Elsevier

The Lancet

Volume 385, Issue 9973, 21–27 March 2015, Pages 1124-1135
The Lancet

Seminar
Hepatitis C

https://doi.org/10.1016/S0140-6736(14)62401-6Get rights and content

Summary

Hepatitis C virus (HCV) infection is a major health problem worldwide. The effects of chronic infection include cirrhosis, end-stage liver disease, and hepatocellular carcinoma. As a result of shared routes of transmission, co-infection with HIV is a substantial problem, and individuals infected with both viruses have poorer outcomes than do peers infected with one virus. No effective vaccine exists, although persistent HCV infection is potentially curable. The standard of care has been subcutaneous interferon alfa and oral ribavirin for 24–72 weeks. This treatment results in a sustained virological response in around 50% of individuals, and is complicated by clinically significant adverse events. In the past 10 years, advances in HCV cell culture have enabled an improved understanding of HCV virology, which has led to development of many new direct-acting antiviral drugs that target key components of virus replication. These direct-acting drugs allow for simplified and shortened treatments for HCV that can be given as oral regimens with increased tolerability and efficacy than interferon and ribavirin. Remaining obstacles include access to appropriate care and treatment, and development of a vaccine.

Introduction

First discovered in 1989, hepatitis C virus (HCV) is a major health problem affecting more than 170 million people worldwide.1 The percentage of people who are seropositive for anti-HCV antibodies worldwide is estimated to have increased from 2·3% to 2·8% between 1990 and 2005.2 Central and east Asia, north Africa, and the Middle East have the highest prevalence (>3·5%), with moderate prevalence in eastern and western Europe (1·5–3·5%).2 Most patients (80–85%) who become acutely infected cannot clear the virus and progress to chronic infection. This percentage is higher for patients who are co-infected with HIV, and is lower for women and children.3, 4 The severe results of chronic infection are cirrhosis, portal hypertension, hepatic decompensation, and the development of hepatocellular carcinoma, with HCV infection ultimately causing around 350 000 deaths per year.5 In regions of high endemicity, chronic viral hepatitis usually accounts for more than 50% of hepatocellular carcinoma and cirrhosis.6 27% of cases of cirrhosis worldwide can be attributed to HCV, and 25% of hepatocellular carcinoma cases are attributable to HCV infection. Individuals chronically infected with HCV have a decreased quality of life compared with the general population.7

For many years, treatment for chronic HCV has been inadequate (success rates of ∼50%, depending on genotype). The standard of care until 2011 was a combination of subcutaneous pegylated interferon (peginterferon) alfa and oral ribavirin. This combination can lead to a sustained virological response (SVR). Because SVR is regarded as a cure, chronic HCV can be cured by medical treatment, although this does not prevent future reinfection. However, treatment is associated with clinically significant adverse events, and is poorly tolerated and less efficacious in patients with advanced disease.8 The introduction of direct-acting antiviral drugs (DAAs), with two protease inhibitor (PI) drugs licensed in 2011, has increased the number of patients who respond to treatment, and marks a new era of HCV treatment (figure 1).9, 10, 11, 12 New DAAs are in various stages of preclinical and clinical development, leading to optimism about future management of chronic HCV.13

Section snippets

Virology

HCV is a positive-sense, single-stranded 9600 kb RNA virus. A single HCV polyprotein of 3011 aminoacids is translated, and then cleaved by cellular and viral proteases into three structural proteins (core, E1, and E2) and seven non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B).14 Related viral sequences have been identified in dogs,15 horses,16 rodents, and bats.17 HCV infections in human populations show extreme genetic diversity, which is partly explained by the long

Immunology

Immune responses to HCV affect the outcome of acute disease and long-term disease progression. Acute responses to HCV include both innate and adaptive branches of the immune system. Polymorphisms in the region of the IFNL3 (also known as IL28B) gene strongly affect spontaneous resolution of infection.29 IFNL3 codes for interferon, lambda 3, which has sustained antiviral activity similar to that of interferon, but with a more restricted receptor distribution. Whether the identified polymorphisms

Epidemiology

HCV is an established parenteral cause of viral hepatitis.38 Transmission via blood transfusion was a major route before universal screening of blood in the developed world, but this transmission route is a problem elsewhere.39 Intravenous drug use, sharing of drug paraphernalia, and reuse of injection needles have become the major routes of HCV transmission.40, 41

The natural history of HCV in pregnancy and in infants born to mothers with HCV is poorly understood, and thus effective methods for

Diagnosis

Diagnosis of HCV relies on detection of antibody to the virus and nucleic acid amplification tests to detect HCV RNA. Antibody tests have improved substantially since their approval by the US Food and Drug Administration in 1990.63 HCV RNA is detected early in infection (∼2 weeks), and will be followed by antibody seroconversion days to weeks later (∼6 weeks), although development of detectable antibody can be delayed, or might not occur at all in immunocompromised patients.64 HCV-specific

Acute HCV

Most acute infections are asymptomatic and anicteric.69 Typically, 10–14 weeks after infection, an increase in serum aminotransaminases occurs.70 The early peak in HCV viral RNA load is sometimes followed by a transient decline,69 and approximately 15–20% of patients will clear acute infection.3, 69, 71 Factors that have been shown to be associated with spontaneous clearance of HCV infection include being female, IFNL3 polymorphisms, high alanine aminotransferase concentrations, presence of

Natural history

HCV infection causes chronic hepatitis, potentially leading to cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma. The onset and accumulation of hepatic fibrosis is clinically silent in the early stages of disease, and identification of disease progression is therefore difficult.79, 80 The yearly incidence of progression of hepatic fibrosis from minimal disease to cirrhosis has been modelled and estimated. The prevalence of biopsy-proven cirrhosis after 20 years of infection has

Treatment

The main goal of treatment for chronic HCV is cure, and thus prevention of disease progression. SVR (defined as HCV RNA <15 IU/mL 12–24 weeks after completion of antiviral therapy) is associated with reduction of both all-cause and liver-related mortality from HCV.84, 85 A combination of peginterferon and ribavirin, given for up to 48 weeks, was previously the mainstay of treatment for all genotypes of HCV, but is being superseded by DAAs (figure 2). No prophylactic vaccine exists, but several

Conclusions

Improved, efficacious and simplified interferon-free and, for most patients, ribavirin-free treatments for HCV infection are now available. Detailed guidelines, treatment algorithms, and licensing information, which will be updated at frequent intervals, are being published to guide clinicians. Simple all-oral regimens of short duration have become a reality. Treatment can now be given to groups of patients for whom interferon was contraindicated. Evidence is emerging that patients on stable

Search strategy and selection criteria

We searched Medline and PubMed with the search terms “HCV” and “hepatitis C virus”, together with “epidemiology”, “clinical manifestation”, “virology”, “diagnosis”, “biopsy”, “treatment”, “drugs”, “immunology”, or “vaccines”. We selected publications mostly from the past 5 years, but did not exclude commonly referenced and highly regarded older publications.

Contributors

All authors contributed equally in writing sections of the manuscript that suited their expertise. All authors reviewed the

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