THE PENROSE INQUIRY
Final Report

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Chapter 15

Knowledge of Viral Hepatitis 2 - 1975 to 1985

Introduction

15.1 This chapter will trace developments in the understanding of viral hepatitis from 1975 to around 1985. As noted at the end of the last chapter, at the end of 1974 expert views published widely in the UK on the aetiology and natural history of viral hepatitis did not reflect developing understanding of the disease in the USA. In this period there were continuing differences in the timing of general acceptance of emerging theories. There were also differences between UK and US sources in the definition of the markers of non-A, non-B Hepatitis (NANB Hepatitis) infection. These differences had a material bearing on the perception of the prevalence of infection in the UK and, correspondingly, of the risks potentially associated with transfusion of blood, blood components and blood products.

15.2 While much of the information from this period is taken from published sources which were available, at least to relevant experts in their particular fields of study, it is apparent that there were also informal exchanges of information among researchers. For example, on 6 January 1975, Dr J Garrott Allen of the Stanford University Medical Centre wrote to Dr William Maycock, Director of the National Blood Transfusion Service (NBTS).^[1] The substance of the letter and Dr Allen's wider involvement in the assessment of risk in the UK are discussed later.^[2] It is an example of written communication. More frequently, telephone exchanges and discussion at international conferences maintained the dialogue. It would not be correct to assume that UK experts were entirely unaware of what was happening elsewhere, particularly in the USA.

15.3 However, between the USA and European countries, including the UK, there were differences in response to emerging knowledge at certain stages. In the background, there was probably a lower prevalence of NANB Hepatitis infection in the UK as a whole than in the USA and the perception that this was the case appears clearly to have influenced opinion. It is therefore appropriate to deal with the bodies of research material from the USA separately from other sources, at least to the end of this period.

15.4 In this chapter, US research dating from the mid-1970s to about 1981 will be described first. By that stage, some firm views had emerged on the prevalence of NANB Hepatitis as understood in the USA. Progress in UK research over approximately the same period, where there was a different view of the diagnostic features of NANB Hepatitis, will be described next. Thereafter, discussion will focus on the second half of the period, 1980-81 to about 1985, but including publications from 1986 which related to the first half of the decade.

Viral hepatitis mid-1970s to 1981

Aetiology and natural history of NANB Hepatitis: research in the United States of America

15.5 For present purposes, it is not necessary to trace in any detail the general history of developments in the knowledge and understanding of hepatitis before about 1973-74. One series of studies on post-transfusion hepatitis in open-heart surgery patients at the National Institutes of Health (NIH), initiated in 1965 and led by Dr Harvey Alter, was to play a major part in developing knowledge, however.^[3] Together, these studies reflect the views of a group of respected researchers working after Blumberg's seminal work on the Australia antigen,^[4] and before the published work of Prince, Feinstone and others on the prevalence of Hepatitis A in post-transfusion hepatitis, discussed below, that led to the conclusion that one or more non-A, non-B hepatitis viruses were implicated in post-transfusion hepatitis. The initial 1965 study demonstrated that there was a high risk of transmission of icteric and anicteric hepatitis (that is, hepatitis with or without clinical jaundice) associated with commercial blood. The second study, begun in 1968, demonstrated that there was a high risk of developing hepatitis from receiving blood contaminated with Hepatitis B surface antigen (HBsAg): half of the patients infected developed icteric hepatitis. By 1970, when the third study began, it had become feasible to fulfil blood requirements solely from volunteer sources and to screen donor blood prospectively for HBsAg. The study examined the effect of the combined exclusion of all commercial and voluntary HBsAg-positive donations. It was concluded that the exclusion of all commercial and volunteer blood donors testing positive for the HBsAg, significantly reduced the rate of transmission of hepatitis.

15.6 As noted in paragraphs 14.32-14.36 of the last chapter, research projects in the USA up to the mid-1970s led to a conclusion that the Hepatitis B virus (HBV) was responsible for only a small proportion of the residual cases of transfusion-associated hepatitis. Research based on cardiac patient groups continued and by 1975 the conclusion on HBsAg was more broadly and starkly expressed in an article by Stephen Feinstone and others:

The preponderance of hepatitis after blood transfusion is unrelated to the hepatitis B virus.^[5]

15.7 By 1974-75 it was also understood that Hepatitis A was not implicated to any material extent in post-transfusion hepatitis.

New York University Hospital

15.8 Opinion had quickly developed to reach that point, however, and it is appropriate to begin the account at a slightly earlier date, with the article by Alfred Prince and others referred to in the last chapter at paragraph 14.65.^[6] The reported research project involved 299 patients. They had undergone major surgery (mostly cardiovascular surgery) at New York University Hospital between May 1969 and August 1972 and presented as an intensively-managed group of patients available for research across a broad front.

15.9 Blood sera from the patients were tested for HBsAg or Hepatitis B antibody (anti-HBs) and serum-transaminases^[7] were measured. All cases with transaminase abnormalities were reviewed by a panel of clinicians, to exclude cases likely to have causes of liver-function abnormality other than post-transfusion hepatitis. 'Hepatitis' was defined as two or more consecutive elevations of serum-transaminase above the upper limit of normal when tested internally or, if tested by an outside laboratory, 2.5 times the upper limit of normal applied by that laboratory, all within specified time limits. This was an approach typical of US researchers at the time. Follow-up was completed for 204 patients. Hepatitis, as defined, was developed in 51 and jaundice in 21. Of the hepatitis cases, 15 showed exposure to Hepatitis B virus by HBsAg or anti-HBs response. A Hepatitis B response without developing hepatitis, as defined, was shown in 25 more. The conclusion of the article, as summarised, was:

An agent other than hepatitis-B (HB) virus seemed to be the cause of 36 (71%) of 51 cases of post-transfusion hepatitis identified during prospective biweekly serological follow-up of 204 cardiovascular-surgery patients. The sera of the 36 cases showed no evidence of the antigen or antibody response expected to accompany infection by HB virus and to be detectable by the sensitive assays used. Incubation periods and clinical and epidemiological features were inconsistent with Hepatitis A. Cytomegalovirus-associated seroconversion was no more common among the HB-negative cases than among HB-positive cases or among patients who did not develop hepatitis. The data suggest that a large proportion of long-incubation post-transfusion hepatitis is unrelated to Hepatitis B ....^[8]

15.10 The paper sought to demonstrate that the condition described was probably not Hepatitis A or Hepatitis B and inferred that the cause was some other, as-yet unidentified virus. This agent proved to be elusive and defied many wide-ranging efforts to identify it. As noted in paragraph 14.71 of the last chapter, the article also commented on the risk that the condition might be associated with progressive liver disease and long-term complications such as chronic hepatitis, cirrhosis, and hepatoma.

National Institutes of Health

15.11 The article by Feinstone and others, published in April 1975 and cited in paragraph 15.6 above, took matters further, and examined 22 patients. The team had continued their work on patients who had received corrective cardiac surgery, covering patients treated at the National Institutes of Health. They postulated that a viral agent, other than the Hepatitis A virus (HAV) or HBV but yet to be identified, was commonly transmitted by blood transfusion and caused hepatitis. The patients in this cohort were selected for study because a diagnosis of hepatitis was well established, serial serum samples were available and HBsAg had not been detected in acute-phase serum samples obtained from them. Hepatitis was defined by transaminases 2.5 times the upper limit of normal within specified time limits and the exclusion of other possible causes for elevated levels of transaminases. The method of identifying Hepatitis A antibody described by Feinstone and others in 1973 was applied.^[9]

15.12 Some of the patients had been exposed to the HAV before transfusion. However, nine patients did not have HAV antibody before transfusion and none of them acquired the antibody after their illness. This was said to be strong evidence that their hepatitis was not caused by HAV. The authors also relied on incubation periods (the common ground of distinction between 'infectious' and 'serum' hepatitis, as discussed in the last chapter) and the lack of intra-familial transmission, in support of their conclusions. As noted in the previous chapter at paragraph 14.66, this work provided a basis for proof of Prince's hypothesis.^[10]

15.13 Further research was reported in an article in The Lancet of 1 November 1975.^[11] Eight of the cases reported by Feinstone and his colleagues in April of that year were subsequently included in a prospective study of post-transfusion hepatitis by Dr Alter and colleagues (including Feinstone). For the purposes of this study a patient was considered to have post-transfusion hepatitis if, other factors being excluded,^[12] between 14 and 180 days after transfusion the patient's alanine-aminotransferase level rose to 2.5 times the upper level of normal and if a second sample not less than a week later exceeded two times the normal level. 108 patients were followed and 12 developed hepatitis, as defined. Four of the 12 developed markers for Hepatitis B in the course of acute hepatitis and the remaining eight were classed as cases of non-B Hepatitis. Testing excluded a serological association with the Hepatitis A virus. The article concluded:

The strongest evidence that non-A, non-B hepatitis is a transfusion-related (and, by inference, virus-related) event is the fact that it appears to occur with a defined incubation period and, more important, that, like type-B hepatitis, it is considerably more common after the receipt of commercial blood than of voluntary donor blood. Thus there is increasing suspicion that there exists one or more previously unrecognised human hepatitis virus(es).^[13]

15.14 These three studies from 1974 and 1975 have been quoted and discussed at some length since they form the cornerstone upon which the recognition of the existence of NANB Hepatitis (subsequently Hepatitis C) is based. The expression 'non-A, non-B Hepatitis' was coined as a collective term for hepatitis in which, at that time, Hepatitis A and Hepatitis B, as well as Cytomegalovirus and Epstein-Barr virus, had been excluded.^[14]

15.15 Studies of post-transfusion hepatitis in the USA over this period increasingly identified the existence of an NANB Hepatitis agent and demonstrated that post-transfusion NANB Hepatitis was by no means uncommon. Depending on the source of the blood, 10% or more of transfusion patients developed ALT levels that remained elevated for weeks or even months, indicating probable non-A, non-B post-transfusion Hepatitis.

15.16 Further work by Dr Alter and colleagues was reported in 1976.^[15] Episodic cyclic patterns of alterations in serum transaminase levels, namely the levels of alanine transminase (ALT) and aspartate transaminase (AST), had been identified, with raised levels alternating with near normal levels in cases of NANB Hepatitis.

Non-A, non-B post-transfusion hepatitis

15.17 On 12 March 1977, Jules Dienstag and others (including Feinstone and Alter) produced a report, 'Non-A, Non-B post-transfusion hepatitis'.^[16] This study, based on an enlarged group of 32 cardiovascular patients, provided powerful evidence that HAV was not the cause of transfusion-associated hepatitis unrelated to HBV and supported the existence of one or more NANB Hepatitis viruses.

15.18 In July, 1977, Jay Hoofnagle and others reported the results of a rather singular study.^[17] Stored sera from experimental studies in the 1950s, in which volunteers had been inoculated with sera from blood donors suspected of having transmitted hepatitis to transfusion recipients, were re-examined. Feinstone was again a member of the group of researchers. The discussion noted that:

Several clinical and epidemiologic features of non-A, non-B hepatitis have become clear from studies such as the present one. First, non-A, non-B hepatitis closely resembles type B hepatitis. The incubation period, the clinical symptoms and signs, and the potential for chronicity appear to be similar to type B hepatitis. Undoubtedly, what was once referred to as "serum hepatitis" included both type B and non-A, non-B hepatitis. Second, non-A, non-B hepatitis appears to be spread predominantly by the parenteral route. Most cases have been described in association with transfusion, intravenous drug use, or serum inoculation. However, as in type B hepatitis, the importance of "non-parenteral" routes of transmission (by saliva, sexual and intimate contact, biting insects) needs to be assessed. Third, non-A, non-B hepatitis appears to be associated with a chronic carrier state in chronic liver disease ... These "implicated" blood donors were, for the most part, asymptomatic, although liver function tests and liver biopsy examinations frequently showed evidence of underlying chronic hepatitis. Finally, non-A, non-B hepatitis appears to be common ... Previous studies on post-transfusion hepatitis have shown that 40% to 71% of such hepatitis is non-A, non-B. Currently all blood donations are screened for HBsAg by radioimmunoassay (or a method of similar sensitivity). Data generated from post-transfusion hepatitis studies done since the institution of such sensitive screening methods suggest that at the present time more than 90% of post-transfusion hepatitis is due to non-A non-B hepatitis.^[18]

15.19 They also stated that:

More and more evidence ... indicates that non-A, non-B hepatitis is due to a transmissible agent that is most likely a virus.

....

Data generated from post-transfusion hepatitis studies... suggest that... at the present time more than 90% of post-transfusion hepatitis is due to non-A, non-B hepatitis. All these features suggest the presence of one or more other human hepatitis viruses....^[19]

15.20 This important paper strengthened the case for a viral aetiology for NANB Hepatitis, predominantly if not exclusively parenterally transmitted, with a significant association with chronic liver disease.^[20] Hoofnagle's figures showed the combined effect of the protective measures introduced, in particular:

• The exclusion of commercial blood and prospective screening of donations for HBsAg from about 1970 in reducing Hepatitis B transmission as a component of total post-transfusion hepatitis.
• The elimination of Hepatitis A as a material component of post-transfusion hepatitis.
• Increasing confidence in the inference that non-A, non-B Hepatitis was the major component of all post transfusion hepatitis.

Other studies

15.21 These US studies of surgical patients and blood donors were quickly followed by a study of hepatitis in haemophilia patients, published in 1977 by Henry Lesesne and others.^[21] Six haemophilia patients who had persistent raised serum transaminase values over a period of six months were studied. Liver biopsies were taken and half of them were found to have 'chronic active hepatitis', characterised by severe liver cell dysfunction and with a frequently poor prognosis. This was the first study in which liver biopsies were taken from haemophilia patients. Patients in the Lesesne study were given prophylactic clotting factor concentrates prior to the biopsy as liver biopsy studies on haemophilia patients were very difficult to organise due to the risk of bleeding from the biopsy site.^[22] The authors argued that biopsy was appropriate in a range of cases because of the therapeutically important histological information obtained and their assessment of the risks associated with the procedure.

15.22 On 22 June 1978, Joel Spero and others published 'Asymptomatic Structural Liver Disease in Hemophilia' in The New England Journal of Medicine.^[23] The paper concluded:

Our results suggest that, throughout the world, a large number of asymptomatic hemophilic patients who have received numerous transfusions must have histologic liver disease. In some, it must be severe. Adequate information is not yet available to evaluate fully hemophilic patients treated only with blood products negative by radioimmunoassay for HBsAg in both donors and final product.^[24]

15.23 By 1978, commercial pharmaceutical companies were beginning to issue hepatitis warnings with their blood products. While a reference to 'hepatitis' was explicit, there was little specification. For example, an information leaflet provided in 1978 with Koate, a Factor VIII product produced by Cutter Biological, contained a warning that 'the presence of hepatitis virus should be assumed' and suggested that the risk of administering the concentrate should be weighed against the medical consequences of withholding it, particularly for persons with few previous transfusions.^[25] A patent for this product was granted, based on discoveries made in the Bayer (Cutter Laboratories) research laboratory during 1978-79.^[26] The patent itself specified that therapeutically active proteins isolated from plasma might contain viruses, for example hepatitis viruses. Among commercial pharmaceutical companies, the view underpinning research by the end of the 1970s was that there was viral transmission of hepatitis by these products generally.

Aggregated research and the emerging ALT screening debate

15.24 In 1978, Alter and others summarised data from a number of countries concerning post-transfusion hepatitis.^[27] Having noted the seminal work of Blumberg and others on Hepatitis B, and Prince and others on Hepatitis A, they stated:

To date, the existence of an infectious agent(s) as the cause of non-A/non-B hepatitis has not been proved since no associated particle has been observed, no growth in tissue culture has been documented, and no specific immunologic test has been developed. In the face of elevated hepatic enzymes, the diagnosis of non-A/non-B hepatitis can only be made by the serologic exclusion of other known hepatitis viruses and by the clinical exclusion of other causes of hepatocellular injury. Nonetheless, there is a rising ground-swell of evidence that substantiates the existence of at least one human hepatitis virus distinct from HAV and HBV....^[28]

15.25 Alter and others tabulated the findings of other researchers for the period 1975-1977, showing that in the cited reports NANB Hepatitis accounted for 63-93% of all cases of post-transfusion hepatitis.^[29] In non-transfusion studies a wider range of NANB Hepatitis infection was noted. With no diagnostic viral blood markers, however, NANB Hepatitis remained a diagnosis of exclusion. The underlying hypothesis was that proof of elevated hepatic enzymes, particularly ALT, coupled with the exclusion of other hepatitis viruses and other causes of hepatic damage, was sufficient for a diagnosis of NANB Hepatitis. This was to divide US and UK researchers. In the USA, it was to have practical implications for clinicians.

15.26 The scene was set for a debate on ALT screening of donors. Dr Alter and his colleagues resisted screening for a time. Their research from the early 1970s had suggested that transaminase tests had not proved to be a practical method of screening donors for hepatitis.^[30] Richard Aach and his colleagues, who had been involved in an extensive study in the USA, the Transfusion-Transmitted Viruses (TTV) study, promoted ALT screening as a safety procedure.^[31] The TTV study had suggested a significant association between the ALT levels of a donor and the likelihood of subsequent hepatitis in the recipient. Alter and his colleagues' reservations had not been overcome by the end of this period, however. The competing positions of the protagonists are discussed more fully in Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis.

Further research

15.27 Meantime, fundamental research continued to be reported. The Lancet published an article by Alter and others, 'Transmissible agent in NANB Hepatitis', on 4 March 1978.^[32] In the study reported, chimpanzees were inoculated with serum from patients with post-transfusion NANB Hepatitis. Histological changes (changes in the microscopic anatomy of cells) in the animals ranged from mild to 'conspicuous' hepatitis and generally correlated with the degree of ALT elevation. There was said to be no evidence of clinical disease and all of the animals went on to biochemical and histological recovery. There was no serological evidence of Hepatitis A or Hepatitis B infection. Hepatitis was transmitted by serum derived from patients with chronic as well as acute hepatitis, strongly suggesting a chronic carrier state for the agent responsible for NANB Hepatitis. It was concluded that NANB Hepatitis seemed to be due to a transmissible agent which could persist and remain infectious for long periods.

15.28 In July 1979, Dr Mones Berman and others (including Dr Alter) published 'The chronic sequelae of NANBH' in the Annals of Internal Medicine.^[33] The conclusions from this study included, importantly for present purposes, a finding that although it could be clinically severe, acute NANB Hepatitis after transfusion was usually an anicteric, mildly symptomatic disease and probably went undetected in most patients not prospectively followed. It was suggested that a very large number of NANB Hepatitis cases might occur each year but that an accurate assessment of its incidence would not be possible until tests were developed that could detect specific serological markers. Among other conclusions, Berman reported that many cases of NANB Hepatitis were associated with prolonged elevation of ALT and that the predominant pathological change associated with chronic NANBH appeared to be chronic active hepatitis.

15.29 In September 1979, Dr Athol Ware and others published a paper entitled 'Etiology of Liver Disease in Renal-Transplant Patients', also in the Annals of Internal Medicine.^[34] No aetiological agent was defined in 27 of 38 patients found to have chronic hepatitis. They concluded that some if not most of these patients had chronic hepatitis secondary to infection with NANB Hepatitis. Almost without exception, the patients had received blood transfusions at the time of transplantation. The analysis added to the growing body of evidence supporting a viral aetiology for NANB Hepatitis.

From aetiology to natural history

15.30 At about this time the debate in the USA was moving on from discussion about whether NANB Hepatitis had a viral aetiology, which was broadly accepted, to discussion of the natural history of NANB Hepatitis infection. In July 1980, Edward Tabor and others made an unqualified comment that:

Non-A, non-B hepatitis is a major health problem, present in up to 89 per cent of patients with post-transfusion hepatitis and 25 per cent of hospitalized patients with sporadic hepatitis. Experimental transmission to chimpanzees of human non-A, non-B hepatitis and passage of an agent of non-A, non-B hepatitis to additional chimpanzees have demonstrated the cause to be a transmissible agent or agents.^[35]

15.31 The natural history of the disease continued to attract comment thereafter. On 16 December 1980, Ronald Koretz and others from the University of California, Los Angeles, published the results of research on 'The Long Term Course of Non-A, Non-B Post-transfusion Hepatitis'.^[36] Sixty-six patients who had contracted NANB Hepatitis had been followed from 1972 for up to five years, the longest defined follow-up available at the time. Liver biopsy had revealed chronic persistent and chronic active hepatitis in all 18 patients on whom biopsy was carried out. Two developed cirrhosis. A third, not biopsied, had signs and symptoms suggesting cirrhosis. Most had, however, remained asymptomatic. The conclusion drawn was that post-transfusion NANB Hepatitis often resulted in chronic biochemical liver disease. However, if the disease progressed to liver failure it was found to do so over a number of years. It appeared to be benign in most instances. This was an influential paper because it reflected at least two to five years' follow-up of the patients in question.

15.32 By this stage, the live issues in the USA were the relevance of elevated enzyme levels, particularly in donors, and the long-term prognosis for patients thought to be infected with NANB Hepatitis. Those disputes had not been resolved but, by the end of this period, it can safely be concluded that in the USA it had been established to a high degree of probability that NANB Hepatitis was due to a transmissible agent that was most likely to be a virus or viruses, though the agent(s) had not been identified.

Aetiology of NANB Hepatitis: UK and other research

Diagnosis

15.33 The US studies referred to are a few only within a large volume of research reports in the later 1970s and into 1980. There were almost no equivalent studies carried out in the UK. There was a significant difference of opinion on what constituted hepatitis. In the US view, 'hepatitis' was defined by raised levels of the enzyme alanine-aminotransferase by specified percentages or factors within specified periods and the absence of other causes of enzyme elevation, such as congestive heart failure and drug, alcohol or anaesthesia-induced conditions. In their 1974 report, the UK's Medical Research Council (MRC) Working Party included in their definition of 'hepatitis' a finding of enzyme elevation in association with other clinical indications of hepatitis. The requirement for additional positive indicators in the UK automatically reduced the groups of patients likely to be identified and hence yielded much lower numbers of infections attributed to post-transfusion hepatitis in UK studies than in equivalent studies in the USA.

15.34 In clinical practice, it appears that the same view of the diagnostic features of hepatitis had a bearing on the diagnosis of post-transfusion NANB Hepatitis in the UK until 1990-91 when a test for the Hepatitis C virus (HCV) became available. Professor Peter Hayes, Professor of Hepatology and Honorary Consultant Gastroenterologist at the Royal Infirmary of Edinburgh, said that until there was a test for Hepatitis C, NANB Hepatitis was a very uncommon diagnosis in the UK. There were many causes of abnormal liver test results and, in his opinion, unless there was a 'trigger event', such as a blood transfusion followed by abnormal results, it was relatively unlikely that a putative viral diagnosis would have been made.^[37]

15.35 The UK approach was, in retrospect, too demanding. The resulting difference in diagnostic criteria applied in the UK probably led to some complacency concerning the prevalence of a possible infective agent affecting UK recipients of blood and blood products (as compared to US recipients) which lasted for over a decade. By way of example only, a comparison of the numbers thought to be infected illustrates the difference. The study by Alter and others (reported in November 1974) identified 12 of 108 patients followed (11%), as having developed hepatitis, as defined in the USA. This compared to the finding of eight out of 768 cases (1%) in which post-transfusion hepatitis had been thought to occur in the UK MRC study reported in the same year. The perception that post-transfusion hepatitis was very rare in the UK appears to have been due largely to the selection of criteria for diagnosis.

15.36 In the UK in particular, so far as there were studies in the period to about 1981, different views developed among transfusion specialists, haemophilia specialists, virologists and public health doctors and it is appropriate to distinguish the haemophilia specialists from other groups. The response of haemophilia clinicians to the use of blood products in the light of growing knowledge is discussed in Chapters 21 and 22.

NANB Hepatitis and haemophilia

15.37 Even among haemophilia clinicians, the position was not uniform throughout Europe. In February 1975, Pier Mannucci and others published a paper on the incidence of asymptomatic liver disease in haemophilia patients treated in Milan.^[38] Seventy-five patients with Haemophilia A and 16 with Haemophilia B were studied and classified according to age group. All had been exposed to replacement therapy with cryoprecipitate, commercial factor concentrates and, in the case of the older patients, fresh-frozen plasma. In the absence of records of the numbers of transfusions, age was selected as a 'rough but reliable parameter' to investigate any relationship between the degree of transfusion exposure and abnormality of liver function tests. Clinically, all were asymptomatic of liver disease. On physical examination five showed mild to moderate liver enlargement and two had hepatosplenomegaly (enlargement of the liver and spleen, implying possible cirrhosis). On testing, there was a high incidence of abnormal liver function test results, increasing with age. Raised ALT levels were observed in 45% of haemophilia patients, possibly caused by one or more NANB viruses. The article noted that the rate of exposure to agent(s) implicated in post-transfusion hepatitis had probably increased after the introduction of highly purified freeze-dried concentrates of Factor VIII and Factor IX manufactured by pools of plasma from many donors.

15.38 The paper, which was published at the very outset of this period and probably written before the papers of Prince, Alter, Feinstone and others had appeared, noted that the data collected suggested that, in haemophilia patients, repeated contact with the NANB Hepatitis agent might cause chronic liver damage that was not associated with overt illness. The discussion is instructive of the state of knowledge among Dr Mannucci's highly respected team at this time. The paper noted:

The clinical and prognostic significance of the observed abnormalities is presently unknown, and the lack of liver biopsies renders the task of clarifying them rather difficult. The great majority of the patients were completely asymptomatic and free of physical signs of liver involvement. It is possible that constant exposure to the infective agent(s) induces a general immunological tolerance conditioning an attenuated pattern of chronic hepatitis. It also seems reasonable to suggest that antibody to hepatitis B surface antigen occurring in haemophiliacs may offer protection.

However, the evidence accumulated with the investigation of asymptomatic carriers of HBsAg suggests that these humoral abnormalities are not entirely benign, since they may be associated with structural changes of the liver similar to those occurring in patients with chronic hepatitis. In haemophiliacs, an answer to these problems can be given only by a long-term prospective evaluation of any possible relationship between the observed abnormalities and the development of overt hepatic dysfunction.^[39]

15.39 The authors recommended regular testing. While still qualified by reservations, this was probably the first suggestion outside the USA that what became known as NANB Hepatitis occurring in haemophilia patients might be more than just a benign condition.

Factor concentrates

15.40 In the UK, the MRC definition of hepatitis persisted. In August 1975, John Craske of the Public Health Laboratory, Dorset, published data on an outbreak of hepatitis following the infusion of commercial Factor VIII in the Bournemouth Haemophilia Centre.^[40] The criteria used for diagnosis of hepatitis were jaundice or raised transaminase levels associated with compatible history and clinical signs of infection. With this publication, NANB Hepatitis had been recognised and reported by a UK haemophilia centre. The references cited did not include the earlier US publications already mentioned. As in the 1974 MRC study, the additional diagnostic criteria differentiated the approach adopted from that generally followed in the USA.

15.41 Work by Prince and Feinstone, as well as Dr Craske's report from Bournemouth, were among the references cited in a draft protocol dated September 1975 for a prospective study of hepatitis in haemophilia associated with the use of factor concentrates in England and Wales.^[41] The reasons for the preparation of the protocol are not clear but, at planning meetings held in 1975 for the World Health Organization (WHO) conference on Economic Aspects of Viral Hepatitis, member states who had sent representatives to the WHO conference in Copenhagen were invited to design 'study protocols' on a limited number of diseases, to carry out pilot studies which would be used to inform regional governments and to invite them to apply and adapt the methodology developed.^[42] The UK protocol provides an insight into the views held in the UK at the time. It acknowledged that the current assays had been of limited efficiency in excluding HBsAg positive donors and said:

This failure to prevent post transfusion hepatitis may be explained by the following hypotheses:

(a) That current methods of detecting HBsAg are still not sensitive enough.

(b) That other known viral agents are responsible, e.g., hepatitis 'A', [Epstein-Barr] virus, cytomegalo virus.

(c) That other, as yet unknown viruses, cause a significant amount of post transfusion hepatitis which is supported by the recent work of Feinstone et al.^[43]

15.42 Against the background of emerging data, the study proposed to address the question:

"Does the administration of factor VIII concentrates to haemophiliacs on regular replacement therapy significantly increase the incidence of transfusion hepatitis?"^[44]

15.43 The proposed study also aimed to identify any difference in 'attack rates' as between commercial and NHS products; the value of the HBsAg positive test; further information on unknown viruses or agents; and the role of radioimmunoassay (RIA) testing for HBsAg of Factor VIII concentrates in the prevention of post-transfusion Hepatitis B. A pilot study was proposed, with the results to be provided at a meeting in Glasgow with a view to enlisting all of the UK Haemophilia Centres in the study. Had the study been carried fully into effect, it would have been a major exercise along the lines of the US investigations initiated in 1974. It was not, however, fully implemented in the UK.

False trails

15.44 UK experts were not alone in finding difficulties with the identification of NANB Hepatitis. At this stage, eminent researchers worldwide continued to develop hypotheses to explain NANB Hepatitis, which were later disproved. In October 1978, Ryoichi Shirachi and others published a paper entitled 'Hepatitis "C" antigen in non-A, non-B post-transfusion hepatitis'.^[45] They claimed to have found evidence for a new hepatitis-specific antigen in sera obtained from patients with post-transfusion NANB Hepatitis. They proposed the designation 'hepatitis C (HC) antigen'. It was to prove to be among a number of false trails.^[46]

15.45 The work of the UK Haemophilia Centre Directors Hepatitis Working Party was an example of another. The Working Party met in Glasgow on 30 September 1980.^[47] Dr Craske presented the Working Party's report for 1979 which set out the results of surveillance for 1978 and 1979.^[48] The report noted that the prevalence of hepatitis was about the same level as that observed in 1976-77. There had been an increase in the proportion of cases of NANB Hepatitis reported in patients with mild disease receiving concentrates for the first time to cover operations. It was suggested that the observed increase in mildly affected haemophilia patients contracting hepatitis was probably due to the fact that most severely affected patients had already been exposed to viruses present in all brands of concentrates and were therefore immune to re-infection, while patients with mild disease had not been so exposed.

Further haemophilia and factor concentrate research

15.46 The natural history of NANB Hepatitis was not understood: as is now known, exposure to HCV does not confer immunity. It was concluded at the time, however, that transaminitis (elevated liver enzyme levels in the blood) was unrelated to current Factor VIII therapy and the level of anti-HBs antibody and was unrelated to a previous history of overt hepatitis. The report stated:

These results suggest that if transaminitis is related to viral hepatitis, the patients who become carriers and develop chronic liver disease will only contract mild or symptomless acute hepatitis, and the most overtly jaundiced patients will fully recover. This is supported by our observations of hepatitis B infections in haemophiliacs.^[49]

15.47 There were other views. As already noted in Chapter 13, Knowledge of Viral Hepatitis Now, paragraph 13.45, in 1978 Dr David Triger and colleagues, of Hallamshire Hospital, Sheffield, published the results of liver biopsies carried out on haemophilia patients with persistent abnormal liver function test results.^[50] These provided a comparison with the work of Lesesne (paragraph 15.21, above). They considered it reasonable to conclude from their findings that a large proportion of haemophilia patients receiving treatment with Factor VIII had important chronic liver disease and that NANB Hepatitis may well have been an important factor, supported by observations in half of the cohort of patients studied. One patient had chronic lobular hepatitis and one micronodular cirrhosis. As indicated earlier, this work does not appear to have had wide immediate impact for the reasons set out in Chapter 13, Knowledge of Viral Hepatitis Now, paragraphs 13.43-13.44.

15.48 In Europe and the USA, however, commercial companies' research had moved ahead and reflected the view that transmission of viral hepatitis by blood products, which was otherwise implicitly assumed, could be avoided by changes to manufacturing processes. A prominent example was illustrated in the work of Norbert Heimburger and a group of employees of the German pharmaceutical company Behringwerke, who in 1980 wrote a paper entitled 'Factor VIII concentrate - now free from hepatitis risk: progress in the treatment of haemophilia'.^[51] Behringwerke had produced a heat-treated factor concentrate which they claimed did not transmit hepatitis. The product was called Factor VIII HS (ie 'hepatitis safe') and had been heated in solution to 60°C for 10 hours. It had been tested first on chimpanzees and then on 12 patients. Both groups had been monitored for a period of six-12 months and there had been no evidence of hepatitis infection. This was claimed to be the first heat-treated concentrate produced and reflected the commercial appreciation of transmission risk and of the need to deal with it. This topic is discussed more fully in Chapter 23, Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985.

15.49 In November 1980, Dr Craske, in a report to the Department of Health, 'Studies on the epidemiology and chronic sequelae of FVIII and IX associated hepatitis in the UK, Appendix II: Chronic Liver disease in Haemophiliacs', stated that, despite multiple transfusions and large numbers of grossly abnormal liver function tests, very few patients showed any evidence of chronic liver disease.^[52]

15.50 Subsequently, on 19 March 1983, the British Medical Journal (BMJ) published a report on behalf of the UK Haemophilia Reference Centre Directors on the treatment of haemophilia and related disorders in the UK between 1976 and 1980.^[53] The paper tabulated the numbers and percentages of patients treated who developed acute hepatitis. The diagnosis was based on clinical and laboratory findings and did not include patients with a known previous history of persistent abnormalities in liver function tests. Furthermore, the term 'acute hepatitis' was not defined in the report and it is likely to have missed many asymptomatic cases of NANB Hepatitis with low elevation of ALT. In the years 1976-80 the incidence in patients with Haemophilia A varied between 1.7% and 3.5% of those treated in any year and was very little different from that seen in the period 1969-74. However, with the first use of US commercial Factor VIII concentrates on a wide scale in haemophilia centres in the UK, the overall incidence of diagnosed hepatitis in patients with Haemophilia A rose from 2.3% to 5.2% in 1974 and then declined to 3.1% in 1976, remaining at about that level thereafter. Although the incidence of overt hepatitis had increased, the level of infection in the UK remained below levels in the USA. The report included the following statement:

In view of the widespread concern about the transmission of hepatitis viruses by giving blood products it is interesting to note that only two deaths were attributed to hepatitis during the five year period. There have been several reports recently of persistently abnormal liver function values and abnormal histological findings in liver tissue from haemophiliacs treated with blood products. Most of these patients are asymptomatic but it remains to be seen how many will develop severe chronic liver disease with the passage of time.^[54]

15.51 In 1981, a paper by Dr May Bamber and others, 'Short incubation NANB transmitted by Factor VIII concentrates in patients with congenital coagulation disorders', was published in the journal Gut.^[55] The patients studied had received infusions of cryoprecipitate and commercial and NHS Factor VIII concentrate. This paper was produced by the leading UK liver unit at the Royal Free Hospital, London, in conjunction with the Royal Free Hospital Haemophilia Unit. Professor Sherlock and Professor Thomas were involved. It described 10 cases of NANB Hepatitis occurring after infusion of Factor VIII concentrates and was mainly concerned with the acute clinical course of the disease. In one group of five cases there was evidence of a direct link to a specific single infusion. In the others the patient's history of therapy confused the position. In another group of five cases the disease was asymptomatic and anicteric but in five it was more severe. None of the patients recovered within six months. The paper concluded that the failure of these patients to recover within the period of study (six-45 months) suggested that NANB Hepatitis was an important cause of liver disease in patients with coagulation disorders. The paper dealt with the histology (appearance under the microscope) of the liver in these patients. The clinical course was not dissimilar to the other clinical descriptions around that time and became much quoted. The paper stated:

Follow-up, both clinical and histological, will be needed to establish the natural history of this disease.^[56]

15.52 The paper also stated that there was evidence for more than one type of short incubation NANB Hepatitis virus, 'only one of which has a high rate of induction of chronic liver disease'. This view was wrong but was entertained by others at the time. The findings were affirmation of the work done at Sheffield, which had previously been controversial.^[57] The Bamber paper, published in 1981, marked the beginning of a significant change in expert opinion. US research published in 1982 pointed in the same direction.^[58]

15.53 On 4 July 1981, an editorial in the BMJ discussed the risk to haemophilia patients. It described post-transfusion hepatitis as the major complication of the modern treatment of haemophilia and stated:

The diagnosis is usually inferred from abnormalities in the results of hepatic biochemical tests rather than from clinical evidence.^[59]

15.54 It referred to the biopsy-based research by Eric Preston and others at Sheffield, reported in 1978, (paragraph 15.47, above) as indicating that changes in liver architecture had occurred in haemophilia patients which were consistent with previous viral assault, including chronic persistent and chronic active hepatitis and cirrhosis. The editorial narrated rather starkly that, in some cases, early death from liver disease might prove to be the price paid by haemophilia patients for the improved quality of life afforded by the easy availability of clotting-factor concentrates. Steps taken to counter the risks were focused on three practices: the risks of collecting plasma from paid as opposed to volunteer donors; the optimum size of the donor plasma pool; and attempts at removing the several viruses of hepatitis from blood products.

15.55 The editorial went on to identify NANB Hepatitis viruses (at least two) as the main cause of chronic liver disease in patients with haemophilia. In relation to the volunteer/paid donor issue, it referred to US evidence of a material reduction in risk when a hospital changed from commercial to volunteer blood. In relation to the attempts at removing viruses of hepatitis from blood products, there was again relevant evidence. The final paragraph stated:

[I]n the absence of specific markers for non-A, non-B hepatitis, overall protection against hepatitis appears remote. A more likely possibility is that hepatitis-free blood products will become available ....^[60]

15.56 The editorial referred to three recent reports dealing with heat-inactivation, chemical treatment with ß-propiolactone and wet-heat treatment processes as more likely to achieve the removal of viral contamination.^[61] By this stage it was being recognised that where NANB Hepatitis was established in blood coagulation patients it carried a risk of chronic liver disease and the biopsy findings reported by Preston and colleagues were being noted.

Post-transfusion NANB Hepatitis

15.57 In contrast to the work published in relation to hepatitis in haemophilia patients, work on post-transfusion hepatitis between 1975 and 1981 was less homogeneous and tended to arise from specific issues. At government level, a plethora of committees and working parties was established by the Department for Health and Social Security (DHSS), the MRC and the Haemophilia Centre Directors. NANB Hepatitis and its relevance to transfusion and haemophilia therapy were discussed, but no studies of post-transfusion hepatitis were established in the UK comparable to the several carried out in the USA.

15.58 There were some peripheral developments in regulation. In the context of public health, 'infective hepatitis' had been listed as a notifiable disease from 1968.^[62] In February 1976, 'viral hepatitis' was prescribed as an industrial disease for the purposes of the Social Security Act 1975. Employees infected in the course of work became entitled to certain forms of benefit, including injury benefit. The circular announcing the development stated:

The prescription includes the two commoner forms of viral hepatitis known as hepatitis A (infectious hepatitis) and hepatitis B (serum hepatitis; Australia antigen positive hepatitis).^[63]

15.59 NANB Hepatitis, in absolute terms or relative to Hepatitis A and B, was not acknowledged.

15.60 Precisely because the signs and symptoms were so mild and the blood tests lacking the results of a comprehensive study, the general opinion in Scotland (outwith haemophilia care) at this stage was that NANB Hepatitis was a rare and relatively unimportant disease. In a letter written on 26 March 1975 to John Wallace, Regional Director of the Glasgow and West of Scotland Blood Transfusion Service, Major General Jeffrey, National Medical Director, SNBTS, commented that in the light of current knowledge a few cases of post-transfusion hepatitis were 'bound to arise'. The letter was copied to Dr McIntyre at SHHD. The General referred to US literature which was clearly known but which, at that stage, had not impressed him as giving rise to significant concern.^[64]

15.61 In 1979, Dr Ajay Chaudhuri and others published in the Communicable Diseases Scotland Weekly Report a paper based on haemophilia and non-haemophilia patients, 'Viral Hepatitis in Glasgow, 1976 - 1977'. It found that:

During the two-year period from January, 1976, to December, 1977, 164 patients with viral hepatitis were admitted to the Infectious Diseases Units at Ruchill and Belvidere Hospitals, Glasgow. Of these, 52 (32 per cent) patients had hepatitis B as they were found to be HBsAg positive. In 112 patients who were HBsAg negative, a diagnosis of non-B hepatitis was made; however, in a majority of these patients, epidemiological findings and clinical course suggested a diagnosis of hepatitis A.^[65]

15.62 Retrospective testing for antibody to HAV showed that two thirds of the non-B cases were attributable to Hepatitis A. Under the heading 'Non-A - non-B Hepatitis' the authors stated:

In four patients with non-B hepatitis, hepatitis developed within 2-6 months of transfusion of blood products. Three male haemophiliacs and a female patient with Christmas disease had received numerous transfusions of factor VIII and cryoprecipitate. These four patients and also two drug addicts with hepatitis had no evidence of hepatitis B infection, nor of hepatitis A infection nor of infection with cytomegalovirus, nor EB virus. At present they are classified as cases of non-A -- non-B hepatitis. Evidence from other countries suggests that a virus (or viruses) may be associated with this type of hepatitis and that a carrier state is possible. With laboratory tests now permitting definitive diagnosis of hepatitis A virus infection, as well as hepatitis B, in 1979 it should be possible to determine the prevalence of non-A - non-B hepatitis in the general population in West Scotland.^[66]

15.63 The paper reflected experience in an infectious diseases unit: only a small proportion of NANB Hepatitis patients had overt clinical symptoms of disease sufficiently severe to lead to referral to the infectious diseases hospital.

15.64 In the international context, there was some recognition of the risk of hepatitis other than A or B at a WHO meeting on the Economic Aspects of Viral Hepatitis in Copenhagen, held between 9 and 11 November 1976. Viral hepatitis was defined as acute inflammation of the liver caused by HAV, HBV, 'or by other hepatitis viruses'. It was reported:

Progress in the specific diagnosis of viral hepatitis has revealed a new type of hepatitis that is unrelated to hepatitis A or B virus. It appears to be now the most common form of hepatitis occurring after blood transfusion in some areas. There are no laboratory tests available as yet for identifying this agent or agents.^[67]

15.65 This report indicated an increasing international awareness of a problem but little direction towards a solution.

15.66 On 8 January 1979, a doctor (name redacted) of the School of Pathology, the Middlesex Hospital, wrote to the DHSS advising that the stimulus for re-convening the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen was to 'upgrade' the 'viral safety' of UK Factor VIII concentrates. The letter also stated:

I have a note to write to you about non-A, non-B hepatitis.

If one or more of these viruses is responsible for the abnormal livers which are evidently common among haemophiliacs then chronic liver disease due to these viruses might also be found among other transfused individuals. What I was asking Y [name redacted]^[68] was whether she could question her patients with chronic liver disease about past transfusions. There could be merits in starting with an actual clinical problem and working backwards.

If we are going to consider non-A, non-B seriously in the Advisory Group it would be logical to co-opt Z [name redacted]^[69] of the PHLS, Manchester. He is making a continuing study of the problem of hepatitis in haemophiliacs.^[70]

15.67 The identity of the author of this letter is not disclosed but may have been Dr David Dane. If it was Dr Dane (a member of the original and reconvened Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen, an eminent pathologist and commentator),^[71] it is unlikely that he was at this stage unaware of the US literature on NANB Hepatitis among transfused patients: the work of Prince and others in and after 1974 had reported on cardiac surgery patients. That they were at risk was known from the earliest days of NANB Hepatitis. However, it appears at least to have been an opening for study of the wider problem and progress followed.

Medical Research Council ad hoc meeting

15.68 On 7 February 1979, a letter was sent out by a Senior Medical Officer of the MRC thanking individuals for agreeing to attend an ad hoc meeting to be held on 12 February 1979.^[72] The meeting was to discuss growing anxiety about the threat of NANB Hepatitis to patients and laboratory staff and the need for research to characterise the agent causing the disease and to develop a test for the organism or its marker. The letter noted that a commercial concentrate had been found to transmit NANB Hepatitis to chimpanzees and, as a result, it had not been given a licence. It quoted advice received from the Institute of Allergy and Infectious Diseases, Bethesda, Maryland:

1) The non-A, non-B agent has not yet been purified from the livers of infected individuals or animals, or from the stool. Most recently it has been reported that the agent has been transmitted to chimpanzees. There is a preliminary report that the non-A, non-B agent has been visualized by electron microscopy in the livers of infected chimpanzees. This, however, needs further documentation. While the chimpanzee is a clumsy experimental animal, this will provide new opportunities for characterising the agent. As with all the hepatitis viruses, non-A, non-B has yet to be cultivated.

2) Your second question concerns antigenic markers and diagnostic tests. These are not yet available, because of the negative results listed in the paragraph above.^[73]

15.69 On 12 February 1979, the MRC hosted the proposed ad hoc meeting.^[74] The meeting was attended by eminent experts including Professors Sherlock and Zuckerman, Sir William Maycock, Dr Craske and Dr Philip Mortimer. Professor Zuckerman had led the previous MRC study published in 1974. The discussion of parenterally transmitted NANB Hepatitis provides an insight into the state of knowledge at the time. There was a view, advanced by Dr Thomas Cleghorn and supported by Professor Sherlock, that post-transfusion hepatitis (PTH) 'must now be rare and that it would be difficult to find many cases.' The ground for the observation appears to have been that, despite the transfusion of 1.5 million units of blood in the previous year, 'very little had been heard of non-A, non-B PTH'. Professor Zuckerman countered by observing that much NANB Hepatitis might be anicteric and that the risk of progression to chronic liver disease remained, however mild the initial infection. Professor Sherlock was concerned about the risks of transmission associated with imported commercial products but Dr Craske reported that his group had also found NANB Hepatitis associated with blood products of NHS origin. The conclusion of this discussion was reported as follows:

The Chairman [Professor Mollison] then asked what exactly constituted a case of non-A non-B hepatitis. It was agreed that HBV infection must be excluded by sensitive tests for HBsAg and anti-HBc, and that recent infection with HAV, EB virus and cytomegalovirus must also be excluded. Blood enzyme tests, particularly SGPT, could be a useful pointer to non-A non-B infection, but there was an urgent need for specific markers of non-A non-B viruses. The Chairman suggested, and Professors Sherlock and Zuckerman agreed, that until there were such markers, a survey of PTH - as suggested by Sir William Maycock - was not warranted.^[75]

15.70 More limited research and arrangements to store sera for later examination were then discussed. The decision not to initiate a survey of post-transfusion hepatitis was to lead to the serious long-term consequences of postponing investigation of the prevalence of post-transfusion NANB Hepatitis in the UK. At that time there was no reasonable prospect of developing a specific marker for NANB Hepatitis in early course. Rather, diagnosis depended on exclusion of other causes of hepatitis in the patient and the participants clearly understood that, as the minute shows. The committee's remit was related to the allocation of research funds and that may explain the decision taken that, until specific markers for non-A, non-B viruses had been developed, a survey of post-transfusion hepatitis was not warranted. The discussion demonstrated, however, that among this eminent group the risk of transfusion-transmitted NANB Hepatitis as understood in the USA was not accepted, though a paper by Dr Alter and colleagues on the 'Transmissible Agent in Non-A, Non-B Hepatitis' was included in the literature before the committee.^[76] As events were soon to show, it was the view of Dr Brian McClelland^[77] that a well-structured study could be devised but the decision at the 1979 meeting hardened views against that course.^[78]

15.71 The Regional Transfusion Directors held their 176th meeting on 3 October 1979.^[79] It was reported that the Advisory Group on the Testing for the Presence of Hepatitis B Surface Antigen and its Antibody was concerned about the incidence of post-transfusion jaundice. The group was particularly anxious to receive from the regions details of patients suffering from NANB Hepatitis and stated that it would appreciate receiving samples of serum from these patients. Directors were reminded of the need to report all cases of post-transfusion hepatitis. It is noteworthy that, as far as the Transfusion Directors were concerned, post-transfusion hepatitis was still being discussed in terms of jaundice at this date.

15.72 At about this time, other evidence of severe liver disease associated with NANB Hepatitis was being reported. In 1979 Sten Iwarson and others reported two cases in which there was a well-documented progression to serious liver disease, in a paper entitled 'Progression of hepatitis non-A, non-B to chronic active hepatitis'.^[80]

Working Party on Post-Transfusion Hepatitis

15.73 The ad hoc meeting in February 1979 led to the MRC setting up a Working Party on Post-Transfusion Hepatitis which met for the first time on 14 February 1980.^[81] The Working Party was chaired by Dr Harold Gunson^[82] and its members included Professors Sherlock and Zuckerman, Dr WJ Jenkins,^[83] Dr McClelland, Drs Craske, Polakoff and Tobin of the Public Health Laboratory Service (PHLS) and Dr Diana Walford of the DHSS.^[84] The function of the Working Party was agreed to be:

[T]o promote research to assess the nature and size of the problem of PTH in the UK, with particular reference to changes in transfusion practice .... Studies should include (1) an assessment of any further need for research into Hepatitis B... (2) investigations to assess the incidence of non-A, non-B hepatitis in the UK, particularly with the risk of introducing the infection by blood transfusions, and (3) the position of research to characterise the agent(s) associated with this form of hepatitis, and to derive diagnostic tests.^[85]

15.74 In respect of the incidence of post-transfusion hepatitis in the UK, it was noted that '[n]o cases of NANB Hepatitis related to whole blood transfusions had yet been reported despite enquiry of hospitals in London where open heart surgery was carried out'. Dr McClelland proposed a multi-centre study, which might be sponsored by the MRC, into the association of NANB Hepatitis with blood transfusion. It was minuted that this proposal was deferred.

15.75 Deferral of Dr McClelland's proposal in effect repeated the decision taken at the ad hoc meeting of the MRC. However, Dr McClelland proceeded to propose a multi-centre prospective study at the next meeting of the Working Party, held on 25 June 1981.^[86] In his evidence to the Inquiry Dr McClelland stated that, in doing so, he clearly behaved as though there had been no agreement to defer the study.^[87] Whatever the accuracy of the minute, Dr McClelland made no progress.

15.76 The second meeting of the MRC Working Party, on 25 June 1981, proved to be the last.^[88] Professor Zuckerman gave a summary of the research work that had been carried out over the past two years on post-transfusion hepatitis among other forms of the disease. He and Dr Howard Thomas spoke of difficulties that had been encountered in devising serological and radioimmunassay techniques for identifying NANB viruses. Other aspects of the meeting, related to the question of a prospective study of post-transfusion hepatitis and particularly in relation to potential surrogate screening, are dealt with in paragraphs 27.78-27.83 of Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis. However, in brief, the demise of the Working Party, implying the exhaustion of its wide remit, put an end to Dr McClelland's proposal for the time being.

15.77 Dr McClelland was not alone in his concern that there should be an investigation. The Advisory Group on the Testing for the Presence of Hepatitis B Surface Antigen and its Antibody presented its third report in 1981.^[89] The group included Professor Sherlock, Professor Zuckerman, Dr Craske, Professor John Cash and Dr Edward Follett among others. In relation to NANB Hepatitis, it stated:

Non-A, non-B hepatitis viruses are a common cause of PTH in the United States and are thought to have been responsible for cases of PTH in the UK. Hepatitis due to these viruses is common among haemophiliacs and follows the administration of imported, and occasionally of British Factor VIII and Factor IX. There is evidence for the occurrence of sporadic cases of non-A, non-B hepatitis in the general adult population and in association with cryoprecipitate therapy in the UK.

There are at the present time no screening tests for detecting non-A, non-B hepatitis viruses in blood donation.

We recommend that research is undertaken in the UK to determine the extent and severity of PTH due to non-A, non-B hepatitis viruses. Unless this is done we will not have the knowledge on which to base any possible future recommendations about screening blood donations for these viruses.^[90]

15.78 Reporting of relevant evidence was encouraged. Separately, in relation to liver function tests, the report stated:

Several categories of people are found to have raised blood transaminase levels which are not associated with viral hepatitis. Some 3% of new donors may be excluded if the criteria of one raised transaminase level is applied. In addition to the need for confirmatory transaminase testing the worry and inconvenience caused to donors would be unlikely to be compensated for by any clinical benefit. Therefore we advise against these tests in screening blood donors at the present time but the subject should be kept under review.^[91]

Knowledge of NANB Hepatitis: Summary as at 1981

15.79 The relevance of elevated enzyme levels was still a live issue in the USA at this stage. The final paragraph of advice quoted above was not altogether out of line with that position. However, along with the reports from other meetings in and after 1979 discussed above, it reflects some of the confusion prevalent at the time. It was correctly acknowledged that several categories of people can have raised transaminases not associated with viral hepatitis. Alcohol and obesity may play a part, for example, but unless all cases of elevated liver enzymes were associated with those categories there had to be a cohort whose elevated enzyme levels might be associated with NANB Hepatitis. The recommendation that there should be research was not followed up, however.

15.80 There were clearly differences in attitude to the possible occurrence of NANB Hepatitis infection. By 1980-81, haemophilia doctors saw NANB Hepatitis as a very frequent infection in haemophilia patients but one usually mild in both course and outcome. Haemophilia clinicians had close and continuing contact with their patients and haemophilia care involved frequent testing of patients' blood. Other health professionals saw NANB Hepatitis following blood transfusion as rare and relatively unimportant. That there were these differences was due at least in part to the fact that there had been no appropriate studies of post-transfusion hepatitis in the UK for a decade.

15.81 Things were, however, beginning to change. By the start of 1981, the UK Advisory Committee on Dangerous Pathogens had been established.^[92] In Scotland also, there was some practical progress. In March 1981, Professor Cash, Medical Director, SNBTS, prepared a brief report for discussion by the SNBTS Directors entitled 'Hepatitis and the Transfusion Service'.^[93] He proposed that the West of Scotland Centre should be nominated as a Hepatitis Reference Centre and that it should establish and issue the necessary protocols and reagents for effective quality assurance. Provision was made for supervision, procedures and reporting. The report set out specific proposals for optimal collection of plasma, screening for anti-HBs and standards for testing. Professor Cash proposed to ask Professor Zuckerman for advice on the safety of current vaccination preparations. There were specific proposals for infants born of mothers who were chronic HBsAg carriers.

15.82 The series of US studies referred to above show that, while there was no proof to the standard of the mathematical certainty of a viral aetiology, the clear balance of opinion in the USA was that a viral aetiology for NANB Hepatitis had been established, probably by the end of 1978 and clearly by 1980.^[94]

15.83 The position in the UK is less easy to define. Virologists and public health experts appear to have implicitly accepted in their publications that there was a viral aetiology. Dr Craske's reports adopted that position in August 1978 and it was implicit in his November 1978 paper. The same position can be inferred from the Middlesex Hospital and MRC letters of January and February 1979. The view was explicit in the reason for setting up the Hepatitis Advisory Group in September 1980. The BMJ editorial of 4 July 1981 explicitly noted two or more NANB Hepatitis viruses as the main cause of chronic liver disease in haemophilia patients.

15.84 So far as haemophilia clinicians were concerned, while some may have been less committed to a viral aetiology, most commentators were aligned with Dr Craske. The papers from Bamber, the Haemophilia Unit at the Royal Free Hospital and from Norkrans and colleagues and the BMJ editorial all subscribed to a viral aetiology. Dr Craske's third and final report of the Oxford project of the United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO), for 1980-81, as presented to the UKHCDO Hepatitis Working Party in September 1980, referred explicitly to NANB viruses. It was not strongly questioned. The minutes of the Glasgow meeting of the Working Party appear less positive. 'Transaminitis' was not unequivocally accepted to be associated with viral hepatitis. The report as published in 1981 still treated the question of the significance of chronic hepatitis in patients with chronically elevated tranasaminases as unanswered.

15.85 Most UK blood transfusion directors still maintained that NANB Hepatitis was a rare condition, seldom seen because they were looking for the wrong thing: acute jaundice. They did, however, acknowledge that a viral aetiology was very probable.

15.86 The 6th edition of Diseases of the Liver and Biliary System by Professor Sheila Sherlock was published in 1981. Excerpts from the book are quoted in the Preliminary Report at paragraphs 6.110-6.114. Significant points made were:

• NANB Hepatitis was largely spread by blood and accounted for about 75% of PTH and possibly 15-20% of sporadic hepatitis; and
• Haemophilia patients receiving factor concentrates obtained from commercial sources were particularly at risk.^[95]
• The NANB Hepatitis agent had not been 'conclusively identified' and its identity remained uncertain; and
• The clinical course of the disease progressed to a 'mild, chronic hepatitis' in about a quarter of patients but this usually improved with time although cirrhosis could develop.^[96]

15.87 Professor Sherlock commented that:

Non-A, non-B hepatitis often progresses to a mild chronic hepatitis. The prognosis of this is, at the moment, uncertain but probably benign.^[97]

15.88 Commenting on this edition, Dr McClelland said in oral evidence:

Well, all I can really say to that is that Professor Sherlock was obviously the doyenne of hepatology in the UK at the time. I would assume that in preparing the various successive editions of her textbook, she would have firstly read the literature pretty well and secondly have consulted experts internationally. So I mean this has to be considered as an authoritative view, which may not be the same as being a correct view.^[98]

15.89 By the end of 1981 there had been further advances. However, particularly because there was still no known reliable marker for the putative virus or viruses causing NANB Hepatitis, there was continuing controversy around the natural history of the disease. Differences among professional groups reflected the fact that, by 1981, there was still very little evidence as to the natural history of NANB Hepatitis - whether arising post-transfusion in general medical or surgical contexts or among haemophilia patients.

15.90 The apparent incidence of post-transfusion NANB Hepatitis varied substantially according to the population of blood donors used and to the methods used to detect it, adding to the complexity of the issues. However, positive developments included the following:

• Discussion was beginning concerning ways of reducing post-transfusion hepatitis by using possible surrogate markers to identify blood carrying a high risk of transmitting NANB Hepatitis virus(es). (The subject of 'surrogate markers' - markers, short of a reliable serological test, that might be indicative of infection - is dealt with in Chapter 27, Surrogate Testing of Donated Blood for non-A, non-B Hepatitis).
• The first attempts were made at viral inactivation in blood products and the recognition (though not satisfactory resolution) of difficulties of maintaining yield of effective Factor VIII and Factor IX activity during processing, especially with heat treatment methods (dealt with in Chapter 23, Viral Inactivation of Blood Products for Haemophilia Therapy up to 1985).
• There was recognition that there was already a problem, namely that the vast majority of severely affected and moderately severely affected haemophilia patients receiving replacement therapy already had been exposed to NANB Hepatitis virus(es) and that many had chronic, although, it was perceived, probably usually mild and asymptomatic, liver disease.

15.91 At this stage, there was no understanding, or probably even perception, of the less tangible symptoms of lethargy, depression and other neurological symptoms of chronic HCV infection which have come to be understood increasingly over the last 15 years. These symptoms are discussed in Chapter 13, Knowledge of Viral Hepatitis Now. At the beginning of the 1980s, and for long thereafter, descriptions of patients as 'asymptomatic' referred to recognised symptoms of significant chronic liver disease, regardless of cause, as they were perceived from time to time. It is now impossible to know what proportion of individuals described as having 'asymptomatic chronic liver disease' did in fact have less tangible, but real, symptoms of disease, since no systematic inquiry was carried out.

15.92 In the UK, studies based on biopsy findings in haemophilia patients with putative NANB Hepatitis, first published by researchers in Sheffield in 1978, were just beginning to be taken up more widely. Work at Sheffield and the Royal Free Hospital was reported at the 11th meeting of the UKHCDO on 30 September 1980.^[99] This would make an impact as the second half of the period progressed.

Viral hepatitis 1982-1985

15.93 The most pressing issues in the period 1982-85, for those dealing with blood and blood products, were AIDS and the steps taken to tackle that disease. These are more fully discussed elsewhere in this Report.^[100] There was increasing apprehension of a disease of epidemic proportions with high mortality. There is at least an element of artificiality is discussing events that had a direct bearing on the developing knowledge of NANB Hepatitis dissociated from the far more pressing background preoccupation with AIDS. As it became accepted that AIDS was a viral disease, the implications of viral infection more generally, including NANB Hepatitis infection, were inevitably examined in a wider context. However, there were important developments in knowledge of NANB Hepatitis, even while the major preoccupation was with AIDS, and the following discussion seeks to identify and comment on these developments.

15.94 In the period 1982-85, evidence from biopsy investigation became more significant in promoting an understanding of the natural history of NANB Hepatitis. A number of studies were reported between 1982 and 1985 in which liver biopsies were taken from patients with NANB Hepatitis - both haemophilia patients and those with presumed NANB Hepatitis following blood transfusion. The studies showed that some patients developed cirrhosis.^[101] These histological findings of extracted liver samples under microscopic analysis suggested that the disease might be more serious than previously thought, despite the fact that few patients, even among those who developed cirrhosis, otherwise suffered clinical symptoms.

15.95 Also in this period, studies in England showed that most haemophilia patients who routinely received Factor VIII and Factor IX blood products, whether manufactured by the National Health Service (NHS) or by commercial companies, were likely to develop NANB Hepatitis.^[102]

15.96 Early heat-treated Factor VIII concentrates were developed but were found to transmit NANB Hepatitis notwithstanding heat-treatment.^[103] Effective heat-treatment would be developed and brought into the production processes after the end of this period.

15.97 Throughout this period, the Hepatitis C virus had still to be identified with the result that there was no direct test for the virus or its antibody. Instead, consideration was given to testing blood donations for certain indirect, or surrogate, markers in the blood of donors (particularly elevated ALT and antibody to the Hepatitis B core antigen (anti-HBc) that studies in the USA had indicated might be so closely associated with the development of NANB Hepatitis in recipients as to be indicative of infection).

15.98 Much of the source material for this period is set out in Chapter 7 of the Preliminary Report. Sources are not repeated here unless it is necessary for an understanding of developing knowledge on particular matters. As before, developments in the USA are noted first.

NANB Hepatitis aetiology and natural history: research in the United States of America

15.99 In the USA, published research dealt increasingly with the natural history of NANB Hepatitis. In 1982, there were conflicting reports of biopsy results. A study by Koretz and others of presumed post-transfusion NANB Hepatitis found chronic hepatitis and/or cirrhosis in about a third of patients. There was a significant association of cirrhosis with those who had persistently abnormal ALT values.^[104] They reported that cirrhosis developed in a clinically silent fashion and usually only after years of virus activity. In another 1982 paper, RJ Gerety and DL Aronson reported progression to chronic hepatitis characterised by widely fluctuating serum aminotransferase levels and histologically severe liver disease in a high proportion of infected individuals and referred to similar findings by Pier Mannucci.^[105]

15.100 In contrast to these reports, the study by Gilbert C White and others of 15 haemophilia patients with intermittently (not persistently) raised ALT, values found no suggestion of chronic liver disease.^[106] They reported that liver biopsies showed chronic persistent hepatitis or other mild forms of liver disease including mild chronic portal inflammation. The authors concluded:

The high frequency of liver function abnormalities in patients with hemophilia coupled with biopsy evidence of chronic active hepatitis and the documentation of progression to cirrhosis have led some authors to question current policies of replacement with concentrates of factor VIII for some patients. While some patients, primarily those with moderately severe and severe enzyme elevations, will have histologic evidence of chronic active hepatitis and/or cirrhosis, the results of the present study indicate that a larger proportion of patients will have milder degrees of enzyme abnormalities and predominantly chronic persistent hepatitis or milder forms of liver disease. Thus, for many transfusion-requiring hemophiliacs, the frequent exposure to factor VIII concentrates is not accompanied by the development of the more severe forms of chronic liver disease.^[107]

15.101 A review by Dienstag in 1983 concluded that after transfusion with blood or blood products, as many as 40-60% of patients with acute NANB Hepatitis would have chronic elevations of serum aminotransferase activity, often in a fluctuating pattern, and histologic features of the liver consistent with chronic active hepatitis, with approximately 10-20% of chronic cases eventuating in cirrhosis.^[108]

15.102 Against this uncertain background, regulators were cautious. The issue of Morbidity and Mortality Weekly Report (MMWR), the journal of the US Centers for Disease Control (CDC), of 7 June 1985 set out a fairly comprehensive statement of current knowledge in the USA of hepatitis viruses and diseases, with guidance on protection against viral hepatitis, including vaccination.^[109] Reflecting only established scientific knowledge, the treatment of NANB Hepatitis was brief. The paper noted that the epidemiological characteristics of NANB Hepatitis were similar to those of Hepatitis B, occurring most commonly following blood transfusion and parenteral (injecting) drug use. Multiple episodes had been observed in the same individuals and were thought to have perhaps been due to different agents. Chronic hepatitis following acute NANB Hepatitis infection varied in frequency from 20% to 70%. Experimental studies in chimpanzees had confirmed the existence of a carrier state which might be present in up to eight per cent of the population.^[110] There were no recommendations for action, although other US comment was more forthright.

15.103 The tentative views set out in the MMWR proved to be incorrect in certain respects. The conclusion that apparent multiple episodes of NANB Hepatitis in the same individuals might be due to different agents would turn out to be incorrect. Also incorrect was the speculation that a carrier state might be present in up to 8% of the general population. It is important, however, to emphasise that these were views of recognised experts and represented advanced thinking based on the data that CDC, reasonably in the circumstances, considered to be reliable.

15.104 In 1985 Dr Alter of the NIH set out what was known, in his view, about post-transfusion hepatitis at that time.^[111] His report provides an important point of reference on this topic. In relation to the natural history of NANB Hepatitis, he stated that the importance of the disease was not in its acute manifestations but in its chronic sequelae, the long-term abnormal conditions resulting from the disease. An 'astounding' number of cases progressed to chronic hepatitis, as judged by persistent ALT elevations. There was accumulating evidence that some cases progressed to severe chronic liver disease. At least 10% of patients who developed chronic ALT elevations following acute post-transfusion hepatitis progressed to cirrhosis. His view was that if these findings were validated, then the clinical implications of NANB Hepatitis were somewhat more serious than previously anticipated. This view was shared by some US specialists but was not universally endorsed by US haemophilia clinicians and other specialists.

15.105 In August 1985 Louis Aledort and colleagues (from different disciplines in New York and other international centres) reported on the largest study at the time of liver biopsies and liver disease among patients with haemophilia.^[112] Dr Aledort was one of the doyens of US haemophilia (and hence world haemophilia) specialists. The other authors represented some of the world's leading and best liver pathologists (from the USA, the UK, Belgium and Switzerland) and at least one leading US clinical liver specialist. Although this paper was published in August 1985, it is of interest that it was submitted for publication on 5 July 1983 and that parts of it were presented at a meeting towards the end of 1981, according to a note in the paper.^[113] Liver samples and associated clinical data were collected from 155 patients from haemophilia centres in the USA and Western Europe. For 115 there were reports of liver biopsies and for the remaining 40 there were autopsy findings.

15.106 The authors reported that in those subjects with haemophilia the incidence of cirrhosis (15%) and chronic active hepatitis (7%) was lower than previously reported. The frequency of severe liver disease (chronic active hepatitis or cirrhosis) in patients receiving large pooled concentrates was no greater than in patients treated principally with cryoprecipitate or plasma. This had not originally been predicted since patients receiving cryoprecipitate or plasma were exposed to far fewer donors per dose as compared to those receiving concentrate. The finding led the authors to conclude that there appeared to be no indication to alter current therapy patterns because of concern over plasma product-related liver disease. It was acknowledged that the comparative lack of severity of the histopathological findings in the materials studied might not be entirely reassuring in the light of other recent findings.^[114] In retrospect, the reservations underestimated the seriousness of the potential progression of the disease, but the assessment reflected a common view at the time among haemophilia specialists.

15.107 The difference of opinion apparent in these reports reflected differences of experience and approach. Dr Aledort (and other haemophilia clinicians in the USA and Europe) had seen the transformative effect of factor concentrates on the lives of patients and had good reason to take a sanguine view of the possible adverse effects of NANB Hepatitis. Dr Alter, Dr Dienstag (two leading US authorities in their field) and others were, however, beginning to understand that what they saw of post-transfusion NANB Hepatitis in liver biopsies might represent a serious cause for concern.

15.108 Dr Dienstag and Dr Alter reviewed the position reached in 1986, after the publication of hundreds of articles. Acknowledging at the outset that 'our understanding of NANB hepatitis is still unsettled and evolving...' and that '[s]trikingly clear is just how much we do not know about NANB hepatitis', they wrote presciently:

In the decade since its discovery, the concept of NANB hepatitis has evolved from that of a benign elevation of aminotransferase activity to that of a serious disease with significant long-term consequences. The longer patients are followed, the more obvious it becomes that [chronic active hepatitis] and cirrhosis are a very real part of the natural history of NANB hepatitis.^[115]

15.109 Since the recognition of NANB Hepatitis as a distinct form of viral hepatitis, studies had shown biochemical evidence of chronic hepatitis in approximately 50% of cases related to transfusion. Among those with chronic ALT elevations who were biopsied, approximately 60% had chronic active hepatitis, cirrhosis, or both. Overall, 10-20% of those with chronic ALT elevations had cirrhosis on initial or repeat biopsy.^[116] Among cases described in published reports, of 20 patients in whom cirrhosis had developed after transfusion, five had died of liver failure. The finding in Dr Aledort's study^[117] of liver biopsies from persons with haemophilia, that cirrhosis had developed in 15% of patients, a prevalence similar to that obtained in non-haemophilia, transfused populations, was said to be alarming. Dienstag and Alter commented:

Although there is a divergence of opinion as to the progressive nature of ... histologic abnormalities in hemophiliacs, a substantial proportion of these patients end up with cirrhosis, an unequivocal histologic diagnosis that leaves little room for argument....^[118]

15.110 The authors noted, furthermore, that indirect evidence for an association between NANB Hepatitis and hepatocellular carcinoma (liver cancer) was beginning to accumulate.^[119]

15.111 On 20 June 1986, the MMWR reported 13 cases of NANB Hepatitis among patients who had undergone cardiovascular surgery and, because of bleeding during surgery, had received Factor IX produced by Alpha Therapeutic Corporation.^[120] The report noted that clotting factor preparations had frequently been linked to the transmission of NANB Hepatitis. In haemophilia patients who routinely received commercial factor preparations, episodes of NANB Hepatitis were common: as many as 50% were observed to go on to develop signs of chronic liver disease. Studies in first-exposed haemophilia patients and in surgical patients who received clotting factor preparations, suggested that the risk of NANB Hepatitis might be close to 100%.^[121]

15.112 The balance was moving towards the views of Dr Alter and his colleagues.

NANB Hepatitis aetiology and natural history: UK and other research

15.113 The discussion of reported research from sources other than those from the USA is necessarily more diffuse and it is difficult to form a view of the circulation and acceptability of other opinion from outside the UK in this period. As with the US source material, much of the relevant published research is described in Chapter 7 of the Preliminary Report and is not repeated in this chapter unless necessary.

Haemophilia

15.114 In the UK, Dr Gunson's report to the European Health Committee of the Council of Europe on 25 June 1982 commented that there appeared to be a low contamination rate of NANB Hepatitis in the UK in patients receiving cryoprecipitate but a high rate following transfusion of Factor VIII concentrates prepared from large pools.^[122] He suggested that avoiding the use of large-pool fractions for those with mild coagulation defects was a practical way of reducing the incidence of post-transfusion NANB Hepatitis. The discussion that followed did not deal with the natural history of infection.

15.115 Comment on the natural history of NANB Hepatitis came in September 1982 when Mannucci and colleagues published a follow-up to their 1978 report on liver disease in haemophilia patients.^[123] One patient had died of gastrointestinal bleeding. Four of the remaining 10 patients continued to have chronic persistent hepatitis, two had developed chronic lobular hepatitis and there was spontaneous improvement of disease activity in three cases. The majority were asymptomatic. The emphasis in the authors' comments was similar to that reported by Aledort and colleagues. Progressive disease was not the rule in haemophilia patients with chronic NANB Hepatitis and only two patients had died from cirrhosis. This view was supported by data from the UKHCDO which showed that apparently only two haemophilia patients had died of cirrhosis in the UK between 1976 and 1980.^[124]

15.116 At that stage, it was thought that there was no evidence that chronic liver disease was a prominent cause of morbidity and death in haemophilia patients. The authors speculated that the course of chronic liver disease in those patients who had progressive disease might be unfavourably influenced by their continuous exposure to blood-borne viruses and by repeated and long-lasting challenge by allogenic plasma proteins transfused in the concentrates, a suggestion that was also to become prominent in relation to AIDS in the early stages of study of that disease.^[125]

15.117 An official from the Public Health Laboratory Service (PHLS) wrote to the DHSS on 10 January 1983, enclosing the terms of a letter which it was proposed to send to The Lancet.^[126] The draft commented:

There is no evidence of which we are aware that indicates that re-exposure to non-A, non-B hepatitis viruses present in concentrates received by patients with severe coagulation defects predisposes them to a higher incidence of serious chronic liver disease than patients with mild disease who receive less frequent transfusions. If the 'hepatitis reduced' concentrates prove to be associated with a reduced risk of non-A, non-B hepatitis with an insignificant loss of factor VIII activity, then these products should be reserved in the first instance for patients with no prior exposure to factor VIII concentrates or those who have received less than 5 batches of factor VIII in the past. Similar considerations would apply to NHS factor IX concentrate, but we have as yet no accurate information concerning the risk of non-A, non-B hepatitis associated with NHS factor IX concentrate. Another study in patients undergoing open heart surgery reported an attack rate of 100% non-A, non-B hepatitis related to transfusions of factor IX concentrate, whereas an attack rate of 3% was reported in patients who received transfusions of whole blood only.^[127]

15.118 It appears that the cut-off point of five batches was an empirical idea not, at that stage, based on rigorous scientific analysis. In a practical sense it provided a ready test of whether a patient had been infrequently transfused. The official's comments were reasonably consistent with the predominant view among haemophilia doctors in the UK in 1982-83 (with the exception of Preston and colleagues).^[128] Haemophilia doctors increasingly recognised the high frequency of NANB Hepatitis infection but still considered its clinical consequences to be benign.

15.119 Among haemophilia experts, significant comment on the natural history of NANB Hepatitis was advanced with the publication in 1983 of the paper by Richard Stevens and others reporting on their study of 12 haemophilia patients in Manchester, 'Liver disease in haemophiliacs: an overstated problem?'^[129] All patients were multi-transfused and all had persistently abnormal liver function tests. Otherwise, patient selection was random. The historical background that effectively set out the position challenged, as reported by Mannucci, Lesesne, Preston, Spero, Schimpf and others, was said to be:

The increasing use of plasma products has resulted in an improved quality of life for many haemophiliacs. However, over the past decade there have been reports of a high prevalence of abnormal liver function tests in multitransfused haemophiliacs. Liver biopsies carried out in such patients have been reported as showing that up to half the cases are associated with abnormal liver histological appearances including chronic active hepatitis.^[130]

15.120 The outcome of the Stevens study was different. Only one patient showed evidence of severe chronic active hepatitis with progression to cirrhosis although a further four patients showed some evidence of mild chronic active hepatitis. On the basis of their findings, the authors stated that the results represented a much lower incidence of severe histological liver damage than many previous reports. They suggested that the true incidence of severe histological liver abnormality in multi-transfused haemophilia patients might be less than previously reported but similar to the more recent results of 115 liver biopsies carried out worldwide by Dr Aledort and colleagues.^[131]

15.121 At the beginning of 1983, pharmaceutical companies continued with practical preparations for the introduction to the market of modified products, reflecting the underlying view that the agent of transmission was a virus that was susceptible to inactivation. It was anticipated in government that the companies would seek to avoid the requirement for a formal clinical trial by the use of transfusions on a named patient basis (an expanded access programme for as-yet unlicensed drugs).^[132]

15.122 On 28 September 1983 Dr Craske produced the Annual Report for 1982-83 of the UKHCDO Hepatitis Working Party.^[133] The report referred to the Oxford study, started in 1981, of hepatitis in infrequently treated haemophilia patients.^[134] The findings had confirmed that the risk of contracting NANB Hepatitis from Factor VIII concentrates on first exposure was 100%, whether NHS or commercial Factor VIII was used. An internationally based trial of Hyland/Travenol's heat-treated Factor VIII (Hemofil T)^[135] had commenced and an Armour heat-treated product (Factorate HT)^[136] would soon be available for evaluation. Mannucci had already announced at the European Society of Haematology that the Hyland product transmitted NANB Hepatitis.^[137] The problem of AIDS had begun to overshadow these developments, however. Directors required to consider the ethical problem of exposing persons with mild haemophilia to commercial material. The ethical problem was expressed as follows:

Since the only way of ensuring the susceptibility to non-A, non-B viruses is by using patients who have not previously received factor VIII or IX concentrate, a choice will have to be made between using heat treated products from commercial sources, which might carry a small risk of AIDS transmission, or using NHS concentrate which appears to carry a 100% chance of transmitting non-A, non-B hepatitis.^[138]

15.123 The report also referred to the Behringwerke heat-treated product mentioned above (paragraph 15.48).

15.124 A report of the Oxford study was published on 10 December 1983.^[139] The factual information presented was the same in all material respects as Dr Craske's report to the UK Haemophilia Hepatitis Working Party on 28 September 1983.

15.125 The Discussion section of the published study included the following observations:

This study shows a high incidence of non-A non-B hepatitis in patients treated with factor VIII who had either not received it previously or had received it only infrequently. All of those who received commercial concentrates developed hepatitis regardless of their transfusion history; those who received NHS factor VIII were less likely to develop hepatitis if they had been treated before. All nine patients who received NHS factor VIII for the first time developed hepatitis, while only eight out of the 15 who had received it previously did so .... It may be that the pool size of NHS concentrates has now increased to the point where the benefit conferred by using plasma from volunteer donors has been lost.^[140]

15.126 The discussion indicated the basis for many of the assertions of risk that were made at about this time and for some time thereafter. The fact that all nine 'virgin' patients developed NANB Hepatitis was the basis of the view that the exposure of new patients to Factor VIII concentrates, of UK origin or otherwise, carried a '100%' risk. The conjecture that the pool size of NHS concentrates may by then have increased to the point where the benefit conferred by using plasma from volunteer donors had been lost reflects the same attitude. These were important observations at the time.

15.127 In an accompanying BMJ editorial,^[141] Dr Jones (Newcastle Haemophilia Centre) stated that liver function tests were 'abnormal in most severely affected haemophiliacs who have had repeated transfusions'. Most post-transfusion hepatitis was now thought to be NANB. Despite the gloomy observations of others, he thought that probably most of the observed changes in liver function represented chronic persistent (perceived to be non-progressive) rather than chronic active (and progressive) hepatitis. Mortality from liver disease remained low. Life expectancy in haemophilia was near normal, due entirely to the widespread introduction of Factor VIII concentrates and comprehensive care.

15.128 It is apparent that by the end of 1983 haemophilia specialists and the medical profession generally had been informed that UK Factor VIII concentrate was highly likely to transmit NANB Hepatitis virus(es) in a majority of those previously transfused and in every person transfused with Factor VIII for the first time. With the benefit of hindsight, however, some commentators were in error as to the long-term prognosis. Because they did not understand the natural history of NANB Hepatitis they thought that it could be inferred, from the observations over the year following infection which showed that most liver tests stabilised and no one remained very 'ill' with hepatitis, that NANB Hepatitis was unlikely to be a serious, long-term problem. That was despite the voices from Sheffield suggesting that this might not be the case and the prevalence of chronic active hepatitis (known by liver doctors to carry a risk of progression), with or without cirrhosis, in 20-35% of the haemophilia patients whose biopsy results had been reported in the series of published studies.

Post-transfusion hepatitis

15.129 As in the USA, early reports of post-transfusion hepatitis in this period were associated with major surgical procedures. In 1982, a five-year study by Giuseppe Realdi and others (Padua, Italy) on post-transfusion hepatitis was reported as showing that five of 21 patients with post-transfusion hepatitis followed for five years or more developed cirrhosis.^[142]

15.130 In 1983 the 7th edition of Patrick Mollison's standard textbook on blood transfusion medicine in the UK was published.^[143] In a discussion of NANB Hepatitis, it was noted that:

As a rule, non-A, non-B hepatitis is symptomatically mild. Patients seldom need to be admitted to hospital. Nevertheless, up to 60% of cases have abnormal [ALT] levels for more than 1 year; if a liver biopsy is taken, most of the cases show histological evidence of a significant chronic liver disease and approximately 10% show features of cirrhosis.^[144]

15.131 The textbook noted the results^[145] of the USA-based TTV Study of 1981:

Although non-A, non-B hepatitis develops in some patients who have received only blood from donors with normal ALT levels, it can be deduced that at least 21% of cases of transfusion-associated hepatitis might be prevented by excluding only 3% of the present donor population ....^[146]

15.132 It was also noted by Mollison that the minimum carrier rate of the NANB Hepatitis virus in volunteer blood donors in the USA had been estimated to be 1.6% and in commercial blood donors to be 5.4%.^[147] The textbook further noted that there was evidence that non-A, non-B viruses played a smaller part in the UK than in the USA.^[148]

15.133 At the meeting of the UK Blood Transfusion Services' Working Party on Transfusion Associated Hepatitis on 27 September 1983, there was discussion of 'apparent non-A non-B hepatitis-like illnesses' in patients receiving high doses of intravenous human normal immune globulin.^[149] Incidence of infection was higher than in intramuscular infusion, the other standard route of delivery. The signs noted were early transaminitis. Dr Thomas thought that the picture was similar to that seen of commercial Factor VIII concentrates from the USA.^[150]

15.134 There were several published reports on these patients.^[151] The most relevant for present purposes is a paper by Dr Andrew Lever and others, published much later, on 10 November 1984.^[152] They reported that the illnesses were acute NANB Hepatitis, clinically and histologically identical to the short-incubation NANB Hepatitis seen in haemophilia patients receiving Factor VIII concentrates. The comments made included the then common view that there were at least two parenterally transmitted NANB Hepatitis viruses with different incubation periods. In relation to the natural history of the postulated short incubation form of the disease, it was stated that the disease was usually mild during the acute phase but that a large proportion, usually greater than 80%, would go on to acquire chronic lesions, sometimes culminating in cirrhosis. Of the postulated long-incubation type, the paper stated that it was also a mild illness, but 20-40% of patients still had abnormal liver function progressing sometimes to cirrhosis.

15.135 Leaving aside the distinction between the types, later disproved, the paper placed a new stress on the natural history of the disease and a growing appreciation in the UK of the potential for serious outcomes associated with NANB Hepatitis infection. Given the date of its publication, the paper may have had more significance for the general dissemination of knowledge in the next sub-period, 1984-1985, but the commentary is illustrative of the views of this group of UK experts at about the end of 1983. The paper made a further comment of some importance:

[T]he finding that the virus can be transmitted in [human normal immune globulin] concentrates suggests either that the general population has a very low level of antibodies to the putative virus or that such antibodies are not virus-neutralising.^[153]

15.136 The second proposition was correct and the first was not irrelevant to other work at the time. A prospective study of post-transfusion hepatitis in patients undergoing heart surgery, reported in November 1983, found that the incidence of post-transfusion NANB Hepatitis after cardiac surgery was low compared with similar studies in other countries, suggesting that blood transfusion using blood collected locally from volunteers rarely led to clinically significant chronic liver disease.^[154]

1984-1985

15.137 The next two years saw some convergence of opinion among experts from a number of groups. The National Institute for Biological Standards and Control (NIBSC) met on 9 February 1984 to discuss the infectious hazards of blood products.^[155] This important body gave scientific advice to the UK licensing authority and to the Committee on the Safety of Medicines. The importance of the meeting lay in bringing together a range of presentations by specialist contributors. There were a number of significant contributions from those whose views had already influenced opinion in specialist forums.

15.138 Dr Thomas (NIBSC) commented on the finding that the first exposure to factor concentrate, from whatever source, was associated with 100% infectivity with NANB Hepatitis. Dr Craske (PHLS, Manchester) provided data on the incidence of jaundice in persons with haemophilia in the UK from 1969 to 1979, and on the prevalence of NANB Hepatitis in the haemophilia population. Dr McClelland (SNBTS, Edinburgh) presented statistical data on the risk to haemophilia patients of transmitting NANB Hepatitis by blood transfusion and factor therapy. In discussion, Dr Eibl (Imuno, Vienna) commented on European experience of managing the blood donation programme. Dr Lane (BPL, Elstree) and Dr Schild (NIBSC) gave information about current work by fractionators aimed at minimising infectious hazards. There were no executive decisions relating to NANB Hepatitis but the NIBSC had collected much relevant information which would be available to government and to the bodies the NIBSC advised. It was an important stage in the development of information available to inform decision-making bodies in the UK.

Haemophilia

15.139 On 9 January 1984 a report was prepared by the Blood Products Sub-Committee of the Haemophilia Society which reviewed the policy of the Society in relation to the supply of blood products in the UK.^[156] It was recorded that the main ground for believing that British-made products were medically preferable to imported products had been the greater risk of hepatitis infection, particularly Hepatitis B infection, from imported products. Improved screening for anti-HBV and improved donor selection procedures employed by manufacturers had resulted in commercial material being of comparable standard to NHS material.^[157] The report commented that:

• Hepatitis B remained a transfusion hazard.
• Regarding the risk of NANB Hepatitis, recent developments suggested that UK material was no better (and might be worse) than imported material.

15.140 In light of the discussion, the Sub-Committee suggested that there was no continuing reason to prefer NHS products. A manuscript note on a copy of the report said that this view would not help convince Regional Health Authorities (in England and Wales) to use the NHS product.

15.141 Trials of the new, possibly safer, imported products became an important topic for Haemophilia Directors. Details are set out in the Preliminary Report and need not be repeated in full.^[158] On 29 March 1984, the Chairmen of the UKHCDO and its Hepatitis Working Party asked for cooperation between the Haemophilia Centre Directors in coordinating trials of the new heat-treated blood products.^[159] The base-line information on transmission was that there was still a 63% infection rate of NANB Hepatitis on first exposure in patients who had not previously received Factor VIII concentrate.

15.142 On behalf of the UKHCDO, Dr Craske proceeded to coordinate a prospective study of hepatitis in previously infrequently treated haemophilia patients.^[160] By that stage, clinical trials had been completed on only one product. A total of eight products were in preparation or available for trial, including two NHS Factor VIII concentrates. Dr Craske sought the cooperation of Directors in identifying suitable patients for coordinated trials.

15.143 In reply to the UKHCDO's request for cooperation in entering suitable patients into trials, Professor Christopher Ludlam (Edinburgh Haemophilia Centre) replied that he wished to reserve places for any patients he might have, for testing Scottish product.^[161] His patients constituted a group that had been treated consistently with PFC Factor VIII and he was unwilling to jeopardise the advantages of their selection for study exclusively in relation to the Scottish product by exposing them to imported products. Professor Cash was anxious to have a study carried out in the West of Scotland.^[162] He wished to assess the incidence of hepatitis and transaminitis in 'virgin' (previously untreated) haemophilia patients who received SNBTS 'hepatitis reduced' Factor VIII by coordinated clinical trials. There were, however, few qualifying patients in Scotland as a whole at the time, or in any given period, available for the sort of study proposed by Professor Cash. The study was aimed at collecting information about what was clinically essential treatment for these patients. Most existing patients receiving factor concentrates for haemophilia therapy had by this date been infected with NANB Hepatitis. Only new patients requiring treatment by factor concentrates for the first time, might benefit if the modified product was effective in removing or reducing the risk of transmission. They constituted a small group at any given time.

15.144 These studies and proposed studies treated NANB Hepatitis as a threat to the health of haemophilia patients that had to be dealt with. They were not primarily concerned with the natural history of the disease or with the analysis of its progression. At this stage, one way of tackling the risk was the development of effective virus-inactivated products. That depended on government funding and, in that context, the balancing of risk and benefit was relevant. The views of SHHD medical advisers were reflected in a memorandum by Dr Bell dated 23 May 1984, commenting on the Common Services Agency's case for funding the production of heat-treated Factor VIII.^[163] Dr Bell noted that, at that time, nearly all newly-treated haemophilia patients became infected with NANB Hepatitis, though not usually of dramatic severity, and that about 40% also showed evidence of infection with Hepatitis B. He said that the longer-term effects of such infection in people with haemophilia were not known with certainty because, until relatively recently, haemophilia patients had little prospect of living into middle or old age. However, he thought that a significant proportion of non-haemophilia patients infected with Hepatitis B went on to suffer severe liver impairment which, apart from the personal aspect, made significant demands on health care resources. The clear implication was that the experience of haemophilia patients was likely to be similar.

15.145 In 1985, reports were published that reflected the results of studies of the incidence of infection. The work of Peter Kernoff and others at the Royal Free Hospital, London, is dealt with in the Preliminary Report.^[164] They found that all of their haemophilia patients treated with commercial Factor VIII developed acute NANB Hepatitis. Ten out of 12 patients who were prescribed NHS concentrate also developed acute NANB Hepatitis. The results were not surprising given the size of the donor pools. The report by Massimo Colombo and others of their study of transmission of NANB Hepatitis by Hyland/Travenol's Hemofil T Factor VIII confirmed that NANB Hepatitis had an attack rate close to 100% in haemophilia patients not previously exposed to blood or blood derivatives who were given that commercial product.^[165] Preston and others reported similar results in two previously untreated patients who were given Armour's heat-treated product, Factorate.^[166]

15.146 The focus of interest changed in June 1985 with the publication by Charles Hay and others (Sheffield) of 'Progressive liver disease in haemophilia: an understated problem?' The authors' discussion is informative. They stated:

Our observations show that progressive liver disease is a potentially serious problem in haemophilia. Of 79 haemophilic patients .... 17 had evidence of progressive liver disease (9 cirrhosis, 8 CAH). Serial liver biopsies showed progression of [Chronic Persistent Hepatitis] to [Chronic Aactive Hepatitis] and cirrhosis within a period of 2 - 6 years.

The prevalence of abnormal liver function tests in haemophiliacs increased rapidly with the widespread introduction of factor VIII and IX concentrates in the mid-1970s. These abnormalities are believed to arise as a sequel to viral infection transmitted by blood products .... Almost all previously untreated haemophiliacs acquire NANB hepatitis after administration of factor VIII concentrate, and regular users may have multiple attacks from more than one NANB agent.^[167]

15.147 As indicated in the Preliminary Report, Hay and others discussed their clinical findings and compared their results to those of Mannucci and colleagues in1982, discussed above. The discussion continued:

Cirrhosis may take several years to develop and it is consequentially not surprising that cirrhosis was more common in our series than in earlier studies with shorter periods of follow-up. This is especially important in view of the fact that the high prevalence of liver disease probably dates from the introduction of factor VIII concentrates ....

A notable feature of our series is that 4 patients with CPH have shown progression to CAH and cirrhosis; this is at variance with the generally accepted view that CPH is benign and non-progressive and leads us to speculate that repeated exposure to hepatitis viruses may modify the usually benign course ....

Although few reports of death attributable to liver disease in haemophilia have appeared, we predict that this will become more common.^[168]

15.148 Mannucci's response is set out in paragraph 7.85 of the Preliminary Report. Since this is an important juncture in the published debate, it is important to note the details:

[S]ince our patients had similar ALT pattern and length of follow-up as those investigated by Hay et al, we think that other factors must be considered to explain the different courses of liver disease. The fact that our patients were considerably younger than those studies by Hay et al ... suggests that the degree of liver damage might be inversely related to the age at which patients become infected. Children with chronic hepatitis B tend to have high levels of virus replication in the liver without severe liver disease. So, in view of the many epidemiological similarities between hepatitis B and non-A, non-B hepatitis, it is not surprising that children with non-A, non-B infection tend to have less progressive and more "tolerated" liver disease than adults with the same infection.^[169]

15.149 The findings by Hay's group were not challenged. A possible explanation of the different outcome was suggested. At least in the case of adult haemophilia patients, the risk of progressive liver disease had been shown to be greater than previously anticipated. In time, this was to become clearer and, as indicated in Chapter 13, Knowledge of Viral Hepatitis Now, paragraphs 13.68-13.73, it is now established that the rate of progression is related to age in patients infected with HCV.

Post-transfusion hepatitis

15.150 In 1984, 'Notes on Transfusion principles and practices' was published jointly by the DHSS, Scottish Home and Health Department (SHHD) and the Welsh Office on behalf of the NBTS and SNBTS.^[170] The 'Notes on Transfusion' discussed Hepatitis A and Hepatitis B in the context of donor selection, and commented:

Very similar illnesses can also be caused by other viruses including the so-called 'non-A non-B' viruses. The latter are also transmissible by transfusion, but as yet no specific laboratory tests have been developed to identify them. The incubation period is also variable extending up to 70 days or more. The clinical course may be acute, or chronic leading to cirrhosis.^[171]

15.151 The notes concluded with instructions on the collection of samples and on the reporting duties of clinicians finding hepatitis. The notes were concerned with practical guidance but would have brought to the attention of any transfusion doctor that there was a risk of transfusion-transmission of viral hepatitis generally and NANB Hepatitis in particular.

15.152 In its annual report to the Office of the Chief Scientist of the DHSS, lodged in May 1984 by the London School of Hygiene and Tropical Medicine, it was stated:

The development of specific serological tests for detection of markers of infection with parenterally-transmitted forms of non-A, non-B hepatitis continues to elude laboratory workers in this field. Similarly the viruses have not yet been identified.^[172]

15.153 The development of specific laboratory tests for NANB Hepatitis remained a matter of high priority.

15.154 In marked distinction to the developments in haemophilia, there was less appreciation among those involved with transfusion, in the UK generally and in Scotland in particular, of the nature of the risks presented by NANB Hepatitis. In July 1984 Dr Follett (laboratory virologist at the Regional Virus Laboratory, Ruchill Hospital, Glasgow) and Dr Brian Dow (Senior Technician, SNBTS, Glasgow) presented the final report on a study of 'Non-A Non-B Hepatitis in the West of Scotland'. The first part of the report examined all notified clinical cases diagnosed as likely to be due to non-B post-transfusion hepatitis in the region over four years. Excluding four haemophilia patients who had been multiply transfused with Scottish and imported blood products, they concluded that there were nine likely cases. The second part of the report contained an examination of ALT levels, and the results of other serological tests, of 10,655 blood donations. They found elevated ALT levels in 367 individuals (3.4%), and markedly elevated levels in 96 cases (0.89%).^[173]

15.155 Interestingly, prison session donors (a number of whom recognised as intravenous drug users) showed 10 times more donations with grossly elevated ALT levels than among other groups of donor. These results discouraged SNBTS from continuing to hold donor sessions in prisons to collect blood for transfusion purposes.^[174]

15.156 The study was poorly funded, however, and limited in scope. There was no follow-up of the 10,655 blood donations. No valid conclusions could be drawn as to the frequency of post-transfusion NANB Hepatitis. Drs Follett and Dow concluded, however, that on the basis of the nine reported clinical cases, NANB Hepatitis was very rare in the region. The authors recognised that sub-clinical forms of post-transfusion hepatitis probably occurred but were not notified.^[175] Like previous studies based on reported incidents, this work probably missed the vast majority of cases of post-transfusion NANB Hepatitis. The sub-clinical forms of infection were noted but not taken into account, although it later transpired that they were the dominant component in the actual pattern of transmitted infection.

15.157 Most unfortunately, the report and the erroneous conclusion drawn, that NANB Hepatitis was very rare in the region, were firmly grasped by the SHHD and its medical advisors and held to be valid, until about 1987-88. This was to lead to a significant lack of understanding of the post-transfusion NANB Hepatitis problem and a marked reluctance to fund other studies.

15.158 Dr McClelland (SNBTS, Edinburgh) presented a rather similar view to that of Drs Follett and Dow at the 18th Congress of the International Society of Blood Transfusion held in Munich in July 1984.^[176] He stated that the risk of Hepatitis B following transfusion of blood or its components was extremely rare. Coagulation factor concentrates had a very high risk of transmitting NANB Hepatitis but clinically apparent post-transfusion NANB Hepatitis was a small problem. A few transfused patients developed asymptomatic elevations of liver enzymes but the importance of that remained undefined.

15.159 Scottish blood transfusion experts were not alone in expressing such views in 1984. An article by Drs Barbara and Tedder (North London Regional Transfusion Centre and University College and Middlesex School of Medicine, London) published in October 1984^[177] commented that most NANB Hepatitis infections were not apparent and were only detected by mild elevation of transaminase levels. It was noted that raised transaminase levels could be caused by other viruses or by factors such as drugs, alcohol, obesity and medications. There were major uncertainties about the consequences of NANB Hepatitis, according to these authors who stated that the usually mild acute NANB Hepatitis infections in haemophilia patients would have little significance but for their possible association with the development of chronic hepatitis. However, they stated, even that was frequently self-limiting and resolved within two years in most cases.

Summary

15.160 By the end of 1985, different views were beginning to emerge, especially among haemophilia clinicians and other experts such as Dr Lever and colleagues. It seems however, that the majority, reputable view from leading groups around the world, outside the USA, was that the likelihood was fairly remote that NANB Hepatitis would become a very significant long-term problem, with many individuals developing cirrhosis. Most reports had lacked any lengthy follow-up and had concentrated on the acute changes which researchers saw in blood tests and liver biopsies over the month or two of the initial illness. While there were a few voices suggesting that chronic liver disease/cirrhosis attributable to NANB Hepatitis was becoming, or likely to become, more and more of a problem, these were in a minority. However, to a great extent, the opinions expressed reflected the researchers' natural biases: differences were of the 'glass half full, glass half empty' variety.

15.161 It seems reasonable to conclude that, until the end of 1985 at the earliest, it was a very tenable position to hold that infusion of Factor VIII concentrates presented a risk of significant long-term liver disease but that fatal liver disease was a very small risk. This position is exemplified by Dr Craske's remark that, to his knowledge, only two patients with haemophilia had died of cirrhosis in the previous 10 years.^[178] It is likely that the view of the majority of these authorities (for most groups anyway) was that the relatively few deaths from cirrhosis among haemophilia patients during the 1970s and early '80s had been caused by the 'rump' of the Hepatitis B cases.

15.162 At that time, commentators were all, to some extent, working in the dark. Research produced findings that could be, and were, described. However, the significance of the findings, in terms of the natural history of NANB Hepatitis, was often unclear.

15.163 In the period between 1975 and 1985, increasingly sensitive tests for the Hepatitis A virus (HAV) and Hepatitis B virus (HBV) were developed. In particular, as the range of HBV viral markers improved, there was increasing understanding of which markers indicated present infection and infectivity and which indicated past infection and immunity. However, until the mid-1980s it was unclear what the various markers which commentators were describing for present infection with Hepatitis B in the blood signified in assessing the long-term prospects for the patient.

15.164 The significance of the various histological appearances of the liver - chronic persistent hepatitis, chronic lobular hepatitis, and chronic active hepatitis - in terms of likelihood of progression to serious liver disease or regression to normal, was also unclear at that time. Few of the patients studied in this period, either in the USA or in Europe, had any specific symptoms. Such evidence as had emerged on relatively long-term follow-up (up to five years) suggested that in most individuals chronic liver inflammation engendered by the putative NANB Hepatitis virus(es) would generally die down. It was only towards the later part of the period that suggestions began to emerge that, in perhaps 10% of those chronically infected, irreversible liver damage - cirrhosis - could develop.

15.165 Although the vast majority, if not all, of the clinical studies of NANB Hepatitis associated with Factor VIII use, up to the end of 1985, had set out descriptions of liver disease acquired in real time before the arrival of HIV/AIDS, by late 1985 all major groups were preoccupied with HIV/AIDS and NANB Hepatitis was regarded as a less urgent problem. Furthermore, as was about to become apparent, co-infection with NANB Hepatitis and HIV/AIDS was to become relatively common and was to further complicate understanding of liver disease for the next two or three years.

15.166 At the end of this period, there remained substantial deficits in knowledge of NANB Hepatitis and its natural history. The clinical dilemma as to whether to provide treatment with available human blood-derived therapeutic products remained but the perceived risks of infection had increased. At the meeting called by NIBSC on 9 February 1984, Dr Thomas expressed the problem clearly: 'The undoubted therapeutic benefit of Factor VIII concentrates was clouded by a well recognised side-effect, namely hepatitis, and also, more recently, by AIDS.' ^[179]

15.167 There were, however, widely differing views at that meeting about the nature and the extent of the risks to patients. Dr McClelland's estimate of the risk of transmitting NANB Hepatitis by blood transfusion was 1 in 100 and he commented that the risks for haemophilia patients were much greater because of their exposure to large numbers of donors. In relation to hepatitis, Dr Craske reported that 30-40% of UK haemophilia patients had abnormal liver function tests, indicative of possible chronic liver damage. However, by 1983 only two haemophilia patients had died of liver disease in 10 years. Throughout this period the low mortality reported in haemophilia patients from complications of hepatitis had a significant impact on the assessment of risk/benefit for the patient receiving blood products.

15.168 The 7th edition of Professor Sherlock's Diseases of the Liver and Biliary System was published in 1985. It provides a useful summary of the position regarding NANB Hepatitis in the UK at that time. At the end of the period discussed in this chapter, it can be taken to represent the information likely to have been available to the general body of clinicians and others in the UK concerned with liver disease at this time. Professor Sherlock noted four clinical types of NANB Hepatitis (among many).^[180] Two were enterically spread and can be ignored for present purposes. The two parenterally spread types were (a) a blood transfusion related type with a relatively long incubation period, and (b) a type associated with the administration of blood products to haemophilia patients, distinguished by a short incubation period. The clinical course of infection was the same in each case. The acute attack was mild but could occasionally be fulminant (rapidly progressing). Approximately 68% of patients developed chronic hepatitis. In 19%, this progressed slowly and almost without symptoms to cirrhosis. Fluctuating transaminases were said to be typical of the chronic state. It was commented, significantly, that a relationship to hepatocellular cancer had not been established. It was noted that there was no test for NANB Hepatitis and that there had been limited progress both in diagnosis and in assessing treatment.

15.169 Professor Sherlock's preface was dated October 1985 and the text is likely to have been completed some months earlier. It is unlikely to have taken account of research in the second half of the year in which Professor Sherlock was not involved. Nevertheless, although it cannot be assumed that there was general knowledge of up-to-date research, the emerging position by the end of 1985, in both the USA and the UK, was that:

• There was increasing concern in some quarters about the potential seriousness of NANB Hepatitis, whether following blood transfusion, in relation to which there was more knowledge and more concern in the USA, or in haemophilia treatment.
• Almost all haemophilia patients who regularly received treatment with concentrates were likely to have been infected by the disease.
• First generation heated concentrates continued to transmit NANB Hepatitis.
• The debate over the benefits and drawbacks of screening blood donors for surrogate markers of NANB Hepatitis continued.

15.170 The last two topics are discussed in Chapters 23 and 27. The next chapter takes up the developing story of NANB Hepatitis after 1985.

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16. Knowledge of Viral Hepatitis 3 - 1986 Onwards >