Editors’ Choice
Recommendations for the management of hepatitis C virus infection among people who inject drugs

https://doi.org/10.1016/j.drugpo.2015.07.005Get rights and content

Highlights

  • HCV testing, linkage to care and treatment is low among PWID.

  • New interferon-free HCV therapies have the potential to enhance HCV care.

  • HCV treatment is safe and effective among PWID.

  • HCV testing, linkage to care and treatment should be offered to all PWID.

  • These recommendations provide a framework to enhance HCV care among PWID.

Abstract

In high income countries, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). In many low and middle income countries large HCV epidemics have also emerged among PWID populations. The burden of HCV-related liver disease among PWID is increasing, but treatment uptake remains extremely low. There are a number of barriers to care which should be considered and systematically addressed, but should not exclude PWID from HCV treatment. The rapid development of interferon-free direct-acting antiviral (DAA) therapy for HCV infection has brought considerable optimism to the HCV sector, with the realistic hope that therapeutic intervention will soon provide near optimal efficacy with well-tolerated, short duration, all oral regimens. Further, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provide a framework for HCV assessment and care. Further research is needed to evaluate strategies to enhance testing, linkage to care, treatment, adherence, viral cure, and prevent HCV reinfection among PWID, particularly as new interferon-free DAA treatments for HCV infection become available.

Introduction

In high income countries, 50–80% of hepatitis C virus (HCV) infection is among people who inject drugs (PWID), and HCV epidemics have emerged among PWID in many low and middle income countries (Hajarizadeh, Grebely, & Dore, 2013). Within this population are ‘current’ or ‘recent’ PWID (Larney et al., 2015), who are at risk of transmitting and acquiring HCV infection (there are varying definitions in the literature, although one month to one year is most common (EMCDDA, 2010, WHO, 2012)). ‘Former’ PWID (people who have ceased injecting drug use) are also of importance, as a large proportion of existing HCV infections are found in this group (Larney et al., 2015). Given the relapsing nature of drug dependence, determining a cut-off to define permanent vs short-term cessation of injecting drug use (and therefore ‘current’/‘recent’ vs ‘former’ PWID) is problematic (Larney et al., 2015). These guidelines, however, are predominantly developed for clinical management of HCV in the current PWID population and the term PWID will in general relate to this population. Given a large proportion of PWID have been HCV-infected for two or more decades, many have progressed to advanced fibrosis (Grebely and Dore, 2011, Hajarizadeh et al., 2013). Rates of advanced liver disease complications, associated healthcare costs, and liver-related morbidity and mortality among PWID continue to rise (Grebely and Dore, 2011, Hajarizadeh et al., 2013).

Until recently, HCV treatment guidelines excluded PWID, due to concerns about poor adherence, adverse events and re-infection (NIH, 1997). Successful HCV treatment studies among PWID challenged this paradigm (Alvarez-Uria et al., 2009, Aspinall et al., 2013, Backmund et al., 2001, Bruggmann et al., 2008, Dalgard, 2005, Dimova et al., 2013, Dore et al., 2010, Grebely et al., 2007a, Grebely et al., 2010, Grebely et al., 2007b, Guadagnino et al., 2007, Hellard et al., 2009, Jack et al., 2009, Jafferbhoy et al., 2012, Jeffrey et al., 2007, Lindenburg et al., 2011, Manolakopoulos et al., 2010, Martinez et al., 2010, Matthews et al., 2005, Mauss et al., 2004, Melin et al., 2010, Neri et al., 2002, Papadopoulos et al., 2010, Robaeys et al., 2006, Sasadeusz et al., 2011, Schaefer et al., 2003, Schaefer et al., 2007, Sylvestre, 2002, Sylvestre et al., 2005, Van Thiel et al., 2003, Van Thiel et al., 1995, Waizmann and Ackermann, 2010, Wilkinson et al., 2009). International guidelines from the American Association for the Study of Liver Disease (AASLD)/Infectious Diseases Society of America (IDSA), the European Study for the Association of the Liver (EASL), the International Network for Hepatitis in Substance Users and the World Health Organization now all recommend treatment for HCV infection among PWID (AASLD/IDSA, 2015, European Association for Study of Liver, 2014, Robaeys et al., 2013, WHO, 2014).

Despite revised guidelines, few PWID have received HCV treatment (Alavi et al., 2014, Grebely et al., 2009, Iversen et al., 2014, Mehta et al., 2008, NCHECR, 2009, Strathdee et al., 2005). Enhanced HCV assessment and treatment in PWID will be required to reduce future HCV-related morbidity and mortality (Hutchinson, Bird, & Goldberg, 2005b). The availability of effective, tolerable and simpler interferon-free direct acting antiviral (DAA) regimens should improve the feasibility of this approach (Dore & Feld, 2015). The International Network for Hepatitis in Substance Users (INHSU) established an expert panel to develop recommendations to enhance HCV assessment, management and treatment among PWID, with the first recommendations published in 2013 (Robaeys et al., 2013). These recommendations have been updated to reflect the rapidly changing landscape of HCV therapy and have been updated to be in line with the methodologies used by international guidelines from AASLD and IDSA (AASLD/IDSA, 2015).

Section snippets

Methods

The guidance is presented in the form of RECOMMENDATIONS. Each RECOMMENDATION is rated in terms of the level of the evidence and strength of the recommendation, using a scale developed by AASLD/IDSA (AASLD/IDSA, 2015). Recommendations are based on scientific evidence and expert opinion (Table 1). Each recommended statement includes a Roman numeral (I, II, or III) that represents the level of the evidence that supports the recommendation, and a letter (A, B, or C) that represents the strength of

Epidemiology and prevention of HCV

HCV prevalence among PWID populations ranges from <20% to >80% (mid-point HCV estimate: 67% antibody positive; 50% RNA positive), with a global estimate of 10 million HCV antibody positive PWID (7.5 million with chronic HCV infection) (Hagan et al., 2008, Nelson et al., 2011). HCV genotypes 1a, 1b, and 3a are common among PWID (Pybus, Cochrane, Holmes, & Simmonds, 2005), 4d is common among PWID in Europe (van Asten et al., 2004), and 6 in Southeast Asia (Sievert et al., 2011). HCV incidence

Natural history of HCV and effects of drugs on the liver

Chronic HCV infection develops in 75% (Grebely et al., 2014, Micallef et al., 2006), with 10–20% developing cirrhosis over 20–30 years infection (Grebely & Dore, 2011). In a meta-analysis of cross-sectional studies of HCV-infected PWID, the 20-year cirrhosis prevalence was 15% (John-Baptiste, Krahn, Heathcote, Laporte, & Tomlinson, 2010). In a systematic review of the progression of fibrosis among PWID with chronic HCV, the average time from HCV infection to the development of advanced liver

Testing of HCV infection

Timely HCV screening, test discussion, and assessment constitute essential measures for prevention (Centers for Disease Control and Prevention, 2012). Recommendations for testing are based on the high HCV prevalence in PWID (Hagan et al., 2008, Nelson et al., 2011), the growing evidence that awareness of HCV status has sustained protective behavioural changes (e.g. injecting risk behaviours) (Aspinall et al., 2014, Bruneau et al., 2014), the potential public health benefit of reducing

Non-invasive liver fibrosis assessment

Liver biopsy is the gold standard for liver fibrosis assessment, but is invasive and logistically difficult. As per international guidelines (AASLD/IDSA, 2015, European Association for Study of Liver, 2014), non-invasive methods such as transient elastography or well-established panels of biomarkers of fibrosis are acceptable for liver disease stage assessment. Non-invasive methods have excellent utility for the identification of HCV-related cirrhosis, but lesser accuracy for earlier stages (

Pre-therapeutic assessment

Guidelines for pre-therapeutic assessment for HCV-infected individuals are available (AASLD/IDSA, 2015, European Association for Study of Liver, 2014). However, HCV-infected PWID often have complex social, medical and psychiatric co-morbidities, complicating decisions around care (reviewed in Grebely & Tyndall, 2011). Poor knowledge and inaccurate perceptions about HCV are barriers for accessing HCV care (Doab et al., 2005, Grebely et al., 2008, Treloar et al., 2011, Treloar et al., 2010).

Indications for treatment

The goal of HCV therapy is to prevent liver disease complications, death from HCV, other extra-hepatic manifestations, and HCV transmission in the population. SVR is associated with improved quality of life, regression of fibrosis, and reduced risk of complications in those with cirrhosis (Seeff, 2002).

According to AASLD/IDSA recommendations, successful HCV treatment results in SVR, which is tantamount to virologic cure, and as such, is expected to benefit nearly all chronically infected

PEG-IFN and DAA-based treatment: treatment recommendations

In PWID, treatment of chronic HCV is safe and effective (Alvarez-Uria et al., 2009, Backmund et al., 2001, Bruggmann et al., 2008, Dalgard, 2005, Dimova et al., 2013, Dore et al., 2010, Grebely et al., 2007a, Grebely et al., 2010, Grebely et al., 2007b, Guadagnino et al., 2007, Hellard et al., 2009, Jack et al., 2009, Jafferbhoy et al., 2012, Jeffrey et al., 2007, Lindenburg et al., 2011, Manolakopoulos et al., 2010, Martinez et al., 2010, Matthews et al., 2005, Mauss et al., 2004, Melin et

Impact of drug use on adherence and SVR

Adherence to HCV therapy is often defined as receipt of ≥80% of scheduled PEG-IFN and ribavirin for ≥80% of the treatment period, but this does not distinguish between missed doses and treatment discontinuation (Weiss, Brau, Stivala, Swan, & Fishbein, 2009). However, these cut-offs may not be applicable in the interferon-free era. Suboptimal PEG-IFN exposure is mainly driven by early treatment discontinuation as compared to missed doses (Grebely, Matthews, Hellard, et al., 2011). Of note, both

Impact of mental health on adherence and SVR

As reviewed in (Schaefer, Sarkar, & Diez-Quevedo, 2013), psychiatric co-morbidity is high among PWID and psychiatric symptoms such as depression may appear during antiviral treatment even with interferon-free treatment regimens (Sulkowski et al., 2014). While interferon-free DAA therapy does not seem to have significant psychiatric side effects, antiviral treatment including PEG-IFN is associated with the development of psychiatric side effects (Schaefer et al., 2013). However, PWID do not in

Treatment management

HCV treatment has been delivered successfully to PWID through various clinical models, including within general hospital liver disease and viral hepatitis clinics, drug detoxification clinics, opioid substitution therapy clinics, prisons and community-based clinics. As reviewed in (Bruggmann & Litwin, 2013) (Meyer et al., 2015), examples of strategies that have been successful for enhancing assessment, adherence or SVR include hospital-based and primary care-based integrated care,

HCV treatment in prisons

Given the close nexus between injecting drug use and imprisonment, acute and chronic HCV infections are prevalent in custodial settings worldwide (reviewed in Larney et al., 2013). Despite the substantial burden of disease in this setting, screening, assessment and treatment rates are very low (reviewed in Post, Arain, & Lloyd, 2013). Interferon-based antiviral treatment has been shown to be feasible and effective, albeit with residual concerns of reinfection and loss to follow-up upon release

Reinfection following successful HCV treatment

There is still some concern that re-infection due to recurrent risk behaviours may negate potential benefits of treatment. Reported rates of reinfection following successful HCV treatment among PWID are low, with estimates generally 1–5% risk per year (reviewed in Cunningham et al., 2015, Grady et al., 2013). Data are needed on reinfection rates in the interferon-free DAA era and studies are needed to evaluate strategies to prevent HCV reinfection.

Treatment of acute HCV

Acute HCV infection refers to the period spanning the first six months following exposure to HCV (Grebely, Matthews, & Dore, 2011). Spontaneous clearance occurs in 25% (Grebely et al., 2014, Micallef et al., 2006). PEG-IFN-based SVR among HCV mono-infected PWID with acute HCV is 55–74% (reviewed in Martinello and Matthews, 2015), with treatment outcomes associated with adherence and social support, but not IDU prior to or during treatment (Dore et al., 2010). No data is available on

HIV/HCV co-infection

Co-infection with HIV accelerates HCV disease progression, leading to greater liver-related morbidity and mortality in HIV/HCV than in HCV mono-infected persons (Chen et al., 2009, Graham et al., 2001, Lo Re et al., 2014). Chronic HCV is the leading cause of non-AIDS death where combination antiretroviral therapy (cART) is accessible (Weber et al., 2006). Additional challenges with HIV/HCV include potential cART-related liver toxicity, multiple medication requirements, drug–drug interactions,

Management of hepatitis B virus (HBV) co-infection

The global prevalence of chronic HBV is 8% among PWID (Nelson et al., 2011). HBV vaccination is effective among PWID and accelerated schedules improve adherence (Hwang et al., 2010). PEG-IFN/ribavirin is effective for the treatment of HCV in those with HBV/HCV (Liu et al., 2009). As recommended by the EASL guidelines, HBV DNA detection and HBV DNA level measurement are essential for the diagnosis, decision to treat and subsequent monitoring of patients (European Association For The Study Of The

Liver transplantation

The proportion of those with a history of IDU undergoing liver transplantation for HCV-related cirrhosis or HCC is 5–10% (De Gottardi et al., 2010, Robaeys et al., 2009). Relapse to drug use following transplantation is rare (De Gottardi et al., 2010, Robaeys et al., 2009). Selection criteria for liver transplantation include: 6–24 months of drug abstinence, controlled psychiatric disease and the presence of stable social support networks (Webb, Shepherd, & Neuberger, 2008). OST is not a

Conclusion

Given the burden of HCV-related disease among PWID, strategies to enhance HCV testing, linkage to care, assessment, treatment and prevention of HCV reinfection in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provides a framework for HCV testing, assessment, management and treatment. However, many studies performed among PWID to date are limited, given retrospective designs, small sample sizes and lack of randomized controlled trial

Conflict of interest statement

All authors have no reported conflicts relevant to the content of the manuscript.

References (199)

  • European Association For The Study Of The Liver

    EASL clinical practice guidelines: Management of chronic hepatitis B virus infection

    Journal of Hepatology

    (2012)
  • E. Fortier et al.

    The effect of social functioning and living arrangement on treatment intent, specialist assessment and treatment uptake for hepatitis C virus infection among people with a history of injecting drug use: The ETHOS study

    International Journal of Drug Policy

    (2015)
  • J. Grebely et al.

    Treatment uptake and outcomes among current and former injection drug users receiving directly observed therapy within a multidisciplinary group model for the treatment of hepatitis C virus infection

    International Journal of Drug Policy

    (2007)
  • J. Grebely et al.

    Barriers associated with the treatment of hepatitis C virus infection among illicit drug users

    Drug and Alcohol Dependence

    (2008)
  • J. Grebely et al.

    Adherence to treatment for recently acquired hepatitis C virus (HCV) infection among injecting drug users

    Journal of Hepatology

    (2011)
  • S.J. Hutchinson et al.

    Influence of alcohol on the progression of hepatitis C virus infection: A meta-analysis

    Clinical Gastroenterology and Hepatology

    (2005)
  • J.H. Ishida et al.

    Influence of cannabis use on severity of hepatitis C disease

    Clinical Gastroenterology and Hepatology

    (2008)
  • A. John-Baptiste et al.

    The natural history of hepatitis C infection acquired through injection drug use: Meta-analysis and meta-regression

    Journal of Hepatology

    (2010)
  • T.P. Kanchana et al.

    Liver transplantation for patients on methadone maintenance

    Liver Transplantation

    (2002)
  • J. Keats et al.

    Assessment and delivery of treatment for hepatitis C virus infection in the opioid substitution treatment setting with integrated peer-based support

    International Journal of Drug Policy

    (2015)
  • J. Lalezari et al.

    Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine

    Journal of Hepatology

    (2015)
  • S. Larney et al.

    Defining populations and injecting parameters among people who inject drugs: Implications for the assessment of hepatitis C treatment programs

    International Journal of Drug Policy

    (2015)
  • A.H. Litwin et al.

    Primary care-based interventions are associated with increases in hepatitis C virus testing for patients at risk

    Digestive and Liver Disease

    (2012)
  • AASLD/IDSA

    Recommendations for testing, managing, and treating hepatitis C

    (2015)
  • M. Alavi et al.

    Assessment and treatment of hepatitis C virus infection among people who inject drugs in the opioid substitution setting: ETHOS study

    Clinical Infectious Diseases

    (2013)
  • M. Alavi et al.

    Continued low uptake of treatment for hepatitis C virus infection in a large community-based cohort of inner city residents

    Liver International

    (2014)
  • M. Alavi et al.

    Effect of treatment willingness on specialist assessment and treatment uptake for hepatitis C virus infection among people who use drugs: The ETHOS study

    Journal of Viral Hepatitis

    (2015, May)
  • G. Alvarez-Uria et al.

    Factors associated with treatment failure of patients with psychiatric diseases and injecting drug users in the treatment of genotype 2 or 3 hepatitis C chronic infection

    Liver International

    (2009)
  • E.J. Aspinall et al.

    Treatment of HCV infection among people who are actively injecting drugs: A systematic review and meta-analysis

    Clinical Infectious Diseases

    (2013)
  • A. Baranova et al.

    Non-invasive markers for hepatic fibrosis

    BMC Gastroenterology

    (2011)
  • J. Berenguer et al.

    Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus

    Hepatology

    (2009)
  • J. Berenguer et al.

    Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus

    Clinical Infectious Diseases

    (2012)
  • E.J. Bini et al.

    Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection

    American Journal of Gastroenterology

    (2005)
  • P. Bruggmann et al.

    Models of care for the management of hepatitis C virus among people who inject drugs: One size does not fit all

    Clinical Infectious Diseases

    (2013)
  • P. Bruggmann et al.

    Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients

    Journal of Viral Hepatitis

    (2008)
  • J. Bruneau et al.

    Sustained drug use changes after hepatitis C screening and counseling among recently infected persons who inject drugs: A longitudinal study

    Clinical Infectious Diseases

    (2014)
  • L. Brunet et al.

    Marijuana smoking does not accelerate progression of liver disease in HIV-hepatitis C coinfection: A longitudinal cohort analysis

    Clinical Infectious Diseases

    (2013)
  • G. Caccamo et al.

    Hepatitis B virus and hepatitis C virus dual infection

    World Journal of Gastroenterology

    (2014)
  • I. Campos-Varela et al.

    Advances in therapy for HIV/hepatitis C virus-coinfected patients in the liver transplant setting

    Clinical Infectious Diseases

    (2015)
  • Centers for Disease Control and Prevention

    Integrated prevention services for HIV infection, viral hepatitis, sexually transmitted diseases, and tuberculosis for persons who use drugs illicitly: Summary guidance from CDC and the U.S. Department of Health and Human Services

    Morbidity and Mortality Weekly Report

    (2012)
  • A. Charlebois et al.

    Factors associated with HCV antiviral treatment uptake among participants of a community-based HCV programme for marginalized patients

    Journal of Viral Hepatitis

    (2012)
  • T.Y. Chen et al.

    Meta-analysis: Increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression

    Clinical Infectious Diseases

    (2009)
  • R.T. Chung et al.

    Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons

    New England Journal of Medicine

    (2004)
  • S. Crawford et al.

    Peer support models for people with a history of injecting drug use undertaking assessment and treatment for hepatitis C virus infection

    Clinical Infectious Diseases

    (2013)
  • B.L. Cullen et al.

    Identifying former injecting drug users infected with hepatitis C: An evaluation of a general practice-based case-finding intervention

    Journal of Public Health

    (2012)
  • E.B. Cunningham et al.

    Mixed HCV infection and reinfection in people who inject drugs-impact on therapy

    Nature Reviews Gastroenterology and Hepatology

    (2015)
  • O. Dalgard

    Follow-up studies of treatment for hepatitis C virus infection among injection drug users

    Clinical Infectious Diseases

    (2005)
  • A. De Gottardi et al.

    Injection drug use before and after liver transplantation: A retrospective multicenter analysis on incidence and outcome

    Clinical Transplantation

    (2010)
  • A.S. de Vos et al.

    Hepatitis C Virus treatment as prevention among injecting drug users: Who should we cure first?

    Addiction

    (2015, June)
  • R.B. Dimova et al.

    Determinants of hepatitis C virus treatment completion and efficacy in drug users assessed by meta-analysis

    Clinical Infectious Diseases

    (2013)
  • Cited by (143)

    • Investigating the sociodemographic and behavioural factors associated with hepatitis C virus testing amongst people who inject drugs in England, Wales and Northern Ireland: A quantitative cross-sectional analysis

      2022, International Journal of Drug Policy
      Citation Excerpt :

      Crucially, testing for HCV once in a lifetime is insufficient for people who currently inject drugs. This is due to the continued risk of infection which can accompany ongoing injecting drug use, borne out of unsafe injecting practices such as sharing injecting equipment (Grebely et al., 2015). Those who have previously successfully cleared the virus can similarly remain at risk of reinfection if they continue to inject drugs (Grebely et al., 2017; Lafferty et al., 2018; Midgard et al., 2016; The Hepatitis C Trust & HCV Action, 2022; Yeung et al., 2022).

    View all citing articles on Scopus
    View full text