Hepatitis C among drug users in Europe : epidemiology, treatment and prevention.
Date: 2016-08-02
Institutions: European Monitoring Centre for Drugs and Drug Addiction
Subjects: disease prevention, drug addiction, epidemiology, health risk, infectious disease, report, social problem, therapeutics

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Hepatitis C 
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Epidemiology, treatment and prevention

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23

 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C 
among drug 
users in Europe

Epidemiology, treatment and prevention

Editors
Matthew Hickman
School of Social and Community Medicine, University of Bristol, 
United Kingdom

Natasha K. Martin
Department of Medicine, University of California, United States 
and University of Bristol, United Kingdom  

EMCDDA project group
Isabelle Giraudon, Lucas Wiessing, Dagmar Hedrich,  
Eleni Kalamara, Paul Griffiths and Roland Simon

23

  Legal notice

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Luxembourg: Publications Office of the European Union, 2016
ISBN 978-92-9168-928-6
doi: 10.2810/967909

© European Monitoring Centre for Drugs and Drug Addiction, 2016
Reproduction is authorised provided the source is acknowledged.

Recommended citations: 

Book: European Monitoring Centre for Drugs and Drug Addiction (2016), Hepatitis C among drug users in Europe: 
epidemiology, treatment and prevention, EMCDDA Insights 23, Publications Office of the European Union, 
Luxembourg.

Chapter: e.g. Pawlotsky, J. M. (2016), ‘Antiviral medications for hepatitis C virus infection’, pp. 73–81 in Hepatitis 
C among drug users in Europe: epidemiology, treatment and prevention, EMCDDA Insights 23, Publications Office 
of the European Union, Luxembourg.

Praça Europa 1, Cais do Sodré, 1249-289 Lisbon, Portugal
Tel. +351 211210200
info@emcdda.europa.eu I www.emcdda.europa.eu
twitter.com/emcdda I facebook.com/emcdda

Contents

  5 

Foreword

  7 

Executive summary

  9 

Acknowledgements

13 

Introduction

17 

33 

45 

59 

73 

83 

89 

CHAPTER 1
 Hepatitis C virus infection among people who inject drugs: epidemiology and 
coverage of prevention measures in Europe
 Isabelle Giraudon, Dagmar Hedrich, Erika Duffell, Eleni Kalamara 
and Lucas Wiessing

CHAPTER 2
 Treatment of hepatitis C virus infection among people who inject drugs: uptake 
and outcome
 Esther Aspinall, Jason Grebely, Hamish Innes, Stephen Corson, Gregory Dore, 
Joseph Doyle, Margaret Hellard, David Goldberg and Sharon Hutchinson

CHAPTER 3
 Strategies to improve hepatitis C care and to enhance treatment uptake and 
adherence among people who inject drugs in Europe
 Philip Bruggmann, Patrizia Carrieri, MÕjca Maticic, Perrine Roux, Vratislav Rehak, 
John Dillon and Sharon Hutchinson

CHAPTER 4
 Hepatitis C prevention among people who inject drugs: role and impact of hepatitis 
C treatment, opioid substitution treatment and needle and syringe programmes
 Natasha K. Martin, Matthew Hickman and Peter Vickerman

CHAPTER 5
 Antiviral medications for hepatitis C virus infection
 Jean‑Michel Pawlotsky

CHAPTER 6
 Scaling up hepatitis C treatment: taking into account the needs and perspectives 
of people who inject drugs
 Magdalena Harris and Tim Rhodes

CHAPTER 7
 A framework for evaluating scale‑up of hepatitis C virus treatment as prevention 
for people who inject drugs
 Daniela De Angelis, Matthew Hickman, Peter Vickerman and Sharon Hutchinson

95  Conclusions

 Isabelle Giraudon, Dagmar Hedrich, Roland Simon and Paul Griffiths

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I  Foreword

This new publication on hepatitis C among drug users in Europe is both timely and 
important. It is estimated that 1.6 % of the population worldwide, or 115 million people, has 
ever been infected with the hepatitis C virus (HCV) and that about two-thirds of the 
infections are active. In the European Union, an estimated 5.5 million individuals are 
coping with chronic infection. Drug use is central to the European HCV problem, with 
people who inject drugs being a key group affected by this disease — national estimates of 
antibody prevalence range anywhere between 15 % and 84 %. Moreover, there is still 
significant ongoing transmission of this disease, with new injectors often becoming 
infected relatively rapidly. This means that HCV prevention remains one of the major 
challenges for Europe’s public health response to drug injecting.

In the 12 years since the European Monitoring Centre for Drugs and Drug Addiction 
(EMCDDA) published its last major report on this topic, Hepatitis C and injecting drug use: 
impact, costs and policy options, much has changed. Importantly, even if some challenges 
still exist, considerable progress has been made during this period in addressing HIV 
infections among people who inject drugs. Until recently, however, the situation in respect 
to HCV infection among this group looked far more pessimistic. There are grounds now for 
greater optimism, due largely to the development of new pharmacological options and 
a growing confidence that these can be offered in ways that are likely to be effective. For 
many years, the treatment of chronic HCV infection was based on therapies that required 
long treatment periods and had side effects that could deter compliance. For these 
reasons, drug users were often regarded as a difficult group to treat, treatment uptake was 
limited and, overall, the efficacy of interventions of all types in this area was disappointing. 
In the last few years, however, treatment has undergone a transformation, with new 
pharmacotherapies becoming increasingly available that appear to overcome many of the 
barriers that existed to offering effective care in this area. With these developments, 
treatment as prevention now emerges as a real possibility in providing an effective 
response to the HCV epidemic among drug injectors in Europe.

This publication provides a timely overview of how this important objective can be realised 
by analysing the hepatitis C epidemic in Europe, with major focuses on treatment and 
prevention. In these pages, you will find a state-of-the-art review of the epidemiology of 
HCV infection in Europe, drawing on information that includes the latest surveillance data 
from our partners in the European Centre for Disease Prevention and Control (ECDC) and 
the estimated prevalence of HCV among drug users, collated by the EMCDDA. This is 
complemented by information from the Reitox network of focal points, which provides an 
overview of the way preventive measures are currently implemented across Europe. 
Chapters written by international experts then address what we know about the treatment 
of HCV infection among people who inject drugs, with an emphasis on how we encourage 
uptake and deliver effective outcomes. Implementation issues are also explored, as are the 
complementary roles of treatment and prevention. An up-to-date overview of the new 
medicines currently available or in development is also provided. Importantly, how to scale 
up HCV treatment is explored in detail from two different viewpoints: evaluating its use as 
a prevention tool, and from the perspective of the drug user. This latter perspective is 
crucial as, in addition to effective therapies, the involvement of patients is likely to be a key 
element of any successful significant expansion of treatment in this area.

5

A clear conclusion emerging from our analysis is that, without effective action, the future 
costs to both individuals and health budgets of not addressing this infection among those 
who inject drugs, or have done so in the past, will be considerable. I am optimistic, 
however, because as this report clearly demonstrates, we now have an opportunity in 
Europe to make real and sustained progress in this area. Recent improvements in HCV 
therapeutic options mean that by combining treatment with adequate prevention and 
harm reduction measures, we now have the necessary tools to control the epidemic. We 
also have examples of good service models that can help us get the implementation right. 
It is also clear that barriers still exist to scaling up responses in this area and these urgently 
need to be overcome. Today in Europe, still far too many people are unaware of their HCV 
infection and still too many of those diagnosed with this disease lack access to effective 
treatment. This is a situation that needs to change. This Insights publication, I believe, 
makes a valuable contribution to achieving this objective, by not only identifying where the 
challenges exist, but also providing us with a better understanding of how improvements 
to the care we provide in this area can be achieved.

Alexis Goosdeel
Director, EMCDDA

6

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionI  Executive summary

Hepatitis C is a disease of the liver caused by the hepatitis C virus (HCV), which if not 
resolved can lead to chronic liver disease, cirrhosis and cancer. The disease, which affects 
many millions of people worldwide, is communicable and is spread by contact with 
infected blood or other bodily fluids. In Europe, the key risk group for HCV infection is 
people who inject drugs. High rates of HCV infection are commonly found in this group and 
people with an injecting history, however brief, as well as current injection drug users, are 
still unaware of their infection status. There are now new opportunities for effective 
treatment and prevention that, if scaled up sufficiently in Europe, could contribute to 
a significant reduction in the health harms associated with this disease.

This Insights publication provides both practitioners and policymakers with an analysis of 
the current epidemiology, harm reduction and treatment measures in relation to HCV 
infection in Europe. It also covers the barriers to treatment and examples of treatment 
scale-up and services organisation. Specifically, it provides an up-to-date overview of the 
new antiviral treatments that have become more available since 2014 and a review of HCV 
treatment initiatives in Europe. Finally, it presents and discusses modelling projections on 
the combined effects and synergies of different harm reduction interventions, and 
examines where improvements in data availability are needed to better inform policy and 
practice in this area.

Chapter 1 gives an insight into the size of the public health problem related to hepatitis C 
in Europe, both in the general population and among people who inject drugs. The chapter 
provides information on the estimation of the size of drug-injecting populations and 
describes the measures in place to prevent HCV infections among these groups. 
Worldwide, it is estimated that about 1.6 % of the population, or 115 million people, has 
ever been infected with HCV and that about two-thirds of the infections are active. In 
Europe, people who inject drugs, or have done so in the past, are now the main group 
affected. In many countries, prevalence of infection among samples of drug users is high, 
commonly in the range of 40–80 %. The chapter warns about new infections and likely 
ongoing transmission, but also about the fact that the coverage of interventions such as 
opioid substitution treatment and needle and syringe programmes in some countries 
continues to be low, when measured against international standards. The chapter 
identifies important gaps and limitations in our knowledge of the situation and the 
responses, which exist to varying degrees in many European countries. Chief among these 
are estimates of the number of people who inject drugs, the incidence and prevalence of 
HCV infection among this group, and the coverage of the main prevention interventions. 
Improving surveillance and monitoring in these areas is important for determining the 
burden of disease and assessing the impact of interventions over time.

Chapter 2 synthesises the available evidence relating to the uptake and outcomes of HCV 
treatment (including treatment adherence, sustained virological response, reinfection and 
morbidity related to liver disease) among people who inject drugs. The analysis suggests 
that treatment of HCV infection can result in acceptable outcomes in individuals who 
report current injecting drug use and who meet standard eligibility criteria for commencing 
HCV treatment. Further work is needed to assess the risk of HCV reinfection among those 
who are actively injecting illicit drugs. It is likely, however, that this risk can only be 
accurately assessed once treatment is scaled up and more equitably provided in this 
population.

7

Chapter 3 discusses the strategies to improve hepatitis C care and to enhance treatment 
uptake and adherence among people who inject drugs. It highlights the importance of 
case-finding and access to testing and also of co-location of hepatitis C treatment with 
community/specialist drug treatment. Three national examples of models of care from 
Europe are presented, with the coordinated actions and outcomes of these initiatives, 
including in prison settings. The chapter concludes that new hepatitis C treatment 
regimens, which are easy to administer and well tolerated, will make it easier in the future 
to deliver comprehensive, multidisciplinary care to people who inject drugs. The chapter 
also reviews examples of good practice from different countries, which show that there is 
no single solution and that even when countries have good national policy plans, room can 
exist for improvements in their implementation.

Through modelling, Chapter 4 analyses the strong theoretical basis for combining 
hepatitis C treatment with other primary prevention measures in order to reduce HCV 
transmission to negligible levels (so-called elimination). In most of Europe, the data 
suggest that after treating people with cirrhosis the next priority would be treating active 
injectors, even if they only have mild to moderate levels of the disease — as a greater 
benefit can be achieved by preventing onward transmission from this group than by 
delaying treatment until they develop cirrhosis and become eligible, or cease injecting. 
Furthermore, hepatitis C case-finding and treatment in prison could be a critical 
component of scaling up hepatitis C treatment in the community. The model projections 
described in this chapter provide strong evidence for the hypothesis that hepatitis C 
treatment of people who inject drugs will be essential to reduce prevalence of HCV 
infection and that treating this group is cost-effective. Empirical data and evaluations of 
the impact of scaling up hepatitis C treatment among people who inject drugs in European 
settings are, however, urgently needed to confirm the conclusions of the currently available 
statistical models.

Chapter 5 points out that treatment of HCV infection has changed dramatically and that 
all-oral, shorter, and better tolerated interferon-free regimens now prevail. The number of 
treatment options is increasing, and the chapter reviews the medications currently 
available and those that are in development. It provides an update on the current HCV 
treatment regimens (2016) and an insight into the future regimens that are likely to 
become available.

Chapter 6 discusses how the scaling up of HCV treatment can take into account the needs 
and perspectives of people who inject drugs. It draws on qualitative research among 
people who inject drugs to illustrate enabling interventions and their role in facilitating HCV 
treatment engagement, initiation and access.

Chapter 7 explains that there is currently a window of opportunity to generate empirical 
data and conduct evaluations of the impact of scaling up HCV treatment among people 
who inject drugs in European settings, as treatment services are geared up to identify and 
deal with severe liver disease. The analysis builds on the HIV experience and discusses the 
implications for HCV, to draw a framework for evaluating the scale-up of HCV treatment as 
prevention for people who inject drugs.

8

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionI  Acknowledgements

The EMCDDA wishes to thank the external contributors and the EMCDDA staff involved, 
including Teodora Groshkova, for their work in preparing this Insights publication. In 
addition, the Centre is grateful to members of the EMCDDA Scientific Committee and 
Christine Larsen, Angelos Hatzakis, Ricardo Baptista Leite, Anneke de Vos, Olav Dalgard, 
and Eberhard Schatz for reviewing parts of the publication.

I  External contributors

Esther Aspinall

Glasgow Caledonian University, School of Health and Life 
Sciences, Scotland, United Kingdom

Philip Bruggmann

Arud Zentren für Suchtmedizin, Zürich, Switzerland

Patrizia Carrieri

French National Institute of Health and Medical research 
(INSERM), Marseille, France

Stephen Corson

University of Strathclyde, Glasgow, United Kingdom

Daniela De Angelis

MRC Biostatistics Unit, University of Cambridge,  
United Kingdom

John Dillon

School of Medicine, University of Dundee, Scotland,  
United Kingdom

Gregory Dore

The Kirby Institute, University of New South Wales, Australia

Joseph Doyle

Erika Duffell

Department of Medicine St Vincent’s Hospital, University of 
Melbourne, Australia

European Centre for Disease Prevention and Control (ECDC), 
Stockholm, Sweden

Gabriele Fischer

Medical University Vienna, Austria

David Goldberg

Health Protection Scotland, Glasgow, United Kingdom

Jason Grebely

The Kirby Institute, University of New South Wales, Australia

Magdalena Harris

London School of Hygiene and Tropical Medicine, United 
Kingdom

Margaret Hellard

Burnet Institute, Melbourne, Australia

Matthew Hickman

School of Social and Community Medicine, University of 
Bristol, United Kingdom

Sharon Hutchinson

Glasgow Caledonian University, School of Health and Life 
Sciences, Scotland, United Kingdom

Hamish Innes

Natasha K. Martin

Mõjca Maticic

Glasgow Caledonian University, School of Health and Life 
Sciences, Scotland, United Kingdom

Department of Medicine, University of California San Diego, 
United States and University of Bristol, United Kingdom

Clinic for Infectious Diseases and Febrile Illnesses, University 
Medical Centre Ljubljana, Slovenia

Jean-Michel Pawlotsky

Hopital Henri Mondor, Créteil, France

9

Vratislav Rehak

Remedis Clinic, Prague, Czech Republic

Tim Rhodes

Perrine Roux

Peter Vickerman

London School of Hygiene and Tropical Medicine, United 
Kingdom

French National Institute of Health and Medical research 
(INSERM), Marseille, France

Department of Social medicine, University of Bristol and 
Health Policy Unit, London School of Hygiene and Tropical 
Medicine, United Kingdom

Corresponding authors

Introduction

Matthew Hickman (matthew.hickman@bristol.ac.uk)

Chapter 1

Chapter 2

Chapter 3

Chapter 4

Chapter 5

Chapter 6

Chapter 7

Isabelle Giraudon (isabelle.giraudon@emcdda.europa.eu)

Esther Aspinall (esther.aspinall@nhs.net)

Philip Bruggmann (p.bruggmann@arud.ch)

Natasha Martin (natasha-martin@ucsd.edu)

Jean-Michel Pawlotsky (jean-michel.pawlotsky@aphp.fr)

Magdalena Harris (magdalena.harris@lshtm.ac.uk)

Daniela De Angelis (daniela.deangelis@mrc-bsu.cam.ac.uk)

Conclusions

Isabelle Giraudon (isabelle.giraudon@emcdda.europa.eu)

EMCDDA project group: Isabelle Giraudon, Lucas Wiessing, Dagmar Hedrich, Eleni 
Kalamara, Paul Griffiths and Roland Simon

10

11

I  Introduction

Matt Hickman, Natasha Martin, David Goldberg, Gabriele Fischer, 
Erika Duffell and Roland Simon

Hepatitis C virus (HCV) is an important cause of liver cancer in Europe. The key risk group 
for HCV infection is people who inject drugs. Preventive interventions targeting people 
who inject drugs will reduce transmission of the virus and future liver disease-related 
morbidity in Europe. Many people with an injecting history, however brief, as well as 
current injecting drug users, are unaware of their infection status. In part this is because 
initial infection with the virus is often asymptomatic, with spontaneous clearance of HCV 
occurring in 18–34 % of infected individuals. The remainder become chronically infected, 
meaning that they remain infectious to others and are at subsequent risk of developing 
liver disease, including cirrhosis and hepatocellular carcinoma.

Among those with chronic HCV infection, the risk of progression to cirrhosis of the liver is 
estimated to be 5–20 % over 20–30 years (Figure 1). Once cirrhosis has developed, the 
annual risk of hepatocellular carcinoma is 1–5 % and the annual risk of hepatic 
decompensation is 3–6 %. Following an episode of decompensation, the risk of death in 
the following year is between 15 % and 20 %.

The total number of people living with chronic HCV infection in Europe and the proportion 
infected through injecting drug use are uncertain. However, surveillance and laboratory 
testing of people who inject drugs shows that in many sites, at least 50 % of this group may 
have been infected with HCV. Opioid substitution treatment and the provision of sterile 
injecting equipment through needle and syringe programmes are the traditional forms of 
primary prevention — and where provision is optimal, considerable numbers of infections 
will have been prevented. But, if progress towards the elimination of hepatitis C is to be 
made, additional interventions for this population are required.

FIGURE 1
Risk of progression to different disease states among those infected with HCV

For every 100 people 
infected with the 
hepatitis C virus

i

T
m
e

Source: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf

13

75–80 will develop chronic infection60–70 will develop chronic liver disease  5–20 will develop cirrhosis1–5 will die of cirrhosisor liver cancerWe live in exciting times for HCV prevention — which is why we have produced this new 
‘Insight’ into HCV. Hepatitis C and HCV-related liver disease in Europe can be prevented. 
The critical change has been the arrival of new drug therapies, as outlined in Chapter 5. 
New all-oral combinations of direct-acting antiviral drugs can eliminate infection in more 
than 90 % of cases, are safe and treatment duration is short (only 8–12 weeks). 
Furthermore, in contrast to existing treatments, the new drugs are effective in those with 
severe liver disease and against all genotypes of HCV. However, these treatments come at 
a cost — up to EUR 70 000 per course — and Pawlotsky (Chapter 5) points out that the 
high costs could become a barrier to widespread scale-up of HCV treatment. Guidelines 
issued by the European Association for the Study of the Liver (EASL) in 2015 recommend, 
for the first time, that treatment be provided to people — such as active injectors — at risk 
of transmitting infection to others, irrespective of disease stage.

The prevalence of HCV-related end-stage liver disease and mortality is increasing. 
Chapter 1 describes the epidemiology of HCV in Europe. It is estimated that over 5 million 
people in Europe have chronic HCV infection. In many European countries more than half 
of those who inject drugs have been infected with HCV, and such individuals constitute the 
largest risk group for HCV infection in Europe. However, the prevalence of severe liver 
disease among infected drug injectors remains unknown. Nor is it clear how many people 
who inject drugs have been treated for HCV infection. In addition, knowledge of the 
coverage of other key HCV primary interventions — opioid substitution treatment and 
needle and syringe programmes — is also patchy. Moreover, in many countries there are 
no reliable estimates of the population currently at risk of HCV infection through injecting 
drug use. Developing better surveillance and evidence on HCV in Europe is important and 
will require collaboration between the EMCDDA and the European Centre for Disease 
Prevention and Control (ECDC) and among individual countries.

The immediate priority across Europe is to scale up HCV treatment in people with severe 
liver disease to reduce HCV-related morbidity and mortality, as rapidly as possible. 
Thereafter, the question is which patients should be prioritised for treatment next — 
should countries target those with moderate liver disease (pre-cirrhotic) or infected active 
injectors, most of whom will have no or mild disease, as recommended by EASL? In other 
words, should a twin strategy that uses HCV treatment to prevent HCV-related liver 
disease deaths while also aiming to minimise HCV transmission and start to reduce HCV 
prevalence in the population be adopted? Chapter 4 emphasises the importance of HCV 
treatment — it is unlikely that the combination of opioid substitution treatment and needle 
and syringe programmes in itself will achieve substantial reductions in HCV prevalence 
among people who inject drugs. So far, the evidence, based on model projections, is 
theoretical. It suggests that prioritising early HCV treatment on people who inject drugs is 
likely to be highly cost-effective — but as yet we lack direct evidence (i.e. that HCV 
transmission is reduced as a result of scaling up HCV treatment).

The reason for a lack of direct evidence is in part because HCV treatment rates among 
people who inject drugs historically have been low, despite evidence, as described in 
Chapter 2, that outcomes among this group can be as good as in other patient groups, but 
also because studies, designed to evaluate the impact of the prevention impact of 
treatment, have not been done. In the context of what was the interferon era and the 
complexities of treating active injectors with a drug regimen which was lengthy, was not 
always effective, involved weekly injections, usually in a hospital setting, and was 
associated with serious adverse effects, this was understandable. With the new 
treatments, however, these barriers do not exist. Chapter 3 argues that national strategies, 
and perhaps a European strategy, are required to redesign and co-locate treatment 
services for managing HCV infection with specialist drug services for injecting drug users. 

14

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionHowever, this is only the first step in addressing stigma and promoting patient-facing 
treatment services for drug injectors, as highlighted in Chapter 6.

Certainly, there is now a window of opportunity to generate empirical data and conduct 
evaluations of the impact of scaling up HCV treatment among people who inject drugs in 
European settings, as treatment services are geared up to identify and deal with severe 
liver disease. How and where the evaluation should be conducted is complex, as discussed 
in Chapter 7. Ideally, potential intervention sites will have established ‘HCV 
treatment-in-the-community’ services, integrated with others that manage and support 
people who inject drugs, and critically sites will need to have mature systems for collecting 
data on behaviour, HCV transmission and HCV prevalence among this client group, and on 
HCV testing and treatment.

In the context of the EASL guidelines and the changing therapeutic landscape of HCV, 
such an evaluation needs to be done now and as quickly as possible.

15

Introduction1CHAPTER 1
Hepatitis C virus infection among 
people who inject drugs: 
epidemiology and coverage of 
prevention measures in Europe
Isabelle Giraudon, Dagmar Hedrich, Erika Duffell, Eleni Kalamara 
and Lucas Wiessing

I  Introduction

Hepatitis C is a disease of the liver caused by a virus, 
which if not resolved can lead to chronic liver disease, 
cirrhosis and cancer. The disease is communicable and is 
spread by contact with infected blood or other bodily 
fluids. Worldwide, it is estimated that about 1.6 % of the 
population, or 115 million people, has ever been infected 
with the hepatitis C virus (HCV) and that about two-thirds 
of the infections are active (Gower et al., 2014). Recent 
estimates for the World Health Organization (WHO) 
European region, which in addition to the countries of the 
European Union and its candidate countries, includes the 
countries of the former Soviet Union among others, put 
the size of the HCV-infected population at between 
9 million (Gower et al., 2014) and 15 million (Hope et al., 
2014). In developed countries, injecting drug use is the 
most common route of transmission of the virus, as the 
infection can be easily transmitted from an infected 
injector to another when the needles and syringes or 
other injection equipment are shared; elsewhere 
nosocomial transmission (that is, acquired in hospitals 
and other healthcare facilities) and other routes of 
transmission are the most common. Thus, in Europe, 
people who inject drugs, or have done so in the past, are 
now the main group affected (Alter, 2011; Hajarizadeh et 
al., 2013; Stephenson, 2001; Wiessing et al., 2008).

Hepatitis C is an important public health problem as 
chronically infected individuals are at risk of serious 
long-term health consequences, including liver fibrosis, 
cirrhosis and hepatocellular carcinoma (Shepard et al., 
2005). In Europe, hepatitis C is a leading cause of 
cirrhosis and primary liver cancer (Blachier et al., 2013) 
and evidence suggests that this burden is high (Blachier 

et al., 2013; Lavanchy, 2004, 2011; Sweeting et al., 2007). 
Worldwide, approximately 500 000 people die each year 
from hepatitis C-related liver diseases (WHO, 2015).

In this context, this chapter aims to give an insight into 
the size of the public health problem related to 
hepatitis C in Europe, both in the general population and 
among people who inject drugs. In addition to data on 
the epidemiology of hepatitis C, the chapter also 
provides information on the estimation of the size of 
drug-injecting populations and describes the measures 
in place to prevent HCV infections among these groups.

I  Sources of data

The epidemiology of hepatitis C reported here is based on 
two principal types of data: notifications of newly 
diagnosed cases and studies on the prevalence of 
antibodies to the virus among the general population and, 
more often, among populations of injecting drug users. 
Between 1995 and 2008, data on hepatitis C notifications 
were collected by the EMCDDA each year through its 
network of national focal points as part of an annual 
reporting exercise on the drug phenomenon in Europe (1). 
The national focal points used a standard questionnaire to 
report aggregated data provided by health authorities in 
the EU Member States, Turkey and Norway. The countries 
were asked to report the total number of cases of HCV 
infection notified by physicians, where possible identified 
as acute or chronic cases, as well as the case definitions 

(1)  Information on the monitoring of infectious diseases among drug 

users is available on the Drug related‑infectious diseases key indicator 
page on the EMCDDA website.

17

used. The questionnaire also asked for the number of 
cases with known risk factor and the number attributed to 
injecting drug use. From this information, it is possible to 
observe trends in the total number of notified cases of 
hepatitis C, and in the proportion of people who inject 
drugs among the cases with valid information on 
exposure category (Wiessing et al., 2008).

Since 2009, the EMCDDA works closely with the 
European Centre for Disease Prevention and Control 
(ECDC), the EU agency to which national hepatitis C 
notification data are now reported. ECDC facilitates the 
surveillance of communicable diseases through the 
European Surveillance System (TESSy), a web-based 
database for the submission and retrieval of data from 
31 EU/EEA countries (the 28 EU Member States, 
Norway, Iceland and Liechtenstein). Data are collected 
from national notification systems using standardised 
case definitions (Duffell et al., 2015; ECDC, 2015).

National notification data for hepatitis C, however, are 
often unreliable due to under-diagnosis (many new 
infections are asymptomatic) and under-reporting of 
diagnoses. An additional limitation to this category of 
data is the incorrect classification, or lack, of information 
on risk group, such as injecting risk. For this reason, the 
EMCDDA monitors HCV antibody prevalence among drug 
users, as a complement to the notifications data. Data 
from HCV antibody prevalence studies among people 
who inject drugs provide complementary information and 
are often more informative, as the studies have usually 
been designed to look at populations of drug injectors, in 
different settings such as drug treatment, low-threshold 
facilities or prisons. Such studies tend to be more 
informative because they can differentiate between 
subgroups of drug injectors, by age or injecting duration, 
which allows to better identify recent infections and 
those that have so far been undiagnosed. Prevalence 
studies, also called ‘bio-behavioural’ studies, often 
include the collection of behavioural data, such as 
whether the persons underwent HCV testing or whether 
they are or have been sharing injection equipment and 
what knowledge they have about ways to prevent 
infection. Many European countries are able to conduct 
regular prevalence studies among people who inject 
drugs. The methods used, however, may vary: studies 
may have different designs, such as ad hoc versus 
routine testing; the data may lack national coverage and 
some studies also may have poor continuity over time.

Analysis of HCV antibody prevalence among subgroups 
of people who inject drugs — those who are younger 
than 25 years or have been injecting for less than 2 years 
— is also carried out by the EMCDDA as part of the 
general monitoring activity of the DRID epidemiological 

key indicator, in order to obtain a proxy estimate of 
incidence of infection (the rate of new cases occurring).

Notifications (through ECDC) and prevalence data 
analysed in this chapter were submitted to the EMCDDA in 
the 2015 national reporting round (the data are available in 
EMCDDA, 2016b, under infectious diseases). Whereas the 
notifications refer to the year 2014, data from prevalence 
studies refer to 2014 or the most recent year available.

In addition to data collected and analysed by the 
EMCDDA, this chapter incorporates the findings of 
a number of key publications in its description of the 
epidemiology of hepatitis C.

Estimates of the numbers of people injecting drugs are 
important in projecting the future epidemiology of HCV 
infection and in planning and evaluating the public 
health responses to the problem. As part of its routine 
monitoring, the EMCDDA gathers data on the numbers 
of people injecting drugs and on the principal relevant 
harm reduction responses in this area — opioid 
substitution treatment and needle and syringe provision 
through specialised programmes — from the Reitox 
network of national focal points. These data are also 
presented in this chapter.

Hepatitis C testing and reporting

Anti‑HCV tests are used to detect the presence of 
antibodies to HCV in blood samples. A positive 
test result indicates that a HCV infection has 
occurred. Routine screening for antibodies to HCV 
is usually carried out with an enzyme‑linked 
immunosorbent assay (also known as an enzyme 
immunoassay or ELISA). These tests cannot 
distinguish between an active (acute or chronic) 
and a resolved infection.

Tests on HCV viral material (RNA) can identify an 
active infection. HCV RNA can be found in the 
blood within 1 to 2 weeks after exposure to the 
virus (Fox, 2013). This test may be done to 
double‑check a positive result on an anti‑HCV 
antibody test, measure the level of virus in the 
blood (called viral load), or show how well 
a person with HCV is responding to treatment.

Chronic infection is defined as detectable 
HCV‑RNA for at least 6 months. A resolved 
infection will have no further health 
consequences, whereas a chronic infection may 
lead to serious liver damage and premature death 
over the course of decades.

18

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 1 I Hepatitis C virus infection among people who inject drugs

Definition: People who inject drugs

The EMCDDA definition for the monitoring of the 
prevalence of drug‑related infectious diseases 
refers to ‘ever injectors among people tested in 
(mostly) drug service settings’. Thus, where the 
study settings are specific for active injectors (e.g. 
needle and syringe programmes), it is likely that 
the sample consists only of active injectors. In 
other drug service or treatment settings, it might 
also include ever injectors who do no inject any 
longer. The providers of each dataset reported to 
the EMCDDA are asked to specify whether it 
refers to active injectors or to ever injectors 
(including active injectors) and in the latter case 
to provide an estimate of the proportion of active 
injectors.

I  Epidemiology

I  Notifications of hepatitis C in Europe

In 2014, 35 321 cases of hepatitis C were reported to 
ECDC in 28 countries (Iceland, Norway and all EU 
Member States except for France and Spain) (ECDC, in 
press). The overall notification rate was 8.8 cases per 
100 000 population. Of these cases, 1.3 % were 
reported as acute, 13.3 % as chronic, 74.7 % as 
‘unknown’ and 10.7 % could not be classified. In 2014, of 
the cases for whom gender was reported, 21 926 were 
males (11.6 per 100 000) and 12 063 were females (6.1 
per 100 000), with a male-to-female ratio of 1.8 to 1. 
Just over half (51 %) of all hepatitis C cases reported in 
2014 were aged between 25 and 44, and 8 % of cases 
were aged under 25 years.

National data on hepatitis C notification rates reported in 
2014 are insufficient to describe the geographic 
distribution of newly diagnosed cases in Europe. Looking 
at countries that have surveillance systems which are 
known to capture data on both acute and chronic cases, 
a picture emerges of countries reporting relatively high 
rates of new diagnoses (Austria, Estonia, Finland, 
Ireland, Latvia, Norway, Sweden, United Kingdom) all 
located in the north of Europe, and those reporting low 
rates (Bulgaria, Croatia, Cyprus, Denmark, Greece, 
Malta, Romania, Slovenia) primarily located in the 
southeast. In addition to being incomplete, the data 
available on hepatitis C notifications are strongly 
influenced by national screening strategies and the 

measures in place in each country to prevent the 
transmission of the virus. These factors compound the 
limitations of surveillance data for a disease such as 
hepatitis C, which is largely asymptomatic until a late 
stage. Notifications may hugely underestimate the real 
number of new infections and they may reflect testing 
practices rather than real occurrence of disease (Duffell 
et al., 2015; Hagan et al., 2002). There are also possible 
large differences in reporting completeness between 
countries.

Data regarding the most likely mode of transmission of 
hepatitis C virus were provided for only 16 % (range 
0–79 %) of the cases reported in 2014. The overall 
completeness of data on transmission has declined since 
2011, when it was 29 %. Overall, the most commonly 
reported route of transmission among newly diagnosed 
cases of hepatitis C was injecting drug use, accounting 
for 78 % of all cases with a known transmission route. 
Although the data are incomplete and it is difficult to 
draw any firm conclusions, there are differences in 
reported transmission routes between countries. While 
nosocomial transmission appears to be an uncommon 
route of transmission in most European countries, it has 
been a commonly reported route in Italy, Latvia, Romania 
and Slovakia, although differences in reporting still 
hamper a clear interpretation of the data. Among 
countries with more complete reporting there are still 
major differences, with injecting drug use accounting for 
over 80 % of all reported cases with a known route of 
transmission in Finland and Ireland but fewer than 10 % 
of cases in Romania, suggesting that real differences 
may exist in HCV transmission patterns between 
countries (Duffell et al., 2015; Wiessing et al., 2008).

I  HCV antibody prevalence

The prevalence of antibodies to HCV among the general 
population in Europe is not systematically monitored by 
national health systems. What information is available 
comes from a variety of studies carried out over periods 
of different durations and with various sampling 
strategies.

A recently published review searched the international 
scientific literature for reports of antibodies to HCV 
among the general population published between 1 
January 2000 and 27 July 2009 (Hahné et al., 2013). In 
the review, 13 EU Member States and Turkey were found 
to have at least one estimate, although only four of the 
estimates were at national level and some estimates 
were nearly 20 years old. Among these countries, the 
prevalence of anti-HCV in the general population varied 
from 0.1 % to 3.5 %, with the highest levels found in 

19

FIGURE 1.1
Estimated prevalence of antibodies to HCV in the 
general population in Europe

Percent

<0.5

0.5–0.9

1.0–1.9

2.0–2.9

≥3.0

No data

Adapted from Hahné et al., 2013.

countries in the south and east of Europe and the lowest 
in the north (Figure 1.1 and Annex Table A1). In addition 
to the data reviewed by Hahné et al. (2013), new or more 
recent estimates based on national health surveys are 
available for a number of countries including France 
(Meffre et al., 2010), Germany (Poethko-Müller et al., 
2013), Lithuania (Liakina and Valantinas, 2012), the 
Netherlands (Vriend et al., 2012) and Slovakia (Schréter 
et al., 2007). Among these countries anti-HIV prevalence 
in the general population ranged from 0.3 % to 2.8 %. 
Trends, where the most recent data are compared with 
the previous estimates available, show an increase in the 
Netherlands (0.3 %) and a decrease in France (0.8 %) 
and Germany (0.3 %). In Lithuania (2.8 %) and Slovakia 
(1.5 %), the available estimates sit within the values seen 
in other European countries, and no trend analysis can 
be made by comparison to previous data.

Hope et al. (2014) collated data on anti-HCV prevalence 
in studies on the general population, and these varied 
from 0.4 % to 5.2 %. They also assembled a data set on 
the prevalence imputed from antibodies to HCV in blood 
donors for almost all EU countries. This data set contains 
a greater range of national values: from 0.1 % to 10.3 %. 
Here too, nevertheless, the highest prevalence levels 
tend to be found in countries in the east and in the 
south, with imputed HCV prevalence levels of 10.3 % in 
Lithuania, 9.2 % in Romania, 7.0 % in Estonia and 4.5 % 
in Bulgaria. However, considering that notable 

20

differences were found between the two variables for 
a number of countries, and that blood donors are a very 
specific group within the population, of which they are 
unlikely to be representative, caution is needed when 
interpreting these results.

From the estimates made by Hope et al. (2014), 
7.4 million people living in the European Union have 
antibodies to HCV, indicating a current or resolved 
infection. Of these, an estimated 5.5 million have 
a chronic infection.

I  HCV among the drug-injecting population

Across Europe, among people who inject drugs — which 
for this analysis includes those who have ever done so — 
a history of infection with HCV is very frequent and HCV 
antibody prevalence is overall high. Hahné et al. (2013) 
found that the estimate of anti-HCV prevalence in people 
who inject drugs, based on the data collected by the 
EMCDDA, was on average almost 50 times higher than 
that in the general population, in the 13 countries that 
had both estimates available. In more recent data 
obtained by the EMCDDA, 13 countries reported on 
anti-HCV prevalence among national samples of drug 
injectors for the years 2013 or 2014. Anti-HCV 
prevalence ranged from 15 % to 84 %, with six of the 
countries reporting rates in excess of 50 % (Figure 1.2).

Monitoring of anti-HCV prevalence within populations 
over time provides an indication of possible changes in 
the transmission of the virus. Among countries with 
national trend data for the period 2008–14, six (Greece, 
Latvia, Hungary, Slovenia, United Kingdom, Turkey) 
observed an increasing trend in HCV-antibody 
prevalence among injecting drug users, while Malta and 
Norway observed a decrease. Beyond national trends, 
trend data in sub-national sources are important as well, 
as shown by increases reported in several areas in 
Europe recently (EMCDDA, 2015). Trends at 
sub-national level show, for example, local increases in 
Budapest (Hungary), Sofia (Bulgaria) and Vienna 
(Austria) (EMCDDA, 2016a).

An increase in HCV prevalence among people who inject 
drugs has previously been associated with an increased 
risk for injection-related HIV outbreaks, and therefore 
increases should be monitored carefully (EMCDDA, 
2015; Vickerman et al., 2013).

As approximations of recently acquired infections or 
incidence, the EMCDDA monitors the prevalence of 
anti-HCV among young injectors (under age 25) and 
among new injectors (those who have injected for less 

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 1 I Hepatitis C virus infection among people who inject drugs

FIGURE 1.2
Anti-HCV prevalence (%) among people who inject drugs in the European Union, Norway and Turkey, 2013–14

Percent

100

80

60

40

20

0

a
t
l
a
M

c

i
l

b
u
p
e
R
h
c
e
z
C

i

m
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e
B

l

i

a
n
e
v
o
S

l

i

a
k
a
v
o
S

l

y
e
k
r
u
T

s
u
r
p
y
C

y
r
a
g
n
u
H

y
l
a
t
I

a
i
r
t
s
u
A

y
a
w
r
o
N

a
i
r
a
g
u
B

l

e
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e
r
G

y
n
a
m
r
e
G

a
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v
t
a
L

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a
l
r
e
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t
e
N

a
i
t
a
o
r
C

i

m
o
d
g
n
K
d
e
t
i
n
U

100

80

60

40

20

0

i

a
n
o
t
s
E

i

a
n
a
u
h
t
i
L

l

a
g
u
t
r
o
P

n
e
d
e
w
S

Samples with national coverage
Samples with sub-national coverage

d
n
a
n
F

i

l

Source: Studies with national and subnational coverage covering the period 2013–14, reported to the EMCDDA by Reitox national focal points. 

FIGURE 1.3
Anti-HCV prevalence (%) among people who inject drugs under age 25 (left) and among those injecting for less than 
2 years (right) in the European Union, Norway and Turkey, 2013–14

Percent

100

80

60

40

20

0

Percent

100

80

60

40

20

0

i

m
u
g
e
B

l

y
l
a
t
I

y
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k
r
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l

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L

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l

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l

Source: Studies with national and subnational coverage covering the period 2013–14, reported to the EMCDDA by Reitox national focal points. 
NB: Samples of less than 10 persons are not included.

Samples with national coverage

Samples with sub-national coverage

21

 
 
 
 
 
 
than 2 years). Estimates for these groups of drug 
injectors are available only for a sub-set of countries, and 
are often based on small samples. Overall, they indicate 
anti-HCV prevalence levels of over 20 % and typically 
between 20 % and 60 % in these groups. Many of the 
countries reported samples where anti-HCV prevalence 
is 40 % or more among young injectors, suggesting high 
levels of transmission in recent years (Figure 1.3).

Estimates of anti-HCV prevalence among new injectors 
ranged from 7 % to 71 % in the 11 countries providing 
recent data. In common with the findings on anti-HCV 
prevalence among injecting drug users of all ages and 
injection history, the highest estimates among new 
injectors were in the south or east of Europe (Figure 1.3).

Of these two indicators for recent infection, the 
prevalence among new injectors is the strongest proxy 
for incidence of HCV infection, given that even young 
injectors, under age 25, may have already injected for 
a number of years. However, data on young injectors may 
help validate the data on new injectors and provide 
insights where prevalence among new injectors is not 
available. The data available are likely to be subject to 
limitations, particularly those that affect small samples 
such as the subgroups of young or recent injectors.

There are also general limitations to the prevalence data. 
Thus, studies among drug injectors are often limited to 
‘convenience samples’ of those attending drug services, 
where no systematic sampling has taken place or where 
procedures and testing completeness are not reported. 
Studies are also often local or regional with unknown 
generalisability to the national level. Due to these 
limitations, it is difficult to generalise findings from these 
samples to people who inject drugs as a group. 
Nevertheless, following changes in prevalence over 
time — in the same settings in particular — may provide 
valuable information.

I  Incidence

Studies reporting on the incidence of primary HCV 
infection among people who inject drugs in Europe have 
been reviewed by Wiessing et al. (2014). In total, 27 
studies were found that reported direct measurements 
of HCV incidence, covering only nine EU Member States 
(Czech Republic, Denmark, Finland, France, Ireland, 
Netherlands, Spain, Sweden, United Kingdom). In these 
studies, the incidence of HCV among people who inject 
drugs was often high (range 2.7–66 per 100 
person-years, median 13). The review found that data on 
incidence of HCV infection among people who inject 
drugs were sparse across Europe, of variable quality and 

not easily comparable. Some of the studies had 
limitations such as being old, conducted in specific 
settings or local. For example, a study in France in 2000; 
a prison study in the Netherlands in 1997; an Irish 
estimate based on one study in Dublin in 1992–1999; 
a needle and syringes programme in Malmö, Sweden. 
While the review covered literature published from 2000 
to 2012, studies more recent than 2005 were found only 
for the Netherlands and the United Kingdom.

I  Genotype

Hepatitis C virus can be classified into seven strains or 
genotypes, numbered 1 to 7, and 67 subtypes (Smith et 
al., 2014). Some of the genotypes (1a, 1b and 3a) have 
become distributed widely because of transmission 
through blood transfusion and needle-sharing among 
people who inject drugs and now represent the vast 
majority of infections in developed countries. These are 
the genotypes that are most commonly encountered in 
clinical settings and for which most information has 
been collected on response to antiviral treatments 
(Simmonds, 2004). Information on genotype is 
important because the response to traditional antiviral 
treatment (which before 2011 was based on 
combination therapy with interferon and ribavirin) varies 
by genotype and therefore treatment has to be tailored 
accordingly (Muir, 2014; WHO, 2014; see also Chapter 4).

In a review of HCV epidemiology (Wiessing et al., 2014), 
36 studies with genotype data were identified from 20 
EU countries, including samples for nearly 6 000 
HCV-infected people who inject drugs which were 
identified to the level of genotype or subtype. HCV 
genotypes 1 and 3 (subtypes 1a and 3a) are the most 
commonly identified among drug injectors in Europe. The 
data suggest that genotype 4, prevalent in the Middle 
East and Africa, particularly in Egypt (Kamal and Nassar, 
2008), may be increasing. Distribution of the genotypes 
varied among drug injectors across Europe (Figure 1.4), 
with the traditionally difficult-to-treat genotypes (1 and 
4) being predominant in certain EU countries (in 
particular Portugal, Romania and Spain), and showing 
a large variation (17–91 %) and a median of 53 %. 
Caution must be exercised in analysing these findings 
for a number of reasons: not all reports assessed mixed 
infections; estimates for six of the countries are based 
on samples of fewer than 100 patients; for 10 countries 
only one study could be located and some studies were 
based on selected populations (such as hospitalised 
patients).

22

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 1 I Hepatitis C virus infection among people who inject drugs

FIGURE 1.4
Proportion (%) of HCV infections among people who 
inject drugs that are genotypes 1 or 4

FIGURE 1.5
Co-infection with HIV among HCV-infected  
people who inject drugs 

Percent
<20

20–39

40–59

60–79

≥80

No data

Percent
<1

1–9

10–19

20–39

≥40

No data

Adapted from Wiessing et al. (2014).

Adapted from Wiessing et al. (2014).

I  HIV co-infection

Co-infection with HIV is another factor that influences 
treatment outcome. Thirty-three published and 15 
unpublished studies were reviewed by Wiessing et al. 
(2014), resulting in 68 HIV–HCV co-infection estimates 
for people who inject drugs in Europe. It should be noted 
that as HCV infection was not confirmed by RNA in many 
studies, antibody prevalence was used across all 
studies. Estimates of HIV–HCV co-infection prevalence 
were available for 22 countries in Europe and 11 
countries had multiple estimates. Among HCV-infected 
people who inject drugs, co-infection with HIV ranged 
from 0 to 70 %, with a median of 3.9 %. The rate of HIV 
co-infection correlated with the HIV prevalence among 
the group. HIV prevalence among people who inject 
drugs differs greatly across Europe (from 0 to 30 %). 
Among those infected with HCV, the range is even wider 
as this is a high-risk group. Levels of co-infection 
prevalence can be classed as low (not more than 4 %) in 
11 countries, moderate (5–15 %) in three countries and 
high (over 15 %) in seven countries (Figure 1.5).

I   Burden of disease, cirrhosis, hepatocellular 

carcinoma and mortality

Information on the current and projected impact of HCV 
infection in terms of disease burden and mortality is 
necessary to inform public health planning and resource 
allocation. Burden of disease studies aim to quantify the 
effect of an illness in terms that are comparable across 
populations and between diseases. Data on the burden 
of disease of hepatitis C in Europe are scarce, outdated 
or inconclusive (Mühlberger et al., 2009).

The review conducted by Wiessing et al. (2014) found 
seven papers that reported on the burden of disease or 
mortality related to HCV infection among people who 
inject drugs in the European Union. Where assessed, the 
disease burden of HCV was found to be high and is 
expected to rise in the next decade. Only two of the 27 
countries included in the review appeared to have 
carried out a modelling study to estimate the effect of 
HCV treatment on the future burden of disease. Without 
treatment, a study in the Netherlands (Amsterdam) 
projected a 36 % increase in the occurrence of 
decompensated cirrhosis or hepatocellular cancer, 
between 2011 and 2025 (Matser et al., 2012), whereas 
in Scotland, UK (Glasgow) increases of 56 % in cirrhosis 
and 64 % in mild liver disease were projected for 
2010–2025. Both studies showed that HCV treatment 

23

would substantially reduce the burden of liver disease 
(Hutchinson et al., 2005).

FIGURE 1.6
Hepatocellular carcinoma-related mortality per 
100 000 population (men)

Mortality in HCV-infected people who inject drugs is 
dependent on competing mortality (e.g. HIV or 
drug-related death) and the duration of persistent HCV 
infection. In the review, all-cause mortality rates among 
HCV-infected drug injectors were estimated at 2.1–2.4 
per 100 person-years in Spain (Hernando et al., 2012) 
and the Netherlands (Grady et al., 2011). A much higher 
rate was estimated for injectors co-infected with HIV in 
Denmark, where all-cause mortality was estimated at 
12.2 per 100 person-years (Omland et al., 2010). The 
high mortality rate in the Danish study may be explained 
by high rates of overdose mortality or differences in 
combination antiretroviral therapy initiation, given that 
a Spanish study reported a crude mortality rate of 2.4 
per 100 person-years among HIV co-infected people 
who inject drugs during a comparable study period. This 
suggests the existence of significant differences 
between countries in mortality rates among HIV-infected 
people who inject drugs, as is found for mortality among 
all drug injectors, and underlines the importance of 
obtaining country-specific mortality estimates. Available 
data on the morbidity and mortality risk due to HCV 
among people who inject drugs are scarce but are 
urgently needed for future planning. More recent large 
cohort studies also show that liver disease (including 
viral hepatitis and cirrhosis) is one of the major causes of 
deaths among drug users (Pierce et al., 2015).

The HCV disease burden among people who inject drugs 
translates to a significant burden in the general 
population. Approximately 500 000 people worldwide 
die annually (2.7 % of all deaths) from hepatitis C-related 
liver diseases, most commonly liver disease including 
liver cancer (WHO, 2015). An estimated 57 % of liver 
cirrhosis cases and 78 % of primary liver cancers result 
from HBV or HCV infection (WHO, 2013). Globally, 27 % 
of all cases of cirrhosis and 35 % of all cases of 
hepatocellular cancer are attributed to HCV infection 
(Bosetti et al., 2007, 2008; WHO, 2013).

In Europe, annual mortality rates from hepatocellular 
cancer vary by country and are generally lower in 
countries in the north-west of Europe compared with 
those in the south-east (Figure 1.6). The main causes of 
hepatocellular cancer are HBV and HCV infections and 
alcohol consumption. In all countries, mortality from 
hepatocellular cancer is higher in males than in females 
(ECDC, 2010). Although these data are not specific to 
people who inject drugs, they provide the scale of 
morbidity and mortality related to infectious liver 
disease, a large proportion of which is accounted for by 
infection acquired through injecting drugs.

24

Per 100 000 population (men)

<1.0

1.0–1.9

2.0–3.9

4.0–5.9

≥6.0

No data

Source: ECDC (2010).

I   Prevention of hepatitis C among 

people who inject drugs

Modelling studies suggest that antiviral treatment could 
play an important and cost-effective role in preventing 
hepatitis C in people who inject drugs by reducing the 
number at risk of transmitting the virus (Martin et al., 
2012; see also Chapter 4). These studies indicate that 
hepatitis C treatment may have a synergistic impact on 
prevention efforts, in particular when combined with the 
harm reduction interventions of opioid substitution 
treatment and needle and syringe programmes 
(Chapter 3). In this section we review the estimated 
prevalence of drug injecting and the coverage of opioid 
substitution treatment and needle and syringe 
programmes in Europe based on data from EMCDDA 
monitoring.

I  Estimated number of people who inject drugs

Relatively recent (2007–2014) estimates of the 
prevalence of drug injecting among the general 
population are available in only 16 of the 30 countries 
monitored by the EMCDDA (2016b). Estimated 

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 1 I Hepatitis C virus infection among people who inject drugs

FIGURE 1.7
Estimates of the prevalence of injecting drug use (rate per 1 000 population aged 15–64), 2007–14 data collection 
(last study available)

Rate per 1 000

12

10

8

6

4

2

0

M
T
)
8
0
0
2
(

s
d
n
a
l
r
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N

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p
S

M
T
)
3
1
0
2
(

a
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)
2
1
0
2
(

s
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4
1
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(

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)
4
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(

y
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)
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/
8
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1
1
/
8
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(

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)
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0
2
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y
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w
r
o
N

M
M

)
3
1
0
2
(

M
C

)
1
1
/
4
0
0
2
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i

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g
n
K
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n
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i

m
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l

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2
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0
2
(

d
n
a
n
F

i

l

T
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2
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0
2
(

T
O

)
9
0
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2
(

g
r
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9
0
0
2
(

a
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t
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M
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2
1
0
2
(

M
T
)
4
1
0
2
(

c

i
l

b
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p
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h
c
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z
C

NB: Data displayed as point estimates and uncertainty intervals. Methods of estimation: CM, combined methods; CR, capture-recapture; HM, HIV 
multiplier; MM, mortality multiplier; OT, other methods; TM, treatment multiplier; TP, truncated Poisson.
Source: EMCDDA, 2016b.

prevalence varies strongly across countries: from less 
than 1 to up to 9 cases per 1 000 population aged 15 to 
64 (Figure 1.7) and uncertainty intervals are often broad. 
Comparisons between countries using different 
methods and acquiring data from different sources 
should be made with caution. However, the magnitude of 
the differences and changes seen in estimates is 
generally confirmed by other data sources.

Based on the available estimates, the highest absolute 
numbers of current injectors are reported in the United 
Kingdom (122 900), the Czech Republic (45 600), 
Finland (15 600), Portugal (14 400), Latvia (12 600) and 
Spain (9 900). These numbers are important as they 
provide a proxy for the size of the group at potential risk 
of infection and transmission of the virus through 
injecting drug use. Combining estimates of injecting 
drug use with HCV prevalence estimates can enable us 
to understand the size and dynamic of the infection 
among this group.

I   Harm reduction measures targeting injecting 

drug use

In the European Union, harm reduction policies form an 
integrated part of the public health response to drug 
use-related health problems (Busch, 2013; Hedrich et al., 
2008; Hedrich and Pirona, in press) and all countries 
implement opioid substitution treatment and needle and 
syringe programmes as core measures for the 
prevention and control of infections among people who 
inject drugs (EMCDDA, 2016a).

The degree to which the provision of these interventions 
meets the needs of the target population can be 
assessed by calculating some measure of coverage 
(Wiessing et al., 2009). For opioid substitution 
treatment, coverage is defined as the proportion of the 
target population (high-risk opioid users) receiving the 
intervention, whereas for specialised needle and syringe 
programmes it is number of units dispensed per head of 
the target population for this intervention (that is people 
who inject drugs). Not all countries are able to provide 
valid estimates of the size of these target populations. 
Coverage estimates can be calculated for 19 EU 

25

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Member States for substitution treatment and for 13 
Member States for needle and syringe programmes. In 
some of these countries, there are considerable 
uncertainties associated with the estimates.

I  Needle and syringe provision

Initiatives to reduce the spread of infectious diseases 
through the sharing of syringes and other drug injecting 
equipment by providing sterile drug use equipment to 
people who inject drugs date back to the mid 1980s 
(Bunning et al., 1986; Hedrich et al., 2008). Needle and 
syringe programmes, integrated into multi-component 
harm reduction interventions, distribute tens of millions 
of syringes each year in Europe. In addition to sterile 
syringes and needles, a range of other injecting 
paraphernalia, including alcohol, pads, water, filters and 
mixing containers as well as equipment for inhaling 
drugs are distributed by harm reduction facilities in order 
to prevent bacterial and viral infections. The estimated 
number of syringes distributed each year per drug 
injector through specialised programmes — excluding 
syringes sold by pharmacies outside of such 
programmes — ranged from less than 50 in Cyprus, 
Sweden, Belgium and Latvia to more than 350 in Estonia 
(Figure 1.8). Comparing these estimates of syringe 
provision against international recommendations, less 

than a third of the countries that can be assessed 
provide syringes at a level judged to support effective 
harm reduction (at least 200 syringes per year per 
person who injects drugs; UNAIDS, 2012). It should be 
noted that the uncertainties around the estimates of size 
of the national drug-injecting population carry over into 
the estimates of coverage.

I  Opioid substitution treatment

Opioid substitution treatment is an effective measure to 
reduce the risk of transmission of infections and other 
drug-related harms among people who inject opioid 
drugs, particularly heroin (see Chapter 4). This 
intervention is targeted at high-risk opioid users, 
a population that, in addition to those injecting opioids, 
includes people using illicit opioids regularly or over 
a long period by other routes of administration. Overall, it 
is estimated that approximately one in two high-risk 
opioid users in Europe received substitution treatment in 
2014 (EMCDDA, 2016a). This is the case for 10 of the 20 
countries able to provide recent data allowing national 
coverage to be estimated. However, the available data 
indicate that in some countries less than 10 % of the 
estimated population of high-risk opioid users receive 
opioid substitution treatment (Figure 1.9).

FIGURE 1.8
Number of syringes provided through specialised needle and syringe programmes per estimated drug injector in 
2014 or latest available year

Syringes

500

450

400

350

300

250

200

150

100

50

0

s
u
r
p
y
C

n
e
d
e
w
S

a
i
v
t
a
L

i

m
u
g
e
B

l

Coverage (syringes per
injecting drug user)

High (>200)

4

Medium (100–200)

4

Low (<100)

6

No data

16

i

a
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o
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s
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e
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y
r
a
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o
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n 
a
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S

y
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r
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N

d
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a
n
F

i

l

NB: Data displayed as point estimates and uncertainty intervals.

26

Hepatitis C among drug users in Europe: epidemiology, treatment and prevention 
CHAPTER 1 I Hepatitis C virus infection among people who inject drugs

FIGURE 1.9
Percentage of the estimated population of high-risk opioid users receiving substitution treatment in 2014

Percent

100

90

80

70

60

50

40

30

20

10

0

i

a
k
a
v
o
S

l

Coverage (proportion
receiving the intervention)

High (>50 %)

9

Medium (30–50 %)

5

Low (<30 %)

6

No data

a
t
l
a
M

l

a
g
u
t
r
o
P

e
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r
F

a
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s
d
n
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r
e
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t
e
N

10

a
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a
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i

a
n
a
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h
t
i
L

s
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r
p
y
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d
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o
P

l

y
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H

y
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a
t
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r
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l

)
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e
a
W
d
n
a

l

d
n
a
g
n
E
(
K
U

y
n
a
m
r
e
G

g
r
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o
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L

e
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e
e
r
G

a
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r
t
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u
A

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b
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p
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R
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z
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i

a
n
e
v
o
S

l

NB: Based on population size estimates of opioid users (2007–2014), and number of people receiving opioid substitution treatment in 2014 (or most 
recent year available).

While improvements in screening and treatment are 
becoming a priority in new hepatitis C strategies in some 
countries, there is evidence that hepatitis C is not being 
addressed in a comprehensive manner, as several 
countries still show important gaps in prevention 
coverage, and HCV treatment provision to people who 
inject drugs continues to be reported as low.

I  Conclusion

The burden of hepatitis C is high in Europe and 
disproportionately affects people who inject drugs. In 
many countries more than half of those who inject drugs 
are infected. Current data indicate new infections and 
likely on-going transmission. The European picture is 
highly variable, with large variations in both the 
epidemiology of the infection and the prevention 
responses undertaken. The coverage of interventions in 
some countries continues to be low when measured 
against international standards and, in some instances, 
it has even been recently decreasing, significantly 
increasing the risk of HCV and other infections among 
people who inject drugs.

There are significant gaps and also general limitations in 
the available data on notifications, prevalence estimates, 
estimates of the numbers of people injecting drugs and 
coverage of the main prevention interventions. Serious 
gaps also exist in estimates of incidence, co-infection, 
genotypes, undiagnosed fraction, treatment entry and 
burden of diseases. All these are valuable indicators for 
monitoring the continuum of care, and they should be 
promoted and their availability improved in several 
countries where they are still underdeveloped.

In May 2016, the World Health Assembly adopted the 
first Global Health Sector Strategy (GHSS) on viral 
hepatitis, aimed at eliminating hepatitis B and C as 
public health threats (WHO, 2016). Against this 
background, and in the context of the on-going 
transformation of hepatitis C treatment, the current 
monitoring framework established by the EMCDDA 
together with the EU Member States and partner 
agencies needs to be further strengthened, and gaps to 
be filled, in order to support policymakers and public 
health planners to prioritise resources and tackle the 
epidemic.

27

 
 
 
 
I  Annex

TABLE A1
Anti-HCV sero-prevalence in the general population in the EU/EEA: summary of available evidence

EU Member States

Anti-HCV 
prevalence (%)

0.1

0.9

1.3

0.2

1.3

0.4

0.5

0.5

1.3

2.7

Belgium 

Bulgaria

Czech Republic

France (1)

Germany 

Greece 

Italy 

Netherlands 

Poland

Romania

Spain 

Sweden

United Kingdom

Year of 
study

2003

1993–4

1999–2000

2001

1997

1998

1997

1997–8

1997

1996–7

1.8–11.5

1983–2006

0.6

0.2

1.9

3.5

2.5

1.6

0.4

0.7

2004

2006

1999

2006–8

1996

1997–9

1991–4

1996

Area

Sampling approach

Sample size

Regional

Regional

Regional

National

Regional

National

Regional

Regional

Regional

National

Regional

Regional

Regional

Regional

National

Regional

Regional

Regional

Regional

Random

Residual sera

Random

Residual sera

1 834

4 055

2 211

2 950

Sentinel GP convenience 

11 804

National health survey

Regional health survey

Random 

Household health survey

Residual sera

6 748

4 310

1 500

718

3 577

Random/convenience

721–3 884

Random

Residual sera

Convenience

1 364

2 200

2 561

Sentinel GP random cluster

13 146

Random

Random

Birth cohort convenience 

Residual sera

2 142

1 170

5 533

6 401

NB: Countries with no available information are not presented in the table.
(1) Another study was conducted in France in 2004 published in 2010, which found an estimate of overall anti-HCV prevalence of 0.84 % (95 % CI: 
0.65–1.10). The HCV RNA prevalence estimates was 0.53 % (95 % CI: 0.40–0.70) (Meffre et al., 2010).
Source: ECDC (2010); Hahné et al. (2013).

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I 

I 

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Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 1 I Hepatitis C virus infection among people who inject drugs

31

2

CHAPTER 2
Treatment of hepatitis C virus 
infection among people who inject 
drugs: uptake and outcome
Esther Aspinall, Jason Grebely, Hamish Innes, Stephen Corson, 
Gregory Dore, Joseph Doyle, Margaret Hellard, David Goldberg 
and Sharon Hutchinson

I  Introduction

Injection drug use is the main mode of hepatitis C virus 
(HCV) transmission in high-income countries, accounting 
for the majority of new and existing infections 
(Hajarizadeh et al., 2013). Efforts to tackle HCV infection 
in people who inject drugs are needed to reduce 
HCV-related morbidity and mortality, and prevent onward 
transmission of the virus (Grebely and Dore, 2011; Martin 
et al., 2011). Combination treatment with pegylated 
interferon (peginterferon) and ribavirin has been shown 
to achieve a sustained virological response in 46 to 52 % 
of cases of infection with HCV genotype 1 and 76 to 80 % 
of cases of infection with genotype 2 or 3, although these 
outcomes were reported in large clinical trials that 
excluded individuals with a recent history of drug use 
(Fried et al., 2002; Hadziyannis et al., 2004).

European guidelines have been recommending for some 
time that drug use should not exclude individuals from 
HCV treatment (EASL, 2015), but many services remain 
reluctant to treat people who inject drugs, citing 
concerns over adherence, increased susceptibility to 
side effects and the risk of reinfection through 
continuing to inject (Bruggmann and Litwin, 2013). This 
chapter evaluates and synthesises the available 
evidence relating to the uptake and outcomes of HCV 
treatment (including treatment adherence, sustained 
virological response, reinfection and morbidity related to 
liver disease) among people who inject drugs.

I  Methods

The chapter updates a previous systematic review (Aspinall 
et al., 2013) that considered treatment outcomes (i.e. 

sustained virological response, adherence and HCV 
reinfection) specifically among individuals who were 
injecting drugs during or after therapy. Further evidence 
sought for this chapter was evidence related to additional 
outcomes not included in the previous review: treatment 
uptake among people who inject drugs (evidence sourced 
from the individual studies already identified in the previous 
review) and the impact of sustained virological response on 
liver disease-related morbidity and mortality (evidence 
sourced from a recently published systematic review of the 
literature). Treatment uptake is defined as the proportion of 
individuals diagnosed as HCV RNA-positive in whom 
treatment for HCV infection was initiated during a period of 
1 year. Liver disease-related morbidity was defined as the 
number or rate of diagnoses or hospitalisations for liver 
cirrhosis or hepatocellular carcinoma, and liver 
disease-related mortality was defined as the number or rate 
of deaths due to liver cirrhosis or hepatocellular carcinoma.

I  Systematic review

The MEDLINE, Embase and Cochrane databases were 
searched for primary articles examining HCV treatment 
with peginterferon and ribavirin among people who 
inject drugs and published between January 2002 and 
January 2014, thus updating the previously published 
systematic review by 2 years (Aspinall et al., 2013). 
Inclusion and exclusion criteria for the systematic review 
are outlined in Table 2.1.

There were very few studies examining the outcome of 
reinfection and, therefore, the inclusion criteria for this 
outcome were broadened to cover those who have ever 
used illicit drugs (rather than only those currently 
injecting drugs) and any treatment for chronic HCV 
(rather than only peginterferon and ribavirin).

33

HCV reinfection rates were calculated per 100 
person-years of follow-up, and exact 95 % confidence 
intervals were calculated assuming a Poisson 
distribution. Meta-analysis was undertaken using 
log-transformed incidence rates and corresponding log 
standard errors in a random effects model. Subgroup 
meta-analysis was used to calculate a pooled reinfection 
rate among those who injected drugs after having 
achieved a sustained virological response. All statistical 
analyses were undertaken using STATA 13 (StataCorp, 
College Station, TX, US).

FIGURE 2.1
Summary of systematic literature search of MEDLINE, 
Embase and Cochrane databases

TABLE 2.1
PICO (population, intervention, comparison and outcome) 
inclusion and exclusion criteria for the systematic review

Inclusion criteria

Population

Study includes individuals who are HCV 
RNA‑positive.
Study includes those currently injecting drugs, 
here defined as either (i) injecting in the 
previous 6 months or (ii) described by the 
study authors as ‘active’ or ‘current’ injectors.
The proportion of the study population 
currently injecting drugs is known. 

Intervention

HCV treatment with peginterferon + ribavirin.

Comparison

Any or no comparison group.

Outcomes

Sustained virological response (the proportion 
of individuals by intention to treat in whom HCV 
RNA was undetectable for at least 24 weeks 
after completion of HCV treatment).
Treatment adherence (80/80/80 adherence: 
the proportion of individuals by intention to 
treat who received 80 % of the peginterferon 
cumulative dose and 80 % of the ribavirin 
cumulative dose for 80 % of the time).
HCV reinfection (the number of individuals who 
tested HCV RNA‑positive following a sustained 
virological response per 100 person‑years of 
follow‑up).

Exclusion criteria

Studies were excluded if they stipulated a 
defined period of drug abstinence prior to 
starting treatment, even if this period was 
shorter than 6 months. For this reason, 
prison‑based studies were excluded (as 
abstinence is a requirement in prison).

Articles that met the inclusion criteria were assessed for 
quality using the Newcastle–Ottawa Scale (Wells et al., 
2014). Studies were assigned a score ranging from 1 
(poor quality) to 9 (high quality). If more than one article 
reported on the same study, the article that provided the 
most comprehensive account of the study population 
was selected. Where appropriate, data were synthesised 
using meta-analysis.

I  Data synthesis

Pooled outcome measures were synthesised for those 
outcomes (sustained virological response, adherence 
and reinfection) for which sufficient data were available. 
Sustained virological response and adherence and their 
exact 95 % confidence intervals (CIs) were calculated 
assuming a binomial distribution, and pooled estimates 
were derived using random effects methods. Subgroup 
meta-analyses were used to obtain pooled estimates of 
sustained virological response by injecting behaviour (all 
study participants versus those currently injecting) and 
HCV genotype (1 or 4 versus 2 or 3).

34

Source: ECDC (2010).

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCitations identified from literature search, January 2002 toJanuary 2014 (n = 2 249)Abstracts screened(n = 342)Full-text articles screened against inclusion criteria (n = 128)Articles meetinginclusion criteria (n = 12)Articles examining sustained virological response (n = 6) and adherence (n = 2) ortreatment uptake (n = 3)Articles examining reinfection (n = 6) Citations excluded as not relevant (n = 1 907)Abstracts excluded as not relevant (n = 214)Articles not meeting  inclusion criteria (n = 116)CHAPTER 2 I Treatment of hepatitis C virus infection among people who inject drugs

I  Results and discussion

The results of the systematic literature search are shown 
in Figure 2.1. A total of 2 249 publications were 
identified, of which 342 abstracts and 128 full text 
articles were reviewed. In total, 12 articles (eight from 
Europe, two from Canada, one from the United States 
and one from Australia) met the inclusion criteria and 
were included in the review.

I  Treatment uptake

Three of the six studies that reported on sustained 
virological response (Table 2.2) also reported on HCV 
treatment uptake (Jack et al., 2008; Wilkinson et al., 
2008; Lindenburg et al., 2011). The three studies included 
a total of 755 ever-users of illicit drugs, although the 
proportion who were current injectors was unknown. 
Participants were recruited from drug services or urban 
primary care services. Two studies offered in-house 
testing and referral to HCV services (Wilkinson et al., 
2008; Lindenburg et al., 2011) and one study offered 
referral to a HCV specialist nurse (Jack et al., 2008).

Lindenburg et al. (2011) identified 196 HCV RNA-positive 
ever-users of illicit drugs, of whom 123 (63 %) completed 
a pre-treatment assessment and 58 (30 %) commenced 
HCV treatment over a period of 4.5 years (equating to an 
annual treatment uptake 6.6 %). Wilkinson et al. (2008) 
identified 441 HCV RNA-positive ever-users of illicit 
drugs, of whom 83 (19 %) attended for an assessment 
and 63 (14 %) commenced treatment over a period of 
2 years (annual treatment uptake 7.1 %). Jack et al. 
(2008) identified 118 HCV RNA-positive ever-users of 
illicit drugs, of whom 86 (73 %) completed 
a pre-treatment assessment and 30 (25 %) commenced 
HCV treatment over a period of 2.9 years (annual 
treatment uptake 8.5 %). Pre-treatment assessments 
included standard assessment for HCV therapy (e.g. 
checking for medical or psychiatric contraindications to 
treatment) as well as an assessment of acute or 
unmanaged housing, financial or legal issues.

The annual treatment uptake figures quoted in these 
studies are higher than current population-based 
estimates of treatment uptake among both non- and 
ever-injectors: for example, annual treatment uptake 
among all individuals estimated to be chronically 

TABLE 2.2
Uptake of HCV treatment among ever-users of illicit drugs

Reference, 
country

Setting

Reasons for not commencing treatment

Lindenburg 
et al. (2011), 
Netherlands

Drug users visiting 
drug services and 
primary care between 
January 2005 and July 
2009 were offered 
testing and referral to 
in‑house treatment

Of 196 HCV RNA‑positive individuals identified:

n  45 (23 %) refused assessment, could not access treatment due to lack of 

health insurance or were lost to follow‑up
n  28 (14 %) had still to complete assessments

Of 123 individuals (63 %) who completed an assessment:

n  47 were not eligible for treatment (for medical, social or psychiatric reasons) or 

treatment was postponed because they had early infection with genotype 1 or 4
n  76 were eligible for treatment but 18 refused (due to fear of therapy and side 

effects, co‑morbidity, lost to follow‑up or not known.)

n  58 started treatment

Annual 
treatment 
uptake 
(%) (1)

6.6

Jack 
(2008), 
United 
Kingdom

Wilkinson et 
al. (2008), 
United 
Kingdom

Two inner‑city general 
practitioners offering 
opioid substitution 
treatment. Drug users 
attending drug 
services or primary 
care between 
February 2005 and 
January 2008 were 
offered referral to 
a HCV nurse

Drug users attending 
a specialist addiction 
unit between March 
2005 and March 2007 
were offered in‑house 
HCV testing and 
treatment

Of 118 HCV RNA‑positive individuals identified:

n  32 (27 %) were not assessed because of loss to follow‑up or death

8.5

Of 86 individuals (73 %) who completed an assessment:

n  43 were not eligible for treatment (because of unstable housing, on‑going 

excessive drug consumption, excess alcohol intake, significant mental illness 
or advanced liver disease)

Of 43 individuals who were eligible for treatment:

n  13 had yet to start treatment at the time of the study
n  30 started treatment 

Of 441 HCV RNA‑positive individuals identified:

n  358 (81 %) chose not to attend for assessment

Of 83 (19 %) who chose to attend for assessment:

n  6 were not eligible for treatment

Of 77 individuals who were eligible for treatment:

n  14 considered therapy but declined
n  63 started treatment 

7.1

(1) Annual treatment initiations among ever-users of illicit drugs (including an unknown proportion of current injectors) who tested positive for HCV RNA.

35

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36

Hepatitis C among drug users in Europe: epidemiology, treatment and prevention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CHAPTER 2 I Treatment of hepatitis C virus infection among people who inject drugs

infected with HCV in the United Kingdom is currently 
around 3 % (Public Health England, 2013). However, the 
studies included in this review are likely to overestimate 
treatment uptake among people who inject drugs, given 
that study participants were involved in specialist and 
well‑established treatment programmes. Figures from 
the Australian needle and syringe programme survey 
suggest that overall treatment uptake among people 
who inject drugs is likely to be much lower, at around 
1.8–2.8 % (Iverson and Maher, 2013).

I   Sustained virological response and treatment 

adherence

Six studies reported on sustained virological response 
following peginterferon and ribavirin treatment 
(Table 2.3): no additional studies not included in the 
previous review (Aspinall et al., 2013) were identified. 
The six studies included a total of 314 ever‑users of illicit 
drugs, of whom approximately 141 (45 %) were current 
injectors. Three studies provided community‑based 
treatment (Jack et al., 2008; Wilkinson et al., 2008; 
Lindenburg, 2011), two studies provided hospital‑based 
treatment (Papadopoulos et al., 2010; Sasadeusz et al., 
2011) and one study initially provided hospital‑based 
treatment but extended into the community as the 
service developed (Jafferbhoy et al., 2012). In two 
studies additional support was provided: in one study 
(Lindenburg et al., 2011), participants received directly 
observed peginterferon, and staff at methadone clinics 
offered support and monitored side effects; in another 
study (Jafferbhoy et al., 2012), drug workers were 
encouraged to attend HCV appointments and provide 
general support to participants.

Across six studies, pooled sustained virological response 
among ever‑users of illicit drugs was 56 % (95 % CI 
50–61 %), and across two studies 80/80/80 treatment 
adherence was 82 % (95 % CI 74–89 %). When 
sustained virological response was analysed by HCV 
genotype, the rate of sustained virological response was 
found to be 37 % (95 % CI 26–48 %) among those 
infected with HCV genotype 1 or 4 and 67 % (95 % CI 
56–78 %) among those infected with genotype 2 or 3. 
Among current injectors, sustained virological response 
was 61 % (95 % CI 51–72 %) regardless of genotype 
(Table 2.4).

The quality of evidence for the sustained virological 
response outcome was assessed as low (because it 
derived from observational studies) and for the 
adherence outcome was assessed as very low (because 
it came from observational studies and because data 
were sparse).

The pooled estimates of sustained virological response 
appear to be slightly lower than those quoted by major 
clinical trials (46–52 % among those infected with HCV 
genotype 1 and 76–80 % in those infected with 
genotype 2 or 3) (Fried et al., 2002; Hadziyannis et al., 
2004). However, across two ‘real‑world’ studies among 
non‑ and ever‑injectors undertaken outside clinical trials, 
sustained virological responses were similar to those 
reported here (see Figure 2.2): 37–39 % among those 
infected with HCV genotype 1 and 70 % among those 
infected with genotype 2 or 3 (Thomson et al., 2008; 
Innes et al., 2012). These findings support current 
guidelines (EASL, 2015) that decisions about treatment 
should be made independently of an individual’s 
injecting status. However, it should be noted that the 

TABLE 2.4
Meta‑analysis of studies examining HCV treatment outcomes among those currently and previously using drugs

Outcome

Inclusion criteria

Number of studies

Pooled estimate (95 % CI) (1)

Heterogeneity 
(I2) (%)

Sustained 
virological 
response

All studies

All genotypes

Genotype 1 or 4

Genotype 2 or 3

Current injectors

All genotypes

Genotype 1 or 4

Genotype 2 or 3

Reinfection

All studies 

Individuals who reported injecting drugs 
after achieving sustained virological 
response 

(1) Random effects method used if I2 ≥ 30 %.

6

4

4

3

2

2

6

5

55.9 % (50.4–61.3 %)

36.9 % (25.6–48.2 %)

67.1 % (55.9–78.3 %)

61.4 % (51.2–71.5 %)

42.9 % (17.5–68.2 %)

73.1 % (55.2–91.0 %)

2.4 (1.0–5.9) per 100 person-years

6.5 (2.5–16.9) per 100 person-years

3

0

46

0

0

0

0

0

37

FIGURE 2.2
Comparison of HCV treatment outcomes (percent 
achieving sustained virological response) in published 
studies of pegylated interferon and ribavirin treatment

Percent

100

80

60

40

20

0

Genotype 1 or 4

Genotype  2 or 3

Aspinall et al., 2013

Innes et al.,  2012

Thomson et al.,  2008

Hadziyannis et al.,  2004

important consideration in any decision about 
commencing HCV treatment.

The results reported here are limited to the small number 
of studies in which all or a known proportion of the study 
participants were current injectors, with the aim of 
providing more relevant information to clinicians 
managing this population group. Consequently, the data 
available were limited, with considerable uncertainty 
around each pooled outcome estimate. However, a review 
by Dimova et al. (2013) that used a wider definition of 
drug use (ever-use of illicit drugs, including injection use) 
reported similar pooled sustained virological responses to 
our review: 44.9 % (95 % CI 41.0–48.9 %) among those 
infected with genotype 1 or 4 and 70.0 % (95 % CI 
62.9–76.3 %) among those infected with genotype 2 or 3.

Treatment adherence was relatively high in this review 
(82 %) compared with previous reports (McHutchison et 
al., 2002), although this estimate was derived from just 
two studies (involving a total of 100 patients). This 
difference may in part be explained by the varying 
definitions of adherence across studies, with some 
calculating on-treatment adherence (i.e. taking into 
consideration the number of missed doses while on 
therapy) and others cumulative adherence (i.e. taking 
into account early discontinuation of therapy) (Weiss et 
al., 2009). Greater standardisation of definitions of 
adherence is needed to allow more meaningful 
comparisons between studies in the future.

The study by Aspinall et al. (2013) is a meta-analysis of studies of people 
who inject drugs; participants in the other three studies were drug users, 
some of whom were ever-injectors — two (Innes et al., 2012; Thomson et al., 
2012) are cohort studies and one (Hadziyannis et al., 2004) is a randomised 
controlled study. The last three studies were not included in the meta-analy-
sis carried out by Aspinall et al. (2013) because they included non-injecting 
participants and an unknown proportion of current or former injectors. 

participants who commenced treatment in these studies 
are likely to be a highly selected population, as treatment 
uptake after assessment was low. Therefore, the results 
of our review are likely to be based on a specific 
population of current injectors who are eligible and 
motivated to attend for assessment and treatment.

Although it was not possible to investigate other factors 
that may have impacted on treatment outcomes 
(because of the small number of studies and a lack of 
comparable data across studies), previous studies have 
suggested that lower social functioning (Dore et al., 
2010) and a history of untreated depression 
(Alvarez-Uria et al., 2009) are associated with a lower 
chance of achieving a sustained virological response. An 
assessment of an individual’s social circumstances and 
the availability of support should therefore be an 

I  Reinfection

Six studies examined reinfection in individuals who had 
achieved a sustained virological response (Dalgard et al., 
2002; Backmund et al., 2004; Currie et al., 2008; Grebely 
et al., 2010; Grady et al., 2012; Hilsden et al., 2013) 
(Table 2.5). Participants comprised a total of 162 people 
who had ever used illicit drugs, an unknown proportion 
of whom were current injectors at HCV treatment 
initiation. The total number of person-years of follow-up 
was 436.9 (range 36.0–131.6 person-years). Five studies 
reported the proportion of the study population that 
injected drugs after having achieved a sustained 
virological response and this ranged from 21 % to 50 %. 
HCV was treated with peginterferon and ribavirin 
(Hilsden et al., 2013), peginterferon/interferon and 
ribavirin (Grebely et al., 2010) or interferon with or 
without ribavirin (Dalgard, 2002; Backmund et al., 2004), 
or was not reported (Currie et al., 2008; Grady et al., 
2012). Advice or counselling on reducing the risk of 
reinfection following treatment was offered in three 
studies (Backmund et al., 2004; Currie et al., 2008; 
Grebely et al., 2010).

38

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 2 I Treatment of hepatitis C virus infection among people who inject drugs

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Across the six studies, the pooled estimate of reinfection 
among ever-users of illicit drugs was 2.4 (95 % CI 
1.0–5.9) per 100 person-years. Among those who 
reported injection drug use after having achieved 
a sustained virological response, the risk of HCV 
reinfection was 6.5 (95 % CI 2.5–16.9) per 100 
person-years (five studies, 47 participants; see 
Figure 2.3 and Table 2.4). The quality of evidence for the 
reinfection outcome was assessed as very low because 
the evidence derived from observational studies and 
because the study population comprised ever-users of 
illicit drugs, rather than current injectors at treatment 
initiation.

The pooled risk of HCV reinfection among people who 
inject drugs was considerably lower than estimates of 
the risk of primary HCV infection among the same group 
(13.6 per 100 person-years (95 % CI 8.1–20.1) versus 
25.0 per 100 person-years (95 % CI 20.2, 30.3) 
respectively) based on studies of users of needle and 
syringe programmes over comparable time periods 
(Grebely et al., 2014; Palmateer et al., 2014). However, 
the total number of person-years of observation across 
the six studies was low, creating considerable 
uncertainty around this estimate. Further, the inclusion 
of former drug users in the study population (for whom 
the risk of relapse to injecting drug use is likely to be 
lower), as well as exposure to specialised treatment and 
harm reduction programmes, may explain the lower rate 
of HCV (re-)infection observed here than typically found 
in drug-injecting populations.

Reinfection risk was higher among those who reported 
injecting after having achieved a sustained virological 
response (although this finding was not statistically 
significant). Further work is needed to assist clinicians in 
identifying individuals who are at risk of resuming 
injecting, in order to allow appropriate harm reduction 
advice to be offered.

I   Impact of sustained virological response on liver 

disease-related morbidity and mortality

No studies have examined the impact of HCV treatment 
on liver disease-related morbidity and mortality 
specifically among ever-users of illicit drugs or those 
currently injecting. However, a recently published 
systematic review identified 19 cohort studies (involving 
both non- and ever-injectors) reporting the association 
between sustained virological response and mortality and 
hospitalisation-related morbidity (Chou et al., 2013). 
Notably, all 19 studies reported lower rates of adverse 
outcomes among participants who achieved sustained 
virological response than among those who did not. The 
adjusted hazard ratios for hepatocellular carcinoma 
ranged from 0.12 to 0.46 (equivalent to a 2.2- to 8.3-fold 
rate reduction). Similarly, adjusted hazard ratios for 
mortality due to liver disease ranged from 0.04 to 0.27 (i.e. 
a 3.7- to 25.0-fold rate reduction). Finally, adjusted hazard 
ratios for all-cause mortality ranged from 0.07 to 0.71 (i.e. 
a 1.4- to 14.3-fold rate reduction). In none of the studies 
was participation restricted to people who inject drugs, 

FIGURE 2.3
Meta-analysis of HCV reinfection risk among people who reported injecting drugs after achieving a sustained 
virological response

Study ID

Grady 2012

Grebely 2010

Currie 2008

Backmund 2004

Dalgard 2002

ES (95 % CI)

 Weight, %

3.44 (0.09, 19.15)

12.60

5.31 (0.64, 19.16)

31.33

28.57 (0.72, 159.19)

12.42

8.40 (1.02, 30.36)

31.44

2.50 (0.06, 13.93)

12.20

Overall (I-squared = 0.0 %, p = 0.738)

6.53 (2.52, 16.90)

100.00

NB: Weights are derived from random effects analysis.

6.53

40

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 2 I Treatment of hepatitis C virus infection among people who inject drugs

but in one study, that of Innes et al. (2012), the majority of 
the participants were current or former injectors with liver 
fibrosis of any stage. An important finding from this study 
was that, although patients who achieved a sustained 
virological response indeed exhibited a reduced risk of 
hospitalisation for liver disease compared with their 
counterparts who failed to achieve a sustained response, 
their risk remained, nevertheless, 10.5 (range 8.7–12.9) 
times higher than that of the general population. The 
studies also over-represent individuals with advanced liver 
disease and under-represent those with milder disease. 
The inference that the benefit demonstrated in individuals 
with advanced fibrosis can be extrapolated to those with 
mild fibrosis needs more investigation. Further, none of the 
studies identified by Chou et al. (2013) collected 
comprehensive data on alcohol consumption and other 
lifestyle factors that may have confounded the 
relationship between exposure to HCV and adverse 
liver-related outcomes. It might be expected that such 
confounding would serve to over rather than 
under-estimate the benefit of a sustained virological 
response.

A recently published simulation model (Innes et al., 2014) 
quantified what patients stand to gain from sustained 
virological response; however, the analysis did not take 
account of the benefits of a potential reduction in onward 
transmission (see Chapter 4). What became apparent 
from this modelling exercise, and novel synthesis of the 
existing evidence base, is that some patients have far 
more than others to gain from a sustained virological 
response. For instance, in a currently injecting 
30-year-old with mild fibrosis, the chance of a sustained 
virological response conferring additional life-years is 
12.6 % (95 % CI 7.8–17.9 %) and the chance of 
a sustained virological response conferring additional 
healthy life-years is 16.6 % (95 % CI 10.5–23.0 %). For 
comparison, a sustained virological response holds a far 
greater attraction for a currently injecting 30-year-old 
with compensated cirrhosis, having a 54.5 % (95 % CI 
42.9–65.4 %) chance of conferring additional life-years 
and a 64.0 % (95 % CI 50.9–75.0) chance of conferring 
additional healthy life-years. Thus, the impact of 
a sustained virological response is far more nuanced 
than the commonly applied ‘sustained virological 
response = cure’ heuristic (Brau, 2013) would suggest.

I  Conclusion

Treatment of HCV can result in acceptable outcomes in 
individuals who report current injecting drug use and 
who meet standard eligibility criteria for commencing 
HCV treatment. Owing to the small number of studies 
available, it was not possible to investigate other factors, 
such as the mode of treatment delivery and the 
availability of treatment support, that are likely to impact 
on treatment outcomes. Treatment decisions need to 
take account of each individual’s social circumstances 
and the availability of support, as well as the anticipated 
clinical benefit of achieving a sustained virological 
response. The risk of HCV reinfection following achieving 
a sustained virological response was found to be 
relatively low, but there is considerable uncertainty 
around this estimate among those who continued to 
inject after achieving a sustained virological response. 
Further work is needed to assess the risk of HCV 
reinfection among people who are actively injecting illicit 
drugs, and it is likely that this risk can be accurately 
assessed only once treatment is scaled up and more 
equitably provided in this population.

I  References
I 

 Alvarez-Uria, G., Day, J., Nasir, A., Russell, S. and Villar, F. 

(2009), ‘Factors associated with treatment failure of patients 

with psychiatric disease and injecting drug users in the 

treatment of genotype 2 or 3 hepatitis chronic infection’, Liver 

International 29, pp. 1051–1055.

 Aspinall, E. J., Corson S, Doyle, J. S., Grebely, J., Hutchinson, 

S. J., Dore, G. J., Goldberg, D. J. and Hellard, M. E. (2013), 

‘Treatment of hepatitis C virus infection among people who 

are actively injecting drugs: a systematic review and 

meta-analysis’, Clinical Infectious Diseases 57 (Suppl. 2),  

pp. S80–S89.

 Backmund, M., Meyer, K. and Edlin, B. (2004), ‘Infrequent 

reinfection after successful treatment for hepatitis c virus 

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 Brau, N. (2013) ‘Evaluation of the hepatitis C virus-infected 

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 Bruggmann, P. and Litwin, A. H. (2013), ‘Models of care for the 

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I 

I 

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41

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I 

I 

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42

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43

3

CHAPTER 3
Strategies to improve hepatitis C care 
and to enhance treatment uptake and 
adherence among people who inject 
drugs in Europe
Philip Bruggmann, Patrizia Carrieri, Mõjca Maticic, Perrine Roux, 
Vratislav Rehak, John Dillon and Sharon Hutchinson

I   Interferon‑free regimens for people 

who inject drugs

People who inject drugs generally have a negative view 
of interferon, and some physicians hesitate to prescribe 
this drug because they fear that it may have 
unacceptable side effects, such as those that resemble 
opioid withdrawal symptoms (Treloar et al., 2014). 
Mental health side effects are especially feared in this 
population, among which the prevalence of psychiatric 
disorders is high. In fact, the potential side effects of 
interferon are diverse and are usually easily managed; 
only in rare cases are they life-threatening. Parenteral 
application also presents a barrier to interferon use for 
many of those who inject drugs.

Interferon-free regimens for the treatment of hepatitis C 
are well tolerated; cure rates are over 95 % and in most 
cases treatment takes only 12 weeks (see Chapter 5). 
Clearly, this makes the delivery of hepatitis C care easier 
as exhaustive management of side effects will no longer 
be necessary. Nonetheless, adherence to treatment will 
remain an important issue not only because of the risk of 
resistance but also because of the cost of the treatment.

Interferon-free regimens are likely to overcome, at least 
to some extent, the reluctance of people who inject 
drugs to undergo treatment for hepatitis C, especially 
the reluctance based on fear of side effects and the 
complexity of application. However, the inability of 
people who inject drugs to access testing and treatment 
facilities and discrimination against injecting drug users 
will remain major barriers to care and, therefore, the 
need for specific settings and measures for this 
population will remain.

I  Local examples from Europe

While the following examples of need-adapted care 
settings for hepatitis care among people who inject 
drugs have been developed in the interferon era, the 
lessons they offer may also guide efforts to improve care 
provision for this patient group under interferon-free 
conditions.

Measures to improve case-finding and access 
to testing

Given the low rates of testing for hepatitis C virus (HCV) 
among people who inject drugs (Hagan et al., 2006; 
McDonald et al., 2010a), the first steps to improve care 
for those infected with the virus should focus on 
additional detection strategies accompanied by 
awareness programmes. People who inject drugs are 
most likely to be successfully tested in places where 
they are in contact with the health care system, for 
example in specialist drug treatment clinics, emergency 
departments (Stepanova et al., 2011) or general 
practices (Senn et al., 2009).

Participation in opioid substitution treatment 
programmes increases the probability of being tested. 
Test rates of more than 90 % have been reported among 
drug users undergoing treatment programmes at 
a general practice in Switzerland (Senn et al., 2009) and 
at a multidisciplinary addiction facility in the Netherlands 
(Lindenburg et al., 2011). Senn et al. (2009) 
demonstrated that a complete assessment, including 
identification of chronic hepatitis C (by testing for HCV 
RNA) and determination of HCV genotype, was feasible 
for 91 % of patients in opioid substitution treatment 

45

programmes (n = 360 patients) treated by one 
office-based general practitioner (GP) in Switzerland 
(Senn et al., 2009). Slightly less favourable (but still 
impressive) results were obtained in another Swiss 
study comparing HCV antibody test rates among drug 
users receiving opioid substitution treatment under GP 
care and those treated in specialised addiction 
outpatient clinics (66 vs. 78 %) (Pelet et al., 2007). The 
lower test uptake among those being treated by GPs 
may be explained by the GPs’ low case loads, which 
were associated with a lack of knowledge of HCV 
(Overbeck et al., 2011). Nonetheless, HCV test rates can 
be higher among individuals in opioid substitution 
programmes than in those less closely in contact with 
health care (Volk et al., 2009).

For these reasons, special efforts should be made to get 
people who inject drugs into opioid substitution treatment 
and to provide additional testing settings for this 
population. Low-threshold facilities can serve as an initial 
point of HCV testing, utilising point-of-care or non-invasive 
(such as dried blood spots) antibody tests. HCV testing in 
low-threshold facilities can also be used to monitor HCV 
prevalence among people who inject drugs in particular 
areas or regions. In addition, discussion of HCV and 
testing for the virus could be provided at facilities 
traditionally not offering health care services, such as 
shelters, consumption rooms or needle and syringe 
programmes (Zabransky et al., 2006). In Zurich, an 
on-going project offers rapid HCV antibody testing and 
discussion in combination with on-site liver transient 
elastography (a non-invasive ultrasound test of level of 
liver disease and cirrhosis) in consumption rooms 
(Bruggmann and Brunner, 2014). Anyone testing positive 
for HCV is referred for further assessment and 
needs-adapted hepatitis C care in specialised units in 
addiction clinics. This service is well accepted and widely 
used. In addition, earlier studies have shown that offering 
transient elastography examinations in low-threshold 
facilities has the potential to raise awareness of liver 
health and facilitate HCV testing and hepatitis C 
management (Foucher et al., 2009; Moessner et al., 2011).

In a systematic review, Jones et al. (2014a) found that 
the following factors may increase uptake of HCV 
testing: targeted case-finding; the provision of support 
and training for GPs; offering dried blood spot testing; 
and the provision of testing through outreach 
programmes. Dried blood testing is a non-invasive blood 
test, necessitating only a needle prick, that requires 
minimal training to undertake and is easy to conduct in 
people with poor venous access — so increasing 
opportunity for HCV testing in drug treatment centres 
and other facilities for people who inject drugs.

According to qualitative studies that have evaluated drug 
users’ reasons for not getting tested for HCV (Swan et 
al., 2010; Jones et al., 2014b), some view hepatitis C as 
a harmless disease, since symptoms are not immediate, 
and some face other problems that are given higher 
priority. Fear of treatment side effects and of invasive 
tests are also contributing factors. Awareness and 
education campaigns, along with information on the 
on-going development of treatment options, are needed 
to allay such fears and counter misconceptions. This 
should be accompanied by continued efforts to make 
the testing process easier, with for example on-site HCV 
RNA or core antigen testing. As patients’ perceptions of 
hepatitis C therapy are influenced mainly by peers, such 
campaigns should consider involving peers in both 
planning and implementation (as outlined in Chapter 6).

In many countries, prisoners constitute a considerable 
gap in the tested population (Arain et al., 2014), yet 
prisons, more than any other community site, provide an 
excellent opportunity to diagnose and treat a large 
number of people with chronic hepatitis C. Chapter 4 
shows that hepatitis C case-finding in prison is 
dependent on uptake of treatment. We recommend that 
all prisoners should be offered an HCV test and the 
opportunity to discuss hepatitis C at the time of 
admission, and that, if they test positive and want to be 
treated, treatment should be made available to the same 
extent as offered in the community.

Measures to improve hepatitis C care

Access to, and uptake of, hepatitis C treatment is lower 
among people who inject drugs than in those who have 
contracted the disease in other ways. However, as 
shown in Chapter 2, it is possible to achieve rates of 
adherence and sustained virological response or cure in 
people who inject drugs that are similar to those seen in 
other groups — although a number of barriers at the 
patient, provider and system level have to be overcome 
before people who inject drugs can receive hepatitis C 
care (Bruggmann, 2012). Many of these obstacles can 
be overcome by taking specific measures as further 
outlined below.

Co-location of hepatitis C treatment with 
community/specialist drug treatment

A successful general approach that involves various 
measures and strategies is to take hepatitis C care to the 
people who inject drugs rather than waiting for them to 
show up in traditional care settings, which often are too 
rigidly structured to be attractive to such individuals.

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Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 3 I Strategies to improve hepatitis C care and to enhance treatment uptake and adherence among people who inject drugs

According to Brunner et al. (2013), in Zurich, treatment 
of hepatitis C (with interferon- and ribavirin-based 
treatments) among people who inject drugs, many of 
whom have other illnesses and continue to use drugs, is 
most likely to be successful if it takes the form of 
integrated primary care-based multidisciplinary 
management under one roof. They reported an overall 
rate of sustained virological response of 62 %, including 
among individuals infected with all HCV genotypes and 
in some cases co-infected with HIV (human 
immunodeficiency virus), a rate comparable to that 
reported in studies of non-drug-using populations. 
Various supporting strategies, such as directly observed 
therapy, weekly consultations for psychosocial support 
and side effect management, peer involvement, and 
psychiatric and social care, were provided on an 
individual basis depending on needs.

In a GP-based model of hepatitis C and addiction care in 
Switzerland, Seidenberg et al. (2013) also achieved 
favourable treatment outcome rates, again even with 
interferon- and ribavirin-based treatments (overall 
sustained virological response rate: 71 %). A GP who has 
received additional training in both hepatitis C care and 
addiction medicine can establish a very efficient 
‘one-stop shop’ service, providing various different 
disciplines in one place (Seidenberg et al., 2013).

A Scottish GP-based model involves a hepatitis clinical 
nurse specialist under the supervision of a secondary 
care-based infectious disease specialist. Patients are 
assessed by the clinical nurse specialist in the GP’s 
office and treatment indication is then determined by an 
interdisciplinary team. Outcomes among patients 
receiving hepatitis C treatment in the GP surgery are 
comparable to those achieved in secondary care units 
(Jack et al., 2009).

In Prague, a programme of comprehensive care has 
been established with the goal of reaching people who 
inject drugs and offering timely and targeted health care 
services, including individually tailored hepatitis C 
therapy. The programme comprises low-threshold 
access to medical services, including primary and 
specialised health care (hepatology, psychiatry); testing 
for blood-borne and sexually transmitted diseases; 
pre- and post-test discussion; harm reduction services 
such as opioid substitution treatment; and psychosocial 
and crisis interventions. All medical and non-medical 
interventions are concentrated in one location. The 
programme is located in an outpatient health care centre 
that is also attended by non-drug users, preventing 
segregation of patients with ‘stigmatising’ disease. 
People who inject drugs share the experience with the 
programme through peer-to-peer networks 

supplemented by targeted information from outreach 
workers. In this setting, the overall rate of sustained 
virological response to hepatitis C treatment (pegylated 
interferon and ribavirin) is over 80 % (unpublished data).

In a community-based addiction unit in London attended 
by homeless people, patients with chronic hepatitis C 
who inject drugs are assessed by a hepatologist in 
collaboration with a nurse. When indicated, treatment is 
offered directly at the outreach clinic by a team 
consisting of the nurse and a psychiatrist. Evaluation 
found that treatment outcome is not affected by 
on-going alcohol or drug consumption (Wilkinson et al., 
2009).

In a controlled multicentre trial in Germany, the effect of 
a series of planned psycho-education sessions on 
treatment retention and outcome was assessed (Reimer 
et al., 2013). Psycho-education was provided in weekly 
1-hour group sessions covering topics such as HCV 
infection, hepatitis C disease course, treatment, side 
effects, coping strategies and the effective use of health 
care support. Sustained virological response rates and 
retention in treatment were positively influenced by 
psycho-education among patients with mental distress 
and those who required a longer course of treatment  
(i.e. those infected with HCV genotype 1 or 4). In 
addition, different forms of peer support models have 
been implemented successfully with benefits for 
hepatitis C assessment, treatment rates and adherence 
(Sylvestre and Clements, 2007; Grebely et al., 2010; 
Stein et al., 2012; Crawford and Bath, 2013), although 
most of these models were developed outside Europe.

A nationally coordinated approach encompassing 
a variety of different measures tailored to the individual 
needs of the different regions is necessary to effectively 
improve access to hepatitis C care. In the following 
section we highlight some key case studies.

I   National and regional coordinated examples in 

Europe: Scotland, France and Slovenia

The Scottish strategy to improve hepatitis C care 
for people who inject drugs

The Scottish strategy and national action plan to 
improve hepatitis C care acknowledges people who 
inject drugs as a key population among those affected by 
hepatitis C, but the national action plan also represents 
a comprehensive approach to hepatitis C at both the 
population and individual level. In this Scottish case 
study, the formation of the action plan will be reviewed 

47

with emphasis on those strands relevant to people who 
inject drugs. In June 2004, Scotland’s health minister 
recognised hepatitis C as one of the country’s most 
challenging public health concerns (Chisholm, 2004). 
This was prompted by a Royal College of Physicians of 
Edinburgh (2004) consensus conference, which 
highlighted that ‘services were struggling to cope with 
the burden of infection’ and that ‘significant resources 
needed to be directed at improving prevention and 
delivery of care’. Subsequently, Scotland’s health 
minister and chief medical officer launched Scotland’s 
hepatitis C action plan in September 2006 (Scottish 
Executive, 2006). Its aims were (i) to prevent the spread 
of HCV, particularly among people who inject drugs, (ii) 
to diagnose HCV-infected people, particularly those who 
would most benefit from treatment, and (iii) to ensure 
that those infected receive optimal treatment, care and 
support; with the overarching strategic aim of reducing 
the mortality and morbidity associated with HCV 
infection.

The plan had four phases:

n  Phase I (2006–08) involved gathering evidence to 

inform proposals for the development of hepatitis C 
services.

n  Phase II (2008–11) (Scottish Government, 2008), 

launched in May 2008, was a detailed plan of action 
with specified actions for responsible organisations 
to bring about a coherent and consistent approach to 
prevention, diagnosis, treatment and care of 
hepatitis C across Scotland, coupled with 
a performance-reporting structure that ensured that 
actions were carried forward.

n  Phases III and IV (2011–20) (Scottish Government, 

2011 and 2015) involved incorporating and 
‘mainstreaming’ the hepatitis C action plan into 
a wider ‘sexual health and blood borne virus 
framework’, including reporting to central 
government on key performance indicators.

The HCV action plan, to be accepted by the clinical and 
non-clinical communities who would have to deliver it, 
needed to be based on the local epidemiology and an 
evidence base of best practice. Approaches adopted to 
generate the evidence involved analysis of existing data 
held on laboratory and clinical databases (Hutchinson 
et al., 2006), questionnaire surveys and face-to-face 
interviews with service providers, systematic reviews 
(Gilles et al., 2010; Palmateer et al., 2010), case-finding 
evaluations (Cullen et al., 2012), record linkage 
exercises (McDonald et al., 2010b) and modelling 
studies to estimate the impact of interventions in 

preventing infection and the burden of disease 
(Hutchinson et al., 2005).

By the mid-2000s, an estimated 50 000 Scots (1 % of 
the population) were living with HCV, and 75 % of these 
were chronic carriers (Hutchinson et al., 2006). Around 
90 % of those infected acquired the virus through 
injecting drug use, and the majority remained 
undiagnosed (Hutchinson et al., 2006). It was estimated 
that only 20 % of those chronically infected had ever 
been in specialist care and only 5 % had received 
a course of antiviral therapy, while over 2 000 were living 
with cirrhosis and 1 000–1 500 injection drug users 
were being infected annually (Table 3.1) (Hutchinson et 
al., 2005). Thus, in a Scottish context, sharing of 
injecting equipment is the principal route of new 
infection and accounts for most prevalent infection. 
However, only a minority of people with chronic 
hepatitis C are current daily injectors, and a large 
proportion of those who inject or who recently have 
ceased injecting drugs are on opioid substitution 
treatment. Importantly, the action plan was based on the 
premise that everyone deserves therapy and that, as 
development of liver disease is not dependent on how 
infection is acquired, treatment services should focus on 
getting people who inject drugs into treatment and care.

For each action within the phase II plan, a desired 
outcome, performance measure and timescale were set 
out, and a lead organisation accountable for delivering 
the action and a network to support the lead 
organisation were identified. Generally, the actions were 
high level in nature (Table 3.1), allowing local National 
Health Service (NHS) boards the freedom to develop 
services in the context of their particular circumstances 
— taking account of existing arrangements for 
hepatitis C service provision and the epidemiology of 
infection in their area. Implementation involved 
representatives from all relevant disciplines and 
organisations, and took a graduated approach, focusing 
first on establishing the necessary infrastructures, prior 
to services being delivered and developed. National 
guidelines were developed to help ensure that 
approaches taken were effective, efficient and, where 
appropriate, consistent. Local and national networks 
were established so that experience, best practice and 
progress could be shared, and support, advice and 
guidance provided.

The first issue to address in any new disease area such 
as hepatitis C is to raise awareness (NHS Scotland, 
2014) among both health care professionals and the 
general public. The majority of health care professionals 
are likely to have left formal education before the 
discovery or recognition of the significance of 

48

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 3 I Strategies to improve hepatitis C care and to enhance treatment uptake and adherence among people who inject drugs

TABLE 3.1
Summary of the key evidence, issues stemming from the evidence, actions designed to address the issues, progress 
made in delivering actions and associated outcomes, in the areas of testing, treatment, care and support

Key evidence and issues

Key actions (2008–11)

Outcomes

Key evidence (Scotland, mid-2000s)

n  Over 60 % of people living with HCV remained 

undiagnosed.

n  Only 20 % of chronically infected people had 
ever been in specialist care and only 5 % had 
been treated. Of 450 persons initiated on 
therapy each year, 4 % were prison inmates.

n  Over 2 000 HCV‑infected persons were living 
with cirrhosis, with over 100 developing liver 
failure each year.

n 

It was estimated that, if 2 000 persons per year 
received antiviral therapy over the next two 
decades, 5 200 cases of HCV‑related cirrhosis 
would be prevented in the future.

n  GPs and other service providers highlighted 
difficulties in taking blood from people who 
inject drugs as a barrier to HCV test uptake.

Major issues

n  The majority of people chronically infected 

with HCV remained undiagnosed and many of 
those diagnosed failed to reach and stay 
within specialist care services.

n 

Insufficient numbers of HCV‑infected persons, 
including prisoners, were receiving antiviral 
therapy.

n  NHS boards were required to have, or be 
affiliated to, a managed care network for 
HCV, comprising representatives of all 
stakeholder sectors.

n  A public and professional website 

was launched (www.
hepcscottland.co.uk), with further 
awareness campaigns in 2010.

n  Testing/treatment services provided by 
NHS boards were expanded to increase 
numbers undergoing therapy in 
Scotland, from 450 per year to 1 500 in 
2010/11 (since revised to 1 000 per year 
owing to financial restraints).

n  Agreements between NHS boards and 

the Scottish Prison Service were 
developed to promote the treatment of 
HCV‑infected inmates in prisons.

n  Awareness‑raising campaigns 
continued to be developed and 
implemented to meet the information 
needs of professionals and promote 
HCV testing among those at risk of being 
infected.

n  New approaches to getting people 
tested for HCV were implemented 
(e.g. dried blood spot testing).

n  A 33 % rise in the annual number of 

new HCV diagnoses between 
2003–08 and 2009–11 was 
achieved; 20 % of new diagnoses in 
2011 were made in specialist drug 
services where dried blood spot 
testing had been introduced.

n  Clinical services developed, leading 

to a doubling in the number of 
initiations of therapy (to 1 049 in 
2010/11); 80 % of those starting 
treatment in 2010/11 were 
ever‑injectors of drugs.

n  A programme of work to evaluate 

n  The number of inmates started on 

approaches to HCV testing (e.g. dried 
blood spot testing) was undertaken.

therapy increased more than 
eightfold between 2007/08 (17) 
and 2010/11 (143).

hepatitis C, but without awareness of hepatitis C among 
the general public there will be no action and no drive to 
diagnosis.

This was achieved in Scotland by separate and staged 
awareness campaigns. The first was directed at health 
care professionals through the conventional routes of 
continuing professional development and education. 
Subsequently, the public was targeted through the 
media and multiple support organisations and patients 
groups. The key was to have reliable vetted sources of 
information available in a variety of formats to suit 
people who inject drugs; information appropriate for 
those with low literacy levels was particularly important, 
with verbal peer-to-peer dissemination of information 
also having a role.

The next issue to address was to convert awareness into 
greater levels of diagnosis. Guidelines were developed to 
determine who should be offered testing for HCV. This 
was combined with a wide range of action plan 
initiatives, and local and national networks played a key 
role in the promotion of hepatitis C testing. In one 
innovative development, test facilities were sited in 
high-prevalence environments. However, this alone is not 
enough to increase diagnosis rates among people who 
inject drugs, as facilities that offer testing are often 

located within conventional health care facilities and, to 
access such facilities, drug users must overcome a host 
of barriers. These include fears about stigma of drug use, 
fears of staff attitudes, accessing services in fixed 
pre-booked time slots and the difficulties of 
venepuncture in this client group.

The use of innovative technology, such as dried blood 
spot testing, combined with locating testing into 
non-clinical facilities, was a key development in 
increasing rates of diagnosis.

As a result of these actions, the number of new 
diagnoses of hepatitis C nationally has increased from 
around 1 500 per year to 2 000 per year, with testing in 
drug treatment services now accounting for around 20 % 
of all new diagnoses.

Furthermore, it is estimated that over half of all people in 
Scotland living with chronic hepatitis C have now been 
diagnosed. There is strong evidence that a real 
breakthrough has been made in getting people who 
inject drugs — particularly those in contact with harm 
reduction services — tested for HCV.

Diagnosing HCV infection is an important first step but is 
not effective or cost-effective unless it results in infected 

49

individuals being treated for hepatitis C and cured. The 
action plan recognised that many of those diagnosed 
would be opioid-dependent and therefore mandated 
each regional managed care network to establish close 
links with drug addiction treatment services and to 
embed hepatitis C treatment services within them, or to 
establish clear and easy pathways into treatment.

This has been highly successful, and currently over 60 % 
of those entering hepatitis C therapy are also receiving 
opioid substitution treatment. Among this group rates of 
sustained virological response are similar to those 
achieved in former drug users or non-drug users (as 
highlighted in Chapter 2).

Over the 3-year period of phase II, annual initiations of 
antiviral therapy increased more than twofold among all 
infected individuals (of whom the vast majority had 
acquired infection through injecting drugs) and more 
than eightfold among infected prisoners, reaching 1 049 
(involving 143 prisoners) in 2010/11, with these 
numbers being maintained at this level since then.

The national plan demonstrates that having a history of 
injecting drug use is no barrier to receiving, and indeed 
fully benefiting from, hepatitis C treatment.

Scotland’s hepatitis C action plan is regarded globally as 
a model of good practice. It is evident that 
a considerable amount of progress has been made in 
improving hepatitis C prevention, diagnosis and 
treatment services. Much of the infrastructure, including 
networks and governance arrangements to ensure that 
hepatitis C is managed as a mainstream condition both 
within and outside NHS settings, has been embedded.

France

French policy for HIV prevention and care in people who 
inject drugs

For several years, until 1996, France experienced an 
unprecedented epidemic of HIV and HCV infection 
among people who inject drugs, with prevalence among 
this group reaching 40 % and 70 % respectively; in 
addition, approximately 500 overdose cases were 
reported annually (Emmanelli and Desenclos, 2005). 
Before then, access to needle and syringe programmes 
was possible but had not yet been scaled up and opioid 
substitution treatment was unavailable.

The health policy revolution for access to care and 
prevention for people who inject drugs started in 1996 
with free and expanded access to antiretroviral therapy, 

opioid substitution treatment (buprenorphine in primary 
care and methadone in specialised centres) and needle 
and syringe programmes (Carrieri et al., 2006).

Needle and syringe programmes were mainly managed 
through special community centres for drug users 
(‘reception and harm reduction support centres for drug 
users’, abbreviated from the French to CAARUD), funded 
by the government. In addition to providing syringes and 
other harm reduction tools, these centres were tasked 
with providing education on reducing injecting and HIV 
and HCV risk behaviours and referring clients to HIV and 
HCV treatment, and to other services appropriate for this 
group (screening, vaccination, social groups for people 
who inject drugs, and infectious disease and psychiatric 
services).

A key component of the services was that — as far as 
possible — the same site was used as specialised centre 
for drug dependence (e.g. in the morning) and as 
a needle and syringe exchange site (e.g. in the 
afternoon). This double function turned out to be 
particularly appealing for people who inject drugs, who 
could rely on many services being available at the same 
site, that is a ‘one-stop shop’.

During this period, the French health authorities were 
aware that they were aiming to control parenteral 
transmission of HIV (and HCV), but they did not realise 
they were also controlling sexual transmission of HIV 
among people who inject drugs by using antiretroviral 
treatment as prevention. The expanded access to 
buprenorphine and methadone in this population also 
was a means of ensuring long-term virological response 
(Roux et al., 2008, 2009), thus making this population 
‘less likely’ to transmit HIV.

The high rate of opioid substitution treatment achieved 
in people who inject drugs (70–80 %), together with 
expanded access to needle and syringe programmes 
and control of HIV viraemia in the community, resulted in 
a striking reduction in HIV prevalence among this group 
of drug users. In 1995, people who inject drugs 
accounted for an estimated 28 % of patients diagnosed 
with acquired immunodeficiency syndrome (AIDS) (an 
acceptable proxy for new HIV diagnoses) (IVS, 1995); by 
2012, people who inject drugs represented less than 1 % 
of new diagnoses of HIV infection (IVS, 2014).

France adopted a shared care model of prevention and 
care to meet the urgent need to control the HIV epidemic 
among people who inject drugs and also to place 
responsibility for prevention of HIV infection and care of 
opioid-dependent drug users on the primary care sector. 
The historical reasons behind this decision were that 

50

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 3 I Strategies to improve hepatitis C care and to enhance treatment uptake and adherence among people who inject drugs

French primary care physicians were already treating 
opioid dependence with palliative treatment (such as 
low-dose buprenorphine) and those offering care to 
people who inject drugs were already working in 
specialised networks, often linked to hospital HIV 
services or dedicated centres for care of dependent drug 
users. Primary care physicians became the main 
stakeholders advocating adequate care for 
opioid-dependent injection drug users (Des Jarlais, 
2016), which in France was based particularly on 
buprenorphine because of its safety profile (Carrieri et 
al., 2006).

To summarise, French health policy compensated for the 
delay in providing access to comprehensive facilities for 
the prevention and treatment of HIV infection among 
people who inject drugs by rapidly scaling up harm 
reduction interventions at community sites and in 
specialised and primary care — which, in combination, 
significantly contributed to the control of HIV infection 
among people who inject drugs.

HCV among people who inject drugs in France: a difficult 
to manage public health imperative

The method of organising HIV prevention and treatment 
services could have been utilised to provide access to 
HCV prevention services and could have been 
particularly helpful in engaging people who inject drugs 
in hepatitis C treatment. However, 10 years after the 
French harm reduction policy was initiated, the 
prevalence of HCV infection had fallen only slightly (from 
70 % to 60 %). Although data are incomplete, the 
evaluation of the last official government hepatitis plan 
(Haut Conseil de la santé Publique, 2013) clearly shows 
that people who inject drugs and migrants still have 
limited access to HCV screening. Moreover, in France 
HCV infection has been linked to the rising use of 
stimulants (crack cocaine) and cocaine, which, owing to 
its short half-life, if injected, needs to be injected several 
times per day. These data show the importance of 
increasing access to HCV screening, treatment and 
innovative prevention measures to address these new 
HCV risks (Aspinall et al., 2013).

Corroboration that controlling the spread of HCV 
infection in France by scaling up HCV treatment and 
strategies for HCV prevention (opioid substitution 
treatment and needle and syringe programmes) is likely 
to be difficult is provided by a recent mathematical 
model. The model projections suggest that hepatitis C 
treatment for prevention is likely to be more effective 
when the baseline prevalence in the targeted population 
is below 40 % (Martin et al., 2011), which is not yet the 
case in France.

In contrast, a recent study estimated the number of 
people who received pegylated interferon and ribavirin 
treatment in 2010 (Razavi et al., 2014) in 22 European 
countries using data supplied from a variety of sources. 
This was actually the last year when all European 
countries had access to a comparable regimen for 
treating hepatitis C. According to this study, France was 
the leading country, with the highest rates of treatment 
(Razavi et al., 2014). There are two possible reasons for 
this. First, hepatitis C is a major public health concern in 
France: based on death certificates, it is estimated that 
in France 2 600 deaths each year are attributable to 
complications of hepatitis C (cirrhosis or liver cancer) 
and 4 000 are attributable to HCV or hepatitis B virus 
(HBV) infection (IVS, 2008). Second, despite the issues 
raised above, access to HCV screening and treatment is 
better in France than in other European countries, as the 
French health insurance system allows even 
marginalised populations to have free access to care 
(Grignon et al., 2008).

Even though France was found to perform well in terms 
of HCV treatment rates, an evaluation of the national 
plan to combat hepatitis identified the decentralisation 
of health care at regional level as a major barrier to 
effective hepatitis C care and equity of access to it. 
Access to HCV screening relies on local initiatives and 
on the availability of regional funds specifically targeted 
at addressing hepatitis C and substance dependence. In 
non-urban areas, the absence of specialised centres for 
the treatment of substance dependence and of 
community prevention centres means that the 
responsibility for getting people who inject drugs living 
with HCV into treatment lies with primary care providers.

In effect, at the regional level, hepatitis C prevention and 
care may be incorporated in the general prevention plan 
and initiatives to implement it depend on the regional 
budget and regional priorities which depend on local 
political will. For example, the establishment of 
a supervised drug consumption room in the Paris area 
will be possible because this initiative is prioritised in the 
allocation of health resources, which was not the case in 
Marseille, though both cities have comparable HCV 
prevalence in people who use drugs. Such unwillingness 
on the part of local authorities is the main structural 
barrier to access to HCV prevention and explains the 
heterogeneity of policies across regions. In addition, 
other potential sources of access to hepatitis C care for 
people who inject drugs are less effective than 
community sites (CAARUD). Although community sites 
are particularly designed to attract marginalised people 
who inject drugs, some injection drug users may avoid 
attending CAARUD or specialised care sites for fear of 
stigmatisation, instead choosing to use their local 

51

pharmacist, who in France can provide injecting 
equipment. Empowering pharmacists to refer people 
who inject drugs to hepatitis C screening and care could 
be an important initiative to capture individuals who 
remain outside the hepatitis C network of care.

Although 2012 data showed that HIV–HCV co-infected 
people who inject drugs enjoy the same rights to access 
treatment as other HCV patients (Salmon-Ceron et al., 
2012), they were more likely to refuse hepatitis C 
treatment initiation because they fear pegylated 
interferon-related side effects (Broers et al., 2005), and 
particularly depressive symptoms and pain due to the 
hyperalgia that develops after prolonged exposure to 
opioids (Carrieri et al., 2007). The availability of 
direct-acting antiviral medicines, characterised by high 
sustained virological response rates and limited toxicity, 
is an opportunity to engage French people who inject 
drugs in HCV care and indirectly contribute to HCV 
prevention, provided that they can be prescribed in 
low-threshold sites and for any stage of liver disease. 
Given the high cost of these medicines people who 
inject drugs found it difficult to access treatment 
because the decision to treat was submitted to 
a multidisciplinary committee of health staff. However, 
the French ministry of health recently announced the 
universal access to direct-acting antiviral medicines and 
authorised community-based rapid HCV testing. These 
decisions will have major repercussions in engaging 
people who inject drugs in HCV care, provided that once 
they have been tested in low-threshold sites they can be 
referred to receive prompt HCV treatment in 
a comprehensive model of care.

Current initiatives aim to improve both prevention and 
treatment of hepatitis C among people who inject drugs:

n  A community-based research project, the 

ANRS-AERLI study, has demonstrated the positive 
impact of an innovative intervention based on 
educational supervision of injection for people who 
inject drugs. It has shown a significant reduction of 
HCV risk practices and local complications at the 
injection site (Roux et al., 2016b) and an increase of 
access to HCV screening (Roux et al., 2016a). 
A scale-up of the AERLi intervention is envisaged 
following the application of the new French health 
law and this is expected to contribute to increasing 
access and provision of HCV prevention and 
screening to people who inject drugs.

n  The diagnosis of liver fibrosis is aided by the 

availability of a non-invasive procedure to measure 
liver stiffness (transient elastography technology) in 
specialised centres for opioid dependence/

community prevention centres (CAARUD) to monitor 
both fibrosis resulting from hepatitis and from 
alcohol consumption in people who are actively 
injecting drugs. The preliminary results from this 
national project, funded by MILDECA (Fédération 
Addiction, 2014), showed that repeated assessment 
of liver stiffness and counselling can help in reducing 
alcohol consumption and its liver-associated sequels.

n  Relaxing the criteria for eligibility for treatment of 
hepatitis C with direct-acting antiviral medicines 
simplifies the clinical management of these patients 
so that hepatologist can share responsibility for care 
with infectious disease specialists (Karine Lacombe, 
Marseille, France, personal communication, 2015) or 
even primary care physicians.

n  The presence of a hepatologist in centres for care of 
dependent drug users, or referral to a hepatologist, 
will increase access to hepatitis C treatment for 
people who inject drugs.

n  Providing hepatitis C screening (rapid testing) and 
treatment to the most marginalised sectors using 
mobile units (e.g. buses by Médecins du Monde) and 
providing a package of services including transient 
elastrogaphy monitoring, treatment education and 
hepatitis C care are approaches that are particularly 
effective in difficult-to-reach populations 
(Bruggmann, 2012).

A priority in France is to increase access to HCV testing. 
Rapid on-site testing for HIV and HCV (Bruggmann and 
Litwin, 2013) has yielded promising results in France 
and should be considered by other countries. It is 
important to note that people who inject drugs, once 
cured, are at risk of HCV reinfection, so HCV prevention 
needs to continue in the community. The French National 
Agency for Research on AIDS and Viral Hepatitis is now 
focused on developing treatments for stimulant 
dependence and medically assisted injectable 
treatments, evaluating alternative standardised 
educational approaches to reduce the risk related to 
injection, increasing access to methadone through 
primary care and developing harm reduction 
interventions for crack users (ANRS, no date).

Hepatitis C prevention and care in French prisons

Imprisonment is an important environmental factor 
facilitating HCV infection but also potentially an 
opportunity to provide treatment for hepatitis C. A recent 
survey among the prison population based on medical 
records (which were available for 70 % of the potential 
study group) found that the prevalence of HCV infection 

52

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 3 I Strategies to improve hepatitis C care and to enhance treatment uptake and adherence among people who inject drugs

was 4.8 % (95 % CI 3.53–6.50 %), with injection drug 
users accounting for 70 % of HCV-positive inmates; of 
those infected, half were classified as ‘viraemic’ 
(Semaille et al., 2013). Currently, overall, only one in five 
prisoners is tested for HCV, and this takes place at the 
time of entry, that is at a time when prisoners are 
concerned more with their loss of freedom than with 
their health, something that was identified as a major 
limitation of the French government’s hepatitis plan 
during its evaluation. Renewing the offer of hepatitis C 
testing during a prison stay may increase uptake of HCV 
testing and detection of individuals living with HCV. The 
evaluation also found that access to a specialist in 
infectious diseases or hepatology depends on the size of 
the prison, that only half of inmates testing HCV-positive 
are investigated for the presence of a chronic infection 
and that fibrosis assessment in prison settings is highly 
heterogeneous, complicating the decision to start 
hepatitis C treatment (Chiron et al., 2013). Further, 
although access to HCV screening for people who inject 
drugs seems to be poorer in prison than in the 
community, access to HCV prevention tools in prison 
settings is even more limited, as demonstrated by the 
PRI2DE study (Michel et al., 2011).

In summary, although France is regarded as an example 
of good practice in the access to hepatitis C treatment it 
offers to those chronically infected with HCV, there 
remains room for improvement; in particular, approaches 
to hepatitis C screening for people who inject drugs are 
still far from ideal. New guidelines for care in prison are 
helping to change and standardise practices, but a novel 
national strategy for prevention and treatment of 
hepatitis in French prisons is urgently needed to ensure 
the principle of equity of access to health care among 
prisoners and the general population in France.

The Slovenian model of care

Among a population of 2 million in Slovenia, 
approximately 10 000 people inject drugs, with an 
estimated HCV seroprevalence rate of 27.3 % (the third 
lowest in Europe) (Drev, 2014). HIV and HCV co-infection 
is also extremely rare, as the rate of HIV seroprevalence 
among people who inject drugs is low, being consistently 
under 1 %. For example, during 2008–2012 only three 
individuals with anti-HIV antibodies were detected 
during unlinked anonymous testing of people who inject 
drugs for surveillance purposes (n = 947) and only one 
new HIV diagnosis was reported among this group of 
drug users (Drev, 2014).

In 1995, 18 Centres for the Prevention and Treatment of 
Drug Addiction (CPTDAs) were founded, managing 

approximately 4 500 people who inject drugs yearly, 
three-quarters of whom receive opioid substitution 
treatment (Kastelic and Kostapfel, 2010). The CPTDAs 
provide HCV testing to people who inject drugs entering 
the programme, and offer regular testing for 6–12 
months for those testing negative. In the first national 
study evaluating the hepatitis C treatment rate among 
people who inject drugs managed by the 18 CPTDAs in 
2006, the prevalence of HCV RNA among 1 450 people 
who inject drugs was 15.6 %, but only 3 % of those 
infected had received hepatitis C treatment by the time 
of the study (Maticic, 2014). The low treatment rate 
among HCV-positive people who inject drugs led to an 
urgent call for action.

Hepatitis C treatment in Slovenia is mostly delivered by 
infectious disease specialists at five hospital-based 
clinics. This is fully funded by the health insurance 
system with no limitations except that treatment must 
be prescribed by approved infectious disease specialists 
(and hepatologists in the case of advanced liver disease) 
in accordance with the guidelines established by the 
National Viral Hepatitis Expert Group in 1997. These 
guidelines do not exclude people who inject drugs from 
hepatitis C treatment (Maticic et al., 1999). In 2007, 
a national multidisciplinary health care network for the 
treatment of HCV infection in people who inject drugs 
was established, regionally integrating the existing 
medical settings of the 18 CPTDAs and five specialised 
clinics for treatment of viral hepatitis. The 
multidisciplinary network team includes clinical care 
providers (addiction therapists and infectious disease 
specialists), psychiatrists and counsellors (nurses, social 
workers) who have undergone additional medical 
education and training, and peers (formerly HCV-positive 
injection drugs user) and other supportive systems (such 
as family, friends, co-workers).

Since 2006, close collaboration among all health care 
workers involved in the management of hepatitis C has 
been encouraged in the form of attendance at annual 
national conferences. These conferences, in addition to 
promoting knowledge sharing among health workers and 
providing a forum for updating guidelines for the 
management HCV of infection in people who inject 
drugs, provide a valuable opportunity to exchange 
experiences. The national conferences played a crucial 
role in the development of an integrated approach for 
the management of HCV infection in people who inject 
drugs and continue to play an important role in 
maintaining this integrated approach. It was a result of 
the national conference in 2006 that national consensus 
guidelines for the management of HCV infection in drug 
users were developed in 2007 (Maticic and Kastelic, 
2009). These outline procedures for the complex 

53

In the era of highly effective interferon-free HCV 
treatment regimens, national clinical guidelines indicate 
direct-acting antivirals to be used on the basis of fibrosis 
stage, extrahepatic manifestations and co-morbidities 
and do not rule out people who inject drugs. Even though 
being safe and patient-friendly, direct-acting antivirals 
are prescribed in a multidisciplinary network under the 
same regimen as interferon-based treatment options. 
Aside from sustained virological response, some 
socio-demographic and behavioural benefits of 
successful treatment may play a crucial role in the future 
management of HCV infection in people who inject 
drugs, strongly influencing decision-makers towards 
even wider inclusion of injecting drug users in treatment 
for hepatitis C.

I  Conclusions

Treatment of hepatitis C among people who inject drugs 
must be specifically adapted to the needs of this 
marginalised population. According to currently available 
evidence and experience from national strategies, 
hepatitis C care should be integrated into existing 
addiction units if it is to reach people who inject drugs. 
New hepatitis C treatment regimens that are easy to 
administer and well tolerated will make it easier in the 
future to deliver comprehensive, multidisciplinary care to 
people who inject drugs. Specific measures to enhance 
engagement with testing and treatment and to support 
adherence delivered at primary care/community level 
will still be needed. Examples of good practice from 
different countries show that there is no single solution 
to close the gaps, and that even countries with good 
national plans have room for improvement, as 
exemplified by the case of France. Activities to improve 
hepatitis C care among people who inject drugs must be 
extended to prisons. Close collaboration between all 
professionals involved in care underpins every 
successful model of care. Primary prevention strategies 
— opioid substitution treatment and needle and syringe 
programmes — remain important and will need to be 
scaled up in some sites in order to maintain low HCV 
incidence and minimise the risk of reinfection.

management of HCV-infected people who inject drugs, 
including improved screening for those who are eligible 
for hepatitis C treatment; the provision of education, 
discussion and motivation-enhancing techniques 
individually tailored by highly qualified addiction 
therapists; and referral to infectious disease specialists 
for the treatment of hepatitis C in accordance with the 
best standard of care.

The guidelines for the care of patients with hepatitis C 
specify that each patient should receive a detailed and 
individualised hepatitis C treatment plan. In addition, 
treatment should be optimised, with side effects being 
aggressively managed and individually tailored 
interventions (e.g. a change in methadone dosage; 
addition of psychotherapeutics due to psychiatric 
comorbidities; additional motivation for adherence to 
treatment) performed at least monthly and in close 
cooperation with an addiction therapist throughout the 
treatment period. A standardised report on the patient’s 
current medical and addiction/psychological condition is 
exchanged monthly between the hepatitis C and drug 
treatment specialists. This system enables hepatitis C 
and drug use, which are treated in separate medical 
settings, albeit in close proximity, to be managed in the 
most effective and rational manner, making use of 
facilities already existing in the country. The close liaison 
between the hepatitis C treatment specialist and the 
drug treatment therapist, and the active cooperation of 
the patient with both of them before and during 
hepatitis C treatment, also plays a crucial role in 
managing HCV infection in people who inject drugs.

As a result of these initiatives, among all the patients 
treated for hepatitis C in Slovenia the proportion of those 
who reported injecting drug increased from 5 % in 
1997–99 to 16 % in 1999–2001, and to 36 % in 2002–
04 (Brinovec et al., 2002, 2004; Maticic, 2014). However, 
since the introduction of the national multidisciplinary 
health care network in 2007, the share of injection drug 
users treated for hepatitis C has increased even further, 
reaching 78 % during the period 2008–10 (Maticic et al., 
2013; Maticic, 2014). In addition, the proportion of 
injection drug users infected with HCV and treated for 
hepatitis C in CPTDAs increased from 3 % in 2006 to 
13 % in 2010 (Maticic et al., 2013). Among those treated, 
a treatment adherence rate of 95.7 % and an overall 
sustained virological response rate of 82 % in the period 
2008–10 have been accompanied by a marked 
improvement in certain lifestyle variables and a major 
decrease in drug use and opioid substitution treatment, 
which in combination justify the use of the 
multidisciplinary network model in Slovenia (Maticic et 
al., 2013, 2014).

54

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 3 I Strategies to improve hepatitis C care and to enhance treatment uptake and adherence among people who inject drugs

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57

4

CHAPTER 4
Hepatitis C prevention among people 
who inject drugs: role and impact of 
hepatitis C treatment, opioid 
substitution treatment and needle 
and syringe programmes
Natasha K. Martin, Matthew Hickman and Peter Vickerman

I  Introduction and overview

There is increasingly strong evidence that traditional 
primary prevention measures such as opioid substitution 
treatment and needle and syringe programmes may be 
effective at preventing hepatitis C virus (HCV) 
transmission. However, modelling projections have shown 
that achieving substantial reductions in HCV prevalence 
among people who inject drugs requires HCV treatment. 
Antiviral treatment for hepatitis C is available and 
effective at curing a majority of individuals. A range of 
medications exist that are judged to be cost-effective in 
European settings — that is, the cost of treatment is lower 
than the amount that it is generally accepted that society 
is willing to pay for the additional years of healthy life that 
treatment will provide. These medications include 
pegylated interferon and ribavirin (NICE, 2004, 2006; 
Sroczynski et al., 2010), as well as newer, direct-acting 
antiviral therapies (Cammà et al., 2012; NICE, 2012a,b, 
2015; Cure et al, 2015a,b). In addition to individual 
benefits, model projections have shown that HCV 
treatment for people who inject drugs could be an 
effective and cost-effective means of prevention in 
settings where chronic HCV prevalence among this group 
is less than 60 %; and that those who inject drugs should 
be prioritised after treating people with severe liver 
disease (Martin et al., 2011a, 2012, 2013a,b, 2016a,b). In 
most European countries, it will be essential to scale up 
hepatitis C treatment if the increasing trend in the 
prevalence of end-stage liver disease is to be reversed 
(Harris et al., 2014; Razavi et al., 2014). However, targeting 
people with cirrhosis, as is the priority in many European 
countries, is unlikely to lead to substantial reductions in 
hepatitis C virus transmission or the prevalence of HCV 
infection among people who inject drugs (Innes et al., 

2014; Harris et al., 2016) as by the time cirrhosis has 
developed injecting drug use behaviour has usually 
ceased. Although much of the HCV treatment as 
prevention modelling work has been done in a few 
countries (Australia, Canada, France, United Kingdom), 
the scenarios reflect the situation in many European cities 
and, therefore, can be generalised. There is a need now to 
generate empirical data and conduct evaluations of the 
impact and cost-effectiveness of scaling up HCV 
treatment among people who inject drugs in European 
settings. In this chapter we discuss the empirical 
evidence and mathematical modelling work regarding 
HCV prevention interventions (harm reduction and 
hepatitis C treatment) among people who inject drugs.

I   Epidemiology of hepatitis C primary 

prevention

Epidemiological evidence indicates that traditional 
primary prevention measures such as opioid 
substitution treatment and needle and syringe 
programmes are effective in reducing self-reported 
syringe sharing. Both of these interventions can reduce 
transmission of human immunodeficiency virus (HIV), 
and evidence is emerging that they can also reduce 
transmission of HCV, in particular among those exposed 
to opioid substitution treatment and high-coverage 
needle and syringe programmes (2) in combination (Van 
Den Berg et al., 2007; Hagan et al., 2011; Turner et al., 

(2)  High‑coverage needle and syringe programmes are those providing 
clients with at least one sterile syringe for each reported injection. 

59

2011). However, it is unlikely that either intervention 
alone can reduce hepatitis C to negligible levels among 
people who inject drugs.

A study of 714 ever-injectors who were part of the 
Amsterdam Cohort Study, published in 2007, found that 
‘full harm reduction’ (defined as consumption of at least 
60 mg methadone daily in the past 6 months and no 
injecting drug use in that period; or consumption of at 
least 60 mg methadone daily, injecting drug use in the 
past 6 months, and all needles used in that period 
obtained via needle and syringe programmes) was 
associated with a relative risk of HCV acquisition of 0.36 
(95 % confidence interval (CI) 0.13–1.03) compared with 
no harm reduction (Van Den Berg et al., 2007). However, 
one recent review and meta-analysis (Hagan et al., 2011) 
found that exposure to needle and syringe programmes 
was associated with a higher risk of HCV acquisition 
(1.62, 95 % CI 1.04–2.52) than no exposure to the 
intervention, though being on opioid substitution 
treatment was associated with a lower risk of HCV 
acquisition (0.6, 95 % CI 0.35–1.03).

A pooled meta-analysis from six UK sites involving 2 986 
people who inject drugs investigated the association 
between opioid substitution treatment and 
high-coverage needle and syringe programmes 
(providing at least one sterile syringe per injection) and 
HCV incidence (Table 4.1). Turner et al. (2011) found that 
being on opioid substitution treatment was associated 
with a 59 % reduced risk of acquiring HCV (adjusted 
odds ratio (AOR) 0.41, 95 % CI 0.21–0.82), and 
participation in high-coverage needle and syringe 
programmes was associated with a 52 % reduction in 
risk (AOR 0.48, 95 % CI 0.25–0.93). Full harm reduction 
(the combination of the two interventions) was 
associated with approximately an 80 % reduction in HCV 
acquisition risk (AOR 0.21, 95 % CI 0.08–0.52).

Recently, there has been a further strengthening of the 
evidence base from non-European countries, with 
results from the Vancouver Injecting Drug Use Study in 
Canada (Nolan et al., 2014) and two other prospective 
studies of people who inject drugs, one in Australia 
(White et al., 2014) and one in San Francisco in the 
United States (Tsui et al., 2014), all of which reported 
that opioid substitution treatment can reduce the risk of 
HCV acquisition by 50 % to 80 % (Vancouver: AOR 0.47, 
95 % CI 0.29–0.76; Australia: AOR 0.18, 95 % CI 0.04–
0.77; San Francisco, AOR 0.39, 95 % CI 0.18–0.87).

A global systematic review on the individual and 
combined effects of opioid substitution treatment and 
needle and syringe programmes on the epidemiology of 
HCV among people who inject drugs is underway (Platt 

et al., 2016) and urgently needed. Similar systemic 
reviews have been performed for the impact of opioid 
substitution treatment (MacArthur et al., 2012) and 
needle and syringe programmes (Aspinall et al., 2014) on 
the incidence of HIV infection.

I   Model projections of impact of 

scale‑up of full prevention

A number of mathematical modelling studies have 
considered the impact of a reduction in syringe sharing 
(Murray et al., 2003; Vickerman et al., 2007, 2009) or in the 
overall level of transmission risk (de Vos et al., 2012; 
Vickerman et al., 2012b, 2013) on the overall dynamics of 
hepatitis C epidemics among people who inject drugs. 
These analyses suggest that syringe sharing has to fall to 
very low levels (<1 syringe shared per month) before large 
reductions in HCV infection prevalence or incidence are 
achieved. In addition, a number of analyses, carried out in 
Australia, the Netherlands and the United Kingdom, have 
considered the impact or cost-effectiveness of opioid 
substitution treatment or needle and syringe programmes 
on HCV transmission. A modelling analysis of the 
Amsterdam injecting drug use cohort (de Vos et al., 2013) 
indicated that the scaling up of harm reduction was 
required to reproduce the full observed declines in HIV 
and HCV incidence, but a large proportion of the decrease 
may be due to changes in the population of injecting drug 
users. The analyses from Australia (Australian Government 
Department of Health and Aged Care, 2009; Kwon et al., 
2009, 2012) used data on the dose–response relationship 
between syringe distribution and syringe sharing to assess 
how reductions in syringe distribution would affect syringe 
sharing and HCV transmission. The results suggested that 
current levels of syringe distribution are cost-effective in 
reducing HIV and HCV transmission (Kwon et al., 2012). 
No equivalent data are available for Europe — but the 
relationship is likely to be similar.

Finally, an analysis from the United Kingdom used 
recently published effect estimates of the extent to 
which opioid substitution treatment and current 
high-coverage needle and syringe programmes reduce 
the risk of HCV acquisition to show that scaling-up of 
harm reduction interventions in the United Kingdom has 
prevented HCV infections. The United Kingdom is among 
several European countries that, in the past decade, 
have achieved very high levels of opioid substitution 
treatment and needle and syringe programmes coverage 
(in the United Kingdom reaching approximately half of 
the drug-injecting population). Modelling indicates that 
without this high level of harm reduction coverage, the 

60

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionTABLE 4.1
Relationship between intervention coverage and the incidence of new HCV infection

Acquired HCV infection

Intervention 
coverage

No (n)

Yes 
(n)

%

Unadjusted 
odds ratio

95 % CI

P

Adjusted 
odds ratio

95 % CI

P

Opioid substitution treatment (OST)

On OST (1)

Not on OST

526

353

14

26

2.6

6.9

Needle and syringe programme (NSP) (2)

≥ 100 % coverage

< 100 % coverage

539

254

21

19

3.8

7.0

Combined OST and NSP

0.36

Ref.

0.52

Ref.

0.19–0.70

0.003

–

–

0.28–0.99

0.045

–

–

0.41

Ref.

0.48

Ref.

0.21–0.82

0.01

–

–

0.24–0.93

0.03

–

–

392

8

2.0

0.19

0.08–0.47

<0.001

0.21

0.08–0.52

0.001

233

134

120

13

6

13

5.3

4.3

9.8

0.52

0.41

Ref.

0.23–1.15

0.10

0.50

0.22–1.12

0.09

0.15–1.12

0.08

0.48

0.17–1.33

0.16

–

–

Ref.

–

–

Full harm reduction: 
≥ 100 % coverage, 
on OST (1)

≥ 100 % coverage, 
not on OST

< 100 % coverage, 
not on OST (1)

Minimal harm 
reduction: < 100 % 
coverage, not on 
OST

Covariates

Gender

Injection 
duration

Crack injection

Homelessness

2.1

1.0

1.9

2.9

1.04–4.34

0.039

0.44–2.07

0.906

0.99–3.78

0.054

1.41–5.97

0.004

(1)  Logistic regression was used to calculate unadjusted and adjusted odds ratios (adjusted for the following covariates: female sex, homelessness in 

(2) 

last year, injected crack in last month, duration injecting < 2.5 years) with probability (P) values and 95 % confidence intervals (CIs).
Includes 86 participants (involving no new HCV infections) who were receiving opioid substitution treatment but reported no injections in the last 
month (cross-sectional studies) or last year (cohort studies).

Source: Turner et al. (2011).

prevalence of chronic HCV infection among people who 
inject drugs could have been as high as 70 %, rather 
than the 40 % seen today (Vickerman et al., 2012b) 
(Figure 4.1). However, further harm reduction scale-up 
may achieve only modest reductions in prevalence, over 
a very long time (20 years), and will necessitate levels of 
coverage that are unachievable or unsustainable 
(Vickerman et al., 2012a).

The prevalence of HCV infection among people who inject 
drugs varies considerably within and between European 
countries (Chapter 1) — but in most sites will be between 
20 % and 60 %. In settings with low levels of harm 
reduction interventions, or none, scaling up opioid 
substitution treatment and high-coverage needle and 
syringe programmes can reduce the prevalence of 
chronic HCV infection among people who inject drugs by 
up to 40 % within 10 years, depending on the baseline 
level of chronic infection (Figure 4.2). However, despite 
the substantial potential impact of harm reduction on 
HCV transmission, model projections suggest that 

reducing the prevalence of HCV infection among people 
who inject drugs by more than 40 % within 10 years 
requires the introduction and scaling-up of hepatitis C 
treatment (Martin et al., 2013a) (Figure 4.2). Therefore, 
a combined strategy that includes hepatitis C treatment 
as a prevention measure is critical if HCV prevalence or 
transmission is to be reduced to very low levels, especially 
in settings where existing coverage of harm reduction 
interventions is high.

I   Potential impact of hepatitis C 

treatment for prevention among 
people who inject drugs

The dramatic improvements in hepatitis C treatment in 
recent years (see Chapter 5) has led to speculation 
about whether antiviral treatment could be used as an 
effective prevention strategy among people who inject 

61

CHAPTER 4 I Hepatitis C prevention among people who inject drugsFIGURE 4.1
Modelling the projected impact of changes in the 
coverage of opioid substitution treatment and needle 
and syringe programmes in the United Kingdom 
(assuming a baseline prevalence of chronic HCV 
infection among people who inject drugs of 40 %) from 
50 % for each intervention to 0, 60, 70 and 90 % for 
opioid substitution treatment and 100 % for needle and 
syringe programmes

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NB: High-coverage needle and syringe programmes (100 % NSP) are 
those providing one or more sterile syringes for each injection reported 
per month. The box plots signify the uncertainty (middle line is median, 
limits of boxes are 25th and 75th percentiles and whiskers are 2.5th and 
97.5th percentiles). 
Source: Vickerman et al. (2012a).

drugs (Hellard et al., 2014). In theory, hepatitis C 
treatment could be even more effective a prevention 
measure than HIV treatment because hepatitis C 
treatment is finite and curative.

No empirical studies have explored whether hepatitis C 
treatment can reduce the prevalence of HCV infection 
among people who inject drugs and prevent onwards 
transmission. However, several theoretical modelling 
studies have indicated that comparatively modest rates 
of hepatitis C treatment in this group, using either 
interferon and ribavirin or direct-acting antiviral 
therapies, can result in dramatic reductions in HCV 
chronic prevalence within 10 to 15 years in a range of 
settings (Zeiler et al., 2010; Martin et al., 2011a,b,c, 
2013a; Vickerman et al., 2011; Durier et al., 2012; Rolls et 
al., 2013; Cousien et al., 2016).

A recent evaluation of selected services in the United 
Kingdom found that treatment rates among people who 
inject drugs varied greatly (ranging from fewer than 5 to 
27 per 1 000 injectors per year) (Martin et al., 2015b). 
Furthermore, model projections indicate that, in general, 
current hepatitis C treatment rates among people who 
inject drugs are insufficient to lead to an observable 
decline in the prevalence of HCV infection in the next 
decade (Martin et al., 2015b), as shown in Figure 4.3.

However, model projections have also shown that an 
achievable increase in hepatitis C treatment rates 
among people who inject drugs with direct-acting 

FIGURE 4.2
Modelling of the combined impact of hepatitis C antiviral treatment, opioid substitution treatment and high-coverage 
needle and syringe programmes on relative reduction of HCV chronic prevalence (%) over 10 years in a population of 
people who inject drugs when the baseline prevalence of chronic hepatitis C is 20 %, 40 % or 60 %

㈀　 ─ 䌀栀爀漀渀椀挀 瀀爀攀瘀愀氀攀渀挀攀

㐀　 ─ 䌀栀爀漀渀椀挀 瀀爀攀瘀愀氀攀渀挀攀

㘀　 ─ 䌀栀爀漀渀椀挀 瀀爀攀瘀愀氀攀渀挀攀

一甀洀戀攀爀 漀昀
琀爀攀愀琀洀攀渀琀猀 
瀀攀爀 礀攀愀爀 瀀攀爀
㄀ 　　　 瀀攀漀瀀氀攀 
眀栀漀 椀渀樀攀挀琀 
搀爀甀最猀

㜀　

㘀　

㔀　

㐀　

㌀　

㈀　

㄀　

㠀　

㘀　

㐀　

㈀　

㈀　

㐀　

㘀　

㠀　

䤀渀琀攀爀瘀攀渀琀椀漀渀 挀漀瘀攀爀愀最攀 ⠀─⤀

NB: The heat colours show the percent relative reduction in chronic HCV at 10 years, which ranges from 0 (dark brown) to over 80 % (white), achieved 
depending on the coverage of combined hepatitis C antiviral treatment among people who inject drugs (y-axis), opioid substitution treatment and 
high-coverage needle and syringe programmes (x-axis). Gradient lines show the contours of relative reductions in 10 % increments (e.g. 10 % relative 
reduction up to 90 % relative reduction).
Source: Martin et al. (2013a).

62

Hepatitis C among drug users in Europe: epidemiology, treatment and prevention　
　
　
　
FIGURE 4.3
Box–whisker plot showing chronic HCV prevalence among people who inject drugs in 2014 (blue boxes) and 
projected HCV prevalence in 2024 with current (white boxes) and scaled-up (black boxes) hepatitis C treatment rates 
at multiple UK sites

HCV
prevalence 
(%)

100

90

80

70

60

50

40

30

20

10

0

Bristol

East London Manchester Nottingham Plymouth

Dundee

North Wales

NB: The blue boxes show estimated chronic HCV prevalence among people who inject drugs in 2014. The white boxes show the projected effects of no 
treatment scale-up of current HCV treatment rates, using pegylated interferon and ribavirin sustained viral response rates from 2005.The black boxes 
show the effect of scaling up treatment to the rate of 26/1000 people who inject drugs (as is currently achieved in Manchester), using interferon-free 
direct-acting antiviral medicines that can achieve 90 % sustained viral response rates for infection with all HCV genotypes in 2016.
Boxes show the interquartile range and whiskers the 95 % confidence intervals. 
Source: Martin et al. (2015b).

FIGURE 4.4
Model projections of HCV chronic prevalence among people who inject drugs over time in Edinburgh, Scotland, 
assuming scale-up of hepatitis C treatment and interferon-free direct-acting antiviral therapy which achieve 
sustained virological response rates of 90 % from 2015

HCV prevalence
(%)

50

40

30

20

10

0

Interferon-free direct-acting 
antivirals

2002

2007

2012

2017

2022

2027

Year

Data

Number treated each year per 1 000 people who inject drugs 

8 

10

20

40

80

NB: Simulations show no scale-up from baseline (dark blue) or scaling up to the level of 10, 20, 40 or 80 per 1 000 people who inject drugs treated 
annually. The model assumes no treatment prior to 2002, linear scale-up to baseline treatment rates during 2002–07 and baseline treatment rates during 
2007–15, then linear scale-up from baseline to the scaled-up rate during 2015–17. HCV prevalence data points with 95 % confidence intervals are shown 
for comparison.
Source: Martin et al. (2013b).

63

CHAPTER 4 I Hepatitis C prevention among people who inject drugsantiviral therapy with 90 % sustained viral response 
could lead to substantial reductions in the prevalence of 
HCV infection in the population (Figure 4.3). For 
example, in Edinburgh (Figure 4.4) a doubling of 
hepatitis C treatment rates could halve chronic HCV 
prevalence and incidence within 10 years (which 
corresponds to an increase from 32 to 64 drug injectors 
treated per year) (Martin et al., 2013b). If, at the same 
time, opioid substitution treatment and high-coverage 
needle and syringe programmes are also expanded, then 
either the impact will be greater or fewer expensive 
antiviral treatments will be required to reduce the 
prevalence of HCV infection (Martin et al., 2013a). 
Further service evaluations and model projections are 
required in other European settings to establish 
hepatitis C treatment rates among people who inject 
drugs and by how much treatment (and other 
interventions) needs to be scaled up to achieve 
observable reductions in the prevalence and incidence 
of HCV infection.

Two studies, one in Australia (Rolls et al., 2013) and one 
in France (Cousien et al., 2016), have modelled the 
impact of hepatitis C treatment for people who inject 
drugs using individual-based network models. Using 
detailed epidemiological data on the injecting network 
connections of people who inject drugs in Melbourne, 
Rolls et al. (2013) found that a strategy of treating all the 
contacts of an infected individual (‘treat your friends’) 
could be more effective than random treatment of 
people who inject drugs. Additionally, a recent modelling 
analysis in France (Figure 4.5) indicates that, because 

current hepatitis C treatment rates among people who 
inject drugs are relatively high, the introduction of 
direct-acting antiviral medicines that can achieve 
sustained virological response rates of 81 % could 
reduce the prevalence of chronic HCV infection among 
this group from 43 % at baseline to 25 % within 10 years 
(Cousien et al., 2016). However, current guidelines 
(European Association for the Study of the Liver, 2014) 
recommend that priority is given to those with moderate 
to severe liver disease (stages F2–F4), a strategy that is 
likely to have minimal impact on HCV transmission 
(scenarios 1 to 5 in Figure 4.5). Extending hepatitis C 
treatment to those earlier disease stages (F0/F1) — as 
shown by scenarios 6 and 7 — would have a dramatic 
impact on HCV incidence and prevalence due to 
a substantially increased pool of eligible people who 
inject drugs.

I   Cost-effectiveness of hepatitis C treatment for 

people who inject drugs

A number of studies have examined the 
cost-effectiveness of hepatitis C treatment for current or 
former drug injectors, consistently finding hepatitis C 
treatment for this risk group cost-effective (Table 4.2). 
The outcomes of these studies are incremental 
cost-effectiveness ratios (ICERs), which determine the 
incremental cost per health outcome gained (usually 
expressed in quality-adjusted life years, QALYs). These 
studies come from a variety of European and other 
developed countries (Australia, New Zealand, United 

FIGURE 4.5
Modelling projections of the 10-year impact on HCV incidence (left) and prevalence (right) of hepatitis C treatment 
for people who inject drugs in France

NB: The model assumes a 10 % annual treatment delivery rate among eligible people who inject drugs. The scenarios are as follows: 1, current cascade of 
care (reference); 2, improvement in HCV testing; 3, improvement in linkage to care; 4, improvement in testing and linkage to care; 5, improvement in 
adherence to treatment; 6, treatment initiated at stage F0; 7, improvement of the entire cascade of care (combination of scenarios 4, 5 and 6).
Source: Cousien et al. (2016).

64

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionTABLE 4.2
Cost-effectiveness studies which have assessed hepatitis C treatment for people who inject drugs

Study

Country Population

Intervention

Comparator

Reinfection

Leal et al. 
(1999)

United 
Kingdom

People who 
inject drugs in 
drugs services

Screening + 
interferon and 
ribavirin

Loubiere 
et al. 
(2003)

France

People who 
inject drugs

Screening + 
interferon and 
ribavirin

Sheerin et 
al. (2004)

New 
Zealand

Stein et al. 
(2004)

United 
Kingdom

People who 
inject drugs in 
substitution 
treatment

People who 
inject drugs in 
drugs services

Substitution 
treatment + 
pegylated interferon 
and ribavirin

Screening + 
pegylated interferon 
and ribavirin

No screening

No

No screening

No

Only substitu‑
tion treatment

No

No screening

No

Thompson 
Coon et al. 
(2006)

United 
Kingdom

Former 
injectors in 
primary care

Case‑finding + 
pegylated interferon 
and ribavirin

No case‑finding

No

Includes 
prevention 
benefit 

ICER (cost per QALY 
gained)

No

No

No

No

No

GBP 9 300

EUR 5 778

NZD 19 000 (approx.) 
per life‑year gained

EUR 14 000 (approx.)

GBP 16 493

Wong et 
al. (2004)

United 
States

People who 
inject drugs

Interferon and 
ribavirin

No treatment

Vickerman 
et al. 
(2008)

United 
Kingdom

People who 
inject drugs

Interferon and 
ribavirin

No treatment

Yes 
(3–15 %/
year)

Yes 
(dynamic)

No

USD 5 600

Yes

GBP 10 500 (approx.)

Martin et 
al. (2012)

United 
Kingdom

Current and 
former drug 
injectors

Pegylated interferon 
and ribavirin 

No treatment

Yes 
(dynamic)

Yes

Visconti et 
al. (2013)

Australia Current and 
former drug 
injectors 

Pegylated interferon 
and ribavirin 

No treatment

Scott et al. 
(2016)

Australia People who 
inject drugs 

Martin et 
al. (2016b)

United 
Kingdom

Current and 
former drug 
injectors

No treatment 

Early or late 
treatment with 
interferon‑free direct 
acting antiviral 
therapy 

Early treatment 
(mild or moderate 
fibrosis) with 
interferon‑free direct 
acting antiviral 
therapy

Treatment at 
cirrhosis with 
interferon‑free 
direct acting 
antiviral therapy

No

No

Yes (6.8 %/
year if 
injecting)

Yes (11 %/
year if 
injecting)

Yes 
(dynamic)

Yes

NB: Costs are presented in original currency and price years. In 2016, EUR 1 = GBP 0.8 = USD 1.15 = AUD 1.5 = NZD 1.6.
ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Current injectors: 
GBP 500–8 000 
(approx.)
Former injectors: 
GBP 6 800 (approx.)

Current injectors: 
AUD 8 000 (approx.)
Former injectors: 
AUD 6 000 (approx.)

Late vs no treatment: 
AUD 5 078
Early vs late 
treatment: 
AUD 17 090

Mild/moderate 
injectors: 
GBP 2 800– 26 000 
(approx.) depending 
on prevalence setting
Mild former injectors: 
GBP 22 932
Moderate former 
injectors: 
GBP 13 081

65

CHAPTER 4 I Hepatitis C prevention among people who inject drugsStates) and make differing assumptions regarding the 
risk of reinfection. Only three studies include the 
possible prevention benefit of hepatitis C treatment 
(Vickerman et al., 2008; Martin et al., 2012, 2016b). 
Indeed, treating people who inject drugs may be more 
cost-effective than treating former or non-injectors 
because of the substantial benefits achieved through 
preventing secondary infections, despite the risk of 
reinfection or lower sustained virological response rates 
among injectors (Martin et al., 2012, 2016a).

The key questions, therefore, given a setting with limited 
resources, are which patients should be targeted as 
treatment is expanded, and which patients can wait. 
Considering that available resources are limited, current 
European guidelines recommend the prioritisation of 
direct-acting antiviral treatments for those with severe 
liver disease (European Association for the Study of the 
Liver, 2014). Updated guildelines in 2015 also 
recommend the prioritisation of those with on-going 
transmission risk, although it is unclear whether and to 
what degree this is being implemented across Eruope 
(European Association for the Study of the Liver, 2015). 
In Figure 4.6 we show the incremental costs and 
benefits of early treatment prioritisation based on liver 
disease stage (mild/moderate) and risk (injectors, former 
or non-injectors) compared with delaying treatment until 

compensated cirrhosis develops. The figure presents 
three population scenarios in which the prevalence of 
chronic hepatitis C among the drug-injecting population 
is 20 %, 40 % or 60 %. In populations with a very high 
prevalence of chronic hepatitis C (60 % or above), it is 
always more cost-effective to treat non-injectors with 
moderate disease, because of high levels of reinfection 
among people who inject drugs (Vickerman et al., 2016).

However, in settings in which the prevalence of chronic 
hepatitis C among people who inject drugs is 20 % or 
40 %, the most cost-effective approach is to target those 
injecting drugs (with moderate and mild disease) before 
targeting non-injectors with moderate disease. 
Therefore, in settings in which the prevalence of chronic 
hepatitis C among people who inject drugs is below 
60 %, both disease stage and risk factor information 
should be used to prioritise treatments. It is too early to 
make direct comparisons between specific 
interferon-free direct-acting antiviral medicines and 
current interferon-based regimens, as full 
cost-effectiveness studies, using dynamic models, of the 
new direct-acting antiviral medicines have not yet been 
undertaken — and the exact drug regime, the drug price 
and the population of patients recommended for 
treatment have not been established throughout Europe. 
However, we do know that hepatitis C treatment needs 

FIGURE 4.6
Cost-effectiveness efficiency frontiers of early treatment for injectors or former injectors and non-injectors with mild 
or moderate hepatitis C using interferon-free direct-acting antiviral medicines, compared with delaying treatment 
until compensated cirrhosis develops, in the setting of a prevalence of chronic hepatitis C among people who inject 
drugs of 20 % (solid black line), 40 % (grey line) or 60 % (dashed grey line)

Ex/non injectors, mild 

Injectors, 
mild 60 %

Injectors, 
moderate 60 %

Injectors, 
mild 40 %

Ex/non injectors, 
moderate

Injectors, 
moderate 40 %

Injectors, 
mild 20 %

Injectors, 
moderate 20 %

Mean incremental 
costs per additional 
treatment
(pounds sterling)

30 000

25 000

20 000

15 000

10 000

5 000

0

0 

0.5 

1 

1.5 

2 

2.5 

3 

3.5 

4 

4.5

Mean incremental QALYs per additional treatment

NB: The frontier curves show the most cost-effective option — HCV treatment for patient groups that do not lie on the frontier (and therefore lie above the 
lines shown) are dominated (are more expensive and provide fewer health benefits) by patient groups on the frontier.
Source: Martin et al. (2016a).

66

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionto be scaled up to make an appreciable impact on HCV 
transmission and that interferon-free direct-acting 
antiviral medicines will play role in enabling more 
patients to be treated and managed in the community. 
Undoubtedly direct-acting antiviral drug costs will need 
to be lower than suggested in some quarters (e.g. lower 
than GBP 35 000 for 12 weeks’ treatment proposed in 
the British National Formulary (Joint Formulary 
Committee, 2014)) for the scale-up of hepatitis C 
treatment for prevention to be affordable by society.

I   Special populations: hepatitis C 

prevention in prison

Among the prison population both absolute numbers 
and the proportions of people who inject drugs are high 
and therefore, inevitably, rates of hepatitis C among 
prisoners are also high (Vescio et al., 2008). As a result, 
prison is an ideal setting for hepatitis C prevention 
interventions. In a recent study in Scotland, the risk of 
HCV transmission in prisons was found to be lower than 
that in the community, mainly because of widespread 
access to opioid substitution treatment in Scottish 
prisons (Hedrich et al., 2012; Taylor et al., 2013). 
However, studies carried out in prisons elsewhere in 
Europe have reported higher risk of blood-borne virus 
transmission in prison than the community (Stark et al., 
1997; Christensen et al., 2000; Vescio et al., 2008; Arain 
et al., 2014). Prisons could play an important role in 
promoting public health and harm reduction among 
people who inject drugs. Rates of hepatitis B vaccination 
among people who inject drugs have increased as 
a result of prison programmes. Prisons also could have 
a role in hepatitis C case-finding and treatment — as 
people who inject drugs and who may not yet be in 
long-term opioid substitution treatment programmes, 
and, therefore, who are at continued risk of transmitting 
infection to others, can be detected and treated. 
A UK-based analysis showed that HCV testing in prisons, 
followed by 24–48 weeks’ treatment with pegylated 
interferon and ribavirin in those testing positive, is 
cost-effective if continuity of care between prison and 
community can be achieved in at least 40 % of cases. In 
other words, because many people who inject drugs are 
incarcerated for relatively brief periods (on average 4 
months in the United Kingdom), it is crucial to ensure 
that infected individuals are referred to treatment and 
remain in referral contact or on treatment after release 
or transfer. The high turnover of prisoners and frequent 
prison transfers in some countries therefore pose 
a challenge. Systems to ensure effective referral onto 
treatment and continuity of care are often not in place, 

which can substantially limit the effectiveness and 
cost-effectiveness of a prison-based treatment as 
a prevention strategy. Until now, the relatively long 
duration of hepatitis C treatment, problems of ensuring 
continuity of care in the community and short durations 
of imprisonment for drugs offences have militated 
against scaling up hepatitis C treatment in the prison 
setting. However, it is likely that treatments of shorter 
duration (8–12 weeks) will mean that a greater 
proportion of people who start on treatment while in 
prison will be able to complete it before being released, 
and this could make treatment in a prison setting more 
cost-effective (Martin et al., 2016b).

Importantly, a number of ethical issues regarding HCV 
testing and treatment in prison have been raised (Levy 
and Larney, 2015; Martin et al., 2015a). There is a need to 
ensure that HCV testing in prison is truly voluntary and 
not a result of coercion due to potentially unequal power 
relationships between prisoners and staff; and 
hepatitis C treatment should be offered alongside other 
harm reduction interventions (such as opioid 
substitution treatment) to reduce the risk of infection or 
reinfection.

I  Conclusions and implications

There is a strong theoretical basis for combining 
hepatitis C treatment with other primary prevention 
measures in order to reduce HCV transmission to 
negligible levels (so-called elimination). Although much 
of the modelling work has been done in a few countries, 
the scenarios reflect the situation in many European 
cities and, therefore, can be generalised. In most 
European cities and countries, after treating people with 
cirrhosis the next priority would be treating people who 
inject drugs — as greater benefit can be achieved by 
preventing secondary infections by treating people who 
inject drugs with mild and moderate disease than by 
delaying treatment until people develop cirrhosis or 
cease injecting. Furthermore, hepatitis C case-finding 
and treatment in prison could be a critical component of 
scaling up hepatitis C treatment in the community, 
although treatment in prison is likely to be cost-effective 
only with new oral direct-acting antiviral medicines and 
shorter (8–12 weeks) treatment durations. The model 
projections provide strong evidence for the hypothesis 
that hepatitis C treatment will reduce the prevalence of 
HCV infection and that treating people who inject drugs 
is cost-effective. Empirical data and evaluations of the 
impact of scaling up hepatitis C treatment among people 
who inject drugs in European settings are urgently 
needed.

67

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CHAPTER 4 I Hepatitis C prevention among people who inject drugs5

CHAPTER 5
Antiviral medications for hepatitis C 
virus infection
Jean-Michel Pawlotsky

I  Introduction

Traditional treatment of hepatitis C virus (HCV) with 
interferon and ribavirin could be effective, but these 
drugs were poorly tolerated and the duration of 
treatment was long (24–48 weeks). The definitive 
cure (3) of infection varied from under 20 % to 80 % in 
different patient groups and depending on HCV 
genotype (approximately 60 % overall). These factors 
have contributed to poor treatment uptake in the past 
decade. Now, however, the appearance on the market of 
new direct-acting antiviral drugs, which are effective 
against HCV, and the development of many others, is set 
to change the HCV treatment landscape in the coming 
years. The drugs currently available and those in 
development are reviewed in this chapter.

I  Available drugs

I  Pegylated interferon and ribavirin

For the past decade, HCV treatment has consisted of 
peginterferon and ribavirin. This treatment regimen was 
poorly tolerated and of long duration (24–48 weeks). 
Furthermore, sustained virological response rates were 
variable: approximately 45 % among those infected with 
HCV genotype 1, but 80 % in those with HCV genotype 2 
or 3 infection; among older patients with more severe 
disease and unfavourable genotype, the rate was below 
20 %. The burden of treatment was high: weekly 
interferon injections were accompanied by frequent 
surveillance and monitoring for potential side effects 
such as anaemia, depression and flu-like symptoms. 
These challenges have resulted in low treatment rates 
over the past decade, with treatment rates among those 

(3)  Definitive cure of infection is defined as the achievement of 
a sustained virological response (SVR), in which HCV RNA is 
undetectable in blood 12 weeks (SVR12) or 24 weeks (SVR24) after 
the end of therapy.

with chronic hepatitis C varying in most European 
countries between 1 % and 4 %; the highest rate was in 
France, at about 6 %.

Pegylated interferon-based treatments are now 
superseded in areas of the world that have access to 
oral-only interferon-free combinations, which are of 
shorter duration (8–24 weeks), highly tolerable and can 
achieve very high sustained virological response rates 
(> 90 %). Ribavirin remains a useful adjunct in some 
interferon-free treatment strategies, in which it is used to 
increase the sustained virological response rates, 
through mechanisms that are still to be elucidated.

I  Direct-acting antiviral drugs

Table 5.1 shows the direct-acting antiviral drugs that 
have been approved or are in clinical development at the 
time of writing (June 2016). Their antiviral effectiveness 
is high, but they differ in their activity against the 
different HCV genotypes (Smith et al., 2014) and in their 
barrier to resistance. Drugs are said to have a low barrier 
to resistance if their administration as a monotherapy 
rapidly selects fit resistant viral variants (Pawlotsky, 
2011). Such resistant variants are naturally present in 
infected individuals, generally but not always as minor 
undetectable populations, and can multiply rapidly, i.e. 
become selected, with the result that the drug quickly 
becomes ineffective. Drugs with a high barrier to 
resistance do not result in the selection of such variants, 
either because these variants do not naturally pre-exist 
in infected patients (a high genetic barrier) or because 
they are not fit enough to replicate at clinically 
meaningful levels if selected (Pawlotsky, 2011). 
Combining drugs from different classes is mandatory to 
raise the barrier to resistance of the combination 
regimen.

73

TABLE 5.1
Direct-acting antiviral drugs approved or in clinical development

Class

Generation/wave

Compound

Manufacturer

Current status or phase of clinical 
development (published or 
presented)

Nucleotide 
analogues

1st‑generation

Sofosbuvir

Gilead

Approved

MK‑3682

Merck

AL‑335

Janssen

Phase II

Phase II

NS5A inhibitors

1st‑generation 1st‑wave

Daclatasvir

Bristol‑Myers Squibb

Approved

Ledipasvir

Gilead

Approved

Ombitasvir

Abbvie

Approved

2nd‑wave Elbasvir

Merck

Approved (US, EU in 2016)

Velpatasvir

Gilead

Approved

Odalasvir

Janssen

Ravidasvir

Presidio

2nd‑generation

Pibrentasvir

Abbvie

MK‑8408

Merck

Phase II

Phase II

Phase III

Phase II

NS3‑4A protease 
inhibitors

1st‑generation 1st‑wave

Telaprevir

Janssen, Mitsubishi

Approved

Boceprevir

Merck

Approved

2nd‑wave Simeprevir

Janssen

Approved

Paritaprevir/r

Abbvie

Approved

Asunaprevir

Bristol‑Myers Squibb

Approved
(Asia, Middle East)

Vaniprevir

Merck

Approved (Japan)

2nd‑generation

Grazoprevir

Merck

Approved (US, EU in 2016)

Glecaprevir 

Abbvie

Voxilaprevir

Gilead

Phase III

Phase III

Non‑nucleoside 
inhibitors of HCV 
RdRp

Palm‑1 inhibitors

Dasabuvir

Abbvie

Approved

NB: ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, grazoprevir/elbasvir, velpatasvir/sofosbuvir, glecaprevir/pibrentasvir and possibly other 
compounds are or will be available as single-pill, fixed dose combinations; /r, ritonavir-boosted.

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Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 5 I Antiviral medications for hepatitis C virus infection

NS3-4A protease inhibitors

Nucleotide analogue inhibitors

NS3-4A protease inhibitors are peptidomimetic 
compounds that bind to the catalytic site of the enzyme 
NS3-4A protease and block post-translational 
processing of the viral polyprotein, preventing the 
release of functional non-structural proteins.

Two first-wave, first-generation NS3-4A protease 
inhibitors, telaprevir (Vertex, Janssen and Mitsubishi) 
and boceprevir (Merck) (Table 5.1), were approved in 
2011 for use in combination with peginterferon and 
ribavirin in patients infected with HCV genotype 1 
(Bacon et al., 2011; Jacobson et al., 2011; Poordad et al., 
2011; Zeuzem et al., 2011). They are active against 
genotype 1 (telaprevir is also active against genotype 2) 
and have a low barrier to resistance. These combinations 
are no longer used because of their poor tolerance.

Second-wave, first-generation NS3-4A protease 
inhibitors are administered once or twice per day. They 
are active against genotypes 1, 2 and 4 at least, but not 
against genotype 3. They have a low barrier to 
resistance, and cross-resistance among drugs in this 
group and with telaprevir and boceprevir is extensive. 
Simeprevir (Janssen) (Rosenquis et al., 2014) was 
approved in November 2013 in the United States and in 
May 2014 in the European Union for use in patients 
infected with HCV genotype 1. It is also active against 
HCV genotype 4. Asunaprevir (Bristol-Myers Squibb) 
(McPhee et al., 2012) was approved for use in 
combination with the NS5A inhibitor daclatasvir in July 
2014 for patients infected with HCV genotype 1b in 
several Asian countries. Paritaprevir (Abbvie) is boosted 
by ritonavir (100 mg/day) to extend dosing intervals 
while increasing patient exposure and reducing side 
effects; it was approved in 2015 in combination with the 
NS5A inhibitor ombitasvir in one single tablet, plus the 
non-nucleoside inhibitor of the RNA-dependent RNA 
polymerase (RdRp) dasabuvir as a different tablet 
(Table 5.1).

Second-generation NS3-4A protease inhibitors are 
purported to have pangenotypic antiviral activity. They 
have a higher barrier to resistance than first-generation 
drugs (Huang et al., 2010; Lahser et al., 2012), but they 
select resistant variants that are selected by 
first-generation compounds (Huang et al., 2010; Lahser 
et al., 2012). They include grazoprevir (Merck) (Summa et 
al., 2012), which will be available in combination with the 
NS5A inhibitor elbasvir in one single tablet in 2016, as 
well as voxilaprevir or GS-9857 (Gilead) and glecaprevir 
or ABT-493 (Abbvie), currently in Phase III clinical 
development (Table 5.1).

Nucleotide analogues act as false substrates for the 
HCV RNA-dependent RNA polymerase (RdRp). They lead 
to chain termination after being incorporated into the 
newly synthesised viral RNA. Activation of nucleotide 
analogues requires two phosphorylations. Owing to their 
mechanism of action, nucleotide analogues are active 
against all HCV genotypes. They have a high barrier to 
resistance, because the viral variants they select do not 
replicate at high levels. The nucleotide analogue 
sofosbuvir (Gilead) (Sofia et al., 2010) was approved in 
the United States in December 2013 and in the 
European Union in January 2014. Other nucleotide 
analogues in clinical development include MK-3682 
(Merck) and AL-335 (Janssen) (Table 5.1).

Non-nucleoside inhibitors of the HCV 
RNA-dependent RNA polymerase

Non-nucleoside inhibitors of HCV RdRp bind to one 
allosteric site at the surface of the enzyme (Haudecoeur 
et al., 2013). By altering the conformation of the RdRp, 
they block its catalytic function, thereby indirectly 
blocking RNA replication. Non-nucleoside HCV RdRp 
inhibitors are generally active mainly against HCV 
genotype 1 and have a low barrier to resistance. HCV 
RdRp is known to have a right-hand shape, with a thumb, 
a palm and finger domains. The palm I domain inhibitor 
dasabuvir has been approved in 2015 for use in 
combination with the ritonavir-boosted NS3-4A protease 
inhibitor paritaprevir and the NS5A inhibitor ombitasvir 
(Table 5.1).

NS5A inhibitors

NS5A inhibitors bind to domain 1 of the NS5A protein 
and block its ability to regulate HCV replication within 
the replication complex (Pawlotsky, 2013). In addition, 
NS5A inhibitors inhibit assembly and release of viral 
particles (Guedj et al., 2013; McGivern et al., 2014). This 
dual mechanism explains the potent and rapid shutdown 
of virus production during the first days of their 
administration. First-generation NS5A inhibitors have 
pangenotypic activity, except ledipasvir which has 
limited activity against genotypes 2 and 3. They have 
a low barrier to resistance (Pawlotsky, 2013). Daclatasvir 
(Bristol-Myers Squibb) (Gao et al., 2010) was approved 
in the European Union in September 2014 and in the 
United States in 2015. It has been used in combination 
with sofosbuvir in many European early access 
programmes for different genotypes and this 
combination currently is the standard-of-care for 

75

patients with HCV genotype 3 infection. Ledipasvir 
(Gilead) (Link et al., 2014) was approved at the end of 
2014 as a single tablet regimen in combination with 
sofosbuvir for genotypes 1, 4, 5 and 6, while ombitasvir 
(Abbvie) (Degoey et al., 2014) was approved within the 
same timeframe for use in combination with 
ritonavir-boosted paritaprevir (one single tablet) with or 
without dasabuvir for genotypes 1 and 4, respectively 
(Table 5.1).

Second-wave, second-generation NS5A inhibitors have 
pangenotypic activity. Their barrier to resistance is 
slightly higher than that of first-generation NS5A 
inhibitors (Lahser et al., 2012), but they select resistant 
viruses that are also selected by first-generation 
compounds. They include elbasvir (Merck), which will be 
available in combination with grazoprevir in one single 
tablet (Coburn et al., 2013), velpatasvir (Gilead), which 
will be available in combination with sofosbuvir in one 
single tablet, odalasvir (Janssen) and ravidasvir 
(Presidio) (Yang et al., 2012).

Second-generation NS5A inhibitors should have 
a substantially improved barrier to resistance compared 
to first-generation drugs. They include pibrentasvir or 
ABT-530 (Abbvie), which will be available in combination 
with glecaprevir in one single tablet, and MK-8408 
(Merck) (Table 5.1).

I   Current HCV treatment regimens 

(2016)

Three new direct-acting antiviral drugs for the treatment 
of HCV infection were approved as single agents in 2014 
and 2015 in the United States and Europe, sofosbuvir, 
simeprevir and daclatasvir. The fixed-dose combination of 
sofosbuvir and ledipasvir in one single pill was approved 
in early 2015, as well as the combination of 
ritonavir-boosted paritaprevir and ombitasvir in one single 
pill with or without dasabuvir according to the genotype. 
The combination of grazoprevir and elbasvir was approved 
in late 2015 in the United States and will be approved in 
mid-2016 in Europe, the combination of sofosbuvir and 
velpatasvir was approved in 2016 on both continents. This 
offers a number of options for interferon-free combination 
therapy. Interferon-free options include: sofosbuvir plus 
ribavirin (genotype 2); sofosbuvir plus simeprevir, with or 
without ribavirin (genotypes 1 and 4); sofosbuvir plus 
daclatasvir, with or without ribavirin (all genotypes); 
sofosbuvir-ledipasvir, with or without ribavirin 
(genotypes 1, 4, 5 and 6); ritonavir-boosted paritaprevir 
and ombitasvir plus dasabuvir, with or without ribavirin 

(genotype 1); ritonavir-boosted paritaprevir and 
ombitasvir, with ribavirin (genotype 4); 
grazoprevir-elbasvir, with or without ribavirin (genotypes 1 
and 4). Sofosbuvir-velpatasvir, with or without ribavirin 
(all genotypes). Peginterferon and ribavirin-based 
regimens should be used only when interferon-free 
regimens are not available.

Sofosbuvir plus ribavirin

This combination is indicated in patients infected with 
HCV genotypes 2 and 3. However, it is suboptimal in 
genotype 3 and other options should be preferred. In 
FISSION (Lawitz et al., 2013b), sofosbuvir plus ribavirin 
treatment for 12 weeks in treatment-naive patients 
yielded sustained virological response rates of 95 % in 
patients infected with HCV genotype 2 (Lawitz et al., 
2013b). In POSITRON, 93 % of patients with genotype 2 
infection who were ineligible for or intolerant to 
interferon-based therapy achieved a sustained 
virological response after 12 weeks of therapy 
(Jacobson et al., 2013b). In FUSION, the sustained 
virological response rate after 12 or 16 weeks of 
treatment was 82 % and 89 %, respectively, among 
patients infected with HCV genotype 2 (Jacobson et al., 
2013b). Finally, in the VALENCE trial, participants 
infected with HCV genotype 2 were treated with 
combined sofosbuvir plus ribavirin for 12 weeks. 
The sustained virological response rate was 97 % in 
treatment-naive patients without cirrhosis, 100 % in 
treatment-naive patients with cirrhosis, 91 % in 
treatment-experienced patients without cirrhosis and 
88 % in treatment-experienced patients with cirrhosis 
(Zeuzem et al., 2014a). The combination of sofosbuvir 
and ribavirin was well tolerated.

Sofosbuvir plus simeprevir

In the phase II COSMOS trial of sofosbuvir plus simeprevir, 
the first cohort of participants comprised patients with 
mild to moderate fibrosis (grades 0–2) according to the 
METAVIR system, who had previously failed to respond to 
treatment. Among this group, the sustained virological 
response rate after 24 weeks was 79 % among those who 
did not receive concomitant ribavirin and 93 % among 
those who did. The corresponding rates after 12 weeks’ 
treatment were 96 % and 93 %. In the second cohort, 
comprising patients with more severe fibrosis (grade 3 or 
4), the sustained virological response rate at week 4 was 
100 % among treatment-naive patients, with or without 
concomitant ribavirin; among those who had previously 
failed to respond to treatment the sustained virological 
response was 100 % in those also receiving ribavirin and 

76

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 5 I Antiviral medications for hepatitis C virus infection

93 % in those who did not receive it (Jacobson et al., 
2013c). Three patients who failed to achieve a sustained 
virological response were infected with HCV genotype 1a 
and had a detectable Q80K substitution in the NS3 
protease sequence at baseline; however, infection was 
eliminated in the majority of such patients with this 
regimen. The combination was well tolerated (Jacobson et 
al., 2013c). These results were confirmed in two Phase III 
studies in patients with genotype 1. In OPTIMIST-1, in 
non-cirrhotic patients 12 weeks of sofosbuvir and 
simeprevir yielded sustained virological response rates of 
97 % and 95 % in treatment-naive and treatment 
experienced patients, respectively (Kwo et al., 2016) In 
OPTIMIST-2, in treatment-naive patients with cirrhosis, the 
rate of cure of infection with sofosbuvir and simeprevir 
was 88 % overall, 84 % in patients with genotype 1b 
infection, 92 % in those with genotype 1a without Q80K, 
and 74 % in those with genotype 1a with Q80K (Lawitz et 
al., 2016). Recent real-world data indicate that the 
combination of sofosbuvir and simeprevir is less 
efficacious than other sofosbuvir-based combinations.

Sofosbuvir plus daclatasvir

Sulkowski et al. (2014) assessed 24 weeks’ treatment 
with a combination of sofosbuvir and daclatasvir, with or 
without ribavirin, in treatment-naive patients and 
patients who had previously failed to respond to 
a combination of pegylated interferon, ribavirin and 
either telaprevir or boceprevir. In the treatment-naive 
group, the sustained virological response rate among 
those infected with HCV genotype 1 was 100 % with or 

without ribavirin and among those infected with 
genotypes 2 or 3 was 100 % with ribavirin and 93 % 
without ribavirin. The corresponding rates in the group of 
previous non-responders were 100 % and 95 %, 
respectively. Forty of the 41 treatment-naive patients 
infected with HCV genotype 1 treated with sofosbuvir 
and daclatasvir without ribavirin had achieved an SVR by 
12 weeks (the remaining patient was lost to follow-up) 
(Sulkowski et al., 2014). This drug combination was well 
tolerated. The efficacy of this regimen has been 
confirmed in patients with genotype 1 with various 
severities of liver disease, including in decompensated 
cirrhosis and in the post-transplant setting, both in 
clinical trials and in real-world studies.

The use of sofosbuvir and daclatasvir as first-line 
treatment for patients infected with genotype 3 is 
supported by two Phase III studies. In ALLY-3, with 
sofosbuvir and daclatasvir, 12 weeks in non-cirrhotic 
patients, the rates of sustained virological response were 
97 % and 94 % in treatment-naive and 
treatment-experienced patients, respectively (Nelson et 
al., 2015). In ALLY-3+, 83 % and 89 % of cirrhotic patients 
responded to 12 and 16 weeks of sofosbuvir and 
daclatasvir with ribavirin, respectively. No data is available 
with 24 weeks with this regimen (Leroy et al., 2016).

Sofosbuvir plus ledipasvir

The results of three phase III trials of treatment-naive and 
treatment-experienced patients infected with HCV 
genotype 1 who received the combination of sofosbuvir 

TABLE 5.2
Rates of sustained virological response at 12 weeks (SVR12) in the ION-1, ION-2 and ION-3 phase III trials in 
patients infected with HCV genotype 1 treated for 8–12 weeks with a fixed-dose combination of sofosbuvir and 
ledipasvir, with or without ribavirin (Afdhal et al., 2014a,b; Kowdley et al., 2014)

Phase III trial

Patient population

Treatment duration 
(weeks)

Ribavirin

SVR12

ION‑1

Treatment naive 

ION‑3

Treatment naive 

ION‑2

Treatment experienced

12 

24 

8 

12 

12 

24 

NB: Proportion of participants with cirrhosis: ION-1, 16 %; ION-2, 20 %; ION-3, 0 %.

No

Yes

No

Yes

No

Yes

No

No

Yes

No

Yes

98 % (209/214)

97 % (211/217)

98 % (213/217)

99 % (215/217)

94 % (202/215)

93 % (201/216)

95 % (206/216)

94 % (102/109)

96 % (107/111)

99 % (108/109)

99 % (110/111)

77

and ledipasvir in a fixed-dose combination (i.e. a single 
pill containing both drugs) were reported (Table 5.2) 
(Afdhal et al., 2014a,b; Kowdley et al., 2014).

In ION-1, in treatment-naive patients, the sustained 
virological response rate after 12 weeks of treatment 
was 98 % and 97 % with or without ribavirin, respectively, 
and 99 % and 98 %, respectively, after 24 weeks of 
treatment (Afdhal et al., 2014a).

recurrence after liver transplantation (96 % in patients 
without cirrhosis and in those with compensated liver 
disease, 85 % in those with Child-Pugh B and 60 % in 
those with Child-Pugh C decompensated cirrhosis) 
(Charlton et al., 2015).

The safety and efficacy of the sofosbuvir–ledipasvir 
combination was confirmed in a large number of 
large-scale real-world studies.

In ION-3, in treatment-naive patients with mild to 
moderate liver disease (fibrosis grade 0–2), the 
sustained virological response rate among those 
receiving 8 weeks’ treatment was 94 % without ribavirin 
and 93 % with ribavirin; among those treated for 
12 weeks with combined sofosbuvir plus ledipasvir but 
without ribavirin the sustained virological response was 
95 % (Kowdley et al., 2014).

In ION-2, treatment-experienced patients were treated 
for 12 or 24 weeks with sofosbuvir plus ledipasvir with or 
without ribavirin. After 12 weeks of therapy, the sustained 
virological response rate was 94 % with and 96 % without 
ribavirin. After 24 weeks of therapy, the corresponding 
rates were 99 % and 99 %, respectively (Afdhal et al., 
2014b). No major safety signal was reported.

I   Ritonavir-boosted paritaprevir and ombitasvir 

plus dasabuvir

The results of six phase III clinical trials of 
ritonavir-boosted paritaprevir co-formulated with 
ombitasvir and dasabuvir have recently been reported. 
Patients with HCV genotype 1 infection, with and 
without cirrhosis, received the combination with or 
without ribavirin for 12 or 24 weeks. The results are 
summarised in Table 5.3.

In SAPPHIRE-I, treatment-naive patients without 
cirrhosis were treated for 12 weeks with the combination 
plus ribavirin. The sustained virological response rate 
was 95 % in those infected with subtype 1a and 98 % in 
those infected with subtype 1b (Feld et al., 2014).

With 12 weeks of sofosbuvir and ledipasvir with ribavirin, 
high rates of sustained virological response (85–90 %) 
were also reported in patients with Child-Pugh B or 
C decompensated cirrhosis, and in patients with an HCV 

In PEARL-IV, participants infected with HCV subtype 1a 
were treated with combined ritonavir-boosted 
paritaprevir plus ombitasvir plus dasabuvir with or 

TABLE 5.3
Rates of sustained virological response at 12 weeks (SVR12) in the SAPPHIRE-I, SAPPHIRE-II, PEARL-II, PEARL-III, 
PEARL-IV and TURQUOISE-II phase III trials in patients infected with HCV genotype 1 treated for 12 or 24 weeks 
with ritonavir-boosted paritaprevir co-formulated with ombitasvir and dasabuvir with or without weight-based 
ribavirin (Feld et al., 2014; Ferenci et al., 2014; Poordad et al., 2014; Zeuzem et al., 2014b)

Phase III trial

Patient population

Previous treatment Cirrhosis

Treatment 
duration 
(weeks)

HCV subtype

Ribavirin

SVR12

SAPPHIRE‑I

Treatment naive

No

PEARL‑IV

Treatment naive 

No

PEARL‑III

Treatment naive 

No

SAPPHIRE‑II

PEARL‑II

Treatment 
experienced 

Treatment 
experienced

TURQUOISE‑II

Mixed

No

No

Yes

12 

12 

12 

12 

12 

12 

24 

1a

1b

1a

1b

1a

1b

1b

Mixed

Yes

Yes

No

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

95 % (307/322)

98 % (148/151)

90 % (185/205)

97 % (97/100)

99 % (209/210)

99 % (207/209)

96 % (166/173)

97 % (119/123)

100 % (91/91)

97 % (85/88)

92 % (191/208)

96 % (165/172)

78

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 5 I Antiviral medications for hepatitis C virus infection

I  Conclusion

The treatment of HCV infection has changed 
dramatically from 2014–2015. All-oral, interferon-free 
regimens now prevail. Global control of infection has 
been set as a reasonable objective for 2020–2030 by 
many countries. As the number of options increases, it 
can only be hoped that drug prices will decrease and 
that access to therapy will be provided to all those in 
need.

I  Conflict of interest disclosure

The author has received research grants from Gilead 
Sciences. He has served as an advisor for Abbvie, 
Bristol-Myers Squibb, Gilead Sciences, Janssen and 
Merck.

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I  Future HCV treatment regimens

Future treatment regimens will include 
second-generation drugs belonging to the same classes, 
i.e. drugs with improved intrinsic performance, in 
particular a higher barrier to resistance, and/or triple 
combination of drugs from different classes. The 
combinations of grazoprevir and elbasvir and of 
sofosbuvir and velpatasvir will be available in the 
European Union by the end of 2016. Looking further 
ahead, regimens in advanced stages of development 
include the combination of glecaprevir and pibrentasvir 
in one single tablet and the combination of sofosbuvir, 
velpatasvir and voxilaprevir, currently in Phase III clinical 
evaluation.

79

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81

6

CHAPTER 6
Scaling up hepatitis C treatment: 
taking into account the needs and 
perspectives of people who inject 
drugs
Magdalena Harris and Tim Rhodes

I  Introduction

The landscape of hepatitis C (HCV) treatment is 
changing. The promise of interferon-sparing or 
interferon-free regimes, accompanied by moves to 
integrate HCV treatment into community settings and 
clinical guidance promoting relaxed eligibility criteria 
(Alavi et al., 2013; EASL, 2014), holds the potential to 
break down current barriers to HCV treatment access 
and uptake for people who inject drugs. Research 
exploring the HCV treatment perspectives of people who 
inject drugs has found that concerns about side effects, 
limited knowledge of HCV, worries that treatment will be 
rationed, experiences of treatment refusal owing to drug 
use, competing priorities, stigma, criminalisation and 
difficult-to-access services pose significant hurdles to 
HCV treatment contemplation, access and uptake (Doab 
et al., 2005; Grebely et al., 2008; Harris and Rhodes 
2013; Rhodes et al., 2013; Swan et al., 2010; Treloar et 
al., 2013; WHO Regional Office for Europe, 2012). While 
changes in the HCV treatment landscape can have 
a positive impact on some of these issues, there is 
a need for a concomitant enabling environment 
interventions informed by the needs and perspectives of 
people who inject drugs. In this chapter, we draw on 
recent qualitative research carried out at the London 
School of Tropical Medicine and Hygiene (see box) 
among people who inject drugs to illustrate three 
components of enabling interventions and their role in 
facilitating HCV treatment engagement, initiation and 
access.

We consider three key themes or enabling environments 
in order to address health inequities and inequalities in 
HCV treatment access and to promote and increase 
uptake of HCV treatment among people who inject 
drugs.

I   Enabling living environments: 

facilitating engagement

For many people who inject drugs HCV is seen as 
a long-term concern, something that may be viewed as 
of lower priority than more immediate short-term issues, 
such as acute health problems, homelessness, 
incarceration and poverty (Harris and Rhodes, 2013; 
Rhodes and Treloar, 2008). Services that have the 
capacity to address these immediate concerns can 
provide a space for HCV treatment contemplation. Here 
we consider the example of accommodation. Rufus and 
George, both long-term homeless, spoke of the role of 
individual providers as ‘access points’ in helping them to 
secure housing. Having a stable place to live was 
experienced as transformative, facilitating a change in 
priorities and leading to HCV treatment contemplation 
and commencement. As Rufus says:

It’s just the feeling of security, I’ve never had that feeling 

of security... It changes everything absolutely, it gives 

you a base you can build on... it gives me the ability to 

think long term as well which is things like coming for 

treatment, sorting my treatment out, sorting out my 

methadone treatment and sorting out my hepatitis 

C treatment... [having a flat] made me feel a lot better 

about everything.

While some community-based services in the United 
Kingdom will facilitate HCV treatment for people who are 
homeless, study participants rarely felt that this was the 
right time for them. As George says:

Then I got the flat... I’m settled now, we talked about it 

[HCV treatment] while I was on the streets but I didn’t 

want to do it then, I didn’t think it would be the right way 

to go about it, being on the streets and all that.

83

Being made homeless can also undo HCV treatment 
possibility. When Alec was first interviewed, he was 
preparing to start HCV treatment. At the second 
interview, some 6 months later, he was yet to start — 
speaking of the havoc wrought in his life by losing his 
accommodation:

I was made street homeless in July … I had to go to 

hospital. I had twenty admissions for being drunk and 

I got really ill … I had to drink just to cope with my 

situation, it was really bad.

Although the advent of interferon-sparing or 
interferon-free regimes with a favourable side-effect 
profile might increase treatment possibility for people 
who are homeless, the contingencies of managing life on 
the streets means that HCV treatment is unlikely to be of 
high priority.

Access to low-threshold opioid substitution treatment — 
as with the provision of stable accommodation — can 
facilitate HCV contemplation and completion. The 
mechanisms of opioid substitution treatment provision 
are important in this regard, with takeaway dose 
provision facilitating expressions of trust, self-worth and 
treatment engagement (Harris et al., 2013). As Jeff says:

I get it [methadone] weekly, I’ve been trusted for a long 

time... The hepatitis [treatment], the last thing you want 

is to run out to the chemist and get your medicine and 

come back... it is a great help having it there.

Conversely, Hakki — on supervised consumption — 
feels untrusted/unworthy and is loath to engage:

I’ve been on the [methadone] script for about 8 months 

now and they still supervise. I don’t know what they think 

I’m going to do... I’m too angry with the system at the 

moment. I don’t really engage... why don’t they trust me?

Qualitative studies on hepatitis C 
treatment

This paper draws on qualitative data from two 
studies carried out at the London School of 
Hygiene and Tropical Medicine.

The ‘Hepatitis C treatment journey study’ (2012–
2016) is a qualitative longitudinal prospective 
study exploring the HCV treatment journey and 
needed supports from patient, provider and 
system perspectives. Data collection was 
primarily carried out at two London HCV 
treatment hospitals and one drug treatment 
service and comprised 100 hours of nurse‑led 
HCV clinic observations and 92 in‑depth 
interviews with 28 people living with HCV, 10 
treatment providers and 8 stakeholders. The study 
is funded by the National Institute for Health 
Research (NIHR‑PDF‑2011‑04‑031).

The ‘Barriers and facilitators to hepatitis 
C treatment for people who inject drugs: 
a qualitative study’ (2011) explored the individual, 
social and structural factors shaping the 
accessibility and quality of HCV service delivery to 
people who inject drugs. Data collection was 
carried out at two London drug treatment 
services and comprised in‑depth interviews with 
35 people living with hepatitis C and 14 service 
providers. The study was funded by the European 
Commission Directorate of Health and 
Consumers, the World Health Organization 
Regional Office for Europe and the National 
Institute for Health Research.

I   Enabling treatment environments: 

facilitating initiation

Enabling living environments can assist HCV treatment 
contemplation; yet this is unlikely to translate into uptake 
and completion if treatment systems are difficult to 
access and engage with. Traditional hospital-based 
treatment poses a number of barriers to access and 
uptake, with high attrition rates between referral and 
specialist appointment documented among people who 
inject drugs (Knight, 2013). Reasons for people who 
inject drugs becoming disillusioned with or giving up on 

HCV treatment include the lengthy period between 
referral and first specialist appointment; multiple 
hospital appointment requirements to assess treatment 
‘readiness’; being refused treatment because of 
substance use; stressful and discriminatory encounters 
with service providers; missing postal reminders as 
a consequence of housing instability; missing rigid 
appointment slots because of life contingencies; and 
being discharged from the system as a result of ‘do not 
attend’ policies (WHO Regional Office for Europe, 2012; 
Rhodes et al., 2013).

Community-based treatment, such as that based in drug 
and alcohol settings, is well placed to overcome some of 
these barriers to access. This is particularly the case if 

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Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 6 I Scaling up hepatitis C treatment

trusting relationships are able to be facilitated with 
providers and holistic care is offered in a ‘one-stop-shop’ 
format (Birkhead et al., 2007; Harris et al., 2013; WHO 
Regional Office for Europe, 2012). Continuity of care was 
considered to be important, with some participants 
expressing frustration at high staff turnover and the 
difficulty of fully engaging in such circumstances:

Such experiences can act to perpetuate mistrust and 
facilitate disengagement. The provision of on-site 
phlebotomy service, where blood is taken as part of 
a collaborative process, with protocols in place for 
jugular, femoral and client self-access, can assist the 
development of trusting relationships and HCV 
treatment engagement (Alavi et al., 2013).

I didn’t feel that where I was with this key worker, I wasn’t 

100 % secure with him... I just didn’t have a real 

connection with anyone up there … I think it’s pretty 

invasive sort of treatment, you go through quite a lot of 

crap … it helps a lot to be able to talk to someone 

properly. (Davey)

Although people who inject drugs might have an 
ambivalent relationship with drug and alcohol services, 
their familiarity and convenience can encourage 
treatment engagement. As Davey also says, ‘it [D&A 
service] was a familiar place to us and that’s what made 
us think, I’ll come back and I’ll try it [HCV treatment]’. Jeff 
speaks of the convenience of seeing two providers under 
the same roof:

I   Enabling policy environments: 

facilitating access

Clinical guidelines at a UK and European level 
recommend that current injecting by itself is not 
a contraindication to HCV treatment access (NICE, 
2004; EASL, 2014). Yet, in the United Kingdom, where 
these guidelines have been in place since 2004, 
eligibility criteria are unevenly deployed. A 2010 UK audit 
of hospitals delivering HCV services found that one in 
seven hospitals refuses NICE-approved treatment to all 
people who inject drugs (All-Party Parliamentary 
Hepatology Group, 2010). As Shane reports:

When I came in [it is] like killing two birds with one stone. 

When I came in on my fortnight thingy, I’ d see my key 

I think their exact words were ‘it’s an expensive drug, 

worker [and] I’ d always see [HCV nurse]. So I’ d deal with 

you’re using on top and we’re not treating people who 

that and then I’ d deal with that at the same time.

are using, because you could get re‑infected couldn’t 

you?’

Drug and alcohol services are often more amenable to 
modification than hospitals, particularly in regard to the 
creation of responsive, flexible treatment systems. 
Appointment and phlebotomy systems are two 
examples. Flexible appointment systems, comprising 
open slots and no do not attend policy, allow for the 
contingencies of people who inject drugs’ daily lives and 
encourage access. James explains:

[Flexibility is important] because sometimes you don’t 

know how you are going to be feeling... you get your ups 

Experiences of, and circulation of narratives about, 
treatment refusal contribute to institutional mistrust and 
diminished treatment expectation among people who 
inject drugs. Although current innovations in HCV 
treatments bring to mind early developments in the 
treatment of human immunodeficiency virus (HIV), 
related activism and expectation among the primary 
affected communities differs considerably — reflected in 
the comment below:

and your downs, it’s a tackle each day really. You’ve got 

They [people who inject drugs] have such low 

bad drug habits, drink habits, depression.

self‑esteem, they won’t make a fuss, and they really 

Many people who inject drugs have difficult venous 
access and can find phlebotomy procedures stressful 
and stigmatising. This is particularly the case in 
environments where phlebotomists are restricted to the 
venous sites they can access, and are reluctant to 
acknowledge the expertise of people who inject drugs in 
this process. As Dillon relates:

don’t jump up and down. The idea that tranches of 

people with haemophilia could not be offered hepatitis 

C treatment because it was inconvenient or something, 

it’s just an extraordinary concept and they would make 

a huge fuss, but the drug users just accept that they’re 

not worth it and they won’t go there. (Hepatology 

consultant)

I kept on saying to [hospital phlebotomist], ‘Look, you 

know, my veins are a nightmare, you know, let me do it’. 

[She said] ‘Oh you people, you think you know about 

your veins and all that, when you know nothing’.

A feeling of being undeserving of treatment is 
unsurprising given the circumstances of many people 
who inject drugs — subject to criminalisation, stigma 
and pervasive societal narratives about their ‘worth’. Bibi 
speaks of institutional mind-sets as: ‘Ah, a drug addict, 

85

she’s inferior and somehow deserves it [illness]’. This 
casts care as a privilege: ‘I can help you, but now you 
have to be grateful!’. As Rhodes et al. (2013) write: 
‘gratitude speaks to powerlessness; an inclusion by 
exception rather than expectation’.

Changes in drug regimens are unlikely to affect 
perceptions of treatment deservedness unless the 
resources for meaningful peer involvement and 
advocacy at all stages of the HCV treatment journey are 
also provided. Training peers to support HCV treatment 
provision and employing them in HCV treatment services 
sends powerful messages regarding trust and worth — 
not only to the individuals involved, but to the larger 
community. Trained peers are uniquely placed to 
advocate for the rights of people who inject drugs and 
provide support at all stages of the HCV treatment 
journey. Alec speaks of the unmet need for this input at 
his service:

It would be really good to have someone sit down with 

you and talk to you, you know, just in a peer mentoring 

way, that would be great for anyone … it could be 

someone like, who’s been through the treatment 

themselves, who can connect on a different level.

Peer-involved and peer-led services can help to engage 
those who are reluctant to draw on traditional services. 
This is particularly pertinent for women who use drugs, 
for whom stigma, criminalisation and attendant fear of 
child removal create additional barriers to access. Abby, 
whose children were permanently removed by social 
services, remarks:

They [women] suffer in silence, they just buy it 

[methadone] on the street... do what they can to survive. 

And then there’s the fear if they’ve got kids. That’s one of 

the big issues, it’s their kids.

I  Conclusion

Current innovations in hepatitis C treatment are 
reflected in a discourse of hope and expectation, with 
references to ‘viral elimination’ increasingly noted in 
policy and academic literature (Watts, 2014; Grebely, 
2013). This sense of hope and expectation is not, 
however, reflected in the narratives of many people who 
inject drugs. Drug user activists and commentators 
drawing on the ‘HIV treatment as prevention’ experience 
have expressed concern that an increased impetus on 
hepatitis C ‘treatment as prevention’ might threaten 
harm reduction ‘prevention as prevention’ initiatives 
such as opioid substitution treatment and needle and 

syringe programmes (Australian Injecting and Illicit Drug 
Users League, 2014; Harris et al., 2015; Lazarus et al., 
2014). These harm reduction initiatives are already 
fragile: politically unpopular, under-resourced and, in 
some countries, such as the United Kingdom, 
increasingly undermined by a ‘recovery agenda’ that 
prioritises abstinence (Home Office, 2010). In many 
countries in Europe the situation is more acute, 
particularly in Eastern Europe and Eurasia, where 
interventions such as opioid substitution treatment can 
be limited or prohibited.

In order for these fears to be allayed and HCV treatment 
access to become an entitlement rather than an 
exception for people who inject drugs, there is a need for 
supportive and enabling environment, treatment and 
policy interventions to sit alongside drug development. 
While interferon-sparing or interferon-free regimes 
promise more efficacious treatment with a limited 
side-effect profile, it is important that this does not lead 
to complacency regarding uptake. Social structural 
issues including criminalisation, stigma, homelessness 
and inflexible service provision are likely to continue to 
impede treatment contemplation and access, however 
efficacious the treatment (Harris and Rhodes, 2013). 
Although a complete overhaul of drug policy will not be 
realisable in the short term, there is a fundamental need 
for enabling community interventions with meaningful 
peer involvement in HCV treatment service provision and 
advocacy. This can aid an investment in and ‘owning’ of 
the virus and its treatment by community groups, such 
as seen in the early days of HIV activism. Continued 
investment in, and scaling up of, harm reduction 
interventions such as opioid substitution treatment and 
needle and syringe programmes is not only an important 
support for people who inject drugs, but necessary if 
‘HCV elimination’ is ever to become a reality.

Integrated services that are flexible and responsive to 
the needs of people who inject drugs are key to 
encouraging HCV treatment access, uptake and 
completion — particularly in the context of limited 
community mobilisation. Help with pressing concerns, 
such as acute health care, can facilitate treatment 
contemplation. Trust in at least one provider — aided by 
continuity of care — can facilitate HCV treatment 
engagement. Community provision of HCV testing and 
treatment, under the same roof as housing, benefit and 
primary health support, can facilitate access. This ideally 
would involve visits by a local hepatologist to the 
community setting for initial assessment appointments, 
with the remainder of care being nurse-led. 
Developments in HCV pharmaceuticals might see 
treatment provision diversified — available at 
pharmacies and in other community-based settings. 

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Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 6 I Scaling up hepatitis C treatment

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

future requirements’, Clinical Infectious Diseases 57, 

 pp. 1014–1020.

 Harris, M. and Rhodes, T. (2013), ‘Hepatitis C treatment 

access and uptake for people who inject drugs: a review 

mapping the role of social factors’, Harm Reduction Journal 

10(7), doi:10.1186/1477-7517-10-7.

 Harris, M., Martin, A. and Rhodes, T. (2013), ‘Taming systems 

to create enabling environments for HCV treatment: 

Negotiating trust in the drug and alcohol setting’, Social 

Science & Medicine 83, pp. 19–26.

 Harris, M., Albers, E. and Swan, T. (2015), ‘The promise of HCV 

treatment as prevention: Meeting the needs of people who 

inject drugs?’, International Journal of Drug Policy.  

26(10):963-9.

 Home Office (2010), Drug strategy 2010. Reducing demand, 

restricting supply, building recovery: Supporting people to live 

a drug free life, Home Office, London.

 Knight, A. (2013), Public Health report on commissioning of 

HCV services in London for people who inject drugs, London 

Joint Working Group for Substance Use and Hepatitis C, 

London.

 Lazarus, J. V., Lundgren, J., Casabona, J., et al. (2014), 

‘Roundtable: hepatitis and HIV’, BMC Infectious Diseases 14 

(Suppl. 6), p. S18.

 NICE (2004), Interferon alfa (pegylated and non‑pegylated) 

and ribavirin for the treatment of chronic hepatitis C, National 

Institute for Clinical Excellence, Manchester.

 Rhodes, T. and Treloar, C. (2008), ‘The social production of 

hepatitis C risk among injecting drug users: a qualitative 

synthesis’, Addiction 103, pp. 1593–1603.

 Rhodes, T., Harris, M. and Martin, A. (2013), ‘Negotiating 

access to medical treatment and the making of patient 

citizenship: the case of hepatitis C treatment’, Sociology of 

Health & Illness 35, pp. 1023–1044.

 Swan, D., Long, J., Carr, O., et al. (2010), ‘Barriers to and 

facilitators of hepatitis C testing, management, and treatment 

among current and former injecting drug users: a qualitative 

exploration’, AIDS Patient Care and STDs, 24, pp. 753–762.

 Treloar, C., Rance, J. and Backmund, M. (2013), 

‘Understanding barriers to hepatitis C virus care and 

stigmatization from a social perspective’, Clinical Infectious 

Diseases 57 (Suppl. 2), pp. S51–S55.

 Watts, G. (2014), ‘Hepatitis C could be virtually eliminated by 

2030, experts believe’, BMJ 348, 348:g2700.

 WHO (World Health Organization) Regional Office for Europe 

(2012), Barriers and facilitators to hepatitis C treatment for 

people who inject drugs: a qualitative study, WHO Regional 

Office for Europe, Copenhagen.

Service providers that are able to provide a broad range 
of services for people who inject drugs, such as harm 
reduction and acute health care, are particularly well 
placed to introduce information and access to HCV 
testing and treatment. Not all people who inject drugs, 
however, feel safe to access services where they may be 
identified as a drug user. This has ramifications not only 
for HCV treatment uptake, but also for harm reduction 
and acute health care access, and it is here that there is 
the greatest need for enabling environment 
interventions.

I  Acknowledgements

The authors thank all study participants. Magdalena 
Harris is funded by an NIHR Post-Doctoral Fellowship 
(NIHR-PDF-2011-04-031).

I  References
I 

 Alavi, M., Grebely J., Micallef, M., et al. (2013), ‘Assessment 

and treatment of hepatitis C virus infection among people who 

inject drugs in the opioid substitution setting: ETHOS study’, 

Clinical Infectious Diseases 57 (Suppl. 2), pp. S62–S69.

 All-Party Parliamentary Hepatology Group (2010), In the dark: 

an audit of hospital hepatitis C services across England, 

All-Party Parliamentary Hepatology Group, London.

 Australian Injecting and Illicit Drug Users League (2014), 

Treatment as prevention? What does the future hold for 

injecting drug users?, World Hepatitis Day webinar  

(https://www.youtube.com/watch?v=1rDtr5i3-

Gk&list=UUML7PAmnLeBNsWTW-Jmiukg).

 Birkhead, G. S., Klein S. J., Candelas, A. R., et al. (2007), 

‘Integrating multiple programme and policy approaches to 

hepatitis C prevention and care for injection drug users: 

a comprehensive approach’, International Journal of Drug 

Policy 18, pp. 417–425.

 Doab, A., Treloar, C. and Dore, G. J. (2005), ‘Knowledge and 

attitudes about treatment for hepatitis C virus infection and 

barriers to treatment among current injection drug users in 

Australia’, Clinical Infectious Diseases 40, pp. S313–S320.

 EASL (2014), EASL recommendations on treatment of 

hepatitis C 2014, European Association for the Study of the 

Liver, Geneva.

 Grebely, J., Genoway, K. A., Raffa, J. D., et al. (2008), ‘Barriers 

associated with the treatment of hepatitis C virus infection 

among illicit drug users’, Drug and Alcohol Dependence 93, 

pp. 141–147.

 Grebely, J., Matthews, G. V., Lloyd, A. R. and Dore, G. D. (2013), 

‘Elimination of hepatitis C virus infection among people who 

inject drugs through treatment as prevention: feasibility and 

I 

I 

I 

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I 

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7

CHAPTER 7
A framework for evaluating scale‑up 
of hepatitis C virus treatment 
as prevention for people who 
inject drugs
Daniela De Angelis, Matthew Hickman, Peter Vickerman and  
Sharon Hutchinson

The availability of new, highly effective, interferon-free 
direct-acting antiviral drugs has refocused the attention 
on treatment strategies to reduce the burden of liver 
disease associated with infection with hepatitis C virus 
(HCV).

In principle, there are two possible strategies to achieve 
this goal. The first is to concentrate on the treatment of 
infected individuals at the initial stages of severe liver 
disease, for example those with METAVIR liver fibrosis 
stage F3 (no sign of cirrhosis) or stage F4 (cirrhosis), 
with the aim of slowing progression and preventing 
serious morbidity. The second strategy, which we 
consider here, is to use treatment as a prevention tool. 
By inducing a reduction in infectiousness in key risk 
groups, primarily people who inject drugs, treatment 
leads to a reduction in HCV transmission, an eventual 
decrease in advanced disease and, importantly, potential 
control of the HCV epidemic.

I   Evaluation of HCV treatment as 

a prevention tool

Results from a number of mathematical modelling 
papers (e.g. Martin et al., 2011, 2013a,b, 2015; Innes et 
al., 2014; and others cited in Chapter 4) have raised the 
expectation that a moderate level of HCV treatment 
among people who inject drugs could lead to 
a significant reduction in the prevalence and incidence 
of HCV infection. It is hypothesised that an HCV 
treatment strategy would be especially effective if 
provided in combination with other primary 
interventions, such as opioid substitution treatment and 
needle and syringe programmes, by reducing the risk of 

spread by removing individuals who have been 
successfully treated from ‘the pool of infected’.

However, these studies, which use models appropriately 
parameterised to reflect epidemic-specific information, 
remain theoretical. It is acknowledged by the modellers 
that reality is more complex, and real-world evidence of 
the impact of scaling up HCV treatment is lacking. Apart 
from important considerations of how to deliver 
case-finding and treatment scale-up in practice over 
time (dealt with, in part, in Chapter 2), the issue of how 
to assess impact or measure the outcome (i.e. the 
prevalence and incidence of HCV infection among 
people who inject drugs living in the community) still 
needs to be resolved. Parallels can be drawn with the 
analogous problem for HIV and lessons can be learnt 
from the HIV experience.

I  The HIV experience

The problem of evaluating effectiveness of public health 
interventions has been recurrent in the field of HIV 
research for some years. The discussion started with the 
need to assess the impact of initiatives to change sexual 
behaviours in developing countries (see, for example, 
Coates, 2008), and more recently the debate has been 
extended to the consideration of antiretroviral therapy as 
prevention, namely as a means of reducing transmission 
and eventually eliminating HIV (HIV Modelling 
Consortium Treatment as Prevention Editorial Group, 
2012). Evidence from the HIV Prevention Trial Network 
052 (HPTN 052) (Cohen et al., 2011, 2012) that 
antiretroviral therapy can greatly reduce HIV transmission 
between partners in stable HIV-discordant couples, has 
stimulated the development of models (see Eaton et al., 
2012, for a review) suggesting that an expanded 

89

antiretroviral therapy programme would have a variety of 
benefits at population level, including elimination of HIV 
within a short timescale. The question of how to assess 
intervention benefits remains, however, controversial. In 
principle, three different approaches to evaluation have 
been explored or suggested: mathematical modelling 
(Hallett et al., 2009; Awad and Abu-Raddad, 2011; 
Pickles et al., 2013; Garnett, et al., 2014), ecological 
studies (Das et al., 2010; Montaner et al., 2010) and 
cluster randomised trials (Hayes et al., 2011).

depend on the ability to identify infected individuals 
through screening, to ensure they access treatment, and 
that they are compliant. At the analysis stage, any biases 
affecting any of these steps need to be understood and 
accounted for to avoid misleading conclusions. Equally 
important are the duration of follow-up needed to allow 
for the time delay in the manifestation of some 
outcomes and the potential for time-varying 
confounders deriving from both behavioural changes 
and natural epidemics dynamics (Hayes et al., 2011).

Mathematical modelling

Mathematical transmission models are an important tool 
to evaluate, by simulation, the potential implications of 
an intervention on disease acquisition and spread. 
However, they may be of more limited value when it 
comes to ‘attributing’ effects to any particular potential 
intervention programme. They have been commonly 
used to obtain ‘counterfactuals’ by simulating scenarios 
of no intervention, and to derive estimates of effects by 
comparing the observed and simulated counterfactual 
outcomes (Garnett et al., 2011). For example, such an 
approach has been recently employed to assess the 
strength of evidence for the impact on HIV transmission 
of a large-scale behavioural intervention in key 
populations in southern India (Boily et al., 2013; Pickles 
et al., 2013). It is recognised, however, that this type of 
model crucially relies on important simplifying 
assumptions, including assumptions about model 
structure and parameterisation, often driven by lack of 
information on the various features of the phenomenon 
being modelled. So, for instance, the chosen structure 
may fail to capture aspects of reality necessary to 
explain observed outcomes (Eaton et al., 2012). 
Alternatively, model outputs might be sensitive to 
parameterisation, resulting in alternative explanations 
for the observed patterns and, consequently, a reduced 
ability to estimate accurately the effectiveness-related 
parameters and to identify attributions robustly.

Cluster randomised controlled trials

Cluster randomised controlled trials are the gold 
standard for the estimation of intervention effects in 
infectious diseases (Hayes et al., 2000). They allow the 
capture of both direct effects at the individual level and 
indirect effects in the population in terms of a reduction 
in disease, due to an intervention-induced reduction in 
the risk of infection (herd immunity). The implementation 
and the interpretation of cluster randomised controlled 
trials are not without challenges. In the case of HIV 
treatment, for example, exposure to the intervention will 

The POPART intervention trial involves a combination of 
increased HIV screening, immediate antiretroviral therapy 
(irrespective of baseline CD4 count) in those testing 
positive and other primary interventions (such as male 
circumcision, providing condoms and early treatment of 
other sexually transmitted infections). The trial is 
currently being carried out in 21 study clusters in Zambia 
and South Africa, with the main outcome, HIV incidence, 
measured over the study period in a population cohort of 
2 500 individuals randomly selected from each cluster. 
The assessment of the intervention is based on the 
comparison of HIV incidence in the population cohort 
across the three study arms, receiving the full POPART 
combination package, a reduced version of the POPART 
package and standard HIV care (Hayes et al., 2014). The 
motivation for such a trial has been the promising 
evidence from the HPTN 052 trial and modelling 
exercises (Cori et al., 2014) and will provide a valuable 
insight into both the substantive problem of evaluating 
interventions to reduce HIV and the feasibility of 
conducting this type of study.

POPART concerns a generalised epidemic in developing 
countries, with the intervention being administered to 
the general population. Modelling studies, similar to that 
in Cori et al. (2014), exist for people who inject drugs and 
equally suggest that early treatment of HIV in would 
reduce disease transmission (Degenhardt et al., 2010). 
However, no evaluation project analogous to POPART 
has been undertaken in this hard-to-reach population 
from which we can learn whether a study of this type is 
at all feasible.

Ecological studies

Some studies have reported an association between 
uptake of antiretroviral therapy and surrogate measures 
of HIV transmission. For example, ecological correlations 
between community measures of HIV viral load and the 
incidence of HIV infection in Vancouver were interpreted 
as evidence that antiretroviral therapy could reduce HIV 
transmission among people who inject drugs (Wood et 
al., 2009). However, concurrent decreases in the 

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Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 7 I A framework for evaluating scale-up of hepatitis C virus treatment as prevention for people who inject drugs

incidence of HCV infection suggest that injecting risk 
may also have decreased, and it is possible that this, 
rather than the scale-up of antiretroviral therapy, could 
explain the decrease in the incidence of HIV infection. 
Limitations of ecological studies in assessing the 
population-level effects of using antiretroviral therapy as 
a prevention tool are recognised (Smith et al., 2012; 
Wilson, 2012). These ‘natural experiments’ can provide 
valuable evidence, but could also provide misleading 
results if not interpreted appropriately. Suitable 
methodologies need to be employed to analyse the 
resulting data, taking into account the observational 
nature of these studies. Related issues are discussed in 
general in guidance issued by the UK Medical Research 
Council (MRC, no date).

I  Implications for HCV

The question is how relevant the HIV experience is for 
HCV in developed countries. HCV treatment has one 
distinct advantage over HIV treatment: duration of 
treatment is comparatively short and results in high 
rates of viral clearance. However, in contrast to the HIV 
generalised epidemic in Africa, HCV transmission in 
developed countries is mainly driven by the risk in people 
who inject drugs.

Similarly to HIV, model projections for HCV have 
provided a theoretical guidance on the conditions for the 
successful implementation of a treatment intervention. 
So, for instance, HCV prevalence is likely to fall more 
rapidly in populations in which the level of chronic HCV 
infection is at or below 40 %, and even more so if the 
prevalence is not more than 20 % (Chapter 4). In the 
case of HIV, the POPART trial represents the best 
opportunity to rigorously address the treatment as 
prevention issue, so would it be possible to adopt 
a similar design to address the same issue for HCV?

There are a number of important aspects and sources of 
uncertainty that need to be fully addressed, particularly 
if the outcomes are changes in the prevalence and/or 
incidence of HCV infection. These are discussed 
individually below.

Quantification of the population ‘at risk’

The injecting drug population is a ‘mixture population’ of 
individuals at risk of acquiring and transmitting infection, 
encompassing current injectors and those who are in 
treatment or prison or have recently ceased injecting 
and are at high risk of relapse. Existing estimates of 
injecting drug use prevalence rarely capture the whole 

population at risk; they typically refer to active injectors 
and exclude those who have temporarily ceased 
injecting, leading to a potential underestimation of the 
true prevalence. In most European countries up-to-date 
estimates are not available (Chapter 1), and those that 
are available are notoriously uncertain (Jones et al., 
2014; Martin et al., 2015) and are often dependent on 
the methodology used to derive them. For instance, the 
estimated size of the drug-injecting population that was 
active in Scotland in 2003 has varied from 19 000 to 
27 000 (King et al., 2009) and in England in 2005 from 
130 000 to 200 000 (De Angelis et al., 2009; Hay et al., 
2009; Harris et al., 2012). However, knowledge of the 
size of the drug-injecting population is essential for 
‘treatment as prevention’ trials, as estimation of the 
number of people who inject drugs who are chronically 
infected with HCV and the derivation of the treatment 
rates required to reduce HCV transmission to specific 
levels depends on this information. Inevitably, therefore, 
as its uncertainty is reflected in all these related 
quantities, trial designs will become more complex 
(Hayes and Moulton, 2009).

Baseline and outcome measures: HCV prevalence 
and incidence

Any trial of HCV treatment requires the baseline 
prevalence of chronic infection and incidence 
consistently estimated at relevant locations over any 
potential trial period.

However, direct measures of the prevalence of HCV 
antibodies (and of chronic HCV infection) among people 
who inject drugs do not exist. Surveillance systems 
necessarily cover only very specific subgroups, are not 
representative of the drug-injecting population and 
provide a multiplicity of pieces of information that, if 
used individually, lead to biased estimates of prevalence. 
In these circumstances, linking and combining the 
various sources of data while accounting for the biases 
can be a viable way of producing meaningful estimates. 
The problem is compounded if the intervention is 
implemented in relatively small geographical areas, as in 
this case paucity of information will add a further 
complication, increasing the uncertainty of relevant 
estimates.

An example of this type of linkage and data synthesis is 
recent work conducted in Scotland. There, by combining 
data from the Scottish drugs misuse database, the HCV 
diagnoses register (Shaw et al., 2003), the Needle 
Exchange Surveillance Initiative (Allen et al., 2012) and 
a capture–recapture study on a recently infected 
population (Overstall et al., 2014), it has been possible, 

91

through a Bayesian evidence synthesis, to derive 
estimates of HCV (antibody) prevalence among people 
who inject drugs by age group and gender in the Greater 
Glasgow and Clyde area and in the rest of Scotland 
(Prevost et al., 2015). A similar exercise in a smaller 
geographical area would provide local estimates of HCV 
prevalence, which would constitute the necessary 
baseline information if a ‘treatment as prevention’ 
strategy were to be evaluated in Scottish Health Boards, 
for instance. Clearly, the issue of uncertain baseline 
prevalence of HCV remains and could jeopardise the 
assessment of the significance in a change in prevalence 
as consequence of the intervention.

Information on the incidence of HCV infection is even 
more crucial to the evaluation of the impact of an 
intervention on transmission, yet incidence is even more 
difficult to quantify as an outcome, particularly if what is 
needed are estimates at local level and, perhaps, over 
time. Estimation would have to rely on community 
surveys of people who inject drugs, with the consequent 
associated biases (Mills et al., 2012), and on laboratory 
reporting of recent (incident) infections diagnosed in 
routine testing, which are also likely to be biased.

Given all the potential biases and uncertainty in the 
measurement of incidence, it will be very difficult to 
detect any difference in incidence as a result of the 
intervention, unless such difference is substantial and 
the trial is powered appropriately.

Opioid substitution treatment and needle and 
syringe programmes as time-varying covariates

HCV treatment may act synergistically with other 
interventions, such as opioid substitution treatment and 
needle and syringe programmes, which could either 
enhance or decrease the impact of HCV treatment on 
the outcome (Martin et al., 2013a). These factors, not 
controlled for at randomisation, could change over time 
(in terms of scaling up or even disinvestment) and 
interact with the intervention, and will need to be 
measured and incorporated into the analysis.

Other factors: heterogeneity in injecting risk/
potential selection biases

People who inject drugs who are at high risk for infection 
as a result of their injecting practices, for example, may 
be more likely to transmit HCV and less likely to enter 
HCV treatment than those considered at low risk. If the 
low-risk population is preferentially treated, then HCV 
treatment may have a lesser impact on HCV 

transmission. In certain circumstances targeting high- or 
low-risk injectors maybe more efficient (De Vos et al., 
2015). Modelling work suggest that if the level of change 
from high- to low-risk behaviours is modest, then there 
will be little or no dilution of the effect of any HCV 
treatment intervention (Martin et al., 2013a). Ongoing 
monitoring of the characteristics of the treated 
populations, any injecting relapse and reinfection rates 
will be required to test these hypotheses.

Final remarks

It is possible that the complexities in the definition of the 
injecting drugs population and in outcome measures 
could preclude the use of cluster randomised controlled 
trials, particularly if information across multiple sites is 
needed. This would be particularly a challenge at 
a European level, given the diversity of both 
epidemiology and the information available. In addition, 
the cost of a cluster randomised controlled trial (in terms 
of HCV drugs) might not be sustainable.

Alternatively, it could be justifiable to conduct 
non-randomised studies in sites where the 
drug-injecting population can be well characterised 
through comprehensive surveillance systems and drug 
users treated for HCV infection, whether in specialised 
services or elsewhere, can be adequately followed up.

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Hepatitis C among drug users in Europe: epidemiology, treatment and preventionCHAPTER 7 I A framework for evaluating scale-up of hepatitis C virus treatment as prevention for people who inject drugs

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decision-making’, PLoS Medicine 9(7) e1001259.

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value most?’, Gut 64, pp. 1800–1809.

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Fallibility of standard capture–recapture methods in the 

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94

Hepatitis C among drug users in Europe: epidemiology, treatment and preventionConclusions
Isabelle Giraudon, Dagmar Hedrich, Roland Simon and Paul Griffiths

I   People who inject drugs are a main 

target group for HCV treatment

With over 5 million people chronically infected with the 
virus, it is self-evident that hepatitis C virus (HCV) 
infection must be regarded as a major threat to public 
health in the European Union. Moreover, even while 
noting the gaps that exist in the available data, and the 
fact that the epidemiological situation varies 
considerably between countries, it is also clear that in 
Europe the health burden accruing from HCV infection is 
disproportionately high among people who inject drugs.  
Furthermore, there is strong evidence of on-going and, in 
some countries, high levels of transmission among 
young injectors, suggesting that infection is acquired 
relatively early in an individual’s injecting career. 
Effective EU public health strategies to tackle HCV 
infection and its long-term consequences must have 
a primary focus on people who inject drugs and those 
who have acquired HCV through injecting.

It is also of note that the recognition of this problem and 
its long-term implications is relatively new. The hepatitis 
C virus was identified for the first time in 1989, but it had 
already been spreading among injecting drug-using 
populations in Europe for years. As people who have 
contracted the virus often remain symptom-free for many 
years, the problem remained a ‘hidden’ epidemic until 
relatively recently, with most cases of infection going 
undiagnosed and untreated. Today, the importance and 
potential costs, both to those infected with this disease 
and in respect to the future impact on health budgets, 
are now becoming more widely recognised. Despite this, 
however, overall there has been a failure to develop 
responses that have managed to impact on the levels of 
infection among people who inject drugs.

I   New treatments have removed 

barriers

Until relatively recently, the main treatment option for 
HCV infection was to use a combination of the antiviral 
drugs interferon and ribavirin. This can be effective, but 

these drugs are often poorly tolerated, have severe side 
effects and the duration of treatment is relatively long; 
both factors that are disadvantageous for encouraging 
uptake. In addition, substantial barriers to access often 
existed for people who inject drugs; for example, some 
clinical guidelines required long periods of abstinence 
before treatment could commence. Moreover, for those 
who were eligible, pathways into treatment were often 
difficult to find, with coordination between specialist 
drug services and medical services addressing hepatitis 
care often not being optimal. This situation is now 
changing, however. To a large extent, this has been 
driven by the introduction over the last few years of new 
medications, direct-acting antivirals, which can be 
administered over much shorter periods and with 
relatively fewer side effects. Thus, there is now 
a possibility of achieving better treatment retention and 
outcomes for drug users, with research evidence 
showing that investments in HCV treatment, even for 
those who continue to inject drugs, is justified on public 
health grounds.

Not only has this led to a greater recognition of the need 
for joined-up approaches between services working with 
drug problems and those addressing hepatitis, it has 
also extended the possibilities of how care can be 
offered. This is because, in many respects, the provision 
of HCV treatment has become less challenging. The use 
of all-oral, interferon-free HCV treatment regimens 
makes them less complex to administer and, therefore, 
more appropriate to use in primary care, prison and drug 
treatment settings. This is helpful, as a recognised 
element of good practice in the delivery of HCV care for 
people who inject drugs is close collaboration between 
the different specialist services involved. There is now 
a growing experience of developing improved care 
pathways, and the potential health gains of more 
effective working in this area appear considerable. 

Taken as a whole, these developments now mean that, 
probably for the first time, a real opportunity exists to 
tackle the high prevalence of HCV infection at the level 
of injecting drug-user communities and thereby make 
a significant impact on the HCV problem in Europe.

95

I  Preventing further infections

Europe is not homogenous with regard to levels of drug 
use and injecting, nor with regard to the prevalence of 
infectious diseases among drug-using populations. 
Moreover, levels of injecting and associated risk 
behaviour can change over time. Recent HIV outbreaks 
have shown, for example, that patterns of use can be 
highly variable, and that they can be influenced by other 
factors like the emergence of new psychoactive 
substances on the drugs market. Any future increase in 
injecting drug use has the potential to be associated 
with increasing the risks of new HCV infections. Health 
promotion activities are, therefore, needed to discourage 
people from injecting drugs, or to change their behaviour 
in order to reduce the risk of contracting the virus if they 
do inject. Measures that have been shown to reduce 
reported injecting risks, such as the adequate provision 
of clean injecting equipment and opioid substitution 
treatment for dependent opioid users, remain key 
elements in current prevention approaches in this area. 
However, coverage of both measures remains 
suboptimal in many countries and, therefore, requires 
strengthening, not only because of potential health gains 
in the area of HCV, but also because they deliver health 
benefits elsewhere. Extending services availability to the 
most chronic, disadvantaged and vulnerable groups, 
such as those in housing need, is likely to be particularly 
important, as these individuals may be at greater risk 
and more difficult to attract to mainstream services. 
Beyond this, however, the experience to date would 
suggest that without the additional component of HCV 
treatment, it will be difficult to impact significantly on 
HCV infection rates at the population level. The 
challenge, therefore, is to develop a comprehensive 
approach to care that ensures that both HCV prevention 
activities and treatment access are adequately 
resourced and proactively delivered.

I  Diagnosing those infected

The fact that many of those infected with HCV are 
unaware of their infection status has consequences for 
the continued transmission of the virus at population 
level and for the long-term health of the individuals 
concerned. A need remains, therefore, to raise both 
public and professional awareness in order to encourage 
those at risk to come forward for testing, and for services 
to be more proactive in offering testing. An important 
caveat here is that testing needs to be accompanied by 
appropriate follow-up and referral mechanisms to 
facilitate access to treatment for positive cases. It is not, 
however, just current injectors who may be unaware of 

their infection status, as those who have ever injected 
are at risk, even if the behaviour has been discontinued. 
Targeted case-finding and public information campaigns 
may also, for this reason, be of value to encourage 
former injectors to come forward for testing.

Monitoring infection rates is also important, as it can 
provide crucial feedback on the effectiveness of current 
interventions and indicate where more resources are 
needed. This represents another strong argument for 
point-of-care testing as a routine element of the health 
service response. In conclusion, offering testing to all 
drug users in care can be regarded as part of good 
practice in this area. This is supported by the newly 
agreed EU minimum quality standards for demand 
reduction (Council of the European Union, 2015), which 
recommend that ‘treatment services provide voluntary 
testing for blood-borne infectious diseases, counselling 
against risky behaviours and assistance to manage 
illness’. In addition to offering screening at drug services, 
there is some evidence to support a more proactive 
approach by extending this provision via 
community-based outreach approaches. The high 
prevalence of those with drug problems within the 
criminal justice sector also means that offering voluntary 
testing in prisons and other places of confinement is 
important. Wherever screening is provided, follow-up 
assessment will also need to take into account other 
factors that may increase the risk of positive cases 
progressing to severe liver damage, including age at 
infection, gender, alcohol use and co-infection with 
infectious agents, such as the human immunodeficiency 
and hepatitis B viruses.

I   The need for greater treatment access 

and referral pathways tailored to the 
needs of people who inject drugs

The potential long-term social and economic costs 
associated with HCV infection are considerable, with 
European countries facing escalating healthcare costs if 
infected populations progress into severe liver disease. 
Epidemiological modelling studies suggest that the 
combination of widespread hepatitis C treatment, 
supported with other primary prevention measures, has 
the potential to reduce HCV transmission to low levels. 
The model projections provide strong theoretical 
evidence for the hypothesis that hepatitis C treatment, if 
scaled up sufficiently, can reduce the prevalence of HCV 
infection and that treating people who inject drugs is 
likely to be cost-effective. There is now a need for more 
empirical data and evaluations of the impact of scaling 

96

Hepatitis C among drug users in Europe: epidemiology, treatment and prevention Conclusions

I  References
I 

 Council of the European Union (2015), Council conclusions on 

the implementation of the EU Action Plan on Drugs 2013‑2016 

regarding minimum quality standards in drug demand 

reduction in the European Union, CORDROGUE 70, doc ST 

11985 2015 INIT (http://www.consilium.europa.eu/register/

en/content/out/?&typ=ENTRY&i=ADV&DOC_ID=ST-11985-

2015-INIT).

I 

 WHO (World Health Organization) (2016), Draft global health 

sector strategies: viral hepatitis, 2016–2021, Report by the 

Secretariat (http://apps.who.int/gb/ebwha/pdf_files/EB138/

B138_30-en.pdf?ua=1).

up hepatitis C treatment among people who inject drugs 
in order to demonstrate how health gains in this area 
may become manifest. Studies that look at how to 
improve responses in areas such as HCV case-finding 
and treatment in prison are likely to be particularly 
important. Scaling up of treatment offers will require the 
development of effective working partnerships between 
specialist services working with drug users and those 
offering HCV treatment and care. In the past, referral 
pathways for drug injectors into specialist hepatitis care 
have represented a critical weak link in this area. This is 
now changing, and good practice models have been 
developed. There remains, however, a need for these to 
be extended, and this is an area in which guidelines and 
clinical practice standards have an important role to 
play. Given the pace of change in respect to the 
availability of new pharmacotherapies, it will be 
necessary to regularly review and adapt guidance in this 
area to new opportunities that are likely to become 
available.

I   International collaboration to support 

ambitious hepatitis elimination 
policies

The opportunities offered by the emergence of direct-
acting new antiviral drugs have been recognised by the 
World Health Organization, which has declared the 
elimination of viral hepatitis as a public health threat by 
2030 as one of its global strategic objectives (WHO, 
2016). This is an ambitious but achievable objective. The 
greatly improved prospects for treating viral hepatitis 
have quickly been translated into new testing and 
treatment guidance, national planning toolkits and 
economic and burden of disease modelling tools. 
Indicators to monitor and report progress at global and 
national level have now also been adopted. The draft 
WHO action plan for the health sector response to viral 
hepatitis in the European Region, currently under 
discussion, contains a number of milestones and targets 
specific to people who inject drugs. Once the WHO 
action plan is adopted, the EMCDDA is committed to 
working with our international, European and national 
partners in this area to ensure that progress is monitored 
effectively and to support the measures necessary to 
ensure that the ambitious public health goals 
established for the elimination of HCV infection are 
realised.

97

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About the EMCDDA

The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is the 
central source and confirmed authority on drug-related issues in Europe. For 
over 20 years, it has been collecting, analysing and disseminating scientifically 
sound information on drugs and drug addiction and their consequences, 
providing its audiences with an evidence-based picture of the drug 
phenomenon at European level.

The EMCDDA’s publications are a prime source of information for a wide range 
of audiences including: policymakers and their advisors; professionals and 
researchers working in the drugs field; and, more broadly, the media and general 
public. Based in Lisbon, the EMCDDA is one of the decentralised agencies of 
the European Union.

About this series

EMCDDA Insights are topic-based reports that bring together current research 
and study findings on a particular issue in the drugs field.

Hepatitis C among drug users in Europe: epidemiology, treatment and 
prevention provides a timely contribution to raising awareness of the hepatitis 
C epidemic in Europe and the opportunities now opening up to tackle this 
problem decisively. A state-of-the-art review of the epidemiology of hepatitis 
C virus (HCV) infection in Europe and an overview of the way preventive 
measures are currently implemented in European countries set the scene. 
International experts address the treatment of HCV infection among people 
who inject drugs, with an emphasis on how we encourage uptake and deliver 
effective outcomes. Implementation issues are also explored, as are the 
complementary roles of treatment and prevention. The new medicines and 
treatment regimens driving the transformation in the HCV treatment landscape 
are reviewed in detail. The challenges of scaling up HCV treatment and 
successfully involving drug-using patients is explored from different viewpoints, 
including that of the drug user.

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