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Hepatitis C 

Hepatitis C
Chapter:
Hepatitis C
Author(s):

Paul Klenerman

, K.J.M. Jeffery

, and J. Collier

DOI:
10.1093/med/9780199204854.003.070522_update_002

Update:

Genetic predictors of acute viral clearance and response to treatment.

Further information on directly acting antiviral agents (DAAs) and new drugs in development.

Updated on 31 May 2012. The previous version of this content can be found here.
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Essentials

Hepatitis C virus (HCV) is an RNA virus that has evolved into multiple genotypes (1–6) and subtypes. Humans are the only known natural host. HCV replication is highly error-prone, hence within any one person the virus exists as a swarm of closely related variants, known as ‘quasispecies’.

Epidemiology—HCV is a major cause of liver disease worldwide, with 170 million people probably infected. Spread is parenteral and usually associated with needle use, most commonly by injection drug users in the West; mother-to-child transmission does occur but is infrequent, as is sexual spread. Before the screening of blood products was introduced, blood transfusion recipients and patients with haemophilia were also at risk, and outbreaks in some countries (e.g. Egypt) have been associated with mass vaccination and parenteral therapy programmes.

Clinical aspects—these are discussed in detail in Chapter 15.21.1, but HCV tends to become persistent in most of those infected, although around 25% clear the virus as a result of effective innate and adaptive immune responses at the time of acute infection. The clinical course is variable in those with persistent infection: most develop some degree of hepatic inflammation and fibrotic liver disease, with a fraction going on to develop cirrhosis, with an increased risk of hepatocellular carcinoma. Cofactors which predispose to progression include simultaneous HIV infection and drinking alcohol.

Treatment: now and in the future—treatment is currently a combination of pegylated interferon-α‎ and ribavirin with or without a protease inhibitor, with outcome dependent on viral genotype. Future therapies will include other compounds directed against specific viral gene products (direct acting antiviral compound, DAA) such as polymerase inhibitors, but the capacity of the virus to mutate and thus evade both drug therapy and immune responses may be a major barrier to universal virus eradication.

Introduction

Hepatitis C virus (HCV) is a major global pathogen. Humans are the only known natural hosts, although chimpanzees have been infected experimentally. The origin of the virus in humans is not well established, but the huge genetic diversity and global distribution, together with analyses of the viral molecular clock, suggest that it has coevolved with human populations for centuries. In the 1990s, spread through changes in medical practice and injection drug use was recognized to have created an emerging problem. The capacity of the virus to persist despite host innate and adaptive immune responses makes it extremely challenging to develop vaccines. Although there have been major improvements in the efficacy of treatment regimens, they are still expensive, hard to deliver, and associated with serious side effects. Therefore, it is important to identify those who are most likely to benefit from the available therapies, based on the observed progression and likely response to treatment. Improved understanding of the viral replication cycle and the most effective immune responses is leading to more selective drugs and vaccines.

Historical perspective

Previously known as non-A, non-B hepatitis, HCV was recognized for many years before its discovery by Kuo and Houghton in 1988. It was soon identified as a major infectious agent and the development of antibody-based assays revealed its prevalence, and allowed the development of screening tools for blood products. The majority of chronic viral carriers were identified by detection of viral RNA in blood, while sequencing and bioinformatics approaches led to the description of diverse viral genotypes. Inability to culture the virus proved a major obstacle, but the development of a replicon system by Bartenschlager in 1999 was a major breakthrough, allowing a dissection of viral replication in vitro. However, no infectious virus system was available until 2005, when several groups used an unusual Japanese strain (JFH-1) to develop cell culture infectious systems.

Aetiology, genetics, pathogenesis, and pathology

HCV is a positive-sense single-stranded RNA virus. It is classed individually as an hepacivirus and is genetically closely related to flaviviruses, such as dengue virus. The viral RNA genome is approximately 10 kb in length and comprises a long, single open reading frame. The genome is typically divided into structural and nonstructural proteins. The structural proteins, contained within virions, comprise core and envelope (E1 and E2). The latter are glycosylated, form a heterodimer, and are important targets for antibodies. They are also highly variable and contain hypervariable regions (HVR1 and HVR2), which evolve rapidly under antibody selection pressure. The nonstructural proteins include enzymes with defined protease and helicase activity, and a viral polymerase.

Viral replication is initiated using an internal ribosomal entry site (IRES) in the 5′‎ untranslated region (5′‎ UTR). The latter is highly conserved, varying only slightly between genotypes and so is an important target for molecular diagnosis. The polymerase replicates the virus through a double-stranded intermediate, which is a substantial trigger for host innate responses. However, the virus can disable triggering of one of these pathways (RIG-I; retinoic acid inducible gene I) through the action of the protease, which cleaves a cellular target (Cardif; CARD adapter inducing interferon (IFN)-β‎). Another important feature is that replication is highly error-prone. Thus, within any one person, the virus exists as a swarm of closely related variants, known as ‘quasispecies’.

HCV usually replicates in hepatocytes. Virus has been observed in other cell types, including lymphocytes and dendritic cells, and within the central nervous system, but it is uncertain how this contributes to disease pathogenesis. A number of cellular receptors for HCV have been described including: CD81 (a member of the tetraspanin family with signalling properties on lymphocytes); the LDL (low-density lipoprotein) receptor; DC-SIGN (dendritic cell-specific ICAM3-grabbing nonintegrin); a macrophage scavenger receptor class B1 (SR B1); and Claudin-1 and Occludin, both components of tight junctions. None of these fully explains the hepatotropism of the virus.

After natural or experimental infection, virus may be detectable for weeks or months without any apparent clinical, biochemical, or immunological disturbance. During this time, virus may replicate to high levels in blood and within the liver, indicating the minimal direct cytopathic effects of the virus in the absence of host immune responses. This silent phase is followed by the onset of acute hepatitis, which is not always clinically apparent. Detailed intrahepatic studies in animal models (not possible in man) reveal that the first responses at this stage of infection are production of innate immune mediators (IFNs, NK cells), followed by an influx of T cells (both CD4+ and CD8+). In human studies of acute hepatitis C, the emergence of highly activated, virus-specific CD8+ T cells correlates quantitatively and temporally with the peak of the alanine aminotransferase (ALT), suggesting that tissue damage at this stage is a result largely of the host T-cell response.

The subsequent events vary substantially between different patients, but three clinical patterns are observed: clearance of virus below the level of detection in blood; persistence of virus without host control; or an intermediate state, where the virus is transiently controlled, but relapses. The immunological differences determining these outcomes are not clear, but include both innate and adaptive components. Polymorphisms linked to the IL28B gene indicate a major role for interferon-lambda in acute outcome (see below). Similarly, the association of specific HLA genes, both class II (such as HLA DR11/DQ3) and class I (such as HLA B27 and B57), with spontaneous resolution point to the importance of T-cell responses. The broader and more sustained in number and function the responses are, the more likely they are to be successful in viral control. B cell responses are also likely to be involved. However, the rapid emergence of viral escape mutants in the hypervariable envelope regions may limit the efficacy of neutralizing antibody responses in containing viral replication. Viral mutation within T-cell epitopes is also a major cause of persistence despite T-cell responses, although other phenomena such as T-cell exhaustion and the emergence of regulatory T-cell subsets also contribute to T-cell failure.

In the 25% in whom virus is cleared below the level of detection long term, antibody and T-cell responses may be detected for many years. In most people, virus persists after the acute hepatitis, despite the presence of antibody. T-cell responses in blood at this stage are weak, but infiltrates of T-cells may be found within the liver.

Liver histopathology due to HCV infection can vary greatly, and there is no diagnostic staining pattern. Portal tract infiltrates of T- and B-cells are typical, sometimes with the emergence of lymphoid follicles within liver tissue. Histological scores (Ishak’s, Metavir) have been developed to quantify the degree of liver damage. These assess the degree of hepatic inflammation (typically portal tract infiltration, ‘interface’ hepatitis, lobular infiltration and necrosis), and the degree of hepatic fibrosis.

The viral genotype is not thought to have a major effect on pathogenesis, although genotype 3 has been associated with the development of hepatic steatosis, which might contribute to increased inflammation and fibrosis.

Epidemiology

HCV is estimated to infect around 170 million people worldwide. Spread is parenteral, and usually associated with needle use (intravenous drug users, patients in parenteral therapy programmes, nosocomial spread) and exposure to infected blood products (recipients of unscreened blood or plasma fractions, haemophiliacs). Mother-to-child infection does occur, but at relatively low rates (around 3–5%), and sexual spread is also infrequent.

In the West, injection drug users have particularly high rates of acquisition and now represent the main focus of the infection. In some countries, notably Egypt, medical programmes have resulted in the spread of HCV in specific groups, and the 20% to 30% prevalence of HCV in some communities in Egypt is the highest worldwide.

HCV has evolved into multiple genotypes (1–6) and subtypes. Molecular typing techniques can trace the spread of individual strains within populations (including those from a single source). The Egyptian outbreak is genotype 4a, the older circulating Western strains were typically genotype 1a and 1b, and the more recent strains acquired by Western drug users are 3a. Genotype 3 viruses were originally found in Asia, where genotype 6 is still prevalent. Genotypes 2 and 5 have remained mainly localized to West and South Africa respectively, but all strains are tending to spread worldwide.

Prevention

Primary prevention

There are no licensed HCV vaccines. Primary prevention of HCV worldwide depends on ensuring a safe blood supply and sterile injection devices for all health care applications. Provision of sterile equipment to injection drug users has been shown to reduce the prevalence of HCV. Infection is not transmitted by normal household exposure, but household contacts of HCV-positive people should avoid sharing razors and toothbrushes. Sexual transmission of HCV is inefficient and studies show a low prevalence (average: 1.5%) of HCV infection in long-term partners of patients with chronic HCV infection who had no other risk factors. Multiple published studies have demonstrated that the prevalence of HCV infection among men who have sex with men (MSM) who were not injecting drugs, was similar to that in heterosexuals. However a high incidence of acute hepatitis C in HIV-positive MSM has recently been recognized.

No intervention has been shown clearly to decrease the risk of mother-to-child transmission of HCV, and breastfeeding is not discouraged. The risk of mother-to-child transmission is increased two- to three-fold if there is HIV/HCV co-infection. Medical workers should ensure aseptic techniques and appropriate equipment and facilities to reduce the risk of percutaneous injury.

Postexposure prophylaxis

Immune globulin is not effective in preventing HCV infection following exposure. Anyone exposed to the virus, e.g. following needlestick injury or perinatally, should be offered follow-up testing for HCV. The average risk of infection following a percutaneous injury is 1.8% (range 0–7%) and those who become infected should be offered early antiviral therapy.

Clinical features

Acute hepatitis C

Acute HCV infection is usually asymptomatic, but is otherwise clinically indistinguishable from other causes of acute viral hepatitis. There is prodromal fever, myalgia, and malaise. Compared with hepatitis A or B, classical symptoms of jaundice, pruritus, pale stools, and dark urine are unusual. Serum transaminase levels can be markedly elevated, although values of up to 10 times the upper limit of normal would be more usual. Fulminant hepatic failure is rare in acute HCV infection. There is evidence that patients with symptomatic acute HCV infection have a higher rate of spontaneous viral clearance than those with asymptomatic infection. Overall, approximately one in four patients will clear the virus spontaneously. In those with persistent virus, serum transaminases may return to normal, but they usually remain elevated at about twice the upper limit of normal (Fig. 7.5.22.1).

Fig. 7.5.22.1 Typical virological and biochemical test results following infection with hepatitis C in (a) patients who clear the virus (acute resolving) and (b) those that go on to get persistent infection (acute persistent). The time lines vary between patients and these are approximations based on human and chimpanzee model infections. Some patients, such as those with HIV, may never develop an antibody response. ALT, alanine aminotransferase.

Fig. 7.5.22.1
Typical virological and biochemical test results following infection with hepatitis C in (a) patients who clear the virus (acute resolving) and (b) those that go on to get persistent infection (acute persistent). The time lines vary between patients and these are approximations based on human and chimpanzee model infections. Some patients, such as those with HIV, may never develop an antibody response. ALT, alanine aminotransferase.

Polymorphisms in the region of the IL28B gene are important predictors of spontaneous clearance. In a single-source outbreak amongst Irish women, those with a favourable polymorphism had an odds ratio for spontaneous clearance of nearly fourfold. However, the mechanism underlying this substantial effect remains unclear.

Chronic infection

Chronic infection with HCV is defined as the persistence of HCV RNA in blood for more than 6 months. Most patients with chronic HCV are unaware of their diagnosis, and many will have been tested following an incidental finding of abnormal liver function tests or on routine screening, e.g. for blood donation, or having given a history of potential HCV exposure, such as injection drug use. Such patients may be asymptomatic or have nonspecific symptoms such as fatigue. Clinical features of liver disease are unlikely to be present unless cirrhosis has developed. Laboratory abnormalities such as hypoalbuminaemia, thrombocytopenia, and coagulopathy suggest cirrhosis, although this can only be confirmed histologically by liver biopsy.

HCV is associated with several extrahepatic manifestations, the best documented of which are HCV-related lymphoproliferative disorders, characteristically with mixed cryoglobulinaemia. Although studies suggest a high prevalence of serum cryoglobulins in HCV-positive patients, they are generally present at low levels with few, if any, symptoms. Occasionally, patients will present with neuropathies, arthralgias, and purpura. In more severe cases, there may be renal involvement (e.g. glomerulonephritis). In some studies, B-cell non-Hodgkin’s lymphomas, porphyria cutanea tarda, Sjögren’s syndrome, lichen planus, autoimmune thyroiditis, and type 2 diabetes mellitus have been found more frequently in association with HCV infection than in control groups.

Prognosis

The rate of progression of HCV is highly variable. Risk factors for progression include: older age at acquisition of infection; male gender; immunosuppression including HIV co-infection; and concurrent heavy alcohol consumption. It is estimated that 7 to 20% will develop cirrhosis within 20 years of infection. Progression rates are highest in those with transfusion-associated hepatitis. However, some groups, such as a cohort of Irish women infected in 1977 through contaminated blood products, show very low rates, with only 3% developing cirrhosis within 20 years of infection.

Once cirrhosis has developed, 80% will have complications such as ascites and variceal bleeding within 10 years. Fifty per cent of these patients will develop liver failure within a further 5 years. Hepatocellular carcinoma occurs only in the presence of cirrhosis, with an incidence of 1 to 5% per year. HIV coinfected patients progress more rapidly to liver failure once complications of cirrhosis have occurred.

Liver transplantation is indicated for decompensated HCV cirrhosis and for cirrhotics who develop a small hepatocellular carcinoma despite good liver function. The infection always recurs in the transplanted liver and progression to cirrhosis occurs in about 10% of transplant recipients within 5 years. Only about 20% of patients with recurrent HCV post-transplantation can be cured with pegylated IFN and ribavirin, which is often poorly tolerated.

Diagnosis

Serology

Initial diagnosis of HCV infection is usually made by detecting HCV antibody to recombinant HCV proteins in sensitive screening immunoassays. In low prevalence populations, the probability of a false positive antibody result is high, and supplementary confirmatory tests should be performed, such as immunoassays using different antigens. Alternatively, highly specific line or strip immunoblots (which have individual synthetic or recombinant antigens applied as separate lines to a solid phase) can distinguish different antigens to which the serum is reacting, and confirm the presence of HCV antibody.

Recent developments include assays which combine tests for antibody and HCV core antigen. These are useful for the diagnosis of acute infection (Fig. 7.5.22.1) as the HCV core antigen can be used to detect HCV infection during the window phase of infection. These assays are likely to be particularly useful for screening programmes (e.g. blood donation services and renal dialysis units). HCV core antigen may also have a role in informing response-guided therapy with treatment regimens whichinclude protease inhibitors. blood donations in developing countries. The appearance of HCV antibody after infection can take up to 2 months in immunocompetent people, and may be delayed or even absent in immunocompromised patients, such as those with HIV infection or those who are on haemodialysis. By 6 months, 97% of those infected will have developed an antibody response. It is good practice to confirm the presence of HCV antibody with a second sample.

HCV RNA testing

Nucleic acid tests are essential for the diagnosis of acute and chronic HCV infection, and should be used as supplementary tests for confirmation of HCV antibody tests. HCV RNA can be detected by polymerase chain reaction (PCR) as early as 2 weeks after infection, before the appearance of antibody. Several amplification techniques, including reverse transcriptase PCR (RT-PCR), transcription-mediated amplification (TMA), and branched DNA (bDNA) are available. Most commercial assays now produce quantitative results with increasingly sensitive limits of detection. Although quantitative tests (i.e. a measure of viral load, which may vary across several logs between individuals) may be important to predict the response to interferon (IFN) therapy (see below), in contrast to HIV infection they are not useful in predicting disease severity or long-term progression. Some countries have successfully introduced nucleic acid screening of pools of samples for blood donation.

Dried blood spot testing for both hepatitis C antibody and RNA is now widely available, and can be used to facilitate screening in certain groups, e.g. injection drug users engaging in needle-exchange programmes.

Pretreatment evaluation

HCV virus genotyping is essential before treatment as it determines the duration of treatment and the response (see below). Most genotyping methods are based on viral sequencing and subsequent phylogenetic analysis, or on the detection of nucleic acid mutations specific for individual genotypes. A pretreatment liver biopsy is frequently, but not always, performed to assess the degree of fibrosis. Noninvasive methods of assessing the degree of liver fibrosis using serum markers, and assessment of liver stiffness using an ultrasound probe (e.g. Fibroscan, FibroSure/FibroTest) are an alternative to liver biopsy as they can differentiate mild fibrosis from cirrhosis.

Genotyping of the patient for IL28B polymorphisms can also contribute to pretreatment evaluation. In genome-wide association studies (GWAS) of interferon/ribavirin therapy for genotype 1, a major impact of those IL28B polymorphisms which favour spontaneous clearance has been shown for treatment response. Together with other clinical markers this information can now be used to provide an indication of the likelihood of a successful response to conventional therapy.

Treatment

The aim of HCV therapy is to eradicate HCV RNA from serum. Although loss of viraemia is associated with improvement in liver histology, the risk of hepatocellular carcinoma remains if cirrhosis is present. Tumours have been detected up to 5 years after successful treatment with antiviral therapy. Screening of cirrhotic patients for hepatocellular carcinoma by ultrasound should therefore be continued.

HCV viraemia may re-emerge within 6 months of stopping treatment (relapse), but those who remain HCV RNA negative for 6 months are considered to be cured (sustained virus response, SVR)) and viraemia will not recur.

Hepatitis C Chronic hepatitis C

Interferon-α‎ and ribavirin underpin current treatments for chronic HCV infection. Interferon-α‎ (IFN-α‎) induces the expression of multiple genes with antiviral and antiproliferative actions, including those encoding RNAses, 2′‎,5′‎-oligoadenylate synthetase, and protein kinase R. It is given as pegylated IFN once weekly in combination with ribavirin. The two types of pegylated IFN-α‎, 2a and 2b, are IFN-α‎ molecules with modified side chains that prolong their half-lives. Ribavirin is a guanosine analogue which does not reduce HCV RNA levels when used alone but sustains virological suppression when combined with IFN-α‎.

Treatment success (SVR) is dependent on virus genotype. Following combination treatment with ribavirin (800–1000 mg/day orally) and pegylated IFN-α‎ (180µg/kg subcutaneously weekly for IFN-α‎2a, or 1.5 µg/kg subcutaneously weekly for IFN-α‎2b) the SVR in genotype 2 and 3 infection is 76 to 82%. For genotype 1 patients, 12  months of combination therapy only achieves an SVR in 42 to 46%. Predictors of an SVR include younger age, absence of cirrhosis, low HCV viral load (<400 000 IU/ml) and in genotype 1 patients, the presence of a favourable IL28B genotype. Response rates in genotype 4 are slightly better than for genotype 1 following 12 months therapy.

The poor response in genotype 1 patients has led to the development of first generation of directly acting antiviral (DAA) compounds with the licensing of two protease inhibitors, to be used in combination with pegylated interferon and ribavirin. In trials, both boceprevir and teleprevir increased the SVR in treatment-naive patients to around 70%, and may allow the duration of therapy to be reduced from 48 to 24 weeks. In previously treated patients who relapsed following therapy within 6 months, retreatment with interferon and ribavirin with the addition of teleprevir or boceprevir resulted in SVR in up to 88% of subjects, with up to 59% SVR rate in partial responders and 33% in previous nonresponders. The absence of a one-log drop in HCV viral load at 4 weeks is a useful predictor of nonresponse. The next generation of protease inhibitors and other DAAs are likely to have efficacy against other genotypes.

Coinfection with HIV is not a contraindication to therapy, although the efficacy of treatment is reduced. Twelve months of ribavirin and pegylated IFN-α‎ results in a sustained viral response in 29% of genotype 1 HCV/HIV coinfected patients and 62% in those with genotype 2 or 3. Data is awaited on the efficacy of newer agents in HCV/HIV coinfected patients.

Side effects of treatment are common and the quality of life is universally affected, although many patients are able to continue work during therapy. Treatment with IFN-α‎ is associated with fatigue, depression, and mood swings. Other adverse effects include rashes and thyroid abnormalities. Influenza-like symptoms are frequent within 6  h of the first dose, but often improve over the first few weeks. Bone marrow suppression is common and may warrant dose reductions, a particular problem in cirrhotic patients who are pancytopenic before starting treatment. IFN-α‎ is contraindicated in renal and cardiac transplant recipients for fear of inducing acute cellular rejection. Ribavirin causes haemolysis and frequently leads to a 2 to 3 g/dl drop in haemoglobin during treatment. As it is excreted by the kidney, it is contraindicated in renal failure. Complications of the protease inhibitors include severe rash (telaprevir) and anaemia (boceprevir).

Acute hepatitis C

The results of treating acute HCV infection are much better than in chronic infection. Up to 50% of patients with acute symptomatic HCV infection may clear the virus spontaneously within the first 3 months. Treatment should be started between 12 and 24 weeks of infection, allowing time to assess whether spontaneous resolution has occurred, without losing the clinical benefit of early treatment. Genotype does not substantially affect response and cure rates of 80 to 95% can be achieved.

The optimal regimen for treatment of acute hepatitis C remains to be determined, but guidelines suggest that pegylated IFN should be used in equivalent doses to those in chronic infection, and that ribavirin may be added (800 mg daily), although success may be achieved with monotherapy. At least 24 weeks of therapy is recommended. In HCV HIV co-infected patients, cohort studies support the addition of ribavirin to pegylated interferon.

Areas of uncertainty or controversy

The significance of finding residual viral RNA in lymphocytes and liver tissue after successful treatment with HCV or spontaneous resolution of acute infection is unclear. The mechanism of action of ribavirin, including its effect on the immune response, is not understood. The role of adaptive immunity in the pathogenesis of HCV and the response to treatment in acute and chronic infection is debated. The functional impact of the polymorphisms in and around IL28B require further dissection and the specific protective role of IFN lambdas remain to be defined.

Hepatitis C Likely future developments

There are more than 50 new DAAs targeting specific HCV enzymes in development: in addition to further protease inhibitors, these include drugs which interfere with NS5B RNA-dependent RNA polymerase, essential for virus replication. Nucleoside inhibitors of the HCV NS5B polymerase have been shown to have antiviral activity against several HCV genotypes, although the non-nucleoside polymerase inhibitors are primarily active against genotype 1. Phase 2 studies have demonstrated potent antiviral effects with polymerase inhibitors in combination with IFN and ribavirin, but drug toxicity has caused some agents to be withdrawn. Resistance to these agents can arise readily, resulting in reduced drug susceptibility. There is some evidence that resistance to the nucleoside inhibitors (which act as chain terminators) may arise less readily than resistance to the non-nucleoside (allosteric) inhibitors.

Other DAAs in development include the cyclophilin inhibitors. Cyclophilins are ubiquitously expressed proteins and have a role in the folding and isomerization of other proteins including those necessary for virus replication. Preliminary clinical studies have shown that in combination with IFN and ribavirin, cyclophilin inhibitors can boost SVR rates in treatment-naive genotype 1 patients, including those with unfavourable IL28B genotypes. Studies are under way in genotype 2 and 3 patients. Potential advantages may include a high barrier to resistance and a lack of cross-resistance with other DAAs.

It is hoped in future that combinations of DAAs acting at different points of the virus life-cycle will provide well tolerated, successful, oral, IFN-free regimens for both treatment-naive and treatment-experienced patients. The combination should be optimized to cross-resistance and prevent virological breakthrough. Proof-of-concept studies of protease and polymerase inhibitor combinations in human subjects achieved profound viral suppression and were well tolerated. In contrast to HIV, eradication of HCV infection should be achievable with short-course combination DAA.

Accessibility of current and newer HCV treatments on a global scale is essential if cirrhosis and hepatocellular carcinoma are to be prevented in most of the world’s HCV-infected population.

Further reading

Bacon BR, et al; HCV RESPOND-2 Investigators (2011). Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med, 364, 1207–17.Find this resource:

Benvegnu L, et al. (2004). Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut, 53, 744–49. [Important study showing the risk of complications of cirrhosis occurring over a 10 year period of follow-up.]Find this resource:

Dienstag JL, McHutchison JG (2006). American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology, 130, 231–64. [Comprehensive review of the management of HCV.]Find this resource:

di Iulio J, et al.; Swiss HIV Cohort Study (2011). Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance. Hepatology, 53, 1446–54. [Study identifying IL28B haplotypes highly predictive of spontaneous hepatitis C clearance.]Find this resource:

    Feld JJ, Hoofnagle JH (2005). Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature, 436, 967–72. [A review of how interferon and ribavirin act to eliminate HCV, with data on viral kinetics during treatment.]Find this resource:

    Ge D, et al. (2009). Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature, 461, 399–401. [Study showing that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3, is associated with an approximately twofold change in response to treatment.]Find this resource:

    Gee I, Alexander G (2005). Liver transplantation for hepatitis C virus related liver disease. Postgrad Med J, 81, 765–71. [Comprehensive review of management of recurrent HCV following liver transplantation and natural history.]Find this resource:

    Hadziyannis SJ, et al. (2004). Peginterferon –alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration ribavirin dose. Ann Intern Med, 140, 346–55. [A study showing that it is possible to treat genotypes 2 and 3 HCV with lower doses of ribavirin and shorter courses of pegylated interferon-α‎.]Find this resource:

    Jacobson IM, et al; ADVANCE Study Team. (2011). Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med, 364, 2405–16. [A study showing that it is possible to treat genotypes 2 and 3 HCV with lower doses of ribavirin and shorter courses of pegylated interferon-α‎.]Find this resource:

    Johnson RJ, et al. (1993). Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med, 328, 465–70. [One of the earliest papers to make a clear association between hepatitis C infection and an extrahepatic disorder.]Find this resource:

    Levine RA, et al. (2006). Assessment of fibrosis progression in untreated Irish women with chronic hepatitis C contracted from immunoglobulin anti-D. Clin-Gastroenterol Hepatol, 4, 1271–7. [Study of young women infected with hepatitis C showing that the risk of progression to cirrhosis 20 years following infection is much lower than 20% in some cohorts.]Find this resource:

    Maheshwari A, Ray S, Thuluvath PJ (2008). Acute hepatitis C. Lancet, 372, 321–32. [A comprehensive review of the presentation and treatment of acute hepatitis C.]Find this resource:

    Manns MP, et al. (2001). Peginterferon alfa -2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic HCV: a randomised trial. Lancet, 358, 958–65. [One of two large studies showing the improved efficacy of pegylated interferon in combination with ribavirin over standard interferon-α‎.]Find this resource:

    McHutchison JG, et al. (2009). Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med, 360, 1827–38. [Shows the added benefit of a novel targeted protease inhibitor in improved SVR and reduced treatment times for genotype 1.]Find this resource:

    Micallef JM, Kaldor JM, Dore GJ (2006). Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat, 13, 34–41. [Although clearance rates in the 19 studies (682 individuals) reviewed in this paper range from 0–80%, the overall clearance rate was 26%, with the largest study (67 individuals) having a clearance rate close to this. Women appeared to have a higher clearance rate than men.]Find this resource:

    Pépin J, Labbé AC (2008). Noble goals, unforeseen consequences: control of tropical diseases in colonial Central Africa and the iatrogenic transmission of blood-borne viruses. Trop Med Int Health, 13, 744–53.Find this resource:

    Poordad F, et al.; SPRINT-2 Investigators (2011). Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med, 364, 1195–206.Find this resource:

    Poynard T, Bedossa P, Opolon P (1997). Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet, 349, 825–32. [The first large retrospective cross-sectional study showing the wide variation in progression of hepatitis C fibrosis with cirrhosis occurring in around 20% within 20 years of infection.]Find this resource:

    Thursz M, et al. (1999). Influence of MHC class II genotype on outcome of infection with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research. Lancet, 354, 2119–24. [A host genetics study confirming the importance of specific HLA Class II genes (and CD4+ T cells) in determining the outcome of HCV.]Find this resource:

    Walker C, Bowen, D (2005). Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature, 436, 946–52. [A comprehensive account of the immunological responses against hepatitis C virus in human and model studies, including a discussion of the importance of immune escape through mutation.]Find this resource:

    Wakita T, et al. (2005). Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med, 11, 791–6. [A description of tissue culture replication competent virus—one of the studies opening the way to address fundamental aspects of HCV biology in vitro.]Find this resource:

    Zeuzem S, et al.; REALIZE Study Team (2011). Telaprevir for retreatment of HCV infection. N Engl J Med, 364, 2417–28. [4 randomised phase III studies demonstrating improved sustained virus response rates with the addition of protease inhibitor agents to interferon-α‎ and ribavirin.]Find this resource:

      Zignego AL, et al. (2006). Extrahepatic manifestations of Hepatitis C Virus infection: A general overview and guidelines for a clinical approach. Dig Liver Dis, 39, 2–17. [A review outlining recent evidence for extrahepatic disorders possibly associated with hepatitis C.]Find this resource: