Review
Hepatitis C virus (HCV) disease progression in people who inject drugs (PWID): A systematic review and meta-analysis

https://doi.org/10.1016/j.drugpo.2015.07.004Get rights and content

Highlights

  • Early engagement in HCV needs to be a policy priority to address HCV as a source of serious disease in PWID.

  • The natural history of HCV among PWID was explored through systematic review and data synthesis.

  • Few people who inject drugs are engaged in needed care for chronic HCV infection.

  • PWID infected with HCV will develop liver sequelae in mid- to late-adulthood if left untreated.

Abstract

Background

Understanding HCV disease progression rates among people who inject drugs (PWID) is important to setting policy to expand access to detection, diagnosis and treatment, and in forecasting the burden of disease. In this paper we synthesize existing data on the natural history of HCV among PWID, including fibrosis progression rates (FPR) and the incidence of compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC).

Methods

We conducted electronic and manual searches for published and unpublished literature. Reports were eligible if they (i) included participants who were chronically infected with HCV and reported current or previous injection drug use; (ii) presented original data on disease progression in a study sample comprised of at least 90% PWID; (iii) published between January 1, 1990, and December 31, 2013; and (iv) included data from upper-middle- or high-income countries. Quality ratings were assigned using an adaptation of the Quality In Prognosis Studies (QUIPS) tool. We estimated pooled FPRs using the stage-constant and stage-specific methods, and pooled incidence rates of CC, DC, and HCC.

Results

Twenty-one reports met the study inclusion criteria. Based on random-effect models, the pooled stage-constant FPR was 0.117 METAVIR units per year (95% CI, 0.099–0.135), and the stage-specific FPRs were F0  F1, 0.128 (95% CI 0.080, 0.176); F1  F2, 0.059 (95% CI 0.035, 0.082); F2  F3, 0.078 (95% CI 0.056, 0.100); and F3  F4, 0.116 (95% CI 0.070, 0.161). The pooled incidence rates of CC, DC, and HCC were 6.6 (95% CI 4.8, 8.4), 1.1 (95% CI 0.8, 1.4), and 0.3 (95% CI −0.1, 0.6) events per 1000 person-years, respectively. Following the stage-constant estimate, average time to cirrhosis is 34 years post-infection, and time to METAVIR stage F3 is 26 years; using the stage-specific estimates, time to cirrhosis is 46 years and time to F3 is 38 years.

Conclusion

Left untreated, PWID with chronic HCV infection will develop liver sequelae (including HCC) in mid- to late-adulthood. Delaying treatment with the new drug regimens until advanced fibrosis develops prolongs the period of infectiousness to perhaps thirty years. Scaling up of effective HCV prevention and early engagement in care and treatment will facilitate the elimination HCV as a source of serious disease in PWID.

Introduction

Hepatitis C virus (HCV) infection is a chronic blood-borne viral infection that is of global importance (Averhoff et al., 2012, Nelson et al., 2011). Approximately 160 million people, or 2–3% of the world's population, have chronic HCV; chronic HCV accounts for one-quarter of cases of cirrhosis and hepatocellular carcinoma (HCC) (Averhoff et al., 2012, Lavanchy, 2011, Nelson et al., 2011, World Health Organization, 2014). The vast majority of incident and prevalent HCV infections in the world are related to unsafe medical and illicit drug injections (Colvin & Mitchell, 2010). In most high-income countries, the primary route of HCV transmission is due to drug injection. HCV is concentrated in people who inject drugs (PWID) in these countries (Aceijas and Rhodes, 2007, Nelson et al., 2011), and approximately 50–80% of PWID are chronically infected (Nelson et al., 2011, Wiessing et al., 2014).

Viral and host factors hinder the detection, diagnosis and treatment of HCV in PWID (Hagan, 2011). Acute infection is typically asymptomatic and chronically infected individuals may not develop significant sequelae for decades after initial infection (Grebely et al., 2012). If left untreated, chronic liver disease will occur in 60–70%, cirrhosis in 5–20%, and 1–5% will die from decompensated cirrhosis or HCC (Rein et al., 2011). It has been estimated that fewer than 5% of PWID have received treatment for chronic HCV (Adeyemi et al., 2004, Grebely et al., 2009).

New HCV treatments feature shorter drug regimens with manageable side effects, and are highly likely to result in cure (Kohli, Shaffer, Sherman, & Kottilil, 2014). However these options are expensive and treatment eligibility guidelines may explicitly exclude active drug users (Fralick, 2014, Harris and Rhodes, 2013Robaeys et al., 2013, World Health Organization, 2014). Many US states’ public insurance programs (e.g., Medicaid) have restricted coverage of these new treatments to those with more advanced disease, i.e., METAVIR fibrosis stages 3 or 4, which may delay treatment for years; this restriction will disproportionately affect PWID and other low-income patients (Viohl & Associates, 2014). These restrictions also are in conflict with new HCV treatment guidelines from the American Association for the Study of Liver Disease (2015), which state explicitly that active injection drug users should be prioritized for treatment in part because of the risk of transmission to susceptible injection partners.

Understanding HCV disease progression rates among PWID is important to setting policy to expand access to detection, diagnosis and treatment, and in forecasting the burden of disease. In this paper we synthesize existing data on the natural history of HCV among PWID, including fibrosis progression rates and the incidence of compensated cirrhosis (CC), decompensated cirrhosis (DC), and HCC. Prior systematic reviews of HCV disease progression in PWID did not explicitly exclude studies of HIV-HCV co-infected patients. Because the majority of PWID with HCV are mono-infected, it is important to characterize this group separately. Estimates from the analysis will be used to inform simulations of the impact and cost-effectiveness of HCV management among PWID. This systematic review and meta-analysis and related simulations are conducted as part of the HCV Synthesis Project (see Hagan et al., 2014, Jordan et al., 2014), which is funded to develop guidance and recommendations for HCV control strategies for the US.

Section snippets

Search strategy

A combination of manual and electronic searches for published literature, including scientific conference websites and abstract books, were conducted within the databases of Ovid, Proquest, PubMed, and Web of Science. Variations of the search string consisted of keywords such as “HCV,” “hepatitis C,” “PWID,” “injection drug use,” “intravenous drug use,” “natural history,” “disease progression,” “survival,” “fibrosis,” “cirrhosis,” “hepatocellular carcinoma,” and “end stage liver disease.” The

Overview of included reports

As presented in Fig. 1, 21 unique reports were included in this review. Table 1, Table 2 present the pooled estimates and characteristics of the included reports for each of the four main outcomes of interest: FPR (10 reports), CC (15 reports), DC (4 reports), and HCC (5 reports). The geographic scope of the data focused largely on Europe where 11 reports (52%) originated; a smaller percentage represented data from the United States (5; 24%) and Australia (5; 24%). A total of 8502 unique PWID

Discussion

This systematic review synthesized the available data on the progression of fibrosis and the incidence of severe hepatic sequelae in PWID with chronic HCV infection. Random-effects estimation generated a stage-constant FPR of 0.117 and stage-specific FPRs of 0.128 (F0  F1), 0.059 (F1  F2), 0.078 (F2  F3), and 0.116 (F3  F4). The stage-constant rate (0.117) is within the range (and near the midpoint) of other stage-constant estimates from samples of HIV-negative patients with HCV infection due to

Acknowledgements

We would like to gratefully acknowledge Dr. Jason Fletcher for his statistical assistance. This study is supported by the National Institutes of Health, grant numbers R01DA034637 and P30 DA011041.
Conflict of interest: The authors have no conflicts of interest to disclose.

References (70)

  • P. McGuinness et al.

    Intrahepatic hepatitis C RNA levels do not correlate with degree of liver injury in patients with chronic hepatitis C

    Hepatology

    (1996)
  • P. Nelson et al.

    The epidemiology of viral hepatitis among people who inject drugs: Results of global systematic reviews

    The Lancet Infectious Diseases

    (2011)
  • S. Pol et al.

    Retrospective analysis of the impact of HIV infection and alcohol use on chronic hepatitis C in a large cohort of drug users

    Journal of Hepatology

    (1998)
  • T. Poynard et al.

    Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C

    Journal of Hepatology

    (2001)
  • D. Rein et al.

    Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States

    Digestive and Liver Disease

    (2011)
  • M. Sweeting et al.

    Estimated progression rates in three United Kingdom hepatitis C cohorts differed according to method of recruitment

    Journal of Clinical Epidemiology

    (2006)
  • Z. Younossi et al.

    The impact of the new antiviral regimens on patient reported outcomes and health economics of patients with chronic hepatitis C

    Digestive and Liver Disease

    (2014)
  • O. Adeyemi et al.

    Hepatitis C treatment eligibility in an urban population with and without HIV coinfection

    AIDS Patient Care STDs

    (2004)
  • American Association for the Study of Liver Diseases, Infectious Diseases Society of America, & International Antiviral Society—USA

    Recommendations for testing, managing, and treating hepatitis C

    (2015)
  • F. Averhoff et al.

    Global burden of hepatitis C: Considerations for healthcare providers in the United States

    Clinical Infectious Diseases

    (2012)
  • T. Babor et al.

    AUDIT. The Alcohol Use Disorders Identification Test: Guidelines for use in primary care

    (2001)
  • Y. Benhamou et al.

    Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients

    Hepatology

    (1999)
  • S. Chen et al.

    The natural history of hepatitis C virus (HCV) infection

    International Journal of Medical Sciences

    (2006)
  • L. de Lucca Schiavon et al.

    Non-invasive diagnosis of liver fibrosis in chronic hepatitis C

    World Journal of Gastroenterology

    (2014)
  • H. Fallatah

    Noninvasive biomarkers of liver fibrosis: An overview

    Advances in Hepatology

    (2014)
  • M. Fralick

    Screening urged for hepatitis C but drug costs are prohibitive

    Canadian Medical Association Journal

    (2014)
  • S. Gordon et al.

    Clinical outcome of hepatitis C as a function of mode of transmission

    Hepatology

    (1998)
  • J. Grebely et al.

    Low uptake of treatment for hepatitis C virus infection in a large community-based study of inner city residents

    Journal of Viral Hepatitis

    (2009)
  • H. Hagan

    Agent, host, and environment: Hepatitis C virus in people who inject drugs

    The Journal of Infectious Diseases

    (2011)
  • H. Hagan et al.

    Hepatitis C virus infection among HIV-positive men who have sex with men: Protocol for a systematic review and meta-analysis

    Systematic Reviews

    (2014)
  • H. Hagan et al.

    A systematic review and meta-analysis of interventions to prevent hepatitis C virus seroconversion in people who inject drugs

    Journal of Infectious Diseases

    (2011)
  • M. Harris et al.

    Hepatitis C treatment access and uptake for people who inject drugs: A review mapping the role of social factors

    Harm Reduction Journal

    (2013)
  • J. Hayden et al.

    Evaluation of the quality of prognosis studies in systematic reviews

    Annals of Internal Medicine

    (2006)
  • J. Hayden et al.

    Assessing bias in studies of prognostic factors

    Annals of Internal Medicine

    (2013)
  • Cited by (76)

    • Empfehlungen zur Hepatitis Versorgung bei Drogenkonsumierenden

      2023, International Journal of Drug Policy
    View all citing articles on Scopus
    View full text