Interventions to Curb Hepatitis C Reinfections Among Men Who Have Sex With Men
Phase: NA
Conditions: Hepatitis C Virus Infection
Sponsor: Public Health Service of Amsterdam

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INTERVENTIONS TO CURB HEPATITIS C REINFECTIONS 
AMONG MEN WHO HAVE SEX WITH MEN  
 
The ICECREAM study 
 
 
 
 
A Randomized Trial  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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INTERVENTIONS TO CURB HEPATITIS C REINFECTIONS AMONG MEN WHO 
HAVE SEX WITH MEN 
 
Protocol ID 
INTERVENTIONS TO CURB HEPATITIS C 
REINFECTIONS AMONG MEN WHO HAVE SEX 
WITH MEN 
Short title 
The ICECREAM Study  
EudraCT number  
Not applicable  
Version 
7.0 
Date 
17-03-2022 
Project leader  
 
Kris Hage, MSc, PhD Student, Public Health Service 
of Amsterdam, University of Amsterdam 
khage@ggd.amsterdam.nl 
020-5555049 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
Public Health Service of Amsterdam  
Prof. dr. Maria Prins, professor of Public Health and 
Epidemiology of Infectious Diseases at the 
Amsterdam University Medical Centers (UMC), 
Location Academic Medical Center (AMC), University 
of Amsterdam and head of the Department of 
Infectious Diseases Research and Prevention of the 
Public Health Service of Amsterdam 
mprins@ggd.amsterdam.nl 
 
Amsterdam UMC, Location AMC 
Dr. M. van der Valk, Infectious Diseases specialist 
and head of the HIV clinic, Amsterdam UMC location 
AMC, m.vandervalk@amsterdamumc.nl 
 
DC Clinic Lairesse, Amsterdam  
Dr. M. van der Valk, Infectious Diseases specialist 
and head of the HIV clinic, DC Clinic Lairesse 
Amsterdam, mvandervalk@dcklinieken.nl 
 
 
 

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Medical Center Jan van Goyen  
Dr. D.W.M. Verhagen, Infectious Diseases specialist, 
Medical Center Jan van Goyen, dverhagen@jvg.nl 
 
Onze Lieve Vrouwe Gasthuis 
Dr. Janneke Stalenhoef, Infectious Diseases 
specialist, Onze Lieve Vrouwe Gasthuis, 
j.e.stalenhoef@olvg.nl 
 
Amsterdam UMC, location VU Medical center  
Dr. M. van der Valk, Infectious Diseases specialist 
and head of the HIV clinic, Amsterdam UMC location 
AMC, m.vandervalk@amsterdamumc.nl 
 
Maasstad Ziekenhuis 
Dr J.G. den Hollander, Infectious Diseases specialist, 
Maasstad Ziekenhuis, 
hollanderj@maasstadziekenhuis.nl 
 
Haaglanden Medical Center 
Dr. E.M.S. Leyten, Infectious Diseases specialist, 
Haaglanden Medical Center, 
e.leyten@haaglandenmc.nl 
 
University Medical Center Utrecht 
Dr. T. Mudrikova, Infectious Disease specialist, 
University Medical Center Utrecht, 
t.mudrikova@umcutrecht.nl 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Public Health Service of Amsterdam (GGD 
Amsterdam) 
 
Subsidising party 
The Netherlands Organisation for Health Research 
and Development (ZonMw) 
 

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Independent expert 
Prof. dr. Joost Wiersinga, MD PhD, chair of the 
Division of Infectious Diseases, Amsterdam UMC, 
Location AMC, University of Amsterdam, 
w.j.wiersinga@amsterdamumc.nl 
 
Laboratory sites 
Virology Laboratory at the Medical Microbiology 
department of the UMC location AMC 
Dr. Janke Schinkel, j.schinkel@amsterdamumc.nl 
 
 
Pharmacy 
Not applicable  
 
 

NL68718.018.19                                                                                                The ICECREAM study  
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department/Principal 
Investigator: 
Prof. dr. Maria Prins, professor of Public 
Health and Epidemiology of Infectious 
Diseases at the AMC and head of the 
Department of Research and Prevention of 
the Public Health Service of Amsterdam  
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................10 
1.1 
Background ............................................................................................................10 
1.2 
HCV in the Netherlands ..........................................................................................10 
1.3 
HCV among men who have sex with men ..............................................................10 
1.4 
HCV treatment .......................................................................................................11 
1.5 
Interventions to prevent HCV reinfection ................................................................12 
2. 
OBJECTIVES ................................................................................................................13 
3. 
STUDY DESIGN ...........................................................................................................14 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 
Population (base) ...................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................17 
4.3 
Exclusion criteria ....................................................................................................17 
4.4 
Sample size calculation ..........................................................................................17 
5. 
TREATMENT OF SUBJECTS .......................................................................................18 
5.1 
Arm I: behavioural intervention ...............................................................................18 
5.2 
Arm II: home-based testing intervention .................................................................20 
5.3 
Arm III: behavioural and home-based testing intervention combined ......................21 
6. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................22 
6.1 
Name and description of the self-sampled dried blot spots .....................................22 
6.2 
Summary of findings from clinical studies ...............................................................22 
7. 
METHODS ....................................................................................................................23 
7.1 
Study parameters/endpoints ...................................................................................23 
7.1.1 
Main study parameter/endpoint .......................................................................23 
7.1.2 
Secondary study parameters/endpoints ..........................................................23 
7.1.3 
Other study parameters ...................................................................................24 
7.2 
Randomisation, blinding and treatment allocation ..................................................25 
7.3 
Study procedures ...................................................................................................25 
7.4 
Withdrawal of individual subjects ............................................................................27 
7.5 
Replacement of individual subjects after withdrawal ...............................................27 
8. 
SAFETY REPORTING ..................................................................................................28 
8.1 
Temporary halt for reasons of subject safety ..........................................................28 
8.2 
Data Safety Monitoring Board (DSMB) / Safety Committee ....................................28 
9. 
STATISTICAL ANALYSIS .............................................................................................29 
9.1 
Primary study parameter(s) ....................................................................................29 
9.2 
Secondary study parameter(s) ...............................................................................30 
9.3 
Other study parameters ..........................................................................................30 
9.4 
Interim analysis ......................................................................................................30 
9.5 
Mathematical modelling ..........................................................................................30 
10. 
ETHICAL CONSIDERATIONS ...................................................................................31 
10.1 
Regulation statement .............................................................................................31 
10.2 
Recruitment and consent........................................................................................31 

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10.3 
Benefits and risks assessment, group relatedness .................................................31 
10.4 
Compensation for injury .........................................................................................32 
10.5 
Incentives ...............................................................................................................32 
11. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................33 
11.1 
Handling and storage of data and documents ........................................................33 
11.2 
Amendments ..........................................................................................................35 
11.3 
Annual progress report ...........................................................................................35 
11.4 
Temporary halt and (prematurely) end of study report ............................................35 
11.5 
Public disclosure and publication policy ..................................................................35 
12. 
REFERENCES ..........................................................................................................37 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AMPrEP project 
Amsterdam PrEP project 
ANRS 
The National Agency of Research on AIDS and viral hepatitis  
CMS 
Content Management System  
DAA 
Direct-Acting Antivirals  
DBS 
Dried Blot Spots 
DSMB 
Data Safety Monitoring Board 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IMB model 
Information-Motivation-Behavioural skills model  
ICECREAM  
Interventions to Curb hEpatitis C Reinfections Among Men who 
have sex with men 
InPrEP project 
Informal PrEP project 
ITT 
Intention To Treat  
METC  
 
Medical research ethics committee (MREC); in Dutch: medisch 
ethische toetsing commissie (METC) 
MOSAIC 
MSM Observational Study of Acute Infection with hepatitis C 
MSM 
Men who have Sex with Men  
NGO 
Non-Governmental Organization  
OR 
Odds Ratio 
PP 
Per Protocol  
PrEP 
Pre-Exposure Prophylaxis  
RNA 
RiboNucleic Acid 
ROC  
Receiver Operating Characteristic 
RT 
Randomized Trial 
SHM 
The Dutch HIV monitoring foundation (in Dutch: Stichting HIV 
Monitoring) 
STI 
Sexually Transmitted Infection  
SVR 
Sustained Virological Response  
WHO 
World Health Organization  
WMO 
 
Medical Research Involving Human Subjects Act (in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
ZonMw 
The Netherlands Organisation for Health Research and 
Development (in Dutch: Nederlandse organisatie voor 
gezondheidsonderzoek en zorginnovatie) 
 
 

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SUMMARY 
 
Rationale: As highly effective therapy against hepatitis C virus (HCV) infection is available 
with rapid uptake, there is newfound optimism for HCV elimination. Nevertheless, HCV 
reinfections cause great concern in at risk populations, including men who have sex with 
men (MSM). In the Netherlands, MSM account for the majority of new HCV (re)infections. 
Although HCV treatment uptake is high in this group, modelling data indicate HCV 
elimination would not be feasible without a reduction in risk behaviour. This finding highlights 
the urgent need for effective interventions aimed at reducing risk behaviour and preventing 
reinfections in MSM.  
Objective: To evaluate interventions aimed at reducing risk behaviour, and ultimately 
preventing HCV reinfections and onward spread of HCV. 
Study design: Using a 3-arm randomised trial comparing run-in and intervention periods, we 
will evaluate the effect of two interventions and its combination on risk behaviour in MSM 
previously infected with HCV.  
Study population: MSM aged 18 years or older with a history of a successfully treated or 
spontaneously cleared HCV infection.  
Interventions: Intervention I is a targeted, online behavioural intervention developed as part 
of the project. Intervention II aims to increase the frequency of testing by offering an 
additional patient-initiated, home-based HCV RNA testing service with the use of self-
sampled dried blot spots. Intervention III is a combination of intervention I and II. 
Main study parameters/endpoints: From run-in and post-randomization questionnaires, we 
will evaluate the proportion at risk of HCV infection (as determined by the HCV-MOSAIC 
score) as the primary outcome. The HCV-MOSAIC risk score is calculated by summing up 
the beta coefficients specific to six self-reported risk factors when present: receptive 
condomless anal sex (beta 1.1), sharing sex toys (beta 1.2), unprotected fisting (beta 0.9), 
injecting drug use (beta 1.4), sharing straws during nasally-administered drug use (beta 1.0), 
and ulcerative sexually transmitted infection (beta 1.4). Secondary outcomes include 
incidence of HCV reinfection, changes in the individual risk behaviour items and changes in 
sexual wellbeing. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: One site visit will be required for all participants to sign the informed 
consent form. All further study procedures will be web-based or will take place from home. 
Participants will be exposed to five online questionnaires, with an interval of 6 months. The 
questionnaires and interventions can make participants more aware of their HCV risk, which 
could make participants feel at unease. However, we think this study poses negligible risk to 
the participants. 

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1. INTRODUCTION AND RATIONALE 
 
1.1 Background  
Hepatitis C Virus (HCV) infection may lead to liver inflammation, cirrhosis, liver cancer and 
death. HCV is a global health problem; about 71 million individuals worldwide are infected 
and every year, 495,000 deaths from HCV infection occur and the burden of disease 
continues to rise.(1-3) HCV is usually spread through blood-to-blood contact. Since 2000, 
outbreaks of sexually transmitted HCV infection have been reported among HIV-positive men 
who have sex with men (MSM). Risk factors independently associated with the acquisition of 
acute HCV among MSM include sexual risk behaviour (e.g. unprotected anal intercourse, 
unprotected fisting) and recreational drug use.(4) HIV/HCV coinfection results in an 
increased risk of both HCV and HIV related mortality.(5, 6) Currently, there is no vaccine 
available to prevent HCV infection. A small proportion (10-15%) of HIV-positive MSM will 
spontaneously clear the infection without treatment.(7, 8) Recent availability of highly 
effective oral HCV therapy (direct acting antivirals (DAA)) for HCV infection with cure rates of 
95% has created optimism towards HCV elimination.  
 
1.2 HCV in the Netherlands  
The Dutch HCV epidemiological patterns are quite unique and the country seems to be in a 
good position for reaching elimination goals. The Netherlands is a country with one of the 
lowest HCV prevalence in the general population worldwide(3) with rapid uptake of 
interferon-free treatment since unrestricted access (i.e., no longer fibrosis stage restrictions) 
to DAA for all chronic HCV patients was authorized in November 2015. Hence, reaching the 
World Health Organization (WHO) HCV elimination goals (i.e., 90% reduction in new chronic 
infections, 65% reduction in mortality)(9), might be more feasible in the Netherlands than in 
other regions. Importantly, in contrast to other regions, over the last decade we have 
observed almost no acute HCV initial and reinfections among the classical HCV risk group of 
people who inject drugs, related to a high uptake of comprehensive harm reduction 
programs.(10-13) Thus, MSM are the sole group with ongoing HCV spread.  
  
1.3 HCV among men who have sex with men  
New HCV infections are typically found in HIV-positive MSM. Incidence of initial infection 
among HIV-positive MSM stabilized and was not markedly declining before DAA became 
widely available.(14-16) Since unrestricted DAA availability in November 2015, HCV 
incidence has been decreasing in the Netherlands.(17, 18) The incidence rate of acute HCV 
infection among HIV coinfected MSM in HIV care was 4.5 diagnoses per 1,000 PY in 2012, 

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6.6 in 2015 and 3.3 in 2017.(18) International data show diverging trends. In Switzerland and 
France for example, HCV incidence in MSM has remained stable or has shown an increase 
respectively(19, 20), since the availability of DAA’s.  
 
Of great concern is the more than ten times higher risk of reinfection when compared to initial 
infection; approximately one third of the MSM who successfully responded to HCV treatment 
acquired a reinfection within 2 years.(21, 22) A subsequent high incidence of HCV reinfection 
has also been observed in other high income countries in MSM who both respond to 
treatment or clear the infection spontaneously.(23, 24) An additional concern is the recent 
finding of a higher HCV prevalence (4.8%) in high risk HIV-negative MSM than previously 
reported.(25) These HCV mono-infected MSM applied for pre-exposure prophylaxis (PrEP) 
to prevent HIV infection and were infected with HCV strains already circulating among HIV-
positive MSM. More recent data shows that the HCV incidence rate in HIV negative MSM on 
PrEP comparable is to that of HIV-positive MSM.(20, 26) Increasingly overlapping sexual 
networks between HIV-positive and HIV negative MSM(27, 28) might put these HIV-negative 
MSM also at risk of HCV reinfection and spread to the larger population of HIV-negative 
MSM cannot be excluded.  
 
1.4 HCV treatment  
The rapid uptake of DAA might contribute to HCV elimination. In the favourable Dutch 
epidemiological setting, targeting HIV/HCV coinfected patients, of whom 69% are MSM(29), 
is a logical first step towards elimination as an estimated 90% of all HIV-positive persons 
living in the Netherlands are regularly seen in HIV care.(18) It is promising that 15 months 
after broadening access of DAA therapy to all HIV/HCV-coinfected patients independent of 
fibrosis stage, 82% of 1471 HIV/HCV coinfected patients in the Netherlands had either 
achieved a sustained virological response (SVR12) or were currently still on DAA 
therapy.(29, 30) Treatment uptake and cure rates were highest in MSM.(29) However, 
modelling data indicate that even in a setting with high DAA uptake among MSM, HCV 
elimination would not be feasible without a reduction in risk behaviour.(31, 32) This reduction 
could be difficult to achieve as it might be that the new highly effective and well-tolerated 
treatments result in a decreased perceived threat of HCV, especially in those successfully 
treated with DAA and at risk of HCV reinfection. An increase in risk behaviour could likely 
surface and counteract treatment benefits.(33) Data indicate that MSM successfully treated 
with DAA are still at substantial risk of HCV reinfection.(34) This and the costs related to 
treatment of (re)infections highlight the urgent need for effective interventions aimed at 
reducing risk behaviour and preventing reinfections among MSM.  
 

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1.5 Interventions to prevent HCV reinfection  
Effective interventions to prevent HCV reinfection targeting MSM are lacking. To our 
knowledge, behavioural interventions aimed at reducing risk behaviour for HCV transmission 
in MSM have only been studied within the Swiss HCVree trial.(35) Preliminary results 
indicated that adding a behavioural intervention to HCV treatment was feasible(36), however 
the results on behavioural outcomes have not been published yet. The behavioural 
intervention reported by the Swiss was offered to HIV/HCV co-infected MSM with 
inconsistent condom use and occasional sex partners, and accompanied the treatment 
phase of the study.(37) Participants received four 45-minutes individual sexual risk 
counselling sessions, assisted by an interactive online tool (n=51). This intervention was an 
adaptation of a previous European randomized multi-center study targeting safer sex in HIV-
positive MSM(38) In this randomized controlled trial, the intervention showed short-term 
effectiveness in HIV-positive MSM; condom use at last intercourse increased more among 
intervention than control participants at 3 months follow-up (odds ratio of 3.83; 95% 
confidence interval 1.15 to 12.76, P = 0.03), but not significantly at 6 months follow-up. In 
addition to behavioural interventions focusing on inconsistent condom use (such as the 
Swiss HCVree trial), effective behavioural interventions targeting the wider range of HCV-
related risk behaviours are urgently required for MSM at risk for HCV reinfection. 
 
Additionally, more frequent testing for HCV might have the potential to change behaviour. 
Infection status notification can lead to a reduction in risk behaviour, as has been 
demonstrated for positive HIV and HCV test results.(39-42) There has been relatively little 
evidence about the effect of receiving a negative test result. Studies evaluating the effect of 
testing HIV-negative in MSM have found heterogeneity in how individuals respond to a 
negative test.(43, 44) There is some evidence that (repeated) negative testing may increase 
sexual risk behaviour.(43, 45-47) On the other hand, more frequent testing could lead to 
earlier detection of HCV reinfection and early treatment. Early treatment reduces the duration 
that reinfected patients may transmit HCV to their sex partners, hereby preventing new HCV 
infections on a population level.(32) Notably, home-based testing using dried blot spots 
(DBS) offers advantages for HCV testing, as it has shown to increase convenience, 
anonymity, perceived control over the testing procedure, patient autonomy and control over 
the own health.(48)  
 
This project will set up, offer and evaluate two interventions (i.e. an online behavioural 
intervention and a home-based HCV testing intervention), alone or in combination, and 
possibly contribute to halting HCV transmission to the wider community of HIV-positive and 
HIV-negative MSM. 

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2. OBJECTIVES 
 
Primary Objective:  
To investigate whether the online behavioural and testing intervention, alone or in 
combination, causes a reduction in at risk behaviour compared to the run-in period (see 
Chapter 7.1.1) 
 
Secondary Objective: 
To evaluate the impact of the behavioural and testing intervention, alone or in combination, 
on reinfection incidence, STI incidence, individual HCV related risk behaviour items and 
sexual wellbeing. Furthermore, we will evaluate the impact of the interventions on reinfection 
incidence and onward transmission using mathematical modelling.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. STUDY DESIGN 
 
We will perform a multi-center 3-arm randomized trial (RT) evaluating the effect of an online 
behavioural intervention, a home-based testing intervention, or a combination of both on 
HCV risk behaviour (Figure 1). The trial will start with a 6 month run-in period (standard 
care). This 6 month run-in period is used to determine at-risk behaviour under no 
intervention. Including a control comparator arm with no intervention was deemed 
unappealing to MSM (personal communication, Paul Zantkuijl, Soa Aids Nederland (NGO)) 
and could lead to high attrition rates. Hence, we decided that the risk of non-differential loss 
to follow-up would outweigh any benefit with using a control arm and we opted for a run-in 
comparison period instead. The intervention period will start at month 6 of the study period. 
Participants will be randomly assigned to one of the three arms (1:1:1 randomization). During 
this period, participants will receive standard care plus one or both interventions. Follow-up in 
the intervention period will end after 18 months. In total, five questionnaire measuring risk 
behaviour over the past period will be offered online every 6 months in the run-in period and 
intervention period (i.e., at month 0, 6, 12, 18 and 24 of the study period). This study will be 
viewed as a pilot approach to evaluate, within each arm, if a significant decrease in at-risk 
behaviour can be observed during the intervention period. 
 
 
 
Figure 1: Study design of the ICECREAM study  
 
 
 
 
 
 

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4. STUDY POPULATION 
 
4.1 Population (base)  
The target population consists of MSM previously infected with HCV and currently in care at 
an HIV treatment center or visiting an STI/PrEP/sexual health center.  
 
HIV-positive MSM with a history of HCV infection 
In 2017, 1022 HIV/HCV coinfected MSM retained in HIV care in the Netherlands, of whom 
910 underwent HCV treatment.(29) We will recruit HIV-positive participants at five HIV 
treatment centers in Amsterdam and via the Public Health Service of Amsterdam (GGD 
Amsterdam):  
• 
Onze Lieve Vrouwe Gasthuis, 200 HIV-positive MSM with a history of HCV 
infection retain in HIV-care.  
• 
Amsterdam UMC - location AMC, 150-200 HIV-positive MSM with a history of HCV 
infection retain in HIV-care.  
• 
DC Clinic Lairesse, 75-100 HIV-positive MSM with a history of HCV infection retain 
in HIV-care. 
• 
Medical Center Jan van Goyen, 30 HIV-positive MSM with a history of HCV 
infection retain in HIV-care.  
• 
VU Medical Center, 30 HIV-positive MSM with a history of HCV infection retain in 
HIV-care. 
• 
Maasstad Ziekenhuis, over 50 HIV-positive MSM with a history of HCV infection 
retain in HIV-care 
• 
Haaglanden MC, over 50 HIV-positive MSM with a history of HCV infection retain 
in HIV-care 
• 
University Medical Center Utrecht, over 50 HIV-positive with a history of HCV 
infection retain in HIV care 
• 
Public Health Service of Amsterdam (GGD Amsterdam): 
o MS2 cohort: the MS2 cohort is a case holding cohort for MSM with a high 
STI risk at the Public Health Service of Amsterdam. Participants are offered 
STI screenings every 3 months, no questionnaires are being collected. 
Approximately 20 HIV-positive MSM with a history of HCV infection are 
enrolled in the MS2 cohort.  
 
 
 
 

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HIV-negative MSM with a history of HCV infection  
HIV-negative MSM with a history of a HCV infection will be invited to participate during their 
visits for STI or PrEP related care. We will start recruitment at two STI/PrEP centers:  
• 
Public Health Service of Amsterdam (GGD Amsterdam):  
o STI outpatient clinic: < 10 HIV-negative MSM were found to have a current 
or past HCV infection.  
o PrEP demonstration projects: there are three PrEP projects currently 
ongoing in HIV-negative MSM: (1) the Amsterdam PrEP (AMPreP) project, 
(2) the Informal PrEP (InPrEP) project and (3) the DISCOVER study. All 
PrEP projects will end in 2020. In total, 31 MSM were found to have a 
current or past HCV infection at baseline or during follow-up.  
o Amsterdam Cohort Studies: in total < 5 HIV-negative MSM were found to 
have a current or past HCV infection at baseline or during follow-up.  
• 
DC Clinic Lairesse: < 10 HIV-negative MSM with a history of a HCV infection 
receive PreP care at the DC Clinic Lairesse. 
• 
Amsterdam UMC - location AMC, HIV-negative MSM are referred to the hospital 
after HCV diagnosis. Following successful treatment or spontaneous clearance 
these patients may be eligible to participate in the trial.    
 
In the Netherlands, the incidence rate of HCV is high among MSM who (start) using PrEP 
and comparable to that observed among HIV-positive MSM.(25, 26) The Minister of Health 
announced that PrEP will partially be reimbursed and PrEP related care will become 
available by mid 2019 for 5 years for key groups who are at risk for HIV acquisition 
(estimated 8,500 MSM).(49, 50) It is unclear how the scale-up of PrEP will affect HCV 
incidence and prevalence among HIV-negative MSM in the coming years. As PrEP use 
increases, condomless anal sex is likely to continue to rise(51), as well as overlap between 
sexual networks of HIV-positive and HIV-negative MSM.(25) Both might lead to the spread of 
HCV to the larger population of HIV-negative MSM. 
 
A potential risk is the willingness of MSM to participate in the randomized trial evaluating the 
effectiveness of interventions. We will strive to maximize the number of recruitment sites in 
the Netherlands. Also international collaborators showed their interest in the randomized trial. 
We submitted a grant application to the Agence Nationale de Recherches sur le Sida et les 
hépatites virales (ANRS) in France in March 2019 to extent the trial to three clinical centres 
in Paris. The grant was awarded by the ANRS in July 2019. Preparations for the project in 
France started in January 2020. The multidisciplinary approach and the involvement of all 
stakeholders including NGOs and end users from the beginning of the project onwards will 

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optimize communication strategies and will match the needs of the target population of MSM, 
enhancing their participation. Furthermore, we would like to emphasize the “pilot” nature of 
the RT.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
• 
Informed consent documented by signature. 
• 
Male individual aged 18 years or older.  
• 
History of a cured or spontaneously cleared HCV infection (positive HCV RNA 
test in the past and/or positive anti-HCV IgG).  
• 
Self-reported MSM who are either (i) HIV-positive seeking care at an HIV 
treatment center or (ii) HIV-negative and seeking care at an STI/PrEP/sexual 
health center.  
• 
Sufficient understanding of Dutch or English. 
• 
Have internet access and an e-mail address. 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
• 
Acute or chronic HCV infection at time of enrolment. 
• 
Under HCV treatment at time of enrolment. 
• 
Unlikely, in the opinion of the clinician, to comply with the study procedures. 
• 
Currently participating in an intervention study that offers extra HCV testing 
and/or a behavioural intervention targeting risk behaviour.  
• 
Investigators or otherwise dependent persons.  
 
4.4 Sample size calculation 
We aim to have a minimum of 78 MSM per arm (total: 234). Assuming a drop-out rate of a 
maximum 5% in the run-in period (based on our experience with ongoing studies), we aim to 
enrol 246 MSM in total (see Figure 1). As we have no initial data on the effects of our 
interventions, we simulated power under varying conditions of at risk behaviour during the 
run-in period and absolute risk reduction during the intervention. With a sample size of 78 in 
each arm, we would have 80% power to demonstrate a statistically significant difference, at a 
type 1 error of 0.05, of a >22% reduction in the primary end-point from a 60% baseline 
prevalence of MSM identified as at risk (HCV-MOSAIC score ≥2.0, see Chapter 9.1). When 

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testing for differences in reduction of the primary end-point between two intervention arms 
(Chapter 9.1), while additionally assuming a 10% reduction in the comparator arm, we would 
have 80% power to demonstrate a statistically significant difference if a reduction of 0.43 was 
observed in the other intervention arm. 
 
5. TREATMENT OF SUBJECTS 
 
Both interventions will be offered after randomization at month 6. The participants will be 
referred to the assigned interventions explained on the (ICECREAM) study website 
(www.icecreamstudy.nl).  
 
5.1 Arm I: behavioural intervention  
The first arm consists of a web-based behavioural intervention. The behavioural 
intervention will be based on the principles of the Information-Motivation-Behavioural 
Skills (IMB) model for behavioural change, which was found effective in the context of HIV 
prevention and treatment adherence.(52, 53) When adapted to the context of HCV, the 
IMB model assumes that acquisition of or improvement in HCV prevention related 
knowledge and motivation will increase the likelihood of the practice of risk-reduction 
behaviour either directly or in combination with the improvement of related behavioural 
skills. In our study we assume that the acquisition of new skills will be decisive for the 
success of our behavioural intervention. The online tailored intervention that is currently 
being developed will address barriers to and skills of applying risk reduction strategies. 
The intervention will consist of several modules to counteract the barriers for reducing 
sexual risk behaviour identified in our previous qualitative study(33), which include the 
following: (1) lack of knowledge regarding effective risk reduction strategies for HCV 
reinfection, (2) risky behavioural norms, and (3) existing behavioural patterns in the sexual 
network that are difficult to manage or change and result in social pressure towards risk. 
Furthermore, the intervention will address HCV-related stigma and non-disclosure of HCV 
status and drug use, as the latter is strongly present in the context of sex clubs and 
(group) sex and directly influence the self-efficacy of men to implement risk reduction 
measures.(54) 
 
The structure of the behavioural intervention will partially be based on the e-health 
assisted counselling intervention embedded in the Swiss HCVree trial (mentioned in 
Chapter 1.4). The behavioural outcomes of the Swiss intervention are currently being 
evaluated in a mixed-methods study and have not been published yet. We received 
personal communication regarding the trial’s preliminary results, related conclusions and 

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lessons learned, which we included in the development process of our behavioural 
intervention. This intervention was guided by the IMB model and included four individual 
sexual risk counselling sessions accompanied by an e-health assisted intervention. For 
the current project, we have opted for a completely web-based intervention, as it will 
improve implementation in routine care when compared to a behavioural intervention that 
includes face-to-face counselling.  
 
The content of the intervention will consist of interactive questions, text-based modules, 
and videos addressing information, motivation, and behavioural skills. It will comprise four 
modules:  
 
- Module 1, “Hepatitis C & I” will focus on self-reflection and exploring participants’ 
intrinsic motivation to reduce the risk of HCV infection using filmed role models. The 
videos are based on modelling principles of behaviour where peers tell real stories about 
their experiences and challenges with HCV related risk behaviours and how they 
addressed these challenges. After watching the video(s), participants will answer self-
reflective questions and questions regarding personal motivation to reduce their HCV risk.  
 
- Module 2, “What is important to know?” will focus on increasing HCV related knowledge. 
Participants will receive tailored information about modes of transmission and a summary 
of personal HCV risk factors based on the participant’s earlier disclosed risk behaviour in 
the study questionnaire (i.e. the items of the HCV-MOSAIC risk score and other HCV 
related risk factors).  
 
- Module 3, “Making my plan”, will identify the necessary steps to achieve behavioural 
goals, lending to a personalized risk reduction plan.  
1. The user will be able to choose tailored personal goals from a set of options based 
on the participant’s answers to the study questionnaire. They will also be offered the 
option to formulate their own goal(s) using an open text field. 
2. Relevant solutions for personal psychosocial/cognitive barriers to reducing HCV-
related sexual risk behaviour will then be offered according to the chosen goals. To 
promote skills efficacy for practicing risk reduction strategies modules will address on 
a tailored basis communication between sex partners, such as suggested 
conversation openers and discussion scenarios. It will also include decision-making 
tips during social-sexual interaction within the high-risk network. Videos will 
demonstrate risk reduction techniques specific to high-risk settings (such as group 
sex) and will link users to available HCV-related risk reduction tools.  

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3. The participant will finalize a personal risk reduction plan. 
 
- Module 4, “Evaluating my plan”, will focus on the evaluation of the risk reduction plan. 
After one or two months, depending on the preference of the participant, the participant 
will receive an email notification to return to the intervention to evaluate the goals. In this 
final module, the participant will be able to reflect on the risk reduction plan and adjust the 
goals if desired. Participants will be encouraged to formulate a new action plan and return 
for evaluation in case goals have not been achieved. If the participant would need extra 
support through personal counselling, webcam or telephone counselling will be offered. 
 
Tailoring 
The intervention will be offered in a tailored fashion, meaning that it will be adapted based 
on the study questionnaire and personal needs of each user. Men will receive information 
related to their situation, making the intervention more concise and relevant, which has 
shown to result in increased adherence to the intervention.(55) Nevertheless, some 
information will generally be relevant and thus provided to all MSM. The persuasive 
design model(56) will be used to select and implement persuasive features (e.g. praise, 
suggestion) in the intervention.  
 
The intervention will be offered during the intervention period of 18 months on a website 
that will be dedicated to the intervention and will be able to be used on a computer or 
mobile phone. Participants can log out and return to the behavioural intervention at any 
time using their personal login code. Men who do not complete all the modules of the 
intervention as intended, will receive an email reminder or text message that reminds 
them to visit the website.  
 
5.2 Arm II: home-based testing intervention  
The second arm will consist of an additional patient-initiated home-based HCV testing 
service. The service will offer 4 free-of-charge HCV RNA tests, which can be obtained via 
email. It involves home-based HCV testing using self-sampled dried blood spots (DBS) 
(i.e., home-collection testing involving a certified laboratory) that was developed, used for 
purchase, and evaluated via the NoMoreC project (www.nomorec.nl) as part of the MC 
free initiative, a collaboration of relevant stakeholders that aims to reduce the incidence of 
HCV infections among MSM in Amsterdam. This service allowed men at high risk for HCV 
infection to take control and test for the presence of HCV-RNA. The self-sampling DBS 
has been previously validated and shown to be effective (see Chapter 6).  
 

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After randomization at month 6, the participant will receive an email from the research 
team (ICECREAM@ggd.amsterdam.nl) asking to reply to indicate their preference for 
delivering the test kits (delivered at the address provided or picked up at the Public Health 
Service of Amsterdam). If the participant prefers to have the test kits delivered to their 
address, the test kits will be delivered in a blank envelop, along with paper instructions 
and package materials for returning the test kits with the self-collected DBS sample. If the 
participant prefers not to have the test kits delivered to a home address, the option will be 
offered to obtain the test kits from the project leader at the Public Health Service of 
Amsterdam. After obtaining the DBS, the DBS kit can be returned by mail to the laboratory 
of the Amsterdam UMC, location AMC for HCV RNA testing. Test results will be uploaded 
by laboratory personnel of the Amsterdam UMC, locatie AMC and can be obtained by the 
project leader via Castor EDC. Accordingly, participants will be informed with their test 
result by secured email. This means that the message can only be encrypted by the 
recipient with a private code. In case of a HCV RNA positive test result, participants will be 
offered linkage to clinical care as soon as possible and start HCV treatment if indicated. A 
referral letter with the test result and information on the type of the test that was done will 
be sent to the participant’s email address to assist MSM to discuss their test results with 
their physician. Partner referral will be provided as part of routine procedures. In addition, 
the project leader will contact participants by telephone to ensure that they are referred to 
adequate medical care.  
 
The HCV RNA testing service can be used for 18 months. We will recommend men to use 
the free-of-charge HCV tests in between visits at their HIV treatment center or 
STI/PrEP/sexual health center, in particular when they perceive themselves at HCV 
reinfection risk, assuming testing behaviour is driven by suspected HCV exposure. A 
reminder to use the tests will be added to the email invitations of the study questionnaire 
at month 12 and 18 (i.e. month 6 and 12 of the intervention period). 
 
5.3 Arm III: behavioural and home-based testing intervention combined 
The third arm combines the behavioural intervention with the testing intervention. In this arm, 
both interventions will be offered to participants for 18 months. We hypothesize that the 
combined intervention will lead to the greatest reduction in risk behaviour. Additional testing 
can have different effects on risk behaviour, as described in Chapter 1.4. However, there is 
no data available on the effect of additional HCV testing among men who have sex with men 
that can support our hypothesis. Nevertheless, we believe that the testing intervention in 
combination with the behavioural intervention can increase awareness around HCV and 
possibly reduce risk behaviour the most. 

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6. NON-INVESTIGATIONAL PRODUCT 
 
6.1 Name and description of the self-sampled dried blot spots 
The home-based HCV-RNA testing service involves self-sampling of blood by finger prick on 
a paper card at home (a dried blood spot, DBS). The participant will be given the home kits 
with paper instructions, including a link to an instructional video, on how to safely self-sample 
5 drops of blood on filter paper (Whatman 903). The participant will sent the DBS sample to 
the laboratory of the Amsterdam UMC, location AMC, according to instructions. 
 
The home kit includes the following items: 
• 
Paper instructions  
• 
Alcohol swap 
• 
2 lancets – Type: BD Microtainer® contact-activated lancet 
• 
Whatman 903 filter paper card with 5 preprinted circles 
• 
Sterile gauze 
• 
Bandaid 
• 
Sealable plastic bag with desiccant 
• 
Return envelope (postage paid) 
When an ssDBS arrives at the lab, the arrival date will be marked on the card. Viral RNA will 
be measured within 3 – 7 days after arrival at the laboratory.  
 
6.2 Summary of findings from clinical studies 
A systematic literature review by Greenman et al. of DBS for HCV RNA detection supports 
the potential use of DBS for HCV RNA detection.(57) DBS is expected to adequately 
detect and quantify HCV RNA for the purpose of diagnosing HCV infection. The reviewed 
DBS studies reported varying viral load detection limits, between 2.2 – 3.4 log IU/ml; 0.5-
1.7 log IU/ml higher compared to plasma sample tests.(58-61) 
 
In addition, DBS self-sampling has been found to be a feasible technique for the detection 
of HCV RNA and was used and evaluated by the research team.(62, 63) They validated 
the use of DBS to measure HCV RNA loads using whole blood samples spotted on 
Whatman 903 filter paper by a laboratory technician. The HCV RNA loads detected were 
1.0-1.6 log IU/ml lower with DBS compared to plasma loads. Although the DBS has higher 
viral load detection limits than plasma tests, it is suitable for diagnosing patients with active 
replication, as most patients have viral loads >3.0 log IU/ml.(59) Therefore, it is anticipated 
that with the use of DBS method, at least 95% of the HCV positive patients will be 
diagnosed.  

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7. METHODS 
 
7.1 Study parameters/endpoints 
7.1.1 Main study parameter/endpoint 
1. From run-in and post-randomization questionnaires, we will evaluate the 
proportion at risk of HCV infection (as determined by a HCV-MOSAIC score ≥ 2.0) 
during the run-in versus intervention periods. The HCV-MOSAIC risk score has 
been previously validated for acute HCV-infection and is calculated by summing up 
the beta-coefficients specific to six self-reported risk factors when present in the past 
6 months: (i) receptive condomless anal sex (beta 1.1), (ii) sharing sex toys (beta 
1.2), (iii) unprotected fisting (beta 0.9), (iv) injecting drug use (beta 1.4), (v) sharing 
snoring equipment during nasally-administered drug use (beta 1.0), and (vi) 
ulcerative sexually transmitted infection (beta 1.4). A reduction in the proportion of 
individuals at risk would demonstrate a positive effect of the intervention on at risk 
behaviour (as explained in more detail in Chapter 9.1).  
 
7.1.2 Secondary study parameters/endpoints  
1. Incidence rate of HCV reinfection (number of cases of HCV reinfection divided 
by total person-years of follow-up at risk for reinfection) (self-reported and 
laboratory data).  
2. Incidence rate of any STI (number of cases of chlamydia, gonorrhoea, 
lymphogranuloma venereum (LGV), genital herpes and/or syphilis divided by 
total person-years) (self-reported).  
3. Changes in HCV-related risk behaviour:  
a. Changes in the number of sex partners. 
b. Changes in the number of condomless anal sex acts with casual 
partners.  
c. Changes in the individual items of the HCV-MOSAIC risk score: 
i. 
Changes in the proportion of individuals reporting receptive 
condomless anal sex.  
ii. 
Changes in the proportion of individuals sharing sex toys.  
iii. 
Changes in the proportion of individuals reporting unprotected 
fisting.  
iv. 
Changes in the proportion of individuals reporting injection drug 
use. 

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v. 
Changes in the proportion of individuals sharing snoring equipment 
during nasally-administered drug use.  
vi. 
Changes in the proportion of individuals reporting ulcerative 
sexually transmitted infection (syphilis, genital herpes or 
lymphogranuloma venereum infection).  
d. Proportion of individuals with change in any of the items of the HCV-
MOSAIC risk score. 
e. Changes in the frequency of recreational drug use before and during sex. 
f. 
Changes in the frequency of individuals engaging in group sex activities, 
including changes in number of events and maximum number of sex 
partners during an event.  
g. Changes in the proportion of individuals sharing lubricants.  
h. Changes in the proportion of individuals sharing anal douches.  
4. Changes in the proportion of individuals disinfecting sex toys, skin and/or sex 
location. 
5. Changes in the sexual wellbeing score. 
 
7.1.3 Other study parameters 
1. Characteristics of the study population:  
a. Age 
b. Ethnicity  
c. Gender identity  
d. Educational level  
e. HIV-status 
f. 
PrEP use  
g. HCV history (number of infection(s), type of treatment, year of 
infection(s), impact of treatment(s)) 
2. Intervention-related endpoints: behavioural intervention 
a. The proportion of individuals reporting change in the risk behaviour 
identified in the goal setting module of the behavioural intervention.  
b. Website statistics: e.g., frequency of use, time spent on the intervention 
and the proportion of individuals completing all modules of the 
intervention.  
c. Type of goals set in the behavioural intervention. 
d. Usability and acceptability of the behavioural intervention. 
3. Intervention-related endpoints: testing intervention  

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a. The proportion of free HCV tests used (the total number of free HCV 
tests used divided by the total number of distributed tests).  
b. The proportion of HCV positive test results (the total number of HCV 
positive test results divided by the total number of free tests used).  
c. Usability and acceptability of the testing intervention.  
4. The number of (home-based) tests obtained and used from other sources.  
 
7.2 Randomisation, blinding and treatment allocation 
Centralized randomization will use computer-generated lists of random permuted 
blocks of six to randomly assign participants to one of the three study arms (1:1:1 
randomization). Randomization will take place using a web-based interface, which will 
immediately inform participants and investigators of the assigned arm. The study will 
be an unblinded randomized trial, meaning that both participants and researchers will 
be unblinded to study arms. Intervention allocations cannot be predetermined prior to 
and during enrolment. 
 
7.3 Study procedures 
Questionnaires 
After the eligibility check and obtaining informed consent, participants will receive a 
login code and a link to the study website by email. All questionnaires will be offered 
online using email notifications or text notifications. After enrolment, participants will 
be invited to fill out the baseline questionnaire (i.e., at month 0). Subsequently, a 
questionnaire will be offered to all participants every 6 months (i.e., at month 6, 12, 18 
and 24), measuring risk behaviour over the past 6 months. Email reminders will be 
sent to the participants in case the questionnaire was not completed 1.5 week and 3 
weeks after the first email notification was sent.  
 
Run-in period  
All participants will receive standard care during the run-in period of six months. HIV-
positive MSM will receive standard care during biannual visits at their HIV treatment 
center, where routine blood testing, including liver enzymes, takes place every 6 
months according to national guidelines.(64) Testing policies for HCV reinfection 
might differ per HIV treatment center; some centers might perform annual testing and 
others might only test for HCV RNA in the presence of elevated liver enzymes. In 
addition, the majority of HIV-positive MSM regularly visits the STI outpatient clinic of a 
Public Health Service for STI testing.  
 

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Standard care among HIV-negative MSM differs. HIV-negative MSM using PrEP will 
usually receive STI testing at an STI/PrEP/sexual health center. MSM participating in 
the PrEP projects will routinely visit the STI clinic of the Public Health Service of 
Amsterdam for PrEP monitoring including STI screening (syphilis, hepatitis B, 
hepatitis C, HIV, chlamydia and gonorrhoea). MSM enrolled in the PrEP projects at 
the Public Health Service of Amsterdam are currently being tested for HCV reinfection 
every 3 to 6 months. HIV-negative MSM not using PrEP are not routinely tested for 
HCV infection, unless they are notified by a HCV positive sex partner.  
 
Intervention period 
After randomization at month 6, participants will be referred to one of the three arms 
on the study website: (1) the behavioural intervention (see Chapter 5.1), (2) the 
testing intervention (see Chapter 5.2), or (3) the combined intervention (see Chapter 
5.3). In addition to standard care as described above, participants will be offered the 
intervention(s) for 18 months (month 6-24).  
 
After the end of the study  
Additional HCV RNA blood testing will retrospectively be performed to test for HCV 
reinfection if: 1) the participant did not receive HCV RNA testing in the 6 months prior 
to the end of the study period, 2) there is a blood sample available for HCV RNA 
testing at the laboratory of the participating site and 3) the participant provided 
consent for retrospective HCV RNA testing in the informed consent form. These blood 
samples are collected during routine visits at the HIV treatment center or during visits 
at the STI/PreP/sexual health center. All study procedures are shown in Table 1.  
 
Study procedures  
Inclusion 
Month 0 
Month 6 
Month 12  Month 18 Month 24 After the 
end of 
the study 
Eligibility check 
x 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
Questionnaire 
 
x 
x 
x 
x 
x 
 
Online randomization 
 
 
x 
 
 
 
 
Behavioural intervention  
 
 
x 
x 
x 
 
 
Testing intervention  
 
 
x 
x 
x 
 
 
Combined intervention 
 
 
x 
x 
x 
 
 

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HCV RNA testing in a 
stored blood sample*  
 
 
 
 
 
 
x 
* in case no HCV RNA test was performed in the last 6 months of the study period.  
Table 1: Study procedures ICECREAM study  
 
7.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
 
7.5 Replacement of individual subjects after withdrawal 
Individual subjects that chose to withdraw from the study will be replaced by other 
participants if recruitment is still ongoing.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8. SAFETY REPORTING 
8.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
8.2 Data Safety Monitoring Board (DSMB) / Safety Committee 
We determine that the associated risk and benefits are negligible for the participants 
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9. STATISTICAL ANALYSIS 
 
9.1 Primary study parameter(s) 
The primary outcome is the proportion at risk of HCV infection (as determined by a HCV-
MOSAIC score ≥ 2.0) during the run-in versus intervention periods. The score is 
calculated by summing up the beta-coefficients specific to six self-reported risk factors 
when present in the previous 6 months (see Chapter 7.1.1). The HCV-MOSAIC risk 
score has been previously validated for acute (primary) HCV-infection in HIV-positive 
MSM and the optimal cut-off to predict HCV positivity was defined at ≥ 2.0.(65) In 
addition, we recently evaluated whether the risk score could also identify individuals at 
high-risk of HCV reinfection, showing comparable performance (The Area Under the ROC 
Curve = 0.76) to that of primary acute HCV-infection.(66) 
 
The six items of the HCV-MOSAIC risk score will be obtained using the answers from the 
study questionnaire every six months. The proportion achieving the primary outcome will 
be summarized at month 6, 12, 18 and 24 visits within each study arm. The probability of 
the primary outcome will be compared between the run-in (month 6) and intervention 
periods (month 12, month 18, month 24) using a mixed-effect logistic regression model. 
In this model, each individual will serve as their own control and between-individual 
differences at baseline will be accounted for using a random-intercept. Pre versus post-
intervention odds ratios (ORs) and their 95% confidence intervals (CI) will be estimated 
and stratified on study arm, allowing us to identify interventions with significant 
differences. No multivariable adjustments will be applied. Additional analysis will be 
conducted in which ORs between arms will be compared by including and testing an 
interaction term between period and arm in the model (two arms at a time, for a possible 
three comparisons). No p-value adjustments will be made for multiple comparisons to 
avoid unnecessary correction on the possibly underpowered test for interaction.(67)  
 
Analyses will be performed by intention to treat (ITT) and per protocol (PP). Both 
analyses will only include individuals completing the lead-in phase (month-6). ITT 
analysis is defined by including all observations, while assuming that any individual lost to 
follow-up did not achieve the primary endpoint. PP analysis is defined by including all 
available observations, while excluding observations after an individual has been lost to 
follow-up. Subgroup analysis will also be conducted in order to determine whether 
individuals with certain characteristics are more likely to have a decrease in HCV-
MOSAIC score.   

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9.2 Secondary study parameter(s)  
Incidence rates of HCV reinfections and STIs will be calculated at the end of follow-up. 
Incidence of HCV reinfection will be examined during the lead-in and intervention periods 
of the RT. Considering few HCV reinfections are likely to occur, we intend to analyse 
differences in periods, along with associated risk-factors, using Bayesian exponential 
survival regression models with non to weakly informative a priori distributions.(68)  
 
For all other secondary study parameters, continuous variables will be summarized using 
means or medians and categorical variables using counts and percentages at each study 
visit. Changes over time will be described for HCV related risk behaviour, disinfection 
behaviour and sexual wellbeing. We will use statistical regression methods specific to the 
endpoint (logistic for binary outcomes, linear for continuous variables), corrected for 
repeated measurements within individuals (using mixed-effect methods) to investigate 
changes between lead-in and intervention periods and associated determinants. 
Outcomes will also be compared across the 3 arms.  
 
9.3 Other study parameters 
Descriptive statistical analyses will be performed to describe study population 
characteristics, intervention-related outcomes (e.g. use of the services, acceptability and 
usability) and the number of (home-based) tests obtained and used from other sources.  
 
9.4 Interim analysis 
No study arms plan to be discontinued due to preliminary signals of inefficaciousness. No 
harmful effects are remotely expected during participation in the arms. Therefore, no 
interim analysis is planned. 
 
9.5 Mathematical modelling  
Using mathematical modelling and incorporating the outcomes of the RT, we will evaluate 
the impact of the RT interventions on reinfection incidence and onward transmission 
taking the increased uptake of DAA and the undiagnosed population into account. The 
impact of HCV awareness, early diagnosis and treatment on this HCV spread will be 
investigated. We will build on previous and ongoing modelling work: a deterministic 
mathematical model that simulates both HCV and HIV transmission dynamics among 
MSM simultaneously, which is currently being developed, and an individual based model 
for HCV and HIV transmission dynamics among people who use drugs.(11) Parameters 
will be derived from the ICECREAM study and from literature. Mathematical modelling will 

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be performed in collaboration with the Infectious Disease Dynamics Group at the 
University Medical Center Utrecht.  
 
10. ETHICAL CONSIDERATIONS 
10.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki 
(Seventh revision, October 2013) and in accordance with the Medical Research 
Involving Human Subjects Act (WMO) of Dutch law. 
 
10.2 Recruitment and consent 
We will invite MSM aged 18 years or older with a history of a cured or spontaneously 
cleared HCV infection and in care at an HIV treatment center or using STI/PrEP related 
care to participate in the RT. Treating physicians and nurses at the study centers will 
propose the study to individuals meeting the inclusion criteria. Treating physicians include 
infectious disease specialists and doctors from the STI outpatient clinic and PrEP projects. 
Nurses include HIV nurse consultants/specialists and nurses from the STI outpatient clinic 
and PrEP projects. The HCV infection in the past will be confirmed by the treating 
physicians or nurses who enrol the participant by checking the laboratory results in the 
patient files. Information will be given both verbally and in a written information brochure. 
Adequate opportunity will be provided to the potential subject to ask questions. After 
written informed consent is obtained, the subjects will be included in the study. A copy of 
the signed informed consent form will be given to the participant. The informed consent 
forms will be retained at the participating site. A copy of the informed consent form will be 
sent to the Public Health Service of Amsterdam (coordinating center).  
 
10.3 Benefits and risks assessment, group relatedness 
In this study, only adults will be included. The questionnaires and interventions that will be 
offered in this study will not pose any other or additional risk than standard care. 
Participants will be exposed to five questionnaires, containing personal questions about 
sexual risk behaviour and drug use. Both the questionnaires and the interventions can 
make the participants more aware of their HCV risk, which could make participants feel at 
unease. However, we think that MSM who do not want to be confronted with their HCV 
risk behaviour and risk will not be interested in participating in this study. 
 
A benefit of participating in the study might be a decreased risk of HCV infection and 
lower levels of risk behaviour, depending on the outcome of the study. Furthermore, the 
participants assigned to the testing or combined intervention will receive 4 free of charge 

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home-based tests, which might lead to more frequent, patient-initiated, testing and 
possibly earlier diagnosis of HCV infection and start of treatment. Another possible benefit 
could be that men can contribute to reducing the spread of HCV in the MSM community.  
 
We classify this study as having a low chance of possible risk and a low degree of harm, 
leading to a negligible risk to participants.  
 
10.4 Compensation for injury 
The sponsor has a liability insurance which is in accordance with article 7 of the WMO. The 
reviewing committee of the AMC is of the opinion that there are no additional risks for the 
research subjects participating in this study, they therefore granted dispensation from the 
WMO subject insurance.  
 
10.5 Incentives  
No incentives will be provided to the participants.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
11.1 Handling and storage of data and documents 
After obtaining informed consent, the treating physician/nurse will send the following 
details of the participant to the project leader at the Public Health Service of Amsterdam 
via Secure-email:  
• 
Registration form:  
o First name and surname. Required for the linkage of the attached informed 
consent form to the participant.  
o Email address. Required for sending login data for the study website, 
email notifications and email reminders for the questionnaires and the 
intervention(s).  
o Telephone number. Required to contact the participants in case of HCV 
RNA positive test results.  
o Date of birth. Required to link reinfection data from the STI outpatient clinic 
to the participant.  
o If the participant is HIV-positive and is recruited at the Public Health 
Service of Amsterdam, HIV treatment center and physician/HIV nurse 
consultant will also be collected via the registration form. Required to link 
reinfection data from the HIV treatment center to the participant. 
• 
A copy of the informed consent form. The informed consent form contains the 
subjects consent regarding linkage of data. The signed forms will be retained at 
the participating site. However, as the linkage will be coordinated by the Public 
Health Service of Amsterdam, a copy of the informed consent form will be 
required at the coordinating site.  
It will be communicated both verbally and written (in the information brochure and the 
informed consent form) that the personal data mentioned above, will be transferred from 
the treating physician/nurse to the project leader at the Public Health Service of 
Amsterdam via Secure email. 
 
The project leader registers the participant in het personal SQL database (database 1) 
and generates a random study number for each participant. The study number is 
communicated to the treating physician/nurse in the inclusion center by a reply email to 
the Secure-email mentioned above.  
  

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Data will be collected as follows:  
• 
Self-reported clinical and behavioural data of participants will be collected by 
online questionnaires using LimeSurvey software.  
• 
Data on the use of the services of the behavioural intervention will be collected 
from the study website, including the exposure to and intensity of use of each of 
the components of the online behavioural intervention (using log-data) if assigned 
to intervention I or III.  
• 
Data on the number of free HCV home-based test(s) used and their test results 
will be collected from Castor EDC platform if assigned to intervention II or III.  
• 
Data on HCV reinfection (HCV RNA test date(s), test results and HCV treatment) 
will be collected from laboratory and clinical files of the participating sites, and the 
Dutch HIV monitoring foundation (in Dutch: Stichting HIV Monitoring, SHM):  
o HIV treatment center: only for HIV-positive participants. Linkage will be 
performed using study number if the participant provided consent via the 
informed consent form. Linkage to SHM data will be through the HIV 
treatment centers using routine procedures.  
o STI/PrEP/sexual health center: for HIV-negative participants and HIV-
positive participants (HIV-positive patients also visit the STI outpatient 
clinic at the Public Health Center of Amsterdam). Linkage will be 
performed using name and date of birth to link the STI data.  
• 
Additional HCV RNA blood testing will retrospectively be performed to test for 
HCV reinfection if: 1) the participant did not receive HCV RNA testing in the 6 
months prior to the end of the study period, 2) there is a blood sample available 
for HCV RNA testing at the laboratory of the participating site and 3) the 
participant provided consent for retrospective HCV RNA testing in the informed 
consent form. These blood samples are routinely collected during visits at the HIV 
treatment center or at the STI/PrEP/sexual health center every 3-6 months (see 
Chapter 7.3) and are retained at the laboratory for a minimum of 2 years 
according to law.  
 
The data manager at the Public Health Service of Amsterdam will import the data from 
the questionnaires, the behavioural intervention, Castor EDC, HCV test results and 
clinical data into the Research SQL database (database 2).  
 
The data of the participants will be stored in two separate databases: 1) containing study 
number and directly identifiable personal data (subject identification code list) and 2) 
containing study number and study data (e.g., sexual risk behaviour data). The subject 

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identification code list will be safeguarded by a key and will only be accessible by the 
project leader and data manager if necessary. A subject identification code list (database 
1) will be used to link the data to the subject. This code list will be kept until 5 years after 
the end of the project. The DBS samples will be kept until 1 year after the end of the 
project. All other study data (database 2) will be stored for 15 years.  
 
11.2 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion. All substantial amendments will be notified to the METC and to the 
competent authority. Non-substantial amendments will not be notified to the accredited 
METC and the competent authority, but will be recorded and filed by the sponsor.  
 
11.3 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial and amendments. We will not be able to trace serious adverse events/ serious 
adverse reactions as only one site visit is required at the start of the study and all further 
study procedures will take place online or at home. No harmful effects are remotely 
expected during participation.  
 
11.4 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as completion of the final 
questionnaire by the last included subject. The sponsor will notify the METC immediately 
of a temporary halt of the study, including the reason of such an action. In case the study 
is ended prematurely, the sponsor will notify the accredited METC within 15 days, 
including the reasons for the premature termination. Within one year after the end of the 
study, the investigator/sponsor will submit a final study report with the results of the study, 
including any publications/abstracts of the study, to the accredited METC.  
 
11.5 Public disclosure and publication policy 
We intent to publish study outcomes in the most appropriate peer-reviewed scientific 
journals and at scientific conferences. Authorship will follow the guidelines defined by the 
international Committee of Medical Journal Editors. In addition, participants, their 

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community and relevant stakeholder will be informed in layman’s terms about (the 
outcomes of) the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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