A Randomized Study of a Rapid HCV Treatment Initiation Strategy (HCV Seek, Test and Rapid Treatment) Compared to Standard Care in Young People Who Inject Drugs
Phase: NA
Conditions: Hepatitis C, Drug Use
Sponsor: Weill Medical College of Cornell University

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HCV ST&RT 
A randomized study of a rapid HCV treatment initiation strategy (HCV Seek, Test and Rapid Treatment 
– HCV ST&RT) compared to standard care in young PWID 
A single center randomized controlled trial 
Investigator-initiated and funded by Gilead Sciences ISR 
PROTOCOL AMENDMENT 1 
Date: 17June2020 
 
NCT03627546 
 
 
Principal Investigator: 
Kristen Marks, MD MSc 
 
Co-Investigators: 
Benjamin J Eckhardt, MD, MSc 
 
Shashi N Kapadia, MD, MSc 
 
 

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Contents 
PROTOCOL TEAM: ......................................................................................................................................... 5 
0.0 Amendment Information ........................................................................................................................ 6 
0.1 Rationale for the Amendment: ........................................................................................................... 6 
0.2 Protocol Changes: ............................................................................................................................... 6 
1.0 Synopsis................................................................................................................................................... 8 
1.1 Purpose of Study: ................................................................................................................................ 8 
1.2 Design:................................................................................................................................................. 8 
1.3 Participant selection: .......................................................................................................................... 8 
1.3.1 Inclusion Criteria .......................................................................................................................... 8 
1.3.2 Exclusion Criteria .......................................................................................................................... 8 
1.4 Study procedures ................................................................................................................................ 8 
1.4.1 Enrollment and sampling ............................................................................................................. 8 
1.4.2 Intervention Arm .......................................................................................................................... 9 
1.4.3 Usual Care Arm .......................................................................................................................... 10 
1.5 Hypothesis ......................................................................................................................................... 10 
1.6 Primary Outcome .............................................................................................................................. 10 
1.7 Secondary Outcomes ........................................................................................................................ 10 
1.8 Schematic .......................................................................................................................................... 11 
1.8.1: Part A Schematic ....................................................................................................................... 11 
1.8.2: Part B Schematic ....................................................................................................................... 12 
2.0 Introduction .......................................................................................................................................... 13 
2.1 Background ....................................................................................................................................... 13 
2.2 Rationale for Study Design ................................................................................................................ 14 
2.2.1 Participant selection .................................................................................................................. 14 
2.2.2 Treatment regimens used .......................................................................................................... 15 
2.2.3 Schedule of follow up and monitoring ....................................................................................... 15 
2.2.4 Outcome selection ..................................................................................................................... 15 
2.3 Summary of Risks and Benefits ......................................................................................................... 15 
3.0 Study Design .......................................................................................................................................... 16 
4. Participant Selection and Enrollment ..................................................................................................... 17 
5 Study Procedures ..................................................................................................................................... 18 

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5.1 Schedule of Events during Part A: ..................................................................................................... 18 
5.2 Schedule of Events during Part B: ..................................................................................................... 20 
5.2 Laboratory evaluations ..................................................................................................................... 22 
5.2.1 HCV RNA PCR ............................................................................................................................. 22 
5.2.2 HIV-1/2 Antibody ....................................................................................................................... 22 
5.2.3 FIB-4 ........................................................................................................................................... 22 
5.2.4 Hepatitis B Panel ........................................................................................................................ 22 
5.2.5 Pregnancy Test ........................................................................................................................... 22 
5.3 Adherence Assessment ..................................................................................................................... 22 
5.4 Qualitative and Questionnaire Evaluation ........................................................................................ 22 
5.5 Monitoring for reinfection ................................................................................................................ 22 
5.6 Monitoring for incident HCV infection .............................................................................................. 23 
5.7 Reinfection Prevention Counseling ................................................................................................... 23 
5.8 Storage of samples for future analyses ............................................................................................ 23 
6. Clinical Management Issues .................................................................................................................... 23 
6.1 Chronic Kidney disease ..................................................................................................................... 23 
6.2 Cirrhosis and severe liver disease ..................................................................................................... 24 
6.3 Incident HIV infection ....................................................................................................................... 24 
6.4 Pregnancy .......................................................................................................................................... 24 
6.5 Hepatitis B Reactivation .................................................................................................................... 24 
6.6 Treatment failure .............................................................................................................................. 24 
6.7 Hepatitis C Reinfection ...................................................................................................................... 24 
6.8 Incident hepatitis  C infection ........................................................................................................... 24 
6.9 Drug Interactions .............................................................................................................................. 24 
6.10 Storage and distribution of medications ........................................................................................ 25 
7 Criteria for discontinuation ...................................................................................................................... 25 
7.1 HCV treatment discontinuation ........................................................................................................ 25 
7.2 Study withdrawal and discontinuation ............................................................................................. 25 
8 Statistical and analytic considerations ..................................................................................................... 25 
8.1 Sample size ........................................................................................................................................ 25 
8.2 Randomization .................................................................................................................................. 26 
8.3 Data Analysis ..................................................................................................................................... 26 
8.3.1 Analysis of clinical outcomes data ............................................................................................. 26 

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8.3.2 Analyses for qualitative data...................................................................................................... 27 
9. References: ......................................................................................................................................... 27 
 
 
 
 

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PROTOCOL TEAM: 
Kristen M Marks, MD MSc 
Weill Cornell Medicine 
Division of Infectious Diseases 
525 East 68th Street, F2437 
New York NY 10065 
markskr@med.cornell.edu  
Shashi Kapadia MD MSc 
Weill Cornell Medicine 
Division of Infectious Diseases 
1300 York Avenue, Room A-421 
New York, NY 10065 
shk9078@med.cornell.edu  
 
External Collaborators: 
Pedro Mateu-Gelabert, PhD 
National Development Research Institute (NDRI) 
71 W 23rd St 
New York, NY 10010 
Role: Co-Investigator  
Benjamin J Eckhardt MD MSc 
New York University Medical Center 
462 1st Avenue, NBV 16S-5 
New York, NY 10016 
Role: Co-Investigator  
Yesenia Aponte-Melendez, PhD 
CUNY School of Public Health and Health Policy 
55 West 125th Street, Room 625  
New York, NY 10027 
Role: Project Director 
 
Chunki Fong, MS 
CUNY School of Public Health and Health Policy 
55 West 125th Street, Room 625  
New York, NY 10027 
Role: Statistician/Data Manager 
 
 
 

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0.0 Amendment Information 
0.1 Rationale for the Amendment:  
The initial protocol proposes a randomized controlled trial of rapid-start hepatitis C (HCV) treatment 
intervention co-located at a syringe service program. Due to the impact of the COVID-19 pandemic in 
New York City, enrollment in this protocol has been temporarily suspended. As New York starts to plan 
recovery from COVID, it is likely that elements of service delivery for people who inject drugs (PWID) will 
be very different. Foremost, the impact of COVID-19 on syringe service programs may limit the ability to 
offer co-located interventions. A recent national survey showed that 43% of programs have reduced 
services and nearly all had eliminated HCV and HIV testing due to the need for person-to-person 
contact.1 The prospect of an economic downturn may further limit the ability of these programs to 
provide health services in a tighter funding environment. 
In the meantime, the need to adapt to the pandemic has rapidly increased the use of telemedicine 
services to engage with patients without physical contact.2 It is not clear whether telemedicine is 
equitably accessible across different patient populations.3 Telemedicine has been found to be 
acceptable for hepatitis C management in patients in several healthcare settings.4,5 Our intervention 
serves a unique population not covered by prior studies: they are currently injecting and recruited from 
the community, and so may face significant healthcare access barriers. On the other hand, they are a 
young population (<30 years old) that may be technologically equipped to embrace telemedicine-based 
HCV treatment. Understanding how to adapt existing community-based healthcare intervention for 
populations with limited healthcare access will be critical in the post-COVID era.  
In this amendment, we will change the enrollment and analysis plans of our randomized study (called 
part A). This will involve conducting the analysis and reporting of comparative data between 
intervention and control arms, with the same study endpoints as the initial proposal. The main reason 
for ending enrollment at this time is the long delay we are likely to face before a co-located intervention 
can be offered in a physical syringe service program space. Instead, we will adapt our intervention to be 
telemedicine-based for continued enrollment into a nonrandomized treatment group (Part B). After the 
end of follow-up for part B, we will describe outcomes and compare to the previously randomized 
control population, to test if telemedicine-based engagement is feasible, safe, and noninferior to the co-
located intervention.   
0.2 Protocol Changes: 
 
1. 
Section 1.2 
Change: Addition of: In Part B, all participants will be enrolled to the  intervention group, modified to 
allow telemedicine delivery.   
2. 
Section 1.4: Intervention Arm 
Change: For participants entering in Part B, the co-located rapid start intervention will be converted to 
telemedicine rapid-start intervention. Consented participants will have same-day or next-
day  telemedicine visits with a hepatitis C provider and baseline blood testing will be arranged on a 
personalized basis utilizing convenient community-based laboratory facilities (including current co-
located SSP and commercial laboratories).  For participants found to be HCV PCR positive, personal 
delivery or pick-up of a 28-day supply of sofosbuvir/velpatasvir  (Epclusa ®) will be 

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arranged.   Telemedicine visits will be arranged two weeks after treatment delivery.  For participants 
who confirm treatment initiation, side effects will be assessed, delivery/pick-up of the final 56-day of 
medication will be arranged, and week 4 monitoring labs will be offered (no longer required) and 
arranged. 
3. 
Section 1.7:  Secondary Objectives 
Change:  To assess the feasibility, safety, and effectiveness of a telemedicine-based rapid start 
intervention for hepatitis C treatment in young people who inject drugs.  
4. 
Section 3:  Study Design 
Change: For participants entering in Part B, randomization will not occur. All participants will be 
assigned to the intervention arm, which we will call the telemedicine arm in this document. 
Rationale: The part B telemedicine arm will not be randomized, and instead will be compared to 
previously randomized arms. This is in order to maximize sample size exposed to the intervention with 
the available remaining budget and grant period. 
5. 
Section 4 :  Participant Selection and Enrollment 
Change: For participants entering in Part B, enrollment may occur in person or remotely (no person-to-
person contact needed) 
Rationale: Remote enrollment procedures will allow continued referral and enrollment even without 
the physical location of the syringe service program. Informed consent will be converted to electronic 
informed consent using a RedCAP survey, a procedure we have successfully implemented at Weill 
Cornell for COVID-related studies. 
6. 
Section 5.1 : Schedule of Study Events  
Change: Week 4 and Week 8 laboratory draws are now changed to optional, to minimize travel and 
physical contact. Monitoring labs for re-infection have been eliminated, and re-infection will not be 
analyzed for the telemedicine cohort. Instead, individuals will reach the study endpoint at either SVR 12 
or at week 48, whichever comes first. The frequency of medical visits will be unchanged but physical 
exams will no longer be performed except as possible through telemedicine. Weekly telephone or video 
check-ins will also continue.  
7. 
Section 5.8: Storage of samples for future analysis 
Change: Storage samples collected only when feasible for Part B. 
Rationale: Since we will now be utilizing clinical laboratories, storage of samples for research purposes 
will occur when feasible, but not required for all participants and all timepoints. 
8. 
Section 8.1 Sample size  
Change:   Data on the randomized controlled portion of the study (Part A) will be analyzed based on 
enrollment through March 1, 2020 so the power to detect a difference between the 2 groups will be 
reduced from what was calculated for a sample size of 54 patients..   
Rationale: The COVID pandemic created a natural break in enrollment and inability to continue study as 
planned. 

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9. 
Section 8: Statistical and Analytic Considerations 
Change: Adding the Part B analysis for comparing the telemedicine arm to the previously enrolled study 
arms. 
Rationale for change: We will compare the proportion of patients who achieve SVR12 in each Part B 
telemedicine to  (1)Part A intervention  (2) Part A control,  using Chi-square or Fishers’ exact testing, 
using an intention-to-treat approach in which participants are analyzed in the group to which they are 
randomized. Participants with negative confirmatory HCV RNA PCR tests on study entry will not be 
included in the analysis, consistent with our existing approach. 
10. 
Consent form: 
The consent form was revised to reflect the addition of Part B.  Part A participants do not need to be 
reconsented. 
1.0 Synopsis 
 
1.1 Purpose of Study: 
The purpose of this randomized study is to determine whether a community-based test and treat model 
of hepatitis C (HCV) care delivery will be superior to the usual care practice of referral to specialist clinics 
for the outcomes of sustained virologic response at 12 weeks after treatment and initiation of HCV 
treatment for persons who inject drugs (PWID) between ages 18 and 29 who are naïve to HCV treatment 
1.2 Design: 
ST&RT is a randomized open-label clinical trial conducted in two parts. In part A, which HCV infected 
PWID between ages 18 and 29 will be randomized to either receive the same-day treatment initiation of 
the FDA-approved fixed dose combination of sofosbuvir 400mg and velpatasvir 100mg (SOF/VEL) with 
follow up and medical monitoring at a community site (Intervention arm) or to receive referral to an 
HCV treatment provider’s office (Usual Care Arm). In Part B, participants will be enrolled to receive 
hepatitis C rapid treatment initiation in a telemedicine model. 
1.3 Participant selection: 
1.3.1 Inclusion Criteria 
Persons are eligible for study inclusion if they: (a) are HCV antibody positive, (b) are 18 to 29 years of 
age, (c) have injected drugs in the past 30 days, (d) are HCV treatment naïve, (e) are English speaking 
1.3.2 Exclusion Criteria 
Persons excluded from the study will be (a) HIV coinfected persons (b) pregnant women, or women 
planning on becoming pregnant (c) participants with end-stage renal disease (d) participants with 
decompensated cirrhosis (c) participants on medications with treatment limiting interactions with 
SOF/VEL (detailed below). In part B only, participants who cannot participate in telemedicine visits (lack 
of telephone, smart phone or computer or internet connection) will be excluded.  
1.4 Study procedures 
1.4.1 Enrollment and sampling 
Potential research participants will be recruited by referral from an ongoing NIH funded study aiming at 
preventing HCV among young current injectors (R01DA041501), hereafter referred to as the parent 

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study.  The parent study will conduct a randomized, controlled trial to assess the effectiveness of a 
“Staying Safe” prevention intervention in reducing injection-related risk behavior and HCV incidence 
among 18-29 year-olds who inject opioids (heroin and/or POs) and test HCV and HIV antibody-negative 
at screening. The parent study is continuing to enroll participants and perform HCV testing. Whereas 
previous procedures would have required that the participant be referred physically to the syringe 
service program, we are now allowing for remote enrollment by phone or video as the first point of 
contact.  Since the parent study is still operating, we expect to continue to receive referrals of HCV-
infected people. Candidates for the parent study who test HCV antibody positive at the screening visit, 
will be immediately offered enrollment in ST&RT.  The target sample size of 27 participants per arm is 
selected to show a hypothesized difference in SVR12 rates of about 35% with 80% power at a level of 
0.05. Participants who are enrolled but negative on confirmatory testing (an expected 25% of 
participants) will be replaced. These participants will not receive treatment interventions but continue 
to be followed for monitoring of HCV re-infection incidence. We anticipate enrolling 36 participants per 
arm to achieve the target of 27 confirmed infections per arm. 
1.4.2 Intervention Arm  
In Part A: Participants randomized to the intervention arm will have a same-day visit with a study 
physician.  Those who are interested in being treated for their HCV, and have no contraindication, will 
(a) have standard of care baseline laboratory testing drawn and be given a one-week ‘Starter-Pack’ (7 
day supply) of sofosbuvir 400mg/velpatasvir 100mg. Subsequent supplies of DAA therapy will be 
distributed to HCV RNA test positive participants as one 21-day and one 56 day supply to complete a 12-
week treatment course. Those participants with negative confirmatory HCV RNA testing will be 
contacted via telephone and instructed not to begin the medication, and will not be given additional 
medication supplies. 
Participants will be contacted weekly while receiving sofosbuvir/velpatasvir by text message to assess 
adherence, potential adverse effects, and offered other tele-support as needed. Scheduled study visits 
will occur at 4 weeks, upon treatment completion or discontinuation (study week 12), study week 16 
(corresponding to SVR4), study week 24 (corresponding to SVR12), study week 36, and study week 48. 
Each study visit will consist of laboratory testing, semi-structured interview, and physician visit. 
Additional medical visits may be scheduled at the participants’ request. Additionally, each participant 
will be scheduled for a one-time counseling session for prevention of reinfection during their course of 
treatment. Referral to harm reduction and/or opioid substitution treatment programs will be provided 
for interested participants, but utilization of these services is not a condition of enrollment in the study 
or of HCV treatment provision. 
In Part B: Participants will be enrolled in the telelmedicine arm, and will have a same-day or next-day 
telemedicine visit with the hepatitis C provider. Initial evaluation will be either via telephone, video, or 
in-person at the syringe service program depending on patient preference. Blood testing will be 
arranged at local community laboratory facilities. Participants with positive HCV RNA will have delivery 
of a 28 day supply of sofosbuvir/velpatasvir, and a 56 day supply after completion. Weekly check-ins will 
occur by phone, and participants will have clinical laboratory monitoring at week 4 (optional), week 12, 
every 12 weeks thereafter until completion of follow up. Participants will complete a short structured 
survey at weeks 0, 12, 24, 36, and 48, also over video or telephone. 

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1.4.3 Usual Care Arm 
During Part A: Participants randomized to the usual care arm will have a same-day lab draw for 
confirmatory HCV RNA testing. Those who test RNA positive will be referred to local clinic or community 
based HCV medical providers.  
Participants will be contacted monthly via telephone for a short questionnaire. Scheduled study visits 
will occur at study weeks 12, 24, 36 and 48 for semi-structured interviews and HCV RNA testing.  
During Part B: no participants will be assigned to the usual care arm 
1.5 Hypothesis 
We hypothesize that the ST&RT intervention will be accepted by HCV infected PWID aged 18-29, and 
lead to higher rates of treatment initiation, completion and SVR12 compared to the usual practice of 
referral to community HCV providers. 
1.6 Primary Outcome 
The proportion of participants who achieve sustained virologic response defined as an undetectable HCV 
RNA viral load 12 weeks after the cessation of treatment (SVR12), in the intervention arm compared to 
the usual care arm by study week 48.  
1.7 Secondary Outcomes 
1. The proportion of participants who initiate treatment for HCV in the intervention arm compared to 
the usual care arm by study week 48. 
2. The proportion of participants who complete the prescribed course of treatment for HCV in the 
intervention arm compared to the usual care arm by study week 48.3. The proportion of participants 
after initiating HCV treatment did not complete it compared to the usual care arm by study week 48. 
4. The proportion of participants in both arms who achieve SVR 12, or are RNA negative at baseline, that 
have HCV reinfection (defined in section 5.5) by study week 48. 
5. To characterize the HCV genotype and presence of resistance associated substitutions (RAS) in those 
treated patients with HCV reinfection or relapse. 
6. To examine impact of engagement in HCV treatment on substance use behaviors and injection risk. 
7. Qualitative assessment using semi-structured interviews to evaluate the acceptability of the 
intervention versus usual care, the barriers to initiate and complete treatment, and factors influencing 
successful treatment outcomes 
8. To assess the feasibility, safety, and effectiveness of a tele-medicine based rapid start intervention for 
hepatitis C treatment in young people who inject drugs.  
 
 

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1.8 Schematic 
1.8.1: Part A Schematic 
 
 
 
 
 
  
 
 
PWID age 18- with 
29 HCV Ab positive, 
HIV Ab neg, and 
current injection 
drug use 
Consent 
Control Arm (n=36); HCV RNA 
test; Referral to Tx ; Interview 
Intervention Arm (n=36); 
Distribution of Rx; HCV RNA test; 
Baseline labs; Interview 
Randomization 
On-treatment visit: Laboratory 
testing, medication pickup 
Post-treatment visit; laboratory 
testing; Interview 
12-week post-treatment visit; 
laboratory testing; Interview 
Final visit; laboratory testing; 
Interview 
Interview; HCV RNA 
testing 
Interview; HCV RNA 
testing 
Interview; HCV RNA 
testing 
Week 4 
Phone check in 
Week 12 
Week 24 
Week 48 
4-week post-treatment visit; 
laboratory testing 
Week 16 
Medication pickup (if RNA positive) 
or return (if RNA negative) 
Week 1 
Week 36 
Interview; HCV RNA 
testing 
24-week post-treatment visit; 
laboratory testing; Interview 

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1.8.2: Part B Schematic 
 
 
 
 
 
 
 
 
PWID age 18- with 
29 HCV Ab positive, 
HIV Ab neg, and 
current injection 
drug use 
Consent 
Telemedicine Arm (n=33); Medical 
evaluation; research interview 
On-treatment telemedicine visit: 
Optional Laboratory testing, 
medication delivery/pickup 
Post-treatment visit; laboratory 
testing; Interview 
12-week post-treatment visit; 
laboratory testing; Interview 
Week 4 
 
Week 12 
Week 24 
4-week post-treatment visit; 
laboratory testing 
Week 16 
Personalized community-based 
laboratory testing 
Week 0 
 
Week 36-48 
 
Continued follow-ups for 
participants not yet at 12-weeks 
post treatment. Laboratory 
testing and research at 12-weeks 
post-treatment. 
Personalized, community-based 
medication pickup or delivery (if 
RNA positive) 

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2.0 Introduction 
 
2.1 Background 
Our proposed pilot study will examine the effectiveness and acceptability of a novel rapid) treatment 
initiation strategy that if found effective could be further studied as part of a new model for HCV 
treatment delivery in young PWID, namely: Seek, Test and Rapid Treat (HCV ST&RT, a modification of 
the well-known Seek, Test and Treat model for HIV). This strategy has potential to avoid the attrition 
observed on the HCV care cascade and reach the population most important for treatment as 
prevention, young PWID.  This study focuses on Rapid Treatment initiation and will not study the Seek 
and Test components, however we will refer to the strategy as HCV ST&RT throughout this proposal for 
simplicity. 
The United States has been experiencing a dramatic opioid epidemic among young people for over a 
decade. Between 2002 and 2013, heroin use in the United States has increased by 63%, with the largest 
increase (109%) in individuals aged 18-25.6 The rise in injection drug use has been accompanied by 
increases in incident HCV infection.7 Cases of acute HCV increased more than 2.5-fold from 2010-2014 
with the greatest increases among people age 20-29.8  Recent HCV outbreaks across several states 
reflect the widespread transmission of HCV in PWID,9-14 and modeling studies indicate that counties with 
higher rates of drug overdose deaths and prescription opioid sales are vulnerable to HCV outbreaks in 
the future.15   
The recent development of direct acting antivirals (DAAs) with high efficacy and tolerability has 
revolutionized treatment of HCV.16,17 Despite this, PWID are faced with multiple barriers to successful 
treatment: in addition to the effects of substance use and its comorbid conditions, PWID face mistrust 
within the medical system, explicit sobriety requirements from insurers, and a lengthy prior 
authorization process which necessitates extensive medical workup before initiating treatment.18-20 
Indeed, data from New York City suggest that only 38% of HCV-diagnosed PWID are engaged in care, and 
only 12% have initiated treatment.21  Engaging and treating HCV in young PWID is further complicated 
by the common reluctance of this population to prioritize an infection that is unlikely to affect them for 
more than a decade.22 
Overcoming the barriers to treat young PWID is essential: DAA therapy has the potential to impact the 
HCV epidemic, and among young PWID, it has the potential to prevent incidence, reduce prevalence, 
and potentially eradicate HCV infections entirely.23-26 However, modelling studies on HCV prevalence 
show that in order to achieve elimination of HCV, extensive treatment scale-up is needed among PWID, 
the group at highest risk of transmitting disease.26-29 The concept of treatment-as-prevention to control 
communicable disease is a cornerstone of public health for a number of diseases, including tuberculosis, 
sexually transmitted infections, and most recently HIV.30 In fact, the demonstration of this concept 
helped to change the paradigm of HIV treatment, supporting early initiation of treatment before CD4 
count reductions. 
Rapid initiation of therapy in individuals at high risk of transmitting disease can help to minimize 
transmission. In a San Francisco study of HIV, the same-day initiation of antiretroviral therapy led to 
significantly faster time to viral suppression without sacrificing effectiveness.31   This outcome was 
accomplished using an intervention consisting of (a) same-day access to an HIV provider, (b) accelerated 
insurance approval process (c) pre-approved regimens (d) 5-day starter packs, (e) observed 
administration of first dose, and (f) telephone follow-up.  A similar model is now being implemented in 
sexually transmitted infection clinics in New York City (JUMPSTART program).  In contrast to HIV where 

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there is an added challenge of retaining patients in care, the curable nature of HCV would appear to 
make it even more amenable to a Rapid Treatment Strategy. 
In the past, a rapid treatment initiation approach would not have been possible for HCV. Interferon 
based therapies came with high toxicity, the need for supervised injection, and extensive medical 
monitoring. The advent of DAAs have allowed for increased decentralization of HCV management and 
treatment: tele-consultation with specialists is allowing treatment prescriptions by primary care 
physicians,32 and the ease of DAA therapy can facilitate treatment to be located at community sites 
rather than in specialty clinics.33,34 Our group, among others, has demonstrated the safety and 
effectiveness of medical evaluation and treatment with DAAs located at a syringe services program (SSP) 
in New York City, with sustained virologic response at 12 weeks (SVR12) of 85%.35, and low rates of re-
infection [unpublished data]. We are now studying this model on a larger scale in a randomized control 
trial comparing accessible SSP-based care with standard of care (R01 DA041298).  However, our 
experience suggests that accessible care may not be sufficient incentive for young PWID to seek HCV 
treatment.  This is especially true for suburban, housed, young PWID who are less likely to frequent 
existing harm reduction services than their older counterparts. To truly impact the prevalence and 
incidence of HCV, models of HCV treatment delivery and prevention need to focus on young, active 
PWID (where ongoing transmission is most concentrated).  
Evidence suggests that high rates of HCV treatment engagement of young PWID is not possible without 
aggressively addressing the various barriers complicating the treatment cascade, specifically the delay 
between HCV confirmation and treatment initiation that currently results not only from the need for 
linkage to an HCV provider but also from (a) extensive pre-treatment lab testing (genotype, fibrosis 
assessment, and resistant testing) and (b) lengthy insurance prior authorization process.   
Our proposed pilot study will examine the acceptability of HCV Seek, Test and Rapid Treatment (HCV 
ST&RT) and the effectiveness of Rapid Treatment Initiation in young PWID involving (1) immediate 
initiation of DAA treatment at time of diagnosis using starter packs, (2) community based treatment 
location, and (3) minimal in-person monitoring with text message-based support during the treatment 
process. We will achieve this using DAA treatment with a pan-genotypic treatment regimen, leveraging 
our existing community partnerships with local SSPs, and using mobile health technology to 
communicate with participants without necessitating frequent office visits.  
2.2 Rationale for Study Design 
2.2.1 Participant selection 
Young PWID face significant challenges engaging with traditional medical care, due to a combination of 
factors. Mutual mistrust within the medical system works against engagement with a traditional, office-
based healthcare status. Desire for confidentiality regarding drug use behaviors, especially among those 
using parental health insurance, may prevent engagement in care. A decreased perception of risk from 
HCV, which has a long latency period, may prevent young adults from prioritizing care for this disease. 
While perceived barriers to receiving treatment are high, and the perceived individual benefit is low, 
there is likely to be a significant societal benefit to treating this population due to the potential to 
prevent transmission among injection networks. HIV co-infected individuals are being excluded, because 
unlike their HIV-uninfected counterparts, significantly more monitoring and engagement than can be 
offered in our study will be needed for this population to address their HIV disease. 

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2.2.2 Treatment regimens used 
The ability to provide same-day treatment is only feasible because of the introduction of pangenotypic 
antiviral regimens in which drug selection and dosing are identical for every HCV genotype and 
regardless of severity of liver disease. We have chosen one such regimen, sofosbuvir/velpatasvir, as our 
drug of choice for this study.  
2.2.3 Schedule of follow up and monitoring 
In keeping with the overall purpose of the intervention, medical visits will be limited to only those that 
are necessary for successful treatment. Current 12-week regimens are well-tolerated with minimal 
toxicity in most patients. At enrollment, HCV RNA PCR, chemistry, liver enzymes, blood count, HIV 
status, HBV status, and a test for liver fibrosis (imaging or laboratory), and a pregnancy test (for female 
patients) will be ordered. HCV RNA positive patients in the intervention arm will be asked to start 
medications after results of laboratory testing are reviewed. After medication start, one laboratory visit 
will be scheduled at 4 weeks to monitor liver enzymes and assess for on-treatment response via HCV 
PCR. Subsequently, liver enzymes and HCV PCR will be drawn at the end of treatment and 12 weeks of 
follow up to confirm response and cure. The purpose of the final monitoring visit will be to assess for 
HCV reinfection. Additional testing may be done if deemed necessary by clinical staff or to follow-up on 
abnormal results. Apart from the 4 study visits, the participants will each be contacted at least monthly 
by secure text message or phone call, and additional visits scheduled only if requested by the participant 
or deemed necessary by clinical staff. Participants randomized to the control arm, and HCV-negative 
participants in the intervention arm, will have text message or phone check in every month to 
determine their HCV treatment status., and study visits every 12 weeks for questionnaire, interview, and 
HCV RNA testing.  
2.2.4 Outcome selection 
The primary outcome of SVR12 is selected as a binary measure, due its use as a surrogate marker for 
HCV cure. Secondary outcomes will assess movements of participants along the HCV treatment 
continuum, and allow for identification of participants who were lost to follow up during treatment, a 
potentially important outcome in this population. There is concern that a participation of current PWID 
may be subject to reinfection after cure, and we will assess for this by repeating HCV RNA at 48 weeks. 
While longer follow-up for reinfection would be valuable, we do not feel it is feasible in the current 
study. Finally, to assess the acceptability of this intervention, examine its impact on substance use 
behaviors and injection risk, and to refine future iterations, we will solicit participant outcomes via 
survey and interview. 
2.3 Summary of Risks and Benefits 
Potential risks of the study include: 
• 
Breach of confidentiality regarding drug use behaviors and hepatitis C disease status 
• 
Adverse events from HCV treatment 
• 
Adverse events from study related laboratory and imaging tests 
• 
In the event of treatment failure, there is a risk of resistance developing to the treatment 
regimen 
• 
Emotional distress from survey and interview questions pertaining to sensitive topics including 
mental illness, sexual health, and substance use behaviors.  

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Potential benefits of the study include: 
• 
In the intervention arm, easily accessible HCV treatment that bypasses insurance authorization 
procedures and associated benefits of HCV cure 
• 
Linkage to harm reduction services for PWID, with facilitated referral to substance use 
treatment if interested 
• 
Public health benefit of HCV treatment in PWID, in terms of theoretical reduction in 
transmission potential. 
• 
Financial compensation for participation in study procedures 
3.0 Study Design 
This is a single-center, open-label, randomized controlled trial, in which 72 HCV antibody positive 
participants between ages 18-29 will be recruited in two parts. During Part A, participants will be 
randomized to either the rapid treatment intervention arm, or the usual care control arm. During Part B, 
participants will be enrolled to the telemedicine arm. Recruited individuals must have used injection 
drugs in the past 30 days, have no medical contraindication to sofosbuvir and velpatasvir treatment, be 
HIV uninfected, and be HCV treatment naïve. During part B, they must have access to technology that 
allows telemedicine interventions (eg telephone, smartphone, or internet connection).  
The goal of the study is to provide same-day, easily accessed medical evaluation and treatment to the 
intervention arm. During part A, participants randomized to the intervention will receive medical 
evaluation, laboratory assessment including confirmatory HCV RNA testing, baseline 
questionnaire/interview, and distribution of a 7-day medication “starter pack” on the day of enrollment. 
Participants who are HCV RNA negative will be notified by phone call, be asked to return their 
medications but continue to be followed for research visits every 12 weeks, similar to the control-arm. 
During part B, participants will have the option of an in-person evaluation at the syringe service program 
or a telemedicine visit on the day of enrollment or the following day. They will receive community based 
laboratory testing at a location that is convenient to them, and participate in study interview. 
During part A, HCV RNA positive participants in the intervention arm will be asked to start medications, 
and return to pick up an additional 21-day supply. They will receive weekly text messages during 
treatment to record adherence. They will receive one follow-up medical visit at 4 weeks with laboratory 
evaluation, with distribution of the remainder of medications, and another visit at the end of treatment. 
One of these two visits (the participants’ choice) will include counseling for prevention of reinfection. 
They will then have HCV RNA PCR testing at end of treatment and 12 weeks post treatment, and at 48 
weeks to assess for reinfection. Each study visit will include a brief questionnaire and qualitative 
interview.  
Participants in the control arm will be provided facilitated referral to community HCV providers by an 
on-site care coordinator already facilitating care at the community site. HCV RNA negative participants 
will be called to inform them of these results, and then discontinued from the study. HCV RNA positive 
participants will be  asked during the semi-structured interviews as at 12, 24, 36 and 48 week if they 
engaged in HCV treatment to assess whether their HCV referral has been filled, and to record their 
current HCV treatment status.  They will also receive repeat HCV RNA testing at week 12, 24, and 48. 
Participants that have started treatment will be asked to sign consent for release of medical records 
pertaining to HCV-related laboratory testing to determine achievement of treatment response.  

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During part B, HCV RNA positive participants will have a 28-day supply of medications delivered, or 
available for pickup, as they prefer. The schedule of visits will be similar except that laboratory testing at 
week 4 will be optional, and all visits will be offered through telemedicine. 
The three arms will be compared for the main outcome of SVR12 using a modified intention to treat 
analysis in which participants will be analyzed in the group they are randomized except for those who 
are (a) discontinued due to HCV RNA negative status or (b) found to have previously undiagnosed HIV at 
enrollment. Secondary outcomes will be compared using the same modified intention to treat design.  
4. Participant Selection and Enrollment 
Participants will be recruited by referral from an ongoing NIH funded study. The parent study aims to 
prevent HCV among young current PWID (R01DA041501). Potential enrollees for the parent study will 
receive baseline HCV antibody testing, and those that test positive will be referred to ST&RT. 
Participants willing to enroll may be offered a same-day or next business day visit to assess for eligibility. 
If eligible for ST&RT, participants will receive informed consent. Ineligible participants may be offered 
enrollment into other ongoing studies. We do not expect to enroll participants from other referral 
sources for this study; however, participants meeting the inclusion criteria from other sources will also 
be considered if otherwise eligible For participants enrolling in part B, enrollment may occur in person 
or remotely (i.e. without person to person contact). 

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5 Study Procedures 
5.1 Schedule of Events during Part A: 
 
Screenin
g 
(perform
ed by 
parent 
study 
Entry 
On-Treatment 
Post-Treatment 
Additional 
tests if 
Treatment 
interrupti
on 
Addition
al tests if 
Reinfecti
on or 
Relapse 
 
 
Week 0 
Week 4 
Week 12 
Week 
16 
Week 24 
Week 36 
Week 48 
 
 
Randomized Arm 
 
Int. 
Con. Int. 
Con. Int. 
Con. In
t 
Co
n 
Int. 
Con. Int. 
Con. Int. 
Con.  
 
HCV Antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HCV RNA 
PCR 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
HIV-1/2 Antibody 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
Hepatic Function 
Panel 
 
X 
 
X† 
 
X† 
 
 
 
X† 
 
 
 
X† 
 
 
 
Hematology (CBCC) 
 
X 
 
 
 
 
 
 
 
X† 
 
 
 
 
 
 
 
Basic Metabolic 
Panel 
 
X 
 
X† 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FIB-4 (calculated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B panel 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(female 
participants) 
 
X 
 
X*
† 
 
X*
† 
 
 
 
 
 
 
 
 
 
 
 
HCV genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X† 
Physical Exam 
 
X 
 
X*
† 
 
X*
† 
 
 
 
 
 
 
 
 
 
 
 
Adherence 
Assessment  
 
 
 
Weekly for Int. arm† 
 
 
 
 
 
 
 
 
 
 

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Reinfection 
Prevention 
counseling 
 
 
 
Once for int. arm† 
 
 
 
 
 
 
 
 
 
 
Questionnaire and 
Interview 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Stored serum / 
plasma** 
 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
*If medically indicated 
**In event phlebotomy is unavailable or unsuccessful, dried blood spots may be obtained by finger stick 
† HCV RNA PCR Positive participants only  
Windows: week 4 has a window of -7 days or + 14 days; Week 12 and 16 have a window of +7 days. Weeks 24 and 36 have a window of -14 to 
+28 days, and Week 48 has a window of -14 days.  
 
 

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5.2 Schedule of Events during Part B: 
 
 
Screenin
g 
(perform
ed by 
parent 
study 
Entry 
On-Treatment 
Post-Treatment 
Additional 
tests if 
Treatment 
interrupti
on 
Addition
al tests if 
Reinfecti
on or 
Relapse 
 
 
Week 
0 
Week 
4 
Week 
12 
Week 
16 
Week 
24 
Week 
36 
Week 
48 
 
 
Arm 
 
Tel. 
Tel. 
Tel. 
Tel. 
Tel. 
Tel. 
Tel. 
 
 
HCV Antibody 
X 
 
 
 
 
 
 
 
 
 
Plasma HCV RNA 
PCR 
 
X 
X‡ 
X 
X‡ 
X 
X 
X 
X 
 
HIV-1/2 Antibody 
X 
 
 
 
 
X 
 
X 
 
 
Hepatic Function 
Panel 
 
X 
X†‡ 
X† 
 
X† 
 
X† 
 
 
Hematology (CBCC) 
 
X 
 
 
 
X† 
 
 
 
 
Basic Metabolic 
Panel 
 
X 
X†‡ 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
 
 
FIB-4 (calculated) 
 
X 
 
 
 
 
 
 
 
 
Hepatitis B panel 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test 
(female 
participants) 
 
X 
X*†‡ 
X*† 
 
 
 
 
 
 
HCV genotyping 
 
X 
 
 
 
 
 
 
 
X† 
Physical Exam 
 
* 
* 
* 
 
 
 
 
 
 
Adherence 
Assessment  
 
 
Weekly † 
 
 
 
 
 
 
Reinfection 
Prevention 
counseling 
 
 
Once† 
 
 
 
 
 
 

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Questionnaire and 
Interview 
 
X 
 
X 
 
X 
X 
X 
 
 
Stored serum / 
plasma** 
 
X‡ 
 
X‡ 
X‡ 
X‡ 
X‡ 
X‡ 
 
X‡ 
*If medically indicated 
**In event phlebotomy is unavailable or unsuccessful, dried blood spots may be obtained by finger stick 
† HCV RNA PCR Positive participants only  
‡ Optional Lab draw 
Windows: week 4 has a window of -7 days or + 14 days; Week 12 and 16 have a window of +7 days. Weeks 24 and 36 have a window of -14 to 
+28 days, and Week 48 has a window of -14 days.  
 
 

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5.2 Laboratory evaluations 
5.2.1 HCV RNA PCR  
HCV RNA PCR will be collected and performed at a clinical laboratory (Roche Diagnostics COBAS 
TaqMan). HCV RNA PCR will be performed for all participants at each study visit, regardless of 
randomized treatment arm.  
5.2.2 HIV-1/2 Antibody 
Participants referred to ST&RT will be required to have a positive HCV antibody and negative HIV 
antibody test prior to consent and randomization. On-site HIV testing will be offered prior to entry to 
participants who do not already have a documented negative antibody. HIV retesting will be every 6 
months thereafter, in keeping with recommendations for individuals at ongoing risk for acquisition.  As 
necessary, patients will be referred for additional HIV testing, including testing for acute retroviral 
infection using HIV-1 RNA PCR 
5.2.3 FIB-4 
The FIB-4 score will be calculated from laboratory testing using the following formula:36 
Fib-4 = Age (years) * AST Level (U/L)  
             Platelet count (109/L)*sq.rt.(ALT(U/L)) 
With a score of >3.25 representing advanced fibrosis.  
5.2.4 Hepatitis B Panel 
HBV testing will consist of HBV surface antigen, HBV surface antibody, HBV core antibody, HBV envelope 
antibody. HBV testing will be performed on all intervention participants at study entry.   
5.2.5 Pregnancy Test 
Serum beta-HCG will be performed for pregnancy test at study entry for all female participants, and may 
be performed again if there is concern for pregnancy. Participants of childbearing age will be provided 
contraceptive counseling, iterating the importance of contraception while on study medications.  
5.3 Adherence Assessment 
Adherence will be assessed for intervention group patients while on treatment. This will be 
accomplished by weekly secure text messaging consisting of a single item question.37 
5.4 Qualitative and Questionnaire Evaluation 
In-person interviews will be conducted for a sample of participants at the end of therapy (week 12), and 
at week 24, and 48. Participants will be asked to identify factors that promote or hinder engagement in 
HCV treatment, harm reduction services or substance use treatment. We will also inquire about 
participants substance use, sexual, and injection risk behaviors pre-, during and post- treatment.  
Participants who refuse interview will still be offered the HCV treatment.  At the end of therapy, 
participants will be asked about changes in these factors, about uptake of safer injecting practices, 
engagement in harm reduction or substance use treatment, and the acceptability of the Seek, Test, and 
Rapid Treatment intervention.  
 5.5 Monitoring for reinfection 
Participants in the intervention arm who receive treatment will have two post-treatment HCV RNA PCR 
tests, at 24 and 48 weeks, to monitor for re-infection after treatment completion. Participants who did 

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not receive treatment, either because of HCV-negative status or because of other reasons, will have HCV 
RNA PCR testing at 24 and 48 weeks. All participants in the control arm, regardless of HCV RNA status, 
will have HCV RNA PCR testing at 24 and 48 weeks, but it is expected that these may not be “post-
treatment,” as we expect treatment initiation to be delayed for the control participants.  
True reinfection will be defined as a positive HCV RNA PCR with a different HCV genotype, occurring 
anytime after a documented SVR 12 (negative HCV RNA PCR 12 weeks or more after treatment 
completion). 
Participants who (1) did not have a documented SVR 12 but did have a documented end-of-treatment 
response or SVR 4, and subsequently have a positive HCV RNA PCR OR (2) have a positive HCV RNA PCR 
after documented SVR12 with the same genotype as the initial infection, will be classified as possible 
reinfections. These participants will then be reclassified as either true reinfections or relapses based on 
viral sequencing of their baseline HCV infection compared to subsequent positive HCV RNA PCRs.38  
5.6 Monitoring for incident HCV infection 
Participants who had a negative HCV RNA PCR at baseline (or whose HCV RNA PCR became negative 
without treatment), who subsequently have a positive HCV RNA PCR will be considered incident HCV 
infections, but not reinfections. 
5.7 Reinfection Prevention Counseling 
All HCV RNA positive participants in the intervention arm will be scheduled for a harm reduction 
counseling session focusing specifically on HCV reinfection prevention. Participants will receive a 
condensed version of Staying Safe (Ssafe). Ssafe is an innovative, strengths-based, socio-behavioral HCV 
prevention intervention for young PWID. Ssafe addresses multi-level “upstream” determinants of risk 
that occur relatively early in the causal chain of risk, including eco-social conditions, social relations and 
risk situations, in addition to directly targeting risky injection practices. Ssafe trains and motivates PWID 
to better manage drug use to avoid situations and practices that promote risky injection (e.g., “binging” 
on drugs), and to implement health-protective behaviors (e.g., promoting risk-reduction norms in 
injection networks).  Additionally, referral to existing LESHRC services will be encouraged including 
syringe exchange, overdose prevention, substance use treatment, and social services 
5.8 Storage of samples for future analyses  
All participants in part A will have plasma samples and/or dried blood spots (in event phlebotomy 
unavailable or unsuccessful) stored at the Weill Cornell Clinical and Translational Science Center 
laboratory. Future analyses will include HCV genotyping in instances of reinfection or treatment failure, 
and phylogenetic analyses of HCV virus. Participants in Part B will have samples stored when feasible, 
which we expect to be uncommon as laboratory testing will largely occur at community sites. 
6. Clinical Management Issues 
6.1 Chronic Kidney disease 
Estimated GFR will be calculated based on the CKD-EPI formula based on baseline laboratory testing. 
Participants with chronic kidney disease stage 4 or 5, defined as estimated GFR < 30 mL/min, or those 
reporting hemodialysis will be discontinued from the study.   Participants with any amount of chronic 
renal impairment will be counseled about the potential for a higher degree of side effects that may be 
observed in these groups, in accordance with national guidelines39  

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6.2 Cirrhosis and severe liver disease 
Participants will have laboratory assessment for cirrhosis via FIB-4 as described in section 5.2. 
Participants with decompensated cirrhosis by physical exam, as determined by the treating physician on 
the basis of variceal bleeding, ascites, hepatic encephalopathy, or jaundice, will be discontinued from 
the study and referred to a hepatology specialist for co-management of cirrhosis and HCV. Participants 
compensated cirrhosis, after completion of HCV treatment, will be referred to primary care or 
hepatology for ongoing evaluation of cirrhosis including HCV screening.  
6.3 Incident HIV infection 
Participants who are initially HIV negative but seroconvert to HIV during the study will remain included 
in the study. They will be analyzed with the arm in which they were randomized. They will be offered to 
linkage to HIV primary care at an HIV provider local to them. 
6.4 Pregnancy 
Participants who initially have a negative pregnancy test but become pregnant during the study and are 
already on HCV treatment will be told the potential risks and benefits regarding continuation, and a joint 
decision between participant and provider will be made regarding continuation of therapy. Participants 
who are found to be pregnant before initiating therapy will not be started on treatment but remain in 
the study. Participants who become pregnant after treatment completion will remain in the study.  
6.5 Hepatitis B Reactivation 
Participants who have evidence of chronic HBV infection (positive HBV surface antigen) will be 
monitored for signs of reactivation including elevation of liver enzymes or clinical symptoms such as 
jaundice. Those who do have signs of reinfection will be provided with facilitated referral to an HBV 
treatment provider for treatment. Those who do not have evidence of HBV immunity (negative HBV 
surface antibody and negative HBV surface antigen) will be referred for HBV vaccination. 
6.6 Treatment failure 
Participants in the intervention arm with treatment failure, defined as positive HCV RNA PCR at end of 
treatment or post-treatment week 4, will be referred to a specialist office for further management of 
their HCV. 
6.7 Hepatitis C Reinfection 
Participants treated in the intervention arm who develop HCV reinfection as defined in section 5.5 will 
be referred to a specialist office for management of their HCV.  
6.8 Incident hepatitis  C infection 
Participants with incident hepatitis C as defined in section 5.6 will be given options for treatment of their 
HCV. These may include enrollment in other studies (if eligible) or referral to an external provider for 
management of their HCV.  
6.9 Drug Interactions 
Participants will be assessed for the following drug interactions based on commonly observed co-
administered medications: H2-receptor antagonists in doses exceeding famotidine 40mg twice daily, 
proton-pump inhibitors in doses exceeding omeprazole 20mg daily, amiodarone, digoxin, topotecan, 
phenytoin, phenobarbital, carbamazepine, oxcarbazepine, rifampin, rifapentine, rifabutin, St John’s 
Wort, rosuvastatin at doses exceeding 10mg. Where alternatives can be found, they will be utilized in 

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conjunction with the prescribing provider. Participants with treatment-limiting drug interactions for 
which no alternative can be found will be excluded from study and referred to HCV treatment specialists 
off-site. 
6.10 Storage and distribution of medications 
Medications will be stored at the treatment site for immediate dispensation to enrollees as described 
above. These will be stored in a combination locked safe, for a maximum of 2 months, with temperature 
maintained below 30 deg C as detailed in the package insert.  
7 Criteria for discontinuation 
7.1 HCV treatment discontinuation 
Participants in the intervention arm who discontinue HCV treatment prematurely for any reason will 
remain in the study. If more than 5 consecutive days of study medication were missed, the study 
investigator will advise treatment be held and offer HCV RNA testing.  Based on these results, the study 
investigator will determine if re-initiation and completion of treatment should occur.  
7.2 Study withdrawal and discontinuation 
Participants may be withdrawn from the study at any time at their own request. They may also be 
discontinued from the study if, at any time, they are considered by study investigators to be unlikely to 
be able to participate in necessary follow up (e.g. due to severe illness, incarceration, change of 
residence). However, in keeping with the overall goal of the intervention, participants who are unwilling 
to partake in interviews or questionnaires, or undergo blood tests, will still remain in the study.  
8 Statistical and analytic considerations 
8.1 Sample size 
Our own data (and others) suggests a SVR12 rate of 85% in active PWID (30), and existing literature 
suggests the control arm will have a very low uptake of HCV treatment (12% initiate treatment). (16) 
Using these estimates and an alpha =0.05, we have 100% power to detect a difference. However given 
the available referral and linkage programs, the control arm may have better HCV uptake and SVR 12 
rates than predicted by literature. Assuming 41% (11/27) of participants in the control arm achieve 
SVR12, we will have 80% power to detect an SVR of 78% in the intervention arm. 
In addition to have an adequate sample size to compare the primary end point of SVR12 rates with the 
control arm, a sample size of 27 HCV infected participants in Rapid Treatment arm allows for 90% power 
to show with reasonable certainty that the underlying true SVR12 rate is greater than 60% in the Rapid 
Treatment arm, assuming that this true rate is actually 85%. 
The table below also shows two-sided exact Blyth-Still-Casella (BSC) 90% CIs for potential observed SVR 
proportions for 27 enrolled participants. With a HCV infected sample size of 27 participants, the CI for 
the true SVR12 rate will be entirely above 60% if 21 or more of the 27 participants achieve SVR12. 
Patients enrolled and found not to have detectable HCV RNA will be replaced. Assuming 75% of HCV 
antibody positive individuals will be infected with HCV (positive HCV RNA), we anticipate have to enroll 
roughly 36 participants in each arm to acquire 27 with confirmed viremia. 
 

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Observed SVR12 Rate 
90% CI for True SVR12 Rate 
85% (23/27) 
(71%, 93%) 
81% (22/27) 
(65%, 90%) 
78% (21/27) 
(62%, 90%) 
74% (20/27) 
(58%, 85%) 
70% (19/27) 
(54%, 84%) 
67% (18/27) 
(50%, 80%) 
 
As of this amendment, data from part A will be analyzed based on enrollment through March 1 2020, so 
the power to detect a difference will be reduced from the above calculation. This is due to the break in 
enrollment that was necessary during the COVID-19 pandemic.  
8.2 Randomization 
Participants will be randomly assigned to the intervention or control condition in a 1:1 ratio using 
randomly permuted blocks.  Participants randomized in the intervention arm will receive medical 
evaluation and distribution of “starter pack.” Participants in the control arm will be provided referral to 
community HCV providers. 
8.3 Data Analysis 
8.3.1 Analysis of clinical outcomes data 
For the primary analysis, after the completion of part A, we will compare the proportion of patients who 
achieve SVR12 in each arm using Chi-square or Fishers’ exact testing, using an intention-to-treat 
approach in which participants are analyzed in the group to which they are randomized. Participants 
with negative confirmatory HCV RNA PCR tests on study entry will not be included in the analysis.  
For secondary analyses, we will: 
- 
Compare the proportion of patients who achieve end-of-treatment response using Chi-square or 
Fishers’ exact testing 
- 
Compare the proportion of patients who complete treatment, using Chi-square or Fishers’ exact 
testing 
- 
Compare the proportion of patients who have HCV reinfection, using Chi-square or Fishers’ 
exact testing 
- 
Describe adherence for participants in the Intervention arm only 
- 
Describe demographic, clinical and behavioral factors for participants who have HCV reinfection 
or incident HCV infection 
We will also perform the same analyses using an “as-treated” approach, in which participants in the 
intervention arm will not be included if they failed to initiate HCV treatment, or discontinued treatment 
for reasons clearly unrelated to the treatment intervention (e.g. relocation, incarceration).  
After the completion of part B, we will compare the proportion of patients who achieve SVR12 in each 
Part B telemedicine to  (1)Part A intervention  (2) Part A control,  using Chi-square or Fishers’ exact 
testing, using an intention-to-treat approach in which participants are analyzed in the group to which 
they are randomized. Participants with negative confirmatory HCV RNA PCR tests on study entry will not 
be included in the analysis. 

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8.3.2 Analyses for qualitative data 
A subset of patients will be selected for qualitative interview from each arm. Participants will be 
recruited using purposive sampling, aiming for diversity of demographic characteristics, HCV risk factors, 
and treatment outcomes. Qualitative interviews will be analyzed using content analysis, creating codes 
and synthesizing them into dominant themes.  
9. References: 
1. 
Glick SN, Prohaska SM, LaKosky PA, Juarez AM, Corcorran MA, Des Jarlais DC. The Impact of 
COVID-19 on Syringe Services Programs in the United States. AIDS Behav. 2020. 
2. 
Mann DM, Chen J, Chunara R, Testa PA, Nov O. COVID-19 transforms health care through 
telemedicine: evidence from the field. J Am Med Inform Assoc. 2020. 
3. 
Rajasekaran K. Access to Telemedicine-Are We Doing All That We Can during the COVID-19 
Pandemic? Otolaryngol Head Neck Surg. 2020:194599820925049. 
4. 
Talal AH, McLeod A, Andrews P, et al. Patient Reaction to Telemedicine for Clinical Management 
of Hepatitis C Virus Integrated into an Opioid Treatment Program. Telemed J E Health. 
2019;25(9):791-801. 
5. 
Cooper CL, Hatashita H, Corsi DJ, Parmar P, Corrin R, Garber G. Direct-Acting Antiviral Therapy 
Outcomes in Canadian Chronic Hepatitis C Telemedicine Patients. Ann Hepatol. 2017;16(6):874-
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6. 
Jones CM, Logan J, Gladden RM, Bohm MK. Vital Signs: Demographic and Substance Use Trends 
Among Heroin Users - United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 
2015;64(26):719-725. 
7. 
Viral Hepatitis Surveillance - United States. In: Division of Viral Hepatitis - Centers for Disease 
Control, ed2013. 
8. 
Viral Hepatitis Surveillance - United States. In: Division of Viral Hepatitis - Centers for Disease 
Control, ed2014. 
9. 
Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis C virus infection related to injection drug 
use among persons aged </=30 years - Kentucky, Tennessee, Virginia, and West Virginia, 2006-
2012. MMWR Morb Mortal Wkly Rep. 2015;64(17):453-458. 
10. 
Peters PJ, Pontones P, Hoover KW, et al. HIV Infection Linked to Injection Use of Oxymorphone 
in Indiana, 2014-2015. N Engl J Med. 2016;375(3):229-239. 
11. 
Centers for Disease C, Prevention. Notes from the field : hepatitis C virus infections among 
young adults--rural Wisconsin, 2010. MMWR Morb Mortal Wkly Rep. 2012;61(19):358. 
12. 
Centers for Disease C, Prevention. Notes from the field: risk factors for hepatitis C virus 
infections among young adults--Massachusetts, 2010. MMWR Morb Mortal Wkly Rep. 
2011;60(42):1457-1458. 
13. 
Centers for Disease C, Prevention. Use of enhanced surveillance for hepatitis C virus infection to 
detect a cluster among young injection-drug users--new York, November 2004-April 2007. 
MMWR Morb Mortal Wkly Rep. 2008;57(19):517-521. 
14. 
Zibbell JE, Hart-Malloy R, Barry J, Fan L, Flanigan C. Risk factors for HCV infection among young 
adults in rural New York who inject prescription opioid analgesics. Am J Public Health. 
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15. 
Van Handel MM, Rose CE, Hallisey EJ, et al. County-Level Vulnerability Assessment for Rapid 
Dissemination of HIV or HCV Infections Among Persons Who Inject Drugs, United States. J Acquir 
Immune Defic Syndr. 2016;73(3):323-331. 
16. 
AASLD/IDSA/IAS-USA. Recommendations for testing, managing, and treating hepatitis C. 2017; 
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17. 
Hoofnagle JH, Sherker AH. Therapy for hepatitis C--the costs of success. N Engl J Med. 
2014;370(16):1552-1553. 
18. 
Edlin BR, Kresina TF, Raymond DB, et al. Overcoming barriers to prevention, care, and treatment 
of hepatitis C in illicit drug users. Clin Infect Dis. 2005;40 Suppl 5:S276-285. 
19. 
Do A, Mittal Y, Liapakis A, et al. Drug Authorization for Sofosbuvir/Ledipasvir (Harvoni) for 
Chronic HCV Infection in a Real-World Cohort: A New Barrier in the HCV Care Cascade. PLoS One. 
2015;10(8):e0135645. 
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Lo Re V, 3rd, Gowda C, Urick PN, et al. Disparities in Absolute Denial of Modern Hepatitis C 
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2015-3.pdf. Accessed 20 May, 2018. 
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Jordan AE, Masson CL, Mateu-Gelabert P, et al. Perceptions of drug users regarding hepatitis C 
screening and care: a qualitative study. Harm Reduct J. 2013;10:10. 
23. 
Edlin BR, Winkelstein ER. Can hepatitis C be eradicated in the United States? Antiviral Res. 
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Grebely J, Dore GJ. Can hepatitis C virus infection be eradicated in people who inject drugs? 
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