Semin Liver Dis 2011; 31(4): 331-339
DOI: 10.1055/s-0031-1297922
© Thieme Medical Publishers

What Is Killing People with Hepatitis C Virus Infection?

Jason Grebely1 , Gregory J. Dore1
  • 1Viral Hepatitis Clinical Research Program, The Kirby Institute for Infection and Immunity in Society, The University of New South Wales, Sydney, Australia
Further Information

Publication History

Publication Date:
21 December 2011 (online)

ABSTRACT

The burden of hepatitis C virus (HCV)-related morbidity and mortality continues to rise. Progression to advanced liver disease among HCV-infected individuals generally requires decades, but we are entering an era where those infected with HCV in the 1970s and 1980s are at significant risk of mortality. Liver disease has overtaken drug-related harm as the major cause of mortality in HCV-infected individuals in many settings. Direct-acting antiviral therapies have provided renewed optimism, but HCV treatment uptake will need to increase markedly to reduce liver disease mortality. This review provides updated information on the natural history of HCV, disease-specific causes of mortality among people with HCV, estimates and projections of HCV-related disease burden and mortality and individual and population-level strategies to reduce mortality. The considerable variability in mortality rates within subpopulations of people with HCV will be outlined, such as in people who inject drugs and those with HIV co-infection.

REFERENCES

  • 1 Thompson A, Patel K, Tillman H, McHutchison J G. Directly acting antivirals for the treatment of patients with hepatitis C infection: a clinical development update addressing key future challenges.  J Hepatol. 2009;  50 (1) 184-194
  • 2 Omland L H, Jepsen P, Krarup H DANVIR Cohort Study et al. Increased mortality among persons infected with hepatitis C virus.  Clin Gastroenterol Hepatol. 2011;  9 (1) 71-78
  • 3 El-Kamary S S, Jhaveri R, Shardell M D. All-cause, liver-related, and non-liver-related mortality among HCV-infected individuals in the general US population.  Clin Infect Dis. 2011;  53 (2) 150-157
  • 4 McDonald S A, Hutchinson S J, Bird S M et al.. The growing contribution of hepatitis C virus infection to liver-related mortality in Scotland.  Euro Surveill. 2010;  15 (18) 19562
  • 5 Amin J, Law M G, Bartlett M, Kaldor J M, Dore G J. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study.  Lancet. 2006;  368 (9539) 938-945
  • 6 Duberg A S, Törner A, Davidsdóttir L et al.. Cause of death in individuals with chronic HBV and/or HCV infection, a nationwide community-based register study.  J Viral Hepat. 2008;  15 (7) 538-550
  • 7 McDonald S A, Hutchinson S J, Bird S M et al.. A population-based record linkage study of mortality in hepatitis C-diagnosed persons with or without HIV coinfection in Scotland.  Stat Methods Med Res. 2009;  18 (3) 271-283
  • 8 Walter S R, Thein H H, Amin J et al.. Trends in mortality after diagnosis of hepatitis B or C infection: 1992-2006.  J Hepatol. 2011;  54 (5) 879-886
  • 9 Altekruse S F, McGlynn K A, Reichman M E. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.  J Clin Oncol. 2009;  27 (9) 1485-1491
  • 10 Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, 1980-2004.  Hepatology. 2008;  48 (1) 137-145
  • 11 Bosetti C, Levi F, Lucchini F, Zatonski W A, Negri E, La Vecchia C. Worldwide mortality from cirrhosis: an update to 2002.  J Hepatol. 2007;  46 (5) 827-839
  • 12 Volk M L, Tocco R, Saini S, Lok A S. Public health impact of antiviral therapy for hepatitis C in the United States.  Hepatology. 2009;  50 (6) 1750-1755
  • 13 NCHECR .Epidemiological and economic impact of potential increased hepatitis C treatment uptake in Australia. Sydney, Australia: National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales; 2010
  • 14 Werb D, Wood E, Kerr T, Hershfield N, Palmer R W, Remis R S. Treatment costs of hepatitis C infection among injection drug users in Canada, 2006–2026.  Int J Drug Policy. 2011;  22 (1) 70-76
  • 15 Lettmeier B, Mühlberger N, Schwarzer R et al.. Market uptake of new antiviral drugs for the treatment of hepatitis C.  J Hepatol. 2008;  49 (4) 528-536
  • 16 NCHECR .HIV, viral hepatitis, and sexually transmissible infections in Australia Annual Surveillance Report. Sydney, Australia: National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales; 2010
  • 17 Mehta S H, Genberg B L, Astemborski J et al.. Limited uptake of hepatitis C treatment among injection drug users.  J Community Health. 2008;  33 (3) 126-133
  • 18 Grebely J, Genoway K, Khara M 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.  Int J Drug Policy. 2007;  18 (5) 437-443
  • 19 Grebely J, Bryant J, Hull P et al.. Factors associated with specialist assessment and treatment for hepatitis C virus infection in New South Wales, Australia.  J Viral Hepat. 2011;  18 (4) e104-e116
  • 20 Strathdee S A, Latka M, Campbell J Study to Reduce Intravenous Exposures Project et al. Factors associated with interest in initiating treatment for hepatitis C Virus (HCV) infection among young HCV-infected injection drug users.  Clin Infect Dis. 2005;  40 (Suppl 5) S304-S312
  • 21 Grebely J, Dore G J. An expanding role for primary care providers in the treatment of hepatitis C virus infection in the community.  Hepatology. 2011. In press
  • 22 Micallef J M, Kaldor J M, Dore G J. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies.  J Viral Hepat. 2006;  13 (1) 34-41
  • 23 Seeff L B. Natural history of chronic hepatitis C.  Hepatology. 2002;  36 (5, Suppl 1) S35-S46
  • 24 Aitken C K, Lewis J, Tracy S L et al.. High incidence of hepatitis C virus reinfection in a cohort of injecting drug users.  Hepatology. 2008;  48 (6) 1746-1752
  • 25 Mehta S H, Cox A, Hoover D R et al.. Protection against persistence of hepatitis C.  Lancet. 2002;  359 (9316) 1478-1483
  • 26 Micallef J M, Macdonald V, Jauncey M et al.. High incidence of hepatitis C virus reinfection within a cohort of injecting drug users.  J Viral Hepat. 2007;  14 (6) 413-418
  • 27 Osburn W O, Fisher B E, Dowd K A et al.. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection.  Gastroenterology. 2010;  138 (1) 315-324
  • 28 Page K, Hahn J A, Evans J et al.. Acute hepatitis C virus infection in young adult injection drug users: a prospective study of incident infection, resolution, and reinfection.  J Infect Dis. 2009;  200 (8) 1216-1226
  • 29 Grebely J, Conway B, Raffa J D, Lai C, Krajden M, Tyndall M W. Hepatitis C virus reinfection in injection drug users.  Hepatology. 2006;  44 (5) 1139-1145
  • 30 van de Laar T J, Molenkamp R, van den Berg C et al.. Frequent HCV reinfection and superinfection in a cohort of injecting drug users in Amsterdam.  J Hepatol. 2009;  51 (4) 667-674
  • 31 Seeff L B. The history of the “natural history” of hepatitis C (1968–2009).  Liver Int. 2009;  29 (Suppl 1) 89-99
  • 32 Freeman A J, Dore G J, Law M G et al.. Estimating progression to cirrhosis in chronic hepatitis C virus infection.  Hepatology. 2001;  34 (4 Pt 1) 809-816
  • 33 Thein H H, Yi Q, Dore G J, Krahn M D. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis.  AIDS. 2008;  22 (15) 1979-1991
  • 34 Thein H H, Yi Q, Dore G J, Krahn M D. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.  Hepatology. 2008;  48 (2) 418-431
  • 35 Kenny-Walsh E. Irish Hepatology Research Group . Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.  N Engl J Med. 1999;  340 (16) 1228-1233
  • 36 Wiese M, Berr F, Lafrenz M, Porst H, Oesen U. Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in Germany: a 20-year multicenter study.  Hepatology. 2000;  32 (1) 91-96
  • 37 Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.  Lancet. 1997;  349 (9055) 825-832
  • 38 Wiley T E, Brown J, Chan J. Hepatitis C infection in African Americans: its natural history and histological progression.  Am J Gastroenterol. 2002;  97 (3) 700-706
  • 39 Sterling R K, Stravitz R T, Luketic V A et al.. A comparison of the spectrum of chronic hepatitis C virus between Caucasians and African Americans.  Clin Gastroenterol Hepatol. 2004;  2 (6) 469-473
  • 40 Vogt M, Lang T, Frösner G et al.. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening.  N Engl J Med. 1999;  341 (12) 866-870
  • 41 Casiraghi M A, De Paschale M, Romanò L et al.. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth.  Hepatology. 2004;  39 (1) 90-96
  • 42 Minola E, Prati D, Suter F et al.. Age at infection affects the long-term outcome of transfusion-associated chronic hepatitis C.  Blood. 2002;  99 (12) 4588-4591
  • 43 Ostapowicz G, Watson K J, Locarnini S A, Desmond P V. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection.  Hepatology. 1998;  27 (6) 1730-1735
  • 44 Harris D R, Gonin R, Alter H J National Heart, Lung, and Blood Institute Study Group et al. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse.  Ann Intern Med. 2001;  134 (2) 120-124
  • 45 Hutchinson S J, Bird S M, Goldberg D J. Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis.  Clin Gastroenterol Hepatol. 2005;  3 (11) 1150-1159
  • 46 Graham C S, Baden L R, Yu E et al.. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis.  Clin Infect Dis. 2001;  33 (4) 562-569
  • 47 Ragni M V, Belle S H. Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C virus infection.  J Infect Dis. 2001;  183 (7) 1112-1115
  • 48 Thomas D L, Shih J W, Alter H J et al.. Effect of human immunodeficiency virus on hepatitis C virus infection among injecting drug users.  J Infect Dis. 1996;  174 (4) 690-695
  • 49 Grebely J, Raffa J D, Lai C et al.. Impact of hepatitis C virus infection on all-cause and liver-related mortality in a large community-based cohort of inner city residents.  J Viral Hepat. 2011;  18 (1) 32-41
  • 50 Pontisso P, Gerotto M, Benvegnù L, Chemello L, Alberti A. Coinfection by hepatitis B virus and hepatitis C virus.  Antivir Ther. 1998;  3 (Suppl 3) 137-142
  • 51 Gaeta G B, Stornaiuolo G, Precone D F et al.. Epidemiological and clinical burden of chronic hepatitis B virus/hepatitis C virus infection. A multicenter Italian study.  J Hepatol. 2003;  39 (6) 1036-1041
  • 52 Monto A, Alonzo J, Watson J J, Grunfeld C, Wright T L. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol.  Hepatology. 2002;  36 (3) 729-736
  • 53 Ratziu V, Munteanu M, Charlotte F, Bonyhay L, Poynard T. LIDO Study Group . Fibrogenic impact of high serum glucose in chronic hepatitis C.  J Hepatol. 2003;  39 (6) 1049-1055
  • 54 Hourigan L F, Macdonald G A, Purdie D et al.. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis.  Hepatology. 1999;  29 (4) 1215-1219
  • 55 Ortiz V, Berenguer M, Rayón J M, Carrasco D, Berenguer J. Contribution of obesity to hepatitis C-related fibrosis progression.  Am J Gastroenterol. 2002;  97 (9) 2408-2414
  • 56 Leandro G, Mangia A, Hui J HCV Meta-Analysis (on) Individual Patients' Data Study Group et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data.  Gastroenterology. 2006;  130 (6) 1636-1642
  • 57 Adinolfi L E, Gambardella M, Andreana A, Tripodi M F, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.  Hepatology. 2001;  33 (6) 1358-1364
  • 58 Singal A G, Volk M L, Jensen D, Di Bisceglie A M, Schoenfeld P S. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus.  Clin Gastroenterol Hepatol. 2010;  8 (3) 280-288, 288, e1
  • 59 Hézode C, Roudot-Thoraval F, Nguyen S et al.. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C.  Hepatology. 2005;  42 (1) 63-71
  • 60 Hsu P C, Federico C A, Krajden M et al.. Health utilities and psychometric quality of life in patients with early- and late-stage hepatitis C virus infection.  J Gastroenterol Hepatol. 2011;  Epub ahead of print
  • 61 Nelson P K, Mathers B M, Cowie B et al.. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews.  Lancet. 2011;  378 (9791) 571-583
  • 62 Degenhardt L, Hall W, Warner-Smith M. Using cohort studies to estimate mortality among injecting drug users that is not attributable to AIDS.  Sex Transm Infect. 2006;  82 (Suppl 3) iii56-iii63
  • 63 Degenhardt L, Bucello C, Mathers B et al.. Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies.  Addiction. 2011;  106 (1) 32-51
  • 64 Gibson A, Degenhardt L, Mattick R P, Ali R, White J, O'Brien S. Exposure to opioid maintenance treatment reduces long-term mortality.  Addiction. 2008;  103 (3) 462-468
  • 65 Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved.  Drug Alcohol Depend. 2009;  105 (1-2) 9-15
  • 66 Gibson A, Randall D, Degenhardt L. The increasing mortality burden of liver disease among opioid-dependent people: cohort study.  Addiction. 2011;  106 (12) 2186-2192
  • 67 Darke S, Kaye S, Duflou J. Comparative cardiac pathology among deaths due to cocaine toxicity, opioid toxicity and non-drug-related causes.  Addiction. 2006;  101 (12) 1771-1777
  • 68 Harris H E, Ramsay M E, Andrews N J. HCV National Register Steering Group . Survival of a national cohort of hepatitis C virus infected patients, 16 years after exposure.  Epidemiol Infect. 2006;  134 (3) 472-477
  • 69 Iloeje U H, Yang H I, Jen C L Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus Study Group et al. Risk and predictors of mortality associated with chronic hepatitis B infection.  Clin Gastroenterol Hepatol. 2007;  5 (8) 921-931
  • 70 Yang H I, Chen C J, Jen C L et al.. Causes of death associated with hepatitis B or hepatitis C virus infections in a long-term population-based cohort study. Paper presented at: Digestive Disease Week 2007; May 19–24, 2007; Washington, DC
  • 71 Thomas D L, Leoutsakas D, Zabransky T, Kumar M S. Hepatitis C in HIV-infected individuals: cure and control, right now.  J Int AIDS Soc. 2011;  14 22
  • 72 Thomas D L, Astemborski J, Rai R M et al.. The natural history of hepatitis C virus infection: host, viral, and environmental factors.  JAMA. 2000;  284 (4) 450-456
  • 73 Thomas D L, Astemborski J, Vlahov D et al.. Determinants of the quantity of hepatitis C virus RNA.  J Infect Dis. 2000;  181 (3) 844-851
  • 74 Goedert J J, Eyster M E, Lederman M M et al.. End-stage liver disease in persons with hemophilia and transfusion-associated infections.  Blood. 2002;  100 (5) 1584-1589
  • 75 Torriani F J, Rodriguez-Torres M, Rockstroh J K APRICOT Study Group et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.  N Engl J Med. 2004;  351 (5) 438-450
  • 76 Hadziyannis S J, Sette Jr H, Morgan T R PEGASYS International Study Group et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.  Ann Intern Med. 2004;  140 (5) 346-355
  • 77 Volberding P A, Deeks S G. Antiretroviral therapy and management of HIV infection.  Lancet. 2010;  376 (9734) 49-62
  • 78 Weber R, Sabin C A, Friis-Møller N et al.. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study.  Arch Intern Med. 2006;  166 (15) 1632-1641
  • 79 Bica I, McGovern B, Dhar R et al.. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection.  Clin Infect Dis. 2001;  32 (3) 492-497
  • 80 Lohse N, Hansen A B, Pedersen G et al.. Survival of persons with and without HIV infection in Denmark, 1995-2005.  Ann Intern Med. 2007;  146 (2) 87-95
  • 81 Gane E J, Roberts S K, Stedman C A et al.. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial.  Lancet. 2010;  376 (9751) 1467-1475
  • 82 Chak E, Talal A H, Sherman K E, Schiff E R, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence.  Liver Int. 2011;  Epub ahead of print
  • 83 Australian Government Department of Health and Ageing .Hepatitis C Subcommittee of the Ministerial Advisory Committee on AIDS SHH, the Blood Borne Virus and Sexually Transmissible Infections Subcommittee of the Australian Population Health Development Committee. National hepatitis C testing policy. Canberra: Australian Government Department of Health and Ageing; 2007
  • 84 Treloar C, Newland J, Harris M, Deacon R, Maher L. A diagnosis of hepatitis C - insights from a study on patients' experiences.  Aust Fam Physician. 2010;  39 (8) 589-592
  • 85 Vergniol J, Foucher J, Terrebonne E et al.. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C.  Gastroenterology. 2011;  140 (7) 1970-1979, 1979, e1–e3
  • 86 Grebely J, Bryant J, Hull P et al.. Factors associated with specialist assessment and treatment for hepatitis C virus infection in New South Wales, Australia.  J Viral Hepat. 2011;  18 (4) e104-e116
  • 87 Arora S, Thornton K, Murata G et al.. Outcomes of treatment for hepatitis C virus infection by primary care providers.  N Engl J Med. 2011;  364 (23) 2199-2207
  • 88 Shepard C W, Finelli L, Alter M J. Global epidemiology of hepatitis C virus infection.  Lancet Infect Dis. 2005;  5 (9) 558-567
  • 89 Hellard M, Sacks-Davis R, Gold J. Hepatitis C treatment for injection drug users: a review of the available evidence.  Clin Infect Dis. 2009;  49 (4) 561-573

Professor Gregory J. Dore

The Kirby Institute for Infection and Immunity in Society, University of New South Wales

CFI Building, Corner of Boundary and West Streets, Sydney NSW 2010, Australia

Email: [email protected]