Conditions: HIV-1 Infection Hepatitis C
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
People who are infected with Hepatitis C Virus (HCV) have a great chance of being cured of the infection when they are treated with sofosbuvir. However, in some instances, treatment with sofosbuvir-containing therapy does not work. It is not known if people respond to retreatment with sofosbuvir, after it did not work the first time. There is an important need to understand retreatment options in those instances. This clinical trial was done to study the response to two different regimens, ledipasvir/sofosbuvir and ledipasvir/sofosbuvir with ribavirin, and to see if they are safe and well-tolerated in HCV-infected persons whose previous treatment with sofosbuvir had failed.

Detailed description:
There is a pressing need to understand appropriate retreatment options for HCV-infected patients who fail direct acting antiviral (DAA)-based regimens. To date, over 100,000 prescriptions have been written for SOF. Recent data indicate that SOF-based treatment defined as SOF/RBV, SOF/pegylated-interferon (PEG-IFN)/RBV or SOF/simeprevir (SIM) +/- RBV have led to treatment response of 70-92% in HCV genotype (GT) 1 patients, depending on the regimen used and presence of liver cirrhosis. Thus, there is a growing number of individuals who have failed SOF-based regimens and are in need of a retreatment strategy, the majority of which are anticipated to be HCV GT1, given the US distribution of genotypes. There are no data to inform retreatment strategies for HIV-infected individuals with SOF failure, who have traditionally represented a harder to treat group and are impacted by DAA-antiretroviral (ARV) interactions.

This was a phase II retreatment study of HCV GT1 and HIV coinfected participants who had previous HCV virologic failure on a SOF-based regimen. Participants were randomized to one of two treatment arms: 12 weeks of LDV/SOF with weight-based RBV (Arm A) or 24 weeks of LDV/SOF alone (Arm B). The targeted sample size was 40, 20 participants in each arm.

Post-entry, the study visits were scheduled at weeks 1, 2, 4, 8, 12, 16, 20 and 24 after study entry (with week 16, 20, 24 visits limited to those on the 24-week regimen), and at 4, 12 and 24 weeks after treatment discontinuation. The total study duration was 36 weeks in Arm A and 48 weeks in Arm B. At each visit, a physical examination and blood collection were conducted. HCV RNA was tested at each visit. For female participants of reproductive potential, pregnancy tests were done. At on-treatment visits, participants also completed an HCV treatment adherence questionnaire. Urinalysis was conducted at all on-treatment visits and at 4 weeks post treatment. At select visits, plasma, whole blood, urine and dried blood spots were collected.

The study was randomized because there was clinical equipoise on the benefits and drawbacks in the two study arms. The study was not designed to be powered for comparisons between the randomized study arms, and no formal statistical comparisons were conducted. The primary analysis was conducted as a single-arm analysis for each regimen.

The study experienced enrollment difficulties due to the small number of HCV treatment failures from select SOF-based regimens who would be eligible for this study, and closed to accrual prematurely. The participants enrolled remained on study until completion of follow-up.

Arms:
arm 1: Ledipasvir/sofosbuvir + ribavirin for 12 weeks, followed by 24 weeks of post-treatment follow-up. arm 2: Ledipasvir/sofosbuvir for 24 weeks, followed by 24 weeks of post-treatment follow-up.

Interventions: intervention 1: Ledipasvir/sofosbuvir intervention 2: Ribavirin
Intervention descriptions: intervention 1: Participants were prescribed one fixed dose tablet of LDV 90 mg/SOF 400 mg orally per day. intervention 2: Based on weight at entry:

For weight \<75 kg, participants were prescribed 1000 mg of RBV per day, divided into two doses to be taken orally.

For weight ≥75 kg: participants were prescribed 1200 mg of RBV per day, divided into two doses to be taken orally.

Protocol document:
Prot_001.pdf: 
 
 
A5348 
 
Phase II Trial of Retreatment Strategies for Difficult-to-Treat 
Hepatitis C Virus (HCV)-Infected Individuals Who Have 
Failed Prior Direct Acting Antiviral (DAA)-Based Regimens 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
DAIDS ES # 12046 
 
 
 
 
 
 
 
 
 
 
This file contains the current ACTG A5348 protocol, which 
includes the following document:  
 
 Letter of Amendment #1, dated 11 April 2016  
 Protocol Version 1.0, dated 29 September 2015  


 
Letter of Amendment #1 
          Page 1 of 8 
11 April 2016 
ACTG A5348 Protocol Version 1.0 
 
Letter of Amendment #1 for: 
 
A5348 
 
Phase II Trial of Retreatment Strategies for Difficult-to-Treat Hepatitis C Virus 
(HCV)-Infected Individuals Who Have Failed Prior Direct Acting Antiviral (DAA)-
Based Regimens 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
DAIDS ES # 12046 
 
Letter of Amendment Date: 11 April 2016 
 
 
 
DATE:  
April 11, 2016 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5348 Protocol Team  
 
SUBJECT: 
Letter of Amendment #1 for Protocol A5348, Version 1.0, 09/29/15 entitled 
“Phase II Trial of Retreatment Strategies for Difficult-to-Treat Hepatitis C Virus 
(HCV)-Infected Individuals Who Have Failed Prior Direct Acting Antiviral (DAA)-
Based Regimens” 
 
 
The following information impacts the A5348 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. This must be approved by your IRB/EC before implementation.  
 
The following information may also impact the Sample Informed Consent. Your IRB/EC will 
be responsible for determining the process of informing subjects of the contents of this 
Letter of Amendment (LOA). 
 
Upon receiving final IRB/EC and any other applicable regulatory entity approvals for this 
LOA, sites should implement the LOA immediately. Sites are still required to submit a LOA 
registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory 
Support Center. Sites will receive a registration notification for the LOA once the DAIDS 
PRO verifies that all the required LOA registration documents have been received and are 
complete. A LOA registration notification from the DAIDS PRO is not required prior to 
implementing the LOA. A copy of the LOA registration notification along with this letter and 
any IRB/EC correspondence should be retained in the site’s regulatory files. 


 
Letter of Amendment #1 
          Page 2 of 8 
11 April 2016 
ACTG A5348 Protocol Version 1.0 
 
 
The following are changes to A5348, Version 1.0, 09/29/15: 
 
1. Schema, Population, second paragraph (first sentence) has been revised to read: 
 
The first 15 HIV co-infected participants taking ritonavir-boosted HIV protease inhibitor 
and tenofovir disoproxil fumarate (TDF) tenofovir are required to participate in the PK 
study.  
 
2. Section 1.3.1 has been revised to read:  
 
To assess the impact of LDV/SOF and ritonavir-boosted HIV protease inhibitor (PI/r) and 
TDF coadministration on the pharmacokinetics (PK) of tenofovir (TFV). 
 
3. Section 1.3.2 has been revised to read:  
 
To assess the impact of LDV/SOF and HIV PI/r and TDF coadministration on any 
associated clinical events attributed to elevated tenofovir levels, including renal toxicity 
(defined as the development of ≥ Grade 2 renal dysfunction or development of new or 
worsened proteinuria or glucosuria).  
 
4. Section 2.2, Rationale, 6th paragraph (second sentence) has been revised to read:  
 
Other studies are planned outside of the ACTG which will evaluate retreatment strategies 
for SOF-failures; however, they exclude HIV/HCV coinfected persons and do not address 
the important drug-drug interaction of ledipasvir with concomitant TDF tenofovir - and 
ritonavir-boosted protease inhibitors. 
 
5. Section 2.2, Rationale, PK evaluation of tenofovir concentrations on participants on PI/r, 
1st sentence has been revised to read:  
 
When given with TDF, LDV/SOF increases tenofovir concentrations. 
 
6. Section 2.2, Rationale, PK evaluation of tenofovir concentrations on in participants on PI/r, 
has been revised to read: 
 
LDV/SOF increases tenofovir concentrations. The extent of the increase in tenofovir 
concentrations is most concerning for persons on PI/rs. In healthy volunteers, LDV/SOF 
increases tenofovir Cmax by 46-47% and Ctau 38- 47% when administered as tenofovir 
disoproxil fumarate (TDF)/FTC/atazanavir (ATV)/r versus TDF/FTC/ATV/r alone. LDV/SOF 
increases tenofovir Cmax by 46-64% and Ctau 52-59% when administered with 
TDF/FTC/DRV/r versus TDF/FTC/DRV/r alone [17]. Staggering the LDV/SOF by 12 hours 
from HIV protease inhibitors did not substantially change the increase in tenofovir 
exposure. Independent of HCV treatment, RTV-boosted ATV and darunavir increase 
tenofovir concentrations by 29-37% (tenofovir package insert) and 22-37% (tenofovir 
package insert), respectively. Due to anticipated increases in tenofovir with LDV/SOF and 


 
Letter of Amendment #1 
          Page 3 of 8 
11 April 2016 
ACTG A5348 Protocol Version 1.0 
 
PI/r coadministration, the current LDV/SOF package insert recommends selecting 
alternative ARV, if feasible, or monitoring for tenofovir-associated adverse reactions [10]. 
However, there can be significant downsides of changing stable ARV, including potential 
loss of HIV virologic suppression, toxicity of new regimens and delay in HCV treatment. As 
that both LDV/SOF and PI/rs increase tenofovir levels in healthy volunteers, a PK 
evaluation of the impact of LDV/SOF on tenofovir concentrations in HIV/HCV coinfected 
patients on PI/r based ARV is warranted with concomitant assessment of any clinical 
impact of elevated tenofovir levels, such as development of renal dysfunction. Given the 
limited duration of HCV treatment (12-24 weeks), it is reasonable to conduct the PK 
evaluation as part of the overall study with close monitoring of participants’ renal function, 
as recommended, rather than prior to this study. The antiretroviral tenofovir alanfenamide 
(TAF) is anticipated to have appears to have less impact on renal function [18] than TDF 
and may be less impacted by drug interactions with LDV/SOF. In a healthy volunteer 
pharmacokinetic study, LDV/SOF given with TAF did not affect TAF or tenofovir 
concentrations. Coadministration of LDV/SOF with the fixed dose combination of 
rilpivirine (RPV)/emtricitabine (FTC)/TAF increased TFV AUC concentration with a 
geometric mean ratio of 1.75 (1.69, 1.81). However, tenofovir concentrations (AUC 
467ng/mL and Cmax 25 ng/mL) were well below concentrations seen with TDF-
containing ART in the absence of HCV treatment. LDV/SOF coadministration with 
elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF (Genvoya) resulted in increased 
tenofovir concentration with  GMR for AUC of 1.27 (1.23, 1.31) and Cmax 1.17 (1.12, 
1.22); however, as with RAL/FTC/TAF, overall tenofovir concentration remained low 
(<500 ng/mL)  [19]. Thus, coadministration of LDV/SOF with TAF containing 
regimens such as TAF/FTC, RPV/TAF/FTC, and EVG/COBI/TAF/FTC is not 
anticipated to lead to significant drug-drug interactions, as indicated in the 
prescribing information [20]. Due to the limited impact of LDV/SOF on tenofovir 
concentrations with TAF-containing regimens, PK evaluation of TFV concentrations 
will be restricted to participants HIV PI/r with TDF-containing ART only. However, 
once approved TAF will not be available to all HIV/HCV coinfected patients due to cost 
and accessibility. Thus it It is important to understand the extent and clinical relevance of 
the tenofovir-ledipasvir drug interaction in HIV coinfected patients taking HIV protease 
inhibitors as TDF-based ARV remains a current mainstay of current ARV treatment. 
 
7. Section 3.0, Study Design, second paragraph has been revised to read: 
 
The first 15 participants on ARV regimens with a HIV PI/r with TDF-containing ART 
tenofovir will be required to participate in the PK component in order to participate in the 
study. These first 15 participants on PI/r with tenofovir TDF who enroll to the study will 
undergo semi-intensive PK sampling (pre-dose, hour 1 and hour 4) at weeks 0 and 4 for 
quantification of tenofovir in plasma. After the first 15 participants have enrolled, 
subsequent participants taking HIV PI/r with tenofovir TDF may opt out of the PK 
evaluations but still participate in the study. PK evaluation of tenofovir concentrations 
will be restricted to participants on ritonavir-boosted HIV protease inhibitors with 
TDF-containing ART only; TAF-containing ART regimens will not be part of the PK 
evaluation.   


 
Letter of Amendment #1 
          Page 4 of 8 
11 April 2016 
ACTG A5348 Protocol Version 1.0 
 
 
8. Section 3.0, Study Design, third paragraph has been revised to read: 
 
Fifteen slots will be held for participants across the study arms whose ARV regimen 
contains an HIV PI/r plus tenofovir TDF for the first 3 months after the study opens to 
enrollment. After 3 months, these slots will no longer be reserved to allow expeditious 
completion of study. Up to 25 participants whose ARV regimen does not contain PI/r plus 
tenofovir TDF or who are not taking ARVs will be enrolled to the study during the first 3 
months of study enrollment. After the first 3 months, additional participants whose ARV 
regimen does not contain a PI/r plus tenofovir TDF or who are not taking ARV may be 
enrolled. The study may end up with fewer than 15 participants whose ARV regimens 
contain HIV PI/r plus tenofovir TDF and more than 25 participants without, including 
participants who are not taking ARVs. 
 
9. Section 4.1.5 c, Inclusion Criteria, NOTE has been revised to read:  
 
Approved ARV is limited to efavirenz, rilpivirine, raltegravir, dolutegravir, TDF,  
EVG/COBI/TAF/FTC (Genvoya), TAF/FTC, RVP/TAF/FTC (Odefsey), abacavir, 
3TC/FTC, RTV-boosted atazanavir, and RTV-boosted darunavir (both 800 mg QD and 
600 mg BID permitted). 
 
10. Section 4.1.6, Inclusion Criteria has been revised to read:  
 
For the first 15 participants taking tenofovir TDF and a PI/r as part of their ARV regimen, 
willingness and intent to participate in PK component.  
 
NOTE: In the event that 15 participants on PI/r and tenofovir TDF have enrolled into 
A5348, participation in the PK evaluation will be optional for subsequent participants.  
 
11. A note has been added to clarify electrocardiogram inclusion criterion in Section 4.1.11. 
The revised language now reads:  
 
4.1.11 
Screening electrocardiogram (ECG) without clinically significant abnormalities as 
determined by the investigator within 42 days prior to study entry. 
 
NOTE: ECG abnormalities that are not of clinical concern for underlying 
heart conditions that may be exacerbated by ribavirin are not exclusionary. 
 
12. Section 6.1, Schedule of Events, footnotes #3 and 6 has been revised to strike “tenofovir” 
and replace with TDF. 


 
Letter of Amendment #1 
          Page 5 of 8 
11 April 2016 
ACTG A5348 Protocol Version 1.0 
 
 
13. Section 6.3.6, Clinical Assessments, Complete Physical has been revised, removing 
standardized blood pressure. The revised language reads as follows: 
 
A complete physical examination must be performed at screening and is to include at a 
minimum an examination of the head, neck and thyroid; eyes, ears, nose, throat, mouth 
and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, 
abdomen; skin, hair, nails; musculoskeletal; neurological.  
 
The complete physical exam will also include diagnoses, signs, and symptoms and vital 
signs (temperature, pulse, respiratory rate, and resting blood pressure). 
 
NOTE: Blood pressure will be measured following the current ACTG Standardization of 
Blood Pressure Measurement SOP.  
 
14. Section 6.3.7, Laboratory Evaluations, Urinalysis has been revised to strike “tenofovir” and 
replace with TDF. 
 
15. Section 6.3.11, Tenofovir PK Samples, first sentence has been revised and now reads:  
 
The tenofovir PK sampling evaluations will be only required for the first 15 participants, 
and consenting participants thereafter, who are taking ritonavir-boosted protease inhibitor 
and TDF-containing ART tenofovir.  
 
16. Section 7.1.3.1, Specific Guidance for Creatinine Clearance, fifth bullet has been revised 
to strike “tenofovir” and replace with TDF. 
 
17. Section 9.3, Randomization and Stratification has been revised and now reads: 
 
The study is randomized to Arm A and Arm B and stratified by the cirrhosis status.  
Initially, 15 slots will be reserved for participants taking a PI/r and tenofovir TDF-
containing regimen across the two study arms. This will be lifted 3 months after the study 
is open to accrual, so that the accrual progress is not constrained by the PK objective on 
tenofovir. 
 
The first 15 participants whose ARV regimen contains HIV PI/r plus tenofovir TDF who 
enroll to the study must be willing to participate in PK sampling (pre-dose, hour 1 and hour 
4) at weeks 0 and 4. After 15 such participants have contributed PK samples, participation 
in the tenofovir PK sampling is optional. Study accrual may conclude with fewer than 15 
participants whose ARV regimen contains HIV PI/r plus tenofovir TDF, since the 
reservation of 15 slots will be lifted 3 months after the study is open to accrual. There is no 
minimum or maximum for such participants. 


 
Letter of Amendment #1 
          Page 6 of 8 
11 April 2016 
ACTG A5348 Protocol Version 1.0 
 
 
18. Section 10.3, Pharmacology Sample Size Considerations, last sentence was revised and 
reads as follows: 
 
However, because expeditious completion of the study is key, the study enrollment may 
be completed without the required number of participants on ritonavir-boosted HIV 
protease inhibitor plus tenofovir TDF. 
 
19. Sample Informed Consent, What do I have to do if I am in this study, fourth paragraph 
(first sentence) has been revised to clarify the number of visits. The revised statement now 
reads: 
 
While you are in this study, you will need to be seen in the clinic about 1110 times (14 13 
times for those in Group B) during the study. 
 
20. Sample Informed Consent, What do I have to do if I am in this study, Genetic Testing, 
second paragraph (first sentence) was revised to clarify use of genetic specimens. The 
revised statement now reads: 
 
Please initial below if you agree to have any of your blood used for ACTG-approved future 
unspecified genetic testing related to HCV and HIV research. 
 
21. Sample Informed Consent, What do I have to do if I am in this study, has been modified to 
add a section for consenting to pharmacokinetic testing, before the Optional Tests section.  
 
The added language reads as follows: 
 
Pharmacokinetic Evaluation  
Participants who are taking an HIV protease inhibitor with ritonavir along with 
tenofovir disoproxil fumarate (TDF) as part of HIV treatment are eligible to 
participate in the pharmacokinetic evaluation at entry and week 4.The first 15 
participants who are taking an HIV protease inhibitor with ritonavir along with TDF 
will be required to participate in this PK evaluation; after the first 15 participants 
eligible for this evaluation enroll, participation in the PK evaluation will be 
optional. If you qualify for and participate in the PK evaluation, you will have blood 
drawn at entry to look at drug concentration in your blood. Additional blood 
samples will be obtained at 1 and 4 hours after your observed dose of HIV 
medications. These evaluations will be repeated at the week 4 visit.  
 


 
Letter of Amendment #1 
          Page 7 of 8 
11 April 2016 
ACTG A5348 Protocol Version 1.0 
Consent to participate in the PK evaluation (Only for participants on HIV ritonavir-
boosted protease inhibitor and TDF): 
 
Please initial below if you agree to participate in the PK evaluation at entry and 
week 4. Please note that participation is required for the first 15 participants who 
qualify and are enrolled in the study, which means that you will not be able to 
participate in the study if you are one of the first 15 participants and you meet the 
criteria, but do not want to participate in the PK evaluation.  
 
________ YES                     ________ NO 
 
22. Sample Informed Consent, What do I have to do if I am in this study, II. Description of 
Study Visits, Pharmacokinetic Evaluations at Entry (first sentence) has been modified to 
clarify TDF use. The revised sentence now reads: 
 
If you are taking part in the PK testing, and are taking an HIV ritonavir-boosted protease 
inhibitor and tenofovir TDF as part of your HIV regimen, you will have an extra evaluation 
(PK testing) done at the entry visit.  
 
23. Sample Informed Consent, What do I have to do if I am in this study, II. Description of 
Study Visits, Post-Entry Visits, third paragraph (fifth sentence) has been revised to clarify 
those participating in PK use. The revised sentence now reads: 
 
If you are participating in the PK studies, you You will have blood drawn several times 
for PK testing. 
 
24. Sample Informed Consent, What do I have to do If I am in this Study, III. Description of 
Study Evaluations, Sample Collections and Laboratory Testing, Blood Sample PK (first 
and second sentences) has been revised to clarify use of TDF. The revised statements 
read as follows: 
 
If you are taking tenofovir TDF-containing HIV medication and an HIV ritonavir-boosted 
protease inhibitor (atazanavir or darunavir) and you give permission to participate in the 
PK evaluation, you will have blood collected three times at each of two visits, which will 
last 4 hours each. The PK samples will be used to measure the levels of the HIV 
medicines (first PK visit and week 4) and study drugs (week 4 only) in your blood since 
there is limited information available about the interaction between tenofovir TDF, HIV 
protease inhibitors and the study drugs. You will not take your study medications or HIV 
medications that morning until you arrive at the clinic and are instructed to do so. Your visit 
will last 4 hours total. 


 
Letter of Amendment #1 
          Page 8 of 8 
11 April 2016 
ACTG A5348 Protocol Version 1.0 
 
 
25. Sample Informed Consent, What are the Risks of the Study, Risk of Study Drug, second 
paragraph: 
 
For those persons taking HIV medicines, there is no clear risk of drug interactions 
between HIV medicines and sofosbuvir. Although sofosbuvir has not been studied with all 
HIV medicines, it has been studied with all first-line HIV medication drug classes and 
there are no recognized clinically significant interactions. This is also true for ledipasvir 
with the exception of one of the HIV medications named tenofovir TDF. Ledipasvir 
increases tenofovir levels in your body. With most other HIV drug combinations this 
increase is not felt to lead to significant risk unless your kidneys don’t work normally. 
However, if tenofovir TDF and ledipasvir are used with HIV protease inhibitors that are 
combined with ritonavir, (which is used to increase the level of your HIV drugs in your 
blood stream), the potential risk of kidney toxicity may be higher. The combination of HIV 
protease inhibitors and ledipasvir and tenofovir TDF has not been studied in HIV-infected 
patients. For this reason there will be monitoring of the kidney function for all participants 
in this study. 
 
 
The above information will be incorporated into the next protocol version as necessary if the 
protocol is amended. 
 
 
 
 


 
 
 
 
 
 
A5348 
 
 
Phase II Trial of Retreatment Strategies for Difficult-to-Treat Hepatitis C Virus 
(HCV)-Infected Individuals Who Have Failed Prior Direct Acting Antiviral (DAA)-
Based Regimens  
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
The National Institute of Allergy 
and Infectious Diseases 
 
Industry Support Provided by 
Gilead Sciences, Inc. 
 
non-IND Protocol 
 
 
 
The ACTG Hepatitis Transformative Science Group:  
Raymond Chung, MD, Chair 
 
 
Protocol Co-Chairs: 
 
Annie Luetkemeyer, MD 
 
 
Jennifer J. Kiser, PharmD  
 
 
DAIDS Clinical Representative: 
 
Trinh Thuy Ly, MD 
 
Clinical Trials Specialist: 
 
KaSaundra M. Oden, PhD, CCRP  
 
 
 
 
FINAL Version 1.0 
September 29, 2015 
 
 


A5348 
 
 
FINAL Version 1.0 
 
 
09/29/15 
 
 
 
 
 
CONTENTS 
 
 
Page 
 
SITES PARTICIPATING IN THE STUDY ..................................................................................... 4 
PROTOCOL TEAM ROSTER ....................................................................................................... 5 
STUDY MANAGEMENT ............................................................................................................... 8 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ...................................................................... 10 
SCHEMA ..................................................................................................................................... 12 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES .................................................................... 13 
1.1 
Hypothesis ........................................................................................................... 13 
1.2 
Primary Objectives .............................................................................................. 13 
1.3 
Secondary Objectives ......................................................................................... 13 
2.0 
INTRODUCTION ............................................................................................................. 14 
2.1 
Background ......................................................................................................... 14 
2.2 
Rationale ............................................................................................................. 15 
2.3 
Study Agent ......................................................................................................... 20 
3.0 
STUDY DESIGN ............................................................................................................. 33 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................. 34 
4.1 
Inclusion Criteria Step 1 ...................................................................................... 34 
4.2 
Exclusion Criteria Step 1 ..................................................................................... 39 
4.3 
Inclusion Criteria Step 2 ...................................................................................... 41 
4.4 
Exclusion Criteria Step 2 ..................................................................................... 41 
4.5 
Study Enrollment Procedures .............................................................................. 41 
4.6 
Coenrollment Guidelines ..................................................................................... 42 
5.0 
STUDY TREATMENT ..................................................................................................... 43 
5.1 
Regimens, Administration, and Duration ............................................................. 43 
5.2 
Study Product Formulation and Preparation ....................................................... 44 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................... 44 
5.4 
Concomitant Medications .................................................................................... 45 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................ 47 
6.1 
Schedule of Events ............................................................................................. 47 
6.2 
Timing of Evaluations .......................................................................................... 52 
6.3 
Instructions for Evaluations ................................................................................. 54 
7.0 
CLINICAL MANAGEMENT ISSUES ............................................................................... 65 
7.1 
Toxicity ................................................................................................................ 65 
7.2 
Pregnancy ........................................................................................................... 70 
7.3 
HCV Virologic Response-Based Stopping Criteria .............................................. 71 


A5348 
 
 
FINAL Version 1.0 
 
 
09/29/15 
CONTENTS (Cont’d) 
Page 
 
8.0 
CRITERIA FOR DISCONTINUATION............................................................................. 71 
8.1 
Permanent and Premature Treatment Discontinuation ....................................... 71 
8.2 
Premature Study Discontinuation ........................................................................ 72 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................ 72 
9.1 
General Design Issues ........................................................................................ 72 
9.2 
Outcome Measures ............................................................................................. 73 
9.3 
Randomization and Stratification ......................................................................... 74 
9.4 
Sample Size and Accrual .................................................................................... 75 
9.5 
Monitoring ............................................................................................................ 75 
9.6 
Analyses .............................................................................................................. 76 
10.0 
PHARMACOLOGY PLAN ............................................................................................... 77 
10.1 
Pharmacology Objectives .................................................................................... 77 
10.2 
Pharmacology Study Design ............................................................................... 77 
10.3 
PharmacologySample Size Considerations ........................................................ 78 
10.4 
Primary and Secondary Data, Modeling, and Data Analysis ............................... 78 
10.5 
Anticipated Outcomes ......................................................................................... 78 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 79 
11.1 
Records to Be Kept ............................................................................................. 79 
11.2 
Role of Data Management .................................................................................. 79 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 79 
11.4 
Expedited Adverse Event Reporting to DAIDS.................................................... 79 
12.0 
PARTICIPANTS .............................................................................................................. 80 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 80 
12.2 
Participant Confidentiality .................................................................................... 81 
12.3 
Study Discontinuation .......................................................................................... 81 
13.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 81 
14.0 
BIOHAZARD CONTAINMENT ........................................................................................ 81 
15.0 
REFERENCES ................................................................................................................ 82 
 
APPENDIX I: SAMPLE INFORMED CONSENT  
 


 
4 
A5348 
FINAL Version 1.0 
 
 
09/29/15 
 
SITES PARTICIPATING IN THE STUDY 
 
A5348 is a multicenter study open to all US clinical research sites (CRSs).   
 
 
 
 
 
 


 
5 
A5348 
FINAL Version 1.0 
 
 
09/29/15 
PROTOCOL TEAM ROSTER 
 
Chair 
Annie Luetkemeyer, MD 
HIV/AIDS Division  
UCSF AIDS CRS 
P.O. Box 0874  
995 Potrero Avenue  
San Francisco, CA 94110 
Phone: 415-476-4082, ext. 130 
FAX:    415-476-6953 
E-Mail: aluetkemeyer@php.ucsf.edu 
 
Co-Chair & Pharmacologist 
Jennifer J. Kiser, PharmD 
Pharmaceutical Sciences 
University of Colorado  
12850 E Montview Boulevard, C238 
Aurora, CO 80045 
Phone: 303-724-6131 
FAX:    303-724-6135 
E-Mail: jennifer.kiser@ucdenver.edu 
 
DAIDS Clinical Representative  
Trinh Thuy Ly, MD 
Complications and Coinfectious Research 
Branch 
CCRB, DAIDS, NIAID, NIH 
5601 Fishers Lane 
Rockville, MD 20852 
Phone: 240-627-3097 
FAX:    301-480-4456 
E-Mail: tly@niaid.nih.gov  
 
Clinical Trials Specialist 
KaSaundra M. Oden, PhD, MHS, CCRP 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3178 
FAX: 301-628-3302 
E-Mail: koden@s-3.com  
 
 
 
 
 
 
Statisticians 
Minhee Kang, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
651 Huntington Avenue 
FXB Building, Room 503 
Boston, MA 02115-6017 
Phone: 617-432-2819 
FAX:    617-432-3163 
E-Mail: mkang@sdac.harvard.edu  
 
Triin Umbleja, MSc 
Statistical and Data Analysis Center 
Harvard School of Public Health 
651 Huntington Avenue 
FXB Building, Room 501 
Boston, MA 02115-6017 
Phone: 617-432-0118 
FAX:    617-432-3163 
E-Mail: tumbleja@sdac.harvard.edu 
 
Data Manager 
Melissa A. Mineo 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Rd 
Amherst, NY 14226 
Phone: 716-834-0900 
FAX:    716-834-8432 
E-Mail: mineo@fstrf.org  
 
DAIDS Pharmacist 
Bijal Patel, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane 
Room 9D35 
Rockville, MD 20852 
Phone: 240-421-8445 
FAX:    240-627-3112 
E-Mail: bijal.patel@nih.gov  
 
 
 
 
 
 


 
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Virologist 
David L. Wyles, MD 
Infectious Diseases/Medicine  
UCSD, AVRC CRS 
SCRB 404 MC 0711 
9500 Gilman Drive 
La Jolla, CA 92093-0711 
Phone: 858-822-1779 
FAX:    858-822-5362 
E-Mail: dwyles@ucsd.edu  
 
Investigators 
Debika Bhattacharya, MD 
Division of Infectious Diseases  
UCLA CARE Center CRS  
David Geffen School of Medicine 
10833 Le Conte Avenue 
Los Angeles, CA 90095 
Phone: 310-206-0527 
FAX:    310-825-3632 
E-Mail: debikab@mednet.ucla.edu  
 
Kristen Marks, MD 
Division of Infectious Diseases 
Weill Cornell Uptown CRS 
525 East 68th Street, F2437 
New York, NY 10021 
Phone: 212-746-4177 
FAX:    212-746-8852 
E-Mail: markskr@med.cornell.edu  
 
Siobhan O’Connor, MD, MPH 
Division of Viral Hepatitis  
Centers for Disease Control and Prevention 
1600 Clifton Road NE, Mailstop A-33 
Atlanta, GA 30329 
Phone: 404-639-2337 
FAX:    404-639-3178 
E-Mail: sbo5@cdc.gov  
 
Marion G. Peters, MD 
Gastroenterology Division 
UCSF AIDS CRS 
513 Parnassus Street, Room S-0537 
San Francisco, CA 94143 
Phone: 415-502-0318 
FAX:    415-476-0659 
E-Mail: marion.peters@ucsf.edu  
 
Field Representatives 
Joan Gottesman, RN, CCRP 
Vanderbilt Therapeutics CRS 
Vanderbilt Health-One Hundred Oaks 
719 Thompson Lane, Ste. 47183 
Nashville, TN 37204 
Phone: 615-936-2664 
FAX:    615-936-2644 
E-Mail: joan.gottesman@vanderbilt.edu  
 
Lisa Kessels, RN, ACRN 
AIDS Clinical Trials Unit 
Washington University Therapeutics CRS 
4570 Children's Place, Suite 1200 
St. Louis, MO 63110 
Phone: 314-747-1096 
FAX:    314-361-5231 
E-Mail: lkessels@dom.wustl.edu  
 
Laboratory Technologist 
Brian Clagett, BA 
Case CRS 
BRB, Room 1048B 
2109 Adelbert Rd 
Cleveland, OH 44106 
Phone: 216-368-4853 
FAX:    216-368-5415 
E-Mail: bmc@case.edu  
 
Community Scientific Subcommittee (CSS) 
Representative 
Andrew H. Kaytes 
3984 Illinois Street #4 
San Diego, CA 92104 
Phone: 619-840-5286 
FAX:    619-546-8541 
E-Mail: stinfu@yahoo.com  
 
Industry Representative 
Richard Haubrich, MD 
HIV Medical Affairs 
Gilead Sciences, Inc.  
333 Lakeside Drive  
Foster City, CA 94404 
Phone: 650-389-8446   
E-Mail: richard.haubrich@gilead.com  
 
 
 


 
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Laboratory Data Manager 
Rachael Henderson, BS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext. 7331 
E-Mail: henderso@fstrf.org  


 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.coreA5348@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to actg.teamA5348@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.protA5348 e-mail 
group. Include the protocol number in the e-mail subject line.  
 
Send an e-mail message to actg.user.support@fstrf.org   
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol team.  
 
Send an e-mail message to actg.coreA5348@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to virologic or pharmacologic laboratory tests, contact the 
protocol virologist or pharmacologist.  
 
Send an e-mail message to actg.coreA5348@fstrf.org (ATTN: David Wyles [virologist] or 
Jennifer Kiser [pharmacologist]). 
 
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 contact Melissa 
Mineo directly.  
 
For other questions, send an e-mail message to actg.coreA5348@fstrf.org (ATTN: Melissa 
Mineo).   
 
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. Call the Statistical and Data Analysis 
Center (SDAC)/DMC Randomization Desk at 716-834-0900 extension 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. 
 


 
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STUDY MANAGEMENT (Cont'd) 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist.  
 
Send an e-mail message to actg.coreA5348@fstrf.org (ATTN: KaSaundra Oden). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGNCC@s-3.com (ATTN: Diane 
Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site 
(https://www.actgnetwork.org). 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation, contact the clinical trials specialist KaSaundra Oden 
(koden@s-3.com) or ACTG Site Coordination group at actgsitecoordination@s-3.com.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Bijal Patel, protocol pharmacist, at 240-421-8445.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5348 team members. 
 
Send an e-mail to actg.teamA5348@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
3TC 
 
lamivudine 
AE 
 
adverse event 
ALT 
 
alanine aminotransferase (also SGPT)  
ANC 
 
absolute neutrophil count 
ARV 
 
antiretroviral  
AST 
 
aspartate aminotransferase (also SGOT)  
ATV 
 
atazanavir 
AUC 
 
area under the curve 
AUCtau  
area under the plasma concentration versus time curve over the dosing interval  
BMI 
 
body mass index 
CrCl 
 
creatinine clearance 
Cmax 
 
maximum observed concentration of drug  
Ctau 
 
observed drug concentration at the end of the dosing interval (tau)  
CTP 
 
Child-Turcotte-Pugh 
d4T 
 
stavudine 
DAA 
 
direct acting antiviral 
ddl 
 
didanosine 
DRV 
 
darunavir 
ECG     
electrocardiogram 
EFV 
 
efavirenz 
Emax 
 
maximal effect 
FDA 
 
US Food and Drug Administration  
FTC 
 
emtricitabine 
GT 
 
genotype (viral) 
HBV 
 
hepatitis B virus  
HCC 
 
hepatocellular carcinoma 
HCV 
 
hepatitis C virus 
ICH 
 
International Conference on Harmonisation 
IFN 
 
interferon 
IL-28B  
IL-28B gene 
ISGs  
IFN stimulated genes 
ITT 
 
intention-to-treat 
LDV 
 
ledipasvir 
LLOQ  
lower limit of quantification  
Hg 
 
mercury 
MCV  
mean corpuscular volume 
PBMC  
peripheral blood mononuclear cell(s)  
PEG 
 
pegylated interferon 
P-gp 
 
P-glycoprotein 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS (Cont’d) 
 
PI 
 
protease inhibitor 
PI/r 
 
ritonavir-boosted protease inhibitor 
PK 
 
pharmacokinetic 
QD 
 
once daily 
r 
 
low dose ritonavir (booster) 
RAL 
 
raltegravir 
RAV 
 
resistant variants 
RBV 
 
ribavirin 
RPV 
 
rilpivirine 
RTV 
 
ritonavir 
RVR 
 
rapid virologic response  
SAE 
 
severe adverse event 
SIM 
 
simeprevir 
SOF 
 
Sofosbuvir, GS-7977 
SVR 
 
sustained virologic response 
SVR4 
sustained virologic response 4 weeks after completion of HCV antiviral therapy 
SVR12 
sustained virologic response 12 weeks after completion of HCV antiviral therapy 
SVR24 
sustained virologic response 24 weeks after completion of HCV antiviral therapy 
TAF 
tenofovir alanfenamide 
TD 
 
target detected 
TDF 
 
tenofovir disoproxil fumarate (prodrug of tenofovir)  
TFV 
 
tenofovir   
TND 
 
target not detected 
t½ 
an estimate of the terminal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the terminal 
elimination rate constant (λz) 
ULN 
 
upper limit of the normal range 
WBR   
weight-based RBV 


 
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SCHEMA 
 
A5348 
 
Phase II Trial of Retreatment Strategies for Difficult-to-Treat Hepatitis C Virus (HCV)-Infected 
Individuals Who Have Failed Prior Direct Acting Antiviral (DAA)-Based Regimens  
 
DESIGN 
Phase II randomized, open-label trial of 12 weeks of ledipasvir/sofosbuvir 
(LDV/SOF) with weight-based ribavirin (RBV) versus 24 weeks of 
LDV/SOF for retreatment of participants with hepatitis C virus (HCV) 
infection and HIV coinfection who have previously failed prior SOF-based 
regimens. Participants will be followed for an additional 24 weeks after 
completion of study treatment.  
 
DURATION 
Up to 36 weeks in Arm A and up to 48 weeks in Arm B 
 
SAMPLE SIZE 
40 participants total, 20 participants per arm  
 
POPULATION 
Genotype (GT) 1 HCV infected men and women, age ≥ 18 years, with 
HIV infection, who have previously been treated for HCV infection with 
SOF-based treatment, including SOF/RBV +/- pegylated interferon (PEG) 
and SOF/simeprevir (SIM), and who experienced virologic failure.  
 
The first 15 HIV co-infected participants taking ritonavir-boosted HIV 
protease inhibitor and tenofovir are required to participate in the PK study. 
See section 3.0 for clarification on enrollment during the first 3 months 
after the study opens. 
 
STRATIFICATION  
Participants will be randomized 1:1 in an open label fashion to one of the 
two specified treatment regimens. Participants will be stratified by 
cirrhosis status.  
 
REGIMEN  
Arm A: 12 weeks of LDV 90 mg/SOF 400 mg fixed dose tablets once 
daily (QD), with weight-based RBV: 1000 mg/day for weight < 75 kg, 1200 
mg/day for weight ≥ 75 kg.  
  
Arm B: 24 weeks of LDV 90 mg/SOF 400 mg fixed dose tablets QD. 


 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 12 weeks of ledipasvir (LDV)/sofosbuvir (SOF)/ribavirin (RBV) and 24 weeks of 
LDV/SOF alone result in an estimated 90% sustained virologic response (SVR) 
12 weeks after stopping HCV antiviral therapy (SVR12) for each regimen when 
used for HCV retreatment after sofosbuvir failure. 
 
1.1.2 12 weeks of LDV/SOF/RBV and 24 weeks of LDV/SOF alone will be safe and 
well tolerated.  
 
1.2 
Primary Objectives 
 
1.2.1 To assess the proportion of participants who attain SVR12 in each study arm. 
  
1.2.2 To evaluate safety and tolerability of each study regimen. 
 
1.3 
Secondary Objectives 
 
1.3.1 To assess the impact of LDV/SOF and ritonavir-boosted HIV protease inhibitor 
(PI/r) coadministration on the pharmacokinetics (PK) of tenofovir (TFV). 
 
1.3.2 To assess the impact of LDV/SOF and HIV PI/r coadministration on any 
associated clinical events attributed to elevated tenofovir levels, including renal 
toxicity (defined as the development of ≥ Grade 2 renal dysfunction or 
development of new or worsened proteinuria or glucosuria).  
 
1.3.3 To assess the proportion of participants who attain SVR4 (i.e., SVR 4 weeks after 
stopping HCV antiviral therapy) and SVR24 (i.e., SVR 24 weeks after stopping 
HCV antiviral therapy) in each study arm.  
 
1.3.4 To evaluate baseline predictors of SVR12, including cirrhosis, prior treatment 
response (relapse, partial response, null responder), HCV genotype (GT)-1a vs. 
1b, race, and IL-28B status. 
 
1.3.5 To evaluate the association between LDV/SOF adherence and SVR12 in both 
arms. 
 
1.3.6 To evaluate the impact of baseline HCV resistance mutations on the SVR12 
attained with retreatment with LDV/SOF (+/- RBV).  
 
1.3.7 To evaluate emergence of HCV resistance mutations in participants who fail to 
attain SVR12 with retreatment with LDV/SOF (+/- RBV). 
 


 
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1.3.8 To evaluate kinetics of HCV RNA during treatment (weeks 1, 2, 4, 8, 12, and in 
Arm B, weeks 16, 20, and 24) and 4, 12, and 24 weeks after treatment 
discontinuation. 
 
1.3.9 To assess the influence of LDV/SOF based retreatment on HIV-specific 
parameters, including maintenance of HIV-1 RNA < 50 copies/mL for participants 
on antiretrovirals and CD4+ cell count during treatment.  
 
1.3.10 To evaluate differences in SVR12 among participants receiving specific 
antiretroviral (ARV) therapy regimens compared to those taking no ARV on 
SVR12. 
 
1.3.11 To compare the SVR12 proportions, safety, and tolerability in the two arms. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
There is a pressing need to understand appropriate retreatment options for HCV-
infected patients who fail direct acting antiviral (DAA)-based regimens. To date, over 
100,000 prescriptions have been written for SOF (Gilead, personal communication). 
Recent data from the multicenter HCV-Target 2.0 cohort of over 2,000 participants 
indicate that the SOF-based treatment defined as SOF/RBV, SOF/pegylated-interferon 
(PEG)/RBV or SOF/simeprevir (SIM) +/- RBV have led to SVR4 in 70-92% of HCV 
genotype (GT) 1 patients, depending on the regimen used and presence of cirrhosis [1]. 
Thus, there are a growing number of individuals who have failed SOF-based regimens 
and are in need of a retreatment strategy, the majority of which are anticipated to be 
HCV GT1, given the US distribution of genotypes. While failure of a SOF-based regimen 
is uncommon, those failing a SOF-based regimen represent some of the most difficult to 
treat patients, given failure of one of the most potent current treatment options and 
limited data to guide retreatment. In addition, given current restrictions on access to HCV 
treatment in the US, many patients accessing SOF-based treatment already have 
advanced fibrosis and need access to curative therapy as soon as possible to reduce 
disease progression and HCV related complications. Therefore, it is a priority to identify 
effective, accessible retreatment strategies for this hard to treat population. Further, 
there are no data to inform retreatment strategies for HIV-infected individuals with SOF 
failure, who have traditionally represented a harder to treat group and are impacted by 
DAA-ARV interactions.  
 
Retreatment of SOF-failure with SOF-based regimens   
 
There is precedent for retreatment after SOF-failures with SOF-containing regimens (see 
Table 2-1). The majority of patients failing SOF regimens do not fail with NS5B 
resistance mutations. When NS5B mutations have rarely occurred, several patients with 
the NS5B mutation S282T or L159F mutations have been successfully retreated with 
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failure demonstrated disappearance of S282T at weeks 24 and 48, suggests the 
potential for SOF use after SOF resistance [2]. 
 
Table 2-1: Successful interferon-sparing SOF-based retreatments of SOF-failures 
Parent Trial Name; Failed treatment regimen; 
Reference 
Genotype 
SVR12 
Successful Re-
Treatment Regimen 
ELECTRON; SOF monotherapy x 12 weeks; 
[2]  
2b 
1/1 
(100%) 
SOF/RBV x 12 
weeks 
LONESTAR; LDV/SOF x 8 weeks; [3] 
1a 
1/1 
(100%) 
LDV/SOF + RBV x 
24 weeks 
SPARE; SOF/RBV x 24 weeks; [4, 5]  
1 
14/14 
(100%) 
LDV/SOF without 
RBV x 12 weeks 
ELECTRON-2; LDV/SOF/RBV x 6 weeks (8 
patients), SOF/RBV x 12 weeks (10), SOF/GS-
9669/RBV x 12 weeks (1); [6]  
1 
19/19 
(100%) 
LDV/SOF + RBV x 
12 weeks 
SOF/PEG/RBV x 12 weeks (25 patients), 
SOF/RBV x 24 weeks (20); [7]  
1 
45/45 
(100%) 
LDV/SOF + RBV x 
12 weeks 
 
While these data are compelling because of the uniformly high response rates, numbers 
were small, no patients received past treatment with SOF/SIM, and the retreatment 
regimens varied. Importantly, none of these retreatment data are from HIV coinfected 
individuals. Therefore, a LDV/SOF-based strategy should be investigated further as a 
promising, currently available retreatment regimen for HIV-coinfected individuals who 
have failed prior SOF-containing therapy.  
 
2.2 
Rationale 
 
We propose a phase II retreatment study of HCV GT1 HIV coinfected patients who have 
previous virologic failure on a SOF-based regimen. SOF-failures represent a challenging 
group to retreat as they have already failed one potent regimen, and in many cases may 
have failed prior regimens as well. Given the current restrictions by many insurers on 
access to SOF-based treatment, patients accessing SOF often have advanced fibrosis 
and thus are in immediate need of available curative therapy. While overall SOF-failures 
represent a small percentage of HCV-infected patients, it is a priority to identify curative, 
immediately available strategies for this growing difficult-to-treat population, enriched for 
advanced fibrosis. Furthermore, there is an additional need for data to inform SOF 
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Studying SOF/RBV, SOF/PEG/RBV and SOF/SIM failures together is rational, since the 
prior SOF-treatment is the most salient consideration when choosing retreatment with a 
LDV/SOF strategy. In addition, the combination of LDV/SOF retreatment has proven 
highly efficacious in a small number of patients with failure of each of these SOF-based 
regimens, as outlined in Table 2-1.  
 
Participants will be randomized in an open-label fashion to 12 weeks of LDV/SOF with 
weight-based RBV vs. 24 weeks of LDV/SOF alone. A small number of previous SOF 
failures have been successfully retreated with 12 weeks of LDV/SOF alone. However, 
given what is known about the population that has received and failed SOF-based 
regimens since approval, this protocol will be enriched with traditionally difficult-to-treat 
patients including those with null response to prior regimen and cirrhosis. Therefore, 12 
weeks of LDV/SOF alone will not be evaluated, given the difficult-to-treat population.  
 
SOF failures represent an uncommon occurrence; therefore, the sample size will be 
constrained by the pool of participants with this infrequent, yet important, event. 
Therefore, we will limit the sample size to 20 participants per arm, a number which can 
be feasibly enrolled in a timely manner to generate meaningful data about each 
treatment strategy. The COSMOS study evaluating simeprevir and sofosbuvir had 
treatment arms of similar size and provided groundbreaking data with an immediate 
impact on HCV clinical practice [3]. COSMOS comprised 168 difficult to treat individuals 
with either advanced fibrosis ( METAVIR F3-4) or prior null response to 
interferon/ribavirin with more limited fibrosis (F0-2) to receive sofosbuvir and simeprevir, 
with or without ribavirin, for 12 to 24 weeks. Participants were assigned to 1 of 8 
treatment arms ranging from 14 to 27 persons per arm. COSMOS demonstrated that 
cirrhotic and treatment-experienced patients could still attain a high SVR with an all oral 
DAA regimen in as short as 12 weeks with a therapy that was generally safe and well 
tolerated. The multiple small arms provided important data on the regimen performance, 
impact of RBV, and treatment duration in different populations. COSMOS led to a swift 
uptake of the investigational regimen, particularly in these harder-to-treat populations 
with cirrhosis or prior null response for which data had been lacking.  
 
Given the limited retreatment options currently available for patients failing SOF-based 
treatment, an SVR12 of 70% or greater would represent an important, immediately 
available retreatment option for this hard-to-treat group, many of whom are anticipated to 
have advanced fibrosis, which prompted initial therapy. While the preliminary data 
support the expectation of a high SVR12 rate, cure rates exceeding 70% would be 
clinically acceptable in this harder to treat population. This threshold is deemed 
acceptable in consideration of the lower bound of the confidence intervals from several 
LDV/SOF retreatment studies to date, which have reported high SVRs of 95-98% [6, 7] 
with a lower confidence interval bounds of down to approximately 85% [7, 8]. Given that 
data are sparse for retreatment of SOF/RBV +/- PEG failures and non-existent for SOF-
SIM failures and for HIV/HCV coinfected patients and we expect the study to be 
enriched for traditionally hard-to-treat patients, we have relaxed the null response rate 
from what is considered acceptable for an initial treatment regimen or even PI-based 
failure retreatment in the DAA era [4, 6, 7]. As a phase II study, this protocol will not be 
powered for direct comparison of SVR12 between the 12 and 24-week arms. 
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characteristics between the two treatment arms.  
 
This study will provide much needed pilot data evaluating retreatment strategies of 
LDV/SOF for prior SOF-failures in HIV/HCV coinfection, including those with cirrhosis. 
Other studies are planned outside of the ACTG which will evaluate retreatment 
strategies for SOF-failures; however, they exclude HIV/HCV coinfected persons and do 
not address the important drug-drug interaction of ledipasvir with concomitant tenofovir- 
and ritonavir-boosted protease inhibitors. This study will add to the HCV mono-infection 
studies. In addition, the data from this study will be useful in the future design of a larger 
conclusive efficacy study based on these initial retreatment strategies. 
 
Rationale for length and composition of retreatment regimens 
 
In the ION-2 study, cirrhotic patients with prior PEG/RBV failure had improved SVR12 
with an extended treatment duration of LDV/SOF for  24 weeks(22/22,100% SVR12) 
compared to 12 weeks of LDV/SOF (19/22, 86% SVR12) [9], leading to the current 
recommendation for 24 weeks of LDV/SOF in treatment-experienced cirrhotics [10]. 
However, several studies have now demonstrated that the addition of RBV to 12 weeks 
of LDV/SOF mitigated the suboptimal SVR12 associated with 12 weeks of LDV/SOF in 
treatment-experienced patients. In pooled data from phase II and III LDV/SOF studies 
with 352 treatment experienced, compensated cirrhotic patients, 12 weeks of 
LDV/SOF/RBV led to SVR12 of 96% compared to SVR12 90% with 12 weeks of 
LDV/SOF alone [11]. Similarly, in the SIRIUS study, compensated cirrhotic participants 
with prior HCV PI failure randomized to 12 weeks of LDV/SOF/RBV attained a 96% 
SVR12 (74/77), comparable to the 97% (75/77) SVR12 with 24 weeks of LDV/SOF 
alone [8]. In addition, extended treatment or addition of RBV may overcome the negative 
impact of baseline NS5a resistance mutations, which are uncommon but may contribute 
to lower SVR in harder-to-treat populations with prior SOF regimen failures. In ION-3 
patients with high level baseline NS5a resistance (>100 fold), 24 weeks of LDV/SOF 
resulted in 100% SVR12, while SVR12 was 69.2% with 12 weeks of LDV/SOF alone[12]. 
Thus, both 12 weeks of LDV/SOF/RBV and 24 weeks of LDV/SOF alone are promising 
retreatment strategies, including in the hardest to treat populations such as cirrhotics. 
Inadequate data exist on the use of either strategy in SOF-failures, and thus there is 
equipoise about which strategy is preferable. Twelve weeks of LDV/SOF/RBV is 
attractive given the shorter duration and therefore reduced cost of therapy; however, 24 
weeks of LDV/SOF avoids inclusion of RBV, which increases pill burden and is 
associated with additional toxicity.  
 
Rationale for evaluation of HIV/HCV coinfected participants  
 
Trials of IFN-sparing, DAA HCV treatment have increasingly demonstrated that HIV 
coinfection has not negatively affected SVR rates. SVR12 rates with 12 weeks of 
LDV/SOF have been 96%-98% among HIV/HCV coinfected individuals [12, 13], similar 
to SVR12 of 95-99% attained with 12 weeks of LDV/SOF in HCV monoinfected patients 
[14, 15]. However, some questions remain about equivalent efficacy in subgroups of 
HIV/HCV coinfected patients. In the ION-4 study, the overall SVR12 was 96% with 12 
weeks of LDV/SOF in HIV/HCV coinfected participants. However, all 10 relapses 
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decreased efficacy in some subgroups, the etiology of which is not yet clear[13]. In 
addition, in the ALLY-2 study, 8 weeks of sofosbuvir and the NS5a daclatasvir led to a 
76% SVR12 rate [16], substantially lower than the SVR12 rate of 94% with the similar 
combination of polymerase/NS5a inhibitor of LDV/SOF for 8 weeks in monoinfected 
patients[14]. The reasons for the decreased SVR12 may be due to a number of factors 
including ARV/DAA drug interactions but the results do raise the question of a differential 
response in HIV/HCV coinfection with some regimens and subgroups. Thus, while 
overall HIV coinfected patients have demonstrated similar SVR rates to HIV mono-
infected counterparts, it is a priority to evaluate LDV/SOF retreatment in HIV/HCV 
coinfection as there are no data examining LDV/SOF to treat HIV-infected patients with 
prior SOF failure. 
 
Interaction between LDV/SOF and HIV antiretrovirals 
 
Consideration of the PK interactions between HCV and HIV treatment is critical. 
LDV/SOF has minimal interactions with ARV, but is not devoid of interactions. SOF, a 
uridine nucleotide analogue, is not metabolized by cytochrome P450 (CYP) enzymes, 
nor does it inhibit or induce any CYP enzymes. SOF is a substrate for membrane efflux 
transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) [12]. 
LDV is a substrate for P-gp and an inhibitor of P-gp, BCRP, and organic anion 
transporting polypeptide (OATP) 1B1/3. Most of a LDV dose is excreted unchanged 
(70%), the other 30% is metabolized primarily by CYP3A4. Potent inducers of P-gp or 
BCRP (e.g., tipranavir) should not be used with LDV/SOF as LDV/SOF concentrations 
may be reduced [13]. 
 
PK evaluation of tenofovir concentrations in participants on PI/r 
 
LDV/SOF increases tenofovir concentrations. The extent of the increase in tenofovir 
concentrations is most concerning for persons on PI/rs. In healthy volunteers, LDV/SOF 
increases tenofovir Cmax by 46-47% and Ctau 38- 47% when administered as tenofovir 
disoproxil fumarate (TDF)/FTC/atazanavir (ATV)/r versus TDF/FTC/ATV/r alone. 
LDV/SOF increases tenofovir Cmax by 46-64% and Ctau 52-59% when administered with 
TDF/FTC/DRV/r versus TDF/FTC/DRV/r alone [17]. Staggering the LDV/SOF by 12 
hours from HIV protease inhibitors did not substantially change the increase in tenofovir 
exposure. Independent of HCV treatment, RTV-boosted ATV and darunavir increase 
tenofovir concentrations by 29-37% (tenofovir package insert) and 22-37% (tenofovir 
package insert), respectively. Due to anticipated increases in tenofovir with LDV/SOF 
and PI/r coadministration, the current LDV/SOF package insert recommends selecting 
alternative ARV, if feasible, or monitoring for tenofovir-associated adverse reactions [10]. 
However, there can be significant downsides of changing stable ARV, including potential 
loss of HIV virologic suppression, toxicity of new regimens and delay in HCV treatment. 
As that both LDV/SOF and PI/rs increase tenofovir levels in healthy volunteers, a PK 
evaluation of the impact of LDV/SOF on tenofovir concentrations in HIV/HCV coinfected 
patients on PI/r based ARV is warranted with concomitant assessment of any clinical 
impact of elevated tenofovir levels, such as development of renal dysfunction. Given the 
limited duration of HCV treatment (12-24 weeks), it is reasonable to conduct the PK 
evaluation as part of the overall study with close monitoring of participants’ renal 
function, as recommended, rather than prior to this study. The antiretroviral tenofovir 


 
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alanfenamide (TAF) is anticipated to have less impact on renal function [18], and may be 
less impacted by drug interactions with LDV/SOF. However, once approved, TAF will not 
be available to all HIV/HCV coinfected patients due to cost and accessibility. Thus it is 
important to understand the extent and clinical relevance of the tenofovir-ledipasvir drug 
interaction in HIV coinfected patients taking HIV protease inhibitors as TDF-based ARV 
remains a current mainstay of current ARV treatment. 
 
Rationale for inclusion of cirrhotic patients 
 
Cirrhotic patients are at the highest risk for death and complications due to liver disease. 
HIV/HCV coinfected patients who have failed SOF-containing regimens thus represent a 
difficult-to-treat population with a critical unmet need for therapy. Cirrhotic patients were 
represented in the small trials of SOF-failures, 7/14 (50%) of 24 week SOF/RBV-
relapsed participants [5] and 15/51 (29%) of SOF-experienced participants [7]. All 
participants attained SVR12. Side effects were minimal, including the absence of Grade 
4 adverse events (AEs). 
 
Treatment strategies for NS5a failures  
 
There is a need to examine strategies for retreatment of NS5a failures, given the US 
approval of two NS5 containing regimens, LDV/SOF and the NS5a ombitasvir containing 
triple regimen of ombitasvir/paritaprevir/dasabuvir. Current limited data suggest that 
LDV/SOF without RBV led to virologic breakthrough in 18-40% of patients, and was 
negatively impacted by the presence of preexisting NS5a mutations, which occur 
commonly at the time of NS5a failure [19]. Therefore, NS5a failures are not included in 
the current retreatment strategy of LDV/SOF +/-RBV. 
 
However, we may include a second cohort comprised of NS5a failures in a future 
protocol when we can secure the best available, optimized retreatment regimen. This 
may be composed of sofosbuvir, the NS5a GS-5816 +/- RBV, or a triple class approach 
(NS5a, HCV polymerase inhibitor, HCV protease inhibitor).    
 
Quantifying LDV/SOF adherence 
 
Clinical trials indicate high rates of SVR from SOF-based HCV treatment. However, a 
number of patients still fail to achieve SVR. Several factors (virologic, immunologic, etc.) 
may contribute to therapeutic failure, but adherence is the primary reason medications 
fail to work as prescribed. There are very limited data on medication adherence with 
DAAs. LDV/SOF concentrations were measured and found to be undetectable in 
participants with HCV viral rebound in the FISSION, VALENCE, PHOTON-1, ION-1 and 
ION-2 studies. Thus, nonadherence appears to exist in the treatment of HCV, even in 
highly selected patient populations in clinical trials, and the contribution of nonadherence 
to SVR has not been determined. 
In this study, we will use LDV and SOF metabolite concentrations as an objective 
measure of adherence and determine the contribution of LDV/SOF adherence to the 
likelihood of SVR. 
 


 
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2.3 
Study Agent: Efficacy and Safety 
 
LDV/SOF 
 
LDV/SOF is an all-oral, once daily treatment regimen for chronic HCV infection. As of 21 
March 2014, 23 clinical studies have been initiated with LDV/SOF alone or in 
combination with RBV, including 344 healthy participants and 3,504 participants with 
chronic HCV infection. 
 
Ribavirin 
 
RBV is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses [14]. RBV monotherapy has little or no effect on the replication of HCV 
but can result in normalization of serum ALT activity and improvement in liver histology. 
When combined with IFN or PEG therapy, RBV decreases substantially the relapse rate 
seen after cessation of IFN therapy [16, 17]. 
 
RBV is a known teratogen (US Food and Drug Administration [FDA] category X). 
Furthermore, RBV is known to accumulate intracellularly where it is cleared slowly, and 
is also excreted in semen. Therefore, extreme care must be taken to avoid pregnancy 
during RBV therapy and for up to 6 months following completion of treatment. A 
comprehensive review of RBV is contained in the package insert/summary of product 
characteristics. 
 
2.3.1    Clinical efficacy in participants with GT-1 HCV infection and HIV  
coinfection 
 
The efficacy data for LDV/SOF in GT-1 and 4 HCV infections are derived from 
the Phase III ION-4 study, which was a multicenter, open-label, single arm study 
of LDV/SOF for 12 weeks. The trial included HCV treatment-naïve and treatment-
experienced (55%) participants and included 20% of participants with cirrhosis. 
Participants were required to be on ARVs and have evidence of HIV viral 
suppression. The allowable ARVs included TDF plus efavirenz (EFV), raltegravir 
(RAL), or rilpivirine (RPV). Overall, the study population was 82% male, 34% 
self-reported black race, 24% IL-28B CC genotype, and 98% GT-1 (75% 1a, 23% 
1b, 8% GT-4). The overall SVR12 was 96% (96% GT-1 and 100% GT-4). 
Virologic failures included 10 participants with relapse after end of therapy and 2 
participants with breakthrough due to nonadherence. One participant was lost to 
follow-up after achieving SVR4 although this participant did return for SVR24 
visit. There was one death for an unrelated event (infectious endocarditis in IDU). 
There was no difference in SVR12 for treatment-naïve (95%), treatment-
experienced (97%), cirrhosis (94%), no cirrhosis (96%), treatment-experienced 
with cirrhosis (98%). In a multivariable analysis only self-reported black race was 
associated with a lower SVR12 (90%). This association of lower SVR12 and race 
was not observed in the mono-infected Phase III program. Further investigations 
to explain this observation in ION-4, including population PK across race, ARV 
regimen, relapse and a candidate gene study of the CYP2B6 polymorphism, 
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resistant variants (RAV) were identified at baseline in 20% of participants; this did 
not associate with lower SVR12 (94% with RAVs at baseline vs 96% without). 
Ten of the 12 virologic failures in the study had RAV at failure, 4 of these were 
relapsers who had the RAVs at baseline. 
 
2.3.2  Clinical Efficacy in HCV Mono-infection 
 
The primary efficacy data for LDV/SOF in GT-1 HCV infection in the clinical 
efficacy section is derived from 3 Phase III ION studies (GS-US-337-0102 [ION-
1], GS-US-337-0109 [ION-2], and GS-US-337-0108 [ION-3]). Studies GS-US-
337-0102 and GS-US-337-0109 evaluated treatment with LDV/SOF±RBV for 12 
or 24 weeks in treatment-naive and treatment-experienced participants, 
respectively, who were infected with GT-1 HCV. Both studies enrolled up to 20% 
of HCV-infected participants who had documented compensated cirrhosis. Study 
GS-US-337-0108 evaluated LDV/SOF±RBV treatment for 8 weeks and LDV/SOF 
treatment for 12 weeks in noncirrhotic treatment-naȉve participants with GT-1 
HCV infection [13]. 
 
Additional data from Phase II studies provide clinical efficacy information for 
retreatment of virologic failures to prior SOF-based regimens (Studies 13-I-0066 
[SYNERGY] and GS-US-337-0118 [LONESTAR]). 
 
Efficacy data across the Phase III ION studies were not pooled or grouped with 
the exception of those for noncirrhotic treatment-naive participants from the 
LDV/SOF 12-week groups in Studies GS-US-337-0102 and GS-US-337-0108. 
These two studies had data for LDV/SOF 12-week groups pooled for purposes of 
subgroup analysis of noncirrhotic treatment-naive participants. With the 
exception of this one subset of participants, different participant populations were 
enrolled in each study. 
 
2.3.3 Participant Disposition 
 
Of the 1,952 participants who received at least one dose of study drug in the 
LDV/SOF Phase III ION studies, 98.1% completed their assigned study 
treatment, and 0.7% of participants discontinued study treatment due to an AE. 
Two participants discontinued treatment due to lack of efficacy, and, in both 
cases, PK data suggested study drug noncompliance (Studies GS-US-337-0102 
and GS-US-337-0109). 
 
2.3.4 Demographics and Baseline Disease Characteristics 
 
Overall, demographic characteristics were generally similar across all treatment 
groups in the LDV/SOF Phase III ION population; however, because Study GS-
US-337-0102 enrolled 40.8% of participants in Europe, notable differences in 
demographics between the US and Europe compared with groups in Studies GS-
US-337-0109 and GS-US-337-0108 were observed for race and body mass 
index (BMI) as follows: in the US, a higher percentage of participants were black 
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(27.3% US vs. 9.3% Europe). Overall, baseline disease characteristics were 
generally similar across all treatment groups. A total of 11.5% of participants had 
cirrhosis at screening: 15.7% and 20.0% of participants had cirrhosis at 
screening in Studies GS-US-337-0102 and GS-US-337-0109, respectively. No 
participants had cirrhosis at screening in Study GS-US-337-0108. The majority of 
participants had GT-1a (73.9%) or 1b (25.5%) HCV infection; 5 participants had 
GT-1 (no subtype per the protocol-specified clinical assays) HCV infection, 2 
participants had GT-4 HCV infection, and 5 participants had no GT determined 
by the protocol-specified clinical assays. The 7 participants who had either GT- 4 
HCV infection or no genotype determined for their HCV infection were 
randomized in violation of the clinical study protocols [20]. 
 
2.3.5 Study GS-US-337-0102 (ION-1): Treatment-Naive Participants 
 
In Study GS-US-337-0102, both 12-week groups met the primary efficacy 
endpoint of an SVR12 rate that was superior to the historical control rate of 60% 
(p<0.001) and the prespecified interim criteria of SVR12 ≥90% in participants 
with and without cirrhosis separately. The SVR12 rates were 97.7% for the 
LDV/SOF 12-week group and 97.2% for the LDV/SOF+RBV 12-week group. 
 
Participants with and without cirrhosis achieved high rates of SVR12: SVR12 
rates in participants with cirrhosis were 94.1% in the LDV/SOF 12-week group 
and 100% in the LDV/SOF+RBV 12-week group; SVR12 rates in participants 
without cirrhosis were 98.3% in the LDV/SOF 12-week group and 96.7% in the 
LDV/SOF+RBV 12-week group. 
 
In the LDV/SOF 12-week group, only one participant relapsed and four 
participants did not have a post treatment week 12 visit and were classified as 
failures. The participant who relapsed had IL-28B TT alleles, cirrhosis, and the 
baseline NS5A resistance-associated variant (RAVs) L31M, and relapsed at the 
post treatment week 4 visit; the participant had completed 12 weeks of LDV/SOF 
without any dose interruptions. In the LDV/SOF+RBV 12-week group, no 
participants relapsed and six participants did not have a post treatment week 12 
visit and were classified as failures. Across all 4 treatment groups, one 
participant in the LDV/SOF 24-week group had on-treatment virologic failure at 
week 8 (breakthrough), associated with documented study drug noncompliance. 
 
Several host and viral factors that have been traditionally predictive of or 
associated with lower rates of SVR (eg, African-American race, cirrhosis, high 
BMI, GT-1a, high viral load, non-CC IL-28B allele) had no notable impact on 
SVR12 rates. The presence of baseline LDV-associated NS5A RAVs in 78 
participants also had no notable impact on SVR12 rates. 
 


 
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2.3.6 Study GS-US-337-0108 (ION-3): Treatment-Naive Participants 
 
All treatment groups met the primary efficacy endpoint of an SVR12 rate that was 
statistically significantly higher (p<0.001) than the adjusted historical SVR null 
rate of 60%. The SVR12 rates were 94.0% for the LDV/SOF 8-week group, 
93.1% for the LDV/SOF+RBV 8-week group, and 95.4% for the LDV/SOF 12-
week group. 
 
The 8-week RBV-free LDV/SOF regimen was noninferior to the 8-week RBV-
containing regimen and the 12-week LDV/SOF regimen, as demonstrated by 
lower bound 95.0% CI of −3.9% and lower bound 97.5% CI of −6.4%, 
respectively, based on the requirement that the lower bound of the CI of the 
difference between two treatment groups was greater than the prespecified 
noninferiority margin of −12%. 
 
The addition of RBV to an 8-week treatment course of LDV/SOF or extension of 
the LDV/SOF treatment duration from 8 to 12 weeks did not substantially 
increase the observed SVR12 rates. Relapse rates were similar in the 8-week 
treatment groups, but were lower in the LDV/SOF 12-week group. 
 
The overall virologic failure rate was low (LDV/SOF 8 Weeks: 5.1%, 
LDV/SOF+RBV 8 weeks: 4.2%, and LDV/SOF 12 weeks: 1.4%). No resistance to 
SOF or LDV was detected in 21 and 7 of the 23 relapsed participants, 
respectively. Virologic failure was associated with single-class LDV resistance in 
16 (69.6%) of the relapse participants. The substitutions V321A and L159F in 
NS5B were each detected in one participant with GT-1a HCV infection at low 
levels at relapse. E237G, a conserved site substitution in NS5B, but distant from 
the active site, was detected in two GT-1a participants at virologic failure. Eleven 
participants who achieved SVR4 did not achieve SVR12: five participants in the 
LDV/SOF 8-week group (three relapsed, one lost to follow-up, and one withdrew 
consent); four participants in the LDV/SOF+RBV 8-week group (three relapsed, 
one lost to follow-up) and two participants in the LDV/SOF 12-week group (two 
participants had visits that had not occurred at time of data cut and were 
considered lost to follow-up). 
 
Prespecified analyses of subgroups indicated that the SVR12 rates across the 
three treatment groups were generally consistent with those observed in the 
overall population, with high SVR12 rates observed in most subgroups. 
 
For the 8-week treatment groups, exact univariate logistic regression analysis 
was used to assess the relationship between relapse and 10 prognostic factors 
(treatment with vs. without RBV, age, sex, race, ethnicity, HCV GT-1 subtype, 
baseline HCV RNA viral load, BMI, IL-28B alleles, and gamma-glutamyl 
transferase). Among the 10 factors included in the analysis, two were found to be 
significant (p<0.05). These were male sex and having a baseline HCV RNA viral 
load ≥800,000 IU/mL. Of note, the analysis showed that the absence of RBV in 
an 8-week regimen consisting of LDV/SOF was not a significant predictor of 
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been predictive of, or associated with, relapse (eg, age >65 years, black or 
African-American, Hispanic or Latino, high BMI, non-CC IL-28B alleles) were not 
found be significant in this analysis. Subsequent exact multivariate regression 
analysis identified only one factor, male sex, to be the most predictive of relapse, 
among the limited number of participants who relapsed. Although the SVR12 rate 
was numerically lower among male participants than female participants, the 
majority of male participants (92.6%, 225 of 243 participants) and female 
participants (98.9%, 178 of 180 participants) achieved SVR12 after 8 weeks of 
therapy (see Table 2-2). 
 
Table 2-2: 8-week LDV/SOF and LDV/SOF+RBV Regimen 
 
 
ION-3 
ION-3 
ION-3 
ION-1 
ION-1 
 
LDV/SOF 
8-Week 
N=215 (%) 
LDV/SOF+ 
RBV 
8-Week 
N=216 (%) 
LDV/SOF 
12-Week 
N=216 (%) 
LDV/SOF 
12-Week 
N=214 (%) 
LDV/SOF+ 
RBV 
12-Week 
N=217 (%) 
Treatment-Naïve Total 
SVR12 
202/215 
(94) 
201/216 
(93) 
206/216 
(95) 
209/214 
(98) 
211/217 
(97) 
95% CI 
89.9 - 
96.7% 
88.8 – 
96.1 
91.7 – 
97.8 
94.6 – 
99.2 
94.1 – 
99.0 
P-value* 
<0.001 
<0.001 
<0.001 
<0.001 
<0.001 
Treatment-Naïve Noncirrhotic 
SVR12 
202/215 
(94) 
201/216 
(93) 
206/216 
(95) 
177/180 
(98) 
178/184 
(97) 
95% CI 
89.9 – 
96.7 
88.8 – 
96.1 
91.7 – 
97.8 
95.2 – 
99.7 
93.0 – 
98.8 
Treatment-Naïve Cirrhotic 
SVR12 
NA 
NA 
NA 
32/34 
(94) 
33/33 
(100) 
95% CI 
-- 
-- 
-- 
80.3 – 
99.3 
89.4 - 
100 
*Compared to historic control of 60% 
 
2.3.7 Clinical Efficacy Conclusions 
 
In the LDV/SOF Phase III clinical program, LDV/SOF±RBV treatment was 
evaluated for 12 or 24 weeks in treatment-naive and treatment-experienced 
participants in studies GS-US-337-0102 and GS-US-337-0109, respectively, with 
GT-1 HCV infection. Both studies enrolled up to 20% HCV-infected participants 
who had documented compensated cirrhosis. Study GS-US-337-0108 evaluated 
LDV/SOF±RBV treatment for 8 weeks and LDV/SOF treatment for 12 weeks in 
noncirrhotic treatment-naive participants with GT-1 HCV infection. Across all 
studies, LDV/SOF demonstrated a high degree of efficacy with point estimates 
for SVR12 >93% in participants with GT-1 HCV infection. 
 


 
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Across the three Phase III studies, the addition of RBV to the LDV/SOF regimen 
did not substantially increase the SVR rate. When the SVR rates are considered, 
extending the duration of LDV/SOF treatment from 8 to 12 weeks in noncirrhotic 
treatment-naive participants in Study GS-US-337-0108 and 12 to 24 weeks in 
noncirrhotic or cirrhotic treatment-experienced participants in Study GS-US-337-
0109 would not enhance the observed SVR12 rates for the majority of 
participants. Concordance analysis between SVR12 and SVR24 in treatment-
naȉve and treatment-experienced participants receiving LDV/SOF for 12 or 24 
weeks was 100% in the Phase III Studies GS-US-337-0102 and GS-US-337-
0109. There was no clinically meaningful impact on SVR12 rates or relapse when 
participants took LDV/SOF with or without food in any study. 
 
Comprehensive analyses showed that no genotypic or phenotypic resistance to 
either SOF or LDV was detected in eight of 37 participants (22%) at virologic 
failure in the Phase III studies. Virologic failure was associated with single-class 
LDV phenotypic resistance in 29 of 37 participants (78%). Low levels of V321A 
and L159F in NS5B, two substitutions previously identified to be SOF treatment-
emergent substitutions with no phenotypic resistance to SOF, were detected in 
one participant with GT-1a HCV infection at relapse by deep sequencing. In 
addition, E237G, a conserved site substitution in NS5B, but distant from the 
active site, was observed in two participants with GT-1a HCV infection and one 
participant with GT-1b infection at virologic failure. The clinical significance of 
these NS5B substitutions is unknown. No genotypic or phenotypic resistance to 
SOF was detected in the remaining participants. 
 
Overall, pre-existing baseline NS5A RAVs have a poor predictive value for 
virologic failure when participants are treated with a dual combination of SOF and 
LDV. Among all participants who had baseline NS5A RAVs, an SVR12 rate of 
89.5% (34/38 participants) or 92.1% (82/89 participants) was observed among 
participants treated with LDV/SOF for 8 or 12 weeks, respectively. Nevertheless, 
among participants with baseline NS5A RAVs, there were slight reductions in 
SVR12 observed, associated with NS5A RAVs expressing higher levels of LDV 
resistance within the treatment-experienced population. From a clinical 
perspective, the lack of a high predictive value between viral sequence and 
treatment outcome coupled with the observation that a large majority of 
participants with NS5A RAVs achieve SVR12 appears to preclude the clinical 
utility of baseline sequencing. 
 
2.3.8 Clinical Safety 
 
The primary safety data for this clinical safety section are derived from the three 
Phase III LDV/SOF ION studies (GS-US-337-0102 [ION-1], GS-US-337-0109 
[ION-2], GS-US-337-0108 [ION-3]) with supporting safety data from other studies 
as appropriate. The ION-4 safety analysis confirmed the clinical safety reported 
in the rest of the ION program. 
 


 
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2.3.9 Adverse Events 
 
Treatment-emergent AEs were any events with onset dates on or after the date 
of the first dose of any study drug up to 30 days after the last dose of any study 
drug. 
 
2.3.10 Overall Summary of Adverse Events 
 
Table 2-3 presents an overall summary of AEs reported in the three Phase III 
ION studies. Of the participants in these studies, 79.1% had at least one AE and 
4.7% had at least one Grade 3 or 4 AE. In addition, 2.6% of participants had at 
least one SAE, with only 0.3% of participants experiencing a treatment-related 
SAE (section 2.3.12). 
 
Overall, <1% of participants receiving LDV/SOF with or without RBV (0.7%) had 
an AE leading to discontinuation of LDV/SOF. The only AEs that led to 
discontinuation of LDV/SOF in >1 participant were palpitations and anxiety (2 
participants each) (section 2.3.14). 
 
A higher proportion of participants in the RBV-containing (LDV/SOF+RBV) 
treatment groups (13.5%) had AEs leading to dose modification or interruption of 
any study drug than participants in the RBV-free (LDV/SOF) treatment groups 
(0.6%). 
 
No treatment-emergent deaths were reported in the three Phase III studies. One 
non-treatment-emergent death was reported in a participant who had an SAE of 
hepatic failure secondary to HCV infection and alcohol use on post treatment 
Day 38. The participant died of liver failure on post treatment Day 121 (Section 
2.3.13). 
 
The difference in the AE profile of RBV-free (LDV/SOF) and RBV-containing 
(LDV/SOF+RBV) treatment groups was also evaluated. The percentage 
differences for the 8-, 12-, or 24-week treatment durations and overall risk 
differences (adjusted for treatment duration based on Mantel-Haenszel 
proportions) were calculated for the AE brief summary and for AEs and 
treatment-related AEs that occurred in at least 5% of participants within any 
treatment group. The addition of RBV to the treatment regimen was associated 
with an increase in the total incidence of AEs for all treatment durations. Overall, 
when adjusted for treatment duration, the addition of RBV increased the risk of a 
participant experiencing any AE by 11.1%, the risk of a participant experiencing 
any treatment-related AE by 25.7%, and the risk of a participant experiencing any 
AE leading to modification or interruption of any study drug by 13.0%. For Grade 
3 or 4 AEs, Grade 3 or 4 treatment-related AEs, SAEs, treatment-related SAEs, 
AEs leading to permanent discontinuation of any study drug, AEs leading to 
permanent discontinuation of LDV/SOF, and AEs leading to interruption of 
LDV/SOF, the risk differences between the LDV/SOF and LDV/SOF+RBV 
treatment regimens were small (<5%). The majority of AEs attributable to the 
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The ION-4 reported 77% of participants with AEs, 4% with Grade 3-4 (only four 
of the 14 were reported as related to the study regimen), eight with severe AE 
(including two diagnoses of hepatocellular carcinoma and two diagnoses of portal 
vein thrombosis). No participant discontinued treatment due to AE. Eleven 
percent of participants had a Grade 3-4 laboratory abnormality but these were all 
transient and asymptomatic (elevated glucose in diabetic participants, elevated 
lipase and creatinine kinase). All participants maintained stable CD4 throughout 
the study and no participant had confirmed HIV virologic rebound. Common AEs 
(≥ 5%) included headache (25%), fatigue (21%), diarrhea (11%), nausea (10%), 
arthralgia (7%), and upper respiratory tract infection (5%). This is quite similar to 
Tables 2-3 and 2-4 below. Due to the drug-drug interaction of LDV and TDF 
leading to increased serum tenofovir levels, all participants had close renal 
monitoring at all study visits. There was no clinically or statistically significant 
increase in serum creatinine or decrease in creatinine clearance (CrCl) during 
the study. Four participants met the study protocol defined criteria of confirmed, 
treatment-emergent, renal insufficiency (creatinine ≥ 0.4 mg/dL). Two of these 
participants were simply monitored and in the absence of any evidence of tubular 
toxicity no changes were made in ARVs. One participant entered the study on 
RAL and had baseline CrCl of approximately 50 mL/min. With worsening CrCl 
but no evidence of tubular toxicity, this participant had dose reduction of TDF as 
per package insert. The fourth participant also entered the study with evidence of 
chronic kidney disease (CKD) with CrCl of approximately 80 mL/min and 
baseline 4+ glucosuria and 2+ proteinuria. This participant had worsening renal 
function on study and due to the concern for tubular damage at baseline, the 
decision was made to switch this participant off of TDF to RAL. The participant 
completed the study on EFV, RAL and lamivudine (3TC) without difficulty and 
achieved SVR12. 
 
 
 


 
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Table 2-3 Overall Summary of Adverse Events in LDV/SOF Phase III Safety Population 
Number (%) of Participants 
Experiencing Any: 
ION-3 
LDV/SOF 
8 Week 
N=215 
RBV-Free 
Regimens 
(ION-1, 2, 3) 
Overall 
(N=1080) 
RBV-
Containing 
Regimens 
(ION-1, 2, 3) 
Overall 
(N=872) 
AE 
145 (67%)
800 (74%) 
745 (85%)
Grade 3 or 4 AE 
2 (0.9%) 
46 (4.3%) 
45 (5.2%) 
Treatment-Related AE 
82 (38%) 
484 
(44.8%) 
617 
(70.8%) 
Grade 3 or 4 Treatment-
Related AE 
0 
11 (1.0%) 
27 (3.1%) 
SAE 
4 (1.9%) 
34 (3.1%) 
17 (1.9%) 
Treatment-Related SAE 
0 
4 (0.4%) 
1 (0.1%) 
AE Leading to Permanent 
Discontinuation of Any Study 
Drug 
0 
6 (0.6%) 
11 (1.3%) 
AE Leading to Permanent 
Discontinuation of LDV/SOF 
0 
6 (0.6%) 
7 (0.8%) 
AE Leading to Modification or 
Interruption of Any Study 
Drug 
0 
6 (0.6%) 
118 
(13.5%) 
AE Leading to Interruption of 
LDV/SOF 
0 
6 (0.6%) 
7 (0.8%) 
Treatment-Emergent Death 
0 
0 
0 
 
2.3.11 Frequent Adverse Events Final 
 
Table 2-4 presents the AEs reported for at least 5% of participants in any 
treatment group by preferred term in the three Phase III ION studies. Overall, the 
three most frequently reported AEs were fatigue (29.3%), headache (23.1%), and 
nausea (13.5%). All of these events were reported more commonly in 
participants receiving LDV/SOF+RBV compared with participants receiving 
LDV/SOF: fatigue (38.0% vs. 22.2%), headache (26.1% vs. 20.6%), and nausea 
(17.4% vs. 10.4%). 
 
The majority of AEs reported in at least 5% of participants occurred more 
commonly in participants receiving LDV/SOF+RBV compared with participants 
receiving LDV/SOF. Furthermore, irrespective of treatment duration (8 vs. 12 vs. 
24 weeks), the AEs with a ≥5% risk difference were generally similar across the 
three treatment durations (8 vs. 12 vs. 24 weeks). Therefore, a pooled analysis, 
which adjusted for treatment duration, was used to identify AEs occurring at ≥5% 
incidence in participants receiving LDV/SOF+RBV compared with participants 
receiving LDV/SOF. These AEs were fatigue, insomnia, anemia, nausea, 
dyspnea, irritability, cough, rash, pruritus, and headache. All of these events 
were associated with the expected safety profile of RBV [15; 18-19]. 
 


 
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When evaluated at the system-organ-class level, numerically higher percentages 
(difference of >5%) of participants receiving LDV/SOF+RBV than participants 
receiving LDV/SOF experienced AEs within the following system organ classes: 
blood and lymphatic system disorders (10.7% vs. 1.5%); gastrointestinal 
disorders (39.6% vs. 30.6%); general disorders and administration site conditions 
(52.5% vs. 33.8%); infections and infestations (23.7% vs. 18.4%); nervous 
system disorders (36.9% vs. 27.8%); psychiatric disorders (29.6% vs. 16.2%); 
respiratory, thoracic, and mediastinal disorders (25.2% vs. 11.5%); and skin and 
subcutaneous tissue disorders (29.7% vs. 14.3%). No system organ class had an 
incidence of AEs higher (>5%) in participants receiving LDV/SOF compared with 
participants receiving LDV/SOF+RBV. 
 
Longer treatment duration (8 vs. 12 vs. 24 weeks) was associated with an 
increase in the total incidence of AEs, both in the LDV/SOF groups (67.4%, 
72.4%, and 81.3%, respectively) and LDV/SOF+RBV groups (76.4%, 85.4%, and 
to 91.5%, respectively). 
 
When comparing the LDV/SOF groups by treatment duration, the differences in 
the incidence of any individual AE between 8 and 12 weeks of treatment or 
between 12 and 24 weeks of treatment were small (<5%); headache was the 
only AE with increased incidence of ≥5% when the treatment durations increased 
from 8 to 12 weeks. 
 
When comparing the LDV/SOF+RBV groups by treatment duration, most of the 
differences in the incidence of any individual AE between 8 and 12 weeks of 
treatment were small (<5%); insomnia, cough, asthenia, and dyspnea were 
exceptions with increased incidence of ≥5% when the treatment durations 
increased from 8 to 12 weeks. Similarly, the differences in the incidence of any 
individual AE between 12 and 24 weeks of treatment were small (<5%), with the 
exception of headache, which had an increased incidence of ≥5% when the 
treatment duration increased from 12 to 24 weeks. 
 
 
 


 
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Table 2-4: Adverse Events in at Least 5% of Participants in Any Treatment Group by 
Preferred Term in the LDV/SOF Phase III Safety Population 
 
ION-3 
LDV/SOF 
8 Week 
N=215 
RBV-Free 
Regimens 
(ION-1, 2, 3) 
Overall 
(N=1080) 
RBV-
Containing 
Regimens 
(ION-1, 2, 3) 
Overall (N=872)
Number (%) of 
Participants 
Experiencing Any AE: 
145 (67%) 
800 (74%) 
745 (85%) 
Fatigue 
45 (21%) 
240 (22.2%) 
331 (38%) 
Headache 
30 (14%) 
222 (20.6%) 
228 (26.1%) 
Nausea 
15 (7%) 
112 (10.4%) 
152 (17.4%) 
Insomnia 
11 (5.1%) 
82 (7.6%) 
155 (17.8%) 
Diarrhea 
15 (7%) 
88 (8.1%) 
67 (7.7%) 
Irritability 
3 (1.4%) 
46 (4.3%) 
95 (10.9%) 
Rash 
3 (1.4%) 
47 (4.4%) 
94 (10.8%) 
Arthralgia 
9 (4.2%) 
68 (6.3%) 
66 (7.6%) 
Cough 
3 (1.4%) 
42 (3.9%) 
90 (10.3%) 
Pruritus 
2 (0.9%) 
33 (3.1%) 
78 (8.9%) 
Dizziness 
6 (2.8%) 
47 (4.4%) 
61 (7%) 
Constipation 
9 (4.2%) 
53 (4.9%) 
42 (4.8%) 
Myalgia 
7 (3.3%) 
47 (4.4%) 
48 (5.5%) 
Asthenia 
1 (0.5%) 
38 (3.5%) 
56 (6.4%) 
Anemia 
2 (0.9%) 
5 (0.5%) 
84 (9.6%) 
Muscle Spasms 
3 (1.4%) 
28 (2.6%) 
57 (6.5%) 
Back Pain 
6 (2.8%) 
43 (4.0%) 
40 (4.6%) 
Dyspnea 
0 
12 (1.1%) 
69 (7.9%) 
Anxiety 
5 (2.3%) 
30 (2.8%) 
49 (5.6%) 
Nasopharyngitis 
3 (1.4%) 
38 (3.5%) 
41 (4.7%) 
Vomiting 
6 (2.8%) 
24 (2.2%) 
40 (4.6%) 
Dry Skin 
1 (0.5%) 
10 (0.9%) 
43 (4.9%) 
Dyspnea Exertional 
0 
6 (0.6%) 
35 (4%) 
 
2.3.12 Serious Adverse Events in Phase III ION Studies 
 
Overall in the Phase III ION studies (GS-US-337-0102, GS-US-337-0109, and 
GS-US-337-0108), few participants (2.6%, 51 of 1952 participants) had any SAE. 
The only SAEs reported in >1 participant across all treatment groups were 
noncardiac chest pain (three participants), and chest pain, colitis, gastroenteritis, 
hand fracture, hypertension, intervertebral disc protrusion, and pneumonia (two 
participants each), suggesting that no trends in SAE type or onset time were 
observed. Only five participants (0.3%) had an SAE that was considered related 
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mesenteric vein thrombosis, salpingitis, and headache. These events are 
described below: 
 
1. A participant in the LDV/SOF+RBV 12-week group had two separate 
treatment-related SAEs of anemia; both events were Grade 3, led to 
interruption of the RBV dose, and resolved.  
2. A participant with cirrhosis in the LDV/SOF 24-week group had a 
treatment-related SAE of mesenteric vein thrombosis; this event was 
Grade 3, led to the interruption of the LDV/SOF dose, and resolved.  
3. A participant with a medical history of hemophilia A in the LDV/SOF 24-
week group, who had received factor VIII supplementation prior to and 
during the study, had a treatment-related SAE of development of factor 
VIII inhibitor; this event was Grade 3, led to the discontinuation of 
LDV/SOF, and was ongoing at the time of the data cut.  
4. A participant in the LDV/SOF 24-week group had a treatment-related SAE 
of salpingitis; this event was Grade 3, did not lead to a dose change for 
LDV/SOF, and resolved.  
5. A participant in the LDV/SOF 24-week group had a treatment-related SAE 
of headache; this event was Grade 3, occurred on post treatment Day 6, 
and was ongoing at the time of the data cut.  
 
2.3.13 Deaths 
 
Participants in Phase III ION Studies  
 
One treatment-emergent death was reported in the LDV/SOF Phase III Safety 
Population. This participant was in the ION-4 trial and was discontinued from the 
study at week 4 due to hospitalization for severe staphylococcal aureus infective 
endocarditis resulting in multi-organ failure and death in a participant actively 
using intravenous drugs. 
 
One non-treatment-emergent death was reported in Study GS-US-337-0102. 
This participant, who had received LDV/SOF for 12 weeks and achieved SVR12, 
was reported to have died of hepatic failure on post treatment Day 121. This 
participant had an SAE of hepatic failure secondary to HCV infection and alcohol 
use on post treatment Day 38; this event was considered not related to study 
drug by the investigator. 
 
2.3.14  Discontinuations Due to Adverse Events: Participants in Phase III ION Studies 
 
Overall, the incidence of AEs leading to permanent discontinuation of any study 
drug was low across all treatment groups (0.9%, 17 of 1952 participants). 
Anemia, anxiety, fatigue, and rash were the only AEs leading to permanent 
discontinuation of any study drug in >1 participant (two participants each); these 
were reported in the LDV/SOF+RBV treatment groups and are consistent with 
the expected safety profile of RBV [15; 18-19]. 
 


 
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All participants who discontinued LDV/SOF were required to discontinue the 
entire study treatment regimen (i.e., for the RBV-containing [LDV/SOF+RBV] 
groups, RBV was also discontinued). Across treatment groups, palpitations and 
anxiety were the only AEs leading to discontinuation of LDV/SOF reported in >1 
participant (2 participants each). All of these events were Grade 1 or 2 in severity 
and resolved following the discontinuation of LDV/SOF. 
 
2.3.15  Clinical Safety Conclusions 
 
The LDV/SOF Phase III clinical program compared the safety and tolerability of 
LDV/SOF with and without RBV for treatment durations of 8, 12, and 24 weeks. A 
total of 1952 participants received at least one dose of study drug and 98.1% of 
these participants completed their assigned study treatment. 
 
Across the LDV/SOF Phase III safety population, treatment with LDV/SOF was 
generally safe and well tolerated. The incidence of AEs leading to permanent 
discontinuation of any study drug was low (0.9%) across all regimens, with no 
AEs leading to permanent discontinuation of any study drug that occurred in >1 
participant in the LDV/SOF treatment groups; the only AEs leading to permanent 
discontinuation of any study drug in >1 participant in the LDV/SOF+RBV 
treatment groups included AEs consistent with the expected safety profile of RBV 
(anemia, anxiety, fatigue, and rash [2 participants each]) [15; 18-19]. Across the 
LDV/SOF Phase III Safety Population, the three most frequently occurring AEs 
were fatigue, headache, and nausea. A higher incidence of each event was 
reported in participants receiving LDV/SOF+RBV compared with participants 
receiving LDV/SOF: fatigue (38.0% vs. 22.2%), headache (26.1% vs. 20.6%), 
and nausea (17.4% vs. 10.4%). 
 
The addition of RBV to LDV/SOF increased the number of AEs experienced by 
participants. Overall, AEs were 11.1% and treatment-related AEs were 25.7% 
more likely to occur in the RBV-containing (LDV/SOF+RBV) groups compared 
with the RBV-free (LDV/SOF) groups. In addition, the need for study drug 
modification or dose interruption due to any AE was 13.0% more frequent in the 
RBV-containing (LDV/SOF+RBV) groups compared with the RBV-free 
(LDV/SOF) groups. The specific AEs that increased in the presence of RBV were 
fatigue, insomnia, anemia, nausea, dyspnea, irritability, cough, rash, pruritus, and 
headache. 
 
For both RBV-free (LDV/SOF) and RBV-containing (LDV/SOF+RBV) regimens, 
increasing treatment duration from 8 to 12 weeks and from 12 to 24 weeks 
resulted in small but consistent increases in the incidence of AEs, but did not 
change the observed AE profile. 
 
No treatment-emergent deaths were reported in the LDV/SOF Phase III safety 
population and few participants (2.6%) had any SAE. The only SAEs reported in 
>1 participant across all treatment groups were noncardiac chest pain (three 
participants), and chest pain, colitis, gastroenteritis, hand fracture, hypertension, 
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that no trends in SAE type or onset time were observed. Only five participants 
(0.3%) had an SAE that was considered related to study drug by the investigator. 
 
Grade 4 laboratory abnormalities were reported in only 1.0% of participants for 
both the RBV-free (LDV/SOF) and RBV-containing (LDV/SOF+RBV) groups. 
Grade 3 laboratory abnormalities were reported in 5.4% of participants in the 
RBV-free (LDV/SOF) groups and 11.4% of participants in the RBV-containing 
(LDV/SOF+RBV) groups. The increased incidence of Grade 3 laboratory 
abnormalities in the RBV-containing (LDV/SOF+RBV) groups compared with 
Grade 3 laboratory abnormalities in the RBV-free (LDV/SOF) groups was driven 
largely by hemoglobin abnormalities. The addition of RBV to a LDV/SOF 
treatment regimen contributed substantially to the incidence of anemia that 
required dose modification or discontinuation (hemoglobin <10 g/dL). A small 
number of participants with changes in non-hematologic laboratory parameters 
met the criteria for Grade 3 and 4 laboratory abnormalities. The most common 
Grade 3 or 4 chemistry laboratory abnormalities across all treatment groups were 
increased lipase (1.7%) and increased serum glucose (1.5%). In participants with 
Grade 3 or 4 increased lipase, no case of Grade 3 or 4 increased lipase was 
associated with clinical signs or symptoms of pancreatitis. Only one case of 
pancreatitis occurred in the entire Phase III program; this event occurred post 
treatment in a participant with a history of chronic pancreatitis and was not 
associated with a Grade 3 or 4 increased lipase. Among participants who 
experienced a Grade 3 or 4 increased serum glucose, all participants had a 
history of diabetes, were taking diabetes medication, or had glucose intolerance 
(denoted by HbA1c >6.0% at screening). 
 
 
3.0 
STUDY DESIGN 
 
This is a Phase II retreatment study of HIV/HCV GT-1-infected participants who have 
failed prior SOF-based regimens (SOF/RBV, SOF/PEG/RBV, or SOF/SIM +/- RBV) due 
to virologic failure. Participants will be randomized 1:1 in an open label fashion to 12 
weeks of LDV/SOF with weight-based RBV or 24 weeks of LDV/SOF alone. The 
participants will be followed for an additional 24 weeks after completion of study 
treatment. There will be 20 participants in each arm, with stratification by cirrhosis status 
(see section 4.1.2).  
 
The first 15 participants on ARV regimens with a HIV PI/r with tenofovir will be required 
to participate in the PK component in order to participate in the study. These first 15 
participants on PI/r with tenofovir who enroll to the study will undergo semi-intensive PK 
sampling (pre-dose, hour 1 and hour 4) at weeks 0 and 4 for quantification of tenofovir in 
plasma. After the first 15 participants have enrolled, subsequent participants taking HIV 
PI/r with tenofovir may opt out of the PK evaluations but still participate in the study. 
 
Fifteen slots will be held for participants across the study arms whose ARV regimen 
contains an HIV PI/r plus tenofovir for the first 3 months after the study opens to 
enrollment. After 3 months, these slots will no longer be reserved to allow expeditious 
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plus tenofovir or who are not taking ARVs will be enrolled to the study during the first 3 
months of study enrollment. After the first 3 months, additional participants whose ARV 
regimen does not contain a PI/r plus tenofovir or who are not taking ARV may be 
enrolled. The study may end up with fewer than 15 participants whose ARV regimens 
contain HIV PI/r plus tenofovir and more than 25 participants without, including 
participants who are not taking ARVs.   
 
The study consists of two steps: on-HCV treatment (Step 1) and post-HCV treatment 
follow-up (Step 2). At study entry, participants enroll in Step 1 to complete 12 weeks of 
LDV/SOF with weight-based RBV (Arm A) or 24 weeks of LDV/SOF alone (Arm B). 
Participants, who experience HCV virologic failure, as defined in section 7.3, will be 
discontinued from study treatment. At treatment discontinuation, including both 
completion and premature treatment discontinuation, participants will enter Step 2 for a 
24-week follow-up with evaluations at 4, 12, and 24 weeks after the end of treatment. 
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria Step 1 
 
4.1.1 Men and Women age ≥ 18 years. 
 
4.1.2 Documentation of Non-cirrhotic or Cirrhotic Status: 
 
 
Non-cirrhotic status as documented by one of the following criteria 
 
Liver biopsy within 24 months prior to study entry demonstrating the 
absence of cirrhosis (Metavir F0-F3, Ishak 0-4, or equivalent); or  
 
FibroScan result of <12.5 kPa within 12 months prior to study entry; or  
 
HCV FibroSURE score of <0.72 and Aspartate aminotransferase to 
platelet ratio index (APRI) <2 within 12 months prior to study entry. 
 
 
 
Cirrhotic status as documented by one of the following criteria: 
 
Liver biopsy at any time prior to study entry demonstrating cirrhosis (ie, 
Metavir >F3, Ishak >4, or the equivalent); or 
 
FibroScan showing cirrhosis with a reading of ≥12.5 kPa  within 12 
months prior to study entry; or  
 
HCV FibroSURE score of ≥0.72 and APRI ≥2 within 12 months of study 
entry. 
 
 
NOTE A: Cirrhotic participants must be Child-Turcotte-Pugh (CTP) Class A. An 
online calculator is available on the A5348 protocol-specific webpage (PSWP). 
For participants taking atazanavir, the direct bilirubin should be used. 
 
NOTE B: The APRI can be calculated with the following formula:  
(AST [IU/L]/AST upper limit of normal ÷ platelet count [x109/L]) x 100. 
 
NOTE C: If a participant is evaluated by more than one testing method, then the 
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criteria should be used next to determine fibrosis stage. If no biopsy or FibroScan 
criteria specified above can be met, then the combination of FibroSURE and 
APRI results can be used. The combined screening FibroSURE/APRI results are 
adequate for enrollment and to determine cirrhosis status if an acceptable biopsy 
or FibroScan are not available. If results from FibroSURE/APRI do not meet the 
criteria above defining the participant as “cirrhotic” or “non-cirrhotic”, the 
participant is considered to have an “indeterminate” liver status and Fibroscan or 
liver biopsy will be required prior to study entry. See Tables 4-1 and 4-2 for liver 
disease classification criteria. 
 
Table 4-1: Interpretation of Serum Markers for Liver Disease Classification 
Interpretation of Serum Markers from tests 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 12 
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. 
 


 
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Table 4-2: Liver Disease Classification 
HCV 
FibroSURE/
APRI 
Histology (Liver 
Biopsy within 2 
years prior to 
study entry) 
Transient Elastography  
(FibroScan) within 12 
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 
Non cirrhotic 
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 
(e.g., “unable to be reported”) must undergo either transient elastography or liver 
biopsy for liver disease stage classification. 
 
4.1.3 For participants with documented cirrhosis, liver imaging within 6 months prior to 
entry demonstrating absence of hepatocellular carcinoma (HCC).  
 
NOTE: Acceptable imaging includes a negative ultrasound, computed 
tomography (CT) scan or magnetic resonance imaging (MRI) within 6 months 
prior to study entry. Participants who have an ultrasound with results suspicious 
for HCC followed by a negative CT or MRI of the liver will be eligible for the 
study. 
 
4.1.4 Presence of HIV-1 infection, documented by any licensed rapid HIV test or HIV 
enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to 
study entry and confirmed by a licensed Western blot or a second antibody test 
by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, 
plasma HIV-1 RNA viral load. Two or more HIV-1 RNA viral loads of >1,000 
copies/mL, at any time prior to screening, are also acceptable as documentation 
of HIV infection. 
 
 
4.1.5    Participants must meet one of the following criteria: 
 
a) 
Not currently on ARV with CD4+ T-cell count >500 cells/mm3 obtained 
within 42 days prior to study entry at any laboratory that has a CLIA 
certification or its equivalent. 
OR 
b) 
Not currently on ARV: elite controllers with HIV-1 RNA < 500 copies/mL on 
all measurements in the 48 weeks prior to study entry and CD4+ T-cell 
count >200 cells/mm3 obtained within 42 days prior to study entry at any 
laboratory that has a CLIA certification or its equivalent. 
OR  


 
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c) 
On a stable, protocol-approved ARV regimen, as noted below, for >8 weeks 
prior to entry with a CD4+ T-cell count >200 cells/mm3 obtained within 42 
days prior to study entry at any laboratory that has a CLIA certification or its 
equivalent and a documented plasma HIV-1 RNA level <50 copies/mL by 
any laboratory, obtained within 42 days prior to study entry, that has a CLIA 
certification or its equivalent.  
 
NOTE: Approved ARV is limited to efavirenz, rilpivirine, raltegravir, 
dolutegravir, tenofovir, abacavir, 3TC/FTC, RTV-boosted atazanavir, RTV 
boosted darunavir (both 800 mg QD and 600 mg BID permitted). 
 
4.1.6 For the first 15 participants taking tenofovir and a PI/r as part of their ARV 
regimen, willingness and intent to participate in PK component.  
 
NOTE: In the event that 15 participants on PI/r and tenofovir have enrolled into 
A5348, participation in the PK evaluation will be optional for subsequent 
participants.  
 
4.1.7 HCV GT-1 within 12 months prior to study entry as determined by the local 
laboratory.  
 
NOTE: Inability to definitively determine genotype or a non-GT-1 will exclude the 
participant from study participation.  
 
4.1.8 Prior virologic treatment failure with SOF-containing regimen (SOF/RBV, 
SOF/PEG/RBV, and SOF/SIM).  
 
NOTE A: See section 6.3.3 for requirements for documentation of prior HCV 
treatment and response. 
 
NOTE B: Prior virologic failure is defined as quantifiable HCV RNA at any time 
after receiving HCV therapy as prescribed that was not attributed to reinfection.  
 
NOTE C: HCV reinfection is defined by (1) documentation of clearance of prior 
infection (as evidenced by prior positive anti-HCV Ab or HCV RNA) either 
spontaneously or after treatment with two negative HCV RNA a minimum of 3 
months apart AND (2) positive HCV RNA after documentation of two negative 
HCV RNA obtained a minimum of 3 months apart or infection with a different 
HCV genotype from the prior infection. 
 
4.1.9 Body mass index (BMI) ≥ 18 kg/m2 within 42 days prior to study entry. 
 
 
 
NOTE A: A BMI calculator is available at the DMC website (http://www.fstrf.org). 
 
 
 
NOTE B: The height and weight measurement used to calculate BMI must be 
obtained on the same day.  
 


 
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4.1.10 The following laboratory values obtained within 42 days prior to study entry by any 
US laboratory that has a CLIA certification or its equivalent. 
 
 
HCV RNA 104 IU/mL   
 
Hemoglobin ≥ 12.0 g/dL for male, ≥11.0 g/dL for female participants 
 
Platelets ≥ 50,000/mm3  
 
International normalized ratio (INR) ≤1.5 x ULN unless participant has known 
hemophilia or is stable on an anticoagulant regimen affecting INR, in which 
case any INR value is acceptable 
 
Albumin ≥ 3.0 g/dL  
 
Creatinine clearance (CrCl) ≥ 60 mL/min, as calculated by the Cockcroft-Gault 
equation (refer to section 6.3.5 for calculator utility link) 
 
Aspartate aminotransferase (AST) (SGOT) < 10 x ULN 
 
Alanine aminotransferase (ALT) (SGOT) < 10 x ULN  
 
Direct bilirubin ≤ 1.5 x ULN 
 
Hgb A1C ≤ 8.5%   
 
4.1.11 Screening electrocardiogram (ECG) without clinically significant abnormalities as 
determined by the investigator within 42 days prior to study entry. 
 
4.1.12 Willing and able to provide written informed consent. 
 
4.1.13 Female participants of reproductive potential (defined as women who have not 
been post-menopausal for at least 24 consecutive months, i.e., who have had 
menses within the preceding 24 months, or women who have not undergone 
surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or 
bilateral salpingectomy) must have a negative serum pregnancy test with a 
sensitivity of at least 25 mIU/mL performed at screening and again, within 48 
hours prior to study entry. 
 
4.1.14 All participants must agree not to participate in a conception process (e.g., active 
attempt to become pregnant or to impregnate, sperm donation, in vitro 
fertilization).  
 
4.1.15 When participating in sexual activity that could lead to pregnancy, all participants 
must agree to use at least two reliable forms of contraceptive simultaneously 
while receiving protocol-specified medications, and for 6 months after stopping 
the medications. Such methods include: 
 
 
Condoms (male or female) with or without a spermicidal agent  
 
Diaphragm or cervical cap with spermicide 
 
Intrauterine device (IUD) 
 
Tubal ligation 
 
Hormone-based contraceptive  
 


 
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NOTE: Providers and participants should be advised that not all contraceptive 
choices listed above can prevent HIV transmission and that some may actually 
increase the risk of HIV acquisition. Study participants who are sexually active 
with HIV-1 negative or unknown HIV-1 serostatus partners should be advised 
that they need to consider effective strategies for reducing the risk of HIV 
transmission, as well as meeting the requirement for effective contraception 
during their participation in the study. Study participants should discuss 
contraceptive choices and HIV risk reduction methods with their health care 
provider. 
 
4.1.16 Participants who are not of reproductive potential (women who have been post-
menopausal for at least 24 consecutive months or have undergone hysterectomy 
and/or bilateral oophorectomy or salpingectomy or men who have documented 
azoospermia or undergone vasectomy) are eligible without requiring the use of 
contraceptives. Acceptable documentation of sterilization and menopause is 
specified below. 
 
Written or oral documentation communicated by clinician or clinician’s staff of 
one of the following: 
 
 
Physician report/letter 
 
Operative report or other source documentation in the patient record (a 
laboratory report of azoospermia is required to document successful 
vasectomy)  
 
Discharge summary 
 
Follicle stimulating hormone-release factor (FSH) measurement elevated into 
the menopausal range as established by the reporting laboratory 
 
4.1.17  Intention to comply with the dosing instructions for study drug administration and 
ability to complete the study schedule of assessments. 
 
4.2 
Exclusion Criteria Step 1 
 
4.2.1  Received investigational drug or device within 60 days prior to study entry.  
 
4.2.2 Prior exposure to a DAA other than SOF and SIM.  
 
NOTE: Prior exposure to other HCV NS3 protease inhibitors given as part of a 
regimen containing only interferon/ribavirin and no other DAA agents will be 
allowed, as long as subsequent failure with SOF-based regimen occurred, as 
outlined in section 4.1.8. 
 
4.2.3 Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s 
disease, α1 antitrypsin deficiency, cholangitis). 
 
4.2.4 Presence of active or acute AIDS-defining opportunistic infections within 42 days 
prior to study entry.  
 


 
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NOTE: A list of AIDS-defining opportunistic infections as defined by the CDC, 
can be found in Appendix B of the following document: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm 
 
4.2.5 Active, serious infection (other than HIV-1 or HCV) requiring parenteral antibiotics, 
antivirals, or antifungals within 42 days prior to study entry.  
 
4.2.6 Infection with hepatitis B virus (HBV) defined as HBsAg positive within 42 days 
prior to study entry.  
 
4.2.7 History of clinically significant hemoglobinopathy (e.g., sickle cell disease, 
thalassemia). 
 
4.2.8 Chronic current use of systemically administered immunosuppressive agents 
(e.g., prednisone equivalent > 10 mg/day for more than 2 weeks). 
 
 
NOTE: Participants taking 10 mg/day or less of prednisone equivalent are not 
excluded, but should be discussed with the team prior to enrollment. 
 
4.2.9 History of solid organ transplantation. 
 
4.2.10  Current or prior history of clinical hepatic decompensation (e.g., ascites, 
encephalopathy or variceal hemorrhage). 
 
4.2.11  History of a gastrointestinal disorder (or postoperative condition) that could 
interfere with the absorption of the study drug. 
 
4.2.12  History of significant or symptomatic pulmonary disease, cardiac disease, or 
porphyria that in the opinion of the investigator would interfere with the study. 
 
4.2.13  History of difficulty with blood collection and/or poor venous access for the 
purposes of phlebotomy. 
 
4.2.14  History of clinically significant illness or any other major medical disorder that 
may interfere with participant treatment, assessment, or compliance with study 
requirements, which may include active drug or alcohol use or dependence. 
 
4.2.15  Use of any prohibited concomitant medications per the LDV/SOF product 
labeling, as noted on the A5348 PSWP, within 42 days prior to study entry.  
 
4.2.16 Known hypersensitivity to RBV, SOF, LDV, their metabolites, or formulation 
excipients or any other contraindication to the use of RBV, SOF or LDV.  
 
NOTE: Individuals with prior intolerance attributed to SOF will not be permitted to 
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4.2.17 Currently receiving zidovudine (ZDV), didanosine (ddI), stavudine (d4T) or 
tipranavir. 
 
4.2.18 Acute HIV infection defined as the phase immediately following infection during 
which anti-HIV antibodies are undetectable.  
 
NOTE: Inclusion of participants with early infection, defined as within the first 6 
months of infection and with a positive HIV antibody, should be discussed with 
the A5348 protocol core team. These individuals may be considered for inclusion 
in the study on a case by case basis with the specific documented approval of 
the protocol chairs. 
 
4.2.19  Known hepatocellular carcinoma.   
 
4.2.20 Breastfeeding or pregnancy. 
 
4.2.21 A male participant with a pregnant female partner. 
 
4.2.22 Received treatment with colony stimulating agents, including but not limited to 
erythropoietin, within 42 days prior to study entry. 
 
4.3  
Inclusion Criteria Step 2 
 
4.3.1  Permanent discontinuation of Step 1 study treatment. 
 
4.3.2  Availability of date of last dose of study treatment in Step 1. 
 
4.4  
Exclusion Criteria Step 2 
 
 
4.4.1 Premature study discontinuation in Step 1. 
 
4.5 
Study Enrollment Procedures 
 
4.5.1 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 should be retained in the 
site's regulatory files. 
 


 
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Upon receiving final IRB and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICF 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a participant for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the parent or 
legal representative if the participant is under guardianship) will be asked to read 
and sign the approved protocol consent form.  
 
For participants from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the Data Management 
Center (DMC) Participant Enrollment System.  
 
4.5.2 Randomization/Participant Registration 
 
At entry, participants will be enrolled according to standard ACTG DMC 
procedures. 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
 
4.6 
Coenrollment Guidelines  
 
US sites are encouraged to coenroll participants in A5128, “Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses.”  
 
If there are concerns about exceeding volume limits for blood draws, please note that 
A5128 allows participants to consent to the study without allowing a blood sample to be 
collected. In these cases, if a future study wants to evaluate a participant’s DNA 
sometime later, sites would be able to access a stored aliquot from the initial study (if 
there are any available). It is also possible for a participant to enroll into A5128 and 
postpone the required blood draw until a later time. For more input, contact the A5128 
team. 
 
 


 
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5.0 
STUDY TREATMENT  
 
A5348 study treatment drugs are defined as ledipasvir (90mg)/sofosbuvir (400mg) 
(LDV/SOF) (brand name: Harvoni) and weight-based ribavirin (RBV). 
 
5.1 
Regimens Administration, and Duration 
 
In this phase II retreatment study, a total of 40 participants will be randomized at entry in 
1:1 open-label fashion to Arm A or Arm B (20 participants per arm), as outlined in Tables 
5-1 and 5-2.  
 
Table 5-1: A5348 Treatment Regimen 
 
Weeks 
Arm A  
Arm B (no RBV) 
1-12 
LDV 90 mg/SOF 400 mg fixed dose tablet once daily  
PLUS 
Ribavirin,  
based on weight at entry 
For weight <75 kg: 1000 mg per day*  
For weight >75 kg: 1200mg per day* 
LDV 90 mg/SOF 400 
mg fixed dose tablet 
once daily 
13-24 
No treatment 
LDV 90 mg/SOF 400 
mg fixed dose tablet 
once daily 
  
*Total daily dose of ribavirin has been divided into two doses. The dose of ribavirin will be based on 
participant’s weight at entry. Changes in weight after entry do not require a change in dose. Doses 
will only be changed for toxicity management. Ribavirin will be available as ribavirin 200mg tablets. 
 
Table 5-2: Weight-based Ribavirin Dose  
Weight (kg) 
 
Morning Dose 
Evening Dose 
< 75 kg 
600 mg  
400 mg  
> 75 kg 
600 mg  
600 mg  
 
5.1.1 Administration 
 
Ledipasvir/sofosbuvir should be taken with morning or evening ribavirin, if 
assigned to a ribavirin-containing therapy (Arm A). Participants should be 
instructed to take all doses of study drug with food. Study drug should be taken 
at the same times and maintain the same time intervals every day. 
 
If a participant forgets to take the ledipasvir/sofosbuvir at the correct time, it may 
be taken later in the day; however, no more than one tablet of  
ledipasvir/sofosbuvir should be taken on any calendar day. The participant 
should resume the standing dosing schedule on the next day. Study medications 
should not be cut or split. If participants miss a dose of ribavirin, they should take 
the missed dose as soon as possible with food during the same day. If an entire 


 
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day has gone by, then the missed dose should be skipped, and the normal 
dosing schedule should be resumed. Participants should not double the next 
dose of either study drug in order to "make up" what had been missed. 
 
5.1.2 Duration 
 
Study treatment may continue for a period of 12 or 24 weeks (as assigned at 
study entry). Study follow-up will be for 24 weeks after treatment completion.  
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1 Formulation 
 
Ledipasvir (90 mg) /sofosbuvir (400 mg) (brand name: Harvoni) is a fixed-dose 
combination tablet. It is an orange colored, diamond shaped, film-coated tablet 
debossed with “GSI” on one side and “7985” on the other side of the tablet. Each 
tablet contains ledipasvir (90 mg) /sofosbuvir (400 mg) as active ingredient. In 
addition to the active ingredients, ledipasvir (90 mg) /sofosbuvir (400 mg) tablet 
contain the following inactive ingredients: colloidal silicon dioxide, copovidone, 
croscarmellose sodium, lactose monohydrate, magnesium stearate, and 
microcrystalline cellulose.  
 
Ribavirin will be supplied as tablets for oral administration, each containing 200 
mg of ribavirin. 
 
5.2.2 Storage 
 
Bottle containing ledipasvir (90 mg) /sofosbuvir (400 mg) should be stored 
at a controlled room temperature. Controlled room temperature is defined 
as 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F to 
86°F). 
 
Ribavirin tablets should be stored at 20°C - 25°C (68°F - 77°F). 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Gilead Sciences, Inc. will provide ledipasvir (90 mg) /sofosbuvir (400 mg) for this 
study; ribavirin will be provided through the study. Study products will be 
available through the NIAID Clinical Research Products Management Center 
(CRPMC). The site pharmacist should obtain the study products for this protocol 
by following the instructions in the manual Pharmacy Guidelines and Instructions 
for DAIDS Clinical Trials Networks in the section Study Product Management 
Responsibilities. 
 
ARV will not be provided through the study. 
 


 
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5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products in US CRSs must be returned to the NIAID CRPMC (or as otherwise 
directed by the sponsor) after the study is completed or terminated. The 
procedures to be followed are in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions.  
Additional drug information may be found on the updated ACTG Drug Interactions 
Database located at: http://tprc.pharm.buffalo.edu/home/di_search. 
 
5.4.1 Required Medications 
 
See inclusion criteria (section 4.1.5) for specifications about ARV. Changes to 
ARV must be discussed with the A5348 protocol core team during the study 
drug dosing period.  
 
5.4.2 Prohibited Medications 
 
For a list of prohibited medications, please refer to the A5348 PSWP, as well as 
the ledipasvir/sofosbuvir package insert, which is available on the A5348 PSWP. 
 
5.4.3 Precautionary Medications 
 
For a full list of precautionary medications, please refer to the 
ledipasvir/sofosbuvir package insert, which is available on the A5348 PSWP. 
 
H2-receptor antagonists may be administered simultaneously with or 12 hours 
apart from ledipasvir/sofosbuvir at a dose that does not exceed doses 
comparable to famotidine 40 mg twice daily.  
 
Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower should 
only be administered simultaneously with ledipasvir/sofosbuvir under fasted 
conditions.   
 
5.4.4 Colony Stimulating Agents 
 
 
Under no circumstances are potential participants to be treated with colony 
stimulating agents during screening to elevate hematology laboratory parameters 
to facilitate entry into the study. Colony stimulating agents, such as 


 
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erythropoiesis stimulating agents or granulocyte colony-stimulating factor, will not 
be provided by the study. 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events 
 
Evaluations 
Screening 
(Within 42 
days prior 
to entry) 
Entry 
STEP 1 
STEP 2 
HCV VF Confirmation 
HIV-1 VF Confirmation 
Prem. Tx/Study 
Discontinuation1 
On-Treatment (Arms A&B)  
Week 
On-Treatment (Arm 
B only) 
Week 
Post-Treatment (Arms A&B) 
(R=Date of Last Dose of Study 
Treatment) 
Week 
1 
2 
4 
8 
121 
16 
20 
241 
R+4 
R+12 
R+24 
(Within ± 3 
days) 
(Within ± 7 days) 
(Within 
-5 to 
+7days)
(Within  
-5 to 
+14days)
(Within 
 -7 to 
+14days)
HIV-1 
Documentation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cirrhosis 
Status 
Documentation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation 
of HCV 
Treatment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology & 
Chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 


 
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Evaluations 
Screening 
(Within 42 
days prior 
to entry) 
Entry 
STEP 1 
STEP 2 
HCV VF Confirmation 
HIV-1 VF Confirmation 
Prem. Tx/Study 
Discontinuation1 
On-Treatment (Arms A&B)  
Week 
On-Treatment (Arm 
B only) 
Week 
Post-Treatment (Arms A&B) 
(R=Date of Last Dose of Study 
Treatment) 
Week 
1 
2 
4 
8 
121 
16 
20 
241 
R+4 
R+12 
R+24 
(Within ± 3 
days) 
(Within ± 7 days) 
(Within 
-5 to 
+7days)
(Within  
-5 to 
+14days)
(Within 
 -7 to 
+14days)
Liver Function 
Tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Hgb A1c  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uric Acid 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Calculated 
CrCl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Lipid Panel 
(fasting)2 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
INR 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Urinalysis 
 
X 
X3 
X3 
X
X3 
X 
X3
X 
X3 
X3
 
 
 
 
 
Urine for spot 
protein and 
creatinine 
 
X 
As indicated (see section 6.3.7) 
Serum 
Pregnancy 
Test4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
Pregnancy 
Test  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
HBsAg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV RNA 
Local lab 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Evaluations 
Screening 
(Within 42 
days prior 
to entry) 
Entry 
STEP 1 
STEP 2 
HCV VF Confirmation 
HIV-1 VF Confirmation 
Prem. Tx/Study 
Discontinuation1 
On-Treatment (Arms A&B)  
Week 
On-Treatment (Arm 
B only) 
Week 
Post-Treatment (Arms A&B) 
(R=Date of Last Dose of Study 
Treatment) 
Week 
1 
2 
4 
8 
121 
16 
20 
241 
R+4 
R+12 
R+24 
(Within ± 3 
days) 
(Within ± 7 days) 
(Within 
-5 to 
+7days)
(Within  
-5 to 
+14days)
(Within 
 -7 to 
+14days)
HCV RNA 
(Real time) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Plasma HCV 
Genotype Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HCV 
Resistance 
Testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Stored Plasma 
for HCV 
Studies (see 
section 6.3.8) 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
Plasma HIV-1 
RNA (real-
time)5 
X 
X5 
 
 
X5 
 
X5 
 
 
X5 
X5 
 
 
 
X5 
X5 
Plasma HIV-1 
RNA 
Resistance 
Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CD4+/CD8+ 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Stored Whole 
Blood Sample  
for Future 
Genetic 
Testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Urine  
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
 
X 


 
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Evaluations 
Screening 
(Within 42 
days prior 
to entry) 
Entry 
STEP 1 
STEP 2 
HCV VF Confirmation 
HIV-1 VF Confirmation 
Prem. Tx/Study 
Discontinuation1 
On-Treatment (Arms A&B)  
Week 
On-Treatment (Arm 
B only) 
Week 
Post-Treatment (Arms A&B) 
(R=Date of Last Dose of Study 
Treatment) 
Week 
1 
2 
4 
8 
121 
16 
20 
241 
R+4 
R+12 
R+24 
(Within ± 3 
days) 
(Within ± 7 days) 
(Within 
-5 to 
+7days)
(Within  
-5 to 
+14days)
(Within 
 -7 to 
+14days)
TFV PK 
Evaluation 
(pre-dose, 1hr, 
4hr)6 
(FASTING) 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dried Blood 
Spots for PK 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
IL-28B 
Genotype 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Prevention 
Counseling 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
Adherence 
Assessments 
(4 day recall, 
pill counts) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Study Drug 
Dispensing 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Medication 
Diary7 
(D=distribution, 
C=collect) 
 
X (D) 
X 
(C/D)
X 
(C/D) 
X 
(C/D) 
X 
(C/D) 
X 
(C/D) 
X 
(C/D) 
X 
(C/D) 
X 
(C/D) 
X (C) 
 
 
 
 
 
 


 
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NOTES 
1 Refer to Section 6.2.3 regarding registration into Step 2. 
2 Participants must be fasting for visits at entry, weeks 12, and 24, and premature discontinuation. If not fasting, they should return within 7 days of 
the visit to repeat the lipid panel that require fasting per section 6.3.7 and within 48 hours fasting to complete the tenofovir PK evaluation, if 
applicable. 
3 Urinalysis at this timepoint is required only for participants on tenofovir/ritonavir-boosted HIV protease inhibitor.  
4Females must have a negative serum pregnancy test with a sensitivity of at least 25 mIU/mL performed at screening and within 48 hours prior to 
study entry. 
5HIV RNA after screening is only required if participant is taking ARV.  
6 For participants on tenofovir and PI/r only. Participants should be in a fasting state until after the 1 hour post dose PK blood draw is obtained. 
7 Use of medication diary is recommended for the two PK visits and is optional for dried blood spot visit (see section 6.3.17).


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening  
 
Screening 
Screening evaluations to determine eligibility must be completed within 42 days 
prior to entry unless otherwise specified and must occur prior to the participant 
starting any study medications, treatments, or interventions. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur at least 24 hours after all screening evaluations 
have been completed. Entry evaluations must be performed before study 
treatment is started. 
 
Participant must be fasting (i.e., no food or drink, except water for taking 
prescription medications, for at least 8 hours) for the lipid panel and TFV PK 
evaluation at entry. 
 
Participant must begin study treatment within 48 hours after randomization. 
 
6.2.3 Post-Entry Evaluations 
 
Step 1: On-Treatment Evaluations  
On-treatment (Step 1) visits are scheduled in reference to the date of study entry. 
Weeks 1 and 2 have a window of ±3 days. Weeks 4, 8, 12, 16, 20, and 24 have a 
window of ±7 days. Only those participants randomized to Arm B will have weeks 
16, 20, and 24 on-treatment evaluations. 
 
Step 2: Post-Treatment Evaluations  
Participants will be registered to Step 2 at their last on-treatment visit. R is the 
date of the last dose of study treatment. Arm A participants will register to Step 
2 at week 12. Arm B participants will register to Step 2 at week 24. Participants 
who prematurely discontinue study treatment will register to Step 2 at the 
premature treatment discontinuation visit.   
 
After the last dose of study drugs, the post-treatment study visits have the 
following windows:  
 
Week R+4: -5 days to +7 days 
 
Week R+12: -5 days and +14 days 
 
Week R+24:  -7 days and +14 days 
 
Study Completion Evaluations  
The week R+24 visit will be completed as the participant’s final study visit.  


 
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6.2.4 Event Driven Evaluations 
 
HCV Virologic Failure/Relapse Confirmation 
Participants with suspected HCV VF, as defined in section 7.3, must have a 
confirmation sample obtained as soon as possible, but within 2 weeks of initial 
notification of HCV RNA meeting criteria for HCV VF. Participants who 
permanently discontinue study treatment for HCV VF (see details in section 7.3) 
will be followed on study/off treatment in Step 2 per the SOE. 
 
Virologic evidence of HCV relapse, defined as HCV RNA <LLOQ at end-of-
treatment but HCV RNA ≥LLOQ during follow-up, will require confirmation and 
the sample should be obtained and the sample sent in real time to the 
designated laboratory as soon as possible but within 2 weeks after determination 
of initial observation. The results will be provided to the site investigators within 2 
weeks of specimen receipt. 
 
HIV-1 Virologic Failure (VF) Confirmation 
Participants with suspected HIV-1 virologic failure, as defined in section 7.1.6, 
must have a confirmation sample obtained within 2 weeks after the initial sample 
was drawn. In addition, participants must complete the evaluations listed for HIV-
1 VF Confirmation, as per section 6.1. If the HIV-1 VF confirmation visit coincides 
with a regularly scheduled visit, the evaluations should be combined.  
 
Participants with confirmed HIV-1 RNA ≥200 copies/mL will have a 
corresponding stored sample submitted for HIV-1 resistance genotyping.  
 
Participants confirmed to have HIV-1 VF will continue to be followed on study/off 
study treatment per the Schedule of Events (SOE), if an HIV-1 regimen 
compatible with study treatment is available. If there are no HIV-1 regimens 
available that are compatible with study treatment, then the participant must 
discontinue study treatment and will be followed on study/off study treatment per 
the SOE (see details in section 7.1.6). 
 
6.2.5 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
Participants who do not start study treatment will be taken off study with no 
further evaluations required. All CRFs must be completed and keyed for the 
period up to and including entry. 
 
Premature Treatment Discontinuation Evaluations  
The protocol core team must be informed, as soon as possible, when a 
participant prematurely discontinues study treatment due to an AE. Participants 
who permanently discontinue study treatment for toxicity or any other reason, 
and who have not met the HCV virologic failure criteria defined in section 7.3 will 
also follow the Step 2 schedule in section 6.1. If applicable, additional or more 
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investigator. 
 
Participants who prematurely discontinue study treatment (i.e., prior to 
completion of the last dose of LDV/SOF per the assigned dosing period) will 
complete the premature treatment discontinuation evaluations within 7 days of 
discontinuation and be registered to Step 2 (R). Participants will remain on study 
and complete the post-treatment visits at weeks R+4, R+12, and R+24 weeks per 
the SOE.  
 
Participants who prematurely discontinue the study treatment for any 
reason will register for Step 2 at their Premature Treatment Discontinuation 
Visit. 
 
NOTE: If LDV/SOF is discontinued, Arm  A participants should discontinue 
RBV. Under no condition should the participant remain on RBV 
monotherapy. 
 
Pregnancy   
Pregnancy will result in immediate and permanent discontinuation of the study 
medications. Please see section 7.2 for detailed information regarding participant 
management. Participants will be followed on-study/off-treatment per the SOE. 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue from the study will have the study 
discontinuation evaluations performed prior to being taken off the study. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
Web site for information about what must be included in the source document: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced
ocappndx.pdf 
 
All stated evaluations are to be recorded on the CRF and keyed into the database 
unless otherwise specified. This includes events that meet the International Conference 
on Harmonisation (ICH) definitions for a serious adverse event: 
 
 
Results in death 
 
Life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity  
 
Congenital anomaly/birth defect 
 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the events listed above.   
 


 
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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 Adverse Events, Version 
2.0 (November 2014), which can be found on the DAIDS RSC Web site: 
 
http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx 
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.4 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation will not be recorded on the CRF. 
 
6.3.2 Documentation of Cirrhosis Status   
 
Section 4.1.2 specifies requirements for documentation of cirrhosis status. 
Documentation will be recorded on the CRF.  
 
6.3.3    Documentation of Prior HCV Treatment and Response  
 
Section 4.1.8 and the table below specify requirements for documentation of prior 
HCV treatment and its response. This documentation will be recorded on the 
CRF.  
 
Table 6-1: Prior HCV Treatment and Response 
 
Past Treatment Response 
Category 
Definition 
Past Treatment Response  
Sub-category 
Treatment-Intolerant 
Participant discontinued prior 
HCV treatment due to a 
laboratory abnormality or 
intolerable side effect. 
Participant did not meet a 
virologic failure criterion. 
 
N/A 
Non-Responder 
Participant did not achieve 
undetectable HCV RNA levels 
(HCV RNA ≥ LLOQ) while on 
HCV treatment. This was the 
reason for discontinuing 
treatment rather than an AE. 
For PEG-IFN/RBV non-
responders, participants should 
be further defined as Null or 
Partial Responders: 
 
Null Responders: HCV RNA <2 
Log10 reduction during the first 
12 weeks of treatment. 
Partial Responders: HCV RNA 
≥2 Log10 reduction during the 
first 12 weeks of treatment. 
Relapse/Breakthrough 
Participant achieved 
undetectable HCV RNA levels 
(HCV RNA 
< LLOQ) during HCV treatment, 
Relapse:  Participant  achieved 
undetectable HCV RNA levels 
(HCV RNA < LLOQ) at end of 
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Past Treatment Response 
Category 
Definition 
Past Treatment Response  
Sub-category 
but did not achieve a SVR. If 
treatment was discontinued 
early, it was because of 
breakthrough rather than an 
AE. 
became detectable after 
treatment was stopped, at or 
before 24 weeks after treatment 
discontinuation. 
 
Breakthrough: Participant 
experienced ≥1 log increase in 
HCV RNA from nadir while on 
treatment. 
 
6.3.4 Medical History 
 
In addition to reporting all diagnoses within the past 42 days, the following 
diagnoses should be reported regardless of when the diagnosis was made: 
 
AIDS-defining conditions  
 
Bone fractures (verbal history accepted)  
 
Coronary heart disease  
 
Cancer (exclusive of basal/squamous cell skin cancer)  
 
Diabetes  
 
Tuberculosis  
 
Chronic hepatitis B 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.5 Medication History 
 
A medication history must be present, including start and stop dates. Table 6-2 
below lists the medications that must be included in the history.  
 


 
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Table 6-2: Medication History 
 
Medication Category 
Complete History or Timeframe 
HIV treatment 
Within 56 days prior to entry 
HCV treatment 
Complete history 
Prescription drugs  
Within 42 days prior to entry 
Non-prescription drugs 
Within 42 days prior to entry 
Complementary and alternative 
therapies 
Within 42 days prior to entry 
 
6.3.6 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 head, neck and thyroid; eyes, ears, 
nose, throat, mouth and tongue; chest (excluding breasts); respiratory; 
cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; 
neurological.  
 
The complete physical exam will also include diagnoses, signs, and symptoms 
and vital signs (temperature, pulse, respiratory rate, and resting blood pressure). 
 
NOTE: Blood pressure will be measured following the current ACTG 
Standardization of Blood Pressure Measurement SOP.  
 
Targeted Physical Exam 
A targeted physical examination must be performed at entry and all subsequent 
visits, as specified in the SOE. It should include vital signs (temperature, pulse, 
and respiratory rate, and resting blood pressure) and is to be driven by any 
previously identified or new signs or symptoms and diagnoses that the participant 
has experienced since the last visit.   
 
NOTE: Blood pressure will be measured following the current ACTG 
Standardization of Blood Pressure Measurement SOP.  
 
Height 
Record height (in centimeters) at screening. 
 
Weight 
Record weight (in kilograms) as indicated in section 6.1. 
 
NOTE: Weight should be done with inner clothing and without shoes. 
 
BMI 
BMI will be calculated at screening using standard formula. BMI will not be 
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A BMI calculator is available at the DMC website (https://www.fstrf.org). 
 
12-Lead ECG 
An electrocardiogram (ECG) will be performed at screening. ECG results will not 
be recorded on the CRF. 
 
NOTE: Participant should rest in a supine position for ≥ 5 minutes prior to making 
a recording. The investigator (or qualified designee) should review the ECG 
traces recorded in real time for gross abnormalities. 
 
Signs and Symptoms 
At entry, all signs and symptoms, regardless of grade, that occurred within 42 
days prior to study entry must be recorded. Post-entry, only signs and symptoms 
Grade 3 and all signs and symptoms that led to a change in treatment 
(excluding indications for RBV dose modification) or that met ICH, EAE, or SAE 
guidelines, regardless of grade, must be recorded, and are defined by the 
protocol as reportable events that will require more detailed event reporting. 
 
Diagnoses 
After entry, record any diagnoses targeted for A5348 that are Grade ≥ 3 identified 
by the ACTG criteria for clinical events and other diseases, any diagnosis 
regardless of grade that led to a change in treatment (excluding indications for 
RBV dose modification), or any diagnosis that met ICH, EAE, or SAE guidelines. 
 
Concomitant Medications 
Record new or discontinued concomitant prescription and nonprescription 
medications. 
 
Study Treatment Modifications 
Record all study drug modifications, including initial doses, participant-initiated 
and/or protocol-mandated modifications, inadvertent and deliberate interruptions 
at each visit. Record any permanent discontinuation of treatment. 
 
Antiretroviral Medications  
Record all modifications to antiretroviral medications including initial doses, 
participant-initiated and/or protocol-mandated modifications, inadvertent and 
deliberate interruption, and permanent discontinuation. 
 


 
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6.3.7 Laboratory Evaluations 
 
At screening and entry, all laboratory values must be recorded. For post-entry 
assessments, record all grades of creatinine and creatinine clearance and all 
other Grade 3 laboratory values. All laboratory toxicities that led to a change in 
treatment (excluding indications for RBV dose reduction), regardless of grade, 
must be recorded.  
 
All Grade 3 or higher laboratory values, any laboratory value that led to a change 
in treatment (excluding indications for RBV dose modification) or that met ICH, 
EAE, or SAE guidelines are defined by the protocol as reportable events that will 
require more detailed event reporting. 
 
The study team should be notified (actg.coreA5348@fstrf.org) of any new or 
worsened Grade ≥ 2 creatinine values, new or worsened Grade ≥2 proteinuria 
or glucosuria after week 4 of study treatment.  
 
Fasting Instructions 
Fasting is defined as nothing to eat or drink except prescription medications and 
water for at least 8 hours. Fasting is only required for blood draws with lipid panel 
and the tenofovir PK evaluation. If participants are in a non-fasting state, they 
can proceed with non-fasting evaluations and have a fasting lipid evaluation (if 
indicated) within 7 days of the visit or undergo the tenofovir PK evaluation (if 
indicated) within 48 hours of the visit.  
 
Hematology 
Hematocrit, hemoglobin (Hgb), platelet count, red blood cell count (RBC), white 
blood cell count (WBC) with differential (absolute) including lymphocytes, 
monocytes, neutrophils, eosinophils, basophils, reticulocyte count, absolute 
neutrophil count (ANC) and MCV. 
 
Hemoglobin A1C: Required at screening only. 
 
Blood Chemistries 
Sodium, potassium, chloride, bicarbonate/CO2, blood urea nitrogen (BUN), 
creatinine, glucose, and lipase.  
 
Uric Acid: required at weeks 0, 12, and 24. 
 
Liver Function Tests 
Total bilirubin, direct bilirubin, indirect bilirubin, albumin, AST (SGOT), ALT 
(SGPT), alkaline phosphatase.  
 


 
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Calculated CrCl 
Estimated each time that a creatinine level is determined.  
 
To estimate calculated CrCl, use the following method of Cockcroft and Gault: 
 
For men: [(140 - age in years) x (body weight in kg)] ÷ (serum creatinine in 
mg/dL x 72). 
 
For women: use the same calculation as for men, then multiply the result by 
0.85. 
 
A calculator is available at the DMC website https://www.fstrf.org/ACTG/ccc.html. 
 
Lipid Panel (fasting) 
Low density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), 
and total cholesterol (TC). 
 
Coagulation Marker 
INR  
  
Urinalysis 
Blood, glucose, leukocyte esterase, pH, protein, urobilinogen. Reflex testing to 
microscopic urinalysis if dipstick result is abnormal. Please note requirement for 
frequency of urinalysis testing is determined by ARV regimen (PI/r/tenofovir vs. 
non-PI/r/tenofovir) as outlined in the SOE, section 6.1. 
 
Record all urinalysis results including glucose and protein results on the CRF. 
 
Urine Spot Protein & Creatinine 
Spot protein and creatinine with calculation of protein/creatinine ratio is required 
at entry. This should be repeated in any participants who develop new proteinuria 
or glucosuria, an increase from entry glucosuria or proteinuria by ≥ 1+ or who 
develop an increase in creatinine of 0.4 from entry or CrCl < 50 (see section 
7.1.3 ). Urine spot protein and creatinine should be conducted at each study visit 
through R+4, unless the preceding visit urinalysis demonstrates resolution of 
proteinuria and/or glucosuria or an increase in creatinine of 0.4 from entry or CrCl 
< 50 has resolved. 
 
Pregnancy Test 
For women with reproductive potential: a serum -HCG documenting a negative 
result will be required at screening and within 48 hours prior to study entry. 
Serum tests should have a sensitivity of at least 25 mIU/mL.  
 
Once a participant has enrolled with a negative documented serum pregnancy 
test and begins using two forms of contraceptives to prevent pregnancy, further 
testing per section 6.1 (during study drug dosing and in post treatment follow-up) 
can be urine testing. Urine test must have a sensitivity of at least 50 mIU/mL; if 
positive, must have immediate confirmation with serum -HCG. 
  


 
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All women of reproductive potential will have a pregnancy test, as indicated in 
SOE. In the event of a positive urine pregnancy result, participants will be 
instructed to stop study drugs immediately and return to the clinic as soon as 
possible for a serum pregnancy test. See section 7.2 for detailed information 
regarding study management.  
 
Serologies 
HBsAg will be done during screening with results available prior to study entry. 
HBsAg will not be recorded on the CRF. 
 
6.3.8 Virologic Studies 
 
HCV RNA (screening) 
The screening HCV RNA must be obtained within 42 days prior to study entry 
using any FDA-approved test for quantifying HCV RNA at any local laboratory 
that has a CLIA certification or its equivalent.  
 
HCV RNA (on-study evaluations) 
At the entry and post-entry visits, HCV RNA quantification will be performed at 
the designated testing laboratory) as follows:   
 
Serum HCV RNA real-time testing will be collected, processed, and shipped 
to the designated testing laboratory (see A5348 laboratory processing chart 
[LPC] for instructions). These results will be reported within 2-3 weeks after 
specimen receipt. 
 
NOTE: The study team should be notified (actg.coreA5348@fstrf.org) of 
detectable HCV RNA after week 4 of study treatment.  
 
HCV Genotype 
At screening, the HCV genotype and subtype result will be obtained locally from 
any laboratory that has a CLIA certification or its equivalent. ONLY IF IT IS NOT 
AVAILABLE LOCALLY should it be done at the designated testing laboratory 
(see A5348 LPC).  
 
Stored plasma will be collected at the entry visit for additional testing and may be 
used for HCV genotype testing if confirmation of genotype is requested by the 
study team. 
 
HCV genotype sample collected at the time of HCV viral failure confirmation will 
not be performed locally, but should be collected and shipped as per the LPC. 
 
HCV Resistance Testing  
HCV resistance testing will be performed at entry for all participants and repeated 
at the time of HCV virologic failure confirmation. Resistance testing at the time of 
virologic failure will be performed real time. Refer to the A5348 LPC for 
collection, storage and shipping information.    
 


 
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Stored Plasma for HCV Studies 
Plasma samples will be collected and stored for potential HCV sequencing and 
other virology studies. For processing and shipping instructions, refer to the 
A5348 LPC.   
 
Plasma HIV-1 RNA (real time) 
A screening plasma HIV-1 RNA level must be obtained within 42 days prior to 
study entry, using an FDA-approved assay from any laboratory or clinic that has 
a CLIA certification or its equivalent. On-study HIV-1 RNA should be performed 
at the designated testing laboratory and is only required for participants taking 
ARV. Refer to the A5348 LPC for processing and shipping information.  
 
Participants on ARV who later experience HIV-1 VF while on HIV therapy should 
be managed as per section 7.1.6. 
 
Plasma HIV-1 Resistance Testing (real-time) 
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 A5348 
testing lab as per the LPC for evidence of drug resistance. 
 
6.3.9 Immunologic Studies 
 
CD4+/CD8+ T-cells 
Screening CD4+/CD8+ testing may be done by any laboratory or clinic that 
possesses a CLIA certification or its equivalent.  
 
During the study, all laboratories must possess a CLIA certification or its 
equivalent and must be certified for protocol testing by the DAIDS Immunology 
Quality Assurance (IQA) Program. 
 
6.3.10 Additional Stored Samples  
 
Plasma will be collected and stored at the indicated visit (see section 6.1) for 
future testing including HCV and HIV resistance testing, HCV genotype 
confirmation if necessary, as well as future ACTG-approved research, and 
shipped according to the A5348 LPC. Plasma will be collected from all 
participants for HIV and /or HCV resistance testing, should virologic breakthrough 
occur. Participants will be asked to provide consent for use of stored specimens 
for future research. 
 
There will be a one-time collection of whole blood for future genetic analyses for 
participants who consent to this sample collection. 
 


 
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Stored Urine  
Urine will be collected and stored for evaluation of retinol binding protein, beta-2 
microglobulin, and creatinine. Refer to A5348 LPC for instructions. 
 
6.3.11 Tenofovir PK Samples 
 
The tenofovir (TFV) PK sampling evaluations will be only required for the first 15 
participants, and consenting participants thereafter, who are taking ritonavir-
boosted protease inhibitor and tenofovir.  
 
The first TFV PK evaluation will occur at entry prior to initiation of LDV/SOF. For 
the entry evaluation, the date and time of the last three doses of TFV and other 
ARVs  
must be recorded on the CRF. The participant will not receive study treatment 
until after all of the PK samples have been obtained. The second TFV PK 
evaluation will occur 4 weeks after initiating LDV/SOF. For the week 4 evaluation, 
the date and time of the reference (current) dose and the last three doses of 
LDV/SOF and the last three doses of ARVs taken immediately prior to the pre-
dose blood sample must be recorded on the CRF.  
 
Weight will also be recorded on the CRF. 
 
For these visits, participants will come in to the clinic approximately 24 hours 
after their previous dose of TDF, following an 8 hour fast. A blood sample will be 
obtained at pre-dose, participants will then take an observed dose of TDF (and 
LDV/SOF at week 4 only), and additional blood samples will be obtained at 1 and 
4 hours post-observed dose. Participants should be fasting until after the 1-hour 
blood draw has been completed. After this draw, participants may eat and no 
specific meal is required.  
 
If the participant is not fasting at the entry visit, all entry evaluations should be 
performed except for the tenofovir PK evaluation and the participant should 
return fasting within 48 hours and before administration of study drug for the 
tenofovir PK evaluation.  
 
Participants will be instructed to keep a written record of the date and time of the 
last three doses of all HIV-1 and HCV drugs taken prior to the PK visit in the 
medication diary (see section 6.3.17), and to bring this information to the clinic. 
 
The week 4 evaluation should be rescheduled if participants are not considered 
to be at steady-state due to missed doses of any ARV or DAA (for the week 4 PK 
visit, excluding ribavirin) within the previous 3 days. 
 
Refer to section 10.2 for more detail on PK plan. For processing and shipping 
instructions, refer to the A5348 LPC.   
 


 
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6.3.12 Dried blood spots (DBS) 
 
One DBS will be collected on ALL participants at required visits regardless of 
ARV regimen, as outlined in section 6.1 to evaluate SOF and LDV blood levels, 
as well as potentially to evaluate tenofovir levels and for other future research 
evaluations in participants who have provided consent for this. The date and time 
of the most recent LDV/SOF and ARV dose will be recorded on the CRF.  
 
For processing and shipping instructions, refer to the A5348 LPC.   
 
6.3.13 IL-28B genotype 
 
IL-28B genotype will be conducted at entry, if no record of prior IL-28B testing is 
available. Testing can be conducted locally at a CLIA-certified laboratory. If not 
available to sites as local standard of care test, IL-28B testing may be conducted 
centrally, as outlined in the A5348 LPC. 
 
6.3.14 Pregnancy Prevention Counseling 
 
Counseling on pregnancy prevention will be conducted as per site’s standard of 
care per the SOE. This will not be recorded on the CRF. 
 
6.3.15 Adherence Assessment  
 
Adherence assessment is performed for study treatment only. 
 
This study will use a combination of three measures of adherence (1) the Adult 
ACTG 4-day recall, (2) pill count, and (3) LDV and SOF metabolite 
concentrations through collection of dried blood spots (DBS). 
 
6.3.16 Study Drug Dispensing 
 
Participants must be instructed to bring back all bottles of study drugs in the 
original container at the post-entry study visits. 
 
 
6.3.17 Medication Diary 
 
The medication diary will be distributed and collected as per the SOE. The diary 
is recommended to be used to record dosing for the three doses of HCV and HIV 
medications prior to the two tenofovir PK visits. They may be used as an optional 
tool for participants to record medication adherence throughout the study and for 
recall at the time of the DBS blood draws. A sample medication diary is provided 
for use on the DMC website (http://www.fstrf.org), but sites may choose to use a 
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7.0 
CLINICAL MANAGEMENT ISSUES 
 
Criteria for participant management, dose interruptions, dose adjustments and 
discontinuation, or changes in treatment will be described only for toxicities attributable 
to study drugs (i.e., SOF, LDV, and RBV).  
 
The grading system for drug toxicities is located in the DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, 
November 2014, which can be found on the DAIDS RSC Web site: http://rsc.tech-
res.com/safetyandpharmacovigilance/gradingtables.aspx. 
 
 
NOTE: The team must be notified via e-mail within 72 hours regarding toxicities that 
result in a change in study regimen (actg.coreA5348@fstrf.org). 
 
7.1    Toxicity  
 
Toxicity management is the responsibility of the site investigator who is encouraged to 
communicate with the core team regarding any management questions. 
 
7.1.1   Management of Side Effects of RBV (Arm A only) 
 
The most common AE of RBV therapy is anemia due to hemolysis. Anemia 
typically occurs within 1 to 2 weeks of initiating RBV therapy and usually resolves 
within 4 to 8 weeks of drug discontinuation or dose reduction. Indirect bilirubin 
elevation is commonly seen in those participants with anemia secondary to RBV-
induced hemolysis.  
 
Another major side effect of RBV is its teratogenicity; therefore pregnant women or 
breastfeeding women and men with pregnant sexual partners should not receive 
RBV. Women who become pregnant on study and men on study whose partners 
become pregnant must discontinue study treatment and will be managed per 
section 7.2. 
 
RBV dosing in this study will be based on weight at study entry (see section 5.0). 
Dose reduction of RBV is the recommended management for RBV associated 
anemia and should be performed according to the product label. Information is 
summarized in Table 7-1 It is recommended that sites contact the protocol core 
team with questions regarding difficult anemia management and/or if it is felt RBV 
discontinuation is required. Participants may continue to take LDV/SOF if RBV is 
temporarily or permanently discontinued.   
 


 
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Table 7-1: Suggested RBV Dose Reduction in the Event of Anemia 
 
Laboratory Values 
Reduce RBV Dose 
to 600 mg/day if: 
HOLD RBV if: 
Hemoglobin in 
participants with no 
cardiac disease 
<10 g/dL 
<8.0 g/dL 
Hemoglobin in 
participants with history 
of stable cardiac 
disease 
≥2 g/dL decrease in 
hemoglobin during 
any 4 week period 
treatment 
<10 g/dL despite 4 weeks at reduced dose
Symptomatic drop in hemoglobin to be managed at the discretion of the site investigator 
and can be discussed with the protocol chairs.  
 
 
Reintroduction of RBV 
If RBV is temporarily stopped due to anemia, the hemoglobin must be rechecked 
within 2 weeks and at 2-week intervals until stable. Once RBV has been withheld due 
to either a laboratory abnormality or clinical manifestation, an attempt may be made to 
restart RBV at 600 mg daily in two divided doses and further increase the dose to 800 
mg daily in two divided doses. However, it is not recommended that RBV be increased 
to the original assigned dose. Please refer to the table below for dosing intervals.  
 
Table 7-2: Suggested RBV Dosing Intervals for Reintroduction 
 
Daily 
Dose 
Morning 
Dose 
Evening Dose 
600 mg 
400 mg 
(2 
tablets) 
200 mg (1 tablet)
800 mg 
400 mg 
(2 
tablets) 
400 mg (2 
tablets) 
 
NOTE A: The half-life of RBV in participants with normal renal function is 290 hours.   
 
NOTE B: The ranges of hemoglobin values used as criteria for triggering dose 
reduction of RBV do not correspond to those used to grade toxicities in the DAIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, 
November 2014. Therefore, sites are expected to use A5348-specific criteria.  
 


 
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7.1.2   Management of Side Effects of LDV/SOF 
 
Dose reduction of LDV/SOF will not be allowed in the study. If LDV/SOF is stopped 
for toxicity, it should not be restarted and the participant should complete the 
treatment discontinuation visit. All participants must complete the week R+4, R+12, 
and R+24 visits. The week R+4, R+12, and R+24 visits will be scheduled from the 
date of the last dose of study treatment.  
 
If LDV/SOF is discontinued, Arm  A participants should discontinue RBV. 
Under no condition should the participant remain on RBV monotherapy. 
 
Participants who meet any of the following laboratory criteria should stop 
treatment with LDV/SOF and RBV: 
 
ALT or AST ≥10 x ULN (see section 7.1.5 for additional detail on elevated 
transaminases) 
 
Confirmed direct bilirubin 3 x ULN and > 2.0 mg/dL 
 
Any Grade 3 or greater rash associated with constitutional symptoms 
 
Any Grade 4 event assessed as related to treatment with LDV/SOF 
 
7.1.3   Specific Guidance for Creatinine Clearance (CrCl) 
 
CrCl will be calculated throughout the study using Cockcroft-Gault method. Refer 
to the Cockcroft-Gault calculator located on the FSTRF web site and using the 
weight obtained at each visit.  
 
7.1.3.1 If a participant experiences a CrCl decrease to <50 mL/min or an increase 
in creatinine of ≥ 0.4 mg/dL from entry creatinine, the following 
evaluations should occur:  
 
 
Within 7 days: repeat evaluation of electrolytes, creatinine, serum 
phosphorus, urinalysis including assessment of proteinuria and 
glucosuria with spot creatinine and protein assessment and 
calculation of protein/creatinine ratio.  
 
 
Assessment of current weight for repeat CrCl calculation. 
 
If calculated CrCl is confirmed to have decreased to <50 mL/min, 
the A5348 protocol core team should be contacted by e-mail at 
actg.corea5348@fstrf.org. 
  
 
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. Study 
DAAs may be continued. Ribavirin should be dose reduced for CrCl 
< 50 as follows: 
 


 
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Table 7-3: Suggested Dose Reduction of Ribavirin 
 
Creatinine 
Ribavirin Dose 
30-50 
200 mg every other day alternating with 400 
mg every other day 
 
< 30 
200 mg daily and consider discontinuation 
 
 
Creatinine and chemistries should be repeated as clinically 
indicated until resolution.  
 
 
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 including 
potentially nephrotoxic ARV including tenofovir must be undertaken 
in consultation with the treating provider.  
 
 
Changes to the ARV regimen require notification of the A5348 
protocol core team by e-mail at actg.corea5348@fstrf.org. Please 
refer to section 7.1.6 for guidance regarding changes in ARV. 
 
 
Continue further medical management as appropriate.  
 
 
If CrCl improves, consideration must be given to the readjustment of 
any dose modifications that have been made.  
 
7.1.3.2 CrCl value <30 mL/min: This should be handled on a case by case basis. 
The site should notify the core team of all participants with a confirmed 
CrCl <30 mL/min. 
 
7.1.4   Specific Guidance for New or Worsening Proteinuria or Glucosuria 
 
Participant who develop new proteinuria or glucosuria (1+ or greater) or an 
increase in glucosuria or proteinuria of ≥1+ from baseline should have the following 
evaluations occur: 
 
 
Within 7 days, repeat urinalysis with spot protein and creatinine, calculation 
of protein/creatinine ratio, repeat serum chemistry, creatinine and 
phosphate.  
 
 
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, as well as assessments 
for causes of proteinuria and/or glucosuria including concomitant disease 
processes such as diabetes and toxicity from current medications including 
HCV treatment. Sites are welcome to consult with the core team with any 
questions or concerns regarding management actg.corea5348@fstrf.org. 
 


 
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If new or worsened proteinuria and/or glucosuria are confirmed, the study team 
should be notified. Urinalysis should be repeated as per the SOE and more 
frequently if clinically indicated.  
 
7.1.5   Specific Guidance for Transaminase Elevations 
 
If a participant experiences an ALT level ≥5 x ULN that is ≥2 x baseline, a 
confirmatory test must be performed within 72 hours. If the ALT is confirmed ≥5 x 
ULN, the management guidelines in Table 7-4 must be followed.  
 
If a participant experiences an increase in ALT by one or more toxicity grades 
compared to the previous nadir (for example, ALT Grade 0 at nadir increases to 
Grade 1 or above, or ALT Grade 1 at nadir increases to Grade 2 or above), safety 
laboratory assessments and clinical evaluation of the participant should be 
conducted within 1 week. 
 
Alternative management of ALT increases requires approval from the A5348 
protocol core team by email at actg.corea5348@fstrf.org. 
 
Table 7-4: Management of Confirmed ALT Levels ≥5 x ULN and ≥2 x Baseline 
ALT ≥10 x ULN 
 
Permanently discontinue study drugs. 
Evaluate and manage the participant 
as medically appropriate. 
ALT >5 x ULN  and >2 x 
baseline 
 
Evaluate and manage the participant 
as medically appropriate. Continue 
study drugs and repeat liver function 
tests within 3 days and as clinically 
indicated until resolution.  Perform 
clinical assessment within 1 week. 
 
If ALT values during follow-up are 
increased >2-fold from the prior 
values, then permanently discontinue 
study drugs. 
 
7.1.6 HIV-1 Virologic Failure  
 
Plasma HIV-1 RNA will be monitored throughout the study for participants on ARV. 
In this study, HIV-1 viral failure will be defined as confirmed increase in HIV-1 RNA 
to ≥200 copies/mL at any time after study entry, only for participants who are taking 
ARV. 
 


 
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Since “blips” in HIV-1 RNA may be observed in individuals on ARV 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 time of 
confirmation will be sent to the designated central laboratory for evidence of HIV-1 
drug resistance. Confirmed HIV-1 VF 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 central laboratory. 
 
Clinical management of HIV-1 VF will be handled by local site investigators 
according to current HIV treatment guidelines and local standard of care. The 
A5348 protocol core team must be contacted to notify of any changes in ARV 
regimen in the event of HIV-1 VF (actg.corea5348@fstrf.org). 
 
Investigators should consult section 5.0 and the package insert. 
  
Regarding the potential for a modified ARV regimen for HIV-1 VF: Possible 
modified ARV regimens should take into account the unique characteristics of the 
participant and the participant’s HIV treatment history as well as known and/or 
anticipated drug interactions with DAA or DAA+RBV therapy. 
 
If no reasonable salvage HIV regimens compatible with continued HCV DAA or 
DAA+RBV therapy are deemed available for an individual participant with HIV-1 VF 
then the participant must discontinue HCV DAA+RBV therapy. 
 
7.2  
Pregnancy  
 
Pregnancy will result in immediate discontinuation of the study medications in both Arm 
A and Arm B; for those in Arm A assigned to RBV, initiation of counseling regarding the 
teratogenicity of RBV. Participants who become pregnant while on study will be followed 
on study/off treatment until study completion. A visit 6 months following the end of 
pregnancy will be conducted for evidence of AEs in the participant and infant, and an 
outcome CRF will be completed. For female participants, obstetrical history will also be 
recorded on the CRF. 
 
Male participants whose partners become pregnant will undergo treatment 
discontinuation and remain on study for continued follow-up until the end of the study. 
They will receive counseling on RBV teratogenicity and the same follow-up visit at 6 
months after their partners’ delivery as outlined for pregnant women. 
 
Participants who become pregnant while taking study treatment or within 6 months after 
discontinuing study treatment and male participants’ sexual partners who become 
pregnant during this time, will have their pregnancies reported to the RBV Pregnancy 
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If a female participant or female partner of a male participant has completed the study or 
chooses to discontinue from the study before the end of the pregnancy, then site staff 
should request permission to contact her regarding pregnancy outcomes at the end of 
pregnancy. If the information is obtained, pregnancy outcomes will be submitted on a 
CRF at the end of the pregnancy.  
 
The intrapartum complications and/or pregnancy outcome will be recorded on the CRFs. 
If applicable, pregnancies that occur on study should be reported by the site investigator 
prospectively to The Antiretroviral Pregnancy Registry. More information is available at 
www.apregistry.com. Phone: 800-258-4263; Fax: 800-800-1052.  
 
7.3 
HCV Virologic Response-Based Stopping Criteria and Confirmation of VF/Relapse 
 
The following on-treatment HCV virologic response-based treatment stopping criteria 
will be utilized for all participants: 
 
 
Confirmed increase in HCV RNA ≥LLOQ if HCV RNA previously declined to 
<LLOQ (detected or not detected). This will be defined as HCV breakthrough. 
 
Confirmed ≥1 log10 IUmL HCV RNA on-treatment increase from nadir. 
 
Confirmed HCV RNA ≥LLOQ at week 8 visit.  
 
Confirmation will be required for all stopping criteria and should be performed as soon 
as possible but within 2 weeks after determination of initial observation (see HCV VF 
Confirmation in section 6.2.4). 
 
HCV RNA measurement to confirm treatment failure or relapse after treatment will be 
performed in real time at the designated laboratory and the results will be provided to the 
site investigators within 2 weeks of specimen receipt. If treatment failure is confirmed, 
then all study treatment should be stopped. However, participants should be followed as 
per section 6.2.4. 
 
Retreatment of HCV virologic failures will not be provided through A5348. 
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Premature Study Treatment Discontinuation 
 
 
Drug-related toxicity (see section 7.1 Toxicity). 
 
Pregnancy in a female participant or in the female partner of male 
participant. 
 
HCV failure as defined in section 7.3. 
 
Failure by the participant to attend three or more consecutive clinic visits. 
 
Seven or more missed consecutive doses of study treatment.  
 
Participant requests to discontinue for any reason. 
 
Requirement for prohibited concomitant medications (see section 5.4). 
 
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 
Clinical reasons believed life threatening by the physician, even if not 
addressed in the toxicity section of the protocol. 
 
8.2 
Premature Study Discontinuation 
 
 
Request by the participant to withdraw. 
 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 
 
Participant judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results. 
 
At the discretion of the Study Monitoring Committee (SMC), ACTG, institutional 
review board (IRB), NIAID, Office for Human Research Protections (OHRP), any 
other government agency as part of their duties, investigator, or industry supporter. 
 
Initiation of alternate non-study HCV treatment. 
 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
A5348 is a prospective, open-label study to evaluate 12-week and 24-week regimens of 
LDV/SOF (Arms A and B, respectively) for the retreatment of HCV among individuals 
with prior treatment failures, with the addition of RBV to the 12-week regimen. It is a 
study to gather timely, pilot data in the retreatment of HCV in HIV-coinfected persons 
and to complement similar studies in HCV mono-infected persons, planned outside of 
the ACTG. The study will randomize the participants to the study arms, since there is 
clinical equipoise on the benefits and drawbacks between a shorter 12-week regimen of 
LDV/SOF with RBV and a 24-week regimen without RBV (see section 2.2 Rationale). 
The primary analysis will be conducted as a single-arm analysis for each regimen. Any 
comparison made between the regimens will be done as a secondary analysis. The 
study has not been designed to be powered for comparison between the two study 
regimens, and as such, any comparison needs to be interpreted with caution. 
 
The study sample size is limited by feasibility. As a study to provide supportive data on 
retreatment options expeditiously in a difficult-to-treat population, the study sample size 
is small. Limitations inherent in most early phase studies apply. Safety and tolerability 
evaluations of each treatment regimen, as well as the virologic response, will inform the 
acceptability of each treatment regimen as a viable strategy for retreatment. Virologic 
outcome will be evaluated using SVR12 as the primary endpoint. 
 
The primary analysis will be conducted as modified intent-to-treat, and all participants 
who meet the eligibility criteria and start study treatment will be included. The standard 
definition of SVR12 that is in use across the ACTG studies and, to our knowledge, the 
industry-sponsored studies will be used, where loss to follow-up or otherwise not 
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The study regimens have different treatment durations and, while the post-treatment 
follow-up time is the same for both study arms, the study durations are different in Arms 
A and B. Assessment of reasons for not achieving SVR12 is an important part of SVR12 
and SVR24 analyses in this study, including loss to follow-up. Differential loss to follow-
up in the two study arms may suggest the benefit of the shorter duration in the 12-week 
regimen or drawback of RBV intolerance. Either way, the SVR endpoints would capture 
the outcome of the regimen. 
 
9.2 
Outcome Measures 
 
9.2.1 Primary Outcome Measures 
 
9.2.1.1   SVR12 defined as HCV RNA < lower limit of quantification (LLOQ) 
(either target detected [TD] or target not detected [TND]) at 12 weeks 
after treatment discontinuation. The sample within the week R+12 (post-
treatment) visit window, as defined in section 6.0, which is closest to the 
targeted time will be used. If there is no HCV RNA sample within this 
window, then the participant will be considered SVR12 failure, unless 
there are preceding and subsequent HCV RNA measurements that are 
both  <LLOQ (either TD or TND). 
 
9.2.1.2    Occurrence of Grade 3 or higher AE (diagnosis, sign, symptom, or 
laboratory abnormality), SAE according to ICH criteria, or AE reported 
as the reason for permanent discontinuation of study treatment, during 
study treatment and up to 30 days after study treatment discontinuation. 
(Event that is ongoing at the same grade from prior to study treatment 
initiation will be excluded.) 
 
9.2.2 Secondary Outcome Measures 
 
9.2.2.1 Renal toxicity: (a) ≥ Grade 2 creatinine clearance after study entry, or 
(b) new proteinuria and/or glucosuria, defined as ≥ 1+ or an increase ≥ 
1+ from baseline.  
 
9.2.2.2 SVR4 defined as HCV RNA < LLOQ (either TD or TND) at 4 weeks 
after treatment discontinuation. The measurement within the week R+4 
visit window that is closest to the targeted time will be used. If there is 
no HCV RNA sample within this window, then the participant will be 
considered SVR4 failure, unless there are preceding and subsequent 
HCV RNA measurements that are <LLOQ (either TD or TND). 
  


 
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9.2.2.3    SVR24 defined as HCV RNA < LLOQ (either TD or TND) at 24 weeks 
after treatment discontinuation. Sample after 20 weeks after treatment 
discontinuation that is closest to the targeted time, not followed by any 
result ≥LLOQ, will be used. 
 
9.2.2.4    HCV RNA <LLOQ (either TD or TND) at post-entry scheduled visits, 
using the visit windows as defined in section 6. 
 
9.2.2.5 HIV-1 RNA > 50 copies/mL at all scheduled visits, using the visit 
windows as defined in section 6. 
 
9.2.2.6    Change in CD4+ cell count from study entry at subsequent scheduled 
visits, using the visit windows as defined in section 6. 
 
9.2.3 Exploratory Outcome Measures  
 
9.2.3.1    HCV resistance mutation at study entry. The set of mutations to be 
considered will be defined prior to analysis based on the latest 
information. 
 
9.2.3.2    Development of resistance mutation in SVR12 failures. 
 
9.2.3.3 Tenofovir area under the curve (AUC) at baseline (prior to study 
treatment initiation) and at week 4. 
 
9.2.3.4 SOF and LDV metabolite concentrations. 
 
9.3 
Randomization and Stratification 
 
The study is randomized to Arm A and Arm B and stratified by the cirrhosis status.  
Initially, 15 slots will be reserved for participants taking a PI/r and tenofovir regimen 
across the two study arms. This will be lifted 3 months after the study is open to accrual, 
so that the accrual progress is not constrained by the PK objective on tenofovir. 
 
The first 15 participants whose ARV regimen contains HIV PI/r plus tenofovir who enroll 
to the study must be willing to participate in PK sampling (pre-dose, hour 1 and hour 4) 
at weeks 0 and 4. After 15 such participants have contributed PK samples, participation 
in the tenofovir PK sampling is optional. Study accrual may conclude with fewer than 15 
participants whose ARV regimen contains HIV PI/r plus tenofovir, since the reservation 
of 15 slots will be lifted 3 months after the study is open to accrual. There is no minimum 
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9.4 
Sample Size and Accrual 
 
9.4.1 Sample Size of 20 per arm 
 
The sample size of 20 participants per arm is determined by feasibility. The team 
anticipates SVR12 of 90% for both regimens. Over 70% is deemed acceptable in 
the study population. Precision associated with the given sample size is 
described here.  
 
If the observed study proportion for SVR12 is 90% with 18 of 20 participants 
achieving SVR12, then the associated 90% confidence interval (CI) is (73.8%, 
96.6%). Hence, the 90% CI for the true SVR12 proportion will be entirely above 
70% if 18 or more of the 20 participants achieve SVR12.  Table 9-1 below shows 
that as a single arm evaluation of 20 participants, the width of the two-sided 90% 
CI varies from 32% to 12%, depending on the observed proportion. 
 
Table 9-1: Evaluation of Study Participants 
Observed SVR12 Proportion 
Two-Sided 90% CI* 
70% (14/20) 
(51.6%, 83.6%) 
75% (15/20) 
(56.8%, 87.3%) 
80% (16/20) 
(62.2%, 90.7%) 
85% (17/20) 
(67.8%, 93.8%) 
90% (18/20) 
(73.8%, 96.6%) 
95% (19/20) 
(80.4%, 98.9%) 
100% (20/20) 
(88.1%, 100%) 
 
* Wilson Confidence Interval 
 
No sample size adjustment is needed for loss to follow-up, because such 
participants are assumed to be SVR12 failures by definition. 
 
We anticipate accrual of 5-10 participants per month to complete enrollment 
under six months. Therefore, a two-stage design is not feasible. 
 
9.5 
Monitoring 
 
The study team will monitor accrual and availability of data and samples for key 
objectives and planned assays. In addition, the core study team will monitor routinely the 
renal toxicity events and HCV RNA results for evidence of virologic breakthrough. The 
DAIDS clinical representative will receive the standard toxicity summary report according 
to the schedule for phase I/II studies.  
 
The study will also be monitored by the ACTG Hepatitis SMC. The SMC will review the 
study six months after the study enrolls its first participant, or when about 40% of study 
participants, about 16 participants have the week 16 data, whichever occurs earlier. 
Because Arm A treatment duration is shorter at 12 weeks, the data will include end of 
treatment data and potentially some SVR4 data from Arm A participants. The SMC 
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request by the SMC or the study team. The SMC review will include accrual, retention, 
renal toxicity events, baseline characteristics, study conduct, data/specimen collection, 
AE summaries, HCV virologic failures, HIV-1 RNA virologic failures, CD4+ cell count, 
and modifications of study treatment and ARV regimens. A formal interim efficacy review 
of SVR12 is not planned, because much of study follow-up will be complete before 
participants reach SVR12, especially in Arm A, due to the anticipated accrual rate and 
the small study sample size. 
 
The details on reports, including purpose, contents, schedules and recipients, will be 
outlined in the Study Monitoring Plan (SMP) and reviewed by the study team and the 
SMC prior to study enrollment. 
 
9.6 
Analyses 
 
As a small study to provide supportive data on SVR12, precision is limited, and analyses 
related to HCV virologic response will be conducted with two-sided 90% CIs. This is 
noting that the lower limits of these two-sided CIs are equivalent to the limits in the 95% 
one-sided lower CIs. Analyses related to safety will be conducted with two-sided 95% 
CIs to be conservative. 
 
The primary objective will be addressed separately in Arms A and B. The proportion of 
participants within each study arm who achieve SVR12 will be estimated with a two-
sided Wilson CI. The analysis will be conducted as modified intent-to-treat (ITT) on 
participants who meet the eligibility criteria and initiate study treatment. Given the 
SVR12 definition, a tabulation of reasons for not achieving SVR12 (e.g., detectable HCV 
RNA, early treatment discontinuation, loss to follow-up) will be an important supplement 
to the primary analysis on SVR12. The primary analysis timeline will be driven by the last 
participant’s completion of the SVR12 visit, rather than the study completion date. 
Results from the primary analysis on SVR12 may be presented publicly - for example, at 
a conference – prior to study database finalization that includes SVR24 completion, 
when SVR12 data are complete. 
 
The secondary HCV virologic measures will also be analyzed with 90% two-sided Wilson 
CIs around the observed proportion in each study arm. 
 
The SVR 4, SVR12 and SVR24 differences between the two study arms will be 
evaluated with 90% two-sided CIs, using the Newcomb score (Wilson) methods. 
 
For the safety analysis, the proportion of participants with events as described in section 
9.2.1.2 will be summarized with 95% Wilson CIs around the observed proportions. The 
worst graded event per participant over time will be used. Descriptive tables 
summarizing the events and the number of participants experiencing the events will be 
provided by grade. Descriptive summaries will also be provided on the participants who 
discontinue the study treatment early, categorized by the reasons for discontinuation. 
HIV-1 RNA statuses (<50 copies/mL) and CD4+ T-cell count changes from baseline at 
scheduled visits will be summarized. The summary on HIV-1 and HCV virologic failures 
will be descriptive, and a listing will be provided with details including time of failure and 
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Given the small study sample size, evaluation of baseline predictors of SVR12 will be 
descriptive, and baseline characteristics (such as cirrhosis, prior treatment response, 
HCV genotype subtype, race, IL-28B, HCV resistance mutation, and ARV regimen) will 
be summarized by SVR12 status. 
 
Renal toxicity events will be described separately, and a listing will be provided with 
information on the time of failure, ARV regimen, and spot protein and creatinine results. 
 
Further details on the analyses will be provided in a separate Study Analysis Plan (SAP). 
See section 10 for the description of PK analyses. 
 
 
10.0 
PHARMACOLOGY PLAN 
 
10.1 
Pharmacology Objectives 
 
10.1.1 Determine the impact of LDV/SOF and RTV-boosted HIV protease inhibitor 
coadministration on the pharmacokinetics of tenofovir. 
 
10.1.2 Determine the association between LDV/SOF adherence and SVR12. 
 
10.2 
Pharmacology Study Design 
 
10.2.1 Participants taking TDF and a HIV PI/r as part of their ARV will undergo two PK 
visits to compare tenofovir PK before and after the addition of LDV/SOF. The first 
visit (entry) will occur prior to initiation of LDV/SOF, and the second visit will 
occur 4 weeks after initiating LDV/SOF. For these visits, participants will come in 
to the clinic approximately 24 hours after their previous dose of TDF and 
following an 8 hour fast. A blood sample will be obtained at pre-dose, participants 
will then take an observed dose of TDF (and LDV/SOF at week 4), and additional 
blood samples will be obtained at 1 and 4 hours post-observed dose. The 
participants will remain in the fasted state until after the 1-hour post-dose sample 
is collected. Whole blood collected in EDTA tubes will be spun down to plasma 
for quantification of tenofovir in plasma using a validated LC/MS-MS method at 
the Colorado Antiviral Pharmacology Laboratory. Tenofovir PK will then be 
compared before and after the addition of LDV/SOF. 
 
10.2.2 To determine the association between LDV/SOF adherence and SVR12, dried 
blood spot samples will be obtained from study participants at each on-treatment 
visit and one off-treatment visit for quantification of LDV and SOF metabolites. 
LDV and SOF metabolite concentrations will be determined using validated 
LC/MS-MS methods at the Colorado Antiviral Pharmacology Laboratory. The 
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10.3 
Pharmacology Sample Size Considerations  
 
In healthy volunteers, LDV/SOF increases tenofovir levels by 47% when administered as 
TDF/FTC/ATV/r versus TDF/FTC/ATV/r alone. LDV/SOF increases TFV between 50-
64% when administered with TDF/FTC/DRV/r versus TDF/FTC/DRV/r alone [17]]. We 
have powered the study to detect a 40% increase in tenofovir AUC 0-24h. We assume that 
the coefficient of variation (CV) for tenofovir is 30% (mean ± SD of TFV AUC 0-24 of 2.29 
± 0.69 mcg*hr/mL in the TDF prescribing information), within-participant correlation is 
0.5, and the AUC reported on the original scale has a log-normal distribution. Then an 
increase of 40% is equivalent to 0.34 on the loge scale, and the variance of the change 
on the log scale is 0.087 (SD=0.30). With 11 participants, there is 90% power to detect a 
40% increase as statistically significant in a within-participant analysis, in a 2-sided t-test 
on the log-transformed AUC with 5% type I error. We aim to collect PK samples from 15 
participants to yield evaluable data from at least 11 individuals receiving this 
combination.  However, because expeditious completion of the study is key, the study 
enrollment may be completed without the required number of participants on ritonavir-
boosted HIV protease inhibitor plus tenofovir. 
 
10.4 
Primary and Secondary Data, Modeling, and Data Analysis 
 
10.4.1 For Aim 1, tenofovir AUC will be determined using non-compartmental methods 
in Phoenix WinNonLin (Certara, Princeton, NJ). Tenofovir AUC will be compared 
before and after the addition of LDV/SOF using paired t-tests. 
 
10.4.2 For Aim 2, LDV and SOF metabolite steady state concentrations (Css) will be 
estimated for each participant using non-linear mixed effects modeling 
(NONMEM, ICON, Dublin, Ireland). Logistic regression will be used to determine 
the association between LDV and SOF metabolite Css and SVR12 with inclusion 
of additional clinical or demographic covariates as appropriate (e.g., cirrhosis 
status). 
 
10.5 
Anticipated Outcomes 
 
Through this study, we will determine the effect of concomitant LDV/SOF and RTV-
boosted HIV PI use on the pharmacokinetics of tenofovir in HIV/HCV coinfected 
individuals. These data are important for establishing the safety of LDV/SOF use in 
persons on TDF and a RTV-boosted HIV protease inhibitor. We will also explore the 
relationship between LDV/SOF concentrations and likelihood of SVR. These data are 
essential for providing context to our clinical findings.    
 
 


 
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11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Case report forms (CRF) will be provided for each participant. Participants must not be 
identified by name on any CRFs. Participants will be identified by the patient 
identification number (PID) and study identification number (SID) provided by the ACTG 
DMC upon (randomization/registration). 
 
11.2 
Role of Data Management 
 
11.2.1 Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
11.2.2 It is the responsibility of the ACTG DMC to 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, CRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
11.3.2  The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB, the site monitors, the NIAID, the OHRP, other 
agencies as part of their duties to ensure that research participants are 
protected, and the industry supporter or designee for confirmation of the study 
data. 
 
11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 Adverse Event Reporting to DAIDS 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at   http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
The DAIDS Adverse Events Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS. In the 
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submitted via the DAIDS EAE Form. For questions about DAERS, please contact 
DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also be sent 
from within the DAERS application itself. 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech-
res.com/safetyandpharmacovigilance/.  For questions about EAE reporting, 
please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
11.4.2  Reporting Requirements for this Study 
 
The SUSAR 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 LDV/SOF 
and RBV.  
 
11.4.3 Grading Severity of Events 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014, must 
be used and is available on the DAIDS RSC Web site at http://rsc.tech-
res.com/safetyandpharmacovigilance/gradingtables.aspx. 
11.4.4 Expedited AE Reporting Period 
 
 
The expedited AE reporting period for this study is the time of enrollment of 
the study participant until the study participant completes study follow-up. 
 
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 
HUMAN PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) 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 
parent, legal guardian, or person with power of attorney for participants who cannot 
consent for themselves, such as those below the legal age of consent). 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, 
parent, or legal guardian, and this fact will be documented in the participant’s record. 
 


 
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12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB, NIAID, OHRP, other 
government agencies as part of their duties to ensure that research participants are 
protected, or the industry supporter or designee.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB, NIAID, OHRP, other 
government agencies as part of their duties to ensure that research participants are 
protected, or the industry supporter 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter(s) prior to submission.  
 
 
14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  


 
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15.0 
REFERENCES 
 
1. 
Jensen DM, et al. Safety and efficacy of sofosbuvir-containing regimens for hepatitis c: 
real-world experience in a diverse, longitudinal observational cohort. (Abstract 45) In 
American Association for the Study of Liver Disease. 2014. Boston, MA. 
2. 
Hedskog C. Evolution of the HCV viral population from the one patient with S282T 
detected at relapse after sofosbuvir monotherapy. In International Workshop on HIV & 
Hepatitis Virus Drug Resistance and Curative Strategies. 2013. Toronto, Canada.  
3. 
Lawitz E, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without 
ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C 
virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet, 2014; 
383(9916):515-23. 
4. 
Osinusi A, et al. Sofosbuvir/ledipasvir in retreatment of hcv genotype-1 patients who 
previously failed sofosbuvir/ribavirin therapy. In EASL. 2014. London. 
5. 
Osinusi A, et al, Re-treatment of chronic hepatitis C virus genotype 1 infection after 
relapse: an open-label pilot study. Ann Intern Med, 2014;161(9):634-8. 
6. 
Gane EJ, et al. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in 
difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 
patients, and genotype-1 patients with prior sofosbuvir treatment experience. Abstract 06 
In 49th Annual Meeting of the European Association for the Study of the Liver. 2014; 
London, England.  
7. 
Wyles D, et al. Retreatment of patients who failed prior sofosbuvir-based regimens with 
all oral fixed-dose combination ledipasvir/sofosbuvir plus ribavirin for 12 weeks (Abstract 
235). In American Association for the Study of Liver Disease. 2014. Boston, MA. 
8. 
Bourliere M, et al. Ledipasvir/sofosbuvir fixed-dose combination is safe and efficacious in 
cirrhotic patients who have previously failed protease-inhibitor based triple therapy 
(Abstract LB-6). In American Association of the Study of Liver Disease. 2014. Boston, 
MA. 
9. 
Afdhal N, et al., Ledipasvir and sofosbuvir for previously treated HCV genotype 1 
infection. N Engl J Med, 2014. 370(16): 1483-93. 
10. 
Luetkemeyer A, et al., Clinical presentation and course of acute hepatitis C infection in 
HIV-infected patients. J Acquire Immune Defic Synd. 2006;41(1): 31-6. 
11. 
Bourliere M, et al. An integrated safety and efficacy analysis of >500 patients with 
compensated cirrhosis treated with ledipasvir/sofosbuvir with or without ribavirin 
(Abstract 82). In American Association of the Study of Liver Disease. 2014. Boston, MA. 
12. 
Dvory-Sobol H, et al. The prevalence of HCV NS5A, nucleoside and protease inhibitor 
resistance associated variants and the effects on treatment with ledipasvir/sofosbuvir ± 
RBV in the Phase 3 ION studies. International Workshop on Antiviral Drug Resistance. 
2014. Berlin, Germany. 
13. 
Gilead Sosfosbuvir Package Insert (August 2015 version). 
14. 
COPEGUS Package Insert. Summary of Product Characteristics. Roche Products 


 
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Limited, Welwyn Garden City, United Kingdom. Revised: January 2015. 
15. 
COPEGUS Package Insert. US Prescribing Information. Roche Laboratories Inc., 
Nutley, NJ. Revised: August 2015. 
16. 
Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alpha2b plus RBV 
for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for 
treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional 
Therapy Group (IHIT). Lancet 1998;352 (9138):1426-32. 
17. 
McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination 
with RBV as initial treatment for chronic hepatitis C: Hepatitis Interventional Therapy 
Group. N Engl J Med. 1998;339 (21):1485-92. 
18. 
Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for patients with chronic 
hepatitis C: results of a placebo-controlled study. J Hepatol. 1996;25 (5):591-8. 
19. 
Ribasphere (ribavirin, USP) Package Insert. US Prescribing Information. Manufactured 
by DSM Pharmaceuticals, Inc., Greenville, NC 27834 for Kadmon Pharmaceuticals, 
LLC., Warrendale, PA 15086. Revised February 2012. 
20. 
Gilead Harvoni Package Insert. Version March 2015.


 
 
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APPENDIX I 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
For protocol: A5348 
 
FINAL Version 1.0, 09/29/15: Phase II Trial of Retreatment Strategies for Difficult-to-Treat 
Hepatitis C Virus (HCV)-infected Individuals Who Have Failed Prior Direct Acting Antiviral 
(DAA)-based Regimens  
 
SHORT TITLE FOR THE STUDY: A5348 FINAL Version 1.0, 09/29/15, 12 weeks of Ledipasvir 
(LDV)/Sofosbuvir (SOF) with Weight-based Ribavirin vs. 24 weeks of LDV/SOF 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with HIV and 
the hepatitis C virus (HCV, a virus that affects the liver) and have been previously treated for 
HCV with a sofosbuvir-containing treatment that did not cure your HCV infection. This study is 
sponsored by the National Institutes of Health. The doctor in charge of this study at this site is: 
(insert name of Principal Investigator). Before you decide if you want to be a part of this study, 
we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
People who are infected with HCV have a great chance of being cured of the infection when 
they are treated with sofosbuvir. However, in some instances, treatment with sofosbuvir-
containing therapy does not work. It is not known if treating people with sofosbuvir again 
(retreatment) after it did not work the first time will work. There is an important need to 
understand retreatment options in those instances. This study is being done to see if two 
different regimens, ledipasvir with sofosbuvir and ribavirin for 12 weeks (Group A) and ledipasvir 
with sofosbuvir for 24 weeks (Group B) are well tolerated in HCV-infected persons where 
previous treatment with sofosbuvir failed. This study will also look at the safety of each regimen 
and how well the combination treatment of ledipasvir/sofosbuvir works in people who have 
cirrhosis (scarring of the liver) or HIV. 
 
 
HOW MANY PEOPLE WILL BE IN THIS STUDY? 
 
About 40 people (men and women age 18 years and older) will take part in this study. 
 


 
 
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HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for up to 48 weeks, depending on the group to which you are assigned.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to join this study, you will be assigned to either Group A or Group B, as shown 
below. Half of participants will be assigned to Group A and half will be in Group B. You will take 
ledipasvir/sofosbuvir (a pill taken once daily by mouth with food) and ribavirin (pills taken twice 
daily by mouth with food and at a dose based on your weight) if you are assigned to Group A 
until the end of treatment in Step 1. You will be given the medications at your study visits to take 
home, and you will need to store the medications in a safe place at room temperature. You will 
not take any ledipasvir/sofosbuvir or ribavirin during Step 2 of the study. 
 
You will continue taking your current anti-HIV drugs if you are receiving them. If you are not 
currently on HIV medications and your provider does not think you need HIV medications during 
the study that is also acceptable.  
 
Study 
Group 
Study Drugs 
Time on Study 
Drugs 
(STEP 1) 
End of 
Treatment/Followup 
(STEP 2) 
Group A 
ledipasvir/sofosbuvir 
+ribavirin 
12 weeks 
No study treatment – 
continue study follow-up 
for 24 weeks 
Group B 
ledipasvir/sofosbuvir 
24 weeks 
No study treatment – 
continue study follow-up 
for 24 weeks 
 
Everyone who enters the study will take ledipasvir/sofosbuvir (and for those in Group A, 
ledipasvir/sofosbuvir and ribavirin), which will be given for free by the study. Anti-HIV drugs will 
not be provided by the study. Note that if you stop taking ledipasvir/sofosbuvir, you must also 
stop taking ribavirin. 
 
While you are in this study, you will need to be seen in the clinic about 11 times (14 times for 
those in Group B) during the study. The longest visit could take up to 2 hours (up to 4 hours for 
the two pharmacokinetic [PK] (pharmacokinetic means an evaluation of medication levels) study 
visits, which are only required for some participants); however, the study staff will tell you about 
how long each visit could be. You may need to come to the clinic if you have side effects or if 
you switch or take new anti-HIV drugs. More information about the study tests is given below. 
During the study, you will get the results from any routine tests that are done during the study 
when they are available.  
 
You must fast for the entry, week 12, week 24 (if Group B), and early treatment/study 
discontinuation visits. If you are participating in the PK analysis, you will need to fast for the 


 
 
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week 4 visit as well. At the PK visits, you will be required to fast until after you have completed 
the 1 hour blood draw. (Fasting means that you cannot eat or drink anything for at least 8 hours 
before your visit. You may only drink water and take your prescription medications during this 
time. If your medications require food, the study staff will talk to you about how you should take 
your medications.) The study staff will remind you to fast before each of these study visits. If you 
do not fast before these visits, you will be asked to come back later for these tests, after fasting. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not qualify to take part in this study, we 
will still use some of your information. As part of the screening visit, some demographic (for 
example, age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
(for example, CD4+ T-cell count, viral load) information is being collected from you so that 
ACTG researchers may see if there are patterns or common reasons why people do not join a 
study. 
 
Required Blood Tests 
Your blood will be drawn from a vein in your arm and used to measure your HCV viral load (the 
amount of HCV in your blood) and genotype (genetic makeup of the HCV virus), to measure 
levels of certain hormones (hormones are chemicals in your blood), and for routine safety tests 
and metabolic tests (to test how your body uses the food that you eat). If you are a woman able 
to become pregnant, you will have a pregnancy test at the screening and entry visits. You will 
have blood drawn to measure your HIV viral load (the amount of HIV in your blood) and your 
CD4+/CD8+ cell counts (these are cells in your blood that fight infection).  You will be told the 
results of these tests when they become available.  
 
You will also have a test for IL-28B genotype; this is a genetic test to see if we can predict how 
well you will respond to HCV treatment. This marker is not currently standard of care, as it is not 
yet known if it is associated with better treatment response with current HCV treatments that do 
not contain interferon. 
 
Some of your blood will also be stored (with no information that will identify you) and used for 
future HCV and HIV resistance tests required for this study. A resistance test is used to 
determine if the HCV/HIV viruses still respond to your medications. In addition, some of this 
blood will be used to understand how the drugs interact with your body and how your body 
responds to the drugs.  
 
Any remaining blood will be stored for future testing required by the study. 
 
Genetic (the message in your DNA) testing 
If you agree, your blood will be drawn and used to examine different genes (pieces of your 
DNA). Results of testing done on these samples may not be given to you because they will be 
done in the future. 
 
Please initial below if you agree to have any of your blood used for ACTG-approved future 
unspecified genetic testing. You may change your mind at any time and your samples will be 
destroyed.  
 
________ YES                     ________ NO 
 


 
 
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Optional Tests 
If you agree, any blood left over after all required study testing is done may be stored (with no 
information that will identify you) and used for future ACTG-approved research. These blood 
samples may be stored for an unknown period of time. Results of testing done on these 
samples may not be given to you because they will be done in the future. 
 
Please initial below if you agree to have any of your leftover blood used for future ACTG-
approved research. You may change your mind at any time and reasonable efforts will be made 
to destroy your samples, though this may not always be possible.  
 
________ YES                     ________ NO 
 
A5348 Study Visits 
 
The study staff can answer any questions you have about individual study visits, the evaluations 
that will occur, or how long each visit will be. The table below can be used as a quick reference 
for you, along with the explanations that follow. 
 
I.  Study Schedule 
 
Evaluation or 
test 
Screening 
Entry
Post-Entry Visits 
Other 
Visits 
Early 
discontinuation 
STEP 1 
STEP 
2 
On-
treat-
ment 
Visits 
End of 
treatment 
Off-
treat-
ment 
Visits 
Consent 
 

 
 
 
 
 
 
Clinical 
assessments 
 
 
 
 
 
 
 
 ECG  
 
 
 
 
 
 
 
 
Samples 
collection & 
laboratory 
testing 
 
 
 
 
 
 
 
 
Urine sample (if 
applicable) 
 


 
 
 
 

Pregnancy test 
(if applicable) 


 
 
 
 
 
Pharmacokinetic 
(PK) studies 
(if applicable) 
 
 
 
 
 
 
 
Pregnancy 
prevention 
counseling  
 
 
 
 
 
 
 
Adherence 
 
 

 
 
 
 


 
 
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Evaluation or 
test 
Screening 
Entry
Post-Entry Visits 
Other 
Visits 
Early 
discontinuation 
STEP 1 
STEP 
2 
On-
treat-
ment 
Visits 
End of 
treatment 
Off-
treat-
ment 
Visits 
assessments 
Study drugs 
distribution and 
storage 
 
 
Every 4 weeks 
 
 
 
Medication 
Diary 
 

 
 
 
 
 
 
II.  Description of Study Visits 
 
Screening 
After you have read and signed the consent form, you will be asked questions about your 
health, medical history, and medication history. You will have several tests, including blood 
tests, to make sure that you qualify to join the study. You will have your height and weight 
recorded. 
 
Some of the blood taken will be shipped to a testing lab. Your HIV infection status will be 
evaluated; your HCV infection and how long you’ve been infected will be confirmed. Also, an 
electrocardiogram (ECG) will be done at this visit. 
 
If you are a woman able to become pregnant, you will have blood taken for pregnancy 
testing.  
 
Entry 
When all of the results from your screening tests are available, you will come back to the 
clinic to have a few tests done before starting the study. You must come in fasting. If you are 
not fasting within the past 8 hours before this visit, you will be asked to come back fasting. 
Your HCV treatment status will be documented. You will be asked about your health and 
medication history. You will have urine and blood samples collected for routine safety tests 
and for some required blood tests (as listed above). For research purposes, you will have 
some blood drawn for a genetic test to see if we can predict how well you will respond to 
HCV treatment (this is called an IL-28B genotype test). 
 
If you are a woman able to become pregnant, you will be asked to provide a blood sample 
for pregnancy testing.  
 
At this visit, you will be given a medication diary and your study drugs. You will be asked to 
record your medications and any reactions in the medication diary. This diary will be 
collected. The study staff will give you enough study drugs to last four weeks; you will be 


 
 
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asked to come in every four weeks to receive more medications. You should take ribavirin (if 
applicable) and ledipasvir/sofosbuvir with food. If you are required to fast before a visit, the 
study staff will discuss with you how to take your medication. At each visit, you must return 
any remaining study drug from the previous visit. If you forget to take ledipasvir/sofosbuvir at 
the correct time, it may be taken later in the day; however, no more than a single daily dose 
(90 mg dose ledipasvir/400 mg dose of sofosbuvir) of ledipasvir/sofosbuvir should be taken 
on any calendar day. You should never cut or split your study medications. If you miss a 
dose of ribavirin, then you should take the missed dose as soon as possible with food during 
the same day. If an entire day has gone by, then you should skip the missed dose, and then 
you should go back to your normal dosing schedule. Do not double the next dose in order to 
"make up" what has been missed. 
 
Pharmacokinetic Evaluation at Entry: 
If you are taking part in the PK testing, and are taking an HIV ritonavir-boosted protease 
inhibitor and tenofovir as part of your HIV regimen, you will have an extra evaluation (PK 
testing) done at the entry visit. You will have blood drawn several times for PK testing, to 
provide a baseline measure of how the drug interacts with your body and how your body 
responds to the drug. You will have blood drawn at the beginning of this visit. You will be 
administered your HIV medications. Additional blood samples will be obtained at 1 and 4 
hours after your observed dose of HIV medications. 
 
Post-entry visits 
Participants assigned to treatment Group A: You will be seen at treatment weeks 1, 2, 4, 8, 
and 12. 
 
Participants assigned to treatment Group B: You will also be seen at treatment weeks 1, 2, 
4, 8, 12, and every 4 weeks for an additional 12 weeks. 
 
All participants will be seen at post-treatment weeks 4, 12, and 24 after taking the last dose 
of study drugs. These visits will last about 1-1 ½ hours each. 
 
You will have urine and blood samples collected for routine safety tests and for some 
required blood tests (as listed above). If you are a woman able to become pregnant, you will 
be asked to provide a urine sample for pregnancy testing. You will have your weight 
measured and you will be asked about your health and any changes in your medicines since 
your last visit. You will be asked how well you are taking your medications. You will have 
blood drawn several times for PK testing. It is recommended that you use your medication 
diary to note any reactions after the PK testing. This diary will be collected at each study 
visit. 
 
Other visits 
During the study, you may have to come back to the clinic for extra visits for testing of any 
laboratory results that are not normal, or to follow-up on a specific side effect or symptom. 
 
Virologic Failure Confirmation 
If laboratory tests show there is evidence of virologic failure (which is detectable HCV or HIV 
when your levels were previously not detected or your virus has not gone down as quickly 
as expected), you will be asked to come back to the clinic to confirm your lab results. If 
virologic failure for HCV is confirmed, you will be asked to stop taking the 
ledipasvir/sofosbuvir and be followed in Step 2 as described above. If virologic failure for 


 
 
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HIV is confirmed, you will continue to be followed on study, if an HIV regimen that works well 
with ledipasvir/sofosbuvir is available. If there are no HIV regimens available that work well 
with ledipasvir/sofosbuvir, you will be asked to stop taking ledipasvir/sofosbuvir and be 
followed, as described above. 
 
Early discontinuation 
There are two types of discontinuation (stopping study treatment or leaving the study early) 
in which you will be asked to come to the clinic for an extra visit in a fasting state. 
 
1. Stop study treatment early 
You or your doctor may decide to stop the study medication that you began at entry. 
 
If you must stop taking the study medication early, the study doctor may ask you to stay 
in the study and come in for some tests. 
 
2. Leave study early 
You or your doctor decides that you will no longer stay in the study or you are notified 
the study is stopped early. You will be asked to complete some evaluations before being 
taken off the study.  
 
III.  Description of Study Evaluations 
 
Consent 
After you read the consent form and have had a chance to ask questions about the study, 
you will sign the consent form if you want to continue to be tested to see if you qualify for the 
study. 
 
Clinical Assessments 
You will have the following clinical evaluations in this study: 
 
Physical examination 
You will have a physical exam. At screening, the study staff will check the different 
systems in your body such as head, neck, eyes, ears, nose, throat, mouth and tongue, 
chest (excluding breasts) for respiratory, heart for cardiovascular, abdomen, skin, hair, 
nails, and muscles and joints. The study staff will also check your vital signs such as 
temperature, pulse, blood pressure, and respiratory rate, and your height and weight will 
be recorded. At each following visits, the physical exam will be more limited and based 
on symptoms or problems that you are experiencing. You will have your weight recorded 
at every visit. 
 
 
Medical and medication history 
You will be asked questions about your health and about any medicines you have taken 
or are taking now. Once you are on treatment, you will be asked about any signs or 
symptoms that you are experiencing and any changes in other medications that you 
have had since your last visit.  
 
 
Electrocardiogram 
You will have an electrocardiogram (ECG) done. An ECG is a test to measure the 
heartbeat. An ECG machine will be used to do an electrical tracing of your heart that can 


 
 
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show how hard it is working. You will have to lie very still for at least 5 minutes while the 
ECG is being done. 
 
Sample collections and laboratory testing 
You will have the following samples collected and tested in this study: 
 
Blood collected 
Blood will be taken from a vein in your arm for various tests during the study. 
Approximately 144 mL (10 tablespoons) of blood will be drawn during any study visit. 
These may include: routine safety lab tests such as kidney and liver function, HIV viral 
load (a test that shows how much HIV is in your blood), CD4+/CD8+ counts (a test that 
shows how many infection-fighting cells you have in your blood), HCV viral load (a test 
that shows how much HCV is in your blood).  
 
You will be asked to fast before some of the visits. This means that you should not eat or 
drink anything except prescription drugs and water for at least 8 hours before the visit. 
 
Resistance testing 
Blood will be drawn and stored for future HCV/HIV resistance testing that is required for 
this study. A resistance test is used to determine if the HCV/HIV viruses still respond to 
your medications.  
 
Stored urine 
Urine will be collected for the evaluation of proteins. You will not receive the results of 
these studies. 
 
Genetic testing 
Blood will be drawn for testing your genes (pieces of your DNA) to understand if you 
naturally were born with a better or worse chance of responding to the medications. This 
is called an IL-28B genotype test. Some of your blood cells will also be tested to see if 
your responsiveness to the therapy is associated with different genes related to 
interferon (IFN) use. An IFN is an antiviral compound that is produced in response to 
many types of infections. You will not receive the results of these studies. 
 
PK Studies 
Blood will be drawn to measure the levels of the study drugs in your blood and to 
understand how the drugs interact with your body and how your body responds to the 
drugs.  
 
Blood sample PK (for some participants only) 
If you are taking tenofovir and an HIV ritonavir-boosted protease inhibitor (atazanavir or 
darunavir) and you give permission to participate in the PK evaluation, you will have 
blood collected three times at each of two visits, which will last 4 hours each. The PK 
samples will be used to measure the levels of the HIV medicines (first PK visit and week 
4) and study drugs (week 4 only) in your blood since there is limited information 
available about the interaction between tenofovir, HIV protease inhibitors and the study 
drugs. You will not take your study medications or HIV medications that morning until 
you arrive at the clinic and are instructed to do so. Your visit will last 4 hours total.   
 


 
 
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You will be given a medication diary to write down when you take your last three doses 
of HIV and HCV medications before the PK visits.  
 
Urinalysis 
Urine samples will be collected for routine safety tests. Some urine will be stored to look 
at markers of kidney function and how these may change during treatment. 
 
Pregnancy test 
If you are a woman who is able to become pregnant, you will have blood taken prior to 
study entry. After you enter the study, you will be asked to provide urine samples for 
pregnancy testing. 
 
Pregnancy prevention counseling 
All participants, male and female, will be counseled on the risk of the study drugs in 
pregnancy and on how to prevent pregnancy.  
 
Adherence assessments 
You will be asked about how well you take your medications and the staff will count the 
number of pills in your medication bottles. The study staff will give you information and 
encouragement to help you take your medications as prescribed. 
 
Study drugs distribution and storage 
You will be given a 4-week supply of study medications at entry and additional medications 
will be given every 4 weeks. You will be asked to store the study medications as instructed 
in the medicine bottle label.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
 
The study is cancelled. 
 
You start taking HCV treatment not provided by the study. 
 
A Study Monitoring Committee (SMC) recommends that the study be stopped early (A SMC 
is an outside group of experts who monitor the study). 
 
Your doctor thinks the study is no longer in your best interest. 
 
The site investigator thinks that you are at significant risk of failing to comply with the 
requirements of the protocol.  
 
The study doctor may also need to take you off the study drugs without your permission if: 
 
 
You continue to experience HCV treatment failure. 
 
You or a female partner of a male participant become pregnant. 
 
You are breastfeeding. 
 
Continuing the study drugs may be harmful to you. 
 
You need a treatment that you may not take while on the study. 
 
You are not able to take the study drugs as required by the study. 
 
You do not have, or are not able to, have required study visits and evaluations. 
 


 
 
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If you must stop taking the study drugs earlier than indicated by the study, the study doctor will 
ask you to remain on the study and complete the post discontinuation visits. 
 
NOTE: For those in Group A, if you stop taking ledipasvir/sofosbuvir , you must also stop taking 
ribavirin. 
 
If I have to permanently stop taking study drugs through the study, or once I leave the study, 
how can I get study drugs? 
 
If you must permanently stop taking ledipasvir/sofosbuvir and ribavirin before the study is over, 
the study staff will talk with you about other options. 
 
After you have finished the study, you will not be able to get ledipasvir/sofosbuvir and ribavirin 
through the study. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, it is 
possible that others could find out that you are participating in this study and that social harm 
may result (because you could become labeled as being infected with HIV and/or HCV). For 
example, you could be treated unfairly or discriminated against by family members, friends, 
and/or the community. 
 
Risks of Drawing Blood 
Drawing blood may cause some discomfort, lightheadedness, bleeding, swelling, or bruising 
where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risks of Study Drugs 
Drug interactions that increase the levels of medicine in your blood may increase the chances of 
side effects. Drug interactions that lower the levels of HIV medicines in your blood could cause 
drug resistance, meaning the drugs no longer work to prevent virus from reproducing. Drug 
interactions that lower the levels of sofosbuvir or ledipasvir in your blood may decrease your 
chances for a cure of hepatitis C and/or cause drug resistance. 
 
For those persons taking HIV medicines, there is no clear risk of drug interactions between HIV 
medicines and sofosbuvir. Although sofosbuvir has not been studied with all HIV medicines, it 
has been studied with all first-line HIV medication drug classes and there are no recognized 
clinically significant interactions. This is also true for ledipasvir with the exception of one of the 
HIV medications named tenofovir. Ledipasvir increases tenofovir levels in your body. With most 
other HIV drug combinations this increase is not felt to lead to significant risk unless your 
kidneys don’t work normally. However, if tenofovir and ledipasvir are used with HIV protease 
inhibitors that are combined with ritonavir, (which is used to increase the level of your HIV drugs 
in your blood stream), the potential risk of kidney toxicity may be higher. The combination of HIV 
protease inhibitors and ledipasvir and tenofovir has not been studied in HIV-infected patients. 
For this reason there will be monitoring of the kidney function for all participants in this study. 
 
Drug resistance may prevent other medicines developed for hepatitis C from working in the 
future. HIV viral load will be monitored regularly to ensure that evidence of early failure of the 


 
 
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HIV regimen is identified quickly. In addition, multiple drug interactions studies have been 
completed to ensure that HIV medications can be safely dosed with sofosbuvir, and there is no 
evidence to suggest that giving sofosbuvir or ledipasvir and any antiretroviral allowed in this 
study will lead to HIV regimen failure. The risk is thought to be very low. To date only two out of 
over 3,000 patients have developed resistance to sofosbuvir, so this risk is also thought to be 
extremely low. Risk of resistance to ledipasvir is high for patients who fail therapy, with most 
patients developing resistance. At this time the effect of resistance to ledipasvir or similar 
medications is not clear, but it may increase the risk of other HCV treatments not working. 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning study drug side effects please ask the medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Ledipasvir/sofosbuvir   
 
Depression  
 
Irritability 
 
Sleep disturbances 
 
Tiredness 
 
Muscle pain 
 
Headaches 
 
Chills 
 
Nausea and vomiting 
 
Stomach pain 
 
Rash 
 
Anemia (low red blood cell levels). Anemia can worsen existing heart and pulmonary (lung) 
conditions. 
 
Lymphopenia (low white blood cell levels) 
 
Itching 
 
Loss of appetite 
 
Diarrhea 
 
Dizziness 
 
Temporary changes in liver function tests (a measure of your liver activity) 
 
NOTE: Some of the side effects associated with ledipasvir/sofosbuvir may be seen more 
frequently when ledipasvir/sofosbuvir is given with ribavirin. 
 
Ribavirin  
 
Anemia (low red blood cell levels). Anemia can worsen existing heart and pulmonary (lung) 
conditions.  
 
Temporary changes in blood platelet levels  
 
Temporary changes in liver function tests (a measure of your liver activity) 


 
 
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 
Stomach and intestinal 
 
Nausea 
 
Vomiting 
 
Indigestion 
 
Stomach discomfort 
 
Skin disorders 
 
Upper respiratory tract inflammation, including cough and trouble breathing (dyspnea)  
 
Teratogenicity (risk to an unborn baby) 
 
Nervous system 
 
Depression 
 
Insomnia (inability to sleep) 
 
Nervousness 
 
Skin tingling 
 
Drowsiness 
 
Light-headedness 
 
Irritability 
 
Hyperuricemia (excess of uric acid in blood which can lead to gout, a painful swelling of 
joints and may lead to kidney disease). 
 
Headache 
 
Fatigue 
 
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. 
 
 
ARE THERE RISKS RELATED TO DELAYING HIV THERAPY? 
 
You are not required to be on HIV medications to enter this study. If you are not on HIV 
medications at the time of your HCV infection and you and your doctor do not think you need to 
start HIV medications, we will not exclude you from the study. We also do not recommend 
delaying HIV medications for entry into the study if your doctor feels they are medically 
necessary. Although the dosing period of the HCV medications is short, a delay in necessary 
HIV medications could allow for progression of HIV disease, which can increase your risk of 
opportunistic infections and long-term after effects of HIV infection. If you have any concerns 
about these risks, we suggest that you discuss them with your medical provider. 
 
 


 
 
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ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drugs or drug combinations in this study may be unsafe for unborn babies. If you are having 
sex that could lead to pregnancy, you must agree not to become pregnant or make a woman 
pregnant. Note that if you become pregnant or your partner becomes pregnant, study drugs will 
be stopped and you will be followed after delivery. 
 
Because of the risk involved, you and your partner must use at least two methods of birth 
control that you discuss with the study staff. You must continue to use both methods until 6 
months after stopping study drugs. You must choose two or more of the birth control methods 
listed below: 
 
 
A condom (male or female) with or without a spermicide 
 
Diaphragm or cervical cap with spermicide 
 
An intrauterine device (IUD) 
 
Tubal ligation 
 
Hormone-based contraceptives  
 
If you can become pregnant, you must have a pregnancy test within 48 hours before starting the 
study. The test must show that you are not pregnant. Pregnancy tests will also be performed at 
most study visits. 
 
Some of the methods listed above may not prevent the spread of HIV to other people. You 
should discuss your contraceptive choices with your health care provider to choose the best 
way for you to both prevent pregnancy as required by this study and to prevent the spread of 
HIV to your partner.  
 
If you think you or your partner may be pregnant at any time during the study, tell your study 
staff right away. Pregnancy will result in immediate discontinuation of the study drugs, and start 
of counseling on RBV’s ability to cause birth defects. You will be followed on study, including 
male participants whose partners become pregnant, until study completion. You will be asked to 
return to the clinic 6 months after the end of your pregnancy to follow up on any side effects. 
Male participants whose partners become pregnant will have treatment discontinued and the 
same followup visit at 6 months after their partner’s delivery as outlined for pregnant women. 
Pregnancies will be reported to the RBV Pregnancy Registry. In addition, pregnancy 
complications and/or pregnancies outcomes will be reported to the Antiretroviral Pregnancy 
Registry.  
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you. You may be cured of your 
hepatitis C infection. Your health may be watched more closely than usual while you are on the 
study, which may help you to feel better. It is also possible that you may receive no benefit from 
being in this study. Information learned from this study may help others who have HIV and HCV. 
 
 


 
 
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WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, you have the choice of: 
 
treatment with prescription drugs currently available to you 
 
treatment with other experimental drugs, if you qualify  
 
no treatment; some people may clear the HCV infection on their own over the first year of 
infection, although this is uncommon. Most (9 in 10) people who clear HCV infection without 
treatment do so in the first 12 weeks of the new infection. 
 
Please talk to your doctor about these and other treatment choices available to you and the 
risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the U.S. Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally.   
 
People who may review your records include the ACTG, Office for Human Research Protection, 
your site’s institutional review board (a committee that makes sure that your rights and safety 
are protected while in the study), National Institutes of Health (NIH), study staff, study monitors, 
and other government agencies as part of their duties, and the pharmaceutical company 
supporting this study. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
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. [Sites: Per US 
federal regulations, this language cannot be modified.] 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drugs, the study visits, physical examinations, 
laboratory tests or other tests required by the study. You or your insurance company, or your 
health care system will be responsible for the costs of your regular medical care as well as for 
the costs of drugs not given by the study.  
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study.   
 
 


 
 
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WILL I RECEIVE ANY PAYMENT? 
 
[Sites: Please indicate whether you will provide payment to participants. If so, please describe 
the amount to be paid or reimbursed, the payment schedule, and any prorated schedule should 
the participant decide to withdraw or is withdrawn early by the investigator.]  
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of taking part in this study, you will be given treatment right away 
for your injuries and be referred for further treatment, if necessary. However, you or your 
insurance company may have to pay for this care. There is no program for compensation either 
through this institution or the NIH. You will not be giving up any of your legal rights by signing 
this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 
you decide not to take part. Your decision will not affect other studies done by NIH in which you 
may be taking part, and will not lead to any penalty or loss of benefits that you have the right to 
expect.   
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or decision to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
 
name of the investigator or other study staff 
 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
 
telephone number of above 


 
 
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SIGNATURE PAGE ACTG Study A5348 
 
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’s 
Legal Representative’s Signature and Date 
Name (print) (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: 
This is ACTG A5348 SAP Version 2.0 with names of authors, names of publication 
writing team members and analysis timeline redacted. 
 
ACTG A5348 
 
Phase II Trial of Retreatment Strategies for Difficult-to-Treat  
Hepatitis C Virus (HCV)-infected Individuals Who Have Failed  
Prior Direct Acting Antiviral (DAA)-based Regimens 
 
ClinicalTrials.gov Identifier: NCT02605304 
 
 
Statistical Analysis Plan  
Version 2.0 
 
Version 1.0 December 18, 2015 
Version 2.0 January 19, 2017 
 
 
 
 


A5348 Statistical Analysis Plan V2.0 2017 
2 
 
Table of Contents: 
1 
Introduction ............................................................................................................................................. 4 
2 
Study Overview ........................................................................................................................................ 4 
2.1 
Study Design ............................................................................................................................................ 4 
2.2 
Study Treatment ...................................................................................................................................... 5 
2.3 
Study Treatment Discontinuation According to HCV Virologic Response ................................................ 5 
2.4 
Hypotheses............................................................................................................................................... 6 
2.5 
Study Objectives ....................................................................................................................................... 6 
2.5.1 
Primary Objectives ........................................................................................................................... 6 
2.5.2 
Secondary Objectives ....................................................................................................................... 6 
2.6 
Visit and evaluation schedule .................................................................................................................. 7 
2.7 
Monitoring ............................................................................................................................................... 7 
2.7.1 
Ongoing Team Monitoring ............................................................................................................... 7 
2.7.2 
SMC Reviews .................................................................................................................................... 7 
2.8 
General Data Analysis Considerations ..................................................................................................... 8 
2.9 
Statistical Methods .................................................................................................................................. 8 
3 
Components in the Reports ...................................................................................................................... 9 
3.1 
SMC Review Reports ................................................................................................................................ 9 
3.2 
Final Primary Analysis Report and SVR24 Supplement ............................................................................ 9 
4 
Description of Components ...................................................................................................................... 9 
4.1 
Administrative and Baseline Characteristics .......................................................................................... 10 
4.1.1 
Study History .................................................................................................................................. 10 
4.1.2 
Accrual ........................................................................................................................................... 10 
4.1.3 
Eligibility Violations and Registration Errors .................................................................................. 10 
4.1.4 
Baseline Characteristics ................................................................................................................. 10 
4.1.5 
Study Treatment Status and Duration of Treatment ..................................................................... 11 
4.2 
Safety ..................................................................................................................................................... 11 
4.2.1 
Adverse Events and Protocol-Required Laboratory Tests ............................................................. 11 
4.2.2 
Pregnancy ...................................................................................................................................... 12 
4.2.3 
Deaths ............................................................................................................................................ 12 
4.2.4 
HIV-Related Measures and Changes in ARV Regimen ................................................................... 12 
4.2.5 
Virologic Failures ............................................................................................................................ 12 
4.3 
Primary Objectives ................................................................................................................................. 13 
4.3.1 
SVR12 ............................................................................................................................................. 13 
4.3.2 
Safety ............................................................................................................................................. 14 
4.4 
Secondary Objectives ............................................................................................................................. 14 


A5348 Statistical Analysis Plan V2.0 2017 
3 
4.4.1 
Tenofovir PK ................................................................................................................................... 14 
4.4.2 
HCV Virologic Responses ............................................................................................................... 15 
4.4.3 
Development of HCV Resistance Mutations .................................................................................. 15 
4.4.4 
HIV RNA and CD4+ Cell Counts ...................................................................................................... 16 
 
 
 


A5348 Statistical Analysis Plan V2.0 2017 
4 
 
1 
Introduction 
This document describes the proposed content for the interim review reports and the primary 
statistical analysis report for ACTG study A5348, focusing on analyses that address the safety and 
HCV virologic outcome measures.  The plan includes the key analyses that will form the core of any 
presentation or publication used to disseminate the primary conclusions of the study.  It also includes 
analyses in interim reports for the Study Monitoring Committee (SMC) while the study is ongoing and 
describes the components shared with the Study Chairs in open interim reports.  It is recognized that 
this statistical analysis plan (SAP) may be modified by the Study Team as new information becomes 
available or to reflect recommendations made by the SMC.   
SAP Version 2.0: The study closed to accrual prematurely on July 21, 2016 due to the enrollment 
challenges. The SAP version 2.0 removes analysis components that are no longer feasible or 
applicable based on 7 study participants, and it updates planned analyses. The final analysis report 
will be descriptive, with the goal of contributing to the sponsor company’s (Gilead’s) manuscript on a 
similar clinical trial. 
 
2 
Study Overview 
2.1 
Study Design 
A5348 is a prospective, phase II, open-label study to evaluate 12-week and 24-week regimens of 
ledipasvir(LDV)/sofosbuvir(SOF) for retreatment of HCV among individuals with prior treatment failure, 
with the addition of ribavirin (RBV) to the 12-week regimen.   
Study population is HCV genotype 1 infected participants, co-infected with HIV, who have previously 
experienced HCV virologic failure on SOF-based treatment, including SOF/RBV +/- pegylated 
interferon (PEG) and SOF/simeprevir (SIM).  For the HIV infection, the participants can be on a stable 
protocol-approved ARV regimen (efavirenz, rilpivirine, raltegravir, dolutegravir, tenofovir, abacavir, 
3TC/FTC, RTV-boosted atazanavir, RTV-boosted darunavir), or they may not be on ARVs. 
Participants will be randomized (1:1) to the two study arms, stratified by cirrhosis status. 
Arm A:  12 weeks of LDV/SOF with RBV (N=20) 
Arm B:  24 weeks of LDV/SOF (N=20) 
 
The study is randomized because there is clinical equipoise on the benefits and drawbacks in the two 
study regimens.  The study is not designed to be powered for comparison between the randomized 
arms. 


A5348 Statistical Analysis Plan V2.0 2017 
5 
All participants receive study treatment for up to 12 or 24 weeks (Step 1) depending on the study arm 
and HCV virologic response (Section 2.3).  The treatment period (Step 1) is followed by 24 weeks of 
observation (Step 2).  
 
* Includes discontinuation due to confirmed HCV virologic failure (VF). 
# Arm A participants complete study treatment at Week 12 and register to Step 2. 
+ Step 1 visits at Weeks 16, 20 and 24 are for Arm B participants only.  Arm B participants complete treatment at 
Week 24 and register to Step 2. 
 
SAP Version 2.0: The study closed to accrual after 7 participants in the study.  All 7 participants will complete 
follow-up as described in the protocol. 
2.2 
Study Treatment 
Arm A: LDV 90 mg/SOF 400 mg fixed dose tablets QD with weight-based RBV (1000 mg/day for 
weight < 75 kg, 1200 mg/day for weight ≥ 75 kg) for up to 12 weeks depending on the HCV virologic 
response 
Arm B: LDV 90 mg/SOF 400 mg fixed dose tablets QD for up to 24 weeks, depending on the HCV 
virologic response 
2.3 
Study Treatment Discontinuation According to HCV Virologic Response 
Study treatment will be discontinued in participants who experience confirmed HCV virologic failure 
(VF) defined as follows. 
a) Confirmed increase in HCV RNA to ≥LLOQ if HCV RNA previously declined to <LLOQ (target 
detected or not detected).  
b) Confirmed ≥1 log10 IUmL HCV RNA increase from HCV viral load nadir. 
c) Confirmed HCV RNA ≥LLOQ at week 8 visit. 
Confirmatory HCV RNA sample should be obtained as soon as possible and no more than 2 weeks 
after receiving initial HCV RNA result.  HCV RNA measurement to confirm failure will be performed in 


A5348 Statistical Analysis Plan V2.0 2017 
6 
real time at the designated laboratory and the results will be provided to the site investigators within 
two weeks of specimen receipt.  Participants who experience confirmed HCV VF will discontinue study 
treatment and are followed on-study/off-treatment for 24 weeks post treatment discontinuation (Step 
2). 
2.4 
Hypotheses 
1. The study regimens (12 weeks of LDV/SOF/RBV and 24 weeks of LDV/SOF) will each result 
in estimated SVR12 of 90%, when used for HCV retreatment after sofosbuvir failure. 
2. Twelve weeks of LDV/SOF/RBV and 24 weeks of LDV/SOF will be safe and well-tolerated. 
2.5 
Study Objectives  
2.5.1 
Primary Objectives  
1. To assess the proportion of participants who attain SVR12 in each study arm 
2. To evaluate safety and tolerability of each study regimen  
2.5.2 
Secondary Objectives  
1. To assess the impact of LDV/SOF and HIV PI/r coadministration on the pharmacokinetics 
(PK) of tenofovir. 
2. To assess the impact of LDV/SOF and RTV-boosted HIV PI coadministration on any 
associated clinical events attributed to elevated tenofovir levels, including renal toxicity 
(defined as the development of ≥Grade 2 renal dysfunction or development of new or 
worsened proteinuria or glucosuria).  
3. To assess the proportion of participants who attain SVR4 (i.e., SVR 4 weeks after stopping 
HCV antiviral therapy) and SVR24 (i.e., SVR 24 weeks after stopping HCV antiviral therapy) in 
each study arm.  
4. To evaluate baseline predictors of SVR12, including cirrhosis, prior treatment response 
(relapse, partial response, null responder), HCV genotype 1a vs. 1b, race, and IL-28B status. 
5. To evaluate the association between LDV/SOF adherence and SVR12 in both study arms. 
6. To evaluate the impact of baseline HCV resistance mutations on the SVR12 attained with 
retreatment with LDV/SOF (+/- RBV).  
7. To evaluate emergence of HCV resistance mutations in participants who fail to attain SVR12 
with retreatment with LDV/SOF (+/- RBV). 
8. To evaluate kinetics of HCV RNA during treatment (weeks 1, 2, 4, 8, 12, and in Arm B weeks 
16, 20, and 24) and 4, 12, and 24 weeks after treatment discontinuation. 
9. To assess the influence of LDV/SOF based retreatment on HIV-specific parameters, including 
maintenance of HIV-1 RNA < 50 copies/mL for participants on antiretrovirals and CD4+ cell 
count during treatment.  
10. To evaluate the differences in SVR12 among participants receiving specific antiretroviral 
therapy (ARV) regimens compared to those taking no ARV. 
11. To compare the SVR12 proportions, safety, and tolerability in the two study arms. 


A5348 Statistical Analysis Plan V2.0 2017 
7 
SAP Version 2.0: As a result of the early enrollment closure, the final analysis report will be descriptive 
and consist primarily of listings of endpoints related to each objective. Secondary Objective 1 will not 
be included in the primary analysis report, because the PK data will be analyzed separately by the 
study pharmacologist, who may develop a joint report with PK data obtained outside of A5348. 
2.6 
Visit and evaluation schedule 
Analyses by study week will use the visit windows provided in the protocol schedule of events 
(Protocol Section 6.1 Schedule of Events). 
Arm A 
 
 
Entry 
Step 1: On-Treatment Visit Week 
Step 2: Post-Treatment Visit Week  
1 
2 
4  
8 
12 
R+4 
R+12 
R+24 
Days 
0 
4-10 
11-17 
21-35 
49-63 
77-91 
R+23 to 
R+35 
R+79 to 
R+98 
R+161 or later 
R= Date of Last Dose of Study Treatment from the Study Treatment Record CRF 
Arm B 
 
 
Entry 
Step 1: On-Treatment Visit Week 
Step 2: Post-Treatment Visit 
Week  
1 
2 
4  
8 
12 
16 
20 
24 
R+4 
R+12 
R+24 
Days 
0 
4 -
10 
11 -
17 
21 -
35 
49 -
63 
77 -
91 
105 - 
119 
133 - 
147 
161 -
175 
R+23 to 
R+35 
R+79 to 
R+98 
R+161 
or later 
R= Date of Last Dose of Study Treatment from the Study Treatment Record CRF 
2.7 
Monitoring 
The study is monitored by the core team (study chairs and medical officer) to review the renal toxicity 
events and HCV RNA results for evidence of virologic breakthrough, and by the ACTG Hepatitis Study 
Monitoring Committee (SMC) to conduct full reviews of study data.  The SMC review is planned to 
occur at least annually, or upon request by the SMC or the study team.  A formal interim review of 
SVR12 by the SMC is not planned, because much of study follow-up will be complete before 
participants reach SVR12, especially in Arm A, due to the anticipated accrual rate (5-10 per month to 
complete enrollment under 6 months) and the small study sample size. 
2.7.1 
Ongoing Team Monitoring 
The core study team will review the renal toxicity events and HCV RNA results on a frequent, routine 
schedule.  The core team will also review routinely availability of data samples for key objectives and 
planned assays.  The study team will monitor accrual.   The Study Monitoring Plan (SMP) describes 
team monitoring reports. 
2.7.2 
SMC Reviews 
The SMC will review the study six months after the study enrolls its first participant, or when about 
40% of the study participants (about 16 participants) have the week 16 data, whichever occurs earlier.  
Because Arm A treatment duration is shorter at 12 weeks, the data will include the end of treatment 


A5348 Statistical Analysis Plan V2.0 2017 
8 
data and potentially some SVR4 data from Arm A participants.   The components of the SMC Review 
Reports as described in the SMP are outlined in Section 3.1. 
2.8 
General Data Analysis Considerations 
• 
Data summaries and analyses will be completed by study arm, unless specified otherwise.  
They will be collapsed across treatment arms for open interim reports. 
• 
All participants who met the study eligibility criteria and received any study treatment will be 
included in the planned analyses, unless specified otherwise.  The participants who are found 
to have been ineligible for the study after enrollment occurred will not be part of the planned 
analyses; if any of such participants received any study treatment, their safety profiles will be 
described separately in an appendix to the report. 
• 
Participants are instructed to discontinue the study prior to initiation of non-study provided 
HCV treatment during follow-up after discontinuation of the study-provided treatment.  If they 
remain on study in error, the data are censored at the time of alternative HCV treatment 
initiation. 
• 
For the summaries on evaluations by study visits, calculated visit weeks will be used 
according to the tables shown above in Section 2.6. Entry value is defined as the evaluation 
from the day of treatment dispensation or the closest preceding evaluation. For the post-entry 
values, the evaluations conducted closest to the targeted dates will be used. 
• 
For the summaries of AEs, diagnoses and opportunistic infections, events with the onset date 
on or after the study treatment initiation date will be summarized. 
• 
In data lists, study participants will be identified by an anonymous patient identifier generated 
at the statistical center (publicID).  Dates will not be shown, but converted to time (e.g. weeks) 
since randomization.  
• 
Each Table/Figure/Listing will be annotated with the name and location of the program used to 
create it, including its location directory.  
• 
Key outcome measures for which analysis programs require validation and the level of 
validation that is required are noted throughout the plan in Section 4. 
2.9 
Statistical Methods 
For binary or categorical measures, number of participants and percent will be provided.   
SAP Version 2: Two-sided 90% Wilson confidence intervals are provided for the key HCV virologic 
endpoints, per protocol.  In addition, two-sided 95% Clopper-Pearson confidence intervals will be 
provided for SVR12, as suggested by the Gilead statistician on the Jan 6, 2017 manuscript call.  For 
the continuous measures, median, lower and upper quartiles (Q1 and Q3), min, max will be provided.  
Additional summary statistics, such as mean with standard deviation (SD) may also be included for 
some measures, if noted below.  


A5348 Statistical Analysis Plan V2.0 2017 
9 
3 
Components in the Reports 
The listed components are described in Section 5. 
3.1 
SMC Review Reports 
The purpose of SMC review reports is to provide data summaries relevant for interim reviews to 
ensure participant safety and to review data quality and study conduct.  As described in the Study 
Monitoring Plan (SMP), the Open Report will be pooled across study arms, and the Closed Report will 
be by study arm. 
SAP Version 2: There was one SMC review on August 18, 2016.  The SMC became aware of the 
early enrollment closure.  An abbreviated SMC report was generated and distributed, in consideration 
of only 7 participants in the study. 
5.1.1 Study History 
4.1.2 Accrual 
4.1.3 Eligibility Violations and Registration Errors 
4.1.4 Baseline Characteristics 
4.1.5 Study Treatment Status and Duration of Treatment (Only in the Closed Report) 
4.2.1 Adverse Events and Protocol-Required Laboratory Tests 
4.2.2 Pregnancy 
4.2.3 Deaths 
4.2.4 HIV-Related Measures and Changes in ARV Regimen (Only in the Closed Report) 
4.2.5 Virologic Failures (Only in the Closed Report) 
4.3.1 SVR12 
4.4.2 HCV Virologic Responses 
• 
The Open Report will be limited to on-treatment HCV RNA.  Only the following component will 
be provided in the Open Report. 
a) Listing of each participant’s HCV RNA results will be provided with calculated visit weeks. 
 
3.2 
Final Primary Analysis Report and SVR24 Supplement 
The purpose of the final analysis report is to complete the main analyses as described in the protocol, 
including the analysis of the primary endpoint SVR12.   
SAP Version 2.0: The final primary analysis report for the study will occur when SVR12 data are 
complete.  All the components of this plan in Section 4 will be included in the Final Primary Analysis 
Report, except for SVR24 results which will not yet be available.  See Appendix Table B for the 
timetable.  Once the study is complete, SVR24 data table will be generated and distributed to the 
study team as a supplement to the final primary analysis report.   
4 
Description of Components 
SAP Version 2: Components have been updated. 


A5348 Statistical Analysis Plan V2.0 2017 
10 
4.1 
Administrative and Baseline Characteristics 
4.1.1 
Study History 
Purpose: To provide a summary of the protocol, any clarification memos and amendments and key 
events during the study that may be relevant to the study conduct. 
a) A summary of changes to and clarifications of protocol. 
b) A summary of recommendations from SMC reviews. 
c) Description of the accrual process and progress. 
4.1.2 
Accrual  
Purpose: To give a summary of accrual and the distribution of enrollment across sites. 
a) Table of number (%) enrolled by site and month/year   
b) Table of number (%)  enrolled by the stratification factor 
c) Number of participants  on each regimen with ritonavir-boosted HIV protease inhibitor and 
tenofovir who participated in the PK sample collection*  
d) Dates of first and last enrollments 
* In consideration of the secondary objective on tenofovir PK. 
4.1.3 
Eligibility Violations and Registration Errors 
Purpose: To document any participants who were accrued to the study but were subsequently 
excluded from analyses due to errors in screening procedures. 
a) Description of each eligibility or screening error and exclusion from analyses. 
4.1.4 
Baseline Characteristics 
Purpose: To describe the study population. 
Notes: For all variables, the numbers of participants with available data will be provided.  For the lab 
measures, the values up to and including treatment initiation date will be considered, and the value 
closest to treatment initiation date will be chosen.   
a) Demographic and health variables: race/ethnicity, sex, age, IVD history, BMI. 
b) Liver-related variables: HCV RNA, APRI, FIB-4, FibroSure, cirrhosis status, method used to 
determine cirrhosis status, HCV genotype 1 subtype, liver function tests.   Listing of HCV 
resistance mutations detected at study baseline. 
c) HIV-related variables: HIV viral load and CD4 count by ARV receipt. 
d) ARV regimen. 
e) Other: prior HCV treatment (e.g. SOF/PEG, SOF/PEG/RBV, SIM/SOF) and response 
(relapse, partial response, null response), IL28B. 


A5348 Statistical Analysis Plan V2.0 2017 
11 
 SDAC Validation: All programs generating variables as study-specific will be validated (e.g. 
APRI, FIB-4). 
4.1.5 
Study Treatment Status and Duration of Treatment 
Purpose: To summarize completeness of study treatment  
a) Study Treatment Status 
• 
Total number of participants who met the eligibility criteria and initiated study treatment 
• 
Number of participants who initiated study treatment regimen 
• 
Number of participants who completed study treatment regimen 
• 
Summary of reasons for treatment discontinuation, including categories for: completion of 
prescribed treatment duration, HCV virologic failure (as protocol-defined clinical event), 
lost to follow-up, adverse events, consent withdrawal, non-adherence, other.  For reasons 
coded as “other”, a listing will be provided.   
b) Summary statistics (median, Q1, Q3) on time on treatment 
 
 SDAC validation: All programs generating variables as study-specific will be validated (e.g. 
treatment regimen, time on treatment). 
4.2 
Safety 
Purpose: To address the safety objectives of the study. 
4.2.1 
Adverse Events and Protocol-Required Laboratory Tests 
a) Descriptive tables summarizing the adverse events and the number of participants 
experiencing the events will be provided by grade and by the site report on relationship to 
study treatment. 
b) Summary table of all diagnoses reported. 
c) Listing of participants with renal toxicity events (defined as Grade ≥2 creatinine clearance 
post-entry or new proteinuria or glucosuria, an increase from entry glucosuria or proteinuria by 
≥1+). 
• 
baseline characteristics: age, sex, race/ethnicity, ART regimen, study treatment, 
cirrhosis status 
• 
all available results on: urinalysis protein and protein, creatinine clearance (CrCl), spot 
protein and creatinine (and protein/creatinine ratio) 
• 
study treatment modifications 
• 
study treatment adherence 
• 
ARV modifications 
Notes:  


A5348 Statistical Analysis Plan V2.0 2017 
12 
1. The protocol requires grading of events according to The Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014, which is available 
on the RCC website: http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx 
2. The protocol requires the collection of signs and symptoms, diagnoses, laboratory events that 
a. are Grade ≥3 post-entry 
b. that led to a change in treatment (excluding indications for RBV dose modification) 
regardless of grade, or  
c. that met ICH, EAE or SAE guidelines regardless of grade. 
In addition, all creatinine, creatinine clearance (CrCl) and urinalysis results are required.  Urine 
spot protein and creatinine are repeated in participants who develop new proteinuria or glucosuria, 
an increase from entry glucosuria or proteinuria by ≥1+, or who develop an increase in creatinine 
of 0.4 from entry or CrCl <50, until resolution. 
3. Summary tables are based on events reported on the following forms:  EVW0314, EVW0315, 
F2860 (Hematology), F2861 (Chemistry), LBW0144 (Creatinine Clearance) and will not explicitly 
include events reported on EAEs to DAIDS.  Before the database is finalized, the data manager 
will ensure that all EAE events deemed ‘reportable’ and included in the SDMC AR001AES table 
are reflected on the study CRFs.   
4. Events with date of onset or specimen date prior to the first study treatment dose will be excluded.  
5. Deaths will be described separately and not included in the safety summary tables. 
 
 SDAC validation: All programs generating variables as study-specific will be validated (e.g. 
variable to indicate participants who experienced a renal toxicity event).  User-specific inputs 
in standard programs will also be validated. 
 
4.2.2 
Pregnancy 
a) List and outcome, if any. 
4.2.3 
Deaths 
a) List and description, if any. 
4.2.4 
HIV-Related Measures and Changes in ARV Regimen 
a) A summary of CD4 cell count and percent CD4 and changes from baseline at study visits.  
b) A summary of HIV RNA detection status at study visits. 
c) A listing of changes in HIV regimens during the study. 
 
 SDAC validation: All programs generating variables as study-specific will be validated (e.g. 
CD4 and HIV RNA categories, changes over time). 
 
4.2.5 
Virologic Failures 
a) HIV Virologic Failure 


A5348 Statistical Analysis Plan V2.0 2017 
13 
• 
Details on participants on ART with undetectable HIV RNA at entry who experience HIV-1 
virologic failure (as defined in the protocol), including adherence to study regimen and ARV 
medications, and dose modifications to study medications and ARVs. 
b) HCV Virologic Failures 
• 
Details on participants who experience HCV virologic failure (as defined in the protocol), 
including ARV regimen, adherence to study regimen and ARV medications, dose 
modifications to study medications and ARVs, and the following baseline information: HCV 
RNA, cirrhosis status, race and ethnicity, HCV genotype, development of resistance-
associated variant at the time of virologic failure.  
 
 SDAC validation: All programs generating variables as study-specific will be validated (e.g. 
HIV breakthrough, HCV breakthrough). 
 
4.3 
Primary Objectives 
4.3.1 
SVR12 
Purpose: To address the primary HCV virologic response objective to assess the proportion of 
participants who attain SVR12 in each study arm. 
a) Two-sided 90% confidence interval around the observed SVR proportion using the Wilson 
confidence limits, per protocol. 
b) Two-sided 95% confidence interval around the observed SVR proportion using Clopper-
Pearson limits, to line up with the Gilead study (in consideration of joint manuscript). 
c) For the non-SVRs, reasons for failure will be provided: detectable HCV RNA after treatment 
discontinuation, HCV virologic failure (VF) as determined by the site, unavailable HCV RNA 
result, other. 
Note on the primary HCV virologic endpoint: 
1. SVR12 is defined in the protocol as HCV RNA < lower limit of quantification (LLOQ), either 
target detected (TD) or target not detected (TND), at 12 weeks after treatment discontinuation.  
The sample within the week R+12 visit window, as described in Section 2.6, which is closest 
to the targeted time will be used.  If there is no HCV RNA sample within this window, then the 
participant will be considered SVR12 failure, unless there are preceding and subsequent HCV 
RNA measurements that are both <LLOQ (either TD or TND). 
2. Participants not providing SVR data (e.g. due to early study discontinuation) will be included 
and counted as SVR failures. 
 
 SDAC Validation: Derivation of SVR12 variable will be validated.  The analysis program that 
summarizes SVR12 and calculates confidence intervals will also be validated. 
 Data sources for the primary endpoint SVR12: HCVRNALDMS (LDMS data table), F1601 (off 
study CRF table), F4003 (off treatment CRF table), F0010 (patient visit CRF data table), 


A5348 Statistical Analysis Plan V2.0 2017 
14 
STATUS (data table on key patient characteristics and date variables including date of last 
dose of study treatment), CMW0029 (concomitant medication CRF table to censor data at 
initiation of alternate HCV treatment in case  any participants erroneously remained on study 
when alternate HCV treatment was initiated), SPW0455 (HCV RNA specimen tracking CRF 
table). 
 
4.3.2 
Safety 
Purpose: To address the primary safety objective. 
a) Number of participants meeting the criteria noted below.  The worst graded event per person 
over time will be used. 
b) Summaries on all reported adverse events and laboratory events and listings described in 
Section 4.2.1 provide supplemental information on safety. 
Notes on the primary safety endpoint: 
1. Occurrence of  Grade ≥3 or higher adverse event (diagnosis, sign, symptom or laboratory 
event), SAE according to ICH criteria, or AE reported as the reason for permanent 
discontinuation of study treatment during study treatment and up to 30 days after study 
treatment discontinuation.   
2. Event that is ongoing at the same grade from prior to study treatment initiation will be 
excluded. 
 
 SDAC Validation: The program deriving the indicator variable on meeting the safety endpoint 
criteria as described above will be validated. 
 Data sources for the primary safety endpoint:  EVW0314, EVW0315, F2860 (Hematology), 
F2861 (Chemistry), HXW0148 (Signs and Symptoms History), LBW0144 (Creatinine 
Clearance), STATUS (data table on key patient characteristics and date variables including 
date of last dose of study treatment), CMW0029 (concomitant medication CRF table to censor 
data at initiation of alternate HCV treatment in case any participants erroneously remained on 
study when alternate HCV treatment was initiated). 
4.4 
Secondary Objectives 
4.4.1 
Tenofovir PK 
Purpose: (Secondary Objective 1)  To assess the impact of LDV/SOF and HIV PI/r co-administration  
 
Note: The tenofovir PK analysis will be described and conducted by the study pharmacologist 
separately. 
 


A5348 Statistical Analysis Plan V2.0 2017 
15 
4.4.2 
HCV Virologic Responses  
Purpose: (Secondary Objective 3 and 8)  To assess the proportion of participants who attain SVR4 
and SVR24 in each study arm.  To evaluate kinetics of HCV RNA during treatment and after treatment 
discontinuation. 
a) Listing of each participant’s HCV RNA results will be provided with calculated visit weeks. 
b) Number and percent of participants with SVR4 with a two-sided 90% confidence interval. 
c) Number and percent of participants with SVR24 with a two-sided 90% confidence interval.  
(SAP Version 2: This will be provided as part of SVR24 supplement to the Primary Final 
Analysis Report.) 
d) Number of participants with relapse. 
Notes:  
1. SVR4 is defined in the protocol as HCV RNA < LLOQ (either TD or TND) at 4 weeks after 
treatment discontinuation.  The sample within the week R+4 visit window, as described in 
Section 2.6, which is closest to the targeted time will be used.  If there is no HCV RNA sample 
within this window, then the participant will be considered SVR4 failure, unless there are 
preceding and subsequent HCV RNA measurements that are both <LLOQ (either TD or 
TND). 
2. SVR24 is defined in the protocol as HCV RNA <LLOQ (either TD or TND) at 24 weeks after 
treatment discontinuation.  Sample after 20 weeks after treatment discontinuation that is 
closest to the targeted, not followed by any result ≥LLOQ, will be used. 
3. Relapse is defined as <LLOQ (either TD or TND) for the latest HCV RNA result prior to the 
end of study treatment and HCV RNA ≥LLOQ after treatment at a subsequent visit. 
 
 SDAC validation: All programs generating variables as study-specific will be validated (e.g. 
HCV RNA variable for each study visit, HCV relapse, SVR4 and SVR24). 
4.4.3 
Development of HCV Resistance Mutations 
Purpose: (Secondary Objective 7) To evaluate emergence of HCV resistance mutations in 
participants who fail to attain SVR12 with retreatment with LDV/SOF (+/- RBV). 
• 
Listing of participants with any targeted HCV resistance mutations detected in any sample 
tested with the SVR12 outcome. 
 
 SDAC Validation: Programs that generate variables as study-specific will be validated (e.g. 
indicator variable on HCV resistance mutation). 


A5348 Statistical Analysis Plan V2.0 2017 
16 
4.4.4 
HIV RNA and CD4+ Cell Counts 
Purpose: (Secondary Objective 9) To assess the influence of LDV/SOF-based retreatment on HIV-
specific parameters, including maintenance of HIV-1 RNA < 50 copies/mL for participants on 
antiretrovirals and CD4+ cell count during treatment.  
This is addressed in Section 4.2.4.