the study medications and initiation 
of counseling regarding the teratogenicity of RBV if in Cohort 1 and lack of 
information of safety in pregnancy with LDV/SOF if in Cohort 2. Participants who 
become pregnant while on study will be followed on study/off treatment until study 
completion. A visit 6 months following the end of pregnancy will be conducted for 
evidence of AEs in the participant and infant, and an outcome CRF will be completed. 
 
In Cohort 1, male participants whose partners become pregnant will undergo 
treatment discontinuation and remain on study for continued followup until the end of the 
study. They will receive counseling on RBV teratogenicity and the same followup visit at 
6 months after their partners’ delivery as outlined for pregnant women. This same risk 
of teratogenicity is not seen with LDV/SOF, thus pregnancy of female partner in 
Cohort 2 is not an indication for treatment discontinuation. 
 
In Cohort 1, participants who become pregnant while taking study treatment or within 6 
months after discontinuing study treatment and male participants’ sexual partners who 
become pregnant during this time will have their pregnancies reported to the Ribavirin 
Pregnancy Registry (www.RibavirinPregnancyRegistry.com). In Cohort 2, a female 
participant who becomes pregnant while taking the study treatment will have her 
pregnancy reported to the sponsor. 
 
If a female participant or female partner of a male participant has completed the study 
or chooses to discontinue from the study before the end of the pregnancy, site staff 
should request permission to contact her regarding pregnancy outcomes at the end of 
pregnancy. If the information is obtained, pregnancy outcomes will be submitted on a 
CRF at the end of the pregnancy. 


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The intrapartum complications and/or pregnancy outcome will be recorded on the CRFs. 
If applicable, pregnancies that occur on study should be reported prospectively to The 
Antiretroviral Pregnancy Registry. More information is available at www.apregistry.com. 
Phone: 800-258-4263; Fax: 800-800-1052. (For studies conducted at sites outside the 
US, report to The Antiretroviral Pregnancy Registry Fax: 44-1628-789-666 or 910-246- 
0637, Phone: 910-679-1598.) 
 
7.3 
HCV Virologic Response-Based Stopping Criteria 
 
The following on-treatment HCV virologic response-based treatment stopping criteria 
will be utilized for all participants: 
• 
Confirmed increase in HCV RNA ≥LLOQ if HCV RNA previously declined to <LLOQ 
(detected or not detected) 
• 
Confirmed ≥1 log10 IUmL HCV RNA on-treatment increase from nadir 
• 
Confirmed HCV RNA ≥LLOQ at week 8 visit (in 12-week course of therapy) 
 
Confirmation will be required for all stopping criteria and should be performed as soon 
as possible but within 2 weeks after determination of initial observation (see HCV VF 
Confirmation in section 6.1). 
 
HCV RNA measurement to confirm treatment failure will be performed in real time at the 
designated VSL and the results will be provided to the site investigators within 2 weeks 
of specimen receipt. If treatment failure is confirmed, then all study treatment should be 
stopped. However, participants should be followed as per section 6.2.4. 
 
Virologic evidence of relapse, defined as HCV RNA undetectable (<LLOQ TND) at end- 
of-treatment but HCV RNA quantifiable (≥LLOQ) during followup, will require 
confirmation and should be performed in real time at the designated VSL as soon as 
possible but within 2 weeks after determination of initial observation and the results will 
be provided to the site investigators within 2 weeks of specimen receipt. 
 
7.4 
HIV-1 Treatment Failure 
 
In this study, HIV-1 viral breakthrough is defined as follows (only applies for participants 
on ART): 
• 
Among participants with unquantifiable HIV-1 RNA at study entry, a confirmed 
increase to ≥200 copies/mL at any time after study entry. 
• 
Among participants with quantifiable HIV-1 RNA at study entry, a confirmed 
increase of ≥200 copies/mL from study entry, at any time after study entry. (This is in 
consideration of possible change in HIV-1 RNA viral load status from screening to 
entry.) 
 
The increase in plasma HIV-1 RNA should be confirmed with repeat local testing as 
soon as possible (not to exceed 4 weeks); see HIV VF Confirmation in section 6.1. For 
participants with confirmed HIV-1 viral breakthrough (≥200 copies/mL), a plasma 
specimen should be obtained and sent to the designated A5327 Virology Support 


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Laboratory (VSL) for evidence of HIV-1 drug resistance. Results will be reported back to 
sites in real-time from the designated A5327 VSL. 
 
Clinical management of HIV-1 virologic breakthrough and treatment failure will be 
handled by local site investigators according to current HIV treatment guidelines and 
local standard of care. The A5327 protocol core team should be contacted before 
switching ART. 
 
HCV medications should be continued unless safety events warrant the 
discontinuation of these medications, as outlined is Section 8.1 of the protocol. 
 
These criteria only apply to participants currently on ARV treatment. They do not 
apply to participants meeting the ARV untreated parameters outlined in section 4.1. 
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Permanent Treatment Discontinuation 
 
• 
Drug-related toxicity (see section 7.1 Toxicity). 
• 
Pregnancy in a female participant. 
• 
Pregnancy in the female partner of male participant (Cohort 1 only). 
• 
HCV efficacy failure as defined in section 7.3. 
• 
Significant protocol violation including noncompliance with study 
assessments. 
• 
Participant request to discontinue for any reason. 
NOTE: It is important to determine whether the treatment discontinuation is 
primarily due to an AE, lack of efficacy, or other reason. 
• 
Requirement for prohibited concomitant medications (see section 5.4). 
• 
Breastfeeding. 
• 
Completion of treatment as defined in the protocol. 
• 
Clinical reasons believed life threatening by the physician, even if not 
addressed in the toxicity section of the protocol. 
 
8.2 
Premature Study Discontinuation 
 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 
• 
Participant judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results. 
• 
At the discretion of the Study Monitoring Committee (SMC), ACTG, IRB, NIAID, 
Office for Human Research Protections (OHRP), any other government agency as 
part of their duties, investigator, or industry supporter. 


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9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This study will evaluate the efficacy and safety of a 12-week regimen of SOF combined 
with RBV (Cohort 1) and an 8-week regimen of LDV/SOF (Cohort 2) for the treatment 
of acute HCV infection among individuals coinfected with HIV. Efficacy will be evaluated 
using SVR12 as the primary outcome measure. A true SVR12 rate of less than or equal 
to 60% will be considered as reasonably ruled out if the two-sided 90% CI for the rate is 
entirely above 60% (this is equivalent to showing that the rate is higher than 60% in a 
one-sided noninferiority test with a Type I error rate of 5%). 
 
The threshold of 60% for the SVR12 rate was chosen based on a summary of nine acute 
HCV treatment studies in HIV-1 coinfected participants identified in a recent report by 
the European AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus 
Panel [AIDS, 2011]. In this summary, 96 (60%) of 159 participants treated with 
PEG/IFN combined with RBV achieved SVR24 (i.e., the conventional definition of SVR 
evaluated at 24 weeks after stopping treatment). 
 
The sample size of 17 participants for the evaluation of the 12-week SOF+RBV 
regimen in Cohort 1 was chosen to provide good power to show noninferiority with 
respect to the 60% threshold assuming that the underlying true SVR12 rate is 90%. In 
part because of the lower than expected observed SVR12 rate for SOF+RBV in 
Cohort 1, the sample size of 27 participants for the evaluation of the 8-week LDV/SOF 
regimen in Cohort 2 was chosen to provide good power to show noninferiority with 
respect to the same 60% threshold assuming that the underlying true SVR12 rate is 
85%. 
 
The primary analysis will be ITT and will include all participants who start study 
treatment. In this ITT analysis, the standard definition of SVR12 will be used, ie, ignoring 
whether or not a participant discontinued study treatment early and considering 
participants who are lost to followup or otherwise unevaluable for SVR12 as not 
meeting the definition for SVR12. An important secondary analysis will include 
participants who are evaluable for SVR12 but exclude participants who prematurely 
discontinue study treatment for nonvirologic reasons (“completer” analysis). To ensure 
that the “completer” analysis is also well-powered, if a participant is discontinued from 
the study treatment for nonvirologic reasons or is not evaluable for SVR12 while 
enrollment is ongoing to the same cohort, then an additional participant may be 
enrolled to that cohort, up to a maximum enrollment for the study as a whole of 50 
participants. 
 
The study has not been designed to be well powered to compare the 12-week 
SOF+RBV and 8-week LDV/SOF regimens. 


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9.2 
Outcome Measures 
 
9.2.1 Primary Outcome Measures 
 
9.2.1.1 SVR12 defined as HCV RNA undetectable (<LLOQ TND) of the assay 
at 12 weeks after date of last dose of study treatment. The 12 week 
measurement will be the measurement obtained closest to 84 days (ie, 
12*7 days), within the window 79 to 112 days inclusive. If a participant 
has no HCV RNA measurement within this window, then the participant 
will be considered as having detectable HCV RNA at 12 weeks unless 
the preceding and subsequent HCV RNA measurements are both 
undetectable (<LLOQ TND). 
 
9.2.1.2 Occurrence of Grade ≥2 AE (diagnosis, sign, symptom or laboratory 
abnormality), SAE according to ICH criteria, or treatment-limiting AE (ie, 
an AE reported as the reason for permanent discontinuation of study 
treatment). Any event occurring after initiation of study treatment 
through to 28 days after date of last dose of study treatment will be 
included (except that an event that is ongoing at the same grade from 
before start of study treatment will be excluded). 
 
9.2.2 Secondary Outcome Measures 
 
9.2.2.1 HCV RNA undetectable (<LLOQ TND) at 1, 2, 4, 8 and, for the 12-week 
regimen, 12 weeks after starting study treatment. Measurements will be 
assigned to these times within windows of 4 to 10, 11 to 17, 21 to 42, 49 
to 70, and 77 to 98 days, inclusive, respectively. If there is more than 
one measurement within a window, then the measurement closest to 
the targeted time will be used. If there is no measurement within a 
window, then the participant will be considered as having detectable 
HCV RNA at the targeted time, unless both the preceding and 
succeeding measurements are undetectable (<LLOQ TND). 
 
9.2.2.2 HCV RNA undetectable (<LLOQ TND) at 2 (SVR2), 4 (SVR4), 8 
(SVR8), and 24 (SVR24) weeks after last dose of study treatment. The 
windows for these measurements will be 9 to 22, 23 to 50, 51 to 78, and 
161 days onwards. If there is more than one measurement within a 
window, then the measurement closest to the targeted time will be used. 
If there is no measurement within a window, then the participant will be 
considered as having detectable HCV RNA at the targeted time, unless 
(for weeks 4 and 8) the preceding and subsequent HCV RNA 
measurements are both <LLOQ TND. 
 
9.2.2.3 To evaluate virologic evidence of relapse, defined as HCV RNA 
undetectable (<LLOQ TND) at end-of-treatment but HCV RNA 
quantifiable (≥LLOQ) during followup, will require confirmation and 


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should be performed as soon as possible but within 2 weeks after 
determination of initial observation. 
 
9.2.2.4 Development of SOF or LDV-associated resistance mutations. The set 
of mutations to be considered will be defined at the time of analysis 
based on information from other studies available at that time. 
 
9.2.2.5 Occurrence of the AEs detailed in section 9.2.1.2 by type of event. 
 
9.2.2.6 Change in HIV-1 RNA from last measurement prior to start of study 
treatment to each subsequent scheduled HIV-1 RNA measurement 
time: for participants on ART at study entry, these will be categorized 
as changes from <50 copies/mL to ≥50 copies/mL, or vice versa; for 
participants not on ART at study entry, quantitative change in log10 
HIV-1 RNA will be considered. Windows for measurements to be 
included and the algorithm for selecting measurements within each 
window will be as described for HCV RNA measurements above. 
 
9.2.2.7 Change in CD4+ cell count from last measurement prior to start of study 
treatment to each subsequent scheduled CD4+ cell count measurement 
time. Windows for measurements to be included and the algorithm for 
selecting measurements within each window will be as described for 
HCV RNA measurements above. 
 
9.2.2.8 Measures of adherence: for each of SOF and RBV (in Cohort 1) or 
LDV/SOF (in Cohort 2) at each visit: (a) self-reported adherence as 
measured by whether or not a participant reports having taken all 
doses; and (b) proportion of doses taken since the previous visit as 
determined by pill count. 
 
9.2.2.9 Immune parameters: changes in magnitude of induction of ISGs by 
Nanostring, changes in IP-10 levels, and changes in T cell function 
(CD4+ proliferative and CD8 CTL assays) at end of treatment and end 
of followup compared to study entry. Analysis will be performed as a 
function of IL28B genotype. 
 
9.3 
Randomization and Stratification 
 
There is no randomization or stratification in this study. The study includes two cohorts 
of participants; these cohorts will be enrolled sequentially. 
 
9.4 
Sample Size and Accrual 
 
In this section, the selection of sample size is described separately for Cohort 1 and 
for Cohort 2. Note that the study has been designed to allow for small increases in 
sample size from 17 in Cohort 1 and 27 in Cohort 2, if some participants prematurely 
discontinue study treatment due to nonvirologic reasons or are not evaluable for the 


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primary outcome measure of SVR12. The rationale for the increase in sample size is 
then to provide similar power in the “completer” analysis (described in section 9.1) as 
there would be in the primary ITT analysis, if no additional participants are enrolled (ie, 
based on 17 participants in Cohort 1 and 27 participants in Cohort 2). In addition, if 
there are participants in screening at the time that first cohort meets its accrual goal, or 
at the time that the second cohort meets its accrual goal, then these participants may 
complete screening and enroll in the study provided that this can be achieved within 30 
days (the site must provide the patient ID for these participants to the study team to 
enable enrollment). Also, if a participant is enrolled in the study and does not start study 
treatment, then the participant will not be followed and may be replaced if enrollment is 
still ongoing. 
 
Cohort 1 enrolled 17 participants in about 4.5 months. It is therefore anticipated 
that it will take about 7 months to enroll 27 participants in Cohort 2. 
 
9.4.1 Sample size of 17 participants in Cohort 1 receiving the 12-week SOF/RBV 
regimen 
 
Version 1.0 of the protocol provided detailed justification for the sample 
size of 17 participants for Cohort 1. In brief, the sample size of 17 
participants for the first cohort has been chosen to provide good power to show 
with reasonable certainty that the underlying true SVR12 rate is greater than 
60%. This was to be established if the two-sided 90% CI for the rate was entirely 
above 60% (this is equivalent to showing that the rate is higher than 60% in a 
one-sided noninferiority binomial test with a Type I error rate of 5%). Assuming 
that the true SVR12 rate was 90% among those treated with the 12-week 
regimen, 17 participants were needed to provide 90% power to establish this. 
With a sample size of 17 participants, the CI for the true SVR12 rate would be 
entirely above 60% if 14 or more of the 17 participants achieved SVR12. 
 
9.4.2 Sample size of 27 participants in Cohort 2 receiving the 8-week LDV/SOF 
regimen 
 
A larger sample size has been chosen for the second cohort of participants than 
for the first cohort to allow for the possibility that the underlying true SVR12 rate 
is 85%. Specifically, the sample size of 27 participants for the second cohort 
has been chosen to provide 90% power to show with reasonable certainty that 
the underlying true SVR12 rate is greater than 60%, assuming that this true rate 
is actually 85%. 
 
In this sample size calculation, no adjustment is needed for loss to 
followup because, by definition, such participants are assumed not to be 
SVR12. However, it is important to note that the study team feels that the 
lost to followup rate will be very low, specifically less than 5%. There is 
support for this from Cohort 1, in which no participants were lost to 
followup, and from an ACTG acute HIV infection study, A5217, in which the 
lost to followup rate within 24 weeks of enrollment was 4.6% (6 of 130 


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participants). The study team considers an underlying true SVR12 rate of 
85% to be plausible based on the results of studies in chronically infected 
participants (see section 2.2.3.1). 
 
The figure below shows the study’s power to establish noninferiority with respect 
to the 60% threshold in the second cohort of 27 participants for a range of 
values of the underlying true SVR12 rate (expressed as a proportion, P1, in the 
figure). As can be seen the study has reasonable power (≥80%) for true 
underlying SVR12 rates greater than about 82%. 
 


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The table below also shows two-sided exact Blyth-Still-Casella (BSC) 90% CIs 
for potential observed SVR proportions for 27 enrolled participants in the 8- 
week treatment arm. With a sample size of 27 participants, the CI for the true 
SVR12 rate will be entirely above 60% if 21 or more of the 27 participants 
achieve SVR12. 
 
Observed SVR12 Rate 
90% CI for True SVR12 Rate 
85% (23/27) 
(71%, 93%) 
81% (22/27) 
(65%, 90%) 
78% (21/27) 
(62%, 90%) 
74% (20/27) 
(58%, 85%) 
70% (19/27) 
(54%, 84%) 
67% (18/27) 
(50%, 80%) 
 
 
9.5 
Monitoring 
 
The study team will monitor accrual, retention, and completeness of key laboratory 
measurements (HCV RNA and HIV-1 RNA). In addition, standard ACTG SDAC AE 
reports and summaries of changes in HIV-1 RNA will be reviewed by the study team 
including the DAIDS Medical Officer every 3 months. The formats of these reports will be 
outlined in the Study Monitoring Plan, developed by the Statistical and Data 
Management Center (SDMC) and reviewed by the study team prior to study enrollment. 
Information about SVR rates will not be reviewed on a routine basis by the study team. 
 
This study is also monitored by the ACTG Hepatitis Study Monitoring Committee 
(SMC). For Cohort 2, because of a hypothetical risk of renal toxicity due to 
increased TFV exposure in participants taking COBI or taking TDF in combination 
with a boosted HIV PI, the SMC will review the study when 5 participants taking 
these regimens have completed 4 weeks of study treatment, and at least annually 
after the first participant is enrolled for as long as participants are taking study 
treatment. The reviews will include information about accrual, retention, completeness 
of key laboratory measurements (HCV RNA and HIV-1 RNA), AEs, changes in HIV-1 
RNA, and efficacy (SVR4, SVR12, SVR24 rates and changes in HCV RNA). 
 
It is not intended that the SMC terminate the study early if the SVR12 rate is very high. 
The SMC may, however, recommend early termination if the SVR4 rate or the SVR12 
rate is unacceptably low, for example if the 90% CI is entirely below 60% (the confidence 
intervals will not be adjusted for interim analyses). The SMC may also make 
recommendations about modification or termination of the study based on safety 
considerations or because of poor accrual. 
 
9.6 
Analyses 
 
A detailed Statistical Analysis Plan (SAP) was developed after Version 1.0 of the 
protocol was finalized. The following provides a brief summary of analyses that will 
address the primary and key secondary objectives. 


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The primary efficacy objective will be addressed by estimating the proportion of 
participants within a cohort who achieve SVR12 in ITT analysis. The denominator will 
be the number of participants in a cohort who start study treatment. A two-sided 90% 
CI will be calculated for proportion using the BSC method for binomial outcomes. If this 
confidence interval is entirely above 60%, then it will be concluded that there is 
reasonable evidence that the underlying true SVR12 rate is greater than 60% (ie, 
noninferior to 60%). An important secondary analysis will use similar methods to 
evaluate the primary outcome measure in the “completer” analysis (defined in section 
9.1). Secondary efficacy objectives (proportions of participants achieving HCV RNA 
undetectable (<LLOQ TND) during study treatment and achieving SVR4, SVR8, and 
SVR24) will be addressed in a similar way. Possible predictors of response (adherence, 
HCV genotype, host IL28B genotype, etc.) will be evaluated using univariate exact 
logistic regression; multivariate models will also be considered if there are sufficient 
numbers of events (eg, of participants not achieving SVR12). Descriptive statistics will 
be used to describe adherence measures at each study visit. 
 
The primary safety objective will be addressed by estimating the proportion of 
participants who have one of the defined AEs. The denominator will be the number of 
participants in a cohort who are dispensed study treatment. A two-sided 90% 
confidence interval will be calculated for each proportion using the BSC method for 
binomial outcomes. Descriptive tables summarizing types of AEs, grades of events, and 
the number of persons experiencing each type/grade of event will be provided. 
Descriptive tables will also be provided for the number of participants discontinuing 
study treatment early, categorized by the reasons for discontinuation. Changes in HIV-1 
RNA and CD4+ cell count at each scheduled measurement time will be described 
separately for participants on versus not on ART at study entry. 
 
Results from Cohort 1 may be presented publicly, for example at a conference or in a 
published manuscript, while followup of participants enrolled in Cohort 2 is ongoing. 
The final analysis of data from Cohort 2 will be undertaken when all participants have 
completed 24 weeks of followup after discontinuing study treatment and data are 
available. However, a preliminary analysis may be undertaken after all participants in 
Cohort 2 have completed 12 weeks of followup after discontinuing study treatment and 
data are available if this facilitates submission of an abstract to a conference for 
presentation of study results. 
 
 
10.0 
PHARMACOLOGY PLAN 
 
Nucleos(t)ide analogs are fundamental components of the treatment for HCV, yet 
there are limited data on the pharmacology of the active form of these drugs, the 
intracellular triphosphate, in vivo. Data from the SPARE trial [Osinusi A, 2013] of 
SOF/RBV in 60 individuals with HCV genotype 1 disease found intracellular RBV 
concentrations were associated with treatment response and the development of 
anemia [Rower, J Antimicrob Chemother, accepted 2015]. Analysis of intracellular 
SOF pharmacokinetics from the SPARE study is ongoing. The PK of these drugs 


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may therefore be important predictors of SVR vs. relapse in A5327. Furthermore, 
traditional tools to monitor adherence (eg, pill counts, self-report, refill histories, 
etc.) have shortcomings and consistently over-estimate drug taking behavior. 
RBV has a long half-life of 10-12 days [Wu, 2015; Rower, J Antimicrob Chemother, 
accepted 2015]. Thus, it can be used as a quantitative objective measure of 
cumulative drug dosing (ie, adherence). These data may be instrumental in 
evaluating response rates (as it was for TDF for pre-exposure prophylaxis). 
Intracellular concentrations of SOF metabolites (GS-331007 triphosphate or “007- 
TP”) may also predict response and reflect cumulative drug dosing. A5327 offers 
a unique opportunity to evaluate the pharmacokinetic-dynamic and adherence- 
response associations for nucleos(t)ide analogs. Additionally, though we are not 
planning to investigate this a priori to limit costs and because there is no pharmacologic 
reason to suspect an interaction, we will also have the potential to investigate 
unexpected drug-drug interactions with ARV agents. 
 
Assessing the Potential Effects of LDV/SOF on TFV Concentrations in Those on 
RTV-Boosted HIV Protease Inhibitors or on COBI-Containing Regimens. 
Healthy volunteer studies indicate that LDV/SOF in combination with ritonavir- 
boosted PIs, increases TFV concentrations by 47-64% [German P, CROI 2015 
abstract 82]. These data were not available at the time of ION-4 enrollment and 
thus boosted HIV PI regimens were excluded from the study. It is therefore 
unknown if this increase in TFV exposure has clinical relevance. A5327 provides 
an opportunity to investigate the clinical significance of increased TFV exposures 
in the setting of concomitant dosing of LDV/SOF, ATV/r or DRV/r, and TDF. Due to 
similar concerns of increased TFV exposure in the setting of COBI usage and an 
increase in TFV AUC similar to that seen in PI/r based regimens A5327 also 
provides the opportunity to investigate the clinical significance of TFV exposures 
in the setting of concomitant dosing of LDV/SOF, COBI, and TDF. 
 
10.1 
Pharmacology Objectives 
 
10.1.1 Develop a population PK model for ribavirin to estimate RBV PK in persons with 
HIV-1 and acute HCV and evaluate covariates, including concomitant 
administration of selected ARV drugs which may affect RBV PK. 
 
10.1.2 Develop a population PK model for LDV and SOF metabolites to estimate 
PK in persons with HIV-1 and acute HCV and evaluate covariates, including 
concomitant administration of selected ARV drugs which may affect LDV 
and SOF metabolite PK. 
 
10.1.3 Determine the associations between adherence assessed using traditional 
measures (eg, self-report and pill counts) and drug concentrations. 
 
10.1.4 Investigate PK-PD relationships for RBV, LDV, and SOF metabolites. 
 
10.1.5 Compare TFV pharmacokinetics in participants on RTV-boosted PIs or 
COBI with TDF before and after the addition of LDV/SOF. 


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10.2 
Pharmacology Study Design 
 
Plasma and DBS will be obtained from all participants prior to initiation of SOF+RBV or 
LDV/SOF, at entry, weeks 1, 2, 4, 8, and 12 following SOF+RBV or LDV/SOF initiation 
(weeks 8 and 12 only in those who receive 12 weeks of treatment), HCV VF and HIV-1 
VF Confirmation and premature discontinuation visits, and at weeks 2, 4, 8, and 12 post- 
treatment. Samples are collected prior to treatment initiation and after discontinuing 
treatment in the event there is a need to retrospectively evaluate the potential for ARV 
drug interactions or adherence, but these samples will not be analyzed a priori to limit 
costs. 
 
Plasma RBV and intracellular ribavirin triphosphate concentrations will be determined 
using validated LC/MS/MS methods, respectively. The HPLC-UV method used to 
quantify ribavirin in plasma has a linear range of 0.1-10 mcg/mL. The LC/MS/MS method 
used to quantify ribavirin triphosphate has a linear range of 0.5-200 pmol/sample 
[Jimmerson LC, 2015]. 
 
Plasma LDV, GS-331007 and intracellular 007-TP concentrations will be 
determined using validated LC/MS-MS methods. The LC-MS/MS method used to 
quantify 007-TP has a linear range of 50-50000 fmol/sample [Rower, submitted to 
Analytical and Bioanalytical Chemistry, 2015]. 
 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
To address objectives 10.1.1 and 10.1.2, nonlinear mixed effects models will be fit to 
the drug concentrations to estimate the PK of the drugs in persons with HIV-1 acutely 
infected with HCV. After the base model is established, the effect of covariates such as 
age, race, gender, and concomitant ARV on PK will be assessed. 
 
To address objective 10.1.3, Pearson correlations will be used to evaluate the 
association between self-reported adherence and drug concentrations and pill 
counts and drug concentrations. 
 
To address objective 10.1.4, logistic regression will be used to investigate the 
relationships between drug concentrations and SVR and RBV PK and anemia 
(hemoglobin <10g/dL). 
 
Objective 10.1.5 will be addressed if there is a signal for renal toxicity in 
individuals receiving RTV-boosted HIV PIs. For this objective, TFV levels will be 
compared before and after the addition of LDV/SOF in those receiving RTV- 
boosted HIV PIs using paired t-tests. 
 
10.4 
Anticipated Outcomes 
 
Through the pharmacology objectives of this study, we will determine the PK of RBV, 
LDV, and SOF metabolites in persons with HIV-1 acutely infected with HCV. We will 


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also evaluate the effect of covariates such as age, race, gender, and concomitant ARV 
on the PK of these agents. We will determine the association between traditional 
measures of adherence (self-report and pill count) and adherence determined 
using drug concentrations. We will explore relationships between RBV, LDV, and 
SOF metabolites with SVR and RBV plasma and intracellular PK and the development 
of anemia. If the need arises, we will assess changes in TFV concentrations with 
the addition of LDV/SOF in individuals receiving RTV-boosted PIs. These data will 
guide optimal use of SOF+RBV or LDV/SOF in the setting of acute HCV. 
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Case report forms (CRF) will be provided for each participant. Participants must not be 
identified by name on any CRFs. Participants will be identified by the patient 
identification number (PID) and study identification number (SID) provided by the ACTG 
DMC upon registration. 
 
11.2 
Role of Data Management 
 
11.2.1 
Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely 
fashion. 
 
11.2.2 
It is the responsibility of the ACTG DMC to ensure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
11.3 
Clinical Site Monitoring and Record Availability 
 
11.3.1 
Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, 
CRFs, supporting data, laboratory specimen records, and medical records 
(physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to 
ensure protection of study participants, compliance with the protocol, and 
accuracy and completeness of records. The monitors also will inspect sites’ 
regulatory files to ensure that regulatory requirements are being followed and 
sites’ pharmacies to review product storage and management. 
 
11.3.2 
The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the NIAID, the 
OHRP, and the industry supporter or designee for confirmation of the study 
data. 


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11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at http://rsc.tech- 
res.com/safetyandpharmacovigilance/. 
 
The DAIDS Adverse Events Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS. In the 
event of system outages or technical difficulties, expedited AEs may be 
submitted via the DAIDS EAE Form. For questions about DAERS, please 
contact DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also 
be sent from within the DAERS application itself. 
 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech- 
res.com/safetyandpharmacovigilance/. For questions about EAE reporting, 
please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2 
Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are ribavirin 
(RBV), sofosbuvir (SOF), and fixed dose combination of 
ledipasvir/sofosbuvir (FDC LDV/SOF). 
 
11.4.3 
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 
(Clarification, August 2009), must be used and is available on the DAIDS RSC 
Web site at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
11.4.4 
Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is the time of enrollment of 
the study participant until the study participant completes study followup. 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
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12.0 
PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendices II and III) and any 
subsequent modifications will be reviewed and approved by the IRB or ethics committee 
responsible for oversight of the study. A signed consent form will be obtained from the 
participant. The consent form will describe the purpose of the study, the procedures to 
be followed, and the risks and benefits of participation. A copy of the consent form will 
be given to the participant, and this fact will be documented in the participant’s record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All 
records will be kept locked. All computer entry and networking programs will be done 
with coded numbers only. Clinical information will not be released without written 
permission of the participant, except as necessary for monitoring by the ACTG, IRB, 
NIAID, OHRP, other government agencies as part of their duties, or the industry 
supporter or designee. 
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB, NIAID, OHRP, other 
government agencies as part of their duties to ensure that research participants are 
protected, or the industry supporter. 
 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter prior to submission. 
 
 
14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 


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refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 


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15.0 
REFERENCES 
 
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United States, 1999-2002. Ann Intern Med 2006; 144:705-14. 
Asboe D, Aitken C, Boffito M, et al. British HIV Association guidelines for the routine 
investigation and monitoring of adult HIV-1-infected individuals 2011. HIV Med 2012;13 (1):1-44. 
Boesecke C, Stellbrink HJ, Mauss S, et al. Does baseline HCV genotype have an impact upon 
treatment outcome of acute HCV infection in HIV co-infected individuals. 18th Conference on 
Retroviruses and Opportunistic Infections. February 27-March 2, 2011; Boston, MA. Abstract 
113. 
Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. 
Cochrane Database Syst Rev. 2010 (1):CD005445. 
COPEGUS 200mg and 400mg Film-coated Tablets. Summary of Product Characteristics. 
Roche Products Limited, Welwyn Garden City, United Kingdom. Revised: March 2010. 
COPEGUS (RBV, USP) TABLETS. US Prescribing Information. Roche Laboratories Inc., 
Nutley, NJ. Revised: February 2013. 
Corey KE, Mendez-Navarro J, Gorospe EC, Zheng H, Chung RT. Early treatment improves 
outcomes in acute hepatitis C virus infection: a meta-analysis. J Viral Hepatitis. 2010; 17:201-7. 
Danta M, Semmo N, Fabris P, et al. Impact of HIV on host-virus interactions during early 
hepatitis C virus infection. J Infect Dis. 2008; 197:1558-66. 
de Kanter C, Blonk M, Colbers A, Fillekes Q, Schouwenberg B, Burger D. The influence of the 
HCV protease inhibitor bocepravir on the pharmacokinetics of the HIV integrase inhibitor 
raltegravir. Presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); 
2012 March 5-8; Seattle, WA. Paper #772LB. 
Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as therapy for chronic hepatitis C. 
A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123 (12):897-903. 
Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for patients with chronic hepatitis C: 
results of a placebo-controlled study. J Hepatol. 1996;25 (5):591-8. 
Gambotti L, Batisse DK, Colin-de-Verdiere N, et al. Acute hepatitis C infection in HIV positive 
men who have sex with men in Paris, France, 2001-2004. Euro Surveill. 2005;10:115-7. 
Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor Sofosbuvir plus RBV 
for hepatitis C. N Engl J Med. 2013;368:34-44. 
Gerlach JT, Giepolder HM, Zachoval R, et al. Acute hepatitis C: high rate of both spontaneous 
and treatment-induced viral clearance. Gastroenterology. 2003;125:80-88. 
German P, Garrison K, Pang PS, et al. Drug-Drug Interactions Between Anti-HCV 
Regimen Ledipasvir/Sofosbuvir and Antiretrovirals. Presented at: 22nd Conference on 
Retroviruses and Opportunistic Infections (CROI); 2015 February 23-26; Seattle, WA. 
Abstract #82. 


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REFERENCES (Cont’d) 
 
 
Gilleece YC, Browne RE, Asboe E, et al. Transmission of hepatitis C virus among HIV-positive 
homosexual men and response to a 24-week course of pegylated interferon and ribavirin. J 
Acquir Immune Def Syndr. 2005;40:41-46. 
Harvoni (ledipasvir and sofosbuvir) Tablets for Oral Use. US Prescribing Information. 
Gilead Sciences. Foster City, CA. Revised March 2015. 
Hulskotte E, Feng HP, Xuan F, et al. Pharmacokinetic interaction between the HCV protease 
inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and 
darunavir. Presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); 
2012 March 5-8; Seattle, WA. Paper #771LB. 
Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in 
subjects without treatment options. N Engl J Med. 2013;368:1867-77. 
Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepatitis C with interferon alfa- 
2b. N Engl J Med. 2001; 345:1452-57. 
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Dec 17. 
Kamal SM, Ismail A, Graham CS, et al. Pegylated interferon therapy in acute hepatitis C: 
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Larghi A, Zuin M, Crosignani A, et al. Outcome of an outbreak of acute hepatitis C among 
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Lawitz E, Mangia A, Wyles D, et al. Sofusbuvir for previously untreated chronic hepatitis C 
infection. N Engl J Med. 2013;368:1878-87. 
Matthews GV, Hellard M, Haber P, et al. Characteristics and treatment outcomes among HIV- 
infected individuals in the Australian trial in acute hepatitis C. Clin Infect Dis. 2009;48:650-8. 
McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with 
RBV as initial treatment for chronic hepatitis C: Hepatitis Interventional Therapy Group. N Engl J 
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Mosley JW, Operskalski EA, Tobler LH, et al. The course of hepatitis C viremia in transfusion 
recipients prior to availability of antiviral therapy. J Viral Hepat. 2008; 15:120-28. 
Naggie S, Patel K, McHutchison J. Hepatitis C virus directly acting antivirals: current 
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(10):2063-9. 
Naggie S, Cooper C, Saag M, et al. Ledipasvir/Sofosbuvir for 12 Weeks in Patients 
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Opportunistic Infections (CROI); 2015 February 23-26; Seattle, WA. Abstract #152LB. 
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PEGASYS (peginterferon alfa-2a) Injection for Subcutaneous Use. US Prescribing Information. 
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Ribasphere (ribavirin, USP) Tablets. US Prescribing Information. Manufactured by DSM 
Pharmaceuticals, Inc., Greenville, NC 27834 for Kadmon Pharmaceuticals, LLC., Warrendale, 
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Rockstroh JK, Puoti M, Rodriguez-Torres M et al. Sofosbuvir and ribavirin therapy for the 
treatment of HIV/HCV coinfected patients with HCV GT1-4 infection: the PHOTON-1 and -2 
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Rower JE, Meissner EG, Jimmerson LC, et al. Plasma and Cellular Ribavirin 
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Rower JE, Jimmerson LC, Chen X, et al. Development and validation of an LC-MS/MS 
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Seden K, Back D, Khoo S. New directly acting antivirals for hepatitis C: potential for interaction 
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Serpaggi J, Chaix ML, Batisse D, et al. Sexually transmitted acute infection with a clustered 
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Soriano V, Mocroft A, Rockstroh J, et al. Spontaneous viral clearance, viral load, and genotype 
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Spada E, Mele A, Berton A, et al. Multispecific T cell response and negative HCV RNA tests 
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Sulkowski M, Rodiguez-Torres M, Lalezari JP, et al. All-oral therapy with sofosbuvir plus 
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Sulkowski M, Gardiner D, Lawitz E, et al. Potent viral suppression with the all-oral combination 
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Sulkowski M, Pol S, Cooper C, et al. Boceprevir + pegylated interferon + RBV for the treatment 
of HCV/HIV-co-infected patients: end of treatment (week-48) interim results. 19th Conference 
on Retroviruses and Opportunistic Infections (CROI); 2012c March 5-8; Seattle, WA. [Paper 
#47]. 
Sulkowski MS, Sherman KE, Dieterich DT, et al. Combination therapy with telaprevir for chronic 
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randomised, double-blind, controlled phase 2 trial. Lancet Inf Dis. June 12, 2013e [online first]. 
Sulkowski MS, Naggie S, Lalezari J, et al. Sofosbuvir and Ribavirin for Hepatitis C in 
Patients With HIV Coinfection. JAMA. 2014;312(4):353-361. 
Teijaro JR, Ng C, Lee AM, et al. Persistent LCMV infection is controlled by blockade of type I 
interferon signaling. Science. 2013;340(6129):207-11. 
The European AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus Panel. 
Acute hepatitis C in HIV-infected individuals: recommendations from the European AIDS 
Treatment Network (NEAT) consensus conference. AIDS. 2011, 25:399-409. 
Thomas D, Thio C, Martin M, et al. Genetic variation in IL28B and spontaneous clearance of 
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Tillman HL, Thompson AJ, Patel K, et al. A polymorphism near IL28B is associated with 
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Van Heeswijk R, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between 
ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. 18th 
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Vogel M, Dominguez S, Bhagani S, et al. Treatment of acute HCV infection in HIV-positive 
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sexually transmitted acute hepatitis C infection HIV-infected individuals. Antivir Ther. 2006; 
11:1097-1101. 


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Wilson EB, Yamada DH, Elsaesser H, et al. Blockade of chronic type I interferon signaling to 
control persistent LCMV infection. Science. 2013;340(6129):202-7. 
Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, 
mortality, and costs in the United States. Am J Public Health. 2000;90:1562-9. 
Wu LS, Rower JE, Burton JR Jr, et al. Population Pharmacokinetic Modeling of Plasma 
and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus. 
Antimicrob Agents Chemother. 2015 Feb 2. pii: AAC.04618-14. [Epub ahead of print] 
Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir + ribavirin for 12 or 24 weeks for 
patients with HCV genotype 2 or 3: the VALENCE Trial. 64th Annual Meeting of the American 
Association for the Study of Liver Diseases (AASLD); 2013 November 1-5: Washington, D.C. 
[Abstract 1085]. 


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APPENDIX I: SCREENING FLOW CHART FOR ACUTE HCV INFECTION 
 
 


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APPENDIX II 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT FOR COHORT 1 
For protocol: A5327 
 
FINAL Version 1.0, 01/02/14: Sofosbuvir Plus Ribavirin Without Interferon For Treatment of 
Acute HCV in HIV-1 infected Individuals (SWIFT-C) 
 
SHORT TITLE FOR THE STUDY: A5327/SWIFT-C FINAL Version 1.0, 01/02/14, SOF/RBV 
Without IFN For Treatment of Acute HCV Infection 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with HIV (the 
virus that causes AIDS) and you have also recently been infected with the hepatitis C virus 
(HCV, a virus that affects the liver). This study is sponsored by the National Institutes of Health. 
The doctor in charge of this study at this site is: (insert name of Principal Investigator). Before 
you decide if you want to be a part of this study, we want you to know about the study. 
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
People who are recently infected with HCV have a great chance of being cured of the infection 
when they are treated with a combination of two drugs within the first 6 months of being 
infected. This study is being done to see if a new drug can replace one of the old drugs to 
provide a safer, more effective, and better tolerated treatment for new HCV infection. The name 
of this new drug is sofosbuvir (SOF), and it will replace pegylated-interferon alfa (PEG-IFN, a 
drug given as a weekly injection under the skin). SOF will be given in combination with ribavirin 
(RBV), a drug approved by the Food and Drug Administration (FDA). 
 
SOF has been approved by the FDA for the treatment of chronic HCV in people who do not 
have HIV. It is also currently being studied in people with HIV and chronic HCV. 
 
All participants in this study will be monitored while on treatment at weeks 1, 2, 4, 8, and 12. All 
participants will be evaluated for a sustained virologic response (SVR) (undetectable HCV RNA 
levels) 1, 2, 4, and 8 (for the 8-week regimen) or 12 (for the 12-week regimen) weeks after 
starting study treatment. After completing treatment, all participants will be evaluated for a SVR 
2, 4, 8, 12, and 24 weeks after the end of treatment. 


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HOW MANY PEOPLE WILL BE IN THIS STUDY? 
 
About 44 people (men and women age 18 years and older) will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for approximately 36 weeks. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to join this study, you will continue taking your current anti-HIV drugs if you are 
receiving them. If you are not currently on HIV medications and your provider does not think you 
need HIV medications during the study that is also acceptable. You will be assigned to either 
group 1 or group 2, as shown below. You will take SOF (a pill taken once daily by mouth with 
food) and RBV (pills taken twice daily by mouth with food and at a dose based on your weight) 
until the end of treatment. You will be given the medications at your study visits to take home, 
and you will need to store the medications in a safe place at room temperature. Following the 
end of the 12-week treatment and based on the HCV RNA results of those who were enrolled in 
group 1, the length of therapy may be shortened in group 2, as shown below. 
 
Study 
Group 
Study Drugs 
SVR Rates 
Time on Study 
Drugs 
End of Treatment 
Group 1 
SOF+RBV 
SVR (week 4) 
results available 
from subjects 
12 weeks 
No study treatment – 
continue study followup 
for 24 weeks 
 
At week 4, the study team will look at SVR results. Group 2 will depend on what the results 
show. We will look to see if SVR is met at week 4. 
 
Study 
Group 
Study Drugs 
SVR Rates 
High Enough? 
Time on Study 
Drugs 
End of Treatment 
Group 2 
SOF+RBV 
IF YES 
8 weeks 
No study treatment – 
continue study followup 
for 24 weeks 
Group 2 
SOF+RBV 
IF NO 
12 weeks 
No study treatment – 
continue study followup 
for 24 weeks 
 
Everyone who enters the study will take SOF and RBV, which will be given for free by the study. 
Anti-HIV drugs will not be provided by the study. Note that if you stop taking SOF, you must also 
stop taking RBV. 


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While you are in this study, you will need to be seen in the clinic about 11 times during the 
study. The study staff will tell you about how long each visit could be. You may need to come to 
the clinic if you have side effects or if you switch or take new anti-HIV drugs. More information 
about the study tests is given below. During the study, you will get the results from any routine 
tests that are done during the study when they are available. 
 
You must fast for the screening, week 4 on-treatment, end of treatment (week 8 or 12), week 12 
post treatment, and early treatment/study discontinuation visits. You may also have to fast for 
the entry visit; the study staff will inform you if you must fast for the entry visit. (Fasting 
means that you should not eat or drink anything for at least 8 hours before your visit. You may 
only drink water and take your prescription medications during this time. If your medications 
require food, the study staff will talk to you about how you should take your medications.) The 
study staff will remind you to fast before each of these study visits. If you do not fast before 
these visits, you will be asked to come back later for these tests after fasting. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not qualify to take part in this study, we 
will still use some of your information. As part of the screening visit, some demographic (for 
example, age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
(for example, CD4+ T-cell count, viral load) information is being collected from you so that 
ACTG researchers may see if there are patterns or common reasons why people do not join a 
study. 
 
Required Tests 
Your blood will be drawn from a vein in your arm and used to measure your HCV and HIV viral 
load (the amount of HCV and HIV in your blood) and genotype (genetic makeup of the virus), to 
measure your CD4+/CD8+ cell counts (these are cells in your blood that fight infection), to 
measure levels of certain hormones (hormones are chemicals in your blood), and for routine 
safety tests and metabolic tests (to test how your body uses the food that you eat). You will be 
told the results of these tests when they become available. 
 
Some of your blood will also be stored (with no information that will identify you) and used for 
future HCV/HIV resistance tests required for this study. A resistance test is used to determine if 
the HCV/HIV viruses still respond to your medications. In addition, some of this blood will be 
used to understand how the drugs interact with your body and how your body responds to the 
drugs. 
Any remaining blood will be stored for future testing required by the study. 
Additional Tests 
If you agree, your blood will be drawn and used for future testing. Results of testing done on 
these samples may not be given to you because they will be done in the future. 
 
Please initial below if you agree to have any of your blood used for future ACTG-approved 
research. You may change your mind at any time and your samples will be destroyed. 
 
  
YES 
  
NO 


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Genetic (the message in your DNA) testing 
If you agree, your blood will be drawn and used to examine different genes (pieces of your 
DNA). Results of testing done on these samples may not be given to you because they will be 
done in the future. 
 
Please initial below if you agree to have any of your blood used for ACTG-approved genetic 
testing. You may change your mind at any time and your samples will be destroyed. 
 
  
YES 
  
NO 
 
Optional Tests 
If you agree, any blood left over after all required study testing is done may be stored (with no 
information that will identify you) and used for future ACTG-approved research. These blood 
samples may be stored for an unknown period of time. Results of testing done on these 
samples may not be given to you because they will be done in the future. 
 
Please initial below if you agree to have any of your leftover blood used for future ACTG- 
approved research. You may change your mind at any time and reasonable efforts will be made 
to destroy your samples, though this may not always be possible. 
 
  
YES 
  
NO 
 
A5327 Study Visits 
The study staff can answer any questions you have about individual study visits, the evaluations 
that will occur, or how long each visit will be. The table below can be used as a quick reference 
for you, along with the explanations that follow. 
 
I. Study Schedule 
 
Evaluation or 
test 
Screen Pre-Entry Entry 
Post-Entry Visits 
Other 
Visits 
Early 
discontinuation 
On-treat- 
ment Visits 
End of 
treatment 
Off-treat- 
ment Visits 
Consent 
✓
 
Clinical 
assessments 
✓
 
✓
 
✓
 
✓
 
✓
 
✓
 
ECG 
✓
 
Samples 
collection & 
laboratory 
testing 
✓
 If required ✓
 
✓
 
✓
 
✓
 
✓
 
✓
 
Urine sample 
✓
 
Pregnancy test ✓
 
✓
 ✓
 
✓
 
✓
 
✓
 
✓
 
✓
 


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Evaluation or 
test 
Screen Pre-Entry Entry 
Post-Entry Visits 
Other 
Visits 
Early 
discontinuation 
On-treat- 
ment Visits 
End of 
treatment 
Off-treat- 
ment Visits 
Pharmacokinetic 
(PK) studies 
✓
 
✓
 
✓
 
✓
 
✓
 
✓
 
Pregnancy 
prevention 
counseling 
✓
 
✓
 
✓
 
✓
 
✓
 
Adherence 
assessments 
✓
 
✓
 
✓
 
Study drugs 
distribution and 
storage 
✓
 At week 4 
At week 8 
for groups 
1 and 2 
on 12-wk 
tx    
schedule 
 
II. Description of Study Visits 
Screening 
After you have read and signed the consent form, you will be asked questions about your 
health, medical history, and medication history. You will have several tests, including blood 
tests, to make sure that you qualify to join the study. Some of the blood taken will be 
shipped to a testing lab. Your new HCV infection and how long you’ve been infected will be 
confirmed. You must come to the visit fasting. If you are not fasting within the past 8 hours 
before this visit, you will be asked to come back fasting. Also, an electrocardiogram (ECG) 
will be done at this visit. 
If you are a female, you will have blood or urine taken for pregnancy testing. 
Pre-entry 
You may be asked to return to the study clinic to have a repeat HCV viral load to confirm 
that you still have the infection. If you do still have the infection, you will come back for the 
entry visit. If you do not have evidence of ongoing infection, you will not enter the study. You 
will be referred back to your doctor for followup to ensure the virus does not come back. If 
you are a female, you will have blood or urine taken for pregnancy testing. 
 
Entry 
When all of the results from your screening tests are available, you will come back to the 
clinic to have a few tests done before starting the study. You will have urine and blood 
samples collected for routine safety tests. If you are a female, you will be asked to provide 
blood or urine sample for pregnancy testing. You may need to come to the clinic fasting 
for this visit (fasting means that you should not eat or drink anything for at least 8 
hours before your visit). The study staff will inform you before the entry visit if you 
have to be fasting. If you are not fasting within the past 8 hours before this visit, you will be 
asked to come back fasting. 


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At this visit, you will get your study drugs. The study staff will give you enough study drugs to 
last until the week 4 visit. You should take RBV and SOF with food. At each visit, you must 
return any remaining study drug from the previous visit. If you forget to take SOF at the 
correct time, it may be taken later in the day; however, no more than a single daily dose 
(400 mg dose) of SOF should be taken on any calendar day. You should never cut or split 
your study medications. If you miss a dose of RBV, then you should take the missed dose 
as soon as possible with food during the same day. If an entire day has gone by, then you 
should skip the missed dose, and then you should go back to your normal dosing schedule. 
You do not double the next dose in order to "make up" what has been missed. 
You will have an extra evaluation (pharmacokinetic [PK] testing) done at the entry visit. This 
evaluation is described below. 
 
Post-entry visits 
You will be seen at treatment weeks 1, 2, 4, 8, and 12 (unless treatment is only planned for 
8 weeks total) AND at post-treatment weeks 2, 4, 8, 12, and 24 after taking the last dose of 
study drugs. These visits will last about 1-1½ hours each. 
 
If you are a woman, you will be asked to provide blood or urine sample for pregnancy 
testing. 
 
Other visits 
During the study, you may have to come back to the clinic for extra visits for testing of any 
lab results that are not normal, or to followup on a specific side effect or symptom. 
 
Virologic Failure Confirmation 
If laboratory tests show there is evidence of virologic failure (which is detectable HCV when 
you were previously undetectable or your virus has not gone down as quickly as expected), 
you will be asked to return to the clinic to confirm your lab results. If virologic failure is 
confirmed, you will then complete an early discontinuation study visit as described below. 
 
Early discontinuation 
There are two types of discontinuation (stopping study treatment or leaving the study early) 
in which you will be asked to come to the clinic for an extra visit in a fasting state. 
 
1. Stop study treatment early 
You or your doctor may decide to stop the study medication that you began at entry. 
 
If you must stop taking the study medication early, the study doctor may ask you to stay 
in the study and come in for some tests. 
 
2. Leave study early 
You or your doctor decides that you will no longer stay in the study or you are notified 
the study is stopped early. You will be asked to complete some evaluations before being 
taken off the study. 


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III. Description of Study Evaluations 
Consent 
After you read the consent form and have had a chance to ask questions about the study, 
you will sign the consent form if you want to continue to be tested to see if you qualify for the 
study. 
 
Clinical Assessments 
You will have the following clinical evaluations in this study: 
 
Physical examination 
You will have a physical exam. The study staff will check the different systems in your 
body such as head, neck, eyes, ears, nose, throat, mouth and tongue, chest (excluding 
breasts) for respiratory, heart for cardiovascular, abdomen, skin, hair, nails, and muscles 
and joints. The study staff will also check your vital signs such as temperature, pulse, 
blood pressure, and respiratory rate, and your height and weight will be recorded. 
 
Medical and medication history 
You will be asked questions about your health and about any medicines you have taken 
or are taking now. Once you are on treatment, you will be asked about any signs or 
symptoms that you are experiencing and any changes in other medications that you 
have had since your last visit. 
 
Electrocardiogram 
You will have an electrocardiogram (ECG) done. An ECG is a test to measure the 
heartbeat. An ECG machine will be used to do an electrical tracing of your heart that can 
show how hard it is working. You will have to lie very still for at least 5 minutes while the 
ECG is being done. 
 
Sample collections and laboratory testing 
You will have the following samples collected and tested in this study: 
 
Blood collected 
Blood will be taken from a vein in your arm for various tests during the study. 
Approximately 144 mL (10 tablespoons) of blood will be drawn during any study visit. 
These may include: routine safety lab tests such as kidney and liver function, HIV viral 
load (a test that shows how much HIV is in your blood), CD4+/CD8+ counts (a test that 
shows how many infection-fighting cells you have in your blood), HCV viral load (a test 
that shows how much HCV is in your blood). 
 
You will be asked to fast before some of the visits. This means that you should not eat or 
drink anything except prescription drugs and water for at least 8 hours before the visit. 
 
Resistance testing 
Blood will be drawn and stored for future HCV/HIV resistance testing that is required for 
this study. A resistance test is used to determine if the HCV/HIV viruses still respond to 
your medications. 


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Genetic testing 
If you agree blood will be drawn for testing your genes (pieces of your DNA) to 
understand if you naturally were born with a better or worse chance of responding to the 
medications. Some of your blood cells will also be tested to see if your responsiveness 
to the therapy is associated with different genes related to IFN use. An IFN is an antiviral 
compound that is produced in response to many types of infections. You will not receive 
the results of these studies because they will be done in the future. 
 
PK Studies 
Blood will be drawn to measure the levels of the study drugs in your blood and to 
understand how the drugs interact with your body and how your body responds to the 
drugs. 
 
Urinalysis 
Urine samples will be collected for routine safety tests. 
 
Pregnancy test 
If you are a woman, you will have blood or urine taken prior to study entry. After you 
enter the study, you will be asked to provide blood or urine samples for pregnancy 
testing. 
 
Pregnancy prevention counseling 
All participants, male and female, will be counseled on the risk of the study drugs in 
pregnancy and on how to prevent pregnancy. 
 
Adherence assessments 
You will be asked about how well you take your medications. The study staff will give you 
information and encouragement to help you take your medications as prescribed. 
 
Study drugs distribution and storage 
You will be given a 4-week supply of study medications at entry, week 4, and at week 8 (for 
a 12-week treatment). You will be asked to store the study medications as instructed in the 
medicine bottle label. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
the study is cancelled. 
• 
a Study Monitoring Committee (SMC) recommends that the study be stopped early (A SMC 
is an outside group of experts who monitor the study). 
• 
your doctor thinks the study is no longer in your best interest. 
• 
the site investigator thinks that you are at significant risk of failing to comply with the 
requirements of the protocol. 


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The study doctor may also need to take you off the study drugs without your permission if: 
• 
you experience HCV treatment failure. 
• 
you or a female partner of a male participant become pregnant. 
• 
you are breastfeeding. 
• 
continuing the study drugs may be harmful to you. 
• 
you need a treatment that you may not take while on the study. 
• 
you are not able to take the study drugs as required by the study. 
• 
you do not have, or are not able to, have required study visits and evaluations 
 
If you must stop taking the study drugs earlier than indicated by the study, the study doctor will 
ask you to remain on the study and complete the post discontinuation visits at 2 weeks, 4 
weeks, 8 weeks, 12 weeks, and 24 weeks from the date that you took the last dose of study 
treatment. Note that if you stop taking SOF, you must also stop taking RBV. 
 
If I have to permanently stop taking study drugs through the study, or once I leave the study, 
how can I get study drugs? 
If you must permanently stop taking SOF and RBV before the study is over, the study staff will 
talk with you about other options. 
 
After you have finished the study, you will not be able to get SOF and RBV through the study. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, it is 
possible that others could find out that you are participating in this study and that social harm 
may result (because you could become labeled as being infected with HIV and/or HCV). For 
example, you could be treated unfairly or discriminated against by family members, friends, 
and/or the community. 
 
Risks of Drawing Blood 
Drawing blood may cause some discomfort, lightheadedness, bleeding, swelling, or bruising 
where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risks of Study Drugs 
For those persons taking HIV medicines, there is no clear risk of drug interactions between HIV 
medicines and SOF. Although SOF has not been studied with all HIV medicines, it has been 
studied with all first-line HIV medication drug classes and there are no recognized clinically 
significant interactions. 
 
Drug interactions that increase the levels of medicine in your blood may increase the chances of 
side effects. Drug interactions that lower the levels of SOF in your blood may decrease your 
chances for a cure of hepatitis C and/or cause drug resistance. To date only two out of over 
3,000 patients have developed resistance to SOF, this risk is thought to be extremely low. Drug 
interactions that lower the levels of HIV medicines in your blood could cause drug resistance, 
meaning the drugs no longer work to prevent virus from reproducing. 


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Drug resistance may also prevent other medicines from working in the future. HIV viral load will 
be monitored regularly to ensure that evidence of early failure of the HIV regimen is identified 
quickly. In addition, multiple drug interactions studies have been completed to ensure that HIV 
medications can be safely dosed with SOF, and there is no evidence to suggest that 
concomitant dosing with SOF and any antiretroviral allowed in this study will lead to HIV 
regimen failure. The risk is thought to be very low. 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning study drug side effects please ask the medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Sofosbuvir (SOF) 
• 
Depression 
• 
Irritability 
• 
Sleep disturbances 
• 
Tiredness 
• 
Muscle pain 
• 
Headaches 
• 
Chills 
• 
Nausea and vomiting 
• 
Stomach pain 
• 
Rash 
• 
Anemia 
• 
Lymphopenia 
• 
Itching 
• 
Loss of appetite 
• 
Diarrhea 
• 
Dizziness 
• 
Elevated liver function tests 
 
Ribavirin (RBV) 
• 
Anemia. Anemia can worsen existing heart and pulmonary (lung) conditions. 
• 
Temporary changes in blood platelet levels 
• 
Temporary changes in liver function tests (a measure of your liver activity) 
• 
Stomach and intestinal 
• 
Nausea 
• 
Vomiting 
• 
Indigestion 


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• 
Stomach discomfort 
• 
Skin disorders 
• 
Upper respiratory tract inflammation 
• 
Teratogenicity (risk to an unborn baby) 
• 
Nervous system 
• 
Depression 
• 
Insomnia (inability to sleep) 
• 
Nervousness 
• 
Skin tingling 
• 
Drowsiness 
• 
Light-headedness 
• 
Hyperuricemia (excess of uric acid in blood which can lead to gout, a painful swelling of 
joints and may lead to kidney disease). 
 
NOTE: There are reports indicating that HIV-infected people taking treatment for HIV and HCV 
have developed high lactate (an acid that can build up in the bloodstream and cause 
life-threatening illness) levels with worsening liver disease. It is not clear if RBV is the 
cause. This may be more common if RBV is taken with didanosine (ddI, Videx) for HIV 
infection. There may be an increased risk of inflammation of the pancreas when 
didanosine is taken with RBV. Because of these risks, didanosine use is not allowed in 
this study. 
 
 
ARE THERE RISKS RELATED TO DELAYING HIV THERAPY? 
 
You are not required to be on HIV medications to enter this study. If you are not on HIV 
medications at the time of your HCV infection and you and your doctor do not think you need to 
start HIV medications, we will not exclude you from the study. We also do not recommend 
delaying HIV medications for entry into the study if your doctor feels they are medically 
necessary. Although the dosing period of the HCV medications is short, a delay in necessary 
HIV medications could allow for progression of HIV disease, which can increase your risk of 
opportunistic infections and long-term after effects of HIV infection. If you have any concerns 
about these risks, we suggest that you discuss them with your provider. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drugs or drug combinations in this study may be unsafe for unborn babies. If you are having 
sex that could lead to pregnancy, you must agree not to become pregnant or make a woman 
pregnant. Note that if you become pregnant or your partner becomes pregnant, study drugs will 
be stopped and you will be followed after delivery. 
 
Because of the risk involved, you and your partner must use at least two methods of birth 
control that you discuss with the study staff. You must continue to use both methods until 6 
months after stopping study drugs. You must choose two or more of the birth control methods 
listed below: 
• 
A condom (male or female) with or without a spermicide 


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• 
Diaphragm or cervical cap with spermicide 
• 
An intrauterine device (IUD) 
• 
Tubal ligation 
• 
Hormone-based contraceptives (except those containing drospirernone) 
 
If you can become pregnant, you must have a pregnancy test within 72 hours before starting the 
study drugs. The test must show that you are not pregnant. Pregnancy tests will also be 
performed at most study visits. 
 
Some of the methods listed above may not prevent the spread of HIV to other people. You 
should discuss your contraceptive choices with your health care provider to choose the best 
way for you to both prevent pregnancy as required by this study and to prevent the spread of 
HIV to your partner. 
 
If you think you or your partner may be pregnant at any time during the study, tell your study 
staff right away. Pregnancy will result in immediate discontinuation of the study drugs, and 
counseling on RBV’s teratogenicity (ability to cause birth defects). You will be followed on study, 
including male participants whose partners become pregnant, until study completion. You will be 
asked to return to the clinic 6 months after the end of your pregnancy to follow up on any side 
effects. Male participants whose partners become pregnant will have treatment discontinued 
and the same followup visit at 6 months after their partner’s delivery as outlined for pregnant 
women. Pregnancies will be reported to the Ribavirin Pregnancy Registry. In addition, 
pregnancy complications and/or pregnancies outcomes will be reported to the Antiretroviral 
Pregnancy Registry. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you. Your health may be watched 
more closely than usual while you are on the study, which may help you to feel better. It is also 
possible that you may receive no benefit from being in this study. Information learned from this 
study may help others who have HIV and HCV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, you have the choice of: 
• 
treatment with prescription drugs currently available to you 
• 
treatment with other experimental drugs, if you qualify 
• 
no treatment; some people may clear the HCV infection on their own over the first year of 
infection, although over 9 in 10 people clear in the first 12 weeks of the new infection 
 
Please talk to your doctor about these and other treatment choices available to you and the 
risks and benefits of these choices. 


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WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the U.S. Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally. 
 
People who may review your records include the ACTG, Office for Human Research Protection, 
your site’s institutional review board (a committee that makes sure that your rights and safety 
are protected while in the study), National Institutes of Health (NIH), study staff, study monitors, 
and other government agencies as part of their duties, and the pharmaceutical company 
supporting this study. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov. This Web site will 
not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time. [Sites: Per US federal regulations, this 
language cannot be modified.] 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drugs, the study visits, physical examinations, 
laboratory tests or other tests required by the study. You or your insurance company, or your 
health care system will be responsible for the costs of your regular medical care as well as for 
the costs of drugs not given by the study. 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Sites: Please indicate whether you will provide payment to subjects. If so, please describe the 
amount to be paid or reimbursed, the payment schedule, and any prorated schedule should the 
subject decide to withdraw or is withdrawn early by the investigator.] 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of taking part in this study, you will be given treatment right away 
for your injuries and be referred for further treatment, if necessary. However, you or your 
insurance company may have to pay for this care. There is no program for compensation either 


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through this institution or the NIH. You will not be giving up any of your legal rights by signing 
this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 
you decide not to take part. Your decision will not affect other studies done by NIH in which you 
may be taking part, and will not lead to any penalty or loss of benefits that you have the right to 
expect. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or decision to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
name of the investigator or other study staff 
• 
telephone number of above 
 
For questions about your rights as a research subject, contact: 
 
• 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
telephone number of above 


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SIGNATURE PAGE ACTG Study A5327 FOR COHORT 1 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
 
Subject’s Name (print) 
Subject’s Signature and Date 
 
 
 
 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print) 
 
 
 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 


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APPENDIX III 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT FOR COHORT 2 
For protocol: A5327 
 
Final Version 2.0, 07/02/15: Sofosbuvir-Containing Regimens Without Interferon For 
Treatment of Acute HCV in HIV-1 Infected Individuals (SWIFT-C) 
 
SHORT TITLE FOR THE STUDY: A5327/SWIFT-C Final Version 2.0, 07/02/15, SOF 
Regimens Without IFN For Treatment of Acute HCV Infection 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with HIV 
(the virus that causes AIDS) and you have also recently been infected with the hepatitis C 
virus (HCV, a virus that affects the liver). This study is sponsored by the National 
Institutes of Health. The doctor in charge of this study at this site is: (insert name of 
Principal Investigator). Before you decide if you want to be a part of this study, we want 
you to know about the study. 
 
This is a consent form. It gives you information about this study. The study staff will talk 
with you about this information. You are free to ask questions about this study at any 
time. If you agree to take part in this study, you will be asked to sign this consent form. 
You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
People who are recently infected with HCV have a great chance of being cured of the 
infection when they are treated with a combination of two drugs within the first 6 months 
of being infected. This study is being done to see if a combination of two new drugs in 
one pill can replace the old drugs to provide a safer, more effective, and better tolerated 
treatment for new HCV infection. The names of the new drugs are ledipasvir (LDV) and 
sofosbuvir (SOF), and they will replace pegylated-interferon alfa (PEG-IFN, a drug given 
as a weekly injection under the skin) and ribavirin (RBV). 
 
The fixed-dose combination of LDV and SOF (LDV/SOF) has been approved by the Food 
and Drug Administration (FDA) for the treatment of chronic HCV genotype 1 in people 
who do not have HIV. HCV genotype 1 is the most common HCV infection in the United 
States. LDV/SOF has also been studied in people with HIV and chronic HCV and was 
found to be safe and effective. 
 
This study started with participants in Group 1 receiving SOF in combination with RBV, a 
drug also approved by the FDA, for 12 weeks. There were a total of 17 participants in 


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APPENDIX III (Cont'd) 
 
 
Group 1 and all completed treatment. All participants were monitored for safety and viral 
response while on treatment. After completing treatment, all participants were evaluated 
for a treatment response after the end of treatment. 
 
If the treatment response in Group 1 was high enough, the study design allowed for the 
possibility to decrease the length of therapy for Group 2 to 8 weeks, using the same 
treatment. However, this did not occur. Combined with the fact that a new and more 
effective treatment for chronic HCV has been approved since the study started, Group 2 
will now receive 8 weeks of LDV/SOF instead of 12 weeks of SOF with RBV. 
 
 
HOW MANY PEOPLE WILL BE IN THIS STUDY? 
 
About 27 people (men and women age 18 years and older) will take part in Group 2 of this 
study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for approximately 32 weeks. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to join this study, you will continue taking your current anti-HIV drugs if you 
are receiving them. If you are not currently on HIV medications and your provider does 
not think you need HIV medications during the study that is also acceptable. You will 
participate in Group 2 and will take LDV/SOF (a pill taken once daily by mouth) for 8 
weeks. You will be given the medications at your study visits to take home, and you will 
need to store the medications in a safe place at room temperature. After you have 
completed 8 weeks of treatment with LDV/SOF, you will continue to have follow-up visits 
for 24 weeks. 
 
Everyone who enters the study will take LDV/SOF, which will be given for free by the 
study. Anti-HIV drugs will not be provided by the study. 
 
While you are in this study, you will need to be seen in the clinic about 10 times during 
the study. The study staff will tell you about how long each visit could be. You may need 
to come to the clinic if you have side effects or if you switch or take new anti-HIV drugs. 
More information about the study tests is given below. During the study, you will get the 
results from any routine tests that are done during the study when they are available. 
 
You must fast for the screening, week 4 on-treatment, end of treatment (week 8), week 12 
post treatment, and early treatment/study discontinuation visits. You may also have to 
fast for the entry visit; the study staff will inform you if you must fast for the entry visit. 
(Fasting means that you should not eat or drink anything for at least 8 hours before your 
visit. You may only drink water and take your prescription medications during this time. 


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APPENDIX III (Cont'd) 
 
 
If your medications require food, the study staff will talk to you about how you should 
take your medications.) The study staff will remind you to fast before each of these study 
visits. If you do not fast before these visits, you will be asked to come back later for 
these tests after fasting. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not qualify to take part in this 
study, we will still use some of your information. As part of the screening visit, some 
demographic (for example, age, gender, race), clinical (for example, disease condition, 
diagnosis), and laboratory (for example, CD4+ T-cell count, viral load) information is 
being collected from you so that ACTG researchers may see if there are patterns or 
common reasons why people do not join a study. 
 
Required Tests 
Your blood will be drawn from a vein in your arm and used to measure your HCV and HIV 
viral load (the amount of HCV and HIV in your blood) and genotype (genetic makeup of 
the virus), to measure your CD4+/CD8+ cell counts (these are cells in your blood that 
fight infection), to measure levels of certain hormones (hormones are chemicals in your 
blood), and for routine safety tests and metabolic tests (to test how your body uses the 
food that you eat). You will also have a urine test. You will be told the results of these 
tests when they become available. 
 
Some of your blood will also be stored (with no information that will identify you) and 
used for future HCV/HIV resistance tests required for this study. A resistance test is used 
to determine if the HCV/HIV viruses still respond to your medications. In addition, some 
of this blood will be used to understand how the drugs interact with your body and how 
your body responds to the drugs. 
Any remaining blood will be stored for future testing required by the study. 
Additional Tests 
If you agree, your blood will be drawn and used for future testing. Results of testing done 
on these samples may not be given to you because they will be done in the future. 
 
Please initial below if you agree to have any of your blood used for future ACTG- 
approved research. You may change your mind at any time and your samples will be 
destroyed. 
 
  
YES 
  
NO 
 
Genetic (the message in your DNA) testing 
If you agree, your blood will be drawn and used to examine different genes (pieces of 
your DNA). Results of testing done on these samples may not be given to you because 
they will be done in the future. 


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APPENDIX III (Cont'd) 
 
 
Please initial below if you agree to have any of your blood used for ACTG-approved 
genetic testing. You may change your mind at any time and your samples will be 
destroyed. 
 
  
YES 
  
NO 
 
Optional Tests 
If you agree, any blood left over after all required study testing is done may be stored 
(with no information that will identify you) and used for future ACTG-approved research. 
These blood samples may be stored for an unknown period of time. Results of testing 
done on these samples may not be given to you because they will be done in the future. 
 
Please initial below if you agree to have any of your leftover blood used for future ACTG- 
approved research. You may change your mind at any time and reasonable efforts will be 
made to destroy your samples, though this may not always be possible. 
 
  
YES 
  
NO 
 
A5327 Group 2 Study Visits 
The study staff can answer any questions you have about individual study visits, the 
evaluations that will occur, or how long each visit will be. The table below can be used as 
a quick reference for you, along with the explanations that follow. 
 
I. Study Schedule 
 
Evaluation or 
test 
Screen 
Pre- 
Entry 
Entry 
Post-Entry Visits 
Other 
Visits 
Early 
discontinuation 
On- 
treatment 
Visits 
End of 
treatment 
Off- 
treatment 
Visits 
Consent 
✓
 
Clinical 
assessments 
✓
 
✓
 
✓
 
✓
 
✓
 
✓
 
ECG 
✓
 
Samples 
collection & 
laboratory 
testing 
✓
 
If 
required ✓
 
✓
 
✓
 
✓
 
✓
✓
 
Urine sample 
✓
 
✓
 
✓
 
✓
 
✓
 
Pregnancy test ✓
 
✓
 ✓
 
✓
 
✓
 
✓
 
✓
✓
 
Pharmacokinetic 
(PK) studies 
✓
 
✓
 
✓
 
✓
 
✓
✓
 
Pregnancy 
prevention 
counseling 
✓
 
✓
 
✓
 
✓
 
✓
 


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APPENDIX III (Cont'd) 
 
 
Evaluation or 
test 
Screen 
Pre- 
Entry 
Entry 
Post-Entry Visits 
Other 
Visits 
Early 
discontinuation 
On- 
treatment 
Visits 
End of 
treatment 
Off- 
treatment 
Visits 
Adherence 
assessments 
✓
 
✓
 
✓
 
Study drugs 
distribution and 
storage 
✓
 
 
II. Description of Study Visits 
 
Screening 
After you have read and signed the consent form, you will be asked questions about 
your health, medical history, and medication history. You will have several tests, 
including blood tests, to make sure that you qualify to join the study. Some of the 
blood taken will be shipped to a testing lab. Your new HCV infection and how long 
you’ve been infected will be confirmed. You must come to the visit fasting. If you are 
not fasting within the past 8 hours before this visit, you will be asked to come back 
fasting. Also, an electrocardiogram (ECG) will be done at this visit. 
If you are a female, you will have blood or urine taken for pregnancy testing. 
Pre-entry 
You may be asked to return to the study clinic to have a repeat HCV viral load to 
confirm that you still have the infection. If you do still have the infection, you will 
come back for the entry visit. If you do not have evidence of ongoing infection, you 
will not enter the study. You will be referred back to your doctor for followup to 
ensure the virus does not come back. If you are a female, you will have blood or urine 
taken for pregnancy testing. 
 
Entry 
When all of the results from your screening tests are available, you will come back to 
the clinic to have a few tests done before starting the study. You will have urine and 
blood samples collected for routine safety tests. If you are a female, you will be asked 
to provide blood or urine sample for pregnancy testing. You may need to come to the 
clinic fasting for this visit (fasting means that you should not eat or drink anything for 
at least 8 hours before your visit). The study staff will inform you before the entry visit 
if you have to be fasting. If you are not fasting within the past 8 hours before this 
visit, you will be asked to come back fasting. 
 
At this visit, you will get your study drugs. The study staff will give you enough study 
drugs to last until the week 8 visit. You do not need to take the study drugs with food. 
If you forget to take the study drugs at the correct time, it may be taken later in the 
day. Then the next day you should continue with the usual schedule that you take the 
study drugs. You should never cut or split your study medications. 


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APPENDIX III (Cont'd) 
 
 
 
You will have an extra evaluation (pharmacokinetic [PK] testing) done at the entry 
visit. This evaluation is described below. 
 
Post-entry visits 
You will be seen at treatment weeks 1, 2, 4, and 8 (end of treatment) AND at post- 
treatment weeks 2, 4, 8, 12, and 24 after taking the last dose of study drugs. These 
visits will last about 1-1½ hours each. 
 
You must return any remaining study drug during the post-treatment visits. 
 
If you are a woman, you will be asked to provide blood or urine sample for pregnancy 
testing. 
 
Other visits 
During the study, you may have to come back to the clinic for extra visits for testing 
of any lab results that are not normal, or to followup on a specific side effect or 
symptom. 
 
Virologic Failure Confirmation 
If laboratory tests show there is evidence of virologic failure (which is detectable HCV 
when you were previously undetectable or your virus has not gone down as quickly 
as expected), you will be asked to return to the clinic to confirm your lab results. If 
virologic failure is confirmed, you will then complete an early discontinuation study 
visit as described below. 
 
Early discontinuation 
There are two types of discontinuation (stopping study treatment or leaving the study 
early) in which you will be asked to come to the clinic for an extra visit in a fasting 
state. 
 
1. Stop study treatment early 
You or your doctor may decide to stop the study medication that you began at 
entry. 
 
If you must stop taking the study medication early, the study doctor may ask you 
to stay in the study and come in for some tests. 
 
2. Leave study early 
You or your doctor decides that you will no longer stay in the study or you are 
notified the study is stopped early. You will be asked to complete some 
evaluations before being taken off the study. 


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APPENDIX III (Cont'd) 
 
 
III. Description of Study Evaluations 
 
Consent 
After you read the consent form and have had a chance to ask questions about the 
study, you will sign the consent form if you want to continue to be tested to see if you 
qualify for the study. 
 
Clinical Assessments 
You will have the following clinical evaluations in this study: 
 
Physical examination 
You will have a physical exam. The study staff will check the different systems in 
your body such as head, neck, eyes, ears, nose, throat, mouth and tongue, chest 
(excluding breasts) for respiratory, heart for cardiovascular, abdomen, skin, hair, 
nails, and muscles and joints. The study staff will also check your vital signs such 
as temperature, pulse, blood pressure, and respiratory rate, and your height and 
weight will be recorded. 
 
Medical and medication history 
You will be asked questions about your health and about any medicines you have 
taken or are taking now. Once you are on treatment, you will be asked about any 
signs or symptoms that you are experiencing and any changes in other 
medications that you have had since your last visit. 
 
Electrocardiogram 
You will have an electrocardiogram (ECG) done. An ECG is a test to measure the 
heartbeat. An ECG machine will be used to do an electrical tracing of your heart 
that can show how hard it is working. You will have to lie very still for at least 5 
minutes while the ECG is being done. 
 
Sample collections and laboratory testing 
You will have the following samples collected and tested in this study: 
 
Blood collected 
Blood will be taken from a vein in your arm for various tests during the study. 
Approximately 144 mL (10 tablespoons) of blood will be drawn during any study 
visit. These may include: routine safety lab tests such as kidney and liver 
function, HIV viral load (a test that shows how much HIV is in your blood), 
CD4+/CD8+ counts (a test that shows how many infection-fighting cells you have 
in your blood), HCV viral load (a test that shows how much HCV is in your blood). 
 
You will be asked to fast before some of the visits. This means that you should 
not eat or drink anything except prescription drugs and water for at least 8 hours 
before the visit. 


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APPENDIX III (Cont'd) 
 
 
Resistance testing 
Blood will be drawn and stored for future HCV/HIV resistance testing that is 
required for this study. A resistance test is used to determine if the HCV/HIV 
viruses still respond to your medications. 
 
Genetic testing 
If you agree blood will be drawn for testing your genes (pieces of your DNA) to 
understand if you naturally were born with a better or worse chance of responding 
to the medications. Some of your blood cells will also be tested to see if your 
responsiveness to the therapy is associated with different genes related to IFN 
use. An IFN is an antiviral compound that is produced in response to many types 
of infections. You will not receive the results of these studies because they will be 
done in the future. 
 
PK Studies 
Blood will be drawn to measure the levels of the study drugs in your blood and to 
understand how the drugs interact with your body and how your body responds 
to the drugs. 
 
Urinalysis 
Urine samples will be collected for routine safety tests. 
 
Pregnancy test 
If you are a woman, you will have blood or urine taken prior to study entry. After 
you enter the study, you will be asked to provide blood or urine samples for 
pregnancy testing. 
 
Pregnancy prevention counseling 
All participants, male and female, will be counseled on the risk of the study drugs in 
pregnancy and on how to prevent pregnancy. 
 
Adherence assessments 
You will be asked about how well you take your medications. The study staff will give 
you information and encouragement to help you take your medications as prescribed. 
 
Study drugs distribution and storage 
You will be given an 8-week supply of study drugs at entry. You will be asked to store 
the study drugs as instructed on the medicine bottle label. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
the study is cancelled. 
• 
a Study Monitoring Committee (SMC) recommends that the study be stopped early 
(An SMC is an outside group of experts who monitor the study for safety). 
• 
your doctor thinks the study is no longer in your best interest. 


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• 
the site investigator thinks that you are at significant risk of failing to comply with the 
requirements of the protocol. 
 
The study doctor may also need to take you off the study drugs without your permission 
if: 
• 
you experience HCV treatment failure. 
• 
you become pregnant. 
• 
you are breastfeeding. 
• 
continuing the study drugs may be harmful to you. 
• 
you need a treatment that you may not take while on the study. 
• 
you are not able to take the study drugs as required by the study. 
• 
you do not have, or are not able to, have required study visits and evaluations 
 
If you must stop taking the study drugs earlier than indicated by the study, the study 
doctor will ask you to remain on the study and complete the post discontinuation visits 
at 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks from the date that you took the 
last dose of study treatment. 
 
If I have to permanently stop taking study drugs through the study, or once I leave the 
study, how can I get study drugs? 
If you must permanently stop taking study drugs before the study is over, the study staff 
will talk with you about other options. 
 
After you have finished the study, you will not be able to get FDC LDV/SOF through the 
study. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, 
it is possible that others could find out that you are participating in this study and that 
social harm may result (because you could become labeled as being infected with HIV 
and/or HCV). For example, you could be treated unfairly or discriminated against by 
family members, friends, and/or the community. 
 
Risks of Drawing Blood 
Drawing blood may cause some discomfort, lightheadedness, bleeding, swelling, or 
bruising where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risks of Study Drugs 
Drug interactions that increase the levels of medicine in your blood may increase the 
chances of side effects. Drug interactions that lower the levels of HIV medicines in your 
blood could cause drug resistance, meaning the drugs no longer work to prevent virus 
from reproducing. Drug interactions that lower the levels of SOF or LDV in your blood 
may decrease your chances for a cure of hepatitis C and/or cause drug resistance. 


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Bradycardia, or slow heart rate, may happen in persons who are taking amiodarone (a 
medicine that is used to treat heart rhythm problems) particularly for those also taking 
beta blockers (medications that reduce blood pressure) or those with a heart disorder 
and/or advanced liver disease. Because of this risk it is not recommended to take 
LDV/SOF with amiodarone and persons taking amiodarone will not be allowed to 
participate in this study. It is also not recommended to take LDV/SOF with other 
medicines that contain SOF. 
 
For those persons taking HIV medicines, there is no clear risk of drug interactions 
between HIV medicines and SOF. Although SOF has not been studied with all HIV 
medicines, it has been studied with all first-line HIV medication drug classes and there 
are no recognized clinically significant interactions. This is also true for LDV with the 
exception of one of the HIV medications named tenofovir (TFV). LDV increases TFV 
levels in your body. With most other HIV drug combinations this increase is not felt to 
lead to significant risk unless your kidneys don’t work normally. However, if TFV and 
LDV are used with HIV protease inhibitors that are combined with ritonavir (RTV) or with 
a drug named cobicistat (COBI), that is not an HIV drug but is used to increase the level 
of your HIV drugs in your blood stream, the potential risk of kidney toxicity may be 
higher. The combination of HIV protease inhibitors or COBI and LDV and TFV has not 
been studied in HIV-infected patients. For this reason there will be monitoring of the 
kidney function for all participants in this study. 
 
Drug resistance may prevent other medicines from working in the future. HIV viral load 
will be monitored regularly to ensure that evidence of early failure of the HIV regimen is 
identified quickly. In addition, multiple drug interactions studies have been completed to 
ensure that HIV medications can be safely dosed with SOF, and there is no evidence to 
suggest that giving SOF or LDV and any antiretroviral allowed in this study will lead to 
HIV regimen failure. The risk is thought to be very low. To date only two out of over 3,000 
patients have developed resistance to SOF, so this risk is also thought to be extremely 
low. Risk of resistance to LDV is high for patients who fail therapy, with most patients 
developing resistance. At this time the effect of resistance to LDV or similar medications 
is not clear, but it may increase the risk of other HCV treatments not working. 
 
The drugs used in this study may have side effects, some of which are listed below. 
Please note that these lists do not include all the side effects seen with these drugs. 
These lists include the more serious or common side effects with a known or possible 
relationship. If you have questions concerning study drug side effects please ask the 
medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications 
are taken with the study drugs. For your safety, you must tell the study doctor or nurse 
about all medications you are taking before you start the study and also before starting 
any new medications while on the study. Also, you must tell the study doctor or nurse 
before enrolling in any other clinical trials while on this study. 
 
Sofosbuvir (SOF) or Ledipasvir/sofosbuvir (LDV/SOF) 
• 
Depression 


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• 
Irritability 
• 
Sleep disturbances 
• 
Tiredness 
• 
Muscle pain 
• 
Headaches 
• 
Chills 
• 
Nausea and vomiting 
• 
Stomach pain 
• 
Rash 
• 
Anemia 
• 
Lymphopenia 
• 
Itching 
• 
Loss of appetite 
• 
Diarrhea 
• 
Dizziness 
• 
Elevated liver function tests 
 
ARE THERE RISKS RELATED TO DELAYING HIV THERAPY? 
 
You are not required to be on HIV medications to enter this study. If you are not on HIV 
medications at the time of your HCV infection and you and your doctor do not think you 
need to start HIV medications, we will not exclude you from the study. We also do not 
recommend delaying HIV medications for entry into the study if your doctor feels they 
are medically necessary. Although the dosing period of the HCV medications is short, a 
delay in necessary HIV medications could allow for progression of HIV disease, which 
can increase your risk of opportunistic infections and long-term after effects of HIV 
infection. If you have any concerns about these risks, we suggest that you discuss them 
with your provider. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drugs or drug combinations in this study may be unsafe for unborn babies. Although 
there is no evidence that these medications can result in birth defects, it is not 
recommended that you get pregnant during therapy. If you are having sex that could lead 
to pregnancy, you must agree not to become pregnant. Note that if you become 
pregnant, study drugs will be stopped and you will be followed after delivery. 
 
Because of the potential risk involved and due to the uncertainty of risk to the fetus, you 
and your partner must use at least two methods of birth control that you discuss with the 
study staff. You must continue to use both methods until 6 months after stopping study 
drugs. You must choose two or more of the birth control methods listed below: 
• 
A condom (male or female) with or without a spermicide 
• 
Diaphragm or cervical cap with spermicide 
• 
An intrauterine device (IUD) 


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• 
Tubal ligation 
• 
Hormone-based contraceptives 
 
If you can become pregnant, you must have a pregnancy test within 72 hours before 
starting the study drugs. The test must show that you are not pregnant. Pregnancy tests 
will also be performed at most study visits. 
 
Some of the methods listed above may not prevent the spread of HIV to other people. 
You should discuss your contraceptive choices with your health care provider to choose 
the best way for you to both prevent pregnancy as required by this study and to prevent 
the spread of HIV to your partner. 
 
If you think you may be pregnant at any time during the study, tell your study staff right 
away. Pregnancy will result in immediate discontinuation of the study drugs. You will be 
followed on study until study completion. You will be asked to return to the clinic 6 
months after the end of your pregnancy to follow up on any side effects. In addition, 
pregnancy complications and/or pregnancies outcomes will be reported to the 
Antiretroviral Pregnancy Registry. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you. Your health may be 
watched more closely than usual while you are on the study, which may help you to feel 
better. It is also possible that you may receive no benefit from being in this study. 
Information learned from this study may help others who have HIV and HCV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, you have the choice of: 
• 
treatment with prescription drugs currently available to you 
• 
treatment with other experimental drugs, if you qualify 
• 
no treatment; some people may clear the HCV infection on their own over the first 
year of infection, although over 9 in 10 people clear in the first 12 weeks of the new 
infection 
 
Please talk to your doctor about these and other treatment choices available to you and 
the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the 
study staff to help keep your personal information private, we have gotten a Certificate of 
Confidentiality from the U.S. Federal Government. This certificate means that 
researchers cannot be forced to tell people who are not connected with this study, such 


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as the court system, about your participation. Also, any publication of this study will not 
use your name or identify you personally. 
 
People who may review your records include the ACTG, Office for Human Research 
Protection, your site’s institutional review board (a committee that makes sure that your 
rights and safety are protected while in the study), National Institutes of Health (NIH), 
study staff, study monitors, and other government agencies as part of their duties, and 
the pharmaceutical company supporting this study. Having a Certificate of 
Confidentiality does not prevent you from releasing information about yourself and your 
participation in the study. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov. This Web 
site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drugs, the study visits, physical examinations, 
laboratory tests or other tests required by the study. You or your insurance company, or 
your health care system will be responsible for the costs of your regular medical care as 
well as for the costs of drugs not given by the study. 
 
Taking part in this study may lead to added costs to you and your insurance company. In 
some cases, it is possible that your insurance company will not pay for these costs 
because you are taking part in a research study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Sites: Please indicate whether you will provide payment to participants. If so, please 
describe the amount to be paid or reimbursed, the payment schedule, and any prorated 
schedule should the participant decide to withdraw or is withdrawn early by the 
investigator.] 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of taking part in this study, you will be given treatment right 
away for your injuries and be referred for further treatment, if necessary. However, you or 
your insurance company may have to pay for this care. There is no program for 
compensation either through this institution or the NIH. You will not be giving up any of 
your legal rights by signing this consent form. 


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WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this 
study or leave this study at any time. The care that you would normally receive will not 
be affected if you decide not to take part. Your decision will not affect other studies done 
by NIH in which you may be taking part, and will not lead to any penalty or loss of 
benefits that you have the right to expect. 
 
We will tell you about new information from this or other studies that may affect your 
health, welfare, or decision to stay in this study. If you want the results of the study, let 
the study staff know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
name of the investigator or other study staff 
• 
telephone number of above 
 
For questions about your rights as a research participant, contact: 
 
• 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
telephone number of above 


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SIGNATURE PAGE ACTG Study A5327 FOR COHORT 2 
 
If you have read this consent form (or had it explained to you), all your questions have 
been answered and you agree to take part in this study, please sign your name below. 
 
 
 
 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
 
 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print) 
 
 
 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 

SAP_000.pdf: 
This is ACTG A5327 Cohort 1 SAP Version 1.0 with names of authors, names of  
publication writing team and analysis timeline redacted. 
 
 
ACTG A5327  
Cohort 1 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Sofosbuvir Plus Ribavirin Without Interferon For Treatment of Acute 
HCV in HIV-1 infected Individuals (SWIFT-C) 
 
 
ClinicalTrials.gov Identifier: NCT02128217 
 
 
 
 
 
 
Version 1.0: 
July 7, 2014 
 
 
 


A5327 Statistical Analysis Plan Version 1.0   
 
 
 
July 7, 2014 
 
Table of Contents: 
 
1 
Introduction ........................................................................................................................ 4 
2 
Core Manuscript Writing Team ............................................ Error! Bookmark not defined. 
3 
Study Overview .................................................................................................................. 4 
3.1 
Study Schema ................................................................................................................................ 4 
3.2 
Hypothesis ..................................................................................................................................... 5 
3.3 
Primary Objectives ........................................................................................................................ 5 
3.4 
Secondary Objectives .................................................................................................................... 5 
3.5 
Visit and Evaluation Schedule ....................................................................................................... 6 
3.6 
A5327 Protocol History ................................................................................................................. 6 
3.7 
Monitoring .................................................................................................................................... 6 
3.7.1 
Ongoing Monitoring .............................................................................................................. 6 
3.7.2 
SMC Reviews ......................................................................................................................... 7 
3.8 
General Statistical Considerations ................................................................................................ 7 
4 
Accrual ............................................................................................................................... 8 
5 
Eligibility Violations and Exclusions .................................................................................... 8 
6 
Baseline Characteristics ..................................................................................................... 9 
7 
Study status and loss to follow up .....................................................................................10 
8 
Study conduct ...................................................................................................................11 
9 
Primary Endpoint Analyses ...............................................................................................11 
9.1 
Efficacy Outcome (Final Analysis) [IP] ......................................................................................... 11 
9.2 
Efficacy Outcome (Interim Analysis) [V] ..................................................................................... 12 
9.3 
Safety Outcome [IP] .................................................................................................................... 12 
10 
Secondary Outcome Measures Analyses ..........................................................................13 
10.1 
HCV RNA while on study treatment ............................................................................................ 13 
10.2 
HCV RNA during follow-up .......................................................................................................... 13 
10.3 
HCV RNA Relapse ........................................................................................................................ 13 
10.4 
SOF-associated resistance mutations ......................................................................................... 14 
10.5 
AEs by type of event ................................................................................................................... 14 
10.6 
Changes in Hemoglobin .............................................................................................................. 14 


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10.7 
Change in HIV-1 RNA ................................................................................................................... 15 
10.8 
Change in CD4+ cell count .......................................................................................................... 15 
10.9 
Adherence ................................................................................................................................... 16 
10.10 
Immune Parameters ............................................................................................................... 16 
10.11 
Pharmacology Analysis............................................................................................................ 16 
11 
Analysis datasets ..............................................................................................................17 
 
 
 


A5327 Statistical Analysis Plan Version 1.0   
 
 
 
July 7, 2014 
 
1 
Introduction 
This document describes the content proposed for the primary statistical analysis of ACTG 
A5327.  The focus of this analysis will examine the primary objectives of safety and efficacy 
outcomes for Cohort 1 (12 weeks of treatment).  Analysis of Cohort 2 will follow a similar plan 
but some details will depend on whether Cohort 2 receives treatment for 12 weeks or 8 weeks.  
A subset of these analyses will form the basis of reports provided to the Hepatitis TSG Study 
Monitoring Committee (SMC) while the study is ongoing.  Also included is a summary of the 
analysis plans for the secondary objectives that will be analyzed either at the time of the primary 
analyses or at a later date as determined per the priorities of the A5327 study team.  It is, 
however, recognized that this analysis plan may be modified by the study as new information 
becomes available outside of the study or to reflect recommendations made by SMC. In 
addition, some analyses, tables or figures may be omitted at interim analyses if there are 
insufficient data to warrant analysis or at the request of the SMC.  
 
2 
Study Overview  
2.1 
Study Schema  
(Extracted from Protocol Version 1.0) 
DESIGN  
SWIFT-C is a Phase I, open-label, two-cohort clinical trial, in which 
between 44 and 50 acutely HCV-infected HIV-1 positive subjects will be 
enrolled and administered oral sofosbuvir (SOF) in combination with 
weight-based ribavirin (RBV). 
 
The study will open the first cohort with treatment for 12 weeks with the 
potential to shorten therapy in a second cohort to 8 weeks if noninferiority 
of the 12-week regimen in the first cohort compared to a historical control 
is met.  The first cohort will open with a planned accrual of at least 17 
subjects.  An interim efficacy analysis on the proportion of subjects with 
undetectable HCV RNA 4 weeks after the last dose of SOF/RBV (SVR4) 
will be conducted after 17 subjects complete the study treatment and are 
evaluated for SVR4.  The second cohort will open with an 8-week 
treatment only if the SVR4 rate from the first 12-week treatment cohort is 
concluded to be noninferior to the study-defined historical sustained 
virologic response (SVR) rate of 60%.  If at the interim analysis the first 
cohort does not meet noninferiority criteria, enrollment for cohort 2 will 
continue with a 12-week treatment duration to completion of the study.  
The second cohort will include at least 27 subjects.  Each cohort will 
occur in two steps: on treatment (Step 1) and followup (Step 2).  The 
cohorts will enroll sequentially. 
DURATION 
32-36 weeks (8-12 weeks on-treatment followed by 24 weeks of follow-
up)  


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SAMPLE SIZE 
A minimum of 44 subjects will be enrolled. If a subject is discontinued 
from study treatment for non-virologic reasons or is not evaluable for 
SVR12 while enrollment is ongoing to the same cohort, then an additional 
subject may be enrolled to that cohort to help ensure that an adequate 
number complete study treatment and are evaluable for SVR12, up to a 
maximum enrollment of 50 subjects. 
POPULATION 
HIV-1 coinfected individuals who have acute HCV infection or reinfection. 
REGIMEN 
SOF 400mg once daily and weight-based RBV (1000 or 1200 mg daily in 
two divided doses) 
 
2.2 
Hypothesis 
An interferon sparing regimen of sofosbuvir (SOF) and ribavirin (RBV) can achieve sustained 
virologic response (SVR) 12 rates that are noninferior to the current standard of care assessed 
by historical control for the treatment of acute HCV in HIV-1/HCV co-infected individuals with an 
improved safety profile and a shorter length of treatment. 
 
2.3 
Primary Objectives 
1. To evaluate HCV treatment response to SOF and weight-based RBV (1000 or 1200 mg 
daily in two divided doses) taken for 12 or 8 weeks as assessed by SVR12, defined as 
HCV RNA undetectable [<lower limit of quantification (LLOQ) target not detected (TND)] 
12 weeks post-treatment in persons with existing HIV-1 infection who are acutely 
infected with any HCV genotype. 
 
2. To evaluate the safety and tolerability of combination oral antiviral therapy with SOF and 
weight-based RBV taken for 12 or 8 weeks in persons with existing HIV-1 infection who 
are acutely infected with any HCV genotype. 
 
2.4 
Secondary Objectives 
1. To evaluate the antiviral efficacy of SOF and weight-based RBV as measured by the 
proportion of subjects with HCV RNA undetectable (<LLOQ TND) at weeks 1, 2, 4, 8, 12 
and at 2 (SVR2), 4 (SVR4), 8 (SVR8), 12 (SVR12) and 24 (SVR24) weeks post-
treatment. 
 
2. To evaluate evidence of relapse, defined as HCV RNA undetectable (<LLOQ TND) at 
end-of-treatment but HCV RNA quantifiable (≥LLOQ) during followup. 
 
3. To assess the emergence of viral resistance to SOF when administered with RBV for 
acute HCV infection. 
 


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4. To estimate RBV pharmacokinetics (PK) and evaluate covariates (including concomitant 
antiretroviral drugs) which may affect RBV PK. 
 
5. To assess the relationship of viral clearance and RBV PK with baseline predictors 
including genetic polymorphisms (eg., IL28B and ITPA), expression of key host immune 
response genes and proteins. 
 
6. To evaluate subjects’ adherence by using several tools, including self-report, pill count, 
and RBV concentrations. 
 
7. To evaluate the hypothesis that successful direct-acting antiviral (DAA)-based therapy 
alleviates type I (IFN)-induced immune dysfunction during acute HCV infection. 
 
2.5 
Visit and Evaluation Schedule 
The Cohort 1 expected schedule for on-treatment clinic visits is shown in Table 1 and the 
expected schedule for post-treatment follow up clinic visits is shown in Table 2 below. Unless 
otherwise noted, analyses by A5327 study week will utilize these study week definitions (defined 
in days); the start time for calculation of study week will be the date of first dose of treatment. 
 
Table 1: Weeks Since Starting Treatment 
 
Baseline 
Week 1 
Week 2 
Week 4 
Week 8  
Week 12  
Days 
0 
4-10 
11-17 
21-42 
49-70 
77-98 
 
Table 2: Weeks Since Starting Post-Treatment Follow up 
 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 24 
Days 
Last day of 
treatment 
9-22 
23-50 
51-78 
79-112 
161 
onwards 
 
2.6 
A5327 Protocol History 
Protocol Version 1.0 (finalized January 2, 2014) 
A5327 Clarification Memo 1, Version 1.0 (03/13/2014) regarding clarification of eligibility criteria 
in Section 4 and the use of plasma HCV RNA in Section 6. 
A5327 Letter of Amendment 1, Version 1.0 (05/21/2014) regarding changes to lipid panel as 
needed at entry and exemption from US FDA IND regulations. 
 
2.7 
Monitoring 
2.7.1 
Ongoing Monitoring 
The A5327 team will monitor the following: 
 
Accrual and study status (monthly) 
 
Adverse events (AEs) (every two months) 


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 
Toxicities which include signs and symptoms, laboratory abnormalities and diagnoses ( 
every three months) 
 
HCV and HIV-1 failures (every 1 to 3 months, as needed) 
Please refer to the most recent version of the Study Monitoring Plan (SMP) for more details. 
2.7.2 
SMC Reviews 
The Hepatitis TSG SMC will review A5327 at least annually after the first subject is enrolled and 
as soon as possible after the SVR4 status is known for the first 17 subjects in the first cohort 
who complete study treatment (i.e. do not prematurely discontinue study treatment for non-
virologic reasons) and are evaluable for SVR4. The SMC will monitor safety and efficacy of 
study treatment.  In particular, the SMC will review outcome data to guide a decision about 
Cohort participants receiving 12 or 8 week duration of study treatment.   
At the request of the SMC, an early interim analysis of the study accrual will occur 6 months 
after the study opens to enrollment. The SMC will examine accrual by site and by month.  
 
Open Report: The following report will be distributed to the Core Team and the SMC. The report 
will include analyses from the following sections of this analysis plan by cohort. 
 
Study Status 
 
Baseline Characteristics  
 
Data Completeness 
 
Safety data 
Closed Report: The following report will be distributed to the SMC members.  The report will 
include analyses from the following sections of this analysis plan with summaries by cohort. 
 
Changes in HCV RNA 
 
SVR4, SVR8, SVR12, SVR24 rates based on the available data for HCV RNA as 
well as rates of virologic failure and relapse. 
 
2.8 
General Statistical Considerations 
Key analysis decisions: 
 
 
Throughout, study entry is defined at the date of entry visit as recorded as the header 
date on the ADM0010 [for interim: if ADM0010 is not in database at the time of data 
retrieval, registration date will be used] 
 
 
The analyzed measurement will, in general, be the measurement closest to the 
scheduled evaluation time, and the acceptable windows will be based on time since first 
study treatment dose 
 


A5327 Statistical Analysis Plan Version 1.0   
 
 
 
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 
Unless otherwise specified, data summaries and analyses will be presented by cohort.  
Final analysis of data from Cohort 1 can occur while the second cohort proceeds.  The 
analysis for Cohort 1 will occur after all subjects have completed follow-up (through 24 
weeks post-treatment, as appropriate per protocol) and final data are available.  Final 
analysis for Cohort 2 will depend on whether Cohort 2 receives 12 weeks of treatment or 
8 weeks of treatment. If Cohort 2 receives 12 weeks of treatment, the analysis will 
combine Cohort 1 and Cohort 2.  If Cohort 2 receives 8 weeks of treatment, the analysis 
will be separate. The analysis plan will be updated after the decision of treatment 
duration is made.  
Notes for conventions used in the SMC and primary analysis reports: 
 
For the primary analysis report (not SMC report): 
o Lists will be sorted by variables in the order given with study participants 
identified using an alternate patient identifier (PubID, i.e. not ACTG patid). 
o Participant-specific dates will not be shown, but converted to time since study 
entry or start of study treatment.  
 
 
Each Table/Figure/Listing will be annotated with the name and location of the program 
used to create it 
 
 
Unless otherwise noted, tables/figures in Sections 4 through 10 will be included in the 
interim analysis reports for the SMC as well as the primary analysis report 
 
 
Validation: 
o Tables/figures requiring SDAC validation of the program used to generate the 
results will be flagged with “[V]”  
o Tables/figures requiring independent programming of results by the SDAC 
validator will be flagged with “[IP]” 
3 
Accrual  
Purpose : To give a summary of accrual and the distribution of enrollment across sites.   
a) Table: Number (%) enrolled overall and by month 
Note: Dates of first and last enrollments will be provided in a footnote to the table 
b) Table Number (%) enrolled by enrolling site 
 
4 
Eligibility Violations and Exclusions 
Purpose; To document why any participants who were enrolled were subsequently excluded 
from analysis and document any other exclusions. 
a) List: violations of eligibility criteria by site and details of exclusions from analyses (if any) 
b) List: participants who did not have treatment dispensed.  These participants will be 
excluded from the analysis. 


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5 
Baseline Characteristics 
Purpose: To describe the study population 
Baseline characteristics will be analyzed as continuous or as categories or both, as appropriate. 
Tables will provide # of subjects, # of missing data points, median, quartiles (Q1-Q3), minimum, 
maximum, mean and standard deviation for the continuous variables (with transformations as 
appropriate) and number (%) for the categorical variables. In calculation of percentages, 
subjects with missing data will not be included in the denominator. 
a)  Table summarizing demographic characteristics 
i. 
Sex: number (%) 
ii. 
Self-reported race/ethnicity: number (%)  
iii. 
Age on the day of study entry (years): N, mean, standard deviation, median, 1st and 
3rd quartile, minimum and maximum; number (%) by age group (18-19, 20-29, 30-
39, 40-49, 50-59; 60-69. 70+  years, rounded down). 
iv. 
Intravenous drug use (IVD) history: number (%) by group (Never, current, previous 
user) 
v. 
Weight (kg) (F0033):N, mean, standard deviation, median, 1st and 3rd quartile, 10th 
and 90th percentile; number (%) by weight group (< 75kg, ≥75kg) 
vi. 
BMI (kg/m2):  N, mean, standard deviation, median, 1st and 3rd quartile, minimum 
and maximum; number (%) by BMI group (Underweight[<18.5], normal [18.5-24.9], 
overweight [25-29.9], obese [>30]) 
 
b) Table summarizing health status information 
i. 
Baseline HIV-1 RNA (copies/ml) and corresponding results for log10 copies/ml 
(F3109): N, median, 1st and 3rd quartile, minimum and maximum; number (%) by 
category (≤50, 50-400, 401 -1,000, 1,000-9,999, >10,000-99,999).   
Note: Baseline is defined as the closest value to starting study treatment. 
ii. 
Baseline CD4+ cell count (/mm3) (LBW0054): N, mean, standard deviation, median, 
1st and 3rd quartile, minimum and maximum; number (%) by category (<50, 50-199, 
200-349, 350-499, 500-649, 650-799, >800) 
Note: Baseline is defined as the arithmetic mean of screening and entry values or, in 
the absence of one value, the one available. 
iii. 
ARV treatment history (HXW0171): number (%) by category (Never used, off at entry 
but previously used, and currently on at entry), number (%) by ARV regimen 
iv. 
Baseline HCV RNA (copies/ml) and corresponding results for log10 copies/ml 
(F3116): N, median, 1st and 3rd quartile, minimum and maximum 
Note: Baseline is defined as the value at A5327 entry 
v. 
IL28B genotype (GENOHUM): number (%) by category (CC, CT, TT) 
vi. 
ITPA genotype (GENOHUM): number (%) by category (CC, CA, AA) 
vii. 
HCV genotype (SRW0028): number (%) by category (1a, 1b, 2a, 2b, 3, 4, 5, 6) 
 
c) Table summarizing laboratory evaluations 


A5327 Statistical Analysis Plan Version 1.0   
 
 
 
July 7, 2014 
 
For each laboratory evaluation the following will be presented unless otherwise 
specified: N, mean, standard deviation, median, 1st and 3rd quartile, minimum and 
maximum; 
i. 
Hematology characteristics (F2850): hematocrit, hemoglobin (g/dL), platelets 
(cells/mm3), red blood cell (RBC) count, white blood cell (RBC) count (cells/mm3), 
WBC differentials (lymphocytes, monocytes, neutrophils, eosinophils, basophils, 
reticulocyte count) and mean corpuscular volume (MCV). 
ii. 
Chemistry characteristics(F2841): alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT), albumin (g/dL), alkaline phosphatase, creatinine, 
total bilirubin, direct bilirubin, glucose (mg/dL), lipase, potassium (mEq/L), thyroid-
stimulating hormone, sodium(mEq/L) and gamma-glutamyl transferase. 
a. ALT/SGPT and AST/SGOT: number (%) by category (≤ 5X ULN, >5X ULN) 
b. Total bilirubin: number (%) by category (≤2XULN, >2XULN)s 
iii. 
Calculated creatinine clearance(LBW0060) 
iv. 
Fasting Lipids (F2841): low density lipoprotein (LDL, mg/dL), high density lipoprotein 
(HDL, mg/dL), triglycerides (TG, mg/dL), total cholesterol (TC, mg/dL), and 
apolipoproteins B, E, and CII. 
Note: Fasting per protocol is defined as nothing to eat or drink except prescription 
medications and water for at least 8 hours prior to the procedure. Only fasting lipids 
will be included; lipid measurements collected non-fasting will be excluded and 
considered as missing.   
v. 
Coagulation Markers (F2850): INR, prothrombin time (PT), activated partial 
thromboplastin (APTT) 
vi. 
Urinalysis (F0869): appearance, blood, color, glucose, leukocyte erterase, PH, 
protein, urobilinogen 
 
d) Table by ARV status at A5327 entry (yes vs no) 
i. 
Baseline HIV-1 RNA (copies/ml) and corresponding results for log10 copies/ml 
(F3109): N, median, 1st and 3rd quartile, minimum and maximum , number (%) by 
category (≤50, 50-400, 401 -1,000, 1,000-9,999, >10,000).   
6 
Study status and loss to follow up 
Purpose: To summarize extend of follow-up on study. 
a)  CONSORT diagram: number of participants enrolled in each cohort, number who 
started treatment, completed treatment, and completed study [ONLY included in primary 
analysis report] 
b) Table: On study treatment number (%) by category (F4003 and F1601) 
Categories included are:  
i. 
Completed planned treatment period and post treatment follow-up 
ii. 
Completed planned treatment period but off study early 
iii. 
Discontinued study treatment early and completed planned post treatment follow-up 
iv. 
Discontinued study treatment early and discontinued post treatment follow-up earl 


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c) List: Reasons off study treatment early (include both the category and text field from 
F4003) 
d) List: Reasons off study early (include both the category and text field from F1601) 
7 
Study conduct 
Purpose: To summarize how compliant participants are with study visits and completeness and 
timeliness of data entry and sample acquisition for key study outcomes [ONLY included in 
interim analysis] 
a) Table: summarize missed visits reflected as the number(%) of expected and observed 
clinic visits in each table of data completeness (see below) 
b) Table: data completeness of for key study outcomes (standard SDAC data availability 
report): 
i. 
HCV RNA (HCVRNALDMS) 
ii. 
HIV-1 RNA (RNALDMS) 
iii. 
CD4 cell count (LBW0054) 
iv. 
ALT(SGPT) and AST(SGOT) (F2841) 
v. 
Stored serum/plasma for HCV/HIV studies (L_ALIQ) 
vi. 
Stored plasma/PBMC (L_ALIQ) 
8 
Primary Endpoint Analyses 
8.1 
Efficacy Outcome (Final Analysis) [IP] 
Primary Outcome Measure (from protocol section 9.2.1.1) 
SVR12 is defined as HCV RNA undetectable (<LLOQ TND) of the assay at 12 weeks after date 
of last dose of study treatment.   
The 12 week measurement will be the measurement obtained closest to 84 days (i.e. 12*7 
days), within the window 79 to 112 days inclusive after study treatment discontinuation.  This 
analysis will be intent to treat (ITT) analysis.  
If a subject has no HCV RNA measurement within this window, then the subject will be 
considered as having detectable HCV RNA at 12 weeks unless the preceding and subsequent 
HCV RNA measurements are both undetectable (<LLOQ TND).  
 
Planned Analysis 
a) Table: summarize proportion and two-sided 90% confidence interval around the 
observed SVR12 proportion using the Blyth-Still-Casella(BSC) method for binomial 
outcomes (HCVRNALDMS) 
b) Table: summarize proportion and two-sided 90% confidence interval around the 
observed SVR12 proportion of subjects who are evaluable for SVR12 but exclude 
subjects who prematurely discontinue study treatment for nonvirologic reasons 
(Completer Analysis) using the Blyth-Still-Casella(BSC) method for binomial outcomes 
(HCVRNALDMS) 


A5327 Statistical Analysis Plan Version 1.0   
 
 
 
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8.2 
Efficacy Outcome (Interim Analysis) [V] 
Primary Outcome Measure (from protocol section 9.5) 
The ACTG Hepatitis SMC will review this study as soon as possible after the SVR4 status is 
known for at least 17 subjects in Cohort 1.  SVR4 is defined as HCV RNA undetectable (<LLOQ 
TND) of the assay 4 weeks after day of last dose of study treatment.   
The 4 week measurement will be the measurement obtained closest to 28 days (i.e. 4*7 days), 
within the window 23 to 50 days inclusive after study treatment discontinuation.  This analysis 
will be ITT analysis. 
 
Planned Analysis 
a) Table: summarize proportion and two-sided 90% confidence interval around the 
observed SVR4 proportion using the Blyth-Still-Casella(BSC) method for binomial 
outcomes (HCVRNALDMS). 
b) Table: summarize proportion and two-sided 90% confidence interval around the 
observed SVR4 proportion of subjects who are evaluable for SVR4 but exclude subjects 
who prematurely discontinue study treatment for nonvirologic reasons (Completer 
Analysis) using the Blyth-Still-Casella(BSC) method for binomial outcomes 
(HCVRNALDMS) 
NOTE: If the SVR4 rate from Cohort 1 (12 weeks of treatment) is concluded to be 
noninferior to the study-defined historical SVR rate of 60% (i.e. the lower confidence 
bound is above 60%), then Cohort 2 will be opened to 8 weeks of treatment.  Otherwise, 
Cohort 2 will receive 12 weeks of treatment.  Other secondary efficacy information 
(detailed below) may be considered by the SMC to make the recommendation of 
treatment duration for Cohort 2. 
8.3 
Safety Outcome [IP] 
Primary Outcome Measure (from protocol section 9.2.1.2) 
Occurrence of a Grade ≥ 2 AE (diagnosis, sign, symptom, or laboratory abnormality), SAE 
according to ICH criteria, or treatment-limiting AE (i.e., an AE reported as the reason for 
permanent discontinuation of study treatment). 
Any event occurring after initiation of study treatment through to 28 days after date of last dose 
of study treatment will be included (except for an event that is ongoing at the same grade from 
before start of study treatment will be excluded). 
 
Planned Analysis 
a) Table: summarize proportion and two-sided 90% confidence interval around the 
proportion of subjects who have one of the defined AEs (EVW0206, EVW0207) 
b) Table: summarize primary safety outcome (i.e. type of AE, grade, whether or not an 
SAE, whether or not it was a treatment limiting AE) 


A5327 Statistical Analysis Plan Version 1.0   
 
 
 
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9 
Secondary Outcome Measures Analyses 
9.1 
HCV RNA while on study treatment 
Secondary Outcome Measure (from protocol section 9.2.2.1) 
HCV RNA undetectable (<LLOQ TND) at 1, 2, 4, 8 and, for the 12-week regimen, 12 weeks 
after starting study treatment.  Measurements will be assigned to these times within windows of 
4 to 10, 11 to 17, 21 to 42, 49 to 70, and 77 to 98 days, inclusive, respectively. If there is more 
than one measurement within a window, then the measurement closest to the targeted time will 
be used. If there is no measurement within a window, then the subject will be considered as 
having detectable HCV RNA at the targeted time, unless both the preceding and succeeding 
measurements are undetectable (<LLOQ TND).    
Planned Analysis 
a) Table: summarize the proportion of HCV undetectable (<LLOQ TND) of the assay at 1, 
2, 4, 8, and, for the 12-week regimen, 12 weeks after starting study treatment.  A 90% 
two-sided confidence interval will be provided around the observed proportions 
(HCVRNALDMS) 
b) Figure: summarize the proportion of HCV undetectable, with the upper and lower limit of 
the confidence interval at 1, 2, 4, 8, and for the 12-week regimen, 12 weeks after starting 
study treatment (HCVRNALDMS). 
9.2 
HCV RNA during follow-up 
Secondary Outcome Measure (from protocol section 9.2.2.2) 
HCV RNA undetectable (<LLOQ TND) at 2 (SVR2), 4 (SVR4), 8 (SVR8), and 24 (SVR24) 
weeks after last dose of study treatment. The windows for these measurements will be 9 to 22, 
23 to 50, 51 to 78, and 161 days onwards.  If there is more than one measurement within a 
window, then the measurement closest to the targeted time will be used.  If there is no 
measurement within a window, then the subject will be considered as having detectable HCV 
RNA at the targeted time, unless (for weeks 4 and 8) the preceding and subsequent HCV RNA 
measurements are both <LLOQ TND. 
Planned Analysis 
a) Table: summarize the proportion of HCV undetectable (<LLOQ TND) of the assay at 2 
(SVR2), 4 (SVR4), 8 (SVR8) and 24 (SVR24) weeks after last dose of study treatment.  
A 90% two-sided confidence interval will be provided around the observed proportions 
(HCVRNALDMS) 
b) Figure: summarize the proportion of HCV undetectable, with the upper and lower limit of 
the confidence interval at 2 (SVR2), 4 (SVR4), 8 (SVR8) and 24 (SVR24) weeks after 
last dose of study treatment (HCVRNALDMS).   
9.3 
HCV RNA Relapse 
Secondary Outcome Measure (from protocol section 9.2.2.3) 


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To evaluate virologic evidence of relapse, defined as HCV RNA undetectable (<LLOQ TND) at 
end-of-treatment but HCV RNA quantifiable (≥LLOQ) during followup, will require confirmation 
and should be performed as soon as possible but within 2 weeks after determination of initial 
observation. 
For analysis purposes, confirmatory values obtained after 2 weeks will be included. 
Planned Analysis 
a) List: Subjects who have virologic evidence of relapse.  The listing will include week of 
HCV RNA undetectable (<LLOQ TND), HCV RNA undetectable at end of study 
treatment, post treatment week of HCV RNA detectable (≥LLOQ) and confirmation of 
HCV RNA detectability (HCVRNALDMS) 
9.4 
SOF-associated resistance mutations 
Secondary Outcome Measure (from protocol section 9.2.2.4) 
Development of SOF-associated resistance mutations. The set of mutations to be considered 
will be defined at the time of analysis based on information from other studies available at that 
time. 
The analysis plan will be updated when additional information is available. 
Planned Analysis 
a) List: Subjects with SOF-associated resistance mutations.  The listing will include sample 
week of resistance testing, whether the subject was off study treatment at that time, 
SOF-associated resistance mutation, and HCV RNA at the time of the resistance testing 
(Table TBD) 
9.5 
AEs by type of event 
Secondary Outcome Measure (from protocol section 9.2.2.5) 
Occurrence of the AEs detailed in section 9.2.1.2 of the protocol (Section 9.1 in this document) 
by type of event.  Type of events include: diagnosis, sign, symptom, laboratory abnormality, 
SAE according to ICH criteria, or treatment-limiting AE.  
Planned Analysis 
a) Table: summarize grades of events and the number (%) of persons experience each 
type/grade (EVW0206, EVW0207).   
9.6 
Changes in Hemoglobin 
Change in hemoglobin from last measurement prior to start of study treatment to each 
subsequent scheduled hemoglobin measurement time.  Windows for measurements to be 
included and the algorithm for selecting measurements within each window will be as described 
for HCV RNA measurements above. 
Planned Analysis 


A5327 Statistical Analysis Plan Version 1.0   
 
 
 
July 7, 2014 
 
a) Table: summarize hemoglobin measurements at each time point (F2850: N, mean, 
standard deviation, median, 1st and 3rd quartile, minimum and maximum)  
b) Table: summarize hemoglobin changes from the last measurement prior to study 
treatment to each subsequent CD4+ cell count measurement (F2850: N, mean, standard 
deviation, median, 1st and 3rd quartile, minimum and maximum) 
c) Figure: summarize hemoglobin median and IQR (Q1, Q3)  
d) Figure: summarize hemoglobin change median and IQR (Q1, Q3) 
 
9.7 
Change in HIV-1 RNA 
Secondary Outcome Measure (from protocol section 9.2.2.6) 
Change in HIV-1 RNA from last measurement prior to start of study treatment to each 
subsequent scheduled HIV-1 RNA measurement time: for subjects on ART at study entry, these 
will be categorized as changes from <50 copies/mL to ≥50 copies/mL, or vice versa; for subjects 
not on ART at study entry, quantitative change in log10 HIV-1 RNA will be considered. Windows 
for measurements to be included and the algorithm for selecting measurements within each 
window will be as described for HCV RNA measurements above. 
Planned Analysis 
Each analysis will be done by ARV use at study entry (yes vs no) (RNALDMS, HXW0171) 
a) Table: summarize HIV-1 RNA measurements at each time point 
b) Table: summarize HIV-1 RNA changes from last measurement prior to study treatment 
to each subsequent HIV-1 RNA measurement 
c) Figure: summarize HIV-1 RNA measurements at each time point 
i. 
For subjects on ARVs at study entry: the figure will summarize the proportion of 
subjects who had HIV-1 RNA < 50 copies/mL with 95% confidence interval around 
the proportion 
ii. 
For subjects not on ARVs at study entry: the figure will summarize the HIV-1 RNA 
median and IQR (Q1, Q3) 
d) Figure: summarize HIV-1 RNA changes at each time point 
i. 
For subjects on ARVs at study entry: the figure will summarize the proportion of 
subjects who had HIV-1 RNA < 50 copies/mL with 95% confidence interval around 
the proportion 
ii. 
For subjects not on ARVs at study entry: the figure will summarize the HIV-1 RNA 
median and IQR (Q1, Q3) 
9.8 
Change in CD4+ cell count 
Secondary Outcome Measure (from protocol section 9.2.2.7) 
Change in CD4+ cell count from last measurement prior to start of study treatment to each 
subsequent scheduled CD4+ cell count measurement time.  Windows for measurements to be 
included and the algorithm for selecting measurements within each window will be as described 
for HCV RNA measurements above. 
Planned Analysis 


A5327 Statistical Analysis Plan Version 1.0   
 
 
 
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a) Table: summarize CD4+ cell count measurements at each time point (LBW0054: N, 
mean, standard deviation, median, 1st and 3rd quartile, minimum and maximum)  
b) Table: summarize CD4+ cell count changes from the last measurement prior to study 
treatment to each subsequent CD4+ cell count measurement (LBW0054: N, mean, 
standard deviation, median, 1st and 3rd quartile, minimum and maximum) 
c) Figure: summarize CD4+ cell count median and IQR (Q1, Q3)  
d) Figure: summarize CD4+ cell count change median and IQR (Q1, Q3) 
9.9 
Adherence 
Secondary Outcome Measure (from protocol section 9.2.2.8) 
Measures of adherence: for each of SOF and RBV at each visit: (a) self-reported adherence as 
measured by whether or not a subject reports having taken all doses; and (b) proportion of 
doses taken since the previous visit as determined by pill count. 
Planned Analysis 
a) Table: summarize proportion of subjects taking all doses of medication within the 3 days 
prior to the evaluation (QL0757) 
b) Table: summarize the number (%) of doses taken since the previous visit, along with 
descriptive statistics (N, mean, standard deviation, median, 1st and 3rd quartile, 
minimum and maximum) (EVW0320) 
c) Adherence analysis based on RBV concentrations are TBD. 
9.10 
Immune Parameters 
Secondary Outcome Measure (from protocol section 9.2.2.9) 
Immune parameters: changes in magnitude of induction of ISGs by Nanostring, changes in IP-
10 levels, and changes in T cell function (CD4+ proliferative and CD8 CTL assays) at end of 
treatment and end of followup compared to study entry.  Analysis will be performed as a 
function of IL28B genotype. [ONLY included in the final analysis] 
Planned Analysis 
The analysis plan may be updated with additional analysis for this secondary outcome.  Immune 
parameter tables are TBD. 
a) Table: summarize ISGs at each time point and change in ISG from baseline 
b) Table: summarize IP-10 levels at each time point and change in IP-10 from baseline 
c) Table: summarize T cell function at each time point and change in T cell function from 
baseline 
 
9.11 
Pharmacology Analysis 
A separate Statistical Analysis Plan will be developed for the Pharmacology objectives. 


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10 Analysis datasets 
Preliminary list of analysis datasets [V] 
baseline – key baseline variables used in multiple summaries 
studystatus – study status information, e.g. on study, off study, reason off study 
hivrna – longitudinal HIV-1 RNA with calculated study weeks 
cd4 – longitudinal CD4 cell count with calculated study weeks 
psafety[IP] – primary safety events with calculated weeks on treatment 
hcvrna[IP] – primary efficacy analysis with longitudinal HCV RNA with calculated study weeks 
NOTE: Other datasets that are created will be added in a later version of this document. 

SAP_001.pdf: 
This is ACTG A5327 Cohort 2 SAP Version 2.0 with names of authors, names of publication writing team 
members and analysis timeline redacted. 
 
ACTG A5327  
Cohort 2 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Sofosbuvir-Containing Regimens Without Interferon For Treatment of 
Acute HCV in HIV-1 Infected Individuals (SWIFT-C) 
 
 
ClinicalTrials.gov Identifier: NCT02128217 
 
 
 
 
 
 
 
Version 2.0: 
March 15, 2017 
 
 
 


A5327 Statistical Analysis Plan Cohort 2 Version 2.0  
 
 
March 15, 2017 
Table of Contents: 
 
1 
Introduction ........................................................................................................................ 4 
2 
Core Manuscript Writing Team ............................................ Error! Bookmark not defined. 
3 
Study Overview .................................................................................................................. 4 
3.1 
Study Schema ................................................................................................................................ 4 
3.2 
Hypothesis ..................................................................................................................................... 5 
3.3 
Primary Objectives ........................................................................................................................ 5 
3.4 
Secondary Objectives .................................................................................................................... 5 
3.5 
Visit and Evaluation Schedule ....................................................................................................... 6 
3.6 
A5327 Protocol History ................................................................................................................. 6 
3.7 
General Statistical Considerations ................................................................................................ 6 
4 
Accrual and Screening [V] .................................................................................................. 7 
5 
Eligibility Violations and Exclusions [V] ............................................................................... 7 
6 
Baseline Characteristics [V] ................................................................................................ 7 
7 
Study status and loss to follow up [V] ................................................................................10 
8 
Study conduct [V] ..............................................................................................................10 
9 
Primary Endpoint Analyses ...............................................................................................10 
9.1 
Efficacy Outcome [IP] .................................................................................................................. 10 
9.2 
Safety Outcome [IP] .................................................................................................................... 11 
10 
Secondary Outcome Measures Analyses ..........................................................................12 
10.1 
HCV RNA while on study treatment [V] ...................................................................................... 12 
10.2 
HCV RNA during follow-up [V] .................................................................................................... 12 
10.3 
HCV RNA Relapse [V] ................................................................................................................... 13 
10.4 
SOF or LDV-associated resistance mutations ............................................................................. 13 
10.5 
AEs by type of event [V] .............................................................................................................. 13 
10.6 
Change in HIV-1 RNA [V] ............................................................................................................. 14 
10.7 
Change in CD4+ cell count and CD4+ cell percentage [V] ........................................................... 14 
10.8 
Adherence [V] ............................................................................................................................. 15 
10.9 
Immune Parameters ................................................................................................................... 15 
10.10 
Pharmacology Analysis............................................................................................................ 15 


A5327 Statistical Analysis Plan Cohort 2 Version 2.0  
 
 
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11 
Analysis datasets ..............................................................................................................15 
 
 
 


A5327 Statistical Analysis Plan Cohort 2 Version 2.0  
 
 
March 15, 2017 
1 
Introduction 
This document describes the content proposed for the primary statistical analysis of ACTG 
A5327.  The focus of this analysis will address the primary safety and efficacy objectives for 
Cohort 2 (8 weeks of treatment) as well as the secondary objectives for which data will be 
available at the time of the primary analysis.  Details about analyses for review by the Study 
Monitoring Committee (SMC) are not included in this SAP as all participants had completed 
study treatment by the time of preparation of this SAP and no further reviews of the study by the 
SMC were to be undertaken. 
2 
Study Overview  
2.1 
Study Schema  
(Extracted from Protocol Version 2.0) 
DESIGN  
SWIFT-C is a Phase I, open-label, two-cohort clinical trial, in which 
between 44 and 50 acutely HCV-infected HIV-1 positive participants will 
be enrolled and administered oral sofosbuvir (SOF) in combination with 
weight-based ribavirin (RBV, cohort 1) or ledipasvir (LDV, cohort 2). 
 
The study will investigate the safety and efficacy of two SOF-containing 
regimens and will assess if the addition of a second DAA allows for a 
shortened course of therapy.  The study will open the first cohort with 
sofosbuvir plus ribavirin (SOF+RBV) for 12 weeks and with a planned 
accrual of at least 17 participants.  The second cohort will open with 
ledipasvir/sofosbuvir (LDV/SOF) for an 8-week treatment.  The second 
cohort will include at least 27 participants.  Each cohort will occur in two 
steps: on treatment (Step 1) and followup (Step 2).  The cohorts will enroll 
sequentially. 
DURATION 
32-36 weeks (8-12 weeks on-treatment followed by 24 weeks of follow-
up)  
SAMPLE SIZE 
A minimum of 44 participants will be enrolled in Cohort 1 and Cohort 2. 
 
Cohort 1: Minimum of 17 participants will be enrolled. 
 
Cohort 2: Minimum of 27 participants will be enrolled. 
  
If a participant is discontinued from study treatment for non-virologic 
reasons or is not evaluable for SVR12 while enrollment is ongoing to the 
same cohort, then an additional participant may be enrolled to that cohort 
to help ensure that an adequate number complete study treatment and 
are evaluable for SVR12, up to a maximum enrollment of 50 participants. 
POPULATION 
HIV-1 coinfected individuals who have acute HCV infection or reinfection 
and have any genotype (Cohort 1) and genotype 1 or 4 (Cohort 2). 
REGIMEN 
Cohort 1: SOF 400mg once daily and weight-based RBV (1000 or 1200 
mg daily in two divided doses). 


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Cohort 2: Daily fixed combination pill of LDV/SOF (90mg/400mg). 
 
2.2 
Hypothesis 
An interferon sparing regimen of sofosbuvir (SOF) and ribavirin (RBV) and/or 
ledipasvir/sofosbuvir (LDV/SOR) can achieve sustained virologic response (SVR) 12 rates that 
are noninferior to the current standard of care assessed by historical control for the treatment of 
acute HCV in HIV-1/HCV co-infected individuals with an improved safety profile and a shorter 
length of treatment. 
 
2.3 
Primary Objectives 
1. To evaluate HCV treatment response to SOF and weight-based RBV (1000 or 1200 mg 
daily in two divided doses) taken for 12 weeks and daily LDV/SOF taken for 8 weeks as 
assessed by SVR12, defined as HCV RNA undetectable [<lower limit of quantification 
(LLOQ) target not detected (TND)] 12 weeks post-treatment in persons with existing 
HIV-1 infection who are acutely infected with any HCV genotype (Cohort 1) or Genotype 
1 or 4 (Cohort 2). 
 
2. To evaluate the safety and tolerability of combination oral antiviral therapy with SOF and 
weight-based RBV taken for 12 weeks and daily LDV/SOF taken for 8 weeks in persons 
with existing HIV-1 infection who are acutely infected with any HCV genotype (Cohort 1) 
or Genotype 1 or 4 (Cohort 2). 
 
2.4 
Secondary Objectives 
1. To evaluate the antiviral efficacy of SOF and weight-based RBV and LDV/SOF as 
measured by the proportion of participants with HCV RNA undetectable (<LLOQ TND) at 
weeks 1, 2, 4, 8, 12 and at 2 (SVR2), 4 (SVR4), 8 (SVR8), 12 (SVR12) and 24 (SVR24) 
weeks post-treatment. 
 
2. To evaluate evidence of relapse, defined as HCV RNA undetectable (<LLOQ TND) at 
end-of-treatment but HCV RNA quantifiable (≥LLOQ) during followup. 
 
3. To assess the emergence of viral resistance to SOF and LDV when administered with 
RBV for acute HCV infection. 
 
4. To estimate RBV pharmacokinetics (PK) and evaluate covariates (including concomitant 
antiretroviral drugs) which may affect RBV PK. (Cohort 1 only) 
 
5. To assess the relationship of viral clearance and RBV PK (Cohort 1) with baseline 
predictors including genetic polymorphisms (eg., IL28B and ITPA), expression of key 
host immune response genes and proteins. 


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6. To assess the effects of LDV on PK or tenofovir (TFV) in persons on tenofovir disoproxil 
fumarate (TDF)-containing regimens. (Cohort 2 only) 
 
7. To evaluate participants’ adherence by using several tools, including self-report, pill 
count, and drug concentrations. 
 
8. To evaluate the hypothesis that successful direct-acting antiviral (DAA)-based therapy 
alleviates type I (IFN)-induced immune dysfunction during acute HCV infection. 
 
2.5 
Visit and Evaluation Schedule 
The Cohort 2 expected schedule for on-treatment clinic visits is shown in Table 1 and the 
expected schedule for post-treatment follow up clinic visits is shown in Table 2 below. Unless 
otherwise noted, analyses by A5327 study week will utilize these study week definitions (defined 
in days); the start time for calculation of study week will be the date of first dose of treatment. 
 
Table 1: Weeks Since Starting Treatment 
 
Baseline 
Week 1 
Week 2 
Week 4 
Week 8  
Days 
0 
4-10 
11-17 
21-42 
49-70 
 
Table 2: Weeks Since Starting Post-Treatment Follow up 
 
Week 0 
Week 2 
Week 4 
Week 8 
Week 12 
Week 24 
Days 
Last day of 
treatment 
9-22 
23-49 
51-78 
79-112 
161 
onwards 
 
2.6 
A5327 Protocol History 
The analysis described in this SAP concerns only Cohort as defined in protocol version 
2.0: 
Cohort 2: 
Protocol Version 2.0 (finalized on July 2, 2015) 
A5327 Clarification Memo 1, Version 2.0 (10/08/15) regarding negative pregnancy tests. 
 
2.7 
General Statistical Considerations 
Key analysis decisions: 
 
 
Throughout, study entry is defined at the date of entry visit as recorded as the header 
date on the ADM0010. 
 


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 
The analyzed measurement will, in general, be the measurement closest to the 
scheduled evaluation time, and the acceptable windows will be based on time since first 
study treatment dose. 
 
 
Data summaries and analyses will be presented for Cohort 2 only (the analysis of data 
for participants in Cohort 1 are included in a separate report).  
Notes for conventions used in the primary analysis report: 
 
For the primary analysis report: 
o Lists will be sorted by variables in the order given with study participants 
identified using an alternate patient identifier (PubID, i.e. not ACTG patid). 
o Participant-specific dates will not be shown, but converted to time since start of 
study treatment (all participants did start study treatment).  
 
 
Each Table/Figure/Listing will be annotated with the name and location of the program 
used to create it. 
 
 
Validation: 
o Tables/figures requiring SDAC validation of the program used to generate the 
results will be flagged with “[V]”. 
o Tables/figures requiring independent programming of results by the SDAC 
validator will be flagged with “[IP]”. 
3 
Accrual and Screening [V] 
Purpose : To give a summary of accrual and the distribution of enrollment across sites.   
a) Table: Number (%) enrolled overall and by month 
Note: Dates of first and last enrollments will be provided in a footnote to the table 
b) Table: Number (%) enrolled by enrolling site 
c) List: participants who were screened by did not enter the study (screen failures)  
 
4 
Eligibility Violations and Exclusions [V] 
Purpose: To document why any participants who were enrolled were subsequently excluded 
from analysis and document any other exclusions. 
a) List: violations of eligibility criteria by site and details of exclusions from analyses (if any) 
b) List: participants who did not have treatment dispensed.  These participants will be 
excluded from the analysis. 
5 
Baseline Characteristics [V] 
Purpose: To describe the study population 


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Baseline characteristics will be analyzed as continuous or as categories or both, as appropriate. 
Tables will provide # of participants, # of missing data points, median, quartiles (Q1-Q3), 
minimum, maximum for the continuous variables (with transformations as appropriate) and 
number (%) for the categorical variables. In calculation of percentages, participants with missing 
data will not be included in the denominator. 
 
a)  Table summarizing demographic characteristics 
i. 
Sex (STATUS): number (%) 
ii. 
Self-reported race/ethnicity (STATUS): number (%)  
iii. 
Age on the day of study entry (years) (STATUS): N, median, 1st and 3rd quartile, 
minimum and maximum; number (%) by age group (18-19, 20-29, 30-39, 40-49, 50-
59; 60-69; 70+  years, rounded down) 
iv. 
Intravenous drug use (IVD) history (STATUS): number (%) by group (Never, current, 
previous user) 
v. 
Weight (kg) (F0033):N, median, 1st and 3rd quartile, minimum and maximum 
vi. 
BMI (kg/m2):  number (%) by BMI group (Underweight[<18.5], normal [18.5-24.9], 
overweight [25-29.9], obese [>30]) 
 
b) Table summarizing HCV disease status 
i. 
Infection status (ANSTAB): number (%) by new acute HCV infection and HCV 
reinfection 
ii. 
Acute HCV eligibility (ANSTAB): number (%) meeting one of the acute HCV infection 
criteria from protocol section 4.1.2 
iii. 
Time from first laboratory evidence of acute HCV to entry (days) (ANSTAB): N, 
median, 1st and 3rd quartile, minimum and maximum 
iv. 
Time from diagnosis of acute HCV to entry (days) (DF0002): N, median, 1st and 3rd 
quartile, minimum and maximum 
v. 
Baseline HCV RNA (IU/ml) and corresponding results for log10 copies/ml (F3116): 
N, median, 1st and 3rd quartile, minimum and maximum 
Note: Baseline is defined as the value at A5327 entry 
vi. 
Baseline HCV RNA: number (%) undetectable and detectable, number (%) < 6 
million IU/mL and ≥6 million IU/mL 
Note: undetectable at baseline may indicate spontaneous clearing occurring between 
screening and baseline. 
vii. 
HCV genotype (SRW0028): number (%) by category (1a, 1b, 2a, 2b, 3, 4, 5, 6) 
viii. 
IL28B genotype (GENOHUM): number (%) by category (CC, CT, TT)  
Note: Batch tested at the end of study. 
 
c)  Table summarizing HIV disease status 
i. 
Baseline HIV-1 RNA (copies/ml) (RNALDMS): number (%) by category (<50 copies, 
≥50 copies)  
Note: Baseline is defined as the closest value on/before date of start of study 
treatment. 


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ii. 
Baseline CD4+ cell count (/mm3) (LBW0054): N, median, 1st and 3rd quartile, 
minimum and maximum; 
Note: Baseline is defined as the arithmetic mean of screening and entry values or, in 
the absence of one value, the one available. 
iii. 
Baseline CD4+ cell percent (LBW0054): N, median, 1st and 3rd quartile, minimum 
and maximum; 
Note: Baseline is defined as the arithmetic mean of screening and entry values or, in 
the absence of one value, the one available. 
 
d) Table summarizing HIV-1 antiretroviral therapy (ARVs) 
i. 
Receiving HIV ARVs prior to entry (ANSTAB): number (%) yes and no 
ii. 
HIV ARV regimen at entry (TXT0004): number (%) on each regimen 
iii. 
HIV ARV regimen of interest for renal functions (TXT0004): number (%) on TDF + 
boosted PI, COBI, and other ARV regimens 
iv. 
NNRTIs (TXT0004): number (%) on efavirenz, rilpivirine, tenfovir, and abacavir 
based regimens 
v. 
Integrase Inhibitors (IIs) (TXT0004): number (%) on raltegravir and dolutegravir 
based regimens 
vi. 
Protese Inhibitors (PIs) (TXT0004): number (%) on boosted PI based regimens 
 
e) Table summarizing baseline laboratory evaluations 
For each laboratory evaluation the following will be presented unless otherwise 
specified: N, median, 1st and 3rd quartile, minimum and maximum.  If the lab value is 
graded, DAIDS grading scale will also be presented.  
Note: Baseline is defined as the last available value on or before the date of starting 
study treatment. Fasting per protocol is defined as nothing to eat or drink except 
prescription medications and water for at least 8 hours prior to the procedure.  If 
nonfasting at the screening visit, the participant should return within 7 days for fasting 
blood draw.  These panels are performed at the designated testing laboratory; see 
A5237 lab processing chart [LPC] for directions. 
 
i. 
Hematology characteristics (F2850): hematocrit, hemoglobin (g/dL), platelets 
(cells/mm3), red blood cell (RBC) count, white blood cell (RBC) count (cells/mm3), 
WBC differentials (absolute and percentage: lymphocytes, monocytes, neutrophils, 
eosinophils, basophils, reticulocyte count) and mean corpuscular volume (MCV). 
ii. 
Chemistry characteristics(F2841): alanine aminotransferase (ALT/SGPT), aspartate 
aminotransferase (AST/SGOT), albumin (g/dL), alkaline phosphatase, creatinine, 
total bilirubin, direct bilirubin, glucose (mg/dL), lipase, potassium (mEq/L), thyroid-
stimulating hormone, sodium(mEq/L) and gamma-glutamyl transferase. 
iii. 
Calculated creatinine clearance(LBW0060) 
iv. 
Fasting Lipids (LDMS table TBD): low density lipoprotein (LDL, mg/dL), high density 
lipoprotein (HDL, mg/dL), triglycerides (TG, mg/dL), total cholesterol (TC, mg/dL), 
and apolipoproteins B, E, and CII. 


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v. 
Coagulation Markers (F2850): INR, prothrombin time (PT), activated partial 
thromboplastin (APTT) 
vi. 
Urinalysis (F0869): appearance, blood, color, glucose, leukocyte erterase, PH, 
protein, urobilinogen 
 
f) Table summarizing history of sexually transmitted infections (STIs) 
i. 
Reported History of STI Diagnosis (DF0002): number (%) with history of STIs and no 
history of STIs.    Within history of STIs, number (%) for each type of STI.  Refer to 
A5327 Targeted Diagnosis list on the protocol specific web page, under 
Genitourinary/Sexually Transmitted Diseases, with the addition of acute Hepatitis B, 
herpes simplex virus and cervicitis. 
 
6 
Study status and loss to follow up [V] 
Purpose: To summarize extent of follow-up on study. 
a)  CONSORT diagram: number of participants enrolled, number who started treatment, 
completed treatment, and completed study  
b) Table: On study treatment number (%) by category (F4003 and F1601) 
Categories included are:  
i. 
Completed planned treatment period and post treatment follow-up 
ii. 
Completed planned treatment period but off study early 
iii. 
Discontinued study treatment early and completed planned post treatment follow-up 
iv. 
Discontinued study treatment early and discontinued post treatment follow-up early 
c) List: Reasons off study treatment early (include both the category and text field from 
F4003) 
d) List: Reasons off study early (include both the category and text field from F1601) 
7 
Study conduct [V] 
Purpose: To summarize how compliant participants are with study visitsTable: summarize 
missed visits reflected as the number (%) of expected and observed clinic visits 
8 
Primary Endpoint Analyses 
8.1 
Efficacy Outcome [IP] 
Note: For clarity of presentation, results for the primary efficacy outcome and for the secondary 
efficacy outcomes concerning HCV RNA will be presented together in the analysis report. 
 
Primary Outcome Measure (from protocol section 9.2.1.1) 
SVR12 is defined as HCV RNA undetectable (<LLOQ TND) of the assay at 12 weeks after date 
of last dose of study treatment.   


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The 12 week measurement will be the measurement obtained closest to 84 days (i.e. 12*7 
days), within the window 79 to 112 days inclusive after study treatment discontinuation.  This 
analysis will be intent to treat (ITT) analysis.  
If a participant has no HCV RNA measurement within this window, then the participant will be 
considered as having detectable HCV RNA at 12 weeks unless the preceding and subsequent 
HCV RNA measurements are both undetectable (<LLOQ TND).  
 
Planned Analysis 
a) Table: summarize proportion and two-sided 90% confidence interval around the 
observed SVR12 proportion using the Blyth-Still-Casella(BSC) method for binomial 
outcomes (HCVRNALDMS) 
b) Table: summarize proportion and two-sided 90% confidence interval around the 
observed SVR12 proportion of participants who are evaluable for SVR12 but exclude 
participants who prematurely discontinue study treatment for nonvirologic reasons 
(Completer Analysis) using the Blyth-Still-Casella(BSC) method for binomial outcomes 
(HCVRNALDMS) 
8.2 
Safety Outcome [IP] 
Note: For clarity of presentation, results for the primary safety outcome and for the secondary 
safety outcomes will be presented together in the analysis report. 
 
Primary Outcome Measure (from protocol section 9.2.1.2) 
Occurrence of a Grade ≥ 2 AE (diagnosis, sign, symptom, or laboratory abnormality), SAE 
according to ICH criteria, or treatment-limiting AE (i.e., an AE reported as the reason for 
permanent discontinuation of study treatment). 
Any event occurring after initiation of study treatment through to 28 days after date of last dose 
of study treatment will be included (except that an event that is ongoing at the same grade from 
before start of study treatment will be excluded). 
 
Planned Analysis 
a) Table: summarize proportion and two-sided 90% confidence interval around the 
proportion of participants who have one of the defined AEs (EVW0206, EVW0207) 
b) Table: list of all events meeting the primary safety outcome definition (includingweeks 
from start of study treatment, type of AE, grade, whether or not an SAE, whether or not it 
was a treatment limiting AE) 
 
 


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9 
Secondary Outcome Measures Analyses 
9.1 
HCV RNA while on study treatment [V] 
Note: A figure showing each participant’s log10 HCV RNA trajectory including on-treatment and 
post-treatment periods will be included.  An appendix to the report will be included listing 
scheduled measurement weeks, calculated weeks of each measurement, HCV RNA value, log10 
HCV RNA value, and reason for any missed measurement. 
 
Secondary Outcome Measure (from protocol section 9.2.2.1) 
HCV RNA undetectable (<LLOQ TND) at 1, 2, 4, and 8 weeks after starting study treatment.  
Measurements will be assigned to these times within windows of 4 to 10, 11 to 17, 21 to 42, and 
49 to 70 days, inclusive, respectively. If there is more than one measurement within a window, 
then the measurement closest to the targeted time will be used. If there is no measurement 
within a window, then the participant will be considered as having detectable HCV RNA at the 
targeted time, unless both the preceding and succeeding measurements are undetectable 
(<LLOQ TND).    
Planned Analysis 
a) Table: summarize the proportion of HCV undetectable (<LLOQ TND) of the assay at 1, 
2, 4, 8 weeks after starting study treatment.  A 90% two-sided confidence interval will be 
provided around the observed proportions (HCVRNALDMS) 
9.2 
HCV RNA during follow-up [V] 
Secondary Outcome Measure (from protocol section 9.2.2.2) 
HCV RNA undetectable (<LLOQ TND) at 2 (SVR2), 4 (SVR4), 8 (SVR8), and 24 (SVR24) 
weeks after last dose of study treatment. The windows for these measurements will be 9 to 22, 
23 to 50, 51 to 78, and 161 days onwards.  If there is more than one measurement within a 
window, then the measurement closest to the targeted time will be used.  If there is no 
measurement within a window, then the participant will be considered as having detectable HCV 
RNA at the targeted time, unless (for weeks 4 and 8) the preceding and subsequent HCV RNA 
measurements are both <LLOQ TND. 
Planned Analysis 
Note: For clarity of presentation, results for the primary outcome measure (SVR12) will be 
included in the following tables.  
a) Table: summarize the proportion of HCV undetectable (<LLOQ TND) of the assay at 2 
(SVR2), 4 (SVR4), 8 (SVR8), 12 (SVR12) and 24 (SVR24) weeks after last dose of 
study treatment.  A 90% two-sided confidence interval will be provided around the 
observed proportions (HCVRNALDMS) 
b) Figure: summarize the proportion of HCV undetectable, with the upper and lower limit of 
the confidence interval at 2 (SVR2), 4 (SVR4), 8 (SVR8), 12 (SVR12) and 24 (SVR24) 
weeks after last dose of study treatment (HCVRNALDMS).   


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9.3 
HCV RNA Relapse [V] 
Secondary Outcome Measure (from protocol section 9.2.2.3) 
To evaluate virologic evidence of relapse, defined as HCV RNA undetectable (<LLOQ TND) at 
end-of-treatment but HCV RNA quantifiable (≥LLOQ) during followup, will require confirmation 
and should be performed as soon as possible but within 2 weeks after determination of initial 
observation. 
For analysis purposes, confirmatory values obtained after 2 weeks will be included. 
Planned Analysis 
a) List: Participants who have virologic evidence of relapse.  The listing will include week of 
HCV RNA undetectable (<LLOQ TND), HCV RNA undetectable at end of study 
treatment, post treatment week of HCV RNA detectable (≥LLOQ) and confirmation of 
HCV RNA detectability (HCVRNALDMS) 
9.4 
SOF or LDV-associated resistance mutations 
Secondary Outcome Measure (from protocol section 9.2.2.4) 
Development of SOF or LDV-associated resistance mutations. The set of mutations to be 
considered will be defined at the time of analysis based on information from other studies 
available at that time. 
Planned Analysis 
a) The analysis will be performed outside of SDAC.  The raw data will be downloaded to 
the final database using the GETBSS HCV script. 
9.5 
AEs by type of event [V] 
Secondary Outcome Measure (from protocol section 9.2.2.5) 
Occurrence of the AEs detailed in section 9.2.1.2 of the protocol (Section 9.1 in this document) 
by type of event.  Type of events include: diagnosis, sign, symptom, laboratory abnormality, 
SAE according to ICH criteria, or treatment-limiting AE.  Additional analysis of selected renal 
safety parameters is included because of a concern that participants taking TDF might be at 
increased risk for such events.  
Planned Analysis 
a) Table: list of events (EVW0206, EVW0207), including HIV ARV regimen.  
b) Table: summarizing creatinine clearance and urinalysis during on study treatment by 
participants who were taking TDF in combination either with a boosted PI or with COBI 
and participants taking other HIV ARV regimens. 
c) Figure: Individual participant plots of creatinine clearance over time distinguishing 
participants who took TDF with a boosted PI, from participants who took TDF with 
COBI,from other participants. 


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d) Table of protein urinalysis results at each scheduled measurement week distinguishing 
participants taking TDF with either a boosted PI or COBI from other partiicpants: Number 
(%) in each protein category. 
9.6 
Change in HIV-1 RNA [V] 
Secondary Outcome Measure (from protocol section 9.2.2.6) 
Change in HIV-1 RNA from last measurement prior to start of study treatment to each 
subsequent scheduled HIV-1 RNA measurement time: for participants on ART at study entry, 
these will be categorized as changes from <50 copies/mL to ≥50 copies/mL, or vice versa; for 
participants not on ART at study entry, quantitative change in log10 HIV-1 RNA will be 
considered. Windows for measurements to be included and the algorithm for selecting 
measurements within each window will be as described for HCV RNA measurements above. 
Planned Analysis 
Each analysis will be done by ARV use at study entry (yes vs no) (RNALDMS, HXW0171) 
a) Table: summarize HIV-1 RNA measurements at each time point 
b) Table: summarize HIV-1 RNA changes from last measurement prior to study treatment 
to each subsequent HIV-1 RNA measurement 
c) Figure: summarize HIV-1 RNA measurements at each time point 
i. 
For participants on ARVs at study entry: the figure will summarize the proportion of 
participants who had HIV-1 RNA < 50 copies/mL with 95% confidence interval 
around the proportion 
ii. 
For participants not on ARVs at study entry: the figure will summarize the HIV-1 RNA 
median and IQR (Q1, Q3) 
d) Figure: summarize HIV-1 RNA changes at each time point 
i. 
For participants on ARVs at study entry: the figure will summarize the proportion of 
participants who had HIV-1 RNA < 50 copies/mL with 95% confidence interval 
around the proportion 
ii. 
For participants not on ARVs at study entry: the figure will summarize the HIV-1 RNA 
median and IQR (Q1, Q3) 
9.7 
Change in CD4+ cell count and CD4+ cell percentage [V] 
Secondary Outcome Measure (from protocol section 9.2.2.7) 
Change in CD4+ cell count from last measurement prior to start of study treatment to each 
subsequent scheduled CD4+ cell count measurement time.  Windows for measurements to be 
included and the algorithm for selecting measurements within each window will be as described 
for HCV RNA measurements above. 
Planned Analysis 
a) Table: summarize CD4+ cell count  and percentage measurements at each time point 
(LBW0054: N, median, 1st and 3rd quartile, minimum and maximum)  


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b) Table: summarize CD4+ cell count and percent changes from the last measurement 
prior to study treatment to each subsequent CD4+ cell count measurement (LBW0054: 
N, median, 1st and 3rd quartile, minimum and maximum) 
c) Figure: summarize CD4+ cell count and percentage median and IQR (Q1, Q3)  
d) Figure: summarize CD4+ cell count and percent change median and IQR (Q1, Q3) 
9.8 
Adherence [V] 
Secondary Outcome Measure (from protocol section 9.2.2.8) 
Measures of adherence: for each LDV/SOF at each visit: (a) self-reported adherence as 
measured by whether or not a participant reports having taken all doses; and (b) proportion of 
doses taken since the previous visit as determined by pill count. 
Planned Analysis 
a) Table: summarize proportion of participants taking all doses of medication within the 3 
days prior to the evaluation (QL0757) 
b) Table: summarize the number (%) of doses taken since the previous visit, along with 
descriptive statistics (N, median, 1st and 3rd quartile, minimum and maximum) 
(EVW0320) 
9.9 
Immune Parameters 
Secondary Outcome Measure (from protocol section 9.2.2.9) 
Immune parameters: changes in magnitude of induction of ISGs by Nanostring, changes in IP-
10 levels, and changes in T cell function (CD4+ proliferative and CD8 CTL assays) at end of 
treatment and end of followup compared to study entry.  Analysis will be performed as a 
function of IL28B genotype.  
Planned Analysis 
The analysis plan may be updated with additional analysis for this secondary outcome.  Immune 
parameter tables are TBD. 
a) Table: summarize ISGs at each time point and change in ISG from baseline 
b) Table: summarize IP-10 levels at each time point and change in IP-10 from baseline 
c) Table: summarize T cell function at each time point and change in T cell function from 
baseline 
 
9.10 
Pharmacology Analysis 
A separate Statistical Analysis Plan will be developed for the Pharmacology objectives. 
10 Analysis datasets 
Preliminary list of analysis datasets [V] 
baseline [V] – key baseline variables used in multiple summaries 
studystatus [V]  – study status information, e.g. on study, off study, reason off study 


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screeninfo [V] – screening failures 
hivrna [V] – longitudinal HIV-1 RNA with calculated study weeks 
cd4 [V] – longitudinal CD4 cell count with calculated study weeks 
arv2 [V] – HIV-1 antiretrovirals at entry and during study 
hcvrxadhere [V] – adherence to study drugs with calculated study weeks 
primsafe[IP] – primary safety events with calculated weeks on treatment 
hcvrna[IP] – primary efficacy analysis with longitudinal HCV RNA with calculated study weeks 
 
NOTE: Other datasets that are created will be added in a later version of this document.