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Chapter 13

Knowledge of Viral Hepatitis Now


13.1 This chapter provides an account of what is known now, in 2014, about Hepatitis C virus (HCV) infection, in particular in relation to the two affected groups with whom the Inquiry is concerned: blood disorder patients receiving therapy and people infected by blood transfusion in the course of medical or surgical procedures. Very little of what is described in this chapter about HCV was known, or could have been known, until well into the 1990s and much, indeed, has been understood only in the past few years.

13.2 The information set out in this chapter is intended, particularly, to inform and illuminate the accounts provided by patients and their relatives of experiences of HCV infection narrated in Chapters 4 and 6 of the Report.

13.3 As further background to an understanding of those accounts, this chapter also discusses the investigative procedures and forms of drug therapy associated with the diagnosis and treatment of HCV infection, with particular reference to the side-effects of treatment.


13.4 At the date of the Inquiry's Preliminary Report (2010), the group of hepatitis viruses had not been finally defined but it was thought there were six, viruses A to E and G, as described in a standard textbook of 2007.[1] The current view is that virus G is not a hepatitis virus in humans. Now known as GBV-C and a member of a family of flaviviruses, it causes hepatitis in marmosets but humans who are infected do not develop liver disease.[2] However, it cannot be assumed that the class is now closed: research continues. Equally, the signs, symptoms, natural history and complications of viral hepatitis, generally and for each specific disease, have been and are the subject of ongoing research and have not been finally resolved. Inevitably, expert perception and understanding of the manifestations of the diseases have changed over time. The natural history of each disease has some features that are generally recognised and are increasingly understood, however. In this changing environment, the Inquiry is particularly grateful to Professor Howard Thomas, Emeritus Professor of Hepatology, Imperial College, London, and Professor Peter Hayes, Professor of Hepatology and Honorary Consultant Gastroenterologist at the Royal Infirmary of Edinburgh (RIE), for their contribution to the understanding of the present state of knowledge of viral hepatitis.

13.5 All five of the human hepatitis viruses currently recognised, A to E, are from different families of the virus kingdom. The viruses are grouped together because they all replicate in the liver and cause inflammation and fibrosis (scarring) in that organ.[3] Two of them, Hepatitis A virus (HAV) and Hepatitis E virus (HEV), are enterically transmitted, through the digestive system, and generally cause a self-limiting infection.[4] Rarely, HAV and HEV may cause fulminant (rapidly progressing) liver failure and a small proportion of patients die from this complication. In general, however, after two or three months the patient's liver function tests and the architecture of their liver return to normal. The virus is eradicated and the person will have protective immunity for the rest of their life against the virus causing the infection.

13.6 Hepatitis B and C viruses (HBV and HCV, respectively) are parenteral, blood-borne infections,[5] transmitted by the introduction of infected material through the skin or mucosal surfaces.[6] They may cause acute, clinically significant hepatitis. A proportion of those infected go on to develop chronic infection. The definition of the 'chronic' condition is statistically based and internationally agreed.[7] In Hepatitis B and C an infection is considered to be chronic if it continues for longer than six months after identification of the virus or antibodies to it.[8] 'Acute' hepatitis is defined as a self-limiting illness lasting less than six months. Estimates of clearance rates for Hepatitis C within the first six months vary from 20% to around 30-40%.[9] The remaining 60-80% of patients progress to chronic infection.

13.7 In Hepatitis B and C cases, many acute infections remain unidentified: they may be asymptomatic. If there are symptoms, they tend to occur in the first few months after infection, whether acute or chronic, and tend to be more severe in a patient with acute infection. These symptoms can include flu-like symptoms, jaundice, loss of appetite and abdominal pain. In the case of an acute self-limiting infection, the level of liver enzymes in the patient's blood, most commonly alanine aminotransferase (ALT), peaks typically at about three months and falls to a persistent normal level at about six months. If HCV is cleared in the earlier stages of developing fibrosis, either spontaneously or as a result of treatment, then the liver will ultimately remodel and go back to normal and the patient will have been cured both of the presence of the virus and of the liver disease.

13.8 In chronic infection, after the initial three-month peak, ALT levels continue to fluctuate, often above the upper limit of normal. Chronic infection puts the individual at risk of 'progressive liver disease', the risk that fibrosis will develop to cirrhosis and this, in the case of cirrhotic patients, in turn creates the greatest risk of developing complications.[10] Progression to cirrhosis indicates that not only is there significant fibrosis but also that the normal architecture of the liver has changed to include structurally abnormal nodules.[11] At that stage the process is probably irreversible: while a patient may manage to clear HCV permanently, the cirrhosis will remain with its potential complications.[12]

13.9 The complications of cirrhosis may be very serious and life-threatening. Two of the main complications of cirrhosis are hepatocellular carcinoma (HCC, primary cancer of the liver cells) and bleeding from oesophageal varices (varicose veins in the stomach and gullet).[13] Further complications of cirrhosis, encephalopathy (damage to the brain characterised by confusion, cognitive impairment and lethargy) and ascites (the accumulation of fluid in the abdomen), are signs of liver failure.[14] A person with cirrhosis of any cause has a risk of developing a hepatocellular cancer of 2-3% a year.

13.10 In general, the progression to End Stage Liver Disease (ESLD) encompasses all of the stages mentioned. The march of events is: acute infection, failing to resolve, leading to chronic infection and then cirrhosis, and then on to the risks of liver cancer and/or liver failure.[15] With very few exceptions, only those HCV-infected individuals who have developed cirrhosis are at risk of liver cancer. In a very small proportion of cases, HCC may develop at an earlier stage.[16] In chronic HBV, too, HCC develops after cirrhosis is established. However, in those infected with HBV in infancy, a pattern of infection found more commonly in the Far East and Africa, HCC may also develop in the non-cirrhotic liver.[17]

13.11 The prevalence of these diseases varies across the world and that is frequently due to causes that are at best indirectly relevant for present purposes. Worldwide, some 350 million people have chronic Hepatitis B, three-quarters of whom were infected at birth. Most of these individuals live in China.

13.12 Worldwide, 170 million people are estimated to have Hepatitis C.[18] Causes of high prevalence of HCV vary. In Bolivia it may be due to tribal scarification practices and in Egypt, which has the highest prevalence of HCV infection in the world, it is probably related to a programme of injection to treat the endemic parasitic disease schistosomiasis from the late 1950s to the early 1980s, which involved the use of unsterilised equipment. There is twice the prevalence of Hepatitis C infection in the general population of the USA when compared with the UK.

13.13 In the UK as a whole, chronic Hepatitis B (now generally a smaller problem than Hepatitis C) has its highest prevalence in first-generation migrants from the Far East, Africa or the Mediterranean where prevalence of the disease is high. The low prevalence of the disease in the general public in the UK was attributed by Professor Thomas to the introduction of universal standards within, and provision of sterile equipment throughout, the National Health Service.[19] In Scotland, while the true prevalence of Hepatitis C in the population as a whole remains unknown,[20] the number of known cases continues to increase with improved and wider ascertainment. A great many of both new infections and newly discovered infections occur amongst intravenous drug users (IVDUs), past or present.

Biology of HCV

13.14 In Hepatitis B the genetic information for the virus is contained in deoxyribonucleic acid (DNA). In Hepatitis C the genetic information for the virus is contained in ribonucleic acid (RNA): it is an RNA virus. HCV exhibits considerable sequence variation, or genetic heterogeneity.[21] There are six major genotypes, with additional differences between the strains (or 'quasi-species')[22] found within a single genotype. The biological behaviour of the different genotypes is encoded by the genetic structure of the virus[23] and there are major biological differences between the genotypes which have a bearing on treatment. Treatment of Genotype 1 virus infection with Interferon and Ribavirin (the first two forms of drug therapy for Hepatitis C which became available) cures a lower proportion of cases than the same treatment of Genotypes 2 and 3.[24] An individual, and particularly an individual with haemophilia, may have been infected with more than one genotype of HCV and may be co-infected with Hepatitis B. In such cases the replication of one virus may interfere with the replication of the other or others, which become apparent only when the first is cleared.[25]

13.15 As with each of the hepatitis viruses, the different genotypes of HCV are not distributed uniformly. The description of the distribution noted in the Preliminary Report remains valid.[26] In the UK as a whole about 50% of HCV is Genotype 1, with Genotypes 2 and 3 making up the other half. In the USA, Genotype 1 predominates, in particular in the haemophilia population, with Genotype 3 coming into play later.[27]

13.16 HCV RNA is detectable in acute, self-limiting, cases up to about six months but not thereafter, since the body will have dealt with the virus. In chronic HCV infection the virus RNA may continue to be detectable indefinitely and is the signature of the chronic condition.[28] The level of viraemia (virus in the blood) probably affects the severity of liver disease.[29]

13.17 The likelihood of developing a self-limiting acute infection is related to an individual's genetic make-up and, in particular, the immune system's recognition proteins (haplotype (HLA type) proteins). A person's HLA type is genetically determined and does not change. Certain HLA types confer a stronger possibility of leading to clearance of the virus after infection. The individual's HLA type forms a significant component in the risk matrix, generally and in relation to the risk of re-infection following clearance. If an individual is infected and clears the virus spontaneously, the same outcome is likely to follow a subsequent infection.[30]

13.18 The sequelae of infection with HCV (the complications associated with the disease) appear to vary among populations in different geographical areas. For example, infection can be associated with a risk of non-Hodgkins B cell lymphoma in southern Europe but is rarely so associated in the UK. Care is therefore needed in applying information from different geographical areas of the world to the UK generally and, within the UK, to Scotland in particular. Understanding of some consequences of infection is still developing. For example, impaired cognitive function ('brain fog') and depressive mood disorders, which occur in some cases, are now thought to be causatively related to HCV infection.[31] Evidence for these sequelae strengthened with the discovery that, independently of the severity of liver disease, virus recovered from the brain of infected patients had a structure in common with that found in peripheral blood lymphocytes but different from the structure of the virus in the liver. The causal connection is now probably established.[32]

Hepatitis C: Identification of the virus

13.19 The discovery of HCV was announced by Chiron, a US pharmaceutical company, in May 1988.[33] Scientific details were published in April 1989.[34] In the same month details were also published of an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HCV.[35] The background to the discovery is discussed in more detail in Chapter 16, Knowledge of Viral Hepatitis 3 - 1986 Onwards. Chiron's work was a significant, and inventive, development in the knowledge of HCV infection. It laid the foundation for research into the genetic structure of the virus set out above and in much of the remainder of this chapter. In the context of transfusion-related transmission and blood product therapy-related transmission, post-transfusion HCV infection now appears to explain most if not all cases of what was once termed 'non-A, non-B Hepatitis' (NANB Hepatitis) virus infection.[36]

13.20 Since the announcement of Chiron's discovery, research into the genomic composition of the Hepatitis C virus has identified variations which now support an increasingly sophisticated system of sub-classification. At the Inquiry's oral hearings, Professor Thomas noted that Japanese researchers had succeeded in growing the virus culture in one particular cell line within the previous five years.[37] There remain problems of easy and reliable replication. These problems affect the application of developing knowledge in the testing of new treatments and the preparation of a vaccine, for example. Research continues and it appears likely that much remains to be discovered before a complete description of the virus in its many sub-types, its sequelae and the most effective means of protection against and treatment for it can be attempted.

The reproductive process of HCV

13.21 During an episode of acute hepatitis in which the virus is eliminated, the body mounts an effective immune response, engaging the CD4 T-helper and CD8 cytotoxic cells. In general, the stronger the response the more likely the patient is to recover. Individuals who become jaundiced have a lower frequency of viral persistence than those who do not: the jaundice is a reflection of the immune system killing infected liver cells.[38] The 'price' of clearing the HCV completely and spontaneously from the body is often a more severe acute clinical illness. In patients developing persistent infection, the CD4 and CD8 responses are less strong, though still detectable, and clinical manifestations at the acute stage are often trivial or absent.[39]

13.22 Where the virus persists, it must replicate. In order to replicate, a virus needs to use many of the enzymes within a living cell. It must, therefore, enter a cell which has a suitable point of entry on its surface. Liver cells have a surface receptor which normally transports fat into the cell, among other functions, and the envelope in which the Hepatitis C virus is contained has the appropriate physical configuration to bind onto the liver cell receptor. HCV gains entry to the liver by docking with the liver cell: the virus 'piggy-backs' its entry onto the normal receptor process.[40]

13.23 When the virus enters the liver cell, it 'hijacks' the replication mechanism of the host cell: the RNA of the virus enters the protein-synthesising machinery of the cell, immediately making use of the apparatus of the cell to make more copies of itself. New viral particles of positive strand RNA are manufactured and then self-assemble in the cell: they 'encode' for a polyprotein comprising all of the structural and non-structural proteins of the virus. The new viral particles follow the same pathway through the cell as fat. The fat globules passing through the liver therefore incorporate virus particles.[41] The virus particles are then excreted from the cell, by the same structures that are normally used to get rid of fat from the liver cell and exit from the liver to circulate in the blood stream.[42]

13.24 HCV does not damage or kill liver cells directly. Rather, the liver cells suffer because of the body's immune response to the virus: small protein molecules called cytokines are released to both shut down virus replication and kill the infected cells.[43]

13.25 There are two highly variable proteins on the surface of the HCV envelope and the new virus particles produced are, in turn, highly variable, although the variability does not extend to shifting the virus from one genotype to another. Rather, HCV creates a swarm of quasi-species: every virus particle in the patient is slightly different in its RNA sequence.[44] Even within an individual infected with a single genotype the genetic sequence of each virus particle is different and changes over time as the virus comes under various selection pressures. Many of the different variations, the quasi-species, produced in replication will be non-viable (unable to replicate). Otherwise they are targeted, initially by the host's immune response and, in more recent times, by potentially therapeutic drugs such as the protease and polymerase inhibitors.

13.26 The patient's antibody response may neutralise most of the virus particles that are viable. As virus neutralising antibodies are made by the host's immune response, new variants of the virus, which existing antibodies do not immediately neutralise are selected.[45] There will be a small number of quasi-species that have antigens (epitopes) that are not targeted by the patient's immune system and, because they are not neutralised, these become dominant and provide the virus with an advantage until the system adapts to find antibodies to them.[46] After a significant new antigen appears, it takes about 10 days for the immune system to produce an antibody.[47]

13.27 HCV exhibits greater genetic diversity than most other viruses and this is a major contributor to the high rate of chronicity, the difficulty in producing a vaccine and the rapid emergence of virus strains that are resistant to new treatments such as protease, polymerase and NS5a inhibitors.[48]

13.28 There are continuing issues relating to HCV infection. Professor Hayes commented on the changing understanding of the natural history of Hepatitis C over time.[49] In the early 1990s people did not know how aggressive the condition was and there is still considerable debate on this point. When a test for HCV infection became available, instead of confirming the diagnosis of NANB Hepatitis in the small number of people who had been so labelled, clinicians here and abroad found that large numbers of people who had not been suspected of having NANB Hepatitis were infected with HCV. In the UK the prevalence of HCV is low, at less than 1%. How the disease would impact on people's lives nevertheless became a major issue. The risk of progression to cirrhosis was originally estimated at 20% but the natural history of the disease is still unclear and is complicated by other major factors such as alcohol consumption and obesity. It is now thought that a large number of HCV-infected patients will go on to develop major complications, including cirrhosis and its sequelae.[50]

13.29 As understanding of the characteristics of HCV has developed, it has become increasingly clear that advances in knowledge are dependent on the science of genetics and on the application of technology that was quite unknown at periods when exposure to risk, at least via transmission by blood or blood products, was greatest and the response to infection was least effective.

13.30 Overall, the circumstances in Scotland were very similar to those described above for the UK as a whole, subject to some variation in percentages.[51]

Risk of transmission of HCV by blood, blood components and blood products

13.31 It is important to note that the risk of transmission of Hepatitis C by transfusion of blood or blood components, or the infusion of blood products, has greatly diminished following the introduction, in current practice, of highly developed testing procedures which are rigorously applied. Separate samples are taken at the time of blood donation to be tested for blood group (ABO, Rhesus and sometimes more minor groups) and microbiology markers (syphilis, HIV, HCV, HBV, and HTLV-I and II by serology and HIV, HBV and HCV by nucleic acid testing). All platelet donations are tested for bacterial contamination.[52] Apart from HCV, serology tests also look for patients with antibodies to infections. Nucleic acid testing is based on polymerase chain reaction, which amplifies RNA or DNA and is highly sensitive. Currently, donations are tested by both techniques.[53] Discretionary tests are carried out for other pathogens.

13.32 New forms of screening are rigorously trialed. A test must be sensitive enough that it is going to be worth doing in the first place but has a specificity level that is manageable without unnecessarily deferring large swathes of people.[54] When screening large numbers of healthy people, the false positive group far outweighs the true positives, so the positive predictive value (the number of true positive results amongst the 'positive calls') of the initial screening test is very poor from that point of view. Normally, there should be at least one kind of confirmatory assay, based on a different platform or technology to the original test, since otherwise there would be no way of sorting out the false positives and the true positives. In addition, legally the test has to be CE marked,[55] under the In Vitro Diagnostics Directive[56], which means it can be marketed in the European Union and, therefore, in this country.[57]

13.33 Samples which are initially reactive on screening are subjected to a hierarchy of very sensitive further tests. This series of tests is made as sensitive as possible to avoid missing people with infection. The aim is to achieve a low false negative result. That, in turn, creates a risk of more false positives. So, typically, in the modern screening, with third or fourth generation tests reflecting much refinement of technology over the last 10 or 20 years, about two per cent of donations have been found to be reactive on initial screening for one or other marker. These samples are withdrawn prior to use. The sample is then tested again twice using the same assay. About 90% of those are repeat reactive negatives, pointing to a system problem in the initial test. Perhaps only about 0.02% are repeat reactive positive at the second stage. It is not concluded even then that the patient has the infection. Rather, at that stage the donation is quarantined for much more detailed examination; samples are sent to a reference laboratory, where a whole series of different tests, based on different kinds of platforms and technology, are applied to try to establish whether or not there is a true positive result. Again, in general terms, around 10% of those repeat reactive samples turn out to be true infections and the other 90% tend to be technical artefacts (an artificial effect introduced by the technology used). The procedure, as described, now ensures that donors are informed of an infection only when the SNBTS is absolutely certain that the diagnosis is correct.[58] The procedure described protects the patient recipients of blood or blood products without exposing the donor to unnecessary anxiety.

13.34 This highly sophisticated system has developed rapidly over the last 20 years. Throughout the material part of the reference period, however, the technology underlying the screening tests available was both less sensitive and less specific. There is no basis in the evidence for concluding that, in general, the best available methods of screening were not used as they became available but it is important to note the steps that have been taken to avoid transmission of infection in the course of modern transfusion practice and the treatment of coagulation disorders.

Transmission of Hepatitis C and risk of repeat infection

13.35 From 1991, when screening of blood became universal practice in the UK, transfusion of blood and blood components and the infusion of blood products have not been associated with the transmission of Hepatitis C to any material extent. In the case of blood products used to treat coagulation disorders, largely retrospective research demonstrated that there had been almost 100% infection with the concentrates that were available before effective virus inactivation began in the mid-1980s, whether commercial materials or the products of the UK public service (NHS) fractionators were used.[59]

13.36 In the case of blood products, the risk of transmission of blood-borne viruses was related to the number of infective donors contributing to a particular batch and to the severity of the patient's condition requiring coagulation factor therapy and therefore the number of infusions required. The very large number of donors contributing to the plasma pools made the prevalence in the general population almost irrelevant.[60]

13.37 Other means of transmission raised different issues, such as the relevance of the level of concentration of virus in the source blood and the risk of sexual and neonatal transmission.[61] Hepatitis B is much more readily transmitted sexually than Hepatitis C. Similarly, Hepatitis B is more easily transmitted in the course of surgical procedures, through the perforation of gloves for example. In each case this is due to the concentration of virus in the source blood. The levels that are typically found in Hepatitis B are around 107 to 108 (10 million to 100 million) virus particles per millilitre. At those levels, neonatal and sexual transmission is seen fairly frequently. In a normal HCV infection a typical concentration may be 105 (100,000), or 106 (a million) virus particles per millilitre. At those levels, it is unusual for either sexual or neonatal transmission to occur.[62] The figure cited in the literature for sexual transmission is 5%. However, Professor Thomas did not think that, in testing spouses, he had ever found a positive case, with the exception of cases of co-infection with HIV where the rate of HCV replication was higher (by one or two logs) and the level of viraemia was relatively high. (The Inquiry identified one such case, the witness given the pseudonym 'Laura'. See Chapter 6, paragraphs 6.228-6.277.)

13.38 Comparison with Hepatitis A and Hepatitis B gave rise to misconceptions about NANB Hepatitis/HCV which were only dispelled during the 1990s when knowledge of the biology and immunology of HCV developed. Patients who had an attack of Hepatitis A or an acute attack of Hepatitis B and recovered, as indicated by the normalisation of liver enzymes (ALT levels), and the appearance of antibodies indicating immunity (anti-HAV, anti-HBV), had cleared the virus from their bodies and would not be infected again. So when, after a putative attack of NANB Hepatitis, the patient's ALT fell to within the normal range, it was initially assumed that the person had cleared the virus, had acquired immunity and would not be infected again. This turned out to be wrong for two reasons. First, many patients with 'indolent' (apparently benign) NANB Hepatitis/HCV infection had intermittently normal liver enzyme levels but were still harbouring the virus and could still develop significant ill health from it. Secondly, it was realised after the discovery of the HCV antibody that, unlike anti-HAV or anti-HBV, anti-HCV did not indicate immunity to further HCV infection, particularly by HCV with a different genotype. Professor Thomas described this as 'an anomaly in virology'.[63]

13.39 So, during the 1970s and 1980s, when an individual haemophilia patient was found to have a 'second infection' (often merely a period of months during which ALT levels in the blood became elevated), haemophilia doctors thought that it was probably caused by a second, quite different virus, when in fact it was often the original HCV infection resurfacing in the form of raised ALT levels. It is now also believed that the same individual can acquire second, third and further infections after recovering from a first infection with Hepatitis C. In some haemophilia patients several genotypes and subtypes of HCV have, albeit rarely, been identified in the same individual.[64]

Developing perception of the severity and natural history of NANB Hepatitis/Hepatitis C liver disease

13.40 Despite significant developments in knowledge, the natural history of HCV is still unclear and tends to be complicated by other factors.[65] The changing perceptions of the severity of NANB Hepatitis/HCV over time are traced in greater detail in Chapters 14-16, Knowledge of Viral Hepatitis 1-3. In this chapter it is necessary only to identify some milestones along the way as markers that may be of assistance in interpreting the statements of patients and their relatives.

13.41 Until the end of the 1970s, the generally accepted view was that NANB Hepatitis was, clinically, relatively unimportant. By 1981 Professor Sheila Sherlock would write in the sixth edition of her highly respected textbook, Diseases of the Liver and Biliary System, that the prognosis of NANB Hepatitis was 'uncertain but probably benign'.[66]

13.42 However, at the time of publication of the sixth edition of Professor Sherlock's book, Dr May Bamber and others, including Professor Sherlock and Professor Thomas, were already engaged in studies based on biopsy findings which demonstrated that patients with chronic NANB Hepatitis had disease that covered the whole spectrum of acute and chronic hepatitis, including cirrhosis.[67] That study was also published in 1981. In retrospect, it marked the beginning of a significant change in expert opinion. US research published in 1982 pointed in the same direction.[68]

13.43 Research into the progression to serious liver disease in Hepatitis B, relying on biopsy findings, had enabled the development of prognostic indicators relating to the pattern of inflammation observed in the liver tissue. Chronic persistent hepatitis, considered to have a very benign prognosis, was related to inflammation in the portal tracts. Inflammation that extended out into the periportal area - chronic active hepatitis - was associated with the risk of subsequent development of cirrhosis. Inflammation spread evenly in the hepatic lobule (chronic lobular hepatitis) was associated with a benign prognosis. Bridging fibrosis, in which fibrous tissue was found between the portal tracts and the central veins, or between the portal tracts themselves, was an indication of the onset of cirrhosis.[69]

13.44 It was initially assumed that the prognostic indicators for NANB Hepatitis/HCV infection were the same as for Hepatitis B.[70] In the early biopsies carried out in patients with NANB Hepatitis, the findings were of chronic persistent or chronic lobular hepatitis and the supposition was that they were unlikely, as a matter of probability, to progress to serious sequelae. Initially, biopsies were performed on putative NANB Hepatitis patients who had biochemical indications of a steep rise in ALT before it returned to normal.[71] It was on the basis of indications from these procedures that it was inferred initially that NANB Hepatitis was a benign prognostic disease, partly because, as already noted at paragraph 13.7, these were the minority of individuals who were likely to recover fully and not develop chronic illness.[72] In retrospect, the widely held supposition that chronic persistent and chronic active hepatitis would follow the same clinical course in Hepatitis C as in Hepatitis B, was wrong.[73]

13.45 A Sheffield study by Dr David Triger and others in 1978 showed cases of cirrhosis in haemophilia patients infected with NANB Hepatitis. There was case selection towards the adverse end of the disease spectrum, however, confounding the picture that emerged.[74] Additionally, the basic characteristic of biopsy, that it targets a minute piece of the liver, gave rise to sampling errors.[75] Further, there were other factors that might have contributed to the progression of disease, such as age at infection, the duration of infection, obesity and alcohol use, which were not necessarily reflected in biopsy findings or properly understood at that time.[76]

13.46 The 1981 study by Bamber and colleagues related to 12 patients, both transfusion patients and patients without a transfusion history, who were diagnosed on serological grounds as having NANB Hepatitis infection. No haemophilia patient was involved. Some patients had cirrhosis; some had chronic active hepatitis with piecemeal necrosis; one had portal-systemic encephalopathy associated with cirrhosis and severe liver dysfunction. There was evidence of fatty change and bile duct damage. The findings were an affirmation of the work of Dr Triger's Sheffield group, which had previously been controversial.[77] By the 8th edition of her book in 1989, Professor Sherlock had changed her stance: she wrote in that edition that 20% of infected individuals would develop cirrhosis over 20 years and that after 30 years the proportion would increase progressively.[78]

13.47 Professor Thomas emphasised that doubt remained:

[S]ome would say, even now, we do not really know the factors that determine the rate of progression and, for instance, in Italy Hepatitis C has a much worse prognosis to what you see in northern Europe ... and ... that's arguably related to all the other factors ... how much alcohol you take, the genetic factors, whether there is co-infection with other viruses, all manner of things.

So I don't think this uncertainty about the natural history that was prevalent between 1978 and 1985 has changed massively. I think we are still wondering: is it 20 per cent or 40 per cent that will develop cirrhosis? All we can deduce from these studies is that some people in the context of normal life ... where we eat and drink ... some people have severe liver disease. But how many, that's an open question still, because none of the studies ... are statistically significant. There isn't a large enough sample of unselected cases.[79]

13.48 As noted above, once a patient already has cirrhosis, it does not disappear even when the causative viral infection is cured. The risk of progression to hepatic decompensation (liver failure) and possible HCC is reduced, however, and the patient is no longer infectious. Cirrhosis does put the patient at risk of liver cell cancer, however. There are patients who had cirrhosis prior to treatment who have undergone a sustained viral response and are cured, virologically speaking; some of them have nonetheless gone on to develop primary liver cell cancers.[80] In current practice, once a person has been identified as having cirrhosis, he or she will be monitored by ultrasound and an alphafetoprotein test every six months in the hope of identifying tumours when they are small and more treatable.[81] The patient will also be regularly monitored for varices by upper gastro-intestinal endoscopy. In this group clinicians do not anticipate a cure of the patient's overall condition because they are still at risk of severe complications.

13.49 The position of a haemophilia patient is complicated by his primary condition. Thus, in terms of the overall effects of their underlying illness on quality of life metrics, the starting Quality of Life score would be unlikely to be the score typical for a member of the general public because of the clinical manifestations of haemophilia itself and possible associated psychological factors. There will also be continuing concern whether the condition has been dealt with.[82] Professor Thomas said:

[I]t's a very complicated situation really. There is the pre-treatment problems. They may have additional problems, other worries, financial worries, you know, and doctors tend to find reassurance, since they are making very difficult decisions ... if there is something objective they can measure, which is the presence or absence of the virus by techniques which are exquisitely sensitive really. And if, when you do that, you come up with a logic, something that you can understand -- when the virus goes down the patient feels better; when it goes up again, he feels unwell -- all that reassures the doctor that he is probably measuring something that's relevant.[83]

13.50 By contrast, he suggested, Quality of Life measures - before and after 'successful' treatment for HCV in haemophilia patients - are much more complex.

13.51 Now, over 20 years after the identification of HCV as the 'culprit' for almost all NANB Hepatitis infections, perceptions have changed. It has recently been estimated that, in the USA at least, the cohort of HCV-positive individuals (the total HCV-positive population) peaked around 2001 and will decline slowly over the following 20 years. Recently, Dr Gary Davis and colleagues observed that, bearing in mind that the prevalence of HCV infection in the population increased very quickly in the 1970s and 1980s (the first part of the HCV 'cohort'), by 1989 cirrhosis is thought to have occurred in about 5% of all cases of chronic Hepatitis C, in 10% of all cases by 1998 and 20% by 2006. It was projected to have risen to 25% in 2010 and to be likely to rise to up to 37% in 2020 and 45% in 2030.[84]

Clinical and other features of Hepatitis C infection

13.52 This section notes clinical and other features associated with Hepatitis C infection in the UK. That excludes some complications found elsewhere. Marked geographical differences occur. For example, as noted above at paragraph 13.18, there is a high prevalence of HCV-positive patients in Mediterranean countries with non-Hodgkin's B Cell Lymphoma (a cancer of the lymphoid system) but there is no epidemiological evidence for the virus being involved in non-Hodgkin's B Cell Lymphoma in northern Europe.[85]

13.53 In the early 1970s, jaundice was thought to be an important diagnostic feature of hepatitis generally and, from the mid-1970s, of NANB Hepatitis in particular. However, jaundice is rare in Hepatitis C infection.[86] Fulminant (rapidly progressing) hepatitis, indicative of liver failure, is very rare. Less than a fifth of cases involve jaundice. Professor Thomas emphasised that the rareness of jaundice was quite important because of the impact it had on the early lack of understanding of the infection. (See Chapters 13-15, Knowledge of Viral Hepatitis 1 to 3.)

13.54 Two factors contribute to the severity of HCV infection. The first is the size of the inoculum (the amount of virus with which the patient is initially infected) and, resulting from that, the rate of spread of infection through the liver and the number of liver cells infected. The second is the speed of response of the immune system. If the immune response is very quick, there is rapid clearance of the infected liver cells, faster than the rate at which liver regeneration can replace the infected cells, and severe and more acute symptoms follow.[87]

13.55 Clinical features common in acute hepatitis include influenza-type symptoms with malaise, myalgia (muscle pain), arthralgia (joint pain), anorexia (loss of appetite) and nausea and there may be mild pyrexia (elevated temperature). These may be followed by the biochemical features of hepatocyte necrosis (liver cell death) as the immune system attempts to clear the virus-infected liver cells. Transaminases (liver enzymes) increase in the blood as they are released from dying liver cells. An increase in serum bilirubin (described below) may occur. In such cases, the patient's urine becomes dark, stools become pale, and the patient may become jaundiced and develop itching.

13.56 Where jaundice does occur in Hepatitis C, it lasts usually one to four weeks and heralds improvement in most cases, though a feeling of malaise and of being generally unwell may last many months.[88] Jaundice occurs when the liver cell mass is reduced, so that bilirubin can no longer be excreted. Bilirubin is a product of the red blood cells of the body, formed from broken-down haemoglobin. It is excreted through the liver and, because of reduced liver cell mass and also the fact that the liver cells swell, inhibiting the passage of the bilirubin into the bile ducts, there is obstruction of bile flow and cholestasis occurs: bile cannot flow from the liver to the duodenum, the first portion of the small intestine. Both factors, reduced liver functioning cell mass and reduced ease of flow of bilirubin into the bile ducts, contribute to a rise in bilirubin in the blood, and the eyes, and sometimes also the skin, become yellow.

13.57 Jaundice does not happen in most cases of Hepatitis C because the initial 'insult' (damage) to the liver is less severe than, for instance, in Hepatitis A or B, when a larger proportion of the liver cells is infected and destroyed by the immune system as the infection is cleared.[89] Post-transfusion screening for jaundice therefore picked up only a small proportion of cases of NANB Hepatitis/HCV infection. This led to differing perceptions among doctors. While transfusionists in Scotland around 1980 believed that post-transfusion NANB Hepatitis was rare, on the basis of low reporting of jaundice, haemophilia centres saw persistent mild liver blood test abnormalities as very common, but probably of little importance.

13.58 There are also extra-hepatic manifestations of infection.[90] The most readily understood of these are renal and dermatological and related to 'cryoglobulinemia', a condition in which the Hepatitis C virus forms an immune complex with associated antibodies and circulates in a patient's blood. When the blood cools in circulation, the complex precipitates out of suspension and this 'cryoprecipitate' can stick in small blood vessels, particularly in the kidney, which sometimes results in renal dysfunction.

13.59 Dermal complications can be related to those immune complexes being deposited in the capillaries or small arterioles in the skin, often on the lower limbs, leading to the formation of small, painful and uncomfortable black nodules: a condition known as cryoglobulinaemia.[91] The nodules look like purpura but are actually thrombosed blood vessels, where the cryoglobulins, the immune complexes, have become stuck in the small blood vessels of the leg. The lower leg is more likely to be affected because, as the circulation is slower there, the lower legs are colder than the upper limbs or trunk and precipitation is more likely.

13.60 Other dermatological features of HCV infection are associated with the problem called 'lichen planus' which manifests in rashes on the skin. Professor Thomas thought there was really no idea, as yet, as to why the infection should be associated with lichen planus.[92]

13.61 Many of the flu-like signs and symptoms, which arise both in acute hepatitis (when the body naturally produces interferon) and in the course of treatment with Interferon for chronic infection, were noted in a 2006 study by Dr Mark Wright and others (including Professor Thomas).[93] This gave rise to a question as to whether the symptoms were caused by treatment rather than by HCV itself.

13.62 Professor Thomas thought that some auto-immune diseases found in association with HCV infection, such as rheumatoid arthritis and autoimmune thyroiditis, were likely to result from a genetic predisposition common to those conditions rather than a causal connection with HCV, but agreed that treatment would exacerbate those conditions in those with a genetic predisposition to them.[94]

13.63 Using validated methods to assess mental and physical wellbeing, it has been shown that Hepatitis C patients have generally reduced mental and physical wellbeing, of a comparable level to what might be seen in diabetes (another chronic disease), for example.[95] Since such neurological and psychological difficulties may occur without serious liver disease, attributing a cause for such symptoms can be difficult in an individual case. Severe liver disease may be the cause, since with liver failure there may be an accumulation of nitrogen compounds derived from the gut which leads to hepatic encephalopathy (confusion, cognitive impairment and lethargy). In some patients, mental acuity is blunted by past use of recreational drugs. If those two are excluded, the third case, what is called 'mental fog' in the USA, represents infection of the central nervous system with HCV.[96]

13.64 Although the association of HCV infection with some of these features of quality of life and brain function is based on 'soft' evidence, these are precisely the symptoms and signs that many patients have complained of in statements provided to the Inquiry. Such symptoms have been under-appreciated in the past but the bulk of evidence now strongly supports an association. Dr Karin Weissenborn and colleagues have recently characterised the well-documented neuropsychological effects of HCV infection on the brain as follows:

A reduction in health related quality of life, chronic fatigue, depression and cognitive decline are characteristic complaints of HCV-infected patients even in the absence of significant liver disease.[97]

13.65 In chronic hepatitis, the measure of severity is related to the rapidity of progression but Professor Thomas' evidence revealed that there is still some uncertainty about causal relationships. He thought that the rapidity of progression (as well as the severity of the infection, as noted in paragraph 13.54) would be related to the size of the initial inoculum but the picture was complicated by that the interaction of other variables, such as co-infection with HIV, immunosuppression due to medication and the rate of reproduction of the virus.[98] In relation to the rate of progression of the disease, he said:

In chronic hepatitis C the presence and quantity of virus in the blood stream is determined by reverse transcriptase polymerase chain reaction (rt-PCR). Levels fluctuate from month to month and tend to be higher in immunosuppressed people such as those infected with HIV. The level of viraemia in HCV does not appear to determine the rate of progression to liver cirrhosis in the non-immunosuppressed. Levels of transaminases also fluctuate over time. The presence of normal transaminases does not exclude significant liver fibrosis. The rate of progression to cirrhosis varies among individuals chronically infected with HCV. Different sub-groups of patients progress at different rates. Major risk factors have been identified: male gender, excess alcohol and age [over] 50 at acquisition.[99]

Factors which influence the outcome of HCV infection

13.66 Professor Thomas agreed generally with the conclusions of the Bassendine Review of Natural History of HIV Infection relating to HCV infection.[100] The Review stated:

The proportion of patients who develop chronic HCV infection may be determined by many factors. These include age at time of infection, gender, ethnicity, presence of symptoms during the acute infection, genotype, immuno-suppression and HIV.[101]

13.67 Professor Thomas expanded on some of these matters.[102] There is consensus that certain factors do influence outcome. Others are postulated but are not confirmed or sustained by other studies. Some factors are not confirmed because they are not direct determinants: they are correlates of something that is a direct determinant. Male gender indicates a more severe outcome in chronic infection, in all studies. Ethnicity plays a role. That is now known to be related to the frequency in which the IL28 genetic polymorphism is found in different ethnic groups. Most people are offered treatment and the mechanism of the response rate to Interferon, which will determine whether the patient does well after infection, has a different frequency in different ethnic groups, again due to differences in the prevalence of the immune system's recognition proteins.

Age at time of infection

13.68 Age at the time of infection is agreed to be a contributory factor in the progression of HCV infection. Above about 50-60 years of age, there is a deterioration of the body's capacity to regenerate, whether it is to replace scar tissue resulting from a simple cut or to replace liver cells killed by the immune response to HCV infection. There is a change in the gradient of the curve measuring progressive liver damage. If an individual is infected after this change, progression is more rapid. After discussion with Professor Oliver James, Medical Assessor to the Inquiry, Professor Thomas said:

[B]oth with Hepatitis B and Hepatitis C, if you get an acute hepatitis in your later years, let's say 60, then there is a syndrome called "failure to regenerate". You ... have a wave of destruction of liver cells, which is essential for part of the recovery process because the cells contain the virus, you have to destroy them to get rid of them, you are then producing antibody to stop the virus moving into the neighbouring cells, but in addition, the neighbouring cells have to regenerate to replace the ones that have been killed.

So there are four components, if I could summarise it. There is the number of infected cells; there is how quickly they are being destroyed, which is dependent on the cellular immune response; there is the production of antibody, which is going to be important to stop the virus released from the destroyed cells to infect the cells next door; and the last thing is you are down on the number of liver cells that you have, because of the ones that have been destroyed, so you are dependent on the liver regenerating. So if any of those components result in a situation of a [reduction] in liver cell mass, then you will ultimately enter liver failure.[103]

13.69 The Inquiry heard evidence from a number of witnesses who added to its understanding of the relevance of age. Dr Graeme Alexander, Consultant Haematologist at Addenbrooke's Hospital, Cambridge, drew on information from the national HCV look-back study[104] of which he was Chairman. He said that the majority of people who were young at the time of infection did not progress to cirrhosis at all.[105] In the case of patients who were relatively young at the date of infection who did progress to cirrhosis, the period from that stage to the development of end stage liver disease would be of the order of 10 years or more. Both the period of evolution from infection to cirrhosis and the period of evolution from cirrhosis to death were shorter in people who were older when they were first exposed to HCV.[106] Publications drawing attention to the importance of age first began to appear in about 1997; before that time, the natural history of Hepatitis C in older patients had been misunderstood. Most clinical experience had been based on an understanding of NANB Hepatitis in patients, most of whom died from the disease that had led to intervention in the first place. A diagnosis of NANB Hepatitis was simply the identification of abnormal liver test results that arose after transfusion, for which there were many possible explanations. The view of what NANB Hepatitis did to patients was artificially skewed. It was not until the introduction of testing for HCV in 1991 that it began to be realised that there were many people who had a disease that was very different from the disease as previously understood. In the clinical context there was not much that could be done. The report on Mr Laing, referred to the Inquiry in Term of Reference 6, provides clear evidence of a high rate of progression in an older man with no aggravating factors. (See Chapter 7.)

13.70 Other evidence supported the view that, among younger patients infected with HCV with no other aggravating factors, progression may be slow and with a mild outcome for considerable periods of time. Long-term follow-up studies over a period of 35 years have been reported of Italian children given HCV-infected 'mini-transfusions' from a single donation at or about the time of birth.[107] In Italy, during the 1960s, mini-transfusion of blood or plasma was a frequent treatment of under-weight or pre-term newborn children. Transfusions of blood from a single donor later found to be HCV-infected were given to 31 children, all of whom were 35 years of age at the date of the report. At enrolment into the study in 1998, 18 were found to have HCV antibody and 16 were HCV-RNA positive. Eleven of the viraemic patients had liver biopsies. Nine of the 11 biopsies showed no fibrosis or mild portal fibrosis, and two had either discrete (Ishak's stage 3) or marked (Ishak's scale 4) fibrosis. None of the individuals was aware of having been transfused during the first weeks of life and none reported a history of jaundice or had signs or symptoms of hepatitis. For all practical purposes, the infections had been silent for 35 years.

13.71 Dr David Mutimer (Consultant Hepatologist, The Queen Elizabeth Hospital, Birmingham) described his experience with relatively young people in the Birmingham area.[108] His data had been derived from a large population of patients who were infected with Hepatitis C. The median time from infection to cirrhosis was thought to be about 30 years: half of the patients had developed cirrhosis at 30 years after infection and the other half had some lesser degree of liver damage at that stage. What distinguished the people who progressed more quickly to cirrhosis was only partly understood. Some factors had been identified but others were not known. The study showed that men progressed more rapidly than women. It had also been established that alcohol would accelerate the progression to cirrhosis. In that cohort it was very rare to see cirrhosis within 10 years of infection in that cohort and it was uncommon to see it within 20 years of infection, unless there were aggravating factors.

Duration of infection

13.72 Duration of infection is a factor. In the USA, much Genotype 1 infection occurrs after blood transfusion, where the onset of infection is known and therefore doctors can work out the duration of the infection, sometimes 20 years later. In Genotype 3, infection occurs mainly in the Asian population and there, in large group studies, it is apparent that a great many of the patients are infected in infancy and the infection turns out in later life to be apparently more severe than Genotype 1. That is probably related to the fact that the reference point at which people present with significant liver disease is 40 years after the onset rather than perhaps 15 or 20 years. Assessing the role of genotypes is frequently confounded by being unable to determine the time when infection was acquired, hence the duration of infection also remains unknown. Immuno-suppression and HIV infection are well documented as being associated with more severe HCV disease. In the haemophilia population, that has clearly been evident, in that those with co-infection have, in the main, had a higher liver-related mortality than those who have had Hepatitis C alone.

13.73 Haemophilia patients present particular problems of analysis. The level of virus might have been constantly topped up by successive infusion of infected coagulation factor concentrates, as indicated by the observation that some patients had several genotypes of the virus present. In their cases, as distinct from transfusion patients, there was the problem that the date when the first infective dose was administered might be the 'unknown variable'.[109] Successive biopsies over a period of years gave data of developing fibrosis on which clinicians could project the progression of the disease and advise on the need for treatment in the case of an individual patient, essentially to stop progression before Ishak's stage 6 (cirrhosis) but the pattern was variable and generalisation difficult.[110] Furthermore, multiple biopsies in haemophilia patients are hazardous and seldom indicated.

Infection with more than one genotype of HCV

13.74 The possibility of infection with more than one genotype of HCV raises a question whether that factor of itself increases the rate of progression of disease. Professor Thomas did not know of any data to suggest that but thought that confronting a wider range of infection might well present a greater challenge to the immune system.[111]

Aggravating factors


13.75 There are some well-recognised aggravating factors that affect the outcome of HCV infection, though the evidence available to the Inquiry was not uniform. In particular there were conflicting views relating to alcohol. Professor Thomas took the more extreme view of the damaging effects of alcohol in patients with Hepatitis C. He contrasted Hepatitis B and Hepatitis C and his evidence was that alcohol affects the progression of Hepatitis C but not Hepatitis B. Data on liver damage seen in Hepatitis B cases where there is evidence of consumption of alcohol suggests that the liver damage found is the summation of the damage due to alcohol and what is due to the disease: the alcohol does not 'synergise' with Hepatitis B. He said that it is now accepted that alcohol increases the level of replication of Hepatitis C and, as a consequence, the liver damage seen in a patient with Hepatitis C who is, in addition, taking significant amounts of alcohol is greater than the sum of the damage due to the alcohol and the Hepatitis C: the two factors are synergistic in HCV but not in HBV.[112]

13.76 In Professor Thomas's view, the synergistic effect of alcohol was established around 2004-05 as a result of studies by Dr Ralf Bartenschlager, using a system of cells which supported replication of a model of HCV. In looking at a variety of factors that altered the effectiveness of replication, the synergistic effect of alcohol was observed.[113] Lifestyle advice, particularly relating to alcohol consumption, had long been common but was given added emphasis as a result of this finding. On this approach, the risk of accelerated liver damage in chronic HCV infection may be associated with quite moderate consumption: it is not limited to groups commonly recognised as alcoholics or those who would be described popularly as 'drunks' or who exhibit functional deficiencies in their ordinary lives.[114]

13.77 For this reason, Professor Thomas said:

[B]efore we had ways of treating patients with Hepatitis C, one important thing to say was that you can slow down the progression of your Hepatitis C if you reduce your alcohol intake, and the ideal scenario would be that you would be abstinent from alcohol.[115]

13.78 Professor Hayes adopted a different stance. In his unit, patients were generally advised to abstain entirely from alcohol if they had cirrhosis, but if their liver disease was short of cirrhosis then drinking within sensible limits of 21 units a week for a man and 14 units for a woman was considered safe (the same recommended safe limits of alcohol as advised for members of the public generally).[116] He did not think that advice based on that view had changed much over time.[117] He was examined on the advice contained in the Scottish Intercollegiate Guidelines (2006) on the management of Hepatitis C that:

Even moderate amounts of alcohol (within government recommended guidelines) have been associated with increased liver fibrosis compared to those who abstain.


Patients with [chronic Hepatitis C] should be advised that drinking alcohol (even in moderation) can accelerate progression of liver disease.[118]

13.79 He thought it debatable whether drinking alcohol in moderation created a risk of progression of chronic Hepatitis C in the mild and moderate categories.[119] He had never been persuaded by the evidence and it had not been drawn to his attention that drinking within the recommended limits would accelerate liver disease.[120]

13.80 Dr Mutimer's experience in Birmingham provided a practical indication of the impact of alcohol. In his experience, the majority of patients with Hepatitis C requiring liver transplants had been infected in their late teens or early twenties and many would have had a history of significant alcohol consumption. He did not suggest that dependency, or the excesses associated with alcoholism, were prerequisites.[121] The average age at which liver transplant was necessary was 55. Dr Andrew Bathgate's findings in that respect were broadly consistent with Dr Mutimer's broadly based investigations.[122]

13.81 It is not yet possible to resolve completely the issue of the extent to which alcohol consumption affects progression of HCV-related liver disease. The scientific basis for Professor Thomas's evidence is strong. Professor Hayes' clinical experience is extensive. Dr Mutimer's evidence correlated advanced liver disease at a relatively early age with significant alcohol consumption in the late teens or early twenties. In general terms it would appear not unreasonable to conclude that the consequences of consumption of alcohol would depend on a range of factors, including the quantity consumed, the regularity of the practice, the duration of the practice and the patient's liver disease profile.


13.82 The Bassendine Review listed smoking tobacco as an aggravating factor.[123] Recent studies have suggested that heavy smoking generally increases both liver fibrosis and inflammatory activity in chronic HCV infection, supporting the Bassendine finding.[124] Initially, French researchers suggested that smoking cannabis might also stimulate fibrosis. It is now known that there is indeed a mechanism by which cannabis causes fibrosis: some cells have cannabinoid receptors to which the cannabis molecule binds and the cells which stimulate fibrosis also have those receptors.[125]


13.83 Obesity is an aggravating factor. Professor Thomas said:

[I]t's becoming increasingly the case that three things are operating adversely in many patients. One is Hepatitis C itself. Second is, as we have mentioned, alcohol, and whether there is obesity, which is associated with deposition of fat in the liver. So what's becoming clear with all of these so-called insults to the liver is that the accumulation of fat, which ultimately may burst the liver cells, is bad news in terms of creating a risk of fibrosis.


And those three things that I have mentioned, alcohol and obesity and certain genotypes of Hepatitis C, all cause an accumulation of fat in the liver. And the genotype that is most involved in the accumulation of fat is genotype 3.[126]

Co-infection with Hepatitis B

13.84 Co-infection of Hepatitis C with Hepatitis B is a significant complication. The risks associated with HBV infection vary with age. Children infected at birth, or up to about two years of age, have a 95-100% risk of becoming chronically infected, with a risk of progressive liver disease. In contrast, after two years of age, right through the middle and later years of adult life, 95% of individuals who are infected develop an acute, self-limiting infection and only 5% develop chronic infection. Of those who have a chronic infection and proceed to develop cancer, 30% (almost all of whom acquired infection in early childhood) will develop a cancer before the stage of cirrhosis, and 70% will already have had cirrhosis before the cancer is developed.[127] Increasing knowledge of the pattern of developing disease as understood from time to time has an important bearing on patient care, and the need to provide treatment before a cirrhotic stage is reached. In co-infection with HBV and HCV the viruses interact with each other and affect immune response. HCV may inhibit HBV replication and vice versa. Combined chronic Hepatitis B with Hepatitis C leads to more severe liver disease and an increased risk of development of HCC.[128]

Do symptoms persist after successful treatment?

13.85 A question arose whether there could be 'occult hepatitis', a persistence of symptoms, or 'extra-hepatic manifestations', after the patient had a negative polymerase chain reaction (PCR) test, showing that the virus had been cleared. Professor Thomas explained the position.[129]

13.86 He said that there could be situations at or within a few months after the end of a period of treatment when the virus could not be detected in the circulating blood but might be present in the liver or in a cell. That had been described in the case of Hepatitis B.[130] However, the extra-hepatic manifestations he had discussed, the renal and dermatological signs and non-Hodgkin's lymphoma,[131] arose without exception where there was continuing viraemia detectable by HCV RNA PCR test systems. In the case of 'brain fog', the majority of the virus was being produced in the liver and the patients had viraemia. Low physical and mental wellbeing scores were not indicative of continuing infection in the absence of viraemia. After a demonstrable sustained viral response (where more than six months after the end of treatment viraemia is undetectable by the most sensitive HCV RNA tests), residual cognitive or other abnormalities are often associated with non-viral related problems: they are not attributable to a continuing 'occult' presence of the virus.[132]

Investigation and Treatment

13.87 Up-to-date knowledge of the natural history of HCV infection is clearly necessary for a proper understanding of the witnesses' evidence. In order fully to understand the evidence of patients and their relatives, however, it is necessary to have regard also to some significant developments in the investigation of the infection and in the treatments available.


13.88 From about 1978 doctors used blood tests to monitor haemophilia patients' ALT levels more or less as a matter of course, although it is not clear whether they had a well-developed understanding of why they were doing so. Biopsy changed the course of investigation. As indicated in paragraph 13.42, by 1981 experts, including Professor Sherlock and Professor Thomas, were already engaged in studies of NANB Hepatitis infection based on biopsy findings.

13.89 Once established in research practice, histology (microscopic examination of samples of tissue) obtained by conventional liver biopsy was thought to be the most reliable way of monitoring the severity of liver disease. The degrees of necro-inflammation (grade) and fibrosis (stage) were key to interpretation and consequent clinical decision-making regarding treatment.[133]

13.90 Generally, the standard method for performing a liver biopsy is to introduce local anaesthetics to the skin overlying the liver, insert a needle into the organ and remove a small core of liver tissue. An alternative method of removing a tissue sample involves inserting a long needle through a vein in a patient's neck to their liver, with the benefit of ultrasound examination. Professor Hayes described a method used in patients with haemophilia in Edinburgh in the late 1980s which involved inserting a small telescope into the abdomen and then inserting gas to give a view of the liver. This allowed the doctor to see the liver directly and so see the part of the liver from which the biopsy was taken. Although originally biopsies were taken during these procedures, it later became the practice for the liver to be inspected without removing tissue.

13.91 Liver biopsy carries with it a risk of haemorrhage and even death, the latter risk being about 1 in 10,000. These risks are significantly increased in patients with haemophilia. Liver biopsy of a patient with haemophilia is not straightforward and there are a few examples of fatal outcomes from the standard method.[134] Occasionally a blood transfusion may be required following haemorrhage. The standard method of liver biopsy causes variable pain but it can be extremely painful.[135] The narrative of the experiences of patients illustrates the impact of these biopsy procedures. More recently the non-invasive procedure FibroScan, using transient elastometry to measure liver stiffness, is employed to assess the degree of fibrosis of the liver.[136]

13.92 Other investigative procedures include endoscopy, used to examine and monitor the patient for upper gastro-intestinal varices. Many patients find the procedure uncomfortable.


13.93 Brief comments on treatment are contained in paragraphs 2.39-2.44 of the Preliminary Report. An excellent national clinical guideline, Management of Hepatitis C, has recently been updated by the Scottish Intercollegiate Guidelines Network (SIGN).[137] The oral evidence, particularly the evidence of Professors Thomas and Hayes, has increased the Inquiry's understanding of the topic. An account of progress in the management of patients and in therapy is contained in Chapters 14-16 Knowledge of Viral Hepatitis 1 to 3. At this stage it is sufficient to note a few significant developments.

13.94 Initially, it was remarkably difficult to treat a condition with an unknown cause. After the Chiron discovery, Alpha Interferon was the first drug that looked promising, though some early trials look less than convincing by contemporary standards.[138] It was used by Professor Thomas and his colleagues from about 1989. In terms of sustained viral response, rates varied between 12% and 15%.[139] This proportion may have been even lower among haemophilia patients.[140] The use of Alpha Interferon in a clinical research setting in 1989 was the first step in England in what would be a lengthy process of controlled trials leading to a licence and approval for use; a licence was granted in November 1994 for Alpha Interferon to be used in the treatment of chronic Hepatitis C. Professor Hayes had no recollection of treating anyone with Interferon before 1991. He treated the first few patients in Scotland in 1991 and 1992.[141] He also found that the drug appeared to be effective in clearing HCV in a minority of patients.[142] It was, however, to be some years before the technology was developed that demonstrated benefit even in those patients.[143]

13.95 The next significant development was the use of recombinant Interferon with Ribavirin, around 1995-96, and then of pegylated Interferon, a longer acting form of Interferon.[144] From the mid-1990s to the early 2000s access to newer treatments was not available outwith clinical trials until the treatments had been approved and licensed.[145] With each stage in development effectiveness improved, from the base level of 10-20% with monotherapy.[146]

13.96 Professor Hayes also pointed out that, to be eligible to participate in a trial at that period, a patient had to agree to liver biopsy before and after treatment since liver histology was deemed the 'gold standard' by which to measure the effect of treatment on the liver. It was a regulatory requirement.[147] Because of the hazards of liver biopsy in haemophilia, very few haemophilia patients entered the studies and thereby benefited from early access to more effective treatment.[148] Clinically, biopsy was considered not to be a sensible risk for haemophilia patients to take unless it was required in clinical practice.[149] Whilst not being included in a trial might well have been a source of frustration for a patient who was aware of a potential new treatment, Professor Hayes considered that not being included in a trial was not 'a major disadvantage'.[150] He gave two reasons for this. First, even if a patient was included in a clinical trial it did not necessarily mean that he received the new treatment, as half of those participating in a trial received the standard treatment and half the new treatment. Secondly, it took about two to four years for a treatment to become available following a trial and Professor Hayes considered that a wait of that duration was not a major disadvantage since the natural history of the condition from the time of infection until it caused symptoms is measured in decades rather than years.[151]

Current guidance

13.97 The current SIGN guidelines (see paragraph 13.93, above) for therapy adopt an evidence-based hierarchy, with treatment based upon HCV genotype.[152]

13.98 For Genotype 1 patients, all 'treatment naïve' patients (those who have not previously undergone antiviral treatment) with Genotype 1 should be considered for treatment with pegylated Interferon and weight-based Ribavarin, with the addition of a protease inhibitor as triple therapy. The same treatment should be considered for those who have failed previous antiviral treatment.

13.99 For Genotype 2 and 3 patients, standard treatment is pegylated interferon and weight-based Ribavarin for 24 weeks. Non-cirrhotic patients with Genotype 2 or 3 who achieve a 'rapid viral response', in which HCV RNA is undetectable, indicating the efficacy of therapy at week four, should be considered for a shortened duration of therapy of 12-16 weeks.

13.100 For patients with Genotypes 4, 5 and 6, standard treatment is 48 weeks of pegylated interferon and weight-based ribavarin.

13.101 In general, a sustained viral response can now be achieved following treatment based upon the above regimes in almost 80% of patients able to tolerate and complete the prescribed courses of treatment. Full details can be found in SIGN 133: Management of Hepatitis C (2013) along with references to the relevant research literature and analysis.[153]

13.102 HCV particles have a relatively short half life in circulation (that is, the virus particles decay quite rapidly in the bloodstream). In contrast, infected liver cells have a relatively long half life (decay is considerably longer). In patients whose treatment is likely to be successful, the initial rate of disappearance of HCV RNA during interferon therapy is rapid and viraemia does not return. This is reflected in the shortened period of therapy noted at paragraph 13.99 above. In patients whose treatment is likely not to be successful, initial clearance is followed by a second phase of less rapid clearance which may reflect the presence of an interferon-resistant second site of HCV infection within or outside of the liver.[154] If HCV RNA is still positive at the twelfth week of therapy, treatment is usually stopped because the chance of a sustained viral response is insignificant.[155]

13.103 In the case of patients treated after they already have cirrhosis, Hepatitis C is unlikely to be cured (partly because they have been infected for so long and partly because they find it harder to tolerate treatment).[156] Cirrhosis does not disappear even when a positive response is achieved and the condition puts the patient at continuing risk of liver cell cancer. In this group clinicians should not be talking about a 'cure' of a patient's overall condition because they are still at risk of this severe complication. However, in these patients the risk of progression to hepatic decompensation and possible HCC is reduced and they are no longer infectious: they have a 'viral cure'.[157]

13.104 The use of the term 'cure' was the subject of questioning during the oral hearing. The expression that had been commonly used was 'sustained viral response' (SVR), meaning undetectable HCV RNA six months after the end of treatment. Professor Thomas thought that it was now appropriate to speak of treatment 'curing' the patient, provided that treatment was given before the patient had developed cirrhosis.[158] He explained that until there had been many years of long-term follow-up showing that viral relapse was a very infrequent occurrence, clinicians were conservative about translating 'SVR' into the word 'cure'. It was not simply a matter of virological 'cure': one wished to know that, if there was sustained viral response, then fibrosis regressed and scarring was re-absorbed.[159] Generally, if HCV RNA were to reappear, it would be within the first few months after the end of treatment. For those who have SVR before the onset of cirrhosis, the liver should ultimately go back to normal. Professor Thomas emphasised the word 'should': there had been only a few years of observation and it might take longer than that period to progress to normal in terms of scarring of the liver; it is an evolving field of investigation. In relation to haemophilia patients it had not been possible to do frequent biopsies. However, non-invasive techniques, using fibro-elastography technology, are now available to subject the liver to an ultrasound wave and measure how much the organ wobbles. The stiffness of the liver is related to the scarring in it and that stiffness should reduce in somebody with an SVR. The evidence now available shows that it does indeed reduce. It may be several years before the liver actually goes back to normal and to date there has not been a large enough cohort of patients to enable clinicians to state definitively that the liver will go back to normal. However, 'cure' is now held to be an appropriate description in non-cirrhotic cases.[160]

13.105 This is an important development for people who, perhaps encouraged by stories spread around patient groups, may have resisted treatment on the grounds that Hepatitis C was not curable and that treatment might not be effective and would have serious side-effects.[161] Professor Hayes commented that there are still some patients who seem to have fairly benign disease and who are happy to have no treatment, despite the fact that treatment is improving.[162] People who do not have Genotype 1 are strongly encouraged to go for treatment.[163] About 20% of individuals do not manage to complete treatment, principally due to side-effects.[164]

Side-effects of treatment

13.106 Interferon alone produced flu-like symptoms and, taken three times a week, it made patients feel awful.[165] Pegylated Interferon is taken once a week with proportionately better impact, although some people still find it debilitating. The side-effects that most concern clinicians are depression and occasional suicidal ideation (thoughts about or preoccupation with suicide). Ribavirin is also associated with side-effects, particularly anaemia. Professor Hayes said that the patients would best understand the side-effects themselves: individual tolerance varied widely but each addition to the cocktail of drugs expanded the range of side-effects. Managing side-effects by reducing doses impacted on success rates. With Ribavirin, it has proved more effective to maintain the standard (weight-based) dose and support haemoglobin by the use of drugs such as erythropoietin. New drugs, while likely to improve the chance of a cure, are likely to have the same side-effects 'plus extra'.[166]

13.107 The common side-effects from pegylated Interferon and Ribavirin are summarised in paragraph 2.44 of the Preliminary Report. A more comprehensive list is set out in the SIGN (Scottish Intercollegiate Guidelines Network) guidelines.[167] In summary these are:

  • Flu-like symptoms, such as fever, myalgia (muscle pain), rigors ('chills'), arthralgia (joint pain) and headache. These symptoms are similar to those experienced in acute hepatitis when the body produces interferon. In therapeutic use, interferon is administered in larger amounts than a body would otherwise produce, with the result that the same symptoms are caused and magnified.[168] These symptoms are usually treated with paracetamol, increased fluid intake and rest. Patients are advised to coordinate their injections of interferon with periods of reduced activity, such as weekends and holidays.
  • Anaemia (decrease in number of red blood cells or less than the normal quantity of haemoglobin in the blood) and neutropenia (an abnormally low number of neutrophils, a type of white blood cell). Anaemia is primarily related to ribavirin. Initially this was treated by reducing the patient's dose of ribavirin which affected the success rate of the treatment.[169] More recently Erythropoietin is prescribed which enables a patient to continue taking the prescribed dose of ribavirin.[170] Likewise, Granulocyte colony stimulating factor may now be prescribed for patients who develop significant neutropenia instead of reducing ribavirin.
  • Depression is a commonly reported and serious side-effect of pegylated interferon and ribavirin treatment in patients, whether they have experienced depression before or not. Occasionally patients experience suicidal ideation. All patients receiving this treatment should be monitored for symptoms of depression before, during and immediately after treatment. Those who experience depression should be considered for treatment with antidepressants and referred to a specialist.
  • Severe skin reactions are uncommon during treatment but dry skin, pruritus (itch) and diffuse eczematous lesions occur in approximately 20% of patients. Psoriasis may be exacerbated by the treatment. Injection site reactions occur in over 50% of treated patients. Such conditions may be treated by emollients and topical corticosteroids.
  • Up to 6% of those treated may develop thyroid dysfunction, both over- and under-active thyroid, as a result of interferon therapy. Females are more at risk of this complication. This side-effect is not always reversible and a patient may require long-term treatment as a result.
  • Weight loss is commonly reported in patients on antiviral treatment. Nutritional support may be required.
  • Shortness of breath is a rarely reported side-effect of treatment. It may be linked to development of anaemia or may be caused by more serious cardiovascular or respiratory conditions.
  • Retinopathy (damage to the retina) during interferon treatment is common but it is usually mild and transient. It resolves spontaneously when the treatment stops and treatment is seldom required.
  • Alopecia is a relatively common reported side-effect of treatment. Hair usually grows again when the treatment stops.
  • Fatigue is one of the most commonly reported side-effects of treatment, with anaemia, under-active thyroid, sleep disturbance and depression all contributing.
  • Other reported side-effects include insomnia, poor concentration, oral disease, nausea and post-treatment withdrawal symptoms.

Timing of treatment and further procedures

13.108 Clinicians' views about when to treat a patient have evolved over the years within the reference period.[171] Prior to 2004, NICE[172] recommended that only those patients with severe disease should be treated and that the assessment of the severity of the disease should be based on a liver biopsy.[173] Due to the additional risks of a liver biopsy for those patients with haemophilia, they were excluded from this requirement.[174] In April 2004 at a Consensus Conference on Hepatitis C in Edinburgh it was decided that a liver biopsy was no longer essential to determine selection of patients for therapy. Then in 2005 the Scottish Executive produced the 'Hepatitis C Action Plan for Scotland'.[175] This highlighted the importance of treating as many people as possible rather than tailoring treatment to those persons clinicians believed needed it most.[176]

13.109 Issues are raised as to how soon after the known date of infection, treatment should be instituted. Treatment within three months of infection as opposed to treatment within months four to six makes no significant difference and most people clear infection within three months anyway, if they are going to do so spontaneously. In the case of surgeons who may contract or transmit infection from or to patients, tests are carried out every two weeks. If viraemia occurs, treatment is instituted within the period three to six months.[177] This is highly successful.

13.110 A person with cirrhosis may be less able to tolerate the treatment complications as well as the problems caused by cirrhosis.[178] It is far better to prevent a person developing cirrhosis than to deal with the consequences of it, although for a clinician it is difficult to identify when adverse developments may occur.

Hepatocellular cancer

13.111 The management of hepatocellular cancer (HCC) is complex. Recent literature on the subject has set out a number of options.[179] If possible, transplantation is the preferred treatment in generally 'well-compensated' patients (patients with good clinical and biochemical profiles) who have either one tumour less than five centimetres in size or up to three tumours each less than three centimetres in size. In these cases, there must be no extra-hepatic spread, and the tumour or tumours must not involve any blood vessels. However, the proportion of patients with hepatocellular cancer who are suitable for a liver transplant is very small.[180] Professor Hayes said:

[L]iver transplant is ... certainly indicated in some patients. It has the advantage that it gets rid of the cirrhotic liver. Once you have started to form one tumour in the liver, we believe that you are likely to form more. There is what we call a field change, and it is not uncommon that if you find a tumour you actually find two or three.[181]

13.112 Liver transplantation is a complex, expensive and risky treatment. Transplant of the liver of a donor without haemophilia cures the haemophilia patient recipient of that condition: the implant synthesises Factor VIII normally.[182] Liver transplantation does not totally remove HCV from the recipient, however, as the virus infects parts of the body other than the liver. Immunosuppressant medication, given to prevent rejection of the transplanted liver, weakens the body's overall ability to deal with the virus. Hepatitis C will therefore always infect the new liver and the natural history from infection to cirrhosis is often considerably accelerated in the transplanted liver - a newly transplanted liver may become cirrhotic within two years of transplantation.[183] One of the reasons for this is that a patient is immunocompromised post-transplant and his ability to clear the virus is therefore impaired.[184] Recent SIGN advice is, therefore, that patients should be considered for antiviral therapy after liver transplant to achieve HCV clearance in cases of recurrent HCV-related liver disease.[185]

13.113 In a very small proportion of clinically well patients with optimal liver function test scores who have small single nodules, surgical resection (to remove the segment of the liver containing the tumour) may be carried out. Professor Hayes noted that targeted treatment risks leaving a liver that is prone to developing new tumours.[186]

13.114 In other patients who are not suitable for surgery, percutaneous radio frequency ablation may be used. This is a procedure whereby, under imaging control, heat generated from a high frequency alternating current is inserted directly into the tumour in order to kill it. Injection with ethanol is indicated for multiple tumours up to three centimetres in size. For tumours up to about five centimetres, trans-arterial chemoembolisation is used if patients do not have widespread disease, vascular involvement, or marked hepatic decompensation. In this procedure the blood vessels supplying the tumour are selectively blocked off following the introduction of the anticancer drugs directly into a tumour via its blood supply. Beyond this, chemotherapy or palliative care is used for cases which are unsuitable for liver transplantation.[187] Chemotherapy treatments are seldom very effective.

Drug therapy

13.115 Several drugs in the class of protease inhibitors (Telaprovir and Boceprovir) have recently been licensed for use alongside pegylated Interferon and Ribavarin and, according to trial data, will increase response rates in Genotype 1 patients to 70-80%. Telaprovir was approved for prescription in December 2011.[188] In addition, variations in the IL28 (lambda) gene appear to influence the chance of response (see paragraph 13.67 above) and this genetic predictive test is now finding a place in the selection of patients for treatment.[189] Health economics will affect availability. The side-effects of using protease inhibitors are expected to be more severe. Professor Thomas discussed both aspects:

I think the side effects will be more severe with the protease inhibitors because when similar ... but not identical compounds, are used in HIV, then they have caused liver toxicity.... [A]ccumulation of fat in the liver, for instance, has been seen with some of the HIV-active protease inhibitors. So how that will work through with Hepatitis C is not 100 per cent clear.

Telaprevir has been causing quite severe rashes. But the final costing is going to be dependent on ... [the] predictive polymorphism of IL28, which is a lambda interferon ... strongly associated with response to treatment. So it might allow you to pick out those people who are going to respond to pegylated interferon and ribavirin from those who won't, and that latter group might then, instead of going through a trial of the pegylated interferon and ribavirin, they might start initially into those two drugs with the protease inhibitor.

And that will influence the health economics. And then there will be the issue of early-stopping rules of the type... [applied to] interferon and ribavirin because if you can, at an early stage, identify those that are going to be successfully cured, then again that will increase the cost-effectiveness. So there are several groups now looking at, in preparation for NICE, what the management algorithm might look like, and I presume that ultimately that may influence what the costs would be.


And the unknown, of course, is the competitive issue as well... telaprovir is made by Vertex and boceprovir is made by Schering-Plough, but they have just been bought by Merck Sharp and Dohme.


One of the figures that was cited was that it might cost up to £18,000 for a combined course of pegylated interferon, ribavirin and one of these protease inhibitors. And ... I think ... a full year's course of interferon and ribavirin probably costs about £10,000, that sort of level. So they are looking at doubling it in anticipation of the doubling the response rate, so that the cost per cure is slightly improved on what it is now. So when you do the cost-effectiveness analysis, it will come out as a significant improvement.[190]

13.116 Professor Hayes said that trial data relating to these two new recently-licensed drug treatments suggests that they could herald a 'quantum improvement' in responses, at least for Genotype 1 patients. He also suggested that new treatments, with the added benefit of being taken in oral form over a short course (rather than by frequent injection), might be on the horizon which could be 'remarkably effective'.[191] Professor Thomas said that there was no condition with more drugs in the pipeline than Hepatitis C: by 2015 there will be about 30 waiting in the wings.[192]

13.117 It is not known at present what the implications are for patients requiring treatment for different genotypes from each of the two relevant treatment groups (haemophilia or post-transfusion patients). Professor Thomas said there was only a relatively small number of relevant patients for whom this is an issue. In the case of haemophilia patients he said:

I think the other thing that has been a problem in treating the haemophilia population is that the interferons have been given subcutaneously and of course, we are worried about forming haematomas by having to inject three times a week. The pegylated interferons ... we only inject now weekly. So that problem is starting to diminish. And initially, when we had to give the injections more frequently, we gave them intravenously to make sure we didn't cause haematomas.

When we were only looking at 12 to 15 per cent response rates, when you are explaining the risk/benefit to the patient, the need for repeated intravenous injections was something that would be considered -- in genotype 1 it would have to continue for a year. That would be discouraging to the patient, I would think.[193]

Co-infection with HIV

13.118 Co-infection with HIV complicates the picture.[194] Professor Thomas explained that the issue has always been whether to give highly active retroviral therapy first and then Hepatitis C treatment, or to do it the other way round. In the main, patients are treated for HIV first and then interferon and ribavirin treatment would be added in. The progression of Hepatitis C in the main is much slower than untreated HIV. If the problems can be decoupled by treating HIV first, the situation is improved: a sustained viral response with standard pegylated interferon and ribavirin after treatment of HIV is more likely. Professor Thomas thought that the overall data suggested that the sustained viral response rates in co-infected patients are probably about half what one would otherwise see, so that, in the case of a Genotype 1 patient, there might be a response rate of around 20-25%, instead of 40%. How much of that would be corrected by prior treatment of the HIV he did not think was known at the moment but logically one would expect it to be improved. In terms of delay, prior treatment of HIV infection would be insignificant in relation to the progression of Hepatitis C.

Morbidity and mortality associated with HCV

13.119 The discussion so far has sought to describe the clinical features, natural history and treatment of chronic Hepatitis C, together with co-morbidities and factors which may accelerate the course of the disease. The two 'populations' affected by Hepatitis C who form the subjects for the Inquiry comprise (i) haemophilia patients, almost all male, the majority of whom were infected in the first 30 years of their lives and many of whom were co-infected with HIV; and (ii) those infected as a result of blood transfusion, the majority of whom were over age 40 at the time of infection. Many of the latter group died in the first two to five years after infection as a result of causes quite unconnected with HCV (very often connected, instead, to the primary condition that required medical intervention including blood transfusion). There have been numerous studies of cohorts of patients in each population that have contributed to understanding of the morbidity and mortality associated with HCV and HCV/HIV infection.

HCV associated with haemophilia treatment

13.120 The clinical and treatment records of 310 haemophilia patients registered at the Royal Free Hospital Haemophilia Centre were analysed by Dr Thynn Thynn Yee and others.[195] The study provided concrete evidence for the generally held view that almost all haemophilia patients treated with Factor VIII concentrates prior to 1985 (when virucidal treatment of concentrates was introduced) were infected with HCV, at least after the introduction of large-pool clotting factors.[196]

13.121 The study concluded that the 25-year follow-up of the whole group showed the potentially lethal combination of HIV and HCV co-infection. Individuals infected with HCV alone showed slow progression of liver disease. In terms of prognosis, the article stated:

HCV infection is now recognised as a major risk factor for HCC and there seems to be an incubation period of two or three decades on average ... HCC... is likely to become more common in this group of patients who were infected from 1977 (median year).[197]

13.122 A major follow-up study among haemophilia patients from Sheffield, Utrecht and including the Royal Free cohort related to 847 patients with HCV antibodies extending for up to 42 years (median 27 years). Of these, 687 (81%) developed chronic Hepatitis C and 210 were co-infected with HIV. There were 199 deaths, 73 of which were attributable to AIDS, and 55 were 'liver related' of whom 31 had HIV/HCV co-infection. Twenty-four HIV-negative patients (4%) had died of liver disease. Seventy-one of the total cohort developed End-stage Liver Disease (ESLD). Thirteen had had a liver transplant. The cumulative incidence of ESLD after 35 years was 11.5% in HIV-negative individuals. The risk of developing ESLD was also associated with age at HCV infection (older patients at date of infection being more at risk) and with history of alcohol abuse.[198]

13.123 In Canada, the federal, provincial and territorial governments agreed to pay compensation to individuals who became infected with HCV through blood and blood product transfusions between 1 January 1986 and 1 January 1990 on the ground that surrogate marker testing for infection, which had been in place in the USA, had not been implemented in most Canadian jurisdictions. Between 10,000 and 16,000 Canadians were thought to have been infected in that period. Patients with post-transfusion chronic HCV infection, haemophilia patients, patients co-infected with HIV and patients with secondary infections (for example, the sexual partners of those with haemophilia and HCV) were covered by the compensation scheme. Compensation, for viraemic patients, was related to a scale of mutually exclusive stages:

Liver fibrosis stage:

  • F0, no fibrosis, to F4, cirrhosis

Clinical status stages:

  • Decompensated cirrhosis
  • Hepatocellular Carcinoma (HCC)
  • Death

13.124 Accurate prognostic data were required to ensure the sufficiency of the compensation fund and that entailed assessment of the clinical characteristics of the claimant cohort to determine annual fibrosis stage-specific transition probabilities. HCV treatment efficacy was factored into the exercise. Dr Hla-Hla Thein and others reported their findings using base-line clinical data on 5004 patients from 2007.[199] By then, 1231 patients had died (including 401 haemophilia patients) and 3773 were alive (including 904 haemophilia patients). Biopsy evidence was available in 1082 cases (including 225 haemophilia patients).

13.125 It was assumed that 20% of individuals who acquired HCV infection would clear the infection within six months, with an annual clearance rate thereafter of 2%.[200] The model did not assume a constant rate of progression of liver fibrosis; rather, it assumed use of up-to-date treatment with pegylated Interferon and Ribavirin for all in need. The researchers found that, 20 years after the index transfusion, 10% of all living claimants had cirrhosis and 0.5% had developed HCC. Predicting forward a further 20 years, the risks were computed, giving the following results for haemophilia patients (HCV and HCV/HIV co-infected patients combined):

  • Risk of HCV-related cirrhosis
  • Risk of HCC
  • Risk of liver-related death

13.126 It was noted that haemophilia patients were usually younger than patients infected post-transfusion and were often co-infected with HIV. For the haemophilia group, the cumulative lifetime risk of cirrhosis was estimated at 45%, and of liver-related death 30%. These figures did not include HCV/HIV co-infected patients.

Post-transfusion chronic Hepatitis C

13.127 Examination of long-term morbidity and mortality from post-transfusion HCV is bedevilled by a number of difficulties. Invariably, a very significant proportion of those infected following transfusion die before the study is completed, often of the morbidity which led to the original need for transfusion. A Scandinavian follow-up over 20 years of over a million transfusion recipients showed standardised mortality rates after one, five and 20 years of 17.6, 2.1 and 1.3 times the general public, respectively.[201] Of these, 65% were dead after 10 years and 77% were dead after 20 years. Furthermore, in look-back studies low proportions of potential subjects come to light and are available for study: there is an unavoidable risk of selection bias and this is reflected in the results brought out.

13.128 In the UK, Dr Helen Harris and colleagues reported on a study of the natural history of HCV after 16 years of infection carried out on behalf of the HCV National Register Steering Group. The patients all had acquired infection from blood transfusion in the UK on an identified date. All had been traced through the national HCV look-back study. They estimated that at median seven years post-transfusion 61% of the patients identified in the look-back had died.[202] Almost none of these patients would have died of HCV-related causes after this short post-transfusion period.

13.129 In Denmark, HCV antibody screening was introduced in 1991. Thereafter, 150 HCV-positive donors were identified.[203] A look-back study of post-transfusion chronic HCV in 1996 identified 1018 recipients of blood from those donors. By then 230 were alive, 22.6%, and 77.4% had already died. The Danish health information systems allowed much fuller and more complete ascertainment of subjects than in the UK. Results of a median follow-up of 18 years (21.8 years in survivors) were published in 2011. The authors found that by 2009 only 121 of 1018 known recipients (11.8%) were still alive.

13.130 In the circumstances, individual studies of morbidity and mortality among surviving patients have to be treated with a degree of caution: the surviving cohort are not necessarily representative of the total population, including those who have died before the date of study. Additionally, data expressed in percentage terms may be misleading. General impressions can nevertheless be gained from a survey of a range of sources. There may be few subjects alive in any sub-group. In the Danish study by Dr SØren Just and colleagues, it was found that there was no difference in all-cause mortality among the 230 HCV-exposed recipients alive in 1996 and followed to 2009 when compared with unexposed controls (a matched group of transfusion recipients not exposed to HCV-infected blood). The authors also found that rates of liver-related disease were not significantly different between the infected and uninfected recipients of HCV-infected blood when adjusted for age, co-morbidity and other factors. Liver-related mortality overall was increased significantly. Relative risk of liver-related death in the HCV-infected group was increased tenfold, although this represented only nine deaths.

13.131 The study by Harris and colleagues found that, after 16 years of infection, transfusion recipients who tested positive or indeterminate for antibodies to HCV were at increased risk of dying from liver disease compared to anti-HCV negative transfusion recipients. They found that, at median 16 years post-transfusion, the relative risk of all-cause mortality compared with transfused but HCV-negative controls was 1.17 (NS);[204] and that relative risk of death directly from liver disease was 2.71 (p = 0.03).[205] There was also a significant - indeed larger - difference in survival to death certified as liver-related at 5.04 (p=0.003).

13.132 A very long-term US follow-up (25 years) by Dr Leonard Seeff and colleagues of the original NANB Hepatitis cohort studies in the USA showed overall mortality of 67% in the HCV-positive cohort versus 65% in HCV-negative controls.[206] As with the UK and Danish studies, liver-related deaths, at 4.1% in HCV-positive patients versus 1.3% in controls, were significantly increased (p=0.05), but represented only a small fraction of overall deaths. The authors stated that:

For the entire cohort of patients initially infected with HCV, the estimate for progression to cirrhosis is 17%. Thus, over an approximate 25-year interval, HCV infection did not lead to increased [overall] mortality and resulted in severe histological lesions in fewer than 20%.

Whether those with histologically defined chronic hepatitis alone will progress to cirrhosis, and whether mortality and morbidity will continue to derive mainly from those with established cirrhosis, remains to be determined.[207]

13.133 In the Canadian study by Thein and colleagues, for post-transfusion HCV patients, among 3699 individuals of whom 857 had liver biopsy evidence, modelling showed:

  • Risk of HCV-related cirrhosis
  • Risk of HCC
  • Risk of liver-related death

13.134 Dr Gary Davis and colleagues have recently reported the results of a multi-cohort natural history modelling study of disease progression in what has become an ageing population of US patients.[208] This study, which is most sophisticated and well-informed, used multiple disease cohorts to study cirrhosis, hepatic decompensation, HCC and death. Projections were developed, differentiated for sex, age at infection and duration of infection up to 30 years. Rates of liver-related morbidity and mortality at 30 years were derived as follows:

Table 13.1: Projections by cohort of all infected patients

Percentage after 30 years
Cirrhosis Decompensated
HCC Liver death
Females: Age 0-30 at infection 4.24 0.44 0.02 0.92
Females: Age 31-50 at infection 7.75 0.79 0.04 1.28
Females: Age over 50 at infection 7.36 0.80 0.12 2.29
Males: Age 0-30 at infection 13.92 1.55 0.19 2.91
Males: Age 31-50 at infection 38.11 5.13 0.50 11.14
Males: Age over 50 at infection 15.24 2.21 0.56 15.06

13.135 The authors cite a number of other studies showing that, after long-term follow-up, all-cause mortality and non-liver mortality may also be increased in older individuals with chronic HCV infection.

13.136 One such study, by Dr Anne Guiltinan and colleagues, dealt with a large number of blood donors for whom records were available at 17 blood centres in western and southern USA.[209] They identified 10,259 confirmed HCV-positive donors who had donated blood between 1991 and 2002, and 10,259 HCV antibody-negative donors matched for year of donation, age, gender and ZIP (postal) code. After a mean follow-up of 7.7 years, they found excess mortality in the HCV infected group as follows:

Table 13.2: Excess mortality in HCV positive donors compared to HCV-negative donor controls[210]

HCV positive HCV negative Total Hazard ratio[211]
Liver-related deaths 90 2 92 45.99
Drug/alcohol-related deaths 64 6 70 10.81
Cancer excluding liver 56 53 109 1.09
Trauma/suicide 106 36 142 2.99
Cardiovascular 60 28 88 2.21
Pulmonary 8 7 15 1.18
Stroke 13 6 19 2.20
Infection 23 2 25 11.73
Other/unknown 33 8 41 4.23
Total deaths 453 148 601 3.13

13.137 The authors commented that the estimated annual risk of death due to liver disease was 1:1000 or, cumulatively, about 2% over 20 years of life following infection. Liver cancer accounted for about one fifth of these deaths, about 0.4% cumulative risk over the same period. Multivariate analysis did not change significantly the association between HCV infection and all-cause mortality.

13.138 The donors were presumed to be unaware of their infection and to have been in apparently good health at the time of donation, having passed blood donor medical selection criteria. Under-reporting of HCV risk factors was likely, however.

13.139 These studies, in unselected post-transfusion patients with acquired chronic HCV infection and in other populations of those infected with HCV, indicate consistently that after 18-25 years or more post-infection:

(i) A relatively small proportion of post-transfusion infected patients remain alive, many having died within a few years of transfusion of causes not related to HCV.

(ii) While mortality directly attributable to liver disease is increased in these patients compared to HCV-negative transfused controls, this has so far amounted to less than five per cent of total deaths among those surviving 10 or more years after transfusion.

(iii) Of the survivors alive more than 25 years post-infection, a significant proportion (up to 25%) may ultimately go on to develop cirrhosis and become exposed to risk of its complications, namely liver failure and HCC.

13.140 There is a possibility that, for reasons as yet unknown, those relatively few survivors of post-transfusion HCV, or the haemophilia patients with HCV in the UK who survive for more than 30 years after acquiring HCV infection, may have a slightly increased all-cause mortality and non-liver-related mortality. It seems more likely, however, that such findings in HCV-positive patients as a whole are due to factors associated with their previous lifestyles rather than to some as yet unidentified non-hepatic factor associated with long-term HCV.

13.141 Many studies have demonstrated that older age at acquisition of HCV infection is associated with more rapid progression of liver disease. However the Inquiry has found no evidence that, in individuals who acquired HCV at younger ages, there is an age-dependent acceleration in the rate of progression of liver disease, independent of other variables (such as alcohol, obesity or smoking, discussed above).

13.142 Finally, can these studies be improved upon? One of the doyens of the study of Hepatitis C, Dr Leonard Seeff (principal author of the study at paragraph 13.132 above), has recently written:

Some [of those infected with HCV] will even progress through life without ever knowing that they are HCV infected, while others may suffer from varying degrees of fatigue and a decreased quality of life. In order to accurately establish the frequency of these variable outcomes, it would be necessary to mount a life long study of a large cohort from the time of infection and follow them until their demise.... [I]t would be almost impossible to pursue a study of this duration...[212]

13.143 It now seems unlikely that any further studies will provide much more definitive information in future. Because of the advent of effective treatment, the era of natural history studies of chronic Hepatitis C has probably passed.

Impact of co-infection with HIV

13.144 As already noted, in patients co-infected with HIV the rate of HCV replication is higher, and the level of viraemia is also relatively high. In the UK many haemophilia patients became co-infected with HIV and HCV. Very few post-transfusion HCV patients, if any, had this problem. Overall, parenteral drug use has caused the majority of cases of HIV/HCV co-infection and studies of this cohort best inform current understanding of the problem.

13.145 The Royal Free Hospital, Sheffield and Utrecht study of 847 haemophilia patients exposed to HCV infection, of whom 210 were co-infected with HIV, showed that the cumulative incidence of ESLD among co-infected individuals was 35.1% at 35 years as against 11.5% in HIV-negative subjects. Deaths from liver disease were 21 of 210, plus 73 deaths from AIDS in the co-infected patients.[213]

13.146 Meta-analysis of 17 studies, reported in 2008, indicated more rapid progression to cirrhosis in patients co-infected with HIV than in patients infected with HCV alone.[214] Drawing on previous reports, 3567 patients were studied. The study also analysed data distinguishing results for patients treated with highly active anti-retroviral therapy (HAART). Over the period studied, HAART did not appear to correct fully the adverse effect on HCV prognosis of co-infection with HIV.

13.147 The estimated mean transition probabilities between fibrosis stages were calculated. There was a significant association between the duration of HCV infection and the rate of progression of fibrosis: with longer duration the rate of progression slowed. By contrast, among co-infected individuals, it was concluded that the rate of fibrosis progression appeared to be constant.

13.148 Prevalence of cirrhosis in co-infected individuals was 21% after 20 years and 49% after 30 years. The overall ratio of cirrhosis in co-infected individuals relative to cirrhosis in patients infected with HCV alone was 2:1. It was concluded that chronic Hepatitis C outcomes were worse for co-infected individuals.


13.149 As indicated in paragraph 13.2, the narrative of patients' experiences of infection with NANB Hepatitis virus/HCV is best understood in light of the most up-to-date knowledge of the disease. In that way, patients' reports of signs and symptoms associated with infection can now be explained even when they would not have been understood at the time of report to be related to NANB Hepatitis virus/HCV infection. Current knowledge provides the appropriate background for an informed appreciation of the accounts patients and their relatives have given of their experiences of HCV infection, whatever the date or dates of those experiences. However, it has to be repeated that very little of the information relating to the natural history of HCV infection which is available now, in 2014, would or could have been known until well into the 1990s, after the patients with whom this Report is concerned were already infected by transfusion of blood, blood components or blood products. Hindsight cannot support a view of what should have been understood at earlier periods.

13.150 The element of hindsight is less material in relation to the pain and discomfort associated with investigative procedures and the side-effects of drug therapy. These factors were available for observation at the time. The general information nevertheless also informs a proper appreciation of the accounts provided.

13.151 Patients' reports of their individual histories are described in Chapters 4 and 6.

1 Hepatitis G was described at paragraph 2.10 of the Preliminary Report. The standard text was Schiff's Diseases of the Liver, 10th edition, 2007

2 Professor Thomas - Day 52, pages 9-11

3 Preliminary Report, paragraphs 2.5 and 2.6

4 Preliminary Report, paragraphs 2.8 and 2.9

5 Strictly speaking a parenteral infection is one spread by a means other than by the introduction of a pathogen to the gastrointestinal tract and, in this general way, does not refer only to blood-borne infections. Medical literature of the time, however, used the term parenteral, at least as regards hepatitis, to mean 'blood-borne' and this usage is retained here.

6 Hepatitis D, referred to in the Preliminary Report at paragraph 2.11, is also a parenterally transmitted RNA virus which affects those already infected with Hepatitis B. It is not relevant to the NHS patients discussed in this Report.

7 Professor Thomas - Day 52, pages 72-75; Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1076

8 Professor Thomas - Day 52, page 12 and pages 72-73

9 Thein et al, 'Prognosis of hepatitis C virus-infected Canadian post-transfusion compensation claimant cohort', Journal of Viral Hepatitis, 2009; 16:802-813 [LIT.001.4184] at 4187; Professor Thomas - Day 52, page 13 and pages 56-57; Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1074

10 Professor Thomas - Day 52, pages 58-59. Increasing fibrosis is measured on the Ishak scale. The scale runs from 1 (no fibrosis) to 6 (cirrhosis) at which stage the individual is at risk of hepatocellular carcinoma.

11 Professor Hayes - Day 78, pages 83-4

12 Professor Thomas - Day 53, page 58

13 Professor Thomas - Day 52, pages 8-12, generally

14 Professor Hayes - Day 78, pages 88-89

15 Professor Thomas - Day 53, page 59

16 Thein et al, 'Prognosis of hepatitis C virus-infected Canadian post-transfusion compensation claimant cohort', Journal of Viral Hepatitis, 2009; 16: 802-813 [LIT.001.4184] at 4187. Cf Professor Thomas - Day 53, page 59 et seq. His evidence was that HCC did not occur without prior development of cirrhosis.

17 Sherlock S. & Dooley J Diseases of the Liver and Biliary System, 9th edition 1993, pages 504-505

18 Professor Thomas - Day 52, page 16

19 Ibid page 48

20 See, however, Chapter 3, Statistics.

21 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1072-3; Professor Thomas - Day 52, pages 38-39

22 Professor Hayes - Day 78, page 98

23 Professor Thomas - Day 52, page 40

24 'Cure' in this context is the permanent eradication of the virus from the patient which, in pre-cirrhotic individuals, allows the liver to return to normal. See paragraphs 13.97-13.101 below for further information on current treatment for each of the main genotypes, which takes account of these factors.

25 Professor Thomas - Day 52, pages 60-61. In practice, Professor Hayes stated that it is very rare to find in clinical practice an individual with more than one genotype, as distinct from quasi-species of a single genotype: Professor Hayes - Day 78, page 98.

26 Preliminary Report, pararaph 2.21

27 Professor Thomas - Day 52, page 49

28 Professor Thomas - Day 52, page 73; Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1075-76. After 20-30 years viral DNA may no longer be readily detected in up to 10% of chronically infected patients. See Watanabe et al, 'Spontaneous elimination of serum hepatitis C virus (HCV) RNA in chronic HCV carriers: A population-based cohort study', Journal of Medical Virology, 2003; 71: 56-61 [LIT.001.4198]

29 Professor Thomas - Day 52, page 58

30 Ibid pages 57-58; Day 53, pages 61-62

31 Professor Thomas - Day 52, pages 61-64; Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1075. See also: Weissenborn et al, 'Hepatitis C virus infection and the brain', Metabolic Brain Disease, 2009; 24:197 - 210 [LIT.001.4204]

32 Professor Thomas - Day 52, pages 64-68. See also: Weissenborn et al, 'Hepatitis C virus infection and the brain' Metabolic Brain Disease, 2009; 24:197-210 [LIT.001.4204]

33 Ezzell, 'Candidate Cause Identified of Non-A, Non-B Hepatitis', Nature; 19 May 1988 [SGH.002.8036]

34 Choo et al, 'Isolation of a cDNA Clone Derived from a Blood-Borne Non-A, Non-B viral Hepatitis Genome', Science; 1989, 244: 359-362 [LIT.001.0629]

35 Kuo et al, 'An Assay for Circulating Antibodies to a Major Etiologic Virus of Human Non-A, Non-B Hepatitis' Science, 1989; 244: 362 [LIT.001.0629] at 0632

36 As noted in Chapter 14, Knowledge of Viral Hepatitis 1, paragraph 14.67, the expression 'non A, non B Hepatitis' (frequently abbreviated to 'NANBH' or 'NANB Hepatitis') was coined in the mid-1970s as a collective term for hepatitis from which, at that time, Hepatitis A and Hepatitis B, as well as cytomegalovirus (CMV) and Epstein-Barr virus (both of which can cause liver inflammation), had been excluded.

37 Professor Thomas - Day 52, page 38

38 Ibid pages 68-69

39 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1075

40 Professor Thomas - Day 52, pages 42-46

41 Ibid page 44 and 50

42 Ibid pages 53-54; Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1073

43 Professor Thomas - Day 52, page 56

44 Ibid page 41

45 Technically 'selected for'.

46 Professor Thomas - Day 52, pages 41-42 and 69-70

47 Ibid page 49

48 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1071-72

49 Professor Hayes - Day 78, page 78; Professor Hayes' report on Hepatitis C [PEN.018.0240]

50 Professor Hayes - Day 78, pages 78-80

51 'Surveillance of known hepatitis C antibody positive cases in Scotland: results to 31 December 2003,' SCIEH Weekly Report, 2004; 38: 150-155 [LIT.001.4176]

52 Professor Turner's statement on practices in Scotland in respect of the collection, testing, processing and distribution of blood [PEN.002.0452] at 0455

53 Professor Turner - Day 7, pages 24-25

54 'Sensitivity' is a function of the test's ability to capture all cases of infection with the target pathogen. 'Specificity' is a function of the test's ability to identify only the target pathogen.

55 CE marking is a manufacturer's declaration that a product meets the requirements of relevant EU directives.

56 98/97/EC of October 1998

57 Professor Turner - Day 7, page 28

58 Ibid pages 26-27

59 Professor Thomas - Day 52, page 76; Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1077. And see, for example: Yee et al, 'The Natural History of HCV in a cohort of haemophilic patients infected between 1961 and 1985', Gut, 2000: 47: 845-851 [LIT.001.4318].

60 Professor Thomas - Day 52, pages 84-85 and pages 89-90; Fletcher et al, 'Non-A, non-B hepatitis after transfusion of factor VIII in infrequently treated patients', British Medical Journal, 1983; 287 [LIT.001.0239]; Kernoff et al, 'High Risk of Non-A Non-B Hepatitis After a First Exposure to Volunteer or Commercial Clotting Factor Concentrates: Effects of Prophylactic Immune Serum Globulin', British Journal of Haematology, 1985; 60: 469-479 [LIT.001.0800]

61 See comments on mini transfusion of neonatal infants below at paragraph 13.72.

62 Professor Thomas - Day 52, page 77

63 Ibid page 83. (See also Chapter 8, Knowledge of HIV/AIDS Now, paragraph 8.23 - exposure to HIV does not provide subsequent immunity to that virus either).

64 Professor Thomas - Day 52, pages 83-84

65 Professor Hayes - Day 78, pages 79-80

66 Sherlock,S. Diseases of the Liver and Biliary System, 6th edition 1981

67 Bamber et al, 'Clinical and histological features of a group of patients with sporadic non-A non-B hepatitis', Journal of Clinical Pathology, 1981; 34: 1175-1180 [LIT.001.0759]

68 Koretz et al, 'Non-A, non-B post-transfusion hepatitis: disaster after decades?', Hepatology, 1982; 2: 687 [LIT.001.3738]; Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1079-80

69 Professor Thomas - Day 52, pages 116-118

70 Ibid page 117

71 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1079; Professor Thomas - Day 52, pages 120-121

72 Professor Thomas - Day 52, pages 117-118

73 Ibid page 119

74 Preston et al, 'Percutaneous liver biopsy and chronic liver disease in haemophiliacs', The Lancet ,1978; (ii): 592-594 [LIT.001.0387]

75 Day 52, pages 121-122

76 Ibid page 136-137. See sections below on these 'aggravating factors'.

77 Professor Thomas - Day 52, page 129; Bamber, Sherlock et al, 'Clinical and histological features of a group of patients with sporadic non-A non-B hepatitis', Journal of Clinical Pathology, 1981; 34: 1175-1180 [LIT.001.0759]

78 Professor Thomas - Day 52, pages 129-131

79 Professor Thomas - Day 52, pages 138-139

80 Professor Thomas - Day 53, page 58

81 Professor Hayes - Day 78, page 88

82 Professor Thomas - Day 53, pages 70-72

83 Ibid pages 72-73

84 Davis et al, 'Aging of Hepatitis Virus (HCV)-infected Persons in the United States: a Multi-cohort Model of HCV Prevalence and Disease Progression', Gastroenterology, 2010; 138: S13 - S21 [LIT.001.4046]

85 Professor Thomas - Day 53, pages 74-75

86 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1080.

87 Professor Thomas - Day 53, pages 10-12

88 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1080

89 Professor Thomas - Day 53, pages 4-5

90 Ibid pages 73-76

91 Ibid pages 76-77

92 Ibid page 74

93 Ibid pages 34-36

94 Ibid pages 75-76

95 'Life score metrics' may be made more complex by background issues affecting the patient which, in the opinion of neurologists, make it difficult to evaluate residual symptoms after an acute illness.

96 Professor Thomas - Day 53, pages 7-9

97 Weissenborn et al, 'Hepatitis C virus infection and the brain', Metabolic Brain Disease, 2009; 24: 197-210 [LIT.001.4204] at 4215

98 Professor Thomas - Day 53, pages 12-14

99 Professor Thomas' Report on Hepatitis C [PEN.017.1071] at 1082

100 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1084

101 'Reviewing the Natural History of Hepatitis C Infection', ('The Bassendine Review') - Annex 4 to the Skipton Fund Review of the support available to individuals infected with Hepatitis C and/or HIV by NHS-supplied blood transfusions or blood products and their dependants [PEN.017.1968] at 2013; Professor Thomas - Day 53, page 15

102 Professor Thomas - Day 53, pages 15-17

103 Ibid pages 27-28

104 The purpose of look-back was to trace NHS patients who had received blood, blood components or blood products derived from donations by donors who tested positive for Hepatitis C antibodies after 1 September 1991, when screening was introduced, and who had previously donated blood which was found by retrospective testing also to have been infective. See Chapter 36, An Investigation into the Steps Taken to Identify the Individuals Who Were Infected.

105 Day 4, pages 35-36

106 Ibid page 36

107 Casiraghi 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: 90-96 [LIT.001.4027]

108 Dr Mutimer - Day 1, pages 110-112

109 Professor Thomas - Day 53, pages 18-19

110 Ibid pages 19-22

111 Ibid pages 29-30

112 Professor Thomas - Day 52, pages 17-18

113 Professor Thomas - Day 53, page 42

114 SIGN 92: Management of Hepatitis C (2006) paragraph 8.4; [PEN.018.0298] at 0317 (Repeated in SIGN 133: Management of Hepatitis C (2013) paragraph 9.4 [LIT.001.5550] at 5574)

115 Professor Thomas - Day 52, page 18

116 Professor Hayes report [PEN.018.0240] at 0243

117 Professor Hayes - Day 78, page 69

118 SIGN 92: Management of Hepatitis C (2006) paragraph 8.4; [PEN.018.0298] at 0317 (Repeated in SIGN 133: Management of Hepatitis C (2013) paragraph 9.4 [LIT.001.5550] at 5574)

119 Professor Hayes - Day 78, page 112

120 Ibid page 113

121 Dr Mutimer - Day 1, page 112

122 Medical Report on Mr Victor Tamburrini [TAM.001.2380] at 2382-83: Dr Bathgate - Day 1, page 25

123 'Reviewing the Natural History of Hepatitis C Infection' ('The Bassendine Review') - Annex 4 to the Skipton Fund Review of the support available to individuals infected with Hepatitis C and/or HIV by NHS-supplied blood transfusions or blood products and their dependants [PEN.017.1968] at 2015

124 Tsochatzis et al, 'Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B', Scandinavian Journal of Gastroenterology, 2009; 44: 752-59; [LIT.001.4418] Hezode et al, 'Impact of smoking on histological liver lesions in chronic hepatitis C', Gut, 2003; 52: 126-129 [LIT.001.4100]

125 Professor Thomas - Day 53, pages 31-32

126 Ibid page 49

127 Professor Thomas - Day 52, pages 13-14

128 Crockett and Keeffe, 'Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection', Annals of Clinical Microbiology and Antimicrobials, 2005; 4:13 [LIT.001.4034]

129 Professor Thomas - Day 53, pages 68-70

130 Ibid pages 65-66

131 As noted in paragraphs 13.18 and 13.52, non-Hodgkin's lymphoma is not associated with HCV infection in northern Europe, but it is relevant to Professor Thomas' opinion.

132 Professor Thomas - Day 53, pages 69-70

133 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1081; Professor Thomas - Day 53, pages 9-10

134 Professor Thomas - Day 52, page 116

135 Professor Hayes - Day 78, pages 56-58

136 SIGN 133: Management of Hepatitis C (2013) paragraph 8.2 [LIT.001.5550] at 5571

137 SIGN 133: Management of Hepatitis C (2013) [LIT.001.5550]

138 Professor Hayes - Day 78, pages 49-50

139 Professor Thomas - Day 53, page 40

140 Professor Hayes - Day 78, page 52

141 Ibid page 51

142 Ibid page 51

143 Ibid pages 61-62

144 Professor Hayes' Report on Hepatitis C [PEN.018.0240] at 0242

145 Professor Hayes - Day 78, pages 54-59, especially Page 54

146 Professor Hayes' report on Hepatitis C [PEN.018.0240] at 0245; Professor Hayes - Day 78, page 93

147 Professor Hayes - Day 78, page 60

148 Ibid pages 54-55

149 Ibid page 57

150 Ibid pages 54-55

151 Ibid pages 55-56

152 SIGN 133: Management of Hepatitis C (2013) [LIT.001.5550] at 5577-82

153 SIGN 133: Management of Hepatitis C (2013) [LIT.001.5550] at 5577-82

154 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1082-83

155 Professor Thomas - Day 53, page 51

156 Professor Hayes - Day 78, page 87

157 Professor Thomas - Day 53, page 58

158 Ibid pages 56-58

159 See also Professor Hayes - Day 78, pages 52-53

160 Recent analysis carried out for SIGN 133 suggests that occult Hepatitis C may persist in macrophages or lymphocytes in a small number of patients who have achieved SVR. There may be a small chance of relapse in this event.

161 Professor Hayes - Day 78, pages 94-95

162 Ibid page 95

163 Ibid page 96

164 Ibid page 97

165 It is the body's natural production of interferon that makes a person with flu feel 'fluey'.

166 Professor Hayes - Day 78, pages 100-104

167 SIGN 92: Management of Hepatitis C (2006) [PEN.018.0298]; SIGN 133: Management of Hepatitis C (2013) [LIT.001.5550]

168 Professor Thomas - Day 53, page 35

169 Professor Hayes - Day 78, page 102

170 Professor Hayes' report on Hepatitis C [PEN.018.0240] at 0247; Professor Hayes - Day 78, page 97

171 Professor Hayes' report on Hepatitis C [PEN.018.0240] at 0245

172 NICE, the National Institute for Clinical Excellence (National Institute for Health and Clinical Excellence since 2005) publishes guidelines for use in the NHS in England and Wales on the use of health technologies and clinical practice.

173 Professor Hayes - Day 78, page 81; Professor Hayes' Report on Hepatitis C [PEN.018.0240] at 0244. The severity of the disease is assessed by the pathologist who, having had regard to the amount of inflammation and scar tissue, grades the liver biopsy samples as mild, moderate and severe.

174 Professor Hayes - Day 78, page 82

175 Hepatitis C Action Plan for Scotland [LIT.001.4948]

176 Professor Hayes - Day 78, pages 84-85

177 Professor Thomas - Day 53, pages 82-84

178 Professor Hayes - Day 78, pages 87-88

179 Bruix and Sherman, 'AASLD Practice Guidelines: Management of Hepatocellular Carcinoma: an Update', Hepatology, 2011; 53: 1020-22 [LIT.001.4326]; Compare Professor Hayes - Day 78, page 91

180 Professor Hayes - Day 78, pages 90-92

181 Ibid page 90

182 Ibid page 90

183 Ibid pages 90-91

184 Ibid page 99

185 SIGN 133: Management of Hepatitis C (2013) [LIT.001.5550]

186 Professor Hayes - Day 78, page 90

187 Ibid pages 89 - 92

188 Ibid page 130

189 Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1083

190 Professor Thomas - Day 53, pages 52-54

191 Professor Hayes - Day 78, pages 105-106

192 Professor Thomas - Day 53, page 55

193 Ibid page 64

194 Ibid pages 79-82

195 Yee et al, 'The Natural History of HCV in a cohort of haemophilic patients infected between 1961 and 1985', Gut, 2000; 47: 845-851 [LIT.001.4318]

196 Factor IX in 1961 and Factor VIII in 1976 in this population.

197 Yee et al, 'The Natural History of HCV in a cohort of haemophilic patients infected between 1961 and 1985', Gut, 2000; 47: 845-851 [LIT.001.4318] at 4323

198 Posthouwer et al, 'Progression to end stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicentre cohort study', Blood, 2007; 109; 3667-3671 [LIT.001.4090]

199 Thein et al, 'Prognosis of hepatitis C virus-infected Canadian post-transfusion compensation claimant cohort', Journal of Viral Hepatitis, 2009; 16: 802-813 [LIT.001.4184]

200 Professor Thomas - Day 52, pages 56-57. The lower end of the range proposed by Professor Thomas was 30%: see Professor Thomas' report on Hepatitis C [PEN.017.1071] at 1074

201 Kamper-Jorgensen et al, 'Survival after blood transfusion', Transfusion, 2008; 48 [LIT.001.4069]

202 Harris et al, 'Survival of a national cohort of hepatitis C virus infected patients, 16 years after exposure', Epidemiology and Infection, 2006; 134: 472-477 [LIT.001.3898]

203 Just et al, 'Long-term follow up among Danish transfusion recipients identified in the national hepatitis C lookback', Transfusion, 2001 [PEN.018.0507]

204 'NS' denotes that there is no significant difference, particularly when the difference between two categories is smaller than the amount of error that is expected to be in the data as 'noise'.

205 A p-value expresses the probability that a given hypothesis is false. The lower the p-value, the more likely it is that the hypothesis is valid. In this case, the p-value indicates that the authors had estimated that, notwithstanding the calculated risk of 2.71 on available data, there was a 3% chance that the calculation was wrong.

206 Seefe et al, 'Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart, Lung, and Blood Institute collaborative study' Hepatology, 2001; 33: 455-463 [LIT.001.3951]

207 Ibid [LIT.001.3951] at 3958

208 Davis et al, 'Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression', Gastroenterology, 2010; 138: 513-521 [LIT.001.4046]

209 Guiltinan et al, 'Increased all cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors', American Journal of Epidemiology, 2008; 167: 743-750 [LIT.001.4061]

210 'Excess' meaning high relative to the general population.

211 Hazard ratio: the risk of death expressed as a ratio of [deaths in HCV+ve donors]/[deaths in HCV-ve donors].

212 Seeff, 'The History of the 'natural history' of hepatitis C (1968 - 2009)', Liver International, 2009; 29:, 89-99:[LIT.001.4100] at 4106

213 Posthouwer et al, 'Progression to end stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study', Blood, 2007; 109: 3667-3671 [LIT.001.4090]

214 Thein et al, 'Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active retroviral therapy: a meta-analysis', AIDS, 2008; 22: 1979-1991 [LIT.001.4077]

14. Knowledge of Viral Hepatitis 1 >