Clinical trial NCT02194998
Conditions: HIV Infections Hepatitis C
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2015-09-16; Completion date: 2018-11-13
Enrollment: 46 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
HIV and hepatitis C virus (HCV) infection are diseases that share the same risk factors and routes of transmission. For this reason, many people infected with HIV are also infected with HCV. Interferon (IFN) is a drug used to treat HCV; however, in people coinfected with HIV and HCV, IFN treatment often does not work well and can cause unwanted side effects. The purpose of this study was to evaluate the safety, tolerability, and effectiveness of IFN-free HCV treatment in HIV/HCV coinfected adults who were taking antiretroviral (ARV) therapy.

Detailed description:
This study evaluated the safety, tolerability, and effectiveness of a combination of drugs to treat HCV in adults who were coinfected with HIV and HCV. The three drugs were paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV). In version 1 of the study, RBV was given to all participants. After revision in version 2, RBV was given only to participants with HCV genotype 1a; participants with HCV genotype 1b did not receive RBV.

This study enrolled HCV genotype 1a or 1b and HIV-1 coinfected participants (HCV treatment-naïve or HCV treatment-experienced) who were on a concurrent integrase inhibitor (INI)-based (raltegravir \[RAL\] or dolutegravir \[DTG\]) or protease inhibitor (PI)-based (darunavir \[DRV\] or atazanavir \[ATV\]) ART regimen. (The ART regimens were not provided by the study.) The participants were assigned to one of four cohorts (Cohorts A, B, C, and D). Participants in Cohorts A and B were on INI-based ART; participants in Cohorts C and D, on PI-based ART. For each group, the study proceeded in two steps: Step 1: on-HCV treatment and Step 2: post-HCV treatment follow-up. Participants in Cohorts A and C received the HCV drugs for 24 weeks; participants in Cohorts B and D, for 12 weeks. The target sample size goal was a total of 100 participants, with 25 participants per cohort.

Total study duration was up to 48 weeks. During Step 1 (on-HCV treatment), all participants had study visits at Weeks 2, 4, 6, 8, 10, and 12. Participants in Cohorts A and C had additional Step 1 study visits at Weeks 16, 20, and 24.

All participants had Step 2 (post-treatment follow-up) study visits 4, 12, and 24 weeks after registration to Step 2. Participants in Cohorts B and D had an additional Step 2 visit 36 weeks after registration to Step 2.

All study visits included a brief physical exam and blood collection. Select study visits included pregnancy testing for participants able to become pregnant, an electrocardiogram (EKG), an IFN gamma-induced protein 10 (IP-10) test, and collection of plasma samples.

Participants were able to coenroll in one of two optional substudies. In one substudy, participants attended two study visits at entry/Day 0 and Week 4 for 12-hour intensive pharmacokinetic (PK) sampling. In another substudy, participants underwent liver biopsies at two time points and PK sampling.

Study accrual was terminated early and participants who enrolled continued on study until completion.

Arms: arm 1: Participants took an INI-based (RAL or DTG) ART regimen for HIV-1 and received the following medications for 24 weeks: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV) (RBV for all participants (version 1) and only for participants with HCV genotype 1a (version 2)). arm 2: Participants took an INI-based (RAL or DTG) ART regimen for HIV-1 and received the following medications for 12 weeks: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV) (RBV for all participants (version 1) and only for participants with HCV genotype 1a (version 2)). arm 3: Participants took a PI-based (DRV or ATV) ART regimen for HIV-1 and received the following medications for 24 weeks: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV) (RBV for all participants (version 1) and only for participants with HCV genotype 1a (version 2)). arm 4: Participants took a PI-based (DRV or ATV) ART regimen for HIV-1 and received the following medications for 12 weeks: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT), dasabuvir (DSV), and ribavirin (RBV) (RBV for all participants (version 1) and only for participants with HCV genotype 1a (version 2)).
Interventions: intervention 1: Paritaprevir/ritonavir/ombitasvir (PTV/r/OBT) intervention 2: Dasabuvir (DSV) intervention 3: Ribavirin (RBV)
Intervention descriptions: intervention 1: PTV/r/OBT: 150/100/25 mg (two 75/50/12.5 mg fixed-dose combination tablets) orally once a day intervention 2: DSV: 250 mg orally twice a day intervention 3: RBV: 1,000 or 1,200 mg (weight-based) dosed in two divided doses orally twice a day (all participants (version 1); only participants with HCV genotype 1a (version2))

Protocol documents:
Prot_001.pdf: 
 
                                                                                                     
A5329 
 
 
Interferon-Free Therapy for Chronic HepAtitiS C Virus GENotype 1 Infection in 
Participants with HIV-1 Coinfection Receiving Concurrent Antiretroviral Therapy  
(C_ASCENT) 
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
The National Institute of Allergy 
and Infectious Diseases 
 
 
Industry Support Provided by: 
AbbVie 
 
 
IND # 122,987 
 
 
 
The ACTG Hepatitis Transformative 
 
Science Group: 
 
 
 
 
Raymond T. Chung, MD, Chair 
 
Protocol Chair: 
Mark S. Sulkowski, MD 
 
 
 
 
Protocol Co-Chair:  
David L. Wyles, MD  
 
 
 
DAIDS Clinical Representative: 
Beverly L. Alston-Smith, MD 
 
 
Clinical Trials Specialist: 
Denise Barr, MS, CCRP 
 
 
 
 
FINAL Version 2.0 
June 8, 2016


 
 
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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 
HYPOTHESES AND STUDY OBJECTIVES.................................................................. 14 
1.1 
Hypotheses ........................................................................................................ 14 
1.2 
Primary Objectives ............................................................................................. 14 
1.3 
Secondary Objectives ........................................................................................ 14 
1.4 
Exploratory Objectives ....................................................................................... 15 
2.0 
INTRODUCTION ........................................................................................................... 15 
2.1 
Background ........................................................................................................ 15 
2.2 
Rationale ........................................................................................................... 19 
3.0 
STUDY DESIGN ........................................................................................................... 26 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................... 27 
4.1 
Step 1 Inclusion Criteria ..................................................................................... 27 
4.2 
Step 1 Exclusion Criteria .................................................................................... 30 
4.3 
Step 2 Inclusion Criteria ..................................................................................... 32 
4.4 
Step 2 Exclusion Criteria .................................................................................... 32 
4.5 
Study Enrollment Procedures............................................................................. 32 
4.6 
Coenrollment Guidelines .................................................................................... 33 
5.0 
STUDY TREATMENT ................................................................................................... 33 
5.1 
Regimens, Administration, and Duration ............................................................ 33 
5.2 
Study Product Formulation and Preparation ....................................................... 35 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 35 
5.4 
Concomitant Medications ................................................................................... 36 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 39 
6.1 
Schedule of Events (Cohorts A and C) ............................................................... 39 
6.2  
Schedule of Events (Cohorts B and D) ............................................................... 42 
6.3 
Timing of Evaluations ......................................................................................... 45 
6.4 
Instructions for Evaluations ................................................................................ 46 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 56 
7.1 
Toxicity .............................................................................................................. 56 
7.2 
Management of Specific Toxicities ..................................................................... 57 
7.3 
Virologic Failure ................................................................................................. 61 
7.4 
Adjustments in ART Regimens Following Cessation of HCV DAA+/-RBV  
Therapy ............................................................................................................. 62 
 


 
 
 
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7.5 
Pregnancy.......................................................................................................... 63 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 64 
8.1 
Permanent and Premature Study Drug Discontinuation ..................................... 64 
8.2 
Premature Study Discontinuation ....................................................................... 64 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 64 
9.1 
General Design Issues ....................................................................................... 64 
9.2 
Outcome Measures ............................................................................................ 66 
9.3 
Randomization and Stratification ........................................................................ 67 
9.4 
Sample Size and Accrual ................................................................................... 67 
9.5 
Monitoring .......................................................................................................... 68 
9.6 
Analyses ............................................................................................................ 69 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 71 
10.1 
Pharmacology Objectives .................................................................................. 71 
10.2 
Pharmacology Study Design .............................................................................. 71 
10.3 
Pharmacokinetics Analysis ................................................................................ 72 
10.4 
Anticipated Outcomes ........................................................................................ 72 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 72 
11.1 
Records to Be Kept ............................................................................................ 72 
11.2 
Role of Data Management ................................................................................. 72 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 72 
11.4 
Expedited Adverse Event Reporting to DAIDS ................................................... 73 
12.0 
PARTICIPANTS ............................................................................................................ 74 
12.1 
Institutional Review Board Review and Informed Consent ................................. 74 
12.2 
Participant Confidentiality ................................................................................. 74 
12.3 
Study Discontinuation ........................................................................................ 74 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 74 
14.0 
BIOHAZARD CONTAINMENT ...................................................................................... 75 
15.0 
 REFERENCES ............................................................................................................. 76 
 
APPENDIX I: CONDITIONS INCLUDED IN THE 1993 AIDS SURVEILLANCE CASE 
DEFINITION 
 
APPENDIX II: A5329 SAMPLE INFORMED CONSENT 
 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5329 is a multicenter study and will be opened only at US AIDS Clinical Trials Group (ACTG) 
clinical research sites (CRSs).  
 
 


 
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PROTOCOL TEAM ROSTER 
 
Chair 
Mark S. Sulkowski, MD 
School of Medicine 
Johns Hopkins University  
1830 East Monument Street 
Suite 448 
Baltimore, MD 21287 
Phone: 410-614-4172 
Fax: 410-614-8488 
E-mail: msulkowski@jhmi.edu 
 
Co-Chair 
David L. Wyles, MD 
Infectious Diseases/Medicine 
UCSD, AVRC CRS 
9500 Gilman Drive 
SCRB 404 MC 0711 
La Jolla, CA 92093-0711 
Phone: 858-822-1779 
Fax: 858-822-5362 
E-mail: dwyles@ucsd.edu 
 
DAIDS Clinical Representative 
Beverly L. Alston-Smith, MD 
Complications and Co-Infectious Research 
Branch 
CCRB, TRP, DAIDS, NIAID, NIH, DHHS 
5601 Fishers Lane, Room 9F50 
Rockville, Maryland 20852 
Phone: 301-435-3773 
Fax: 240-627-3106 
E-mail: balston@niaid.nih.gov 
 
Clinical Trials Specialist 
Denise Barr, MS, CCRP 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3393 
Fax: 301-628-3302 
E-mail: DBarr@s-3.com 
Study Statisticians 
Kimberly Hollabaugh, MS  
Statistical & Data Analysis Center  
Harvard School of Public Health 
FXB Building, Room 549 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-1352 
Fax: 617-432-3163 
E-mail: hollabau@sdac.harvard.edu 
 
Laura Smeaton, MS 
Statistical & Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 511 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-2525 
Fax: 617-432-3163 
E-mail: smeaton@sdac.harvard.edu 
 
Data Manager 
Laura Weichmann, MPH 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7281 
Fax: 716-834-8675 
E-mail: weichman@fstrf.org 
 
DAIDS Pharmacist 
Lynette Purdue, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH, DHHS 
5601 Fisher’s Lane, Room 9E28 
Rockville, Maryland 20852 
Phone: 240-627-3061 
Fax: 240-627-3112 
E-mail: lpurdue@niaid.nih.gov 


 
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PROTOCOL TEAM ROSTER (Cont'd) 
 
Immunologist  
Donald Anthony, MD, PhD 
Case Western Reserve University 
Department of Medicine 
Biomedical Research, Building 1028 
2109 Adelbert Road 
Cleveland, OH 44106 
Phone: 216-368-3540 
Fax: 216-368-2034 
E-mail: dda3@case.edu 
 
Virologists  
William A. Meyer III, PhD, MT 
Quest Diagnostics Incorporated 
Retrovirology Department 
1901 Sulphur Spring Road 
Baltimore, MD 21227-0580 
Phone: 410-536-1593 
Fax: 410-737-1266 
E-mail: 
william.a.meyer@questdiagnostics.com 
 
David L. Wyles, MD 
Infectious Diseases/Medicine 
UCSD, AVRC CRS 
9500 Gilman Drive 
SCRB 404 MC 0711 
La Jolla, CA 92093-0711 
Phone: 858-822-1779 
Fax: 858-822-5362 
E-mail: dwyles@ucsd.edu 
 
Pharmacologists  
Gene D. Morse, PharmD 
Translational Pharmacology Research Core 
NYS Center of Excellence in Bioinformatics 
and Life Sciences 
701 Ellicott Street 
Buffalo, NY 14203 
Phone: 716-881-7464 
Fax: 716-645-3635 
E-mail: emorse@buffalo.edu 
Charles Venuto, PharmD 
Center for Human Experimental 
Therapeutics  
University of Rochester Medical Center 
265 Crittenden Blvd., CU 420694 
Rochester, NY 14642-0694 
Phone: 585-276-5622 
E-mail: charles.venuto@chet.rochester.edu 
 
Investigators 
Ashwin Balagopal, MD 
Johns Hopkins University School of 
Medicine 
855 Wolfe Street 
Room 535 
Baltimore, MD 21205 
Phone: 443-287-7666 
E-mail: abalago1@jhmi.edu 
 
Debika Bhattacharya, MD 
UCLA Division of Infectious Diseases, 37-
121 CHS 
David Geffen School of Medicine 
10833 Le Conte Avenue 
Los Angeles, CA 90095 
Phone: 310-825-0137 
Fax: 310-825-3632 
E-mail: debikab@mednet.ucla.edu 
 
Andrew H. Talal, MD, MPH 
Department of Medicine 
University of Buffalo 
875 Ellicott Street, Suite 6090 
Buffalo, NY 14203 
Phone: 716-888-4737 
Fax: 716-854-1397 
E-mail: ahtalal@buffalo.edu 
 
Field Representative 
Michelle Saemann, RN 
University of Cincinnati CRS 
Eden Ave and Albert Sabin Way 
Cincinnati, OH 45267-0405 
Phone: 513-584-2245  
Fax: 513-584-8454 
E-mail: saemanmd@uc.edu 


 
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PROTOCOL TEAM ROSTER (Cont'd) 
 
Laboratory Technologist 
Christopher Lane, AAS 
University of Rochester CRS 
Box 689 
601 Elmwood Avenue 
Rochester, NY 14642 
Phone: 585-276-5574 
Fax: 585-442-9328 
E-mail: 
christopher_lane@urmc.rochester.edu 
 
Community Scientific Subcommittee (CSS) 
Representative 
Edward Barron 
New Jersey Medical School Clinical 
Research Center CRS 
122 Plane Street, Apt. 6 
Boonton, NJ 07005 
Phone: 973-590-4999  
E-mail: barron.ed12@gmail.com 
 
Industry Representative  
Rolando M. Viani, MD, MTP 
AbbVie 
Dept. R48U, Bldg. AP30-3 
One North Waukegan Road 
North Chicago, IL 60064 
Phone: 847-938-2010 
Fax: 847-938-9874 
E-mail: rolando.viani@AbbVie.com 
 
Laboratory Data Manager  
Oswald Dadson, MS 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7238 
Fax: 716-833-0655 
E-mail: dadson@fstrf.org 
 


 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.coreA5329@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to actg.coreA5329@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.protA5329 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 
(ConMed), and coenrollment, contact the protocol team. Send an e-mail message to 
actg.coreA5329@fstrf.org. Include the protocol number, patient identification number (PID), and 
a brief relevant history. 
 
Immunology 
For questions specifically related to immunologic tests, contact the protocol immunologist. Send 
an e-mail message to actg.coreA5329@fstrf.org (ATTN: Donald Anthony). 
 
Pharmacology 
For questions specifically related to pharmacologic laboratory tests, contact the protocol 
pharmacologists. Send an e-mail message to actg.coreA5329@fstrf.org (ATTN: Gene Morse 
and Charles Venuto). 
 
Virology 
For questions specifically related to virologic laboratory tests, contact the protocol virologists. 
Send an e-mail message to actg.coreA5329@fstrf.org (ATTN: William Meyer and David 
Wyles). 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), 
the CRF schedule of events, randomization/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 Laura 
Weichmann (weichman@fstrf.org) directly.  
• 
For other questions, send an e-mail message to actg.coreA5329@fstrf.org (ATTN: Laura 
Weichmann).  
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration  
For randomization/participant registration questions or problems and study identification 
number SID lists.  
• 
Send an e-mail message to rando.support@fstrf.org. 


 
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STUDY MANAGEMENT (Cont'd) 
 
• 
Call the Statistical and Data Analysis Center (SDAC)/DMC Randomization Desk at 716-898-
7301.  
 
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.coreA5329@fstrf.org (ATTN: Denise Barr). 
 
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 website 
(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 
Lynette Purdue, protocol pharmacist, at 301-496-8213. 
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
For any questions related to the IND submission, contact the DAIDS RSC at Regulatory@tech-
res.com or call 301-897-1706. 
 
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 A5329 team members. 
• 
Send an e-mail to actg.coreA5329@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 
 
ABT-267 
 
ombitasvir, A-1233617 
ABT-333 
 
dasabuvir, A-998821 
ABT-450 
 
paritaprevir, A-1043422 
ABT-450/r 
 
ritonavir-boosted paritaprevir 
ABT-450/r/ABT-267  150/100/25 mg fixed-dose combination tablet 
APRI  
 
aspartate aminotransferase to platelet ratio index  
ATV 
 
 
atazanavir 
BOC   
 
boceprevir 
CMP  
 
comprehensive metabolic panel  
DAA 
 
 
direct-acting antivirals 
DAA+/-RBV therapy OBT/PTV/r/ + DSV +/- RBV 
DRV 
darunavir  
DRV/r 
ritonavir-boosted darunavir 
DDI 
 
 
drug-drug interaction  
DSV 
 
 
dasabuvir, non-nucleoside inhibitor (NNI) of HCV NS5B polymerase  
DTG 
 
 
dolutegravir 
Exviera  
 
dasabuvir, AbbVie 
FTC   
 
emtricitabine 
HCC 
 
 
hepatocellular carcinoma 
HCV 
 
 
hepatitis C virus infection 
IAS 
 
 
International Antiviral Society 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
IFN 
 
 
interferon 
INI  
 
 
integrase inhibitor  
kPa 
 
 
kilopascal 
LPC 
 
 
laboratory processing chart 
MRI 
 
 
magnetic resonance imaging 
NK 
 
 
natural killer 
NNI 
 
 
non-nucleoside polymerase inhibitor 
NS5A  
 
non-structural 5A (NS5A) protein of hepatitis C virus (HCV)  
N(t)RTI 
 
nucleoside/nucleotide reverse transcriptase inhibitor 
OATP1B1 
 
organic anion transporting polypeptide transporter 
OBT 
 
 
ombitasvir, inhibitor of HCV NS5A  
PegIFN 
 
pegylated interferon 
PI 
 
 
protease inhibitor 
PTV 
 
 
paritaprevir, inhibitor of HCV NS3/4A PI 
PTV/r  
 
ritonavir-boosted paritaprevir 
PTV/r/OBT  
 
150/100/25 mg fixed-dose combination tablet 


 
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GLOSSARY (Cont'd) 
 
RAL   
 
raltegravir 
RBV 
 
 
ribavirin  
RVR 
 
 
rapid virologic response 
RTV or /r 
 
ritonavir 
SDD 
 
 
spray-dried solid dispersion  
SVRx  
 
sustained virologic response (at X weeks) 
TAF 
 
 
tenofovir alafenamide 
TDF 
 
 
tenofovir disoproxil fumarate 
TVR 
 
 
telaprevir 
Viekira Pak 
  
OBT, PTV, and RTV tablets; DSV tablets 
VF 
 
 
virologic failure 
vRVR  
 
very rapid virologic response 
 
 


 
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SCHEMA 
 
A5329 
Interferon-Free Therapy for Chronic Hepatitis C Virus Genotype 1 Infection in Participants with 
HIV-1 Coinfection Receiving Concurrent Antiretroviral Therapy 
(C_ASCENT) 
   
DESIGN 
Non-randomized, open-label, phase II study of interferon (IFN)-free 
hepatitis C virus (HCV) therapy for 24 or 12 weeks in sequentially 
enrolled cohorts of participants with HIV-1 coinfection who are taking 
protocol-defined antiretroviral treatment (ART). 
 
DURATION 
Up to 48 weeks per participant 
 
SAMPLE SIZE 
100 participants, 25 participants per cohort 
 
POPULATION  
HCV genotype 1a or 1b and HIV-1 coinfected participants (HCV 
treatment-naïve or HCV treatment-experienced) who are on a 
concurrent integrase inhibitor (INI)-based (raltegravir [RAL] or 
dolutegravir [DTG]) or protease inhibitor (PI)-based (darunavir [DRV] 
or atazanavir [ATV]) ART regimen. 
 
 
Participants will be categorized according to evidence of cirrhosis (yes or 
no). 
 
 
For each 25-participant cohort, the number of participants enrolled with 
cirrhosis will be limited to 7.  
 
REGIMENS  
Among participants taking an INI-based (RAL or DTG) ART regimen for 
HIV-1: 24 (Cohort A) or 12 (Cohort B) weeks of HCV treatment with HCV 
direct-acting antivirals (DAA) paritaprevir/ritonavir/ombitasvir 
(PTV/r/OBT) + dasabuvir (DSV) +/- ribavirin (RBV) therapy (DAA+/-RBV 
therapy):   
• 
Drug 1: PTV/r/OBT (150/100/25 mg; two 75/50/12.5 mg fixed -dose 
combination tablets) orally (PO) once a day (QD) plus 
• 
Drug 2: DSV (250 mg) PO twice per day (BID) plus 
• 
Drug 3: RBV (1000 or 1200 mg weight-based) dosed in two divided 
doses PO BID (participants with HCV genotype 1a only; 
participants with HCV genotype 1b will not receive RBV) 
 
Among participants taking a HIV-1 PI-based (DRV or ATV) ART 
regimen for HIV-1: 24 (Cohort C) or 12 (Cohort D) weeks of HCV 
treatment with HCV DAA+/-RBV therapy:   
• 
Drug 1: PTV/r/OBT (150/100/25 mg; two 75/50/12.5 mg fixed-dose 
combination tablets) PO QD plus 
• 
Drug 2: DSV (250 mg) PO BID plus 


 
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SCHEMA (Cont'd) 
 
• 
Drug 3: RBV (1000 or 1200 mg weight-based) dosed in two divided 
doses PO BID (participants with HCV genotype 1a only; 
participants with HCV genotype 1b will not receive RBV) 
 
Details for the qualifying ART concomitant regimens are in protocol 
section 5.4.1. 
 
Each cohort will include two steps: on-HCV treatment (Step 1) and post-HCV treatment 
follow-up (Step 2). 
 
 
 
 
 
Cohort A 
N=25 
 
 
 
 
Cohort B 
 
N=25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort C 
N=25 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort D 
N=25 
 
 
 
 
 
 
PTV/r/OBT + DSV +/- RBV 
PTV/r/OBT + DSV +/- RBV 
Group 1: INI-based (DTG or RAL) ART regimen (48 weeks total) 
SVR36 
24 weeks 
12 weeks 
PTV/r/OBT + DSV +/- RBV 
PTV/r/OBT + DSV +/- RBV 
SVR36 
SVR24 
24 weeks 
Group 2: HIV-1 PI-based (ATV or DRV) ART regimen (48 weeks total) 
12 weeks 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Combination therapy with the hepatitis C virus (HCV) direct-acting antiviral (DAA) 
treatment regimen of paritaprevir (PTV)/r (ritonavir)/ombitasvir (OBT) plus 
dasabuvir (DSV), with and without ribavirin (RBV) (DAA+/-RBV therapy) will be 
safe and well tolerated.  
 
1.1.2 DAA+/-RBV therapy will result in sustained virologic response (SVR12) rates higher 
than 70% corresponding to the SVR12 rates observed with telaprevir (TVR) and 
boceprevir (BOC) plus pegylated interferon (PegIFN)/RBV.  
 
1.2 
Primary Objectives 
 
1.2.1 To evaluate the safety and tolerability of DAA+/-RBV therapy in participants 
coinfected with HIV-1.  
 
1.2.2 To estimate the efficacy of DAA+/-RBV therapy in HCV/HIV-1 coinfected 
participants, as measured by the SVR at 12 weeks (SVR12) after DAA+/-RBV 
therapy discontinuation, where SVR12 is defined as HCV RNA in the blood less than 
the assay lower limit of quantification (LLOQ). 
  
1.3 
Secondary Objectives 
 
1.3.1 To evaluate HIV-1 virologic failure (VF), defined in section 7.3, in HCV/HIV-1 
coinfected participants during coadministration of antiretroviral therapy (ART) and 
DAA+/-RBV therapy. 
 
1.3.2 To evaluate acquisition of major HIV-1 resistance mutations in HCV/HIV-1 coinfected 
participants who experience HIV-1 VF during coadministration of ART and DAA+/-
RBV therapy and during the initial four-week period following discontinuation of 
DAA+/-RBV therapy. 
 
1.3.3 To characterize HCV resistant variants before, during and after the initial 12 week 
period following discontinuation of DAA+/-RBV therapy in all participants not 
attaining SVR12. 
 
1.3.4 To estimate the population plasma pharmacokinetic (PK) parameters of DAA+/-
RBV therapy, during coadministration with antiretrovirals (ARVs) in HCV/HIV-1 
coinfected participants, and to compare the participant-specific PK parameters 
obtained with those reported in prior studies for HIV-1 seronegative participants. 
 
1.3.5 To assess the relationship of markers of immune activation, including IP10 and 
sCD14, measured before, during and after administration of DAA+/-RBV therapy and 
DAA+/-RBV therapy outcome (SVR12) and/or the presence of HCV resistance 
mutations before, during and after administration of DAA+/-RBV therapy. 


 
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1.3.6 To estimate the efficacy of DAA+/-RBV therapy HCV/HIV-1 coinfected participants, 
as measured by the sustained virologic response at 24 weeks (SVR24) after DAA+/-
RBV therapy discontinuation where SVR24 is defined as HCV RNA in the blood less 
than the assay LLOQ. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To evaluate LPS, IL-6, CD4+, and CD8+ T cell HLA DR/CD/38 coexpression, natural 
killer (NK) 16+56- subset frequency and NKP30, NKG2A, IFNaR1/IFNaR2 
expression, hyaluronic acid (HA),D-dimer, high-sensitivity C-reactive protein 
(hsCRP), and I-FABP measured before, during, and after administration of DAA+/-
RBV therapy. 
 
1.4.2 To describe the kinetics of innate and adaptive immune responses over the course of 
HCV treatment with DAA+/-RBV therapy to gain insight into mechanisms underlying 
innate and adaptive immune impairment. 
 
1.4.3 To explore associations of ARV and DAA PK parameters with covariates such as 
cirrhosis classification and, presence of single nucleotide polymorphisms in the 
human genome. 
 
1.4.4 To explore associations of participant-specific ARV and DAA PK parameters with 
HIV-1 and/or HCV VF, and with occurrence of selected toxicities including elevation 
in serum alanine aminotransferase (ALT) levels. 
 
1.4.5 To estimate the population plasma PK parameters of ARVs when taken alone 
and when taken with DAA+/-RBV therapy in HCV/HIV-1 coinfected participants, 
and to compare the participant-specific PK parameters before versus after 
dosing to steady-state of the DAA+/-RBV therapy. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Shared risk factors and routes of transmission have resulted in a disproportionate 
prevalence of chronic HCV infection in those with HIV-1 infection. Across participants 
enrolled in ACTG studies the HCV antibody prevalence was found to be 16% [1]. Following 
the introduction of highly active antiretroviral therapy (HAART), end stage liver disease, 
largely due to HCV, has emerged as a leading cause of mortality in HIV-1 infected 
participants [2]. HCV infection in those with HIV-1 also results in accelerated liver disease 
progression and poor response to PegIFN + RBV therapy [3-5]. In addition to marginal 
efficacy, PegIFN therapy is particularly problematic in this population due to the high 
prevalence of co-morbidities such as depression and cytopenias (eg, neutropenia). In 
practice, these limitations have led to low rates of HCV treatment in participants with HIV-1 
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protease inhibitors (PIs), TVR and BOC, added to PegIFN/RBV in this population there is a 
great medical need for effective, IFN-free HCV treatment options in the HCV/HIV-1 
coinfected population [7, 8]. Accordingly, a key portion of the ACTG Hepatitis 
Transformative Science Group’s (HEPTSG) mission is to advance therapy for HCV infection 
through the study of novel HCV antivirals.  
 
Therapy for chronic HCV infection has evolved rapidly with the introduction of multiple DAAs 
targeting distinct aspects of the viral life-cycle. In particular, DAAs targeting the HCV NS3/4A 
protease, NS5A protein, and the NS5B RNA polymerase are among the most promising and 
have been evaluated in combination with PegIFN and RBV as well as in IFN-free 
combinations. Specific compounds of interest for this protocol include; 1) PTV, an NS3/4A 
PI, 2) OBT an NS5A inhibitor, and 3) DSV a non-nucleoside NS5B polymerase inhibitor 
(NNI). This combination (OBT, PTV, RTV + DSV tablets [Viekira Pak]) constitutes an 
HCV treatment regimen approved by the US Food and Drug Administration (FDA) on 
December 19, 2014, for the treatment of chronic HCV genotype 1 infection in persons 
with and without HIV-1 coinfection. AbbVie released addenda dated November 19, 
2015, for the PTV, OBT, and DSV IBs dated June 10, 2015. 
 
PTV is a highly selective and potent NS3/4A PI with a sub-nanomolar 50% effective 
concentration (EC50s) against HCV genotypes 1a and 1b in vitro [Investigational Product: 
PTV, ABT-450 (A-1043422); AbbVie; 8th Edition, June 10, 2015]. PTV is highly protein 
bound (99.5%) with metabolism primarily via cytochrome P450 (CYP) isoenzyme 3A4. RTV 
or r dosed at 100 mg daily increases the area under the concentration time curve (AUC) and 
C24 of a single 300 mg dose of PTV by 50 and >300-fold, respectively. PTV is a moderate 
inhibitor of the organic anion transporting polypeptide transporter, (OATP1B1 [SLCO1B1]), 
and an inhibitor of UGT1A1 (IC50 4.4 μM). PTV does not inhibit the CYP isoforms 1A2, 2C9, 
2C19, 2D6, or 3A4 in human liver microsomes. PTV with RTV has generally been safe and 
well tolerated in both healthy human volunteers and HCV infected individuals. In the ongoing 
pivotal phase II M11-652 study (n=448; detailed below) Grade 3 ALT elevations (>5x ULN) 
were noted in 5 participants (0.9%). Importantly, these elevations were associated with a 
higher dose of PTV/r (200/100 mg) (4 participants); concomitant increases in bilirubin were 
not seen and ALT elevations resolved with continued dosing of PTV in most cases. In this 
same study, asymptomatic Grade 3 bilirubin elevations, presumed due to inhibition of 
OATP1B1, were seen in 1.9% of participants and resolved with continued therapy. 
 
OBT is a potent NS5A inhibitor with an in vitro EC50 of 56-190pM in the presence of 40% 
human serum assayed in a genotype 1 subgenomic replicon system [Investigational 
Product: OBT, ABT-267 (A-1233617); AbbVie; 6th Edition, June 10, 2015]. OBT is highly 
protein bound (99.98%) with a half-life of 18-26 hours and is primarily metabolized by CYP 
3A4. Despite predominantly CYP 3A4 metabolism, RTV 100 mg only increased OBT 
exposure by about 50%. The bioavailability of OBT is decreased by roughly 40% in the 
fasted state. OBT has a low potential for drug-drug interaction as evidence by a lack of 
inhibition of CYP isoforms with the exception of weak inhibition of CYP 2C8. OBT has been 
safe and well tolerated in both healthy volunteers and HCV infected participants. At this 
time no apparent OBT specific side effects or laboratory abnormalities have been identified 
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DSV is a potent NS5B NNI with EC50s in genotype 1 replicon cells of 21-99nM (40% human 
serum) [Investigational Product: DSV, ABT-333 (A-998821); AbbVie; 8th Edition, June 10, 
2015]. DSV is also highly protein bound (>99%) with a half-life of 5-8 hours and is primarily 
metabolized by CYP 2C8, and to a lesser extent, CYP 3A4. Of note the formulation of DSV 
(dosed at 400 mg twice per day [BID]) used in phase II studies has been improved resulting 
in a roughly 50% increase in bioavailability resulting in dosing at 250 mg BID in subsequent 
studies. Ingestion of DSV with a high fat meal increases exposure by about 40%. DSV has a 
low potential for drug-drug interactions with inhibition (IC50) of CYP 2C9 and 2C19 at 9 and 
18μM, respectively. The IC50 for CYP 3A4 inhibition is >40 μM. During in vitro 
electrophysiology assays DSV was found to have an IC50 of 0.3μg/mL in the human Ether-
á-go-go Related Gene (hERG) assay. During intensive electrocardiogram (EKG) monitoring 
studies in healthy volunteers at doses of 1200-2000 mg, DSV increased the corrected QT 
interval by no more than 6.4msec. [See Investigational Product: DSV, ABT-333]. Based on 
the DSV dose of 250 mg BID with the new formulation the expected impact on the QTc 
interval is minimal. Similar to OBT, DSV has been well tolerated in both healthy volunteers 
and HCV-infected participants without clear unique side effects or associated laboratory 
abnormalities beyond those attributed to PTV/r in a dose related fashion. 
 
While multiple HCV DAA combination regimens are being developed, some of the most 
promising are based on various combinations of HCV DAAs paired with RTV boosted PTV 
(PTV/r). In two small studies (PILOT [NCT01306617] and CO-PILOT [NCT01221298]), 
PTV/r was studied in combination with two different NNIs (DSV or ABT-072) plus RBV. This 
combination was administered for 12 weeks to HCV mono-infected participants who were 
HCV treatment-naïve and participants who had been previously treated with PegIFN/RBV 
and failed to achieve a SVR. Among the treatment-naïve participants, SVR was observed 
in 91-95% of participants, whereas SVR was achieved in only 47% of participants with 
prior treatment failure [9, 10].  
 
In a follow-up phase II study, 570 HCV genotype 1 monoinfected participants are being 
treated with the PTV/r in combination with a NS5A inhibitor (OBT) with or without the NNI 
(DSV) and/or RBV [11]. This study (M11-652, NCT01464827) has enrolled both HCV 
treatment-naïve and treatment-experienced, null virologic responders and is testing different 
lengths of therapy (8, 12, and 24 weeks) as well as different combinations of ARVs. 
Treatment-naïve participants treated with DAA+/-RBV therapy for 12 weeks showed SVR12 
rates of 99% and sustained virologic response at week 24 (SVR24 rates) of 96% in an 
intention to treat analysis [11]. Omission of RBV in the 12-week arm resulted in an SVR12 
rate of 90% and SVR24 of 87%. Based on the excellent response rate in the treatment-naïve 
population for 12 weeks, it is not surprising that extension of the duration to 24 weeks 
resulted in a similar SVR12 rate (93%). Among the more difficult to treat population of null 
responders to prior PegIFN/RBV, this regimen given for 12 weeks led to SVR12 and SVR24 in 
93% of participants. Extension to 24 weeks in the null responder population increased the 
SVR12 to 98% and SVR24 to 95%. The regimen was safe and well tolerated for durations of 
therapy up to 24 weeks.  
 
In November 2012, phase III clinical trials were initiated for HCV mono-infected participants 
who are HCV treatment-naïve (SAPPHIRE-I, NCT01716585), and treatment-experienced 
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note, these studies are utilizing a once a day (QD), fixed-dose combination tablet that 
contains two DAAs plus RTV (PTV/r/OBT) plus BID dosing of DSV and RBV (DAA+/-RBV 
therapy). In addition, studies are underway to evaluate PTV/r/OBT without RBV and without 
DSV (PEARL-I, NCT01685203). 
 
In Study M11-646 (SAPPHIRE-I), a total of 631 participants were randomized and received 
at least one dose of study drug, of which 67.7% had HCV genotype 1a and 32.3% had HCV 
genotype 1b.The SVR12 rate for treatment-naïve participants receiving 3-DAA + RBV for 12 
weeks was 96.2%. VF was noted in 7/322 (2.2%) genotype 1a participants (on treatment 
VF: n=1; relapse: n=6) and 1/151 (0.7%) genotype 1b participants (relapse).  
 
In Study M13-098 (SAPPHIRE-II), a total of 394 participants were randomized and 
received at least one dose of study drug, of which 58.4% had HCV genotype 1a, 41.4% had 
HCV genotype 1b, 49.0% were prior pegIFN/RBV null responders, 21.9/% were prior 
pegIFN/RBV partial responders, and 29.2% were prior pegIFN/RBV relapsers. The SVR12 
rate for treatment-experienced participants receiving 3-DAA + RBV for 12 weeks was 
96.3%. VF (all relapse) was noted in 5/173 (2.9%) genotype 1a participants and 2/123 
(1.6%) genotype 1b participants. 
 
The above regimen is also being studied in the HCV mono-infected participants with 
compensated cirrhosis in a phase III randomized controlled trial. The M13-099 study 
(TURQUOISE-II, NCT01704755) enrolled compensated cirrhotic participants. A total of 380 
participants were randomized and received at least one dose of study drug, of which 
68.7% had HCV genotype 1a, 31.3% had HCV genotype 1b, 42.1% were treatment-naïve, 
36.1% were prior pegIFN/RBV null responders, 8.2% were prior pegIFN/RBV partial 
responders, and 13.7% were prior pegIFN/RBV relapsers.  
 
The SVR12 rates for participants with compensated cirrhosis treated with 3-DAA + RBV for 
12 or 24 weeks were 91.8% and 95.9%, respectively. VF was noted in 13/208 (6.3%) 
participants (on treatment VF: n=1; relapse: n=12) receiving the 12-week regimen and 
4/172 (2.3%) participants (on treatment VF: n=3; relapse: n=1) receiving the 24-week 
regimen. 
 
In Study M14-490 (TURQUIOSE-III), a total of 60 HCV mono-infected patients with 
compensated cirrhosis and HCV genotype 1b were treated with 3-DAA (Viekira Pak) 
alone (no RBV) for 12 weeks. SVR12 was achieved in all 60 patients with no VF. Based 
on this result, HCV treatment guidelines [16] were modified to state that patients 
infected with HCV genotype 1b should be treated with 3-DAA (Viekira Pak) alone, 
including those with cirrhosis and HIV-1 infection.   
 
In Part 1a of the study M14-004 (TURQUIOSE-I), 63 patients with HIV-1 and HCV 
genotype 1a or 1b coinfection were treated with 12 or 24 weeks of 3D (Viekira Pak) + 
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2.2 
Rationale 
 
Based on the FDA approval of this combination and the immense medical need in the 
HCV/HIV-1 coinfected population, a study of DAA+/-RBV therapy in this population is 
attractive and continues to be urgently needed. 
 
Rationale for inclusion of raltegravir (RAL) or dolutegravir (DTG) plus tenofovir disoproxil 
fumarate (TDF)/emtricitabine (FTC) or abacavir (ABC)/lamivudine (3TC) as protocol-
defined ART regimen Group 1 
RAL is a well-tolerated HIV strand transfer integrase inhibitor (INI) that is currently a 
component of recommended first line therapy for adults with susceptible HIV-1 infection by 
the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines 
for Adults and Adolescents [41]. Important for this study, RAL has a low potential for drug-
drug interactions (DDIs) due to its primary metabolism via UGT1A1. Further, DAA+/-RBV 
therapy was coadministered with RAL 400 mg BID to steady state for a duration of 14 days 
in healthy volunteers. Based on the preliminary PK analysis, no clinically relevant changes 
in PTV, OBT, DSV, or DSV M1 exposures (based on comparison with historical data) were 
observed during coadministration of DAA+/-RBV therapy with RAL. The exposures of RAL 
during coadministration with DAA+/-RBV therapy were 2- to 2.3-fold of RAL administered 
alone. Based on the U.S. FDA summary basis of approval for RAL, up to a 2-fold increase in 
RAL exposures are expected to be safe and well tolerated. In addition, in the phase III 
studies of RAL, coadministration of RAL with acid suppressing agents, which showed 3- to 
4-fold increases in RAL exposures in phase I studies, were demonstrated to be safe [38]. 
Given the high therapeutic index of RAL and the lack of an effect of RAL on the DAA 
regimen it is appropriate to proceed with a study in coinfected participants with HCV on a 
RAL-based ART regimen. 
 
TDF in combination with FTC and 3TC are nucleos(t)ide reverse transcriptase inhibitors that 
are well tolerated and currently a component of recommended first line therapy for adults 
with susceptible HIV-1 infection by the DHHS Panel on Antiretroviral Guidelines for Adults 
and Adolescents [41]. PK studies for 7 to 14 days analysis shows that TDF (300 mg QD)  
and FTC (200 mg QD) exposures at steady state were not affected (≤25% higher) by 
coadministration of OBT, PTV/r + DSV. The steady state exposures of PTV, DSV and OBT 
were also not affected (up to ± 30% change) when PTV/r + DSV + OBT were 
coadministered with TDF and FTC. The coadministration of multiple doses of TDF and FTC 
with PTV/r + DSV +OBT was safe and well tolerated. Accordingly, no dose adjustment is 
expected to be required for RAL plus TDF and FTC or 3TC, PTV/r, DSV, and OBT during 
coadministration.  
 
DTG is a well-tolerated HIV strand transfer INI that is currently a component of 
recommended first line therapy for adults with susceptible HIV-1 infection by the 
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents [41]. Important 
for this study, DTG has a low potential for DDIs as it does not inhibit nor induce CYP 
isoenzymes. DTG is primarily metabolized by UGT1A1, with minor contribution by 
CYP3A4. It is also a substrate for the transporters P-glycoprotein and breast cancer 
resistance protein. A PK study performed in healthy adults (n=12) administered DTG 
(50mg QD) and OBT/PTV/r (25/150/100mg QD) with DSV (250 mg BID) (AbbVie study 


 
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M14-228). DAA exposures (Cmax, AUC, and Ctrough) were minimally affected. There was 
a 34% and 28% decrease in PTV and RTV Ctrough concentrations, respectively, which 
were not considered clinically significant changes. OBT, DSV, and DSV M1 metabolite 
exposures were up to 16% lower. DTG exposures (Cmax, AUC, and Ctrough) were 22% to 
38% higher. These PK changes are not considered to be clinically significant, and 
therefore, no dose adjustment is expected for the DAA regimen or DTG.       
 
Rationale for inclusion of darunavir (DRV) or atazanavir (ATV) plus TDF/FTC or ABC/3TC 
or DTG as protocol defined ART regimen Group 2 
DRV is a well-tolerated HIV-1 PI that is currently a component of recommended first line 
therapy for adults with susceptible HIV-1 infection by the DHHS Panel on Antiretroviral 
Guidelines for Adults and Adolescents [41].  
 
In healthy volunteers, the DAA+/-RBV therapy (containing 100 mg of RTV) was 
coadministered with DRV 600 mg + RTV 100 mg BID and DRV 800 mg + RTV 100 mg QD 
to steady state for a duration of 14 days. Preliminary PK analysis shows that during 
coadministration of the DAA+/-RBV therapy with DRV 600 mg + RTV 100mg BID, the steady 
state exposures of OBT were unaffected (only about 25% lower), while PTV and DSV were 
modestly lower (up to ± 45% lower). During coadministration of the DAA+/-RBV therapy with 
DRV 800 mg + RTV 100 mg QD, the steady state exposures of OBT and DSV were 
unaffected, while PTV exposures were modestly higher (about 30% to 50%). DRV 
exposures (Cmax and AUC) at steady state were not affected (up to 25% lower) following 
coadministration of the DAA+/-RBV therapy with DRV + RTV QD and BID regimens; but, 
DRV C12 levels were about 43% lower and C24 levels were only about 10% lower during 
coadministration of DRV 600 mg + RTV 100 mg BID with 3- HCV DAA combination. 
Similarly, DRV C24 levels were about 50% lower during coadministration of DRV 800 mg + 
RTV 100 mg QD with the DAA+/-RBV therapy. The comparable Cmax, AUC and lower C12 or 
C24 levels of DRV observed with coadministration are not expected to significantly affect the 
safety or efficacy based on prior DRV clinical trials. The PK-pharmacodynamic (PK-PD) 
analyses of DRV from two large phase III trials, the ODIN and ARTEMIS studies, showed no 
apparent relationships between DRV AUC24 and Ctrough (C24) and the change in log10 HIV-1 
viral load from baseline at Week 48 and the proportion of participants achieving plasma 
viral load ≤50 copies/mL at Week 48 [39, 40]. In these studies, the median DRV Ctrough was 
about 37-fold higher than the EC50 of the wild-type virus. Hence, during coadministration 
with the DAA+/-RBV therapy, DRV C24 from the DRV 800 mg + RTV 100 mg QD regimen is 
expected to be ~18-fold higher, while DRV C12 and C24 from the DRV 600 mg + RTV 100 mg 
BID regimen are expected to be ~18-fold and ~33-fold higher, respectively, than the EC50 of 
the wild-type virus. The coadministration of DRV + RTV as QD and BID regimens with the 
DAA+/-RBV therapy was safe and well tolerated with adverse events (AEs) and laboratory 
abnormalities being mostly mild and not clinically significant. There were no clinically 
significant changes from baseline in vital signs, clinical laboratory tests or EKGs. 
Accordingly, adjustment is expected to be required for ritonavir-boosted darunavir (DRV/r) 
QD plus TDF and FTC or 3TC, PTV/r, DSV, and OBT during coadministration. Participants 
will be required to switch to DRV 600 mg BID with RTV dosed separately only with the 
evening dose of DRV since the morning dose of DRV is boosted by the RTV coformulated 
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ATV is an HIV-1 PI and is considered an alternative agent for use in cART for adults 
with susceptible HIV-1 infection according to the DHHS Panel on Antiretroviral 
Guidelines for Adults and Adolescents [41]. ATV is metabolized by CYP3A4 and is 
recommended to be dosed at 300 mg with 100 mg of RTV QD. ATV inhibits CYP3A4 
and CYP2C8, as well as, UGT1A1. Because of inhibition of UGT1A1, the main adverse 
effect associated with ATV/r is reversible indirect hyperbilirubinemia. The safety and 
PKs of ATV/r (300/100 mg) with PTV/r/OBT (150/100/25 mg QD) and with DSV (250 mg 
BID) has been studied in healthy volunteers (Abbvie Study M13-394). A total of 24 
participants received ATV QD in the morning or evening. The RTV component of ATV 
was administered as part of the 3-DAA regimen for those taking ATV in the morning. 
For ATV in the evening, RTV 100 mg was coadministered with the evening dose of 
ATV and thus, participants received 200 mg total daily of RTV (100 mg with the DAA 
and 100 mg with the evening dose of ATV). PTV Cmax and AUC during 
coadministration with ATV QD (morning) and QD (evening) were up to 1.5- to 2-fold 
and 2- to 3-fold, respectively. PTV Ctrough were 3.2-fold and 12-fold higher during 
coadministration with ATV QD (morning) and QD (evening), respectively. OBT and 
DSV (and M1 metabolite) exposures were minimally affected (up to 25%) during 
coadministration with ATV/r in the morning or evening. ATV QD (morning) AUC and 
Cmax were comparable when given with the DAAs, while Ctrough was approximately 9% 
lower with the DAAs. RTV QD (morning) Cmax was approximately 20% lower, and AUC 
and Ctrough were up to 10% lower with coadministration of the DAAs. ATV QD (evening) 
AUC approximately 20% higher and Ctrough was 68% higher when coadministered with 
the DAAs, while Cmax values were comparable. RTV BID (evening) Cmax and AUC were 
35% and 125% higher, respectively, while Ctrough was approximately 14-fold higher 
during coadministration with DAAs. Grade 3 total bilirubin elevations were observed 
when ATV/r was given with 3-DAA; however, these were common during dosing with 
ATV/r alone and did not worsen when the DAAs were added.           
 
Rationale for enhanced HIV-1 RNA monitoring during coadministration of DAA therapy 
While unlikely based on the available healthy volunteer DDI data and the delivery of the 
HCV regimen for only 12 or 24 weeks, the potential for HIV-1 viral failure during this study 
presents unique issues due to the use of low-dose RTV to boost levels of PTV. Participants 
experiencing HIV-1 VF would be exposed to 100 mg of RTV daily and could potentially 
select for HIV-1 PI resistance mutations. RTV monotherapy at 400-600 mg BID sequentially 
selects for resistance mutations beginning with the V82A/F mutant followed by the 
accumulation of additional mutants at positions 54, 71, and 36 in the protease gene over the 
course of weeks to months [12]. Whether the exposure obtained with 100 mg of RTV is 
sufficient to select for HIV-1 protease resistance mutations is unknown. In addition the 
V82A/F mutant does not confer significant cross-resistance to commonly used PIs such as 
DRV or ATV; given that the selection of additional protease mutants requires extended 
exposure, frequent HIV-1 RNA monitoring is likely to prevent the accumulation of clinically 
significant HIV-1 PI resistance mutations. The excellent preliminary efficacy data for the 
proposed HCV treatment regimen [11], combined with the high burden of HCV disease in 
the coinfected population and the need for more effective therapies present an overall 
favorable risk-benefit profile for the proposed study. Importantly, the risk of exposure of 
replicating HIV-1 to low-dose RTV is further reduced by 1) limiting duration of RTV-
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participants with documented suppression of HIV-1 RNA for at least 6 months prior to HCV 
treatment; 3) frequent monitoring of HIV-1 RNA, utilizing a strategy that is based on the 
intensive HIV-1 RNA monitoring framework used in A5294 (treatment of participants taking 
HIV-1 PI-based ART during the administration of BOC, a HCV PI, known to result in lower 
exposure to the HIV-1 PI).  
 
Rationale for omission of RBV in treatment regimens for participants with genotype 
1b HCV infection 
The role RBV plays in virologic response to the study regimen has been evaluated in 
several large studies. In two companion phase III studies, treatment-naïve non-
cirrhotic participants with genotype 1a (n=305) and genotype 1b (n=419) were 
randomized to treatment with PTV/r/OBT plus DSV with or without weight-based RBV 
for 12 weeks [13]. Genotype 1a participants treated without RBV had a significantly 
lower SVR12 rate compared with those who received RBV (90.2% vs. 97.0%). In 
contrast, no such difference in SVR rates was seen in genotype 1b participants; 
99.5% without RBV versus 99.0% with RBV. Based on these data, the prescribing 
information [14] and guidelines recommendations omit RBV from treatment regimens 
for genotype 1b non-cirrhotic patients.  
 
Until recently, data on the treatment of genotype 1b cirrhotic patients with PTV/r/OBT 
plus DSV in the absence of RBV was lacking. The recently published phase IIIb 
TURQUOISE III study addressed this issue in an open-label single arm study of 60 
treatment-naïve and treatment-experienced genotype 1b cirrhotic participants treated 
for 12 weeks with PTV/r/OBT plus DSV alone [15]. A 100% SVR12 rate was seen in this 
study strongly suggesting, despite the lack of a control arm, that RBV can be omitted 
from this regimen when treating genotype 1b patients including those with cirrhosis 
and treatment experience. Notably, the Infectious Diseases Society of 
America/American Association for the Study of Liver Diseases (IDSA/AASLD) 
guidelines have been updated, supporting the approach of omitting RBV from the 
treatment regimen for all genotype 1b patients [16].  
 
Despite the lack of a dedicated trial evaluating the role of RBV in HIV-1 coinfected 
genotype 1b patients, we believe omission of RBV is justified in the treatment 
regimens of genotype 1b participants in this study because: 1) the compelling data 
that RBV is not needed to optimize results in HCV monoinfected genotype 1b 
patients, 2) generally similar results seen in HIV-1-HCV coinfected patients when 
compared with HCV mono-infected participants treated with DAA regimens and 3) the 
increased risk of side effects and AEs when RBV is included in an HCV treatment 
regimen. While RBV side effects can certainly be managed, in this case, there is no 
compelling reason to believe inclusion of RBV will offer any benefit to genotype 1b 
HIV-1 coinfected participants. Based on this assessment, weight-based RBV will not 
be administered to genotype 1b-infected participants in Version 2.0 of the A5329 
protocol. 
 
Rationale for inclusion of participants with compensated cirrhosis 
Coinfected participants with cirrhosis form a group with a significant unmet medical need 
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population. The DAA regimen of once daily (QD), fixed-dose combination tablet which 
contains two DAAs plus RTV (ABT-450/r/ABT-267) plus BID dosing of ABT-333 and RBV 
(DAA+/-RBV therapy) is being studied in the HCV mono-infected participants with 
compensated cirrhosis in a phase III randomized controlled trial (M13-099, NCT01704755). 
A total of 380 participants were randomized and received at least one dose of study drug. 
The SVR12 rates for participants with compensated cirrhosis treated with 3-DAA + RBV for 
12 or 24 weeks were 91.8% and 95.9%, respectively. VF was noted in 13/208 (6.3%) 
participants (on treatment VF: n=1; relapse: n=12) receiving the 12-week regimen and 
4/172 (2.3%) participants (on treatment VF: n=3; relapse: n=1) receiving the 24-week 
regimen. 
 
Safety data from this trial suggests a safety profile consistent with the known profile for the 
DAA+/-RBV therapy. The majority of treatment-emergent AEs were mild or moderate in 
severity, with few events occurring more frequently in the 24-week arm compared with the 
12-week arm. Serious adverse events (SAEs) occurred in 5.5% overall, with similar rates in 
each arm, and few patients discontinued because of AEs (2.1% overall). Hemoglobin 
decline of Grade ≥2 occurred in 7.2% of patients in the 12 week arm and 11.0% in the 24 
week arm. For patients in both treatment duration arms, hemoglobin decline was 
successfully managed with ribavirin dose modifications, without a negative impact on SVR12. 
Bilirubin elevation occurred at a higher frequency in this cirrhotic population than observed 
in clinical trials of the same regimen in patients without cirrhosis. Elevations in indirect 
bilirubin with this regimen are likely related to ribavirin-associated hemolysis, along with 
inhibition of the bilirubin transporter OATP1B1 by PTV, as has been reported for other NS3 
PIs. Bilirubin levels were not treatment limiting, typically peaked at about two weeks of 
treatment, were not associated with elevations in ALT, and resolved to baseline levels 
during the post-treatment period.  
 
Given the available preliminary data and high unmet medical need in this population, 
coinfected patients with cirrhosis form a priority population for study in A5329. However, 
patients with decompensated cirrhosis (Child-Pugh classification B and C) are 
excluded from enrollment in A5329. This is based on the report from the FDA of 26 
patients with advanced liver disease who experienced serious liver injury during 
treatment with 3-DAA in the post-market setting. While details of these patients and 
their treatment are limited, 3-DAA is contraindicated in this patient population, and 
such patients are not eligible for participation in A5329. 
 
Rationale for peripheral immune activation, inflammation, and adaptive immunity studies 
NK cell function is regulated by a balance of activating and inhibitory receptors/signals. NK 
phenotype correlates with course of HCV infection. Pairing of NK cell inhibitory KIR2DL3 
and its weaker binding ligand (HLA-C1) are associated with self-clearance of HCV [17], and 
KIR2DL3 genotype and increased NKG2C expression are associated with response to IFN-
α therapy [18-20]. In addition to the conventional CD56+ NK cells, a CD16+CD56- NK cell 
subset has been observed to expand during chronic HIV-1 [21, 22], and HCV infection [23]. 
The degree of peripheral blood CD16+CD56- NK cell expansion in chronic HCV infection is 
negatively associated with PegIFN/RBV treatment response [23]. We have recently 
performed an analysis of immunologic predictors of PegIFN/RBV response in HCV-HIV-1 
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These preliminary data from NWCS322 indicate baseline CD16+CD56- NK expansion 
negatively predicts therapy response during HCV-HIV-1 coinfection [24]. Other data from 
our group indicate that in HCV monoinfection IL28B genotype and race are associated with 
CD16+56- NK subset IFN-αR expression, which in turn is associated with IFN-α induced 
pSTAT1 and viral decline magnitude [25]. The dependence of these factors on each other 
are yet to be determined, and whether these relationships hold with a larger sample size, or 
are extended to HCV/HIV-1 coinfection is not known. 
  
Persistent activation of the immune system is well described during progressive HIV-1 
infection. This can be quantified by soluble markers including cytokines and sCD14, as well 
as markers of T, B, NK, and myeloid cell activation [26-28]. Because immune activation may 
be predictive of HIV-1 disease progression [29], it has been proposed that immune 
activation directly contributes to disease pathogenesis [27]. HCV infection is also associated 
with elevated levels of sCD14 and activated CD8+ T cells [30-32], and these markers 
likewise correlate with HCV and HIV-1 disease progression in the context of HCV mono-
infection or HCV/HIV-1 coinfection [30, 31]. Downstream effects of immune activation 
include increased T cell turnover, accumulation of effector T cells within lymph nodes, and 
increased availability of targets for HIV-1 infection [27]. Effects such as these may directly 
contribute to impaired host control of HIV-1 and other pathogens within the infected host 
[33]. Whether immune activation plays a role in predicting outcome of HCV therapy has 
been unclear. Our data from NWCS322 suggest monocyte activation as reflected by plasma 
sCD14 level, and perhaps T cell immune activation, predict IFN therapy response [24]. 
Recent data published by another group is supportive of the same concept [34]. 
Additionally, in our data set sCD14 level correlated with baseline HCV level and 
CD16+CD56- NK cell frequency, and greater frequencies of CD16+CD56- NK cells at 
baseline correlated with lower rate of HCV decline during PegIFN/RBV therapy [24]. Again, 
the dependence of these variables upon each other is not known. However, it appears that a 
number of parameters of innate immune activation are associated with each other, and also 
with therapy outcome. One possibility is that in vivo IFN conditioning attributable to host 
response to chronic HCV infection contributes to these observations. Specifically, IFN may, 
in combination with HCV itself, directly activate monocytes (resulting in sCD14 release) and 
activate NK cells (resulting in NK subset skewing, IFN resistance, yet preservation of IFN 
signaling in the appropriately conditioned NK cells with the favorable IL28B genotype). 
 
Whether these factors predict IFN free therapy response, relapse, or resistance is not 
known. Furthermore, the interaction between the innate and adaptive immune systems 
during HCV immune restoration has not been clarified. The presence of HIV-1 coinfection is 
further likely to modulate this interaction. The present study offers a unique opportunity to 
begin to explore these issues. 


 
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Rationale for formulating the primary outcome of SVR12 based solely upon LLOQ of the 
assay 
The assays for HCV RNA can yield false positives below the linear range of the assay (ie, 
<LLOQ). In a recent retrospective analysis by FDA of the BOC and TVR phase III trials [35], 
it was observed that in the post treatment setting a result of target detected but <LLOQ was 
generally a false positive whereas during HCV antiviral therapy, the same result was 
typically a true positive. Because the probability that a person would be truly HCV-infected 
at post-treatment week 12 and have viremia <LLOQ is very low, the SVR12 outcome for 
A5329 will be based upon being <LLOQ to define 'response' without regards to whether 
target is detected or not (TD versus TND). This follows the recommended terminology and 
definition recently published by FDA and the Forum for Collaborative HIV Research [36]. 
Moreover, this formulation of the primary outcome parallels the definition being used in the 
other planned and on-going studies of this HCV DAA regimen. Outcomes using HCV RNA, 
particularly those during the HCV treatment period, will separately describe those 
unquantifiable (U using the nomenclature proposed by the Forum [37]), as TND (target not 
detected) versus TD (target detected). More details about this are in section 9.0 (Statistical 
Considerations), and the study's Statistical Analysis plan. 
 
Rationale for PK substudy A5334s of RAL and DRV/r before and during combined 
administration with the HCV DAA+/-RBV regimen  
A5334s is an open-label, two-arm, intensive PK substudy of DDIs in participants enrolling 
in A5329. Based on the DDIs observed in healthy volunteers described above, substudy 
A5334s will test the hypothesis that HCV/HIV-1 coinfected participants will have lower 
exposure to DRV and similar exposure to RAL during coadministration with PTV/r/OBT, and 
DSV. A5334s will provide important data on possible PK changes that may occur in 
participants with HCV/HIV-1 coinfection who are being treated for both infections. 
Potential participants for substudy A5334s will be in screening for A5329 with no known 
eligibility violations and plans to enroll in A5329 within the next 7 calendar days following 
enrollment in substudy A5334s. Participants enrolled in substudy A5334s will not be 
permitted to enroll in the Liver Biopsy Substudy A5335s described below. 
 
Overall, substudy A5334s will enroll 12 participants each in ART #1 and #2 (total of 24 
participants) which is expected to yield 10 participants per ARV regimen with complete PK 
data at each of the intensive PK substudy visits. The first PK visit will occur 1 to 7 days prior 
to initiating PTV/r/OBT, DSV, and RBV, participants will complete a 12-hour intensive PK 
study to characterize participant-specific ARV disposition in the absence of HCV DAA+/-
RBV therapy. Four weeks after starting PTV/r/OBT, DSV, and RBV, 12-hour intensive PK 
sampling will be repeated, to characterize the disposition of both ARVs and HCV drugs 
when they are coadministered. 
 
After the second intensive PK evaluation at approximately week 4 on study A5329, 
participation in substudy A5334s will be complete. 
 
Additional details may be found in substudy protocol A5334s entitled: “Pharmacokinetic 
Studies of RAL and DRV/r before and During Combined Administration with PTV/r/OBT, 
DSV and RBV in HCV/HIV-1 Coinfected Participants: A Substudy of A5329”. 
 


 
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Rationale for liver biopsy substudy A5335s to assess intrahepatic HCV dynamics and 
pharmacology 
The HCV kinetic responses to antivirals are indicative of distinct mechanisms of viral control: 
First phase decline of HCV RNA is thought to be due to impaired release of virions by 
infected hepatocytes, while second phase decline is associated with clearance of infected 
hepatocytes. Eradication of HCV from the liver during treatment with HCV DAA+/-RBV 
therapy depends on: i) the suppression of new hepatocyte infections; ii) the clearance of 
HCV-infected hepatocytes; iii) Intrahepatic HCV drug concentrations. To date, the most 
common route for failure to achieve SVR following treatment with HCV DAA+/-RBV therapy 
has been HCV viral relapse, indicating the failure of HCV therapy to clear HCV-infected 
hepatocytes; however, the mechanism of such treatment failure is unknown. The substudy 
will provide first estimates of hepatic clearance of HCV-infected hepatocytes in an IFN-free 
regimen during HCV/HIV-1 coinfection and of intrahepatic drug concentration in 
participants on an IFN-free regimen. 
 
Substudy A5335s is an open label, intensive tissue and serum/plasma viral kinetics (VK) 
and PK study in participants enrolled in A5329. Potential participants for substudy A5335s 
will be in screening for A5329 with no known eligibility violations and will not be permitted to 
enroll in the PK substudy A5334s (described above). Twelve (12) participants will be 
enrolled in substudy A5335s and will undergo liver biopsy #1 before administration of HCV 
DAA+/-RBV therapy (day 1) for single cell laser capture microdissection (scLCM) and 
histologic staging. HCV DAA+/-RBV therapy will be administered following liver biopsy 
intensive HCV VK assessments. On Day 8, participants will undergo liver biopsy #2 for 
scLCM and measurement of HCV DAA drug concentrations. After the evaluations, including 
second liver biopsy at approximately week 1 on A5329, participation in substudy A5335s will 
be complete. 
 
Using scLCM of 400-500 hepatocytes per liver biopsy, intrahepatic HCV RNA will be 
quantified in single hepatocytes along with the expression of IFN stimulated genes (ISGs) 
and intra-hepatic DAA drug concentrations. The primary objective of substudy A5335s is to 
estimate the 1-week change in intrahepatic HCV infection on DAA+/-RBV using scLCM.  
 
Additional details may be found in the substudy protocol A5335s entitled: “Coinfected 
Participants Treated with HCV Direct-Acting Antivirals Plus Ribavirin: Intrahepatic HCV 
Dynamics and Pharmacology: A Substudy of A5329.” 
 
 
3.0 
STUDY DESIGN 
 
Non-randomized, open-label, study of IFN-free HCV therapy in sequentially enrolled cohorts  
receiving HCV therapy for 12 or 24 weeks, respectively, in participants with HIV-1 
coinfection on qualifying ART regimens.  
 
By having the longer treatment-period (24 week) cohorts enroll first, and then 
subsequently enrolling the shorter treatment-period (12 week) cohorts, follow-up 
among these groups is anticipated to facilitate a more uniform timing of closure to 
follow-up to allow the study to proceed to the final analysis phase in an expedient 


 
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manner. Each cohort will be analyzed separately. See section 9.0 for more details on 
analysis. 
 
DAA+/-RBV therapy will include a RTV boosted NS3/4A PI, PTV/r/; an NS5A inhibitor, OBT; 
an NS5B non-nucleoside polymerase inhibitor, DSV; with or without weight-based RBV. 
The study will consist of two study cohorts per ART regimen (n=25 per cohort). Each cohort 
will occur in two steps: on-HCV treatment (Step 1) and post-HCV treatment follow-up (Step 
2). 
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Step 1 Inclusion Criteria 
 
4.1.1 Men and women age ≥18 to ≤70 years at study entry. 
 
4.1.2 Body mass index (BMI) from ≥18 to <38 kg/m2 within 42 days of study entry. BMI is 
calculated as weight measured in kilograms (kg) divided by the square of height 
measured in meters (m). 
 
4.1.3 HIV-1 infection, documented by any licensed rapid HIV-1 test or HIV-1 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-1 and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA 
viral load. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit. 
 
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 must 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 (eg, indirect 
versus competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
 
4.1.4 CD4+ cell count ≥200 cells/uL and CD4+ cell percentage ≥14% within 42 days of 
study entry at any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification. 
 
4.1.5 On a stable, qualifying ART regimen for at least 8 weeks prior to entry. 
 
NOTE: Qualifying ART regimens are detailed in section 5.4.1. 
 
NOTE: Changes in DRV dosing from QD to BID are permitted within the 8 week 
window. For participants on DRV/r, the dose of DRV/r must be 600/100 PO BID for 
at least 2 weeks prior to study entry. 
 


 
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4.1.6 HIV-1 RNA <50 copies/mL for at least 6 months prior to study entry by any US 
laboratory that has a CLIA certification or its equivalent. HIV-1 RNA testing must 
have been performed at least once during the 6 months prior to study entry. 
 
NOTE: Single detectable HIV-1 viral loads at ≥50 copies/mL are not exclusionary if 
followed by an HIV-1 viral load <50 copies/mL. 
 
NOTE: For participants on DRV/r, HIV-1 virologic suppression as detailed in 4.1.6 
must have been attained while the participant was taking a dose of 800/100 mg PO 
QD. 
 
4.1.7 Presence of chronic HCV infection, defined as: 
 
Positive for anti-HCV antibody or HCV RNA at least 6 months before screening, and 
positive for HCV RNA at the time of screening. 
 
OR 
 
Positive for HCV RNA at the time of screening with a liver biopsy consistent with 
chronic HCV infection any time prior to study entry.  
 
4.1.8 HCV treatment-naïve or unsuccessful treatment with pegylated or standard IFN 
alfa with or without RBV. 
 
NOTE: No prior exposure to HCV NS3/4A PI (including but not limited to TVR, BOC, 
simeprevir), NS5A inhibitors (including but not limited to daclatasvir or ledipasvir), 
NS5B NNI or NI inhibitors (including but not limited to sofosbuvir) is allowed. 
 
4.1.9 HCV genotype 1a or 1b infection confirmed by testing at the A5329 VSL Quest 
Diagnostics. Please refer to the laboratory processing chart (LPC) on the 
A5329 protocol-specific web page (PSWP). 
 
4.1.10 Serum HCV RNA >10,000 IU/mL obtained within 42 days prior to study entry by any 
assay performed by the designated A5329 VSL Quest Diagnostics. 
 
4.1.11 The following laboratory values obtained within 42 days prior to study entry. 
• 
Absolute neutrophil count (ANC) ≥750/mm3 
• 
Hemoglobin ≥12 g/dL for men and ≥11 g/dL for women 
• 
Platelet count ≥ 90,000/mm3 
• 
International normalized ratio (INR) ≤1.5  
• 
Participants with known inherited bleeding disorder and INR ≥1.5 may be 
enrolled 
• 
Calculated creatinine clearance (CrCl) using Cockcroft-Gault method ≥60 mL/min   
• 
ALT ≤7 x upper limit of the normal range (ULN)  
• 
Aspartate aminotransferase (AST) ≤7 x ULN range  


 
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• 
Total bilirubin <3 mg/dL for participants not on ATV and <6 mg/dL for 
participants on ATV 
• 
Direct bilirubin ≤1.5 x ULN 
• 
Albumin ≥3.5 g/dL  
• 
Serum alfa-fetoprotein (AFP) <100 ng/mL 
 
4.1.12 Classification of liver disease as cirrhotic or non-cirrhotic prior to study entry 
according to criteria in section 6.4.3.  
 
4.1.13 Participants classified as cirrhotic must have no evidence of hepatocellular 
carcinoma (HCC) as indicated by a negative ultrasound (U/S), computed tomography 
(CT) scan or magnetic resonance imaging (MRI) within 6 months prior to study entry.  
 
NOTE: Participants who have an U/S with results suspicious of HCC followed by a 
subsequent negative CT or MRI of the liver will be eligible for the study. 
 
4.1.14 Females of reproductive potential (defined as women who have not been post-
menopausal for at least 24 consecutive months, ie, who have had menses within 24 
months prior to study entry, or women who have not undergone surgical sterilization, 
specifically hysterectomy, tubal ligation, and/or bilateral oophorectomy) must have a 
negative serum or urine pregnancy test with a sensitivity of ≤25 mIU/mL within 42 
days prior to study entry by any US laboratory that has a CLIA certification or its 
equivalent. 
    
4.1.15 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). 
 
4.1.16 If participating in sexual activity that could lead to pregnancy, the participant (men 
and women) with HCV genotype 1a infection who will receive RBV must agree to 
use two reliable methods of contraception simultaneously while receiving study 
treatment and for 6 months after stopping study treatment and participants (men 
and women) with HCV genotype 1b infection who will not receive RBV must 
agree to use two reliable methods of contraception simultaneously while 
receiving study treatment and for 30 days after stopping study treatment. 
 
A combination of TWO of the following contraceptives MUST be used appropriately: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
IUD (intrauterine device) 
 
NOTE: Hormone-based contraceptives are NOT considered an acceptable form of 
contraception.  
 
4.1.17 Participants who are not of reproductive potential (women who have been post-
menopausal for at least 24 consecutive months or have undergone hysterectomy, 
bilateral tubal ligation, and/or bilateral oophorectomy or men who have documented 


 
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azoospermia) are eligible without requiring the use of 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 participant record (a 
laboratory report of azoospermia is required to document successful vasectomy)  
• 
Discharge summary 
• 
Laboratory report of azoospermia 
• 
Follicle stimulating hormone-release factor (FSH) measurement elevated into the 
menopausal range as established by the reporting laboratory. 
 
4.1.18 Ability and willingness of participant to provide written informed consent. 
 
4.2 
Step 1 Exclusion Criteria 
 
4.2.1 Breastfeeding.  
 
4.2.2 Pregnant sexual partner for male participants with HCV genotype 1a infection 
who will receive RBV. This criterion does not apply to male participants with 
HCV genotype 1b infection who will not receive RBV. 
 
4.2.3 Known allergy/sensitivity or any hypersensitivity to components of study drugs or 
their formulation. 
 
4.2.4 Acute or serious illness requiring systemic treatment and/or hospitalization within 42 
days prior to study entry. 
 
4.2.5 Active hepatitis B infection (positive HBsAg) within 42 days prior to study entry. 
 
4.2.6 History of decompensated liver disease (including but not limited to encephalopathy, 
variceal bleeding, or ascites) prior to study entry. 
 
4.2.7 Any cause of liver disease other than chronic HCV infection, including but not limited 
to the following: 
• 
Hemochromatosis 
• 
Alpha-1 antitrypsin deficiency 
• 
Wilson's disease 
• 
Autoimmune hepatitis 
• 
Alcoholic liver disease 
• 
Drug-related liver disease 
 
NOTE: Steatosis and steatohepatitis on a liver biopsy coincident with HCV-related 
changes would not be considered exclusionary unless the steatohepatitis is 
considered to be the primary cause of the liver disease. 


 
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4.2.8  Uncontrolled or active depression or other psychiatric disorder within 24 weeks prior 
to study entry that in the opinion of the site investigator might preclude adherence to 
study requirements. 
 
4.2.9  Active drug or alcohol use or dependence that, in the opinion of the site investigator, 
would interfere with adherence to study requirements. 
 
4.2.10  Serious illness including uncontrolled seizure disorders, active coronary artery 
disease within 24 weeks prior to study entry, or other chronic medical conditions that 
in the opinion of the site investigator might preclude completion of the protocol. 
 
4.2.11  Presence of active or acute AIDS-defining opportunistic infections within 12 weeks 
prior to study entry.  
 
NOTE: A list of AIDS-defining opportunistic infections as defined by the CDC can be 
found in Appendix I. 
 
4.2.12  Active or history of malignancy within 5 years prior to study entry other than basal 
cell carcinoma of the skin and/or cutaneous Kaposi’s sarcoma (KS) and/or cervical or 
anal dysplasia or carcinoma in situ. 
 
4.2.13  Clinically significant abnormal EKG, or EKG with QT interval corrected for heart rate 
(QTc) using Fridericia's correction formula (QTcF) >450 msec within 42 days of study 
entry.  
 
 
For Fridericia's correction, refer to the calculator located on the FSTRF website at 
www.fstrf.org. 
 
4.2.14  Use of colony stimulating factors, such as granulocyte colony stimulating factor 
(GCSF) or erythropoietin within 42 days of study entry.  
 
4.2.15  Infection with any HCV genotype other than genotype 1, or mixed genotype infection 
any time prior to study entry. 
 
4.2.16  History of major organ transplantation with an existing functional graft any time prior 
to study entry. 
 
4.2.17  History of hemoglobinopathy (eg, thalassemia) or any other cause of or tendency to 
hemolysis any time prior to study entry. 
 
4.2.18  Child-Pugh score of >6 at screening (cirrhotic participants only). 
 
 
NOTE: To calculate the Child-Pugh score, refer to the following website: 
http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality 
 
 


 
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4.3 
Step 2 Inclusion Criteria 
 
4.3.1 Completion or premature discontinuation (including HCV VF) of Step 1 study 
treatment (ie, HCV) regimen.  
 
NOTE:  See section 8.1 for premature treatment discontinuation.  
 
4.4 
Step 2 Exclusion Criteria 
 
4.4.1 Premature study discontinuation. 
 
NOTE: See section 8.2 for premature study discontinuation.  
 
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(s) approved, as appropriate, by 
their local institutional review board (IRB)/ethics committee (EC) 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 must be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, 
sites must implement the amendment immediately. Sites are required to submit an 
amendment registration packet to the DAIDS PRO at the RSC. Site-specific ICF(s) WILL 
NOT be reviewed and approved by the DAIDS PRO and sites will receive an Amendment 
Registration Notification from the DAIDS PRO that approves the site specific ICFs and 
indicates successful completion of the amendment protocol registration process. A copy of 
the final amendment Registration Notification issued by the DAIDS PRO must 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.  
 


 
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For participants from whom a signed informed consent has been obtained, an ACTG 
Screening Checklist must be entered through the Data Management Center (DMC) 
Participant Enrollment System.  
 
4.5.1 Participant Registration 
 
At the study entry visit, participants will be enrolled according to standard ACTG 
data management procedures.  
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the protocol, 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 A5329 protocol 
chairs.  
• 
Participants enrolled in A5329 may coenroll in only one of the two substudies, A5335s 
or A5334s. Coenrollment into both substudies is not permitted.  
• 
For specific questions and approval for coenrollment in other studies, sites must contact 
the protocol chairs via e-mail as described in the Study Management section. 
 
 
5.0 
STUDY TREATMENT  
 
A5329 study drugs consist of PTV/r/OBT plus DSV with or without weight-based RBV. 
Participants with HCV genotype 1a infection will take weight-based RBV plus 
PTV/r/OBT plus DSV. Participants with HCV genotype 1b infection will take PTV/r/OBT 
plus DSV only. 
 
All participants will receive the same dose of PTV/r/OBT and DSV. For participants with 
HCV genotype 1a infection, the RBV dose will be based on the participant’s body weight 
at entry. Changes in weight after study entry do not require a change in RBV dose. After 
study entry, changes in RBV dose will be only for toxicity management. 
 
No changes in dose are permitted for PTV/r/OBT or DSV. 
 
5.1 
Regimens, Administration, and Duration 
 
ACTG A5329 Version 2.0 revises the study treatment regimens to add the alternative 
of DTG for Cohorts A and B, add the alternative of ATV for Cohorts C and D, and 
eliminate RBV for all cohorts for participants with HCV genotype 1b. 


 
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Administration Instructions for All Cohorts 
• 
Participants (with a negative pregnancy test, if applicable) will be administered the first 
dose of study drugs by the study site personnel and receive instructions for self-
administration of all study drugs through the end of the Treatment Period depending on 
the duration of their assigned treatment cohort as detailed above. DAA+/-RBV therapy 
must be started within 72 hours of study entry. 
• 
Participants will be instructed to take study medication at the same time(s) every day.  
• 
All study drugs should be taken with approximately 240 mL of water within ½ hour after 
eating food.  
• 
All tablets of the study drug regimen are to be taken at the same time (within minutes of 
the other tablets).  
• 
Separate the morning and evening doses by 12 hours. 
• 
If on DRV or ATV regimens (Cohorts C and D), the morning dose of DRV or ATV is to 
be taken with the morning dose of the study drug regimen. 
 
5.1.1 Cohort A (currently on the qualifying RAL or DTG regimen) (24-week duration). 
• 
PTV/r/OBT 75 mg/50 mg/12.5 mg tablets x 2 tablets for a total dose of 150 mg 
PTV/100 mg RTV/25 mg OBT orally (PO) every morning with food. 
• 
DSV 250 mg 1 tablet PO every 12 hours with food. 
• 
For participants with HCV genotype 1a only, RBV will be dosed as follows: 
 
Participants weighing >75 kg: RBV 600 mg PO every 12 hours with food 
for a total daily dose of 1200mg. 
 
Participants weighing ≤75 kg: RBV PO every 12 hours with food in 
divided doses of 400 mg and 600 mg for a total daily dose of 1000 
mg.  
 
5.1.2 Cohort B (currently on the qualifying RAL or DTG regimen) (12-week duration). 
• 
PTV/r/OBT 75 mg/50 mg/12.5 mg tablets x 2 tablets for a total dose of 150 mg 
PTV/100 mg RTV/25 mg OBT PO every morning with food. 
• 
DSV 250 mg 1 tablet PO every 12 hours with food.  
• 
For participants with HCV genotype 1a only, RBV will be dosed as follows: 
 
Participants weighing >75 kg: RBV 600 mg PO every 12 hours with food 
(1200 mg per day).  
 
Participants weighing ≤75 kg: RBV 400 mg PO every morning with food 
and 600 mg PO every evening with food (1000 mg per day). 
 
5.1.3 Cohort C (currently on the qualifying DRV BID or ATV regimen) (24-week duration). 
• 
PTV/r/OBT 75 mg/50 mg/12.5 mg tablets x 2 tablets for a total dose of 150 mg 
PTV/100 mg RTV/25 mg OBT PO every morning with food. 
• 
DSV 250 mg 1 tablet PO every 12 hours with food.  
• 
For participants with HCV genotype 1a only, RBV will be dosed as follows: 
 
Participants weighing >75 kg: RBV 600 mg PO every 12 hours with food 
(1200 mg per day).  
 
Participants weighing ≤75 kg: RBV 400 mg PO every morning with food 
and 600 mg PO every evening with food (1000 mg per day). 


 
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• 
The morning dose of DRV or ATV is to be taken with the morning dose of the 
study drug regimen. 
• 
Omit the concomitant (non-study) medication RTV 100 mg tablet taken with the 
morning DRV or ATV dose while taking DAA+/-RBV therapy. 
 
5.1.4  Cohort D (currently on the qualifying DRV BID or ATV regimen) (12-week duration). 
• 
PTV/r/OBT 75 mg/50 mg/12.5 mg tablets x 2 tablets for a total dose of 150 mg 
PTV/100 mg RTV/25 mg OBT PO every morning with food. 
• 
DSV 250 mg 1 tablet PO every 12 hours with food.  
• 
For participants with HCV genotype 1a only, RBV will be dosed as follows: 
 
Participants weighing >75 kg: RBV 600 mg PO every 12 hours with food 
(1200 mg per day).  
 
Participants weighing ≤75 kg: RBV 400 mg PO every morning with food 
and 600 mg PO every evening with food (1000 mg per day). 
• 
The morning dose of DRV or ATV is to be taken with the morning dose of the 
study drug regimen. 
• 
Omit the concomitant (non-study) medication RTV 100 mg tablet taken with the 
morning DRV or ATV dose while taking DAA+/-RBV therapy. 
 
5.2 
Study Product Formulation and Preparation 
 
Each dose of open-label DAA study drug will be dispensed in the form of tablets 
(PTV/r/OBT, DSV, and RBV). 
 
The formulations are as follows: 
• 
PTV/r/OBT will be provided as 75 mg/50 mg/12.5 mg tablets. PTV/r/OBT will be taken 
PO as 2 tablets QD in the morning which corresponds to a 150 mg. PTV/100 mg RTV/25 
mg OBT dose QD. 
• 
DSV will be provided as 250 mg tablets. DSV will be taken PO as 1 tablet BID, which 
corresponds to a 250 mg dose BID. 
• 
RBV will be provided as 200 mg tablets for participants with HCV genotype 1a only. 
RBV has weight-based dosing of 1000 to 1200 mg QD taken as divided doses 600 mg 
BID or 400 mg QD in the morning/600 mg QD in the evening (BID). 
 
Storage conditions for all medications are from 15° to 25°C (59° to 77°F). 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
DAA+/-RBV therapy will be available through the NIAID Clinical Research Products 
Management Center (CRPMC). PTV/r/OBT and DSV are manufactured and 
provided by AbbVie, Inc. Ribasphere® (ribavirin, RBV) is manufactured by DSM 
Pharmaceuticals, Inc. for Kadmon Pharmaceuticals, LLC. The site pharmacist 
must obtain the study product(s) for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks.  


 
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Any study product not provided by the study must comply with the NIAID (DAIDS) 
policy that outlines the process for authorizing the use of study products not 
marketed in the US in NIAID (DAIDS)-supported and/or –sponsored clinical trials. 
This policy is available on the NIAID (DAIDS) website at: 
http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/
NonFDAapprovedProducts.pdf. 
 
ART will not be provided through the CRPMC. 
 
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. At US CRSs, all 
unused study products 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 provided in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks.  
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, site 
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. 
 
Additional drug information may be found on the updated ACTG Drug Interactions Database 
located at: http://tdm.pharm.buffalo.edu/home/di_search/Search. 
 
5.4.1 Qualifying Antiretroviral Regimens  
 
Participants must currently be on one of the following HIV-1 ART regimens for at 
least 8 weeks prior to entry.  
 
The N(t)RTIs combinations in the stable, qualifying ART regimen must be one of the 
following: 
 
• 
TDF or TAF PO QD plus FTC PO QD (individual ARV components or as the 
fixed-dose combination TDF/FTC [Truvada] or TAF/FTC [Descovy]) 
 
• 
TDF or TAF PO QD plus 3TC PO QD or PO BID (individual ARV components) 
 
• 
ABC PO QD plus 3TC PO QD (individual ARV components or as the fixed-
dose combination ABC/3TC (EPZICOM or when dosed with DTG, TRIUMEQ) 
 
Participants with cirrhosis receiving abacavir should receive ABC 200 mg BID 
(re: Ziagen Package insert, dosing for hepatic impairment). 


 
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Participants will maintain the same dose and dosing interval of their NRTI backbone 
upon initiating the DAA+/-RBV therapy.  
 
INI ART regimen group: The INI in the stable qualifying ART regimen must be one 
of the following: 
• 
RAL 400 mg PO BID 
• 
DTG 50 mg PO QD alone or as part of a combination tablet or DTG 50 mg 
PO BID  
 
RAL or DTG will be maintained at the same dose and dosing interval upon initiating 
the DAA+/-RBV therapy.  
 
PI regimen group: The PI in the stable qualifying ART regimen must be one of 
the following: 
• 
DRV 800mg PO QD coadministered with RTV 100 mg PO QD or DRV 800 
mg/Cobicistat 150 mg PO QD 
• 
ATV 300 mg PO QD coadministered with RTV 100 mg PO QD 
 
More details on PIs: 
Participants taking DRV ART (boosted by RTV or Cobcistat are required to 
modify their regimen and be on a stable BID RTV-boosted BID DRV regimen for at 
least 2 weeks prior to study entry: 
• 
DRV 600 mg PO BID coadministered with RTV 100 mg PO BID. 
 
In this study, the DAA+/-RBV therapies are PTV/r/OBT 150/100/25 mg QD + DSV 
250 mg BID + weight-based RBV. The DAA morning dose includes 100 mg of RTV. 
Hence, participants receiving the HIV-1 DRV ART regimen that includes DRV PO 
BID coadministered with RTV PO BID will stop the morning RTV component of their 
HIV-1 ART regimen upon initiating the DAA+/-RBV therapy. The AM DRV dose 
should be coadministered with the morning dose of DAA+/-RBV therapy. 
 
In the case of DAA+/-RBV therapy interruption or discontinuation, participants on 
the DRV ART regimen should resume the AM RTV component of their HIV-1 ART 
regimen (RTV 100 mg BID with DRV 600 mg PO BID). 
 
NOTE: Participants on the DRV ART regimen may return to 800 mg/100 mg DRV/r 
daily dosing once they have been off the HCV DAA regimen for at least 2 weeks.  
 
In this study, the DAA+/-RBV therapies are PTV/r/OBT 150/100/25 mg QD + DSV 
250 mg BID + weight-based RBV. The DAA morning dose includes 100 mg of 
RTV. Hence, participants receiving the HIV-1 ATV ART regimen that includes 
ATV coadministered with RTV PO QD will stop the RTV component of their 
HIV-1 ART regimen upon initiating the DAA+/-RBV therapy. The ATV dose 
should be coadministered in the morning with the morning dose of DAA+/-RBV 
therapy. 


 
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In the case of DAA+/-RBV therapy interruption or discontinuation, participants 
on the ATV ART regimen should resume the RTV component of their HIV-1 
ART regimen (RTV 100 mg QD with ATV 300 mg PO QD). 
 
5.4.2 Prohibited and Precautionary Medications 
 
Refer to the Prohibited and Precautionary Medication Tables posted on the PSWP.  


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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events (Cohorts A and C) 
 
Evaluation 
(Cohorts A and C) 
Screening 
Entry  
Step 1: On Treatment 
(Weeks) 
Treatment 
Completion 
Step 2: Post-treatment 
(weeks) 
 
R=Registration to Step 2 
HCV VF Confirmation 
HIV-1 VF 
Confirmation 
Premature Study and 
/or Treatment 
Discontinuation 
Evaluations 1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
(R+4) 
(R+12) 
(R+24) 
Window ± 3 days 
Window ± 7 days 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Chronic HCV 
Infection  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Cirrhosis 
Status  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Creatinine Clearance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Liver Function Tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
INR 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Pregnancy Testing 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+ 
X 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
IFN Gamma-Induced Protein 10 
(IP-10) and sCD14 Plasma 
Samples 
 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
 
X 


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Evaluation 
(Cohorts A and C) 
Screening 
Entry  
Step 1: On Treatment 
(Weeks) 
Treatment 
Completion 
Step 2: Post-treatment 
(weeks) 
 
R=Registration to Step 2 
HCV VF Confirmation 
HIV-1 VF 
Confirmation 
Premature Study and 
/or Treatment 
Discontinuation 
Evaluations 1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
(R+4) 
(R+12) 
(R+24) 
Window ± 3 days 
Window ± 7 days 
IL28B Genotype 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Plasma HIV-1 Resistance 
Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum HCV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Plasma HCV Genotype/Subtype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum AFP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculated Child-Pugh Score for 
Cirrhotic Participants 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
Radiographic or Liver U/S Tests 
for Cirrhotic Participants2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Plasma for HCV and HIV-
1 Resistance Testing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stored Plasma for Analysis of 
Soluble Markers of Immune 
Activation/Immunity 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Stored PBMC for Analysis of 
Cellular Markers of Immune 
Activation and Adaptive 
Immunity (Advanced Flow 
Cytometry) 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
X 
Stored PBMC for Analysis of 
Proviral HIV-1 DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Single Convenience PK Sample 
for quantification of ARV and 
DAA concentrations 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Evaluation 
(Cohorts A and C) 
Screening 
Entry  
Step 1: On Treatment 
(Weeks) 
Treatment 
Completion 
Step 2: Post-treatment 
(weeks) 
 
R=Registration to Step 2 
HCV VF Confirmation 
HIV-1 VF 
Confirmation 
Premature Study and 
/or Treatment 
Discontinuation 
Evaluations 1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
(R+4) 
(R+12) 
(R+24) 
Window ± 3 days 
Window ± 7 days 
Single PK Sample, 2-10 hours 
post-dose3, for quantification of 
ARV and DAA concentrations 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
 
Single PK sample for 
quantification of plasma RBV 
and RBV-TP from RBCs 
obtained via dried blood spot 
(genotype 1a participants 
only) 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
1  All participants who discontinue treatment before the scheduled end of treatment must enter the post treatment evaluations as outlined. 
2 
See 6.4.13 below regarding U/S, CT or MRI. Sites should consider imaging study to rule out HCC. 
3 
See 6.4.16 below regarding time of day to schedule the visit for optimal PK sampling. Timing of dose and sample collection must be recorded. 


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6.2  
Schedule of Events (Cohorts B and D) 
 
Evaluation 
(Cohorts B and D) 
Screening 
Entry 
Step 1: On Treatment 
(Weeks) 
Treatment 
Completion 
Step 2: Post-treatment (PT) 
(Weeks) 
 
R=Registration to Step 2 
HCV VF Confirmation 
HIV-1 VF Confirmation 
Premature Study and /or 
Treatment Discontinuation 
Evaluations1 
2 
4 
6 
8 
10 
12 
(R+4) 
(R+12) 
(R+24) 
(R+36) 
Window ± 3 days 
Window ± 7 days 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Chronic HCV 
Infection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of Cirrhosis Status  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Creatinine Clearance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Liver Function Tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
INR 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
Pregnancy Testing 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
HBsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+ 
X 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 


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Evaluation 
(Cohorts B and D) 
Screening 
Entry 
Step 1: On Treatment 
(Weeks) 
Treatment 
Completion 
Step 2: Post-treatment (PT) 
(Weeks) 
 
R=Registration to Step 2 
HCV VF Confirmation 
HIV-1 VF Confirmation 
Premature Study and /or 
Treatment Discontinuation 
Evaluations1 
2 
4 
6 
8 
10 
12 
(R+4) 
(R+12) 
(R+24) 
(R+36) 
Window ± 3 days 
Window ± 7 days 
IFN Gamma-Induced Protein 10 
(IP-10) and sCD14 Plasma 
Samples 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
 
X 
IL28B Genotype 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Plasma HIV-1 Genotype 
Resistance Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum HCV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Plasma HCV Genotype/Subtype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum AFP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculated Child-Pugh Score for 
Cirrhotic Participants 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
Radiographic or Liver U/S Tests for 
Cirrhotic Participants2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Plasma for HCV and HIV-1 
Resistance Testing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Stored Plasma for Analysis of 
Soluble Markers of Immune 
Activation/Immunity 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 


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Evaluation 
(Cohorts B and D) 
Screening 
Entry 
Step 1: On Treatment 
(Weeks) 
Treatment 
Completion 
Step 2: Post-treatment (PT) 
(Weeks) 
 
R=Registration to Step 2 
HCV VF Confirmation 
HIV-1 VF Confirmation 
Premature Study and /or 
Treatment Discontinuation 
Evaluations1 
2 
4 
6 
8 
10 
12 
(R+4) 
(R+12) 
(R+24) 
(R+36) 
Window ± 3 days 
Window ± 7 days 
Stored PBMC for Analysis of 
Cellular Markers of Immune 
Activation and Adaptive Immunity 
(Advanced Flow Cytometry) 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
Stored PBMC for Analysis of 
Proviral HIV-1 DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Single Convenience PK Sample, for 
quantification of ARV and DAA 
concentrations 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Single PK Sample, 2-10 hours post-
dose3, for quantification of ARV and 
DAA concentrations 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
Single PK sample for quantification 
of plasma RBV and RBV-TP from 
RBCs obtained via dried blood spot 
(genotype 1a participants only) 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
1 
All participants who discontinue treatment before the scheduled end of treatment must enter the post treatment evaluations as outlined. 
2 
See 6.4.13 below regarding U/S, CT or MRI. Sites should consider imaging study to rule out HCC. 
3 
See 6.4.16 below regarding time of day to schedule the visit for optimal PK sampling. Timing of dose and sample collection must be recorded. 


 
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6.3 
Timing of Evaluations 
 
6.3.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant being enrolled to the 
study or starting any study medications, treatments, or interventions. 
 
Screening evaluations to determine eligibility must be completed within 42 days 
prior to study 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 on a Screening Failure Results form 
and entered into the ACTG database. 
 
Screening evaluations that determine eligibility are entered on the eligibility 
checklist. Beginning at study entry, all evaluations, including screening 
evaluations that do not determine eligibility are recorded on the case report form 
(CRF) and keyed into the database. 
 
6.3.2 Entry Evaluations 
 
Study entry evaluations must occur at least 24 hours after screening evaluations 
unless otherwise specified. Entry evaluations must occur prior to dispensation of 
study treatment. DAA+/-RBV therapy must be started within 72 hours of study 
entry.  
 
6.3.3 Post-Entry Evaluations 
 
On-Treatment Evaluations  
Evaluations must occur after registration and after study treatment is dispensed. 
Study visits must be scheduled on the weeks indicated in sections 6.1 and 6.2, 
within the ±3 day visit window, as appropriate for the visit. 
 
Treatment Completion Evaluations  
Clinical assessment and laboratory evaluation, as outlined in sections 6.1 and 
6.2, will be performed at treatment completion. 
 
Post-Treatment Evaluations  
Following treatment completion, participants will immediately enter Step 2 and 
undergo evaluations as outlined in sections 6.1 and 6.2, within the ± 7 day visit 
window, as appropriate for the visit.  
 
6.3.4 Study Completion Evaluations 
 
Final study visit occurs at week R+24 (Cohorts A and C) or week R+36 (Cohorts 
B and D), where R=registration to Step 2. 
 


 
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6.3.5 Event-Driven Evaluations  
 
HCV VF Confirmation 
HCV VF, as defined in section 7.3.1, must have a confirmatory specimen 
drawn within one week after the results of the initial sample have been 
received for participants with suspected HCV VF using criteria for HCV VF in 
section 7.3.1. HCV VF stemming from the criterion of HCV RNA >LLOQ at week 
6 does not require confirmation. 
 
HIV-1 VF Confirmation 
HIV-1 VF, as defined in section 7.3.2, must be confirmed in all participants 
within 2 weeks after results have been received. Participants with confirmed 
HIV-1 RNA ≥200 copies/mL will have a corresponding stored sample submitted 
for HIV-1 resistance genotyping.  
 
6.3.6 Discontinuation Evaluations 
 
Evaluations for Registered Participants Who Do Not Start Study Treatment 
All case report forms (CRFs) must be completed and keyed for the period up to 
and including week 0. 
 
Premature Treatment Discontinuation Evaluations  
Participants who discontinue study treatment for any reason will have the 
premature treatment discontinuation evaluations performed as per the SOE.  
 
At the time of premature discontinuation evaluations, these participants will then 
enter the post-treatment evaluation period (Step 2) and will be followed as per 
the SOE. 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue from the study will have the premature 
study discontinuation evaluations performed as per the SOE prior to being taken 
off the study. 
 
6.4 
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 
website for information about what must be included in the source document: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced
ocappndx.pdf 
 
All non-screening evaluations are to be recorded on the CRF and keyed into the 
database unless otherwise specified.  
 
A subset of AEs recorded on the CRF requires more detailed reporting on the CRF. The 
reporting requirements of these events are detailed in sections 6.4.6 and 6.4.8. 
 


 
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To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric AEs (DAIDS AE Grading 
Table), Version 1.0, December 2004 (Clarification, August 2009), which can be found on 
the DAIDS RSC website: http://rsc.tech-res.com/safetyandpharmacovigilance/.  
 
6.4.1 Documentation of HIV-1 
 
Section 4.1.3 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the CRF. 
 
6.4.2 Documentation of Chronic HCV Infection  
 
Positive for anti-HCV antibody or HCV RNA at least 6 months before screening, 
and positive for HCV RNA at the time of screening 
 
OR 
 
Positive for HCV RNA at the time of screening with a liver biopsy consistent with 
chronic HCV infection any time prior to study entry.  
  
6.4.3 Documentation of Cirrhosis Status  
 
Participants will be considered to be non-cirrhotic if the absence of cirrhosis is 
documented by one of the following criteria: 
• 
Liver biopsy within 24 months prior to study entry demonstrating the absence 
of cirrhosis; or  
• 
HCV FibroSURE score of <0.72 and Aspartate Aminotransferase to Platelet 
Ratio Index (APRI) <2 within 6 months of study entry; or 
• 
FibroScan result of <12.5 kPa within 6 months of study entry. 
 
The APRI can be calculated with the following formula:  
AST (IU/L)/AST upper limit of normal ÷ platelet count (x109/L) x 100. 
 
An online calculator is available at: http://hepatitisc.uw.edu/page/clinical-
calculators/apri 
 
Participants will be considered to have cirrhosis if it is documented by one of the 
following criteria: 
• 
Liver biopsy at any time prior to study entry demonstrating cirrhosis; or 
• 
HCV FibroSURE score of ≥0.72 and Aspartate Aminotransferase to Platelet 
Ratio Index (APRI) ≥2 within 6 months of study entry; or 
• 
FibroScan result of ≥12.5 kPa within 6 months of study entry. 
 
Participants with indeterminate blood tests (ie, discordant FibroSURE and APRI 
values) are required to have results of either a liver biopsy or FibroScan test to 
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Interpretation of Serum Markers from tests within 6 months prior to study entry 
for Liver Disease Classifications 
HCV 
FibroSURE 
APRI 
Classification 
<0.72 
<2 
Non cirrhotic 
≥0.72 
≥2 
Cirrhotic 
<0.72 
≥2 
An additional test required to establish the liver 
disease classification as presence or absence of 
cirrhosis. This test may be either Transient 
Elastography (FibroScan) or Histology (liver 
biopsy). The liver disease will be classified 
according the result of the additional test 
≥0.72 
<2 
An additional test required to establish the liver 
disease classification as presence or absence of 
cirrhosis. This test may be either Transient 
Elastography (FibroScan) or Histology (liver 
biopsy). The liver disease will be classified 
according the result of the additional test 
Unable to 
report result 
Any 
An additional test required to establish the liver 
disease classification as presence or absence of 
cirrhosis. This test may be either Transient 
Elastography (FibroScan) or Histology (liver 
biopsy). The liver disease will be classified 
according the result of the additional test 
 
Interpretation of Transient Elastography for Liver Disease Classifications 
Liver Stiffness (kPa) from testing within 6 
months prior to study entry 
Classification 
<12.5 
Non-cirrhotic 
≥12.5 
Cirrhotic 
 
If data from more than one classification methodology are available, classification 
will be determined according to the histology or transient elastography results. If 
both histology and transient elastography are available, classification will be 
determined according to the histology result.  
 
HCV 
FibroSURE/
APRI 
Histology (Liver 
Biopsy within 2 years 
prior to study entry) 
Transient Elastography 
(FibroScan) within 6 
months prior to study 
entry 
Classification 
Any 
Non cirrhotic  
Not available 
Non cirrhotic  
Any 
Cirrhotic (any time) 
Not available 
Cirrhotic 
Any 
Not available 
<12.5 
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HCV 
FibroSURE/
APRI 
Histology (Liver 
Biopsy within 2 years 
prior to study entry) 
Transient Elastography 
(FibroScan) within 6 
months prior to study 
entry 
Classification 
Any 
Not available 
≥12.5 
Cirrhotic  
Any 
Non cirrhotic  
Any 
Non cirrhotic  
Any 
Cirrhotic (any time) 
Any 
Cirrhotic 
NOTE: Participants with a FibroSURE that is not reported as a numerical value 
(eg, “unable to be reported”) must have undergone either transient elastography 
or liver biopsy prior to study entry for liver disease stage classification. 
 
6.4.4 Medical History 
 
The medical history must include all diagnoses identified by the ACTG criteria for 
clinical events and other diagnoses. All diagnosis within the past 30 days and 
history of any of the following will be recorded:  
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis (TB) 
• 
Chronic HCV 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.4.5 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history.  


 
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Medication Category 
Complete History or Timeframe 
Record on 
the CRF? 
ART 
Within 90 days before study entry 
Yes 
Prior ART failure with 
HIV-1 
genotype/resistance 
profile (if available) 
Complete history  
Yes 
HCV treatment 
Complete history 
Yes 
Prescription drugs for 
treatment of opportunistic 
infections 
Within 42 days before study entry 
Yes 
Prescription drugs for 
prophylaxis of opportunistic 
infections 
Within 42 days before study entry 
Yes 
Prescription drugs (other) 
Within 42 days before study entry 
Yes 
Non-prescription drugs 
Within 42 days before study entry 
Yes 
 
6.4.6 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 skin, head, mouth, and neck; 
auscultation of the chest; cardiac exam; abdominal exam; and examination of the 
lower extremities for edema. The complete physical exam will also include vital 
signs (temperature, pulse, respiration rate, and blood pressure). 
 
Targeted Physical Exam 
A targeted physical examination must be performed at study entry and all 
subsequent visits and is to include vital signs (temperature, pulse, respiration 
rate, and 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 previous visit. 
 
Height 
Height (recorded in centimeters) will be measured at screening. 
 
Weight 
Weight (recorded in kilograms) will be measured at screening and all subsequent 
visits. 
 
Signs and Symptoms 
At study entry, all signs and symptoms regardless of grade, that occurred within 
42 days before study entry must be recorded; post-entry, only signs and 
symptoms Grade ≥2 must be recorded. Record all signs and symptoms that led 
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The signs and symptoms which lead to premature or permanent discontinuation 
of either HCV study treatment or HIV ARV treatment, or which met EAE or ICH 
SAE guidelines will require more detailed event reporting on the CRF. 
 
NOTE: Any grade sign and symptom that led to a permanent discontinuation of 
HIV or HCV treatment is reported on the Event Report form. All Grade ≥2 sign 
and symptom are also reported on the Signs and Symptoms form. 
 
Diagnoses 
Any diagnoses that lead to either HIV or HCV treatment discontinuation or meet 
EAE or ICH SAE guidelines will require more detailed reporting on the CRF. 
 
Concomitant Medications 
Record all current prescription medications (with start and stop dates).  
 
ARV Medications 
Record all modifications to ARV medications including initial doses, participant-
initiated and/or protocol-mandated interruptions, modifications, and permanent 
discontinuation. 
 
Study Treatment (Intervention) Modifications 
Record all study drug modifications, including initial doses, participant-initiated 
and/or protocol-mandated modifications, inadvertent and deliberate interruptions 
of more than one day at each visit. Record any permanent discontinuation of 
treatment. 
 
Detailed Adverse Event Reporting 
After entry, more detailed reporting is required for the following: All Grade ≥3 ALT 
elevations, any event leading to premature HCV treatment discontinuation or HIV 
ARV discontinuation, and those events that meet EAE or International 
Conference on Harmonisation (ICH) reporting requirements. 
 
6.4.7 EKG 
 
An EKG will be performed at screening, week 12, week 24 (Cohorts A and C 
only), and at any premature study treatment discontinuation visits. 
 
6.4.8 Laboratory Evaluations 
 
All required laboratory values must be recorded, regardless of grade. ALT values 
Grade ≥3, lab values that prompt premature HCV treatment or HIV-1 ARV 
discontinuation, or that meet EAE or ICH SAE guidelines will require more 
detailed event reporting on the CRF.  
 
Chemistry 
Sodium, potassium, chloride, bicarbonate/CO2, blood urea nitrogen (BUN), 
creatinine, glucose, albumin, and uric acid.  
 


 
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Creatinine Clearance (CrCl) 
CrCl will be calculated throughout the study using Cockcroft-Gault method. Refer 
to the Cockcroft-Gault calculator located on the FSTRF website at 
www.fstrf.org. 
 
Hematology 
Hemoglobin, hematocrit, white blood cell count (WBC), ANC, and platelets. 
  
Liver Function Tests 
Total bilirubin, indirect bilirubin, direct bilirubin, AST (SGOT), ALT (SGPT), and 
alkaline phosphatase. 
 
International Normalized Ratio (INR) 
This will be performed at a local laboratory. 
 
Pregnancy Testing 
Serum or urine β-HCG (urine test must have a sensitivity of ≤25 mIU/mL).  
 
A second negative serum or urine pregnancy test result is required within 24 
hours prior to starting study treatment.  
 
Hepatitis B Surface Antigen (HBsAg) 
HBsAg test must be done within 42 days prior to study entry. 
 
6.4.9 Immunologic Studies 
 
CD4+ 
Obtain absolute CD4+ cell count and percent within 42 days prior to study entry 
from a laboratory that possesses a CLIA certification or equivalent.  
 
During the study, all laboratories must possess a CLIA certification or equivalent 
and must be certified for protocol testing by the DAIDS Immunology Quality 
Assurance (IQA) Program. 
 
Advanced Flow Cytometry 
Advanced flow analysis requires a CD4+ and WBC with differential from a 
sample obtained at the same time. 
 
Peripheral blood NK cell subset (CD16+CD56-, CD16+CD56+, CD16-CD56+, 
CD56hi and dim) frequency and expression of IFN-αR, NKP30, and NKG2a will 
be measured by flow cytometry. Proportions of CD4+ and CD8+ T cells that 
express HLA DR, CD38, and PD1 will also be measured by flow cytometry. 
Proportions of live gated cells that are CD14+CD16+, CD14+CD16-, and 
CD16+CD14lo monocytes will be quantified by flow cytometry.  
Plasma sCD14 will be measured by ELISA. 
 


 
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IFN Gamma-Induced Protein 10 (IP-10)  
Plasma IP-10 samples will be obtained at baseline, on treatment, and during post 
treatment follow up as indicated in the SOE. 
 
Interleukin 28B (IL28) Genotype 
Whole blood will be collected and shipped according to the A5329 LPC. 
 
NOTE: IL28B will not be collected on participants with a documented baseline 
IL28B genotype result. 
 
6.4.10 Virologic Studies 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 42 days prior to study entry by a 
laboratory that possesses a CLIA certification or equivalent. Eligibility will be 
determined based on the screening value.  
 
After the screening visit, HIV-1 RNA quantification assay will be performed in 
real-time at the protocol designated centralized laboratory. For study entry and 
post-entry evaluations, the laboratory must be certified by the DAIDS Virology 
Quality Assurance (VQA) Program. See the LPC for processing, shipping, and 
storage information.  
 
Plasma HIV-1 Genotype Resistance Testing 
If there is a confirmed HIV-1 VF (HIV-1 VL ≥200 copies) in a participant while 
taking HCV treatment (or within 4 weeks after permanent discontinuation), a 
plasma specimen must be obtained at the time of the confirmation sample and, if 
HIV-1 VF is confirmed with an HIV-1 VL ≥200, the sample must be sent to the 
designated A5329 VSL for evidence of drug resistance.  
 
Serum HCV RNA 
HCV RNA samples on study will be processed and shipped to the designated 
A5329 VSL Quest Diagnostics for real-time quantitative HCV RNA analysis. 
Please refer to the LPC. 
 
Screening HCV RNA must be performed within 42 days prior to study entry 
and will also be processed and shipped to the designated A5329 VSL Quest 
Diagnostics for real-time quantitative HCV RNA analysis. Please refer to the 
LPC.   
 
Plasma HCV Genotype/Subtype 
At screening, the HCV genotype/subtype result must be confirmed by testing at 
the A5329 VSL Quest Diagnostics. Please refer to the LPC. 
 
6.4.11 Serum Alpha-Fetoprotein (AFP)  
 
Serum AFP will be determined in all participants at screening. 
 


 
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6.4.12 Calculated Child-Pugh Pugh Score 
 
Calculated Child-Pugh Score is needed only for those participants classified as 
cirrhotic at study entry. 
 
To calculate the Child-Pugh score, refer to the following website: 
http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality 
 
6.4.13 Radiographic or Liver Ultrasound (U/S) Tests for Cirrhotic Participants 
 
Participants classified as cirrhotic must have no evidence of HCC as indicated 
by a negative U/S, CT scan or MRI within 6 months prior to study entry.  
 
Liver U/S for cirrhotic participants is needed only if imaging results (U/S, CT, or 
MRI) are not available within 6 months prior to study entry.  
 
NOTE: Participants who have an U/S with results suspicious of HCC followed 
by a subsequent negative CT or MRI of the liver will be eligible for the study. 
 
6.4.14 Stored Plasma  
 
Stored Plasma for HCV and HIV-1 Resistance Testing 
Plasma will be stored at the indicated visits for future HCV and/or HIV-1 
sequencing to assess for resistance mutations. Samples will be shipped and 
stored according to the A5329 LPC. 
 
Stored Plasma for Analysis of Soluble Markers of Immune Activation/Immunity 
Stored plasma will be collected at the indicated visits for future studies and 
shipped according to the A5329 LPC. 
 
6.4.15 Stored PBMCs 
 
Stored PBMC for Analysis of Cellular Markers of Immune Activation and Adaptive 
Immunity (Advanced Flow Cytometry) 
Stored PBMC will be collected at the indicated visits for future studies and 
shipped according to the A5329 LPC. 
 
Stored PBMC for Analysis of Proviral HIV-1 DNA 
Stored PBMC will be collected at the indicated visit for future studies and shipped 
according to the A5329 LPC. 
 
6.4.16 PK Studies  
 
For participants enrolled in the PK substudy A5334s, the A5329 PK sample for 
measurement of HIV-1 ARVs and/or HCV DAAs need not be drawn if the 
A5334s intensive samples are being collected the same day. 
 


 
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Participants who coenroll in A5334s will be given supplemental instructions to 
take all medications on either a q12h or a q24h schedule to allow for accurate PK 
studies to be completed in the sub-study. 
 
The prior three doses of all DAAs, RBV (genotype 1a only), and ARVs will be 
collected on the CRFs. 
 
If any of the prior three doses are missed the PK sample collection should be 
rescheduled and obtained after the prior three doses are taken as scheduled. 
 
Single convenience PK sample for quantification of ARV and DAA concentrations 
Single convenience PK samples will be drawn at study entry and at the time of 
premature study and/or treatment discontinuation. A convenience sample is one 
that is obtained at no particular post-dose time. The exact time of the prior dose 
and the exact time of the blood sample should be recorded on the CRF. 
 
Single PK sample, 2-10 hours post-dose for quantification of ARV and DAA 
concentrations 
Single scheduled PK samples for ARVs and DAAs plasma drug quantification will 
be collected at the study weeks indicated in the Schedule of Events. 
 
At weeks 2, 6 and 12, the visit should be scheduled such that the PK sample can 
be collected 2-4 hours after morning doses of the BID drugs. At week 8, the visit 
should be scheduled such that the PK sample can be collected 5-7 hours after 
morning doses of the BID drugs. At weeks 4 and 10, the visit should be 
scheduled such that the PK sample can be collected 8-10 hours after morning 
doses of the BID drugs. (If the participant is enrolled into the PK substudy 
A5334s, the parent study week 4 samples for ARV and DAA assessment 
should not be collected.) This distribution of sample times allows good 
representation across the dosing interval for each participant. At the time of 
HCV or HIV-1 VF, the visit should be scheduled such that the PK sample can be 
collected 2-10 hours after the morning does of BID drugs. The exact time of the 
prior dose and the exact time of the blood sample should be recorded on the 
CRF.   
 
Single PK sample for quantification of plasma RBV and RBV-TP from RBCs 
obtained via dried blood spot (genotype 1a participants only) 
Single PK samples for RBV plasma drug quantification and RBV dried blood 
spots for triphosphate drug quantification, collected at weeks 4 and 8 and at the 
time of HCV or HIV-1 VF, should be collected around the same time as the 
scheduled PK sample for ARV and DAA quantification. (The sample need not be 
drawn at any particular time relative to the preceding RBV dose.) The exact time 
of the prior dose and the exact time of the blood sample should be recorded on 
the CRF. 
 
 
 
 


 
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7.0 
CLINICAL MANAGEMENT ISSUES 
 
7.1 
Toxicity  
 
It is expected that DAA+/-RBV therapy will be much better tolerated than conventional 
PegIFN-based HCV therapy. However, it is possible that some participants will 
experience transient or prolonged AEs related to (reasonable possibility) DAA+/-RBV 
therapy during the study. Some participants may need to adjust dosing of RBV. To 
minimize the effects of these dosing modifications on the eventual evaluation of the 
safety, tolerability, and activity of DAA+/-RBV therapy, the principles in the following 
sections will be used to determine the appropriate dose adjustment. 
 
If possible, DAA+/-RBV therapy must not be held or eliminated. This recommendation 
stems from the very high SVR rates seen in HCV monoinfected phase IIb studies and 
concerns that extended periods of lowered drug concentrations in the blood may be 
associated with the replication of more resistant clones of the virus, resulting in a lack of 
sustained response.  
 
Participants who develop a DAA+/-RBV therapy-related (reasonable possibility) mild or 
moderate AE or Grade 1 or 2 laboratory abnormality (other than those discussed 
separately for hemoglobin parameters (section 7.2.2), elevated total bilirubin (section 
7.2.1), hepatic transaminase parameters (section 7.2.3), and CrCl parameters (section 
7.2.4) may continue DAA+/-RBV therapy with follow-up per the study protocol. If the AE 
or laboratory parameter does not improve or normalize within two scheduled study visits 
and an etiology other than DAA+/-RBV therapy has not been determined, then the 
A5329 protocol team must be notified within 24 hours by e-mail at 
actg.corea5329@fstrf.org to further discuss participant management. Participants may 
continue study drug; interruption of DAA+/-RBV therapy is not required. 
 
With the exception of Grade ≥3 elevations in uric acid or glucose in participants with a 
history of diabetes mellitus, if a participant experiences a Grade ≥3 laboratory 
parameter during the study (other than those discussed in the toxicity management 
sections 7.2.1 through 7.2.4), the abnormal laboratory test must be repeated within 72 
hours. If the Grade ≥3 abnormality is confirmed, DAA+/-RBV therapy must be interrupted 
and the laboratory parameter followed until it reaches Grade ≤1. DAA+/-RBV therapy 
can be restarted if the laboratory parameter reaches Grade ≤1 within 7 days of DAA+/-
RBV therapy interruption. If DAA+/-RBV therapy is interrupted and restarted and 
abnormality recurs at Grade ≥3, then DAA+/-RBV therapy must be permanently 
discontinued. If the abnormality does not improve to Grade ≤1 within 7 days of 
interruption, DAA+/-RBV therapy must be permanently discontinued. 
   
NOTE: If DAA+/-RBV therapy is held in participants on a DRV- or ATV-based ARV 
regimen 100 mg of RTV must be added to the ATV or morning DRV dose for as long as 
the DAA+/-RBV regimen is held. 
 
If the site investigator believes that the confirmed Grade ≥3 laboratory abnormality can 
be managed medically without interruption, then the A5329 protocol team must be 
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DAA+/-RBV therapy administration with medical management. If the laboratory 
abnormality does not improve with medical management within two scheduled study 
visits, then DAA+/-RBV therapy must be interrupted and the laboratory abnormality 
followed. If the laboratory abnormality does not improve within 7 days, then DAA+/-RBV 
therapy must be permanently discontinued. DAA+/-RBV therapy can be restarted if the 
laboratory parameter reaches Grade ≤1 within 7 days, of DAA+/-RBV interruption. If the 
laboratory abnormality recurs at Grade ≥3 upon restart, then DAA+/-RBV therapy must 
be permanently discontinued. 
 
7.2 
Management of Specific Toxicities 
 
7.2.1 Elevated Bilirubin 
 
Asymptomatic elevation of indirect (unconjugated) bilirubin is anticipated in this 
study due to the inhibition OATP1B1 from paritaprevir and hemolysis from RBV. 
Based on these mechanisms, elevations in direct bilirubin would be atypical; 
therefore, elevations in bilirubin which are predominantly direct must be worked 
up per the site investigator's usual management. 
 
Participants may be maintained on DAA+/-RBV therapy for isolated elevations 
in total bilirubin which is predominantly indirect. These elevations are expected to 
be transient and asymptomatic and not associated with concomitant elevations in 
transaminases. For Grade ≥3 total bilirubin levels which are predominantly 
indirect, the site investigator may manage per his/her discretion and can refer to 
the paragraph on management of Grade ≥3 laboratory parameters above. 
 
7.2.2 Anemia for Participants with HCV Genotype 1a Who Are Receiving RBV 
 
Reductions in hemoglobin are a well characterized side effect of RBV exposure. 
Hemoglobin abnormalities must be managed according to Table 1. Management 
will be different for participants without a history of known cardiac disease and 
participants with cardiac disease. 
 
If a participant experiences a hemoglobin decrease (as outlined in Table 1), a 
confirmatory test must be performed within 2 weeks. If the hemoglobin decrease 
is confirmed, the management guidelines in Table 1 must be followed. 
Depending on the rapidity and severity of anemia and any delays in obtaining 
confirmatory hemoglobin it may be advisable to initiate management measures 
while waiting for confirmatory testing. 
 
Use of hematologic growth factors (such as erythropoietin [EPO]) or blood 
transfusions are not recommended; any use of growth factors must be discussed 
with the A5329 protocol team by e-mail at actg.corea5329@fstrf.org prior to 
institution. Management of hematologic growth factor therapy is the responsibility 
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Table 1. Management of Hemoglobin Abnormalities for Participants with HCV 
Genotype 1a Who Are Receiving RBV 
Hemoglobin in Participants with No History of Cardiac Disease 
Hemoglobin <10.0 g/dL, 
but 
≥8.5 g/dL 
DAA+RBV therapy may be continued. 
Reduce RBV dose by 200 or 400 mg and continue to 
monitor hemoglobin per protocol. 
If hemoglobin increases to ≥10 g/dL, may increase RBV; 
with gradual dose increases in 200 mg increments. If Hb 
decreases to <8.5 g/dL see appropriate row below. 
Hemoglobin <8.5 g/dL 
Hold RBV. Restart RBV 600 mg once hemoglobin >10 
g/dL. Remainder of DAA+RBV therapy may be continued. 
Manage the participant as medically appropriate. 
Hemoglobin decrease of 
≥4 g/dL between two 
scheduled study visits 
but hemoglobin ≥10 g/dL 
Reduce RBV dose by 400 or 600 mg. Manage the 
participant as medically appropriate. DAA+RBV therapy 
may be continued. 
 
Hemoglobin in Participants with History of Stable Cardiac Disease 
Hemoglobin decrease of ≥2 
g/dL during a 4-week 
treatment period (Hb ≥10 
g/dL) without symptoms 
and/or signs of cardiac 
disease 
DAA+RBV therapy may be continued. 
Reduce RBV dose by 400 or 600 mg. 
Continue to monitor hemoglobin levels per protocol. 
If subsequent hemoglobin result is greater than the 
level that triggered the dose reduction, the site 
investigator may elect to increase RBV, with gradual 
dose increases in 200 mg increments at two-week 
intervals towards original dose. 
If hemoglobin does not increase; site investigator may 
manage the participant as medically appropriate. If 
hemoglobin decreases to <10 g/dL see appropriate row 
below. 
Hemoglobin decrease of ≥2 
g/dL during a 4-week 
treatment period (Hb ≥10 
g/dL) with symptoms and/or 
signs of cardiac disease 
If the participant has symptoms consistent with their 
cardiac disease manage participant as medically 
appropriate. 
Hold RBV. Restart RBV 600 mg once hemoglobin has 
increased by >1 g/dL and symptoms resolved. 
Other DAA+RBV therapy may be continued, consider 
management as for those without cardiac signs and 
symptoms in the rows above. 
Hemoglobin decrease 
≥4 g/dL between study visits 
but hemoglobin ≥10 g/dL 
Hold RBV. Restart RBV 600 mg once hemoglobin has 
increased by >1 g/dL 
Site investigator must manage participant as medically 
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Hemoglobin in Participants with History of Stable Cardiac Disease 
Other DAA+RBV therapy may be continued. 
Hemoglobin <10.0 g/dL, but 
≥8.5 g/dL 
DAA+RBV therapy may be continued. 
Reduce RBV dose by 400 or 600 mg and continue to 
monitor hemoglobin per protocol. 
If hemoglobin increases to ≥10 g/dL, may increase 
RBV; with gradual dose increases in 200 mg 
increments. 
If hemoglobin <10 g/dL despite 4 weeks at RBV 600 
mg, permanently discontinue RBV (if alternative 
management of anemia is considered then the study 
team must be contacted); manage as medically 
appropriate. DAA therapy may be continued. 
If discontinuation of DAA+RBV therapy is being 
considered, contact the A5329 protocol team by e-mail 
at actg.corea5329@fstrf.org. 
Hemoglobin <8.5 g/dL 
Hold RBV. Restart RBV 600 mg once hemoglobin 
>10g/dL. 
Remainder of DAA+RBV therapy may be continued. 
Manage the participant as medically appropriate. 
 
7.2.3 Transaminase Elevations 
 
As discussed in section 2.0, PTV/r at higher doses has been associated with 
transaminase elevations in a minority of participants. At the dose being 
studied (PTV/r 150/100 mg) Grade 3 ALT elevations were seen in <1% of 
participants. 
 
If a participant experiences an ALT level ≥5 × ULN that is ≥2 × Baseline, a 
confirmatory test must be performed within 72 hours. If the ALT is confirmed 
as a level that is ≥5 × ULN that is ≥2 × Baseline, the management guidelines 
in Table 2 must be followed.  
 
Alternative management of ALT increases requires approval from the A5329 
protocol team by e-mail at actg.corea5329@fstrf.org. 
 
Table 2. Management of Confirmed ALT Levels ≥5 × ULN and ≥2 × Baseline 
ALT ≥10 × ULN 
or 
ALT ≥5 × ULN but  
<10 × ULN with symptoms and 
signs of hepatitis present (eg, 
jaundice, nausea, vomiting , 
abdominal pain) 
 
Permanently discontinue study drugs. 
Update concomitant medications on CRF (if 
applicable) and evaluate and manage the 
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ALT ≥5 × ULN but  
<10 × ULN without symptoms or 
signs of hepatitis 
Update concomitant medications on CRF (if 
applicable), and evaluate and manage the 
participant as medically appropriate. 
Continue study drugs and repeat LFTs and 
INR within 72 hours and as clinically indicated 
until resolution. 
If ALT values during follow-up are increased 
>2-fold from the prior values, or increasing 
direct bilirubin, (>2x ULN), or increasing INR 
(>2-fold), or symptoms/signs of hepatitis then 
permanently discontinue study drugs. 
 
7.2.4 Changes in CrCl 
 
CrCl will be calculated throughout the study using Cockcroft-Gault method 
 
Refer to the Cockcroft-Gault calculator located on the FSTRF website at 
www.fstrf.org. 
 
If a participant experiences a CrCl decrease to <50 mL/min, a confirmatory 
test must be performed within 2 weeks. If calculated CrCl is confirmed to 
have decreased to <50 mL/min, medical evaluation must include a full review 
of current medications, including those taken on an as needed basis, those 
which are sold over the counter, and any dietary and herbal supplements. 
   
In addition, the following must occur: 
• 
Concomitant medication dose reduction based on CrCl must be done (if 
applicable). 
• 
A5329 protocol team must be contacted by e-mail at 
actg.corea5329@fstrf.org to discuss whether dose modification or drug 
substitution may be required. Drug interactions between concomitant 
medications and the DAA+/-RBV therapy for example, could potentially 
increase antihypertensive medication exposure and may reduce renal 
function. If antihypertensive medications are adjusted, vital signs must be 
monitored to ensure appropriate blood pressure control.  
• 
RBV dose must be adjusted per package insert. Alternative management 
of RBV dose in the setting of reduced renal function will require approval 
of the A5329 protocol team by e-mail at actg.corea5329@fstrf.org. 
• 
A urine specimen must be obtained for urinalysis (including urine for 
albumin). 
• 
Creatinine and chemistries must be repeated within 7 days and as 
clinically indicated until resolution or stabilized. 
• 
CrCl value <30 mL/min, all study medications will be discontinued. 
• 
If CrCl does not improve in the subsequent two scheduled study visits 
(two CrCl values still <50 mL/min) then consideration of discontinuation of 
all potentially nephrotoxic medications must be undertaken. Continuation 
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conjunction with discussion with the A5329 protocol team by e-mail at 
actg.corea5329@fstrf.org.  
• 
Changes to the ART regimen require notification and should not be 
instituted without discussion with the A5329 protocol team by e-mail at 
actg.corea5329@fstrf.org. 
• 
Continue further medical management as appropriate.  
• 
If CrCl improves, consideration must be given to the readjustment of any 
dose modifications that have been made.  
 
7.3 
Virologic Failure 
 
7.3.1 HCV VF 
 
The following criteria will be considered evidence of HCV VF. Participants 
demonstrating any of the following will be permanently discontinued from DAA+/-
RBV treatment, and entered into Step 2 for post-treatment follow-up: 
 
• 
Confirmed increase from nadir in HCV RNA (defined as two consecutive HCV 
RNA measurements of >1 log10 IU/mL above nadir) at any time point; 
 
• 
Failure to achieve HCV RNA <LLOQ by week 6 
 
• 
Confirmed HCV RNA ≥LLOQ (defined as two consecutive HCV RNA 
measurements ≥LLOQ) at any point after HCV RNA <LLOQ during HCV 
treatment; 
 
NOTE: Confirmatory HCV RNA should be drawn as soon as possible and no 
later than one week after receiving initial HCV RNA VF result. Please refer to the 
LPC. 
 
All participants who discontinue DAA+/-RBV therapy because of HCV VF will 
continue in the study following the post-treatment SOE, which is Step 2 (see 
sections 6.1 and 6.2). 
 
7.3.2 HIV-1 VF 
 
Plasma HIV-1 RNA will be monitored throughout the study. Since all 
participants will be taking a qualifying ART regimen, HIV-1 viral failure will 
defined as follows:  
 
• 
Confirmed increase in HIV-1 RNA to ≥200copies/mL at any time after study 
entry until 4 weeks after permanent discontinuation of DAA+/-RBV therapy. 
 
Since “blips” in HIV-1 RNA may be observed in individuals on ART in the 
absence of HIV-1 VF, any increase in plasma HIV-1 RNA ≥200 copies/mL must 
be confirmed with repeat testing as soon as possible (not to exceed 2 weeks). 
For participants with confirmed HIV-1 VF, a plasma specimen obtained at the 
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HIV-1 drug resistance. Confirmed HIV-1 failure specimens must have repeated 
detection of ≥200 copies/mL for HIV-1 drug resistance testing. Results will be 
reported back to sites in real-time from the designated A5329 VSL. 
 
Clinical management of HIV-1 VF will be handled by local site investigators 
according to current HIV treatment guidelines and local standard of care. 
 
Participants who experience confirmed HIV-1 VF may require discontinuation of 
DAA+/-RBV therapy. 
• 
Participants at ≥week 12 of DAA+/-RBV therapy should discontinue HCV 
DAA+/-RBV therapy in the event of confirmed HIV-1 VF. (These participants 
will enter Step 2 and continue follow-up in the post-treatment evaluation 
schedule). 
 
• 
Participants at <week 12 of DAA+/-RBV therapy may continue on HCV 
therapy if the investigator believes that the confirmed HIV-1 VF can be 
managed medically without DAA+/-RBV therapy discontinuation.  
o The A5329 core team should be contacted prior to discontinuation of HCV 
DAA+/-RBV therapy (actg.corea5329@fstrf.org) 
 
Clinical management of HIV-1 VF will be handled by local site investigators 
according to current HIV treatment guidelines and local standard of care; 
however, the A5239 protocol core team must be contacted to discuss continued 
DAA+/-RBV therapy before any switch to the ART regimen in the event of HIV-1 
VF (actg.corea5329@fstrf.org).  
 
• 
The core team and the local site PI must discuss HIV treatment options and 
agree on an appropriate HIV-1 salvage regimen for participants to continue 
on HCV DAA+/-RBV study treatment. 
 
• 
Investigators should consult section 5.4.2 and the table of contraindicated 
medications (posted on the PSWP) to inform discussions with the A5329 core 
team regarding the potential for a modified ART regimen for HIV-1 VF. 
Possible modified ART regimens should take into account the unique 
characteristics of the participant and the participant’s HIV-1 treatment 
history as well as known and/or anticipated drug interactions with DAA+/-RBV 
therapy. 
 
• 
If no reasonable salvage HIV regimens compatible with continued HCV 
DAA+/-RBV treatment are deemed available for an individual participant 
with HIV-1 VF then the participant must discontinue HCV DAA+/-RBV 
therapy (and enter Step 2 in order to continue post-treatment follow-up 
evaluations). 
 
7.4 
Adjustments in ART regimens following cessation of HCV DAA+/-RBV therapy 
 
Following completion of dosing with DAA+/-RBV therapy, study participants on DRV or 
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for the 2 weeks prior to entry. Specifically, RTV 100 mg must be administered with the 
morning dose of DRV or ATV to replace the RTV dose which was part of the HCV DAA 
+/- RBV therapy.  
 
NOTE: Participants on the DRV ART regimen may return to 800 mg/100 mg DRV/r 
daily dosing once they have been off the HCV DAA regimen for at least 2 weeks.  
 
7.5 
Pregnancy   
 
All participants 
For all participants (either female participants who become pregnant or male 
participants whose partners become pregnant), intrapartum complications and/or 
pregnancy outcome will be recorded on a CRF 6 months following the end of the 
pregnancy. If a participant has completed the study or chooses to discontinue 
from the study before the end of the pregnancy, then site staff should request 
permission to contact her/him regarding pregnancy outcomes 6 months following 
the end of pregnancy. If the information is obtained, pregnancy outcomes will be 
submitted on a CRF.  
 
Pregnancies that occur on study should be reported prospectively to The 
Antiretroviral Pregnancy Registry. More information is available at 
www.apregistry.com (phone: 1-800-258-4263; fax: 1-800-800-1052).   
 
Participants with HCV genotype 1a who are receiving RBV 
For participants with HCV genotype 1a who are receiving RBV, pregnancy (either 
female participants or male participants whose partners become pregnant) will result 
in immediate permanent discontinuation of RBV therapy and participants will be 
counseled on the teratogenicity of RBV. Participants will remain on DAAs and be 
followed per the Schedule of Events (sections 6.1 and 6.2) in Step 1 (on-HCV 
treatment) and Step 2 (post-HCV treatment) until study completion.  
 
Participants with HCV genotype 1a who are receiving RBV and who become 
pregnant while taking study treatment or within 6 months after discontinuing study 
treatment and male participants who have sexual partners who become pregnant 
during this time will have their pregnancies reported to the RBV Pregnancy Registry 
(www.RibavirinPregnancyRegistry.com).  
 
Participants with HCV genotype 1b 
For participants with HCV genotype 1b, participants (either female participants 
who become pregnant or male participants whose partners become pregnant) will 
remain on DAAs and be followed per the Schedule of Events (sections 6.1 and 6.2) 
in Step 1 (on-HCV treatment) and Step 2 (post-HCV treatment) until study 
completion.  
 
 
 
 
 


 
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8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Permanent and Premature Study Drug Discontinuation 
 
• 
HCV VF (see section 7.3.1) 
• 
Drug-related toxicity requiring permanent discontinuation (see section 7.1 Toxicity) 
• 
Requirement for prohibited concomitant medication. 
• 
Pregnancy (in a female participant or the male participant’s female partner) or 
breast-feeding. (These participants will discontinue RBV only, if applicable, but 
remain on DAAs.) 
• 
Completion of treatment as defined in the protocol. 
• 
Request by participant to terminate treatment. 
• 
In the site investigator’s judgment, participant repeatedly noncompliant with study 
drugs as prescribed.  
• 
Failure by the participant to attend three or more consecutive clinic visits. 
• 
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 or site investigator if s/he thinks the study is no 
longer in the best interest of the participant. 
• 
Participant judged by the site 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 IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), SMC, ACTG, other government agencies as part of their duties, site 
investigator, or industry supporter. 
 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
Open-label, study of IFN-free HCV therapy for 24 or 12 weeks in participants with 
HCV/HIV-1 coinfection on specific ART regimens. DAA+/-RBV therapy (study treatment 
intervention) will include a NS3/4A protease inhibitor plus an NS5A inhibitor plus an 
NS5B non-nucleoside, plus weight-based RBV among those infected with HCV 
genotype 1a.  
 
NOTE:  In Version 1.0 of this study, all participants (regardless of HCV genotype), 
received RBV as part of the HCV study treatment regimen. See below for further 
discussion of the implications of this change. 
 


 
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The study will consist of sequentially enrolled study cohorts determined by ARV regimen 
and direct allocation (not randomized) to the duration of DAA+/-RBV therapy (24 
followed by 12 weeks).  
 
INI-based ARV regimen group (RAL or DTG)  
Cohort A: DAA (+RBV for genotype 1a) HCV therapy for 24 weeks 
Cohort B: DAA (+RBV for genotype 1a) HCV therapy for 12 weeks 
 
PI-based ARV regimen group (DRV or ATV)  
Cohort C: DAA (+RBV for genotype 1a) HCV therapy for 24 weeks 
Cohort D: DAA (+RBV for genotype 1a) HCV therapy for 12 weeks 
 
NOTE: In Version 1.0, the HIV ARV regimens allowed in the cohorts were more 
restrictive (current INI-based regimen group was formerly RAL only, and current 
PI-based regimen group was formerly DRV only). The allowed NRTIs as part of the 
ARV regimen were also more restricted for all participants regardless of cohort in 
Version 1.0.   
 
Because of the sequential nature of study design that meant that only Cohorts A 
and C enrolled under protocol Version 1.0, the distribution of ARV regimens that 
participants are taking may vary between the longer HCV treatment-period 
Cohorts (A and C), and the shorter HCV treatment-period Cohorts (B and D) which 
are anticipated to accrue exclusively under Version 2.0 of the protocol. 
 
Additionally, as result of the sequential cohort study design and exclusion of RBV 
among HCV genotype 1b participants only among those enrolled during Version 
2.0 means that the longer HCV treatment cohorts may represent a mixture of HCV 
treatments among those with HCV genotype 1b. 
 
In general, analyses for the study will not be performed differently or adjusted for 
protocol version, and will combine all available data across participants enrolling 
or participating in any version of the study. Any exceptions to this general rule 
will be noted either in the analysis section below, or in the study’s statistical 
analysis plan (SAP). The version changes will not affect the key analyses, because 
each cohort will be described and analyzed separately in this phase II study with 
small sample sizes. 
 
Each study Cohort (A-D above) will enroll a total of 25 participants (for a total of 100 
participants).  
 
Study follow-up is 48 weeks following study entry for each participant. Each cohort will 
occur in two steps: on-HCV treatment (Step 1) and post-HCV treatment follow-up (Step 
2). 
 
The primary completion date will be prior to each participant’s study completion; 
primary completion based upon the SVR12 outcome will be 12 weeks following HCV 
treatment discontinuation. Assuming completion of HCV treatment without premature 
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(12 weeks of anti-HCV treatment), and at the 36 week visit for those assigned to a 
longer duration cohort (24 weeks of anti-HCV treatment). 
 
Data will be summarized by individual Cohort (A, B, C, and D, as defined above) for 
analyses, but will not be analyzed separately by protocol version, as noted above. 
 
9.2 
Outcome Measures 
 
9.2.1 Primary Outcome Measures 
 
9.2.1.1 
Primary Efficacy Outcome Measure: SVR12 evaluated at least12 weeks 
post HCV treatment discontinuation. Responders will be those whose 
HCV RNA is less than the assay LLOQ. For those whose HCV early 
responses prior to SVR12 evaluation meet the guidelines for HCV VF, 
their SVR12 outcome will be defined as non-response. (Other 
considerations for the primary outcome are outlined below in analyses 
section 9.6 or in the SAP.) 
 
9.2.1.2 
Primary Safety and Tolerability Outcome Measures:    
 
9.2.1.2.1 SAEs as defined by ICH criteria 
 
9.2.1.2.2 Premature HCV study treatment discontinuation due to any 
reason other than HCV VF 
 
9.2.1.2.3 Signs/Symptoms Grade ≥3 during HCV study treatment and 
up to 30 days following HCV study treatment discontinuation 
 
9.2.1.2.4 Diagnoses leading to HCV study treatment or HIV-1 ARV  
discontinuation 
 
9.2.1.2.5 Laboratory Abnormalities Grade ≥3 during HCV study 
treatment and up to 30 days following HCV study treatment 
discontinuation 
 
9.2.2 Secondary Outcome Measures 
 
9.2.2.1 
HIV-1 VF as defined in section 7.3 above 
 
9.2.2.2 
Presence of genotypic mutations conferring major resistance to any 
HIV-1 PI at time of HIV-1 RNA VF (or confirmation of HIV-1 RNA VF) 
 
9.2.2.3 
Baseline, end of treatment and PTwk12 (post-treatment week 12 = 
same time as SVR12 evaluation) sCD14 levels; and baseline, end of 
treatment and PTwk12 IP10 levels as biomarkers of immune activation   
 
9.2.2.4 
HCV mutations conferring resistance to any component of the HCV 
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among the subset of participants who are non-responders for SVR12 
(PTwk12 measurement if available, and premature treatment 
discontinuation or final available specimen otherwise) 
 
NOTE: The exact list of relevant mutations is given in study’s SAP. 
 
9.2.2.5 
SVR24  
 
9.2.3 Exploratory Outcome Measures 
 
9.2.3.1 
Participant-specific estimates of ARV PK parameters AUC, clearance, 
Cmax and Cmin, estimated from nonlinear mixed-effect population PK 
models (see sections 10.2 and 10.3 for details) 
 
9.2.3.2 
Participant-specific estimates of DAA PK parameters AUC, clearance, 
Cmax and Cmin, estimated from nonlinear mixed-effect population PK 
models (see sections 10.2 and 10.3 for details) 
 
9.3 
Randomization and Stratification 
 
There is no randomization in this study. Allocation to cohorts will be fully deterministic 
according to HIV-1 ART regimen, and for each ART regimen, assigned to duration of 
HCV treatment by the timing of accrual (longer duration cohorts first, followed by shorter 
duration cohorts), and whether RBV is part of the HCV treatment is determined by 
the participant’s HCV genotype. Duration of (and inclusion of RBV in) HCV 
treatment will be necessarily open-label (ie, unblinded or unmasked) at the participant 
level, and at the team level because of the nature of the study design. The stratification 
factor (and levels) that will be used to control proportions of the following key subgroup 
within each cohort is cirrhosis (yes versus no). The enrollment to the strata level for 
cirrhosis=yes will be limited to no more than 30% (ie, no more than 7 participants) 
within any particular study cohort.  
 
9.4 
Sample Size and Accrual 
 
The goal of this phase II study is to gather safety and efficacy data on the proposed HCV 
regimens in HCV/HIV-1 coinfected participants on certain HIV-1 ART regimens. The 
primary study objective is framed as a one-sample evaluation testing whether or not a 
fixed point estimate can be excluded. 
 
To justify the sample size of 25 per cohort for the primary efficacy outcome analysis 
SVR12 is the dichotomous (Bernoulli distributed) outcome used, with assumptions of a 
one-sided significance level of 5% (compared to a standard one-sided type I error of 
2.5%), and requiring at least 85% statistical power. The fixed point estimate to be 
excluded is 70% SVR12, meaning that the alternative hypothesis will be accepted if the 
data support a conclusion of the SVR12 rate being higher than 70%. This estimate of 
70% comes from studies among HCV/HIV-1 coinfected participants using the first 
approved DAAs [9, 10].  
 


 
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Power estimates given cohort size of 25 were calculated under various alternative 
hypotheses, With 25 participants, there is 86% power to conclude that SVR12 is greater 
than 70% when the true SVR12 rate is 92%. Other alternative hypotheses are presented 
in the table below. Note that these calculations use the exact binomial test, which 
differs from the proposed method for analyses (see section 9.6 below). However, 
this difference is motivated for being more conservative in calculations used for 
sample size estimates.  
 
True SVR12 
Proportion 
Power 
.90 
77% 
.92 
86% 
0.94 
94% 
0.96 
98% 
 
Under Version 2.0, the anticipated accrual rate is approximately 10 to 15 participants 
per month. This rate would result in full accrual to a 25-person cohort in 1.67 to 2.5 
months following implementation of Version 2.0. 
 
9.5 
Monitoring 
 
This study will be monitored at least annually by an ACTG -appointed SMC (via the 
standing committee for the HEPTSG). This initial review will occur when the first of 
either 25 participants enrolled onto the study (irrespective of cohort) have at least 
12 weeks of follow-up data available, or the 1-year anniversary of the first 
participant enrolling to the study (first participant enrolled September 16, 2015) 
occurs.   
 
Any/all SMC reviews will include administrative/conduct data as well as safety data 
according the safety-related outcomes enumerated above, and any data (eg 
accrual, conduct, key specimen availability, and safety) from substudies (if/as 
available). 
 
Note that since efficacy outcomes in the substudies are not being assessed in 
real-time, but being performed in retrospective, batch testing, that efficacy 
outcome data from substudies will likely not be available at the time of A5329 
interim reviews, and therefore no efficacy outcome data will be presented, even if 
initial batch testing has commenced.  
 
For the main study, there are no plans for formal interim monitoring of the efficacy 
outcome of SVR12 or related earlier HCV RNA outcomes. However, HCV RNA 
descriptive summaries will be provided to the SMC. While HIV-1 VF has been 
removed as a safety event of interest in Version 2.0, HIV-1 RNA descriptive 
summaries will be provided to the SMC. 
 
The following routine monitoring reports are distributed to core team and are 
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study status, data and sample completeness. The routine safety monitoring report 
is distributed to the DAIDS Clinical Representative (separately by cohort) and a 
subset of the core team (collapsed over cohort) every 3 months. 
 
Further details about monitoring of this study are available in the SMP. 
 
9.6 
Analyses 
 
The analysis phase of this study will be initiated upon study completion (when the 
final participant has his/her final study evaluation visit and comes off study 
follow-up). 
 
9.6.1 Primary Efficacy Analysis 
 
The primary efficacy outcome (SVR12) will be estimated within each study cohort, 
with a point-wise estimate as well as a 95%, one-sided lower confidence bound. 
The confidence bound will be calculated with exact binomial distribution 
according to the method of Clopper-Pearson. (Corresponding, two-sided, 90% 
confidence intervals may also be calculated). A one-sided exact test for a single 
binomial population will use the null hypothesis response rate of 70%, applied to 
each of the two analysis groups as defined above. 
 
Those missing a HCV RNA result from the week 12 post-HCV therapy 
discontinuation visit (and missing all subsequent evaluations) will be considered 
as non-responders. However, if HCV RNA evaluations subsequent to week 12 
PT are non-missing, then the first HCV RNA subsequent to week 12 PT will 
instead be used to define the primary outcome as per section 9.2.1.1. 
 
As mentioned in the general statistical considerations section, the primary 
analyses of this study will be performed without regard to the protocol 
version under which participants enrolled or under which data were 
collected. The changes from Version 1.0 to Version 2.0 affected both ARV 
regimen and HCV study treatment. Due to sequential cohort enrollment 
these protocol version updates are anticipated to have differential 
implications by cohort; and cohort groups are expected to be 
heterogeneous, and some of this heterogeneity will have been caused by 
protocol version updates. 
 
9.6.2 Secondary Analyses 
 
Safety and tolerability outcomes will be summarized by cohort. Descriptions of 
the absolute and relative frequency and incidence of outcomes will also be 
summarized. The method of Kaplan-Meier can be used to estimate the 
cumulative probability of these outcomes (eg, time to first SAE, or time to first 
qualifying sign/symptom), at various follow-up times, but no comparisons to 
internal or external (ie, historical controls) groups is planned. Note that these 
analyses will be as-treated, as the outcomes are as-treated, where “as-treated” is 
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of HCV therapy and for 30 days following HCV therapy discontinuation (including 
premature discontinuation). 
 
PK outcome measures analyses are outlined in section 10 below. 
 
The outcomes of HIV-1 VF and related outcome of presence of genotypic 
mutations (which are only measureable among those with VF) will be 
summarized and described (nature, timing, potential triggers, and supporting 
data). Because these outcomes are anticipated to be extremely rare (and maybe 
not ever observed), no formal statistical inference or comparisons are planned. 
Similar to safety and tolerability outcomes, HIV-1 VF outcome is evaluated only 
while HCV treatment is being received or within 4 weeks following permanent 
discontinuation (see section 7.3 for more details). Resistance outcome will 
consider whether observed mutations are associated with ARV drugs received in 
the past, currently, or never received. As noted in the definition of the outcome, 
resistance will be defined for mutations that confer major resistance of any HIV-1 
PI. Resistance to other ARVs may also be described. 
 
The distribution of baseline immune function markers (eg, sCD14 and IP-10) will 
be summarized and described as continuous outcomes (eg, key percentiles and 
graphics such as box-plots or dot-plots), and no transposition is anticipated. This 
will be repeated by cohort. To address the objective relating these markers to the 
outcome of SVR12, a Wilcoxon Rank-Sum test where groups are defined by SVR 
will compare the distribution of baseline immune marker. If some signal is 
observed here, multivariable logistic regression for the outcome of SVR12, and 
exploring the independent contribution of baseline immune markers when 
controlling for other factors prognostic for the SVR outcome will be fit.  
 
HCV mutations among the subset who have this outcome defined (ie, non-
responders for SVR12 outcome) will be summarized by participant for patterns, 
and across participants by mutation location, for frequency. The list of relevant 
HCV mutations at the time of this protocol was provided by AbbVie and will be 
included on the PSWP or LPC. If additional relevant mutations are identified prior 
to analysis, these will be specified in the study’s SAP. Baseline and follow-up 
samples will be compared for matching of genotype so that possible evolution (or 
selection of existing minor variants) of resistance can be described. 
 
SVR24 outcome will be summarized and described using methods parallel to the 
primary SVR12 outcome as described above in section 9.6.1. The visit window for 
SVR24 will start at the week 24 PT, and use imputation parallel to that for SVR12 
to account for missing data, if relevant, and only as subsequent data are 
available during study follow-up for evaluation. 
 
Additional details regarding all analyses will be pre-specified in the study’s SAP. 
 
 


 
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10.0 
PHARMACOLOGY PLAN 
 
10.1 
Pharmacology Objectives 
 
(There are no primary objectives related to pharmacology) 
 
10.1.1 Secondary objective:  See section 1.3.4. 
 
10.1.2 Exploratory objectives:  See sections 1.4.3 to 1.4.5. 
 
10.2 
Pharmacology Study Design 
 
10.2.1 PK Objectives 
 
In the context of PK substudy A5334s, intensive PK sampling will be conducted 
prior to and 4 weeks (+ 1 week) after initiation of HCV drugs, and participant-
specific ARV and DAA PK parameters will be estimated using noncompartmental 
methods. Summary statistics for these parameters will be used as inputs to (prior 
information for) nonlinear mixed-effects population PK models, which will be fit to 
drug concentrations obtained from the sparse PK sampling conducted on all 
participants in A5329. For each participant, single samples (ranging from 2-10 
hours after the preceding dose of both QD and BID drugs) will be collected at 
multiple occasions; see section 6.0 for details of sample collection.  
 
The larger (compared to the substudy) number of participants available for 
these population models will provide: (1) an alternate assessment of the effects 
of the DAAs on ARV PK (via assessment of a covariate representing pre-HCV 
treatment (week 0) vs. post-HCV treatment (weeks >0), and (2) an alternate 
assessment of the effects of the ARVs on DAA PK (via comparison of A5329 
participant-specific DAA estimates with external control group(s) of participants 
not taking ARVs (data from AbbVie). The larger number of participants will likely 
represent a wider and more representative distribution of factors that could affect 
PK such as age, sex, race, status of selected SNPs, and degree of cirrhosis, 
thereby providing an important alternative assessment of ARV-DAA DDIs. 
 
10.2.2 PD Objectives 
 
To examine the association of DAA systemic exposure with HCV treatment 
outcomes, participant-specific estimates (from the population PK models) of 
DAA clearance (or another PK parameter) will be used as independent variables 
in models of HCV treatment response as the dependent variable. Similarly, 
participant-specific estimates (from the population PK models) of ARV 
clearance (or another PK parameter) will be used to explain any observed cases 
of HIV-1 VF. Drug clearances will also be used as independent variables in 
models for the occurrence of selected toxicities. 
 


 
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10.3 
Pharmacokinetics Analysis  
 
PTV, OBT, DSV will be assayed at AbbVie Bioanalysis using mass spectrometry. RAL, 
DTG, DRV, ATV, and RTV will be assayed by the UB PSL. RBV plasma and dried blood 
spots will be assayed by the UCHS PSL. 
 
For each drug, separate nonlinear mixed-effects population PK models will be fit, as 
described in section 10.2.1 above. Additional details will be specified in the Statistical 
Analysis Plan. 
 
10.4 
Anticipated Outcomes  
 
We anticipate that participants taking both ARVs and DAAs will have similar or greater 
exposure to RAL, DTG, DRV, ATV, PTV/r/OBT, and DSV, compared to participants 
taking only ARVs or only DAAs. The proposed clinical pharmacology objectives will 
provide important data on possible PK changes that may occur in participants with 
HCV/HIV-1 coinfection. However, since the number of participants taking individual 
ARVS within the same cohort regimen group is not controlled, there may be some 
ARVs for which there are too few observations in which to perform a population 
PK model, and therefore inference for those ARVs will not be possible because of 
sparse data. 
 
To provide context for these potential alterations to ARV and DAA exposure in 
participants treated for both infections, through PD models we will examine 
associations between altered drug exposure and treatment outcomes.  
 
 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
CRFs 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 randomization. 
 
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 assure 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, 


 
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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 (eg, consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB/EC, the site monitors, the FDA, the NIAID, the 
OHRP, and the industry supporter or designee for confirmation of the study 
data.  
 
11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 AE Reporting to DAIDS 
Requirements, definitions and methods for expedited reporting of 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 CRMSSupport@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: 
o PTV/r/OBT 
o DSV  
o RBV 
 
11.4.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs 
(DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 
2009), must be used and is available on the DAIDS RSC website at 
http://rsc.tech-res.com/safetyandpharmacovigilance/. 


 
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11.4.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is per the EAE manual.  
• 
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 
information). 
 
 
12.0 
PARTICIPANTS 
 
12.1 
Institutional Review Board Review and Informed Consent 
 
This protocol and the informed consent document (Appendix II) 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 
(or legal guardian or person with power of attorney for participants who cannot consent 
for themselves). 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 or legal guardian 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/EC, FDA, NIAID, OHRP, or 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/EC, FDA, NIAID, OHRP, 
or the industry supporter, or other government agencies as part of their duties to ensure 
that research participants are protected.  
 
 
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.  
 
 


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


 
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15.0 
REFERENCES 
 
1. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among 
patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the 
US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002 Mar 15;34(6):831–7.  
2. Smith C. Factors associated with specific causes of death amongst HIV-positive 
individuals in the D:A:D Study. AIDS Lond. Engl. 2010 Jun 19;24(10):1537-48. 
3. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ. Influence of 
human immunodeficiency virus infection on the course of hepatitis C virus infection: a 
meta-analysis. Clin Infect Dis. 2001 Aug;33(4):562-9.  
4. Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus 
interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl 
J Med. 2004 Jul;351(5):451-9. 
5. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin 
for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004 
Jul;351(5):438-50. 
6. Mehta SH, Lucas GM, Mirel LB, et al. Limited effectiveness of antiviral treatment for 
hepatitis C in an urban HIV clinic. AIDS 2006 Nov;20(18):2361-9. 
7. Dieterich D, Soriano V, Sherman KE, et al. Telaprevir in combination with pegylated 
interferon-a-2a+RBV in HCV/HIV-co-infected patients: A 24-week treatment interim 
analysis. Seattle, WA USA: 2012.  
8. Mallolas J, Pol S, Rivero A, et al. 50 Boceprevir plus peginterferon/ribavirin for the 
treatment of HCV/HIV co-infected patients: end of treatment (week 48) interim results. J 
Hepatol. 2012 Apr;56, Suppl 2(0):S22. 
9. Poordad F, Lawitz E, Kowdley KV, et al. 1399 12-Week interferon-free regimen of ABT-
450/R +ABT-333 +ribavirin achieved SVR12 in more than 90% of treatment-naive HCV 
genotype-1-infected subjects and 47% of previous non-responders. J Hepatol. 2012 
Apr;56, Suppl 2(0):S549-S550. 
10. Lawitz E, Poordad F, Kowdley KV, et al. 13 A 12-Week interferon-free regimen of ABT-
450/R, ABT-072, and ribavirin was well tolerated and achieved sustained virologic 
response in 91% of treatment-naive HCV IL28B-CC genotype-1-infected subjects. J 
Hepatol. 2012 Apr;56 Suppl 2(0):S7. 
11. Kowdley KV, Lawitz E, Poordad F, et al. 3 Safety and efficacy of interferon-free 
regimens of ABT-450/r, ABT-267, ABT-333 +/− ribavirin in patients with chronic HCV 
GT1 infection: results from the AVIATOR Study. J. Hepatol. 2013 Apr;58, Supplement 
1:S2. 
12. Molla A, Korneyeva M, Gao Q, et al. Ordered accumulation of mutations in HIV protease 
confers resistance to ritonavir. Nat Med. 1996 Jul;2(7):760-6. 


 
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REFERENCES (Cont'd) 
 
13. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and davabuvir with 
or without ribavirin for HCV. N Engl J Med 2014;370:1983-1992.  
14. Viekira Pak Prescribing Information. AbbVie Inc., North Chicago, IL. Revised April 
2016. 
15. Feld JJ, Moreno C, Trinh R, et al. Sustained virologic response of 100% in HCV 
genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and 
dasabuvir for 12 weeks. J Hepatol 2016;64:301-7. 
16. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. 
http://www.hcvguidelines.org. Accessed April 2016. 
17. Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in 
resolving hepatitis C virus infection. Science 2004,305:872-4. 
18. Golden-Mason L, Castelblanco N, Rosen HR. Pre-treatment activatory natural killer 
receptor (NKR) expression on natural killer (NK) and natural T (NT) cell subsets 
correlates with successful anti-viral therapy for chronic hepatitis C viral (HCV) infection. 
15th International Symposium on Hepatitis C Virus and Related Viruses 2008:abstract 
186. 
19. Harrison B, Khakoo A. Natural killer cell phenotypes in chronic hepatitis C infection: 
correlation with genetics and the outcome of treatment. Hepatol. 2008;48 (Suppl):785. 
20. Vidal-Castineira JR, Lopez-Vazquez A, Diaz-Pena R, et al. Effect of killer 
immunoglobulin-like receptors in the response to combined treatment in patients with 
chronic hepatitis C virus infection. J Virol. 2010;84:475-481. 
21. Hu PF, Hultin LE, Hultin P, Hausner MA, Hirji K, Jewett A, et al. Natural killer cell 
immunodeficiency in HIV disease is manifest by profoundly decreased numbers of 
CD16+CD56+ cells and expansion of a population of CD16dimCD56- cells with low lytic 
activity. J Acquir Immune Defic Syndr Hum Retrovirol 1995;10:331-40. 
22. Mavilio D, Lombardo G, Benjamin J, et al. Characterization of CD56-/CD16+ natural 
killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic 
individuals. Proc Natl Acad Sci U S A 2005;102:2886-91. 
23. Gonzalez VD, Falconer K, Bjorkstrom NK, et al. Expansion of functionally skewed CD56-
negative NK cells in chronic hepatitis C virus infection: correlation with outcome of 
pegylated IFN-alpha and ribavirin treatment. J Immunol. 2009;183:6612-18. 
24. Anthony DD, Conry SJ, Medvik K, et al. Baseline levels of soluble CD14 and CD16+56- 
natural killer cells are negatively associated with response to interferon/ribavirin therapy 
during HCV-HIV-1 coinfection. J Infect Dis. 2012;206:969-73. 
25. Conry SJ, Meng Q, Hardy GA, et al. Genetically associated CD16+56- NK-cell IFNaR 
expression regulates signaling and is implicated in IFNa-induced HCV decline J Infect 
Dis. 2012. 
26. Sandler NG, Wand H, Roque A, et al. Plasma levels of soluble CD14 independently 
predict mortality in HIV infection. J Infect Dis 2011;203:780-90. 
27. Douek DC, Roederer M, Koup RA. Emerging concepts in the immunopathogenesis of 
AIDS. Annu Rev Med 2009;60:471-84. 


 
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REFERENCES (Cont'd) 
 
28. De Maria A, Moretta L. NK cell function in HIV-1 infection. Curr HIV Res 2008;6:433-40. 
29. Giorgi JV, Hultin LE, McKeating JA, et al. Shorter survival in advanced human 
immunodeficiency virus type 1 infection is more closely associated with T lymphocyte 
activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect 
Dis. 1999;179:859-70. 
30. Sandler NG, Koh C, Roque A, et al. Host response to translocated microbial products 
predicts outcomes of patients with HBV or HCV infection. Gastroenterology. 
2011;141:1220-30. 
31. Kovacs A, Karim R, Mack WJ, et al. Activation of CD8 T cells predicts progression of 
HIV infection in women coinfected with hepatitis C virus. J Infect Dis. 2010;201:823-34. 
32. Valdez H, Anthony D, Farukhi F, et al. Immune responses to hepatitis C and non-
hepatitis C antigens in hepatitis C virus infected and HIV-1 coinfected patients. AIDS. 
2000;14:2239-46. 
33. Gonzalez VD, Landay AL, Sandberg JK. Innate immunity and chronic immune activation 
in HCV/HIV-1 co-infection. Clin Immunol. 2010;135:12-25. 
34. Marchetti G, Nasta P, Bai F, et al. Circulating sCD14 is associated with virological 
response to pegylated-interferon-alpha/ribavirin treatment in HIV/HCV co-infected 
patients. PLoS One 2012;7. 
35. Harrington P, Zeng W, Naeger L.Clinical relevance of detectable but not quantifiable 
hepatitis C virus RNA during boceprevir or telaprevir treatment. Hepatology 
2012;55:1048-57. 
36. Lontok E, Mani N, Harrington PR, Miller V. Closing in on the target: Sustained virologic 
response in hepatitis C virus genotype-1 infection response-guided therapy. Clin Infect 
Dis. 2013 Jan 29. [Epub ahead of print] 
37. Wedemeyer H, Jensen DM, Godofsky E, Mani N, Pawlotsky JM, Miller V; 
Definitions/Nomenclature Working Group* of the HCV DrAG (HCV Drug Development 
Advisory Group), under the auspices of the Forum for Collaborative HIV Research. 
Recommendations for standardized nomenclature and definitions of viral response in 
trials of hepatitis C virus investigational agents. Hepatology. 2012 Dec;56(6):2398-403. 
38. Iwamoto M, Wenning LA, Nguyen B-Y, et al. Effects of omeprazole on plasma levels of 
raltegravir. Clin Infect Dis. 2009 Feb 15;48(4):489–92.  
39. Cahn P1, Fourie J, Grinsztejn B, et al. Week 48 analysis of once-daily vs. twice-
daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS 
2011;25:929-39. 
40. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-
daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected 
treatment-naïve patients in the ARTEMIS trial. HIV Med 2013;14:49-59. 
41. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the 
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department 
of Health and Human Services. Available at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. 
Section accessed March 2016.


 
 
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APPENDIX I: CONDITIONS INCLUDED IN THE 1993 AIDS  
SURVEILLANCE CASE DEFINITION 
 
• 
Candidiasis of bronchi, trachea, or lungs  
• 
Candidiasis, esophageal  
• 
Cervical cancer, invasive *  
• 
Coccidioidomycosis, disseminated or extrapulmonary  
• 
Cryptococcosis, extrapulmonary  
• 
Cryptosporidiosis, chronic intestinal (greater than 1 month's duration)  
• 
Cytomegalovirus disease (other than liver, spleen, or nodes)  
• 
Cytomegalovirus retinitis (with loss of vision)  
• 
Encephalopathy, HIV-related  
• 
Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, 
pneumonitis, or esophagitis  
• 
Histoplasmosis, disseminated or extrapulmonary  
• 
Isosporiasis, chronic intestinal (greater than 1 month's duration)  
• 
Kaposi's sarcoma  
• 
Lymphoma, Burkitt's (or equivalent term)  
• 
Lymphoma, immunoblastic (or equivalent term)  
• 
Lymphoma, primary, of brain  
• 
Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary  
• 
Mycobacterium tuberculosis, any site (pulmonary * or extrapulmonary)  
• 
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary  
• 
Pneumocystis carinii pneumonia  
• 
Pneumonia, recurrent *  
• 
Progressive multifocal leukoencephalopathy  
• 
Salmonella septicemia, recurrent  
• 
Toxoplasmosis of brain  
• 
Wasting syndrome due to HIV  
*Added in the 1993 expansion of the AIDS surveillance case definition.  
 
(http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm) 


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APPENDIX II: A5329 SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
For protocol: A5329 
Interferon-Free Therapy for Chronic HepAtitiS C Virus GENotype 1 InfecTion in Participants 
with HIV-1 Coinfection Receiving Concurrent Antiretroviral Therapy  
(C_ASCENT), FINAL Version 2.0, 06/08/16 
 
SHORT TITLE FOR THE STUDY: Interferon-Free Therapy for HCV Genotype 1 
 
ABBREVIATED TITLE: HCV GT 1 AbbVie 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with the 
human immunodeficiency virus (HIV), the virus that causes AIDS and the hepatitis C virus 
(HCV). This study is sponsored by the National Institutes of Health (NIH). 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, the A5329 protocol team wants 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? 
 
New drugs are being developed to treat people who are infected with the hepatitis C virus 
(HCV). These drugs are being tested as a part of drug regimens that do not contain the drug 
interferon (IFN). These regimens could be useful in treating people who are infected with both 
HCV and HIV because these people often do not respond well to interferon (it does not treat 
their HCV effectively and they may have complications from taking the drug, such as 
depression). 
 
These new drugs have not yet been adequately tested in people who are infected with both HIV 
and HCV. These are the goals of this study: 
1. To see if these drugs can effectively treat HCV in people who are infected with both HCV 
and HIV. 
2. To see if these drugs are safe and well-tolerated in people who are infected with both HCV 
and HIV. 


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APPENDIX II (Cont’d) 
 
 
The drugs used in this study are: 
• 
Drug 1: paritaprevir/ritonavir/ombitasvir (PTV/r/OBT) fixed-dose combination tablet 
approved by the US Food and Drug Administration (FDA) for the treatment of HCV 
• 
Drug 2: dasabuvir (DSV) approved by the FDA for the treatment of HCV 
• 
Drug 3: ribavirin (RBV) approved by the FDA for the treatment of HCV genotype 1a only 
 
Hepatitis C is divided into genotypes. A genotype is a way to describe the virus based on 
genetic material in the virus itself. This current study includes participants with HCV 
genotype 1a and 1b. Recent studies show patients with HCV genotype 1b do not have 
any added benefits when they take RBV as part of their HCV treatment regimen. Similar 
results have been seen in studies with patients who are infected with HIV and HCV.   
 
Prior studies show patients with HCV genotype 1a do benefit from including RBV as part 
of an HCV treatment regimen.  
 
Therefore, in the current study, RBV will be provided to you if you have HCV genotype 1a 
only.   
  
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Screening 
After you read and sign the consent form, you will have a screening visit to make sure you are 
able to join the study. This visit will last about 1-2 hours. 
• 
Your HIV infection will be confirmed. If there is no record available, you will have another 
HIV test. You may have to sign a separate consent form before having this test. 
• 
You will have a physical exam and will be asked about your health and medicines you have 
taken in the past and are taking now. Also, an EKG (electrocardiogram, a recording of the 
heart’s electrical activity) will be done at this visit.  
• 
You will have about 3 tablespoons (40 mL) of blood drawn to measure your HCV viral load 
(the amount of HCV virus in your blood) and genotype (genetic makeup of the HCV virus), 
CD4+ cell counts (these are cells in your blood that fight infection), evidence of hepatitis B 
virus infection, and HIV viral load (the amount of HIV in your blood), and for routine safety 
tests. You will be told the results of these tests when they become available.  
• 
You will have a blood test to look for Serum Alpha-Fetoprotein (AFP) in your blood. AFP is 
normally made by a fetus's liver and yolk sac. It's the main protein during the first three 
months of development. AFP greatly decreases by age 1 and should only be found in adults 
in very low levels. Some people with cirrhosis or chronic active hepatitis also have higher 
blood levels of AFP. You will be told the results of these tests when they become available. 
• 
If you are a woman able to become pregnant, you will be asked to give a urine or blood 
sample to see if you are pregnant. You will not be able to enroll in this study if you are 
pregnant. You will be told the result of the test when it becomes available.  
• 
If you are a male with a female partner who is able to become pregnant, you will be 
asked if your partner is pregnant. You will not be able to enter the study if you have 
HCV genotype 1a and your partner is pregnant. 


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APPENDIX II (Cont’d) 
 
• 
If you have been diagnosed with cirrhosis (a liver disease) and have not had imaging (CT, 
MRI, or ultrasound) of your liver in the last 6 months you will have an ultrasound of your 
liver. An ultrasound is a non-invasive procedure – waves of sound will pass through your 
skin and bounce off of your liver. You will not feel these waves. A computer will collect the 
waves that bounce back and make a picture of your liver. You will be told the results of 
these tests when they become available. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of the screening visit, some demographic (age, 
gender, race), clinical (disease condition, diagnosis), and laboratory (CD4+ cell count, viral load) 
information is being collected from you so that ACTG researchers may help determine whether 
there are patterns or common reasons why people do not join a study. 
 
Entry 
If you are eligible for the study, you will come in for a study entry visit. At this visit:  
• 
You will have a brief physical exam. 
• 
Medical and medication history will be collected at the study entry visit.  
• 
You will have about 6 tablespoons (90 mL) of blood drawn to measure HCV viral load, HIV 
viral load, CD4+ cell counts, and for some routine safety tests. You will be told the results of 
these tests when they become available.  
• 
If you are a woman able to become pregnant, you will be asked to give a urine or blood 
sample to see if you are pregnant. You will not be able to enter the study if you are 
pregnant. You will be told the result of the test when it becomes available.  
• 
If you are a male with a female partner who is able to become pregnant, you will be 
asked if your partner is pregnant. You will not be able to enter the study if you have 
HCV genotype 1a and your partner is pregnant. 
• 
You will have about 1 tablespoon (15 mL) of blood drawn for a genetic test to see if we can 
predict how well you will respond to HCV treatment (this is called an IL28B genotype test).  
• 
You will have about 1 tablespoon (15 mL) of blood drawn and stored for future HCV/HIV 
studies, including resistance studies. A resistance test is used to determine the genetic 
makeup of your HCV virus. In addition, some of your blood will be stored for future testing 
required by the study. 
• 
You will have to have IFN Gamma-Induced Protein 10 (IP-10) test to look at the protein 
levels in your blood that can become elevated in people infected with HCV genotype 1. 
• 
You will have soluble CD14 (sCD14) plasma sample taken to see how well your body 
responds to treatment of your HIV and HCV. sCD14 is a biomarker (biological molecule 
such as proteins and DNA) found in your plasma (clear, yellowish, fluid part of the blood that 
carries the blood cells).  
 
You will be assigned to a study group based on which medicines you take for your HIV and how 
long you take the study drugs. The study will require that you be on a specific antiretroviral 
therapy (ART) regimen containing either integrase inhibitor (INI) raltegravir (RAL) or 
dolutegravir (DTG) or protease inhibitor (PI) darunavir (DRV) or atazanavir (ATV), but this 
regimen will not be provided by the study.   
 


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APPENDIX II (Cont’d) 
 
The groups are described below. You and your study doctor will know the study drugs that 
you are taking. You will have about 1 tablespoon (15 mL) of blood drawn after your first 
dose of study drugs to measure the drug levels in your blood. 
 
Group A 
• 
Take study drugs for 24 weeks 
• 
Take ART regimen containing raltegravir or dolutegravir 
 
Group B 
• 
Take study drugs for 12 weeks 
• 
Take ART regimen containing raltegravir or dolutegravir 
 
Group C 
• 
Take study drugs for 24 weeks 
• 
Take ART regimen containing darunavir or atazanavir  
  
Group D 
• 
Take study drugs for 12 weeks 
• 
Take ART regimen containing darunavir or atazanavir 
 
Study Visits While Taking Study Drugs (Weeks 2, 4, 6, 8, and 10) Group A, B, C, and D: 
• 
You will have a brief physical exam. 
• 
You will have about 3 tablespoons (45 mL) of blood drawn for routine safety blood tests and 
to measure your HCV and HIV viral loads. You will be told the results of these tests when 
they become available.  
• 
You will have blood drawn to measure CD4+ cell counts (week 4). You will be told the 
results of these tests when they become available.  
• 
If you are a woman able to become pregnant, you will be asked to give a urine or blood 
sample to see if you are pregnant (at week 4 and week 8). You will be told the result of the 
test when it becomes available.  
• 
You will have about 1 tablespoon (15 mL) of blood drawn and stored for future testing 
required by the study. 
• 
You will have about 1 tablespoon (15 mL) of blood drawn to measure the levels of study 
drugs in your blood. 
• 
You will have to have an IP-10 test (at week 2 and week 4). 
• 
You will have sCD14 plasma samples taken (at week 2 and week 4). 
 
If you are assigned to Group B or D, you will stop taking study drugs at week 12. 
 
If you are assigned to Group A or C, you will stop taking study drugs at week 24, so you will 
have three more study visits while taking study drugs. 
 
Study Visits While Taking Study Drugs (Weeks 12, 16, and 20) Group A and C Only: 
• 
You will have a brief physical exam.  
• 
You will have an EKG (at week 12). 


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APPENDIX II (Cont’d) 
 
• 
You will have about 3 tablespoons (45 mL) of blood drawn for routine safety blood tests, and 
to measure your HCV and HIV viral loads. You will be told the results of these tests when 
they become available.  
• 
If you are a woman able to become pregnant, you will be asked to give a urine or blood 
sample to see if you are pregnant. You will be told the result of the test when it becomes 
available.  
• 
You will have about 1 tablespoon (15 mL) of blood drawn to measure the levels of study 
drugs in your blood (week 12 only).  
• 
You will have about 1 tablespoon (15 mL) of blood drawn and stored for future testing 
required by the study. 
• 
You will have and IP-10 test and sCD14 plasma samples taken (week 12). 
• 
You will have blood drawn to measure CD4+ cell counts (week 12). You will be told 
the results of these tests when they become available. 
 
Treatment Completion Visit (Groups A, B, C, and D) 
When you are done taking your study drugs, you will have a treatment completion visit (at week 
12 for Groups B and D; at week 24 for Groups A and C). At this visit: 
• 
You will have a brief physical exam, including an EKG. 
• 
You will have about 6 tablespoons (90 mL) of blood drawn to measure your HCV viral load, 
HIV viral load, CD4+ cell counts, and for some routine safety tests. You will be told the 
results of these tests when they become available.  
• 
If you are a woman able to become pregnant, you will be asked to give a urine or blood 
sample to see if you are pregnant. You will be told the result of the test when it becomes 
available.  
• 
You will have about 1 tablespoon (15 mL) of blood drawn to measure the levels of study 
drugs in your blood. (Groups B and D only)  
• 
You will have about 1 tablespoon (15 mL) of blood drawn and stored for future testing 
required by the study. 
• 
You will have to have an IP-10 test. 
• 
You will have sCD14 plasma samples taken. 
 
You will not take any more study drug after this visit, but you will have study visits to follow your 
health.  
 
Post-Treatment Visits (Post-treatment weeks 4, 12, and 24 for Groups A and C; Post-treatment 
weeks 4, 12, 24 and 36 for Groups B and D) 
• 
You will have a brief physical exam. 
• 
You will have about 6 tablespoons (90 mL) of blood drawn to measure your HCV viral load, 
your HIV viral load, your CD4+ cell counts (at some visits), and for some routine safety 
tests. You will be told the results of these tests when they become available.  
• 
If you are a woman able to become pregnant, you will be asked to give a urine or blood 
sample to see if you are pregnant. You will be told the result of the test when it becomes 
available.  
• 
You will have about 1 tablespoon (15 mL) of blood drawn and stored for future testing 
required by the study. 


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APPENDIX II (Cont’d) 
 
• 
You will have and IP-10 test and sCD14 plasma samples taken (at some visits). 
 
If you are assigned to Group A or C, you will have 3 post-treatment visits and be done with the 
study after your post-treatment week 24 visit. 
 
If you are assigned to Group B or D, you will have 4 post-treatment visits and will be done with 
the study after your post-treatment study visit week 36 visit. 
 
If You Have to Stop Taking the Study Drugs Early or You Have to Stop the Study Early 
If you have to stop taking the study drugs early, you will come to the clinic for an additional visit. 
This visit will last about 1 hour. At this visit: 
• 
You will have a brief physical exam. 
• 
You will have about 5 tablespoons (75 mL) of blood drawn to measure HCV viral load, HIV 
viral load, CD4+ cell counts, and for some routine safety tests.  
• 
If you are a woman able to become pregnant, you will be asked to give a urine sample or 
blood sample. You will be told the result of the test when it becomes available.  
• 
You will have about 1 tablespoon (15 mL) blood drawn to measure the level of study drugs 
in your blood.  
• 
You will have about 1 tablespoon (15 mL) of blood drawn and stored for future testing 
required by the study. 
• 
You will have an EKG test. 
• 
You will have to have an IP-10 test. 
• 
You will have sCD14 plasma samples taken.  
• 
You will have about 1 tablespoon (15 mL) of blood drawn to measure the study drug 
levels in your blood. 
 
After this visit, you will either: continue “on study/off study drugs,” if you agree and it is 
safe for you to continue; or you will be taken off the study altogether. If you continue “on 
study/off study drugs,” you will have the post-treatment visits as described above for 
your group. 
 
Virologic Failure 
If you experience HCV virologic failure (when your HCV worsens) or HIV virologic failure (when 
your ART fails to suppress and sustain your viral load to less than 200 copies/mL), a blood 
sample (1 teaspoon) will be collected to confirm this result. This collection may be combined 
with another study-scheduled visit. You will also have these tests done: 
• 
You will also have about 1 tablespoon (15 mL) of blood drawn to measure the levels of 
study drugs in your blood.  
• 
You will have about 1 tablespoon (15 mL) of blood drawn and stored for future 
testing required by the study. 
• 
You will have routine safety labs done (for HCV virologic failure). 
• 
You will have and IP-10 test and sCD14 plasma samples taken (for HCV virologic 
failure). 
• 
You will have about 1 teaspoon of blood drawn for HIV-1 resistance testing (for HIV 
virologic failure).  


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Your study doctor will talk to you about the plan for future treatment. 
 
For HCV virologic failure: You must stop taking HCV study drugs right away. You will 
continue “on study/off study drugs” and have the post-treatment visits as described 
above for your group. 
 
For HIV virologic failure: You may or may not need to stop taking HCV study drugs. Your 
study doctor will discuss this with you. If it is safer for you to stop taking HCV study 
drugs, you will continue “on study/off study drugs” and have the post-treatment visits as 
described above for your group. 
 
Other 
Some of your blood that is left over after all required study testing is done may be stored (with the 
usual protectors of your identity) and used for ACTG-approved HIV-related research. Refusing to 
have your blood stored will not affect your participation in this study. We will not store your samples 
with any information that will identify you. These samples may be stored for an indefinite period. 
You might not receive the results of testing performed on these samples. 
 
Please indicate now if you agree to allow your leftover blood to be used for future ACTG-
approved HIV-related research. You may still change your mind at any time and we will destroy 
your samples.  
 
________ YES, I AGREE                  ________ NO, I DO NOT AGREE 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
 About 100 people will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for up to 11 months.     
 
 
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.) 
• 
you are not able to attend the study visits as required by the study 
• 
your primary care provider or investigator thinks the study is no longer in your best interest 
 
 


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The study doctor may also need to take you off the study drugs without your permission if: 
• 
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 miss 3 or more clinic visits in a row 
• 
you experience HCV virologic failure 
• 
you become pregnant or breast-feed (for females on study) 
• 
your female partner becomes pregnant (for males on study)  
 
If you must stop taking the study drugs before the study is over, the study doctor may ask you to 
continue to be part of the study and return for some study visits and procedures. 
 
 
IF I HAVE TO PERMANENTLY STOP TAKING STUDY-PROVIDED DRUGS OR ONCE I 
LEAVE THE STUDY, HOW WOULD DRUGS BE PROVIDED? 
 
During the study: 
If you must permanently stop taking study-provided drugs before your study participation is 
over, the study staff will discuss other options that may be of benefit to you. 
 
After the study: 
After you have completed your study participation, the study will not be able to continue to 
provide you with the drugs you received on the study. If continuing to take these or similar 
drugs/agents would be of benefit to you, the study staff will discuss how you may be able to 
obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of Social Harm 
Although the study site staff will make every effort to protect your privacy and confidentiality, it is 
possible that other people could find out that you are in a study and this could cause problems 
for you. For example, other people might figure out that you are infected with HIV. If  
this happens, people could treat you unfairly or family members, friends, and/or the community 
might not accept you. 
 
Risks of Drawing Blood 
Taking 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 EKG 
An EKG has no serious risks and does not give off electrical charges, such as shocks. You may 
develop a mild rash where the electrodes (soft patches) were attached. This rash often goes 
away without treatment. 
 
 


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Risks of Study Drugs 
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 the additional 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. 
 
Risks of paritaprevir/r/ombitasvir and dasabuvir 
• 
Abnormal EKG (the changes may be associated with abnormal heart rhythms) 
• 
Fatigue 
• 
Headache 
• 
Abnormal liver tests (inflammation of the liver) 
• 
High bilirubin level, may cause yellowing of the skin and eyes 
• 
High alkaline phosphatase level in the blood (may be associated with gall bladder disease) 
• 
Headache: 7.3%, about 7 in 100 participants  
• 
Diarrhea: 3.6%, about 4 in 100 participants 
• 
Nausea: 2.9%, about 3 in 100 participants 
• 
Dizziness: 2.9%, about 3 in 100 participants  
• 
Constipation: 2.5%, about 3 in 100 participants 
• 
Common cold symptoms: 2.2%, about 2 in 100 participants 
 
More than 5,000 HCV-infected patients have been treated with a paritaprevir/r-based 
interferon-free, combination DAA HCV treatment regimen during phase II/III and currently 
ongoing clinical trials. 
 
Side effects which were considered related to the 3-DAA+ ribavirin (RBV) medications are 
listed below from most frequent to least frequent. These events occurred at least 5% 
more often in patients receiving 3-DAA + RBV medications than with patients who 
received a sugar pill (placebo) in the placebo-controlled phase III studies. 
• 
Very common (>1/10): tiredness (34.2%, about 34 in 100 patients), nausea (22.3%, 
about 22 in 100 patients, itching (15.7%, about 16 in 100 patients), trouble sleeping 
(14.0%, about 14 in 100 patients), weakness (13.5%, about 14 in 100 patients)  
• 
Common (>1/100 to <1/10): low blood count (5.3%, about 5 in 100 patients)  
• 
The side effect that was considered related to the 3-DAA medications alone (without 
RBV) was itching (6%, in about 6 of 100 patients) 
 
Risk of liver problems and failure 
A small number of patients have experienced severe liver problems while on the 3-DAA 
medicines, some of whom died or required liver transplantation. These liver problems 


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included confusion, abdominal fluid accumulation and swelling, bleeding, and changes 
in blood tests that measure the function of the liver.  
 
It is unknown whether these liver problems were directly caused by the 3-DAA medicines 
or were a result of their advanced liver disease. Most patients who died or needed a liver 
transplant already had advanced disease before starting the 3-DAA medicines. Blood 
tests that measure your liver function will be performed during the study, and your 
doctor will monitor you for signs of severe liver problems. Let your doctor know if you 
have swelling of the stomach area, bleeding, or are feeling confused. 
 
Risk of ALT elevations 
About 1 in 100 patients (1%) being treated with 3-DAA medicines experienced an 
increase in ALT (a blood test that increases when your liver is inflamed) levels. Increased 
levels of ALT happened more often in patients receiving medicines containing ethinyl 
estradiol, which many birth control pills contain. These increased ALT levels did not 
cause symptoms, usually happened during the first 4 weeks of treatment, and got better 
with continued treatment with the 3-DAA medicines.  
 
Patients who are taking ethinyl estradiol-containing medicines will be asked to stop 
taking these medicines before starting treatment with the 3-DAA medicines. Ethinyl 
estradiol-containing medicines include pills, patches, or rings that deliver ethinyl 
estradiol for the purpose of contraception or for other clinical indications, including 
some hormone replacement therapy. Estrogens used to treat symptoms of menopause 
like vaginal creams do not typically contain ethinyl estradiol. If you are using an 
estrogen, it is important for your physician to check what type of estrogen it contains.   
(FOR STUDY M13-101 ONLY: The dose of paritaprevir is <200 mg in both the approved 
HCV medication as well as in most of the clinical trials, except for the study M13-101 in 
which the dose administered is 200 mg. If you are in this M13-101 study and receiving 
paritaprevir at the 200mg dose, the risk of ALT elevations is increased when compared 
with participants receiving paritaprevir at <200 mg dose.) 
 
If you are taking an ethinyl estradiol-containing medication for birth control, your doctor 
may switch you to a different method of birth control (for example, a progestin-only 
containing contraceptive or non-hormonal form of birth control). You may restart your 
ethinyl estradiol-containing medicine about 2 weeks after your 3-DAA medicine treatment 
is completed. Your blood levels of ALT will be measured during this study. Let your 
doctor know if you have new onset of fatigue, weakness, lack of appetite, nausea and 
vomiting, jaundice, or discolored feces. 
 
Increased bilirubin levels 
Some patients taking the 3-DAA medicines, especially those who were also taking 
ribavirin or the HIV medicine ATV, had increased levels of bilirubin (a substance 
measured in your blood that is produced when red blood cells are broken down) that can 
cause yellowing in the eyes or under the tongue in a small number of people. These 
bilirubin increases can be temporary and may not be caused by damage to the liver. 


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Increases in bilirubin usually reach their highest level in the first week after starting the 
3-DAA medicines and get better with continued 3-DAA treatment. 
 
In some cases, increases in bilirubin can get worse. If bilirubin increase occurs with 
other signs such as swelling of the stomach area, vomiting of blood, or confusion, it may 
be a sign of a severe liver problem. 
 
Hemoglobin decreases 
RBV is known to cause anemia (low hemoglobin levels from having low red blood cell 
counts). See RBV-related risks. In studies in which patients received the 3-DAA 
medicines with RBV, hemoglobin levels decreased during treatment and got better after 
treatment was finished. Low hemoglobin levels were usually treated by decreasing the 
dose of RBV given. Patients rarely required blood transfusions or other medicines to 
increase hemoglobin levels. 
 
General information 
The study medications may interfere/interact with some medications. One such 
interaction is with a type of blood pressure medicine called calcium channel blockers. In 
studies done in Japanese patients, 5% of patients taking calcium channel blockers 
developed leg swelling, a known side effect of calcium channel blockers, after starting 
DAA (study medications).  
 
Some drug interactions may be serious or life-threatening. You must let your doctor 
know about any medications (oral, inhaled, topical, or other), including herbals or 
vitamins that you are taking.  
 
In addition, as with any medicines, the 3-DAAs may cause unexpected allergic reactions. 
Allergic reactions, including lip and tongue swelling, have been observed in patients 
taking the 3-DAA medications. 
 
Information about pregnancy 
The risks of AbbVie’s 3-DAA medicines in pregnancy are not known.  
 
Risks of Ribavirin (RBV) 
• 
Anemia (decreases in your red blood cells caused by breakdown of your red blood cells). 
Anemia can worsen existing heart and pulmonary conditions.  
• 
Temporary changes in blood platelet levels  
• 
Temporary changes in liver function tests (a measure of your liver activity) 
• 
Stomach and intestinal 
o Nausea 
o Vomiting 
o Indigestion 
o Stomach discomfort 
o Skin disorders 
• 
Upper respiratory tract inflammation 
• 
Teratogenicity (risk to an unborn baby) 


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• 
Nervous system 
o Depression 
o Insomnia (inability to sleep) 
o Nervousness 
o Skin tingling 
o Drowsiness 
o 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 ribavirin is the 
cause. This may be more common if ribavirin 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 ribavirin. Because of these risks, didanosine use is not allowed in this study. 
RBV is associated with birth defects and should not be taken by pregnant women or 
men with pregnant sexual partners. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drug or drug combinations in this study are unsafe for unborn babies. The risks to unborn 
babies for each drug are listed in the section called “What Are The Risks Of The Study?”  
 
If you are having sex that could lead to pregnancy, you must agree not to become pregnant or 
make a woman pregnant. 
 
Because of the risk involved, if you are participating in sexual activity that could lead to 
pregnancy, you and your partner must use two methods of birth control that you discuss with 
the study staff. You may choose two of the birth control methods listed below: 
• 
Condoms (male or female) with or without a spermicidal agent  
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
 
You and your partner must use two reliable methods of birth control simultaneously 
while receiving study drugs. If you will be taking RBV on study, then you must continue 
to use two reliable methods of birth control at the same time for 6 months after stopping 
study drugs. Ribavirin is known to cause birth defects and can lead to the death of an 
unborn child. If you will not be taking RBV on study, then you must continue to use two 
reliable methods of birth control at the same time for 30 days after stopping study drugs.  
 
If you are a woman who can become pregnant, you must have a pregnancy test within 24 
hours prior to starting the study drugs. The test must show that you are not pregnant. 
Pregnancy tests will also be performed at most study visits. If you think you may be pregnant at 


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any time during the study, tell your study staff right away. The study staff will talk to you about 
your choices. 
 
If you are a man on study and you think your female partner may be pregnant at any time 
during the study, tell your study staff right away.  
 
For participants with HCV genotype 1a who are receiving RBV: 
Pregnancy (either women or men whose female partners become pregnant) at any time 
during the study will result in immediate discontinuation of RBV and counseling on ribavirin 
teratogenicity (ability to cause birth defects). You will continue on DAAs. You will continue to 
be followed on study and have the visits as described above for your group until study 
completion.  
 
For participants with HCV genotype 1b: 
Women or men with women partners who become pregnant at any time during the study 
will continue on DAAs. You will continue to be followed on study and have the visits as 
described above for your group until study completion.  
 
All participants: 
You will be contacted by the study staff 6 months after the end of the pregnancy to follow 
up on any side effects. In addition, the study staff will report pregnancies to the Ribavirin 
Pregnancy Registry (if you were taking RBV) and the Antiretroviral Pregnancy Registry. 
These are websites housing information about any side effects seen in babies who were 
exposed to RBV or anti-HIV drugs during pregnancy.  
 
Breastfeeding 
It is unknown whether the study drug or study drug combinations pass through the breast milk 
and may cause harm to your infant. You will not be allowed to participate in the study if you are 
breastfeeding. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. 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 available to you 
• 
treatment with experimental drugs, if you qualify  
• 
no treatment 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 


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WHAT ABOUT CONFIDENTIALITY? 
 
The A5329 team 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 Protections 
(OHRP) or other government agencies as part of their duties, Food and Drug Administration 
(FDA), (insert name of site) institutional review board (IRB) (a group that protects the rights and 
well-being of people in research), National Institutes of Health (NIH), study staff, study monitors, 
drug companies supporting this study, and their designees. Having a Certificate of 
Confidentiality does not prevent you from releasing information about yourself and your 
participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, the A5329 team will be required to tell the proper 
authorities. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. 
law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
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.) 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. 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. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
The A5329 protocol team will tell you about new information from this or other studies that may 
affect your health, welfare, or willingness 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 
 
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 
 
 
 
____________________________ 
________________________________________ 
Participant’s Legal Representative (print) 
Legal Representative’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
_________________________________________ 
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: 
ACTG A5329 
Primary Statistical Analysis Plan 
Version 3.0 
 
 April 29, 2019  
 
 
Page 1 of 16 
ACTG A5329 
Primary Statistical Analysis Plan 
Version 3.0 
 
Interferon-Free Therapy for Chronic HepAtitiS C Virus GENotype 1 Infection in 
Participants with HIV-1 Coinfection Receiving Concurrent Antiretroviral Therapy 
(C_ASCENT) – Version 2.0 (06/08/16), LOA #4 (06/06/2018) 
 
ClinicalTrials.gov Identifier: NCT02194998 
 
 April 29, 2019  
 
 


ACTG A5329 
Primary Statistical Analysis Plan 
Version 3.0 
 
 April 29, 2019  
 
 
Page 1 of 16 
 
1 
INTRODUCTION .................................................................................................................................... 3 
1.1 
Purpose ........................................................................................................................................ 3 
2 
STUDY OVERVIEW ............................................................................................................................... 3 
2.1 
Study Schema ............................................................................................................................. 3 
2.2 
Hypotheses (copied from protocol document v2.0 06/08/2016 and not revised in 
any subsequent LOA) ..................................................................................................... 5 
2.3 
Study Objectives ......................................................................................................................... 5 
2.3.1 
Primary Objectives ............................................................................................... 5 
2.3.2 
Secondary Objectives .......................................................................................... 5 
2.4 
A5329 Protocol History .............................................................................................................. 6 
2.5 
Overview of Sample Size Considerations ................................................................................ 7 
2.6 
Overview of Formal Interim Monitoring .................................................................................... 7 
3 
STATISTICAL PRINCIPLES ................................................................................................................. 8 
3.1 
General Considerations ............................................................................................................. 8 
3.1.1 
Key Analysis Decisions: ....................................................................................... 8 
4 
OUTCOME MEASURES ....................................................................................................................... 8 
4.1 
Primary Outcome Measures ...................................................................................................... 8 
4.1.1 
Primary Efficacy Outcome .................................................................................... 8 
4.1.2 
Primary Safety and Tolerability Outcomes ........................................................... 9 
4.2 
Secondary Outcome Measures ............................................................................................... 12 
4.2.1 
HIV-1 Virologic Failure ....................................................................................... 12 
4.2.2 
HIV-1 Resistance Mutations ............................................................................... 13 
4.2.3 
Biomarkers of Immune Activation ...................................................................... 14 
4.2.4 
Measurement of SVR24 ...................................................................................... 14 
5 
REPORT CONTENTS ......................................................................................................................... 16 
DOCUMENT APPROVAL*: ............................................................. ERROR! BOOKMARK NOT DEFINED. 
 
 
 
 


ACTG A5329 
Primary Statistical Analysis Plan 
Version 3.0 
 
 April 29, 2019  
 
 
Page 2 of 16 
Version History 
Version 
Changes Made 
Date Finalized 
3 
 
Protocol amendment reviews (LOAs #1-#4) – see dates below 
 
Removed ‘Other Outcome Measures’ section as the outcomes are 
linked to exploratory objectives that will be addressed in the 
secondary analysis plan 
 
Removed exploratory objectives pertaining to biomarkers and 
immune response based on decision from team conference call 
summary (02/05/2019) 
 
Removed exploratory objectives pertaining to PK parameters based 
on decision from team conference call summary (01/08/2019) 
 
Removed secondary outcomes and measures pertaining to HCV 
resistance mutation of participants who were HCV virologic failure 
based on decision of abandonment from team conference call 
summary (06/05/2018) 
 
Updated study schema from protocol version 1.0 to version 2.0. 
 
Updated A5329 Protocol History 
o 
A5329 Letter of Amendment 1, Version 2.0 (11/07/2016) 
o 
A5329 Letter of Amendment 2, Version 2.0 (07/07/2017) 
o 
A5329 Letter of Amendment 3, Version 2.0 (08/04/2017) 
o 
A5329 Letter of Amendment 4, Version 2.0 (06/06/2018) 
 
Updated key analysis decisions 
 
Updated schedule of evaluation windows to coincide with Version 2.0 
of the protocol. 
 
Included an overview of sample size considerations. 
 
Included an overview  of formal interim monitoring 
 
Included a note on primary safety and tolerability outcome. 
 
Updated report contents section to provide additional detail 
 
Reformatted document to new template 
 
Added appendices with writing team roster and analysis timeline 
4/24/2019 
2 
 
Updated included population: remove references to HCV treatment 
naïve) 
 
Updated ARV regimen 
o 
Cohort A and B = integrase inhibitor (INI)-based (raltegravir 
[RAL] or dolutegravir [DTG]) ARVT regimen 
o 
Cohort C and D = protease inhibitor (PI)-based (darunavir 
[DRV] or atazanavir [ATV] ART regimen 
o 
Updated Abbvie’s HCV drug names 
 
ABT-450/r/ABT-267 = 
paritaprevir/ritonavir/ombitasvir (PTV/r/OBT) 
 
ABT-333 = dasabuvir (DSV) 
o 
HCV genotype 1a participants are receiving ribavirin (RBV), 
while HCV genotype 1b participants are not receiving RBV.  
References to DAA+RBV have been changes to DAA+/-
RBV 
 
Updated objectives to match Version 2.0 objectives 
o 
Removed one objective from Version 1.0 and moved one 
secondary objective to exploratory objective. 
06/21/2016 


ACTG A5329 
Primary Statistical Analysis Plan 
Version 3.0 
 
 April 29, 2019  
 
 
Page 3 of 16 
 
Clarified calculations of analysis windows 
 
Updated monitoring section to match Version 2.0 of the protocol 
 
Clarified safety outcome 
 
Update Secondary Outcome Measures Analyses to reflect the 
changes in objectives for Version 2.0 of the protocol 
 
1 
Original Version 
10/06/2015 
 
1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcome 
measures and additional outcome measures of the A5329 study that will be included in the 
primary manuscript, and which address, at a minimum, the major primary and secondary 
objectives of the study. The Primary SAP outlines the general statistical approaches that will be 
used in the analysis of the study. It has been developed to facilitate discussion of the statistical 
analysis components among the study team, and to provide agreement between the study team 
and statisticians regarding the statistical analyses to be performed and presented in the primary 
analysis report. It also describes the results for the primary and secondary outcome measures 
that will be posted on ClinicalTrials.gov.  
Detailed outlines of tables, figures, and coding descriptions that will be included in the Primary 
Analysis Report are included in the Analysis Implementation Plan (AIP).  
Analyses for the Primary Analysis Report will be performed after the last participant has 
completed his/her last study visit at 24 weeks post-treatment, all queries have been resolved, and 
the study database closure/data lock has been completed.  
Note: Primary Completion Date (PCD) is May 17, 2018.  Results must be submitted to 
ClinicalTrials.Gov by one year after PCD. 
1.2 
Version History  
See table above 
2 
Study Overview 
2.1 
Study Design 
(Extracted from Protocol Version 2.0) 
DESIGN 
Non-randomized, open-label, phase II study of interferon (IFN)-free hepatitis C 
virus (HCV) therapy for 24 or 12 weeks in sequentially enrolled cohorts of participants with HIV-1 
coinfection who are taking protocol-defined antiretroviral treatment (ART). 


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DURATION 
Up to 48 weeks per participant 
SAMPLE SIZE 100 participants, 25 participants per cohort 
POPULATION  HCV genotype 1a or 1b and HIV-1 coinfected participants (HCV treatment-naïve 
or HCV  treatment-experienced) who are on a concurrent integrase inhibitor (INI)-based 
(raltegravir [RAL] or dolutegravir [DTG]) or protease inhibitor (PI)-based (darunavir [DRV]  or 
atazanavir [ATV]) ART regimen. 
 
 
Participants will be categorized according to evidence of cirrhosis (yes or no). For 
each 25-participant cohort, the number of participants enrolled with cirrhosis will be limited to 7.  
REGIMENS  
Among participants taking an INI-based (RAL or DTG) ART regimen for HIV-
1: 24 (Cohort A) or 12 (Cohort B) weeks of HCV treatment with HCV direct-acting antivirals (DAA) 
paritaprevir/ritonavir/ombitasvir (PTV/r/OBT) + dasabuvir (DSV) +/- ribavirin (RBV) therapy 
(DAA+/-RBV therapy):   
Drug 1: PTV/r/OBT (150/100/25 mg; two 75/50/12.5 mg fixed -dose 
combination tablets) orally (PO) once a day (QD) plus 
Drug 2: DSV (250 mg) PO twice per day (BID) plus 
Drug 3: RBV (1000 or 1200 mg weight-based) dosed in two divided 
doses PO BID (participants with HCV genotype 1a only; participants with 
HCV genotype 1b will not receive RBV) 
Among participants taking a HIV-1 PI-based (DRV or ATV) ART regimen for HIV-
1: 24 (Cohort C) or 12 (Cohort D) weeks of HCV treatment with HCV DAA+/-RBV 
therapy:   
Drug 1: PTV/r/OBT (150/100/25 mg; two 75/50/12.5 mg fixed-dose 
combination tablets) PO QD plus 
Drug 2: DSV (250 mg) PO BID plus 
Drug 3: RBV (1000 or 1200 mg weight-based) dosed in two divided 
doses PO BID (participants with HCV genotype 1a only; participants with 
HCV genotype 1b will not receive RBV) 
Details for the qualifying ART concomitant regimens are in protocol section 5.4.1. 
Each cohort will include two steps: on-HCV treatment (Step 1) and post-HCV 
treatment follow-up (Step 2). 


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2.2 
Hypotheses (copied from protocol document v2.0 06/08/2016 and not revised in 
any subsequent LOA) 
1.1.1 
Combination therapy with the hepatitis C virus (HCV) direct-acting 
antiviral (DAA) treatment regimen of paritaprevir (PTV)/r (ritonavir)/ombitasvir 
(OBT) plus dasabuvir (DSV), with and without ribavirin (RBV) (DAA+/-RBV 
therapy) will be safe and well tolerated.  
 
1.1.2 
DAA+/-RBV therapy will result in sustained virologic response (SVR12) 
rates higher than 70% corresponding to the SVR12 rates observed with telaprevir 
(TVR) and boceprevir (BOC) plus pegylated interferon (PegIFN)/RBV. 
2.3 
Study Objectives 
This Primary SAP addresses the following primary and secondary objectives listed in the study 
protocol. Other study objectives in the protocol will be addressed in subsequent analysis plans.  
2.3.1 
Primary Objectives 
1. To evaluate the safety and tolerability of DAA+/-RBV therapy in participants 
coinfected with HIV-1. 
 
2. To estimate the efficacy of DAA/-+RBV therapy in HCV/HIV-1 coinfected 
participants, as measured by the SVR at 12 weeks (SVR12) after DAA+/-RBV 
therapy discontinuation, where SVR12 is defined as HCV RNA in the blood less 
than the assay lower limit of quantification (LLOQ). 
Note:  the LLOQ was not specified in the protocol in case a more sensitive assay was 
available at time of final analysis.  The LLOQ and assay specifications will be 
documented in the final analysis report. 
2.3.2 
Secondary Objectives  
Note: (only bolded objectives below addressed in this primary SAP) 
1. To evaluate HIV-1 virologic failure (VF), defined in section 7.3 of protocol and 
section 10.1 of this document) in HCV HIV-1 coinfected participants during 
coadministration of antiretroviral therapy (ART) and DAA+/-RBV therapy.  
 
2. To evaluate acquisition of major HIV-1 resistance mutations in HCV/HIV-1 
coinfected participants who experience HIV-1 VF during coadministration 
of ART and DAA+/-RBV therapy and during the initial four-week period 
following discontinuation of DAA+/-RBV therapy. 
 
3. To estimate the population plasma pharmacokinetic (PK) parameters of DAA+/-
RBV therapy, during coadministration with antiretrovirals (ARVs) in HCV/HIV-1 
coinfected participants, and to compare the participant-specific PK parameters 
obtained with those reported in prior studies for HIV-1 seronegative participants. 
[Note:  this objective is being deferred to the secondary analysis.] 
 


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4. To assess the relationship of markers of immune activation, including IP10 
and sCD14, measured before, during and after administration of DAA+/-
RBV therapy and DAA+/-RBV therapy outcome (SVR12)  
 
5. To estimate the efficacy of DAA+/-RBV therapy in HCV/HIV-1 coinfected 
participants, as measured by the sustained virologic response at 24 weeks 
(SVR24) after DAA+/-RBV therapy discontinuation where SVR24 is defined as 
HCV RNA in the blood less than the assay LLOQ.  
2.4 
A5329 Protocol History 
Protocol Version 1.0 (finalized May 19, 2014, IND# 122,987) 
A5329 Clarification Memo 1, Version 1.0 (09/04/2015) regarding clarification on serum alfa-
fetoprotein (AFP) entry criteria (Protocol Section 4.1.11). There was a typing error.  The AFP 
value listed as ≤100 ng/dL should be ≤100 ng/mL. 
A5329 Clarification Memo 2, Version 1.0 (09/25/2015) regarding clarification on referencing the 
Lab Processing Chart (LPC) for appropriate testing laboratories (protocol sections: Glossary; 
4.1.9; 4.1.10; 6.4.10; 7.3.1). 
A5329 Protocol Version 2.0 (finalized June 8, 2016, IND# 122,987) 
A5329 Letter of Amendment #1, Version 2.0 (11/07/2016).  Abbvie released an updated 
Investigator’s Brochure (IB), which resulted in changes to the background and risk list.  A 
specimen collection was added to the treatment discontinuation visit for participants in cohorts B 
and D.  In addition, any partner of a participant would also need to comply with the same 
contraceptive approaches.  ATV 300mg/Cobicistat 150 mg PO QD was added to the list of 
qualifying ART regimens for the PI regimen group.  Enrollment of eligible participants into Cohorts 
A and C closed; enrollment of eligible participants B and D opened.  HCV genotype 1a-infected 
participants with cirrhosis and prior interferon-based treatment-experience are not eligible to 
enroll into Cohorts B and D. 
A5329 Letter of Amendment #2, Version 2.0 (07/07/2017).  Participants must be screened for 
A5335S when screening for A5329.  If he/she is not eligible to participate in A5335S, then he/she 
will not be able to continue in A5329.  Participants must be classified as non-cirrhotic prior to 
study entry.  
A5329 Letter of Amendment #3, Version 2.0 (08/04/2017).  For participants on DRV,  HIV-1 
virologic suppression must have been attained while the participant was taking a dose of DRV/r 
800/100 mg PO QD or DRV/c 800/150 mg PO QD. 
A5329 Letter of Amendment #4, Version 2.0 (06/06/2018).  These were updates to team 
membership, and updates to fulfill DAIDS requirements regarding informing participants that  
other US, local, and international regulatory entities may review study records.  There were not 
updates to the study design, or analysis plan. 


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2.5 
Overview of Sample Size Considerations 
The goal of this study is to gather safety and efficacy data on the proposed regimens in HCV/HIV-
1 co-infected participants on certain HIV-1 ART regimens; the primary study objective is framed 
as a one-sample evaluation testing whether or not a fixed point estimate can be excluded. 
The planned sample size of 25 participants per cohort for the primary efficacy outcome analysis 
of SVR12, a dichotomous (Bernoulli distributed) outcome, was based on assumptions for a one-
sided significance level of 5% (compared similarly to a standard one-sided type I error of a 2.5%), 
and requiring at least 85% statistical power.  If the data support a conclusion of the SVR12 rate 
higher than 70% (the excluded fixed point estimate), then the alternative hypothesis will be 
accepted.  With 25 participants in each cohort, there is 86% power to conclude that SVR12 is 
greater than 70% when the true SVR12 rate is 92%.  
Refer to section 9.4 of protocol version 2.0 for additional details on sample size considerations. 
2.6 
Overview of Formal Interim Monitoring 
This study will be monitored at least annually by an ACTG-appointed Study Monitoring 
Committee (SMC). This initial review will occur when the first of either 25 participants enroll onto 
the study (irrespective of cohort) have a least 12 weeks of follow-up data available, or the 1-year 
anniversary of the first participant enrolling to the study (first participant enrolled September 16, 
2015) occurs.   
Any/all SMC reviews will include administrative/conduct data as well as safety data according to 
the safety-related outcomes, and any data (eg accrual, conduct, key specimen availability, and 
safety) from the substudies (A5334s/A5335s if/as available). 
Note that since efficacy outcomes in the substudies are not being assessed in real-time, but 
being performed in retrospective, batch testing, that efficacy outcome data from substudies will 
likely not be available at the time of A5329 interim reviews, and therefore no efficacy outcome 
data will be presented, even if initial batch testing has commenced.  
For the main study (A5329), there are no plans for formal interim monitoring of the efficacy 
outcome of SVR12 or related earlier HCV RNA outcomes. However, HCV RNA descriptive 
summaries will be provided to the SMC.  While HIV-1 VF has been removed as a safety event of 
interest in Version 2.0, HIV-1 RNA descriptive summaries will be provided to the SMC.  
The interim analysis report will be distributed to the Core Team (as identified in the Study 
Monitoring Plan, and is a subset of the named protocol team on the protocol), and the SMC. The 
report will include analyses for the following by cohort (and by cirrhosis status, if needed): 
 
Accrual and Study Status  
 
Baseline Characteristics   
 
Data Completeness  
 
Safety information 
 
HCV RNA and HIV-1 RNA summaries 


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3 
Statistical Principles 
3.1 
General Considerations 
3.1.1 
Key Analysis Decisions: 
 
Throughout, study entry is defined at the date of first dose of study medications.  For 
interim analyses, if the date of first dose of study medications 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.  For the protocol and analysis windows of each study visit, refer to 
the study’s AIP.  For SVR, see SVR outcome definitions below. 
 
Because persons who never start study treatment are taken off study following entry of 
baseline visit CRF (per protocol section 6.3.6), persons who never start study treatment 
will be excluded from all analyses.  For interim and final analyses, the CONSORT 
diagram will explain the difference between number of participants enrolled and number 
in the analysis sample (and thus number and reasons for exclusion due to never starting 
treatment), but then all subsequent analyses (accrual, baseline and post baseline follow-
up), will exclude these persons and thus be limited to those who started (or for interim 
analyses who intend to start—to allow for data entry delay for start of RX date) study 
treatment. 
 
In SMC reports: 
o 
Lists will be sorted by variables in the order given with study participants 
identified using an alternate participant identifier (PubID, i.e. not ACTG patid). 
o 
Participant-specific dates will not be shown, but converted to time since start of 
study treatment or time since discontinuing study treatment, when applicable.  
 
Data will be summarized by individual Cohort (A, B, C, and D, as defined above) for 
analyses and analysis subgroups (i.e. cirrhosis classification), but will not be analyzed 
separately by protocol version, as noted above. [Note:  this is an update from earlier 
protocol versions which made reference to analysis groups, which combined data across 
cohorts.  With updates to the protocol, all groupings used for analysis and report will be 
the cohorts A-D, irrespective of version (with information provided to show how protocol 
version may have resulted in ARV or HCV treatment variation within cohort). 
4 
Outcome Measures 
Note: Italicized texts in section 4 of this document are formatted in the results style of 
ClinicalTrials.gov 
4.1 
Primary Outcome Measures 
4.1.1 
Primary Efficacy Outcome 
Measure Title: Sustained Virologic Response at 12 Weeks after HCV Treatment discontinuation 
Measure Description: SVR12 evaluated at least 12 weeks post HCV treatment discontinuation. 
Responders will be those whose HCV RNA is less than the assay LLOQ. For those whose HCV 
early responses prior to SVR12 evaluation meet the guidelines for HCV VF, their SVR12 outcome 


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will be defined as non-response.  Two-sided 90% confidence interval using exact binomial 
distribution according to the method of Clopper-Pearson will be calculated. 
Time Frame: At least 12 weeks after date of last dose of study treatment.  The duration for study 
treatment for Cohorts A and C and Cohorts B and D are 24 and 12 weeks, respectively. 
Population Description:  Participants who enrolled and initiated study treatment. 
Reporting Groups: Cohorts A, B, C, and D. 
Unit: Percentage of Participants 
Summary statistics: Point wise estimate and associated 90% two-sided confidence interval. 
Statistical analysis: A one-sided exact test for a single binomial population will use the null 
hypothesis response rate of 70%. 
Analysis Approaches:  The unit of outcome, SVR12, is binary/dichotomous (responder or non-
responder).  SVR12 will be evaluated at least 12 weeks post HCV treatment discontinuation.  
Responders will be those whose HCV RNA is less than the assay of LLOQ. 
For those whose HCV early responses prior to SVR12 evaluation meet the guidelines for HCV 
virologic failure, their SVR12 outcome will be defined as non-response.  Those missing a HCV 
RNA result from the week 12 post HCV therapy discontinuation visit, which can occur as early as 
10 weeks post treatment discontinuation, (and missing all subsequent evaluations) will be 
considered non-responders.  However, if HCV RNA evaluations subsequent to week 12 post 
treatment are non-missing, then the first HCV RNA subsequent to week 12 post treatment will 
instead be used to define the primary outcome. 
[Note:  2-sided, 90% exact interval corresponds to 2, one-sided exact bounds each at 5% 
significance level.] 
For participants who are non-responders, reasons for not achieving SVR12 will be enumerated 
and summarized.   
The analysis will be performed within each cohort and estimation (but not testing) will also be 
repeated within the subgroups defined by the following baseline characteristics:  sex, HCV 
genotype, HCV treatment experience, cirrhosis status. 
4.1.2 
Primary Safety and Tolerability Outcomes 
Safety and tolerability outcomes will be summarized within each cohort. The method of Kaplan-
Meier can be used to estimate the cumulative probability of these outcomes (eg, time to first SAE, 
or time to first qualifying sign/symptom), at various follow-up times, but no comparisons to internal 
or external (ie, historical controls) groups is planned. Note that these analyses will be as-treated, 
where “as-treated” is defined as participants being evaluated for these outcomes only during 
receipt of HCV therapy and for 30 days following HCV therapy discontinuation (including 
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sites must refer to the DAIDS Table for Grading the Severity of Adult and Pediatric AEs (DAIDS 
AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009), which can be found 
on the DAIDS RSC website:  http://rsc.tech-res.com/safetyandpharmacovigilance/.  
Note: Only primary events can count towards a safety outcome.  If a participant experienced 
multiple events of the same type, the most serious grade will be counted for summarizing 
outcome severity grading.   If a participant’s entry information meets the safety outcome definition 
(eg. Entry lab abnormality is grade 3), then post-treatment initiation safety information must be 
one grade worse than baseline to meet the safety outcome definition. 
4.1.2.1 
SAEs as Defined by ICH Criteria 
Measure Title: Participants with an Occurrence of SAEs as Defined by ICH Criteria 
Measure Description: Participants experiencing any Serious Adverse Events (SAEs) as defined 
by ICH occurring after initiation of study treatment through 30 days after the date of last dose of 
study treatment. 
Time Frame: From treatment initiation until 30 days post HCV study treatment discontinuation 
(whether planned or premature discontinuation). The duration for HCV study treatment for 
Cohorts A and C and Cohorts B and D are 24 and 12 weeks, respectively. 
Population Description: Participants who enrolled and initiated study treatment. 
Reporting Groups: Cohorts A, B, C, and D. 
Unit: Number of Participants 
Summary statistics: Number of participants with at least one observed SAEs 
Statistical analysis: None 
Analysis Approaches: Refer to Section 4.1.2 of this document. 
4.1.2.2 
Premature HCV Study Treatment Discontinuation Due to Any Reason Other than 
HCV VF 
Measure Title: Participants who Prematurely Discontinued HCV Study Treatment for Any 
Reason Other than HCV Virologic Failure. 
Measure Description: Participants who discontinue HCV study treatment prematurely due to any 
reason other than HCV virologic failure.   
Time Frame: From treatment initiation until either 24 or 12 weeks later. The duration for HCV 
study treatment for Cohorts A and C and Cohorts B and D were 24 and 12 weeks, respectively. 
Population Description: Participants who enrolled and initiated study treatment. 
Reporting Groups: Cohorts A, B, C, and D. 


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Unit: Number of Participants 
Summary statistics: Number of participants with premature HCV study treatment 
discontinuation 
Statistical analysis: None 
Analysis Approaches: Refer to Section 4.1.2 of this document. 
4.1.2.3 
Occurrence of Signs/Symptoms Grade 3 or Higher 
Measure Title: Participants with an Occurrence of Signs/Symptoms Grade 3 or Higher 
Measure Description:  Signs/symptoms of Grade 3 or higher after initiation of study treatment 
through 30 days after the date of last dose of study treatment. Participants with grade 3 
sign/symptom prior to initiation of study treatment must have one grade higher than pre-
treatment. 
Time Frame: From treatment initiation until 30 days post HCV study treatment discontinuation 
(whether planned or premature discontinuation). The duration for HCV study treatment for 
Cohorts A and C and Cohorts B and D are 24 and 12 weeks, respectively. 
Population Description: Participants who enrolled and started first dose of study treatment. 
Reporting Groups: Cohorts A, B, C, and D. 
Unit: Number of Participants 
Summary statistics: Number of participants with premature HCV study treatment 
discontinuation 
Statistical analysis: None 
Analysis Approaches: Refer to Section 4.1.2 of this document. 
4.1.2.4 
Diagnoses Leading to HCV Study Treatment or HIV-1 ARV Discontinuation 
Measure Title: Participants with an Occurrence of Diagnosis Leading to premature HCV Study 
Treatment or HIV-1 ARV Discontinuation 
Measure Description:  Participants who had diagnoses leading to premature HCV study 
treatment or HIV-1 ARV discontinuation. 
Time Frame: From treatment initiation until end of study follow-up at 48 weeks.The planned 
duration for HCV study treatment for Cohorts A and C and Cohorts B and D are 24 and 12 weeks, 
respectively. 
Population Description: Participants who enrolled and initiated study treatment. 


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Reporting Groups: Cohorts A, B, C, and D. 
Unit: Number of Participants 
Summary statistics: Number of participants with diagnoses leading to HCV study treatment or 
HIV-1 ARV discontinuation 
Statistical analysis: None 
Analysis Approaches: Refer to Section 4.1.2 of this document. 
4.1.2.5 
Occurrence of Laboratory Abnormalities Grade 3 or Higher 
Measure Title:  Participants with an Occurrence of Laboratory Abnormalities Grade 3 or Higher 
Measure Description: Participants with an observed laboratory abnormalities Grade 3 or higher.  
If entry (pre-treatment) lab result was grade 3, then a grade 4 result would be required to meet 
this outcome. 
Time Frame: From treatment initiation until 30 days post HCV study treatment discontinuation 
(whether planned or premature discontinuation). The duration for HCV study treatment for 
Cohorts A and C and Cohorts B and D are 24 and 12 weeks, respectively. 
Population Description: Participants who enrolled and initiated study treatment. 
Reporting Groups: Cohorts A, B, C, and D. 
Unit: Number of Participants 
Summary statistics: Number of participants with an occurrence of laboratory abnormality of 
Grade 3 or higher. 
Statistical analysis: None 
Analysis Approaches: Refer to Section 4.1.2 of this document. 
4.2 
Secondary Outcome Measures 
4.2.1 
HIV-1 Virologic Failure 
Measure Title: Participants who experienced HIV-1 Virologic Failure 
Measure Description:  HIV-1 virologic failure defined as two consecutive HIV-1 RNA results  ≥ 
200 copies/mL  
Time Frame: From treatment initiation until 4 weeks after permanent discontinuation of HCV 
study treatment.  The duration for HCV study treatment for Cohorts A and C and Cohorts B and D 
are 24 and 12 weeks, respectively. 
Population Description: Participants who enrolled and started first dose of study treatment. 


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Reporting Groups: Cohorts A, B, C, and D. 
Unit of measure: Number of Participants 
Summary statistics: Number participants who experience HIV-1 virologic failure. 
Statistical analysis: None. 
Analysis Approaches:  Detailed presentation listing of HIV-1 VF case(s) that includes: pre-
treatment/history information, ARV and HCV treatment information, longitudinal safety 
information, other conduct information, longitudinal plasma HIV-1 RNA during the study, HCV 
RNA (only as adherence surrogate for HCV medications), HIV-1 resistance information, and 
narrative of HIV-1 failure. 
 
4.2.2 
HIV-1 Resistance Mutations 
Measure Title: Selected HIV-1 Resistance Mutations among participants who experience HIV-1 
Virologic Failure  
Measure Description:  Presence of genotypic mutations conferring major resistance to any HIV-
1 protease inhibitor drug, from plasma sample drawn following confirmed HIV-1 virologic failure 
outcome.   
Time Frame: From treatment initiation until confirmation of HIV-1 virologic failure.  The duration 
for HCV study treatment for Cohorts A and C and Cohorts B and D are 24 and 12 weeks, 
respectively. 
Population Description: Participants who experienced HIV-1 virologic failure outcome. 
Reporting Groups: Cohorts A, B, C, and D. 
Unit: Number of Participants 
Summary statistics: Number of participants with one or more genotype mutations in protease 
conferring major resistance to any Protease Inhibitors antiretroviral drug. 
Statistical analysis: None. 
Analysis Approaches:  Listing to include:  week of first HIV RNA ≥  200 IU/mL, week of 
confirmed HIV RNA ≥ 200 IU/mL, assigned cohort and list of all significant (ie. associated with 
ARV PI resistance), mutations, and the resistance interpretation at the ARV level. Listing will note 
whether observed mutations are associated with ARV drugs currently being received. 


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4.2.3 
Biomarkers of Immune Activation 
4.2.3.1 
Measurement of Soluble CD14 (sCD14) Levels 
Measure Title: Changes in Monocyte Activation from entry as measured by biomarker soluble 
CD14  
Measure Description:  Absolute change from entry in sCD14 levels in plasma  
Time Frame: End of HCV treatment (EOT), and 12 weeks post (EOT).  The end of HCV study 
treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively. 
Population Description: Participants who enrolled and initiated study treatment. 
Reporting Groups: Cohorts A, B, C, and D. 
Unit (of measure): ng/mL 
Summary statistics: Median (Inter-Quartile Range), N with observed results 
Secondary analysis: None 
Analysis Approaches:  sCD14 levels will be summarized at entry, end of HCV treatment, and 
post-treatment week 12; changes of sCD14 levels from baseline will also be summarized.   
4.2.3.2 
Measurement of Interferon Gamma-Induced Protein 10 Levels 
Measure Title: Changes in inflammation from entry as measured by biomarker CXCL10  Levels  
Measure Description:  Absolute change from entry in CXCL10 (also known as Interferon 
gamma-induced protein 10 (IP-10) levels in plasma. 
Time Frame:.  End of HCV treatment (EOT), and 12 weeks post (EOT).  The end of HCV study 
treatment for Cohorts A and C and Cohorts B and D are 24 and 12 weeks, respectively. 
Population Description: Participants who enrolled and initiated study treatment. 
Reporting Groups: Cohorts A, B, C, and D. 
Unit (of measure): pg/mL 
Summary statistics: Median (Inter-Quartile Range), N with observed results 
Statistical analysis: None. 
Analysis Approaches:  Details are parallel to section 4.2.3.1. 
4.2.4 
Measurement of SVR24  
Measure Title:  Sustained Virologic Response 24 weeks after discontinuation of HCV Treatment 


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Measure Description: Responders will be those whose HCV RNA is less than the assay LLOQ. 
For those whose HCV early responses prior to SVR24 evaluation meet the guidelines for HCV VF, 
their SVR24 outcome will be defined as non-response.   
Time Frame: At least 24 weeks after date of last dose of HCV study treatment.  The duration for 
study treatment for Cohorts A and C and Cohorts B and D are 24 and 12 weeks, respectively. 
Population Description: Participants who enrolled and initiated study treatment. 
Reporting Groups: Cohorts A, B, C, and D. 
Unit: Percentage of participants 
Summary statistics: Point wise estimate and associated 2-sided 90%, exact (Clopper-Pearson) 
confidence interval 
Statistical analysis: None 
Analysis Approaches: The SVR24 outcome will be summarized and described using parallel 
methods to the primary SVR12 outcome as described in Section 9.6.1 of the protocol and Section 
4.1.1 of this document.   
The visit window for SVR24 will start at the week 24 post-treatment (which can occur as early as 
20 weeks post discontinuation), and use imputation parallel to that for SVR12 to account for 
missing data, if relevant. 
 
 
 


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5 
Report Contents 
 
1. CONSORT Diagram 
2. Accrual summary 
3. Baseline characteristics  
a. Demographics (sex, age, race/ethnicity, IVDU, BMI) 
b. HIV-1 Disease Status (CD4 , HIV-1 RNA) and ART regimen 
c. HCV Disease Characteristics (HCV RNA, Prior Rx status, Cirrhosis classification, 
FIB-4 score, HCV genotype, IL28-B genotype, time since chronic HCV diagnosis) 
d. Labs: Chemistries, Hematologies and Liver Function Tests 
e. Medical History: Diagnoses, ongoing signs/symptoms, ongoing concomitant 
medications 
4. Study status disposition and loss to follow-up 
5. Treatment Disposition 
a. RBV use, dose and modification 
b. HCV study treatment modification  
c. Premature HCV study treatment discontinuation  
d. HIV-1 ART treatment modification 
6. Data availability 
a. Study visits 
b. HCV RNA 
c. Biomarkers of immune activation (sCD14, IP-10) 
7. Safety Results 
a. Number of participants with each safety outcome by type 
b. Details of type of outcomes (including severity grade) 
c. Kaplan-Meier plots for time to outcome  
8. Efficacy Results 
a. SVR12 estimation 
i. Assay and LLOQ 
ii. Overall estimation of SVR and separately by cohort and by subgroup 
iii. Details of non-responders 
b. HIV-1 Virologic  Failure & HIV-1 Resistance mutation (presence of any mutations 
conferring resistance to Protease Inhibitors) 
c. Biomarkers of immune activation (sCD14, IP-10)  
i. Summary statistics of distributions at baseline, EOT and 12 wks post Rx 
discontinuation, and also changes from baseline 
d. SVR24 estimation 
i. Overall estimation and separately by cohort and by subgroup 
ii. Details of non-responders