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CHAPTER 6

HEPATITIS 1974 TO 1981

Synopsis:

Existence of Non-A Non-B Hepatitis (NANB Hepatitis) viruses established - acknowledgement of high prevalence of NANB Hepatitis in haemophilia patients - first studies of haemophilia patients using liver biopsies - acknowledgement that liver function tests are not good predictors of liver disease - 1-Deamino-8-D-Arginine Vasopressin (DDAVP) suggested as the appropriate treatment for mild haemophilia patients - prioritising of research into NANB Hepatitis by Department of Health and Social Security (DHSS) - focus on research into viral inactivation of factor concentrates by heat treatment - acknowledgment that NANB Hepatitis accounts for the majority of post-transfusion hepatitis - first discussion of the possibility of screening donors for NANB Hepatitis by surrogate testing - continuing uncertainty as to the natural history of liver disease.

Introduction

6.1 The current state of knowledge of hepatitis viral infections is described in Chapter 2. In contrast, the generally accepted state of knowledge at the beginning of the reference period in 1974 was rudimentary. This chapter is primarily concerned with developing knowledge concerning hepatitis viruses and transmission of these viruses by blood products during the period 1974–1981.

6.2 By the mid 1960s, it was generally understood that hepatitis could be transmitted in water-borne form (enterally), in the case of ‘infective hepatitis’, or in blood-borne (parenteral) form, in the case of ‘serum hepatitis’. The first association of blood transfusion with the development of hepatitis was reported in 1943.[1] The first report in the United Kingdom (UK) of hepatitis transmission by the use of Cryoprecipitate appeared in 1969.[2] The report noted one previous case reported in 1966.[3] The English correspondents indicated that there had been extensive use of the product, without mishap, but re-emphasised the potential danger of Cryoprecipitate, and the importance of ensuring its use only when strictly needed. The first description of possible transmission of hepatitis by Factor VIII concentrate was in 1963 by Maycock et al in a comprehensive report of English experience of the early use of human anti-haemophilic globulin concentrate.[4] The authors’ conclusions supported the use of concentrate as a reliable means of controlling bleeding in haemophilia patients, noting that ‘there are no contra-indications to its prolonged or repeated use’.

6.3 Maycock et al observed that, in relation to the possible cases of jaundice, there were no environmental factors indicating infective hepatitis. However, there was still little real understanding of the distinctions between the two types of what were presumed to be virally induced hepatitis, even by the mid 1960s, nor had any agents responsible for enteral or parenteral hepatitis been reliably identified. The prognosis for patients contracting post-transfusion hepatitis (PTH) had not been fully understood. So, writing in The Practitioner in August 1965, Dr J Grant of the Regional Blood Transfusion Centre, Oxford said:

The development of Homologous Serum Hepatitis is a hazard which besets rather less than 1% of recipients of whole blood or small pool-plasma. It is caused by the transmission of a virus from a carrier to a susceptible patient. The donor is probably not aware that he is a carrier, he gives no history of ever having had infective hepatitis himself (otherwise he would have been excluded from the donor panel) and no single test or battery of liver function tests has yet been devised which will reliably distinguish carriers of virus from normal subjects.

Recipients vary in their susceptibility…

Some patients suffer no upset from the transmitted virus, some may have only a transient liver dysfunction with or without jaundice and yet others may develop a rapidly fatal hepatic necrosis. The incubation period of infective hepatitis is about 20 to 40 days, whereas that of homologous serum hepatitis is 40 to 160 days…[5]

6.4 By the beginning of the reference period, it was recognised by medical scientists and practitioners that factor concentrates generally were associated with a risk of transmitting hepatitis.[6] Writing in 1974, Buchholz said that among diseases transmitted by transfusion:

…hepatitis reigns supreme as the major cause of transfusion-associated disease.[7]

6.5 Generally, however, the increased risk of clinical illness was thought to be insufficient to overbalance the advantages of the use of Cryoprecipitate and concentrates in clinical treatment of haemophilia.[8]

6.6 By 1971, the incidence of post-transfusion jaundice in haemophilia and Christmas disease patients had been studied by a Medical Research Council (MRC) Working Party, and reported to the United Kingdom Haemophilia Centre Directors Organisation (UKCHDO).[9] The study related to 1066 patients, covering a wide distribution of ages (with a mean age of 21.9) who were being treated at 30 Haemophilia Centres. 2.8% were jaundiced during 1969 or early 1970. Three patients had died. Two of the three had been treated with Cryoprecipitate only. The third had been treated with Cryoprecipitate and Factor VIII concentrate. Meanwhile, a smaller study of 208 haemophilia patients in Oxford showed that seven had developed jaundice. Other data, again derived from patients treated at the Oxford centre, indicated the incidence of Hepatitis B associated antigen and antibody. It was reported that, of the sample of 60 patients, 11 had a positive test for Hepatitis B antigen or antibody and that of these only one developed ‘clinical hepatitis’.

6.7 On the basis of the data from the 60 patients, it was reported that, whereas about 18% of individuals had evidence of infection with the Hepatitis B Virus (HBV) at this time, only 2.8% had overt illness. This led to the incorrect conclusion at the time (1972) that persons with haemophilia had ‘considerable resistance’ to clinical infection with HBV. The view expressed was that:

Although the surveys do not involve large numbers it is likely that the prevalence of hepatitis virus in the materials used to treat haemophiliac patients is approximately as expected. The overall low incidence of clinical illness is presumably due to the fact that the patients became immunized in childhood.

6.8 It appears that the focus in both PTH and hepatitis among haemophilia patients treated with blood products (Cryoprecipitate, then concentrate) was on acute, clinically observed, hepatitis. In 1971 it was thought that this was largely due to HBV infection. The possibility of any form of chronic disease was ill understood and little appreciated. The increased risk of clinical illness was not thought to be so great as to overbalance the advantages of the use of concentrates in particular.

6.9 Dr Biggs published data in 1974[10] relating to the incidence of jaundice in patients treated for Haemophilia A and B (Christmas disease) in the period 1969 to 1971. This paper referred to data collected from 37 Haemophilia Centres over a three year period. PTH was described as a rare complication of two rare diseases. But the disease was described as one of the two most alarming complications associated with the treatment of haemophilia patients. The paper stated:

Transfusion hepatitis is a disease caused by several viruses which may occur in donor plasma. There is every reason to suppose that these viruses may be present in the various protein fractions used to treat haemophilia and Christmas disease (cryoprecipitate, human antihaemophiliac globulin…and factor-IX concentrate). The incidence of the Hepatitis B virus in the donor population was of the order of 1 per 800 donations at the time that these observations were made…Since then the screening of all donors for hepatitis B antigen has been instituted and the incidence of samples grossly contaminated with hepatitis B virus is now certainly less. Screening, however, is unlikely to remove all infected samples because more than one virus is involved and because the screening method is not sufficiently sensitive to detect all samples infected with Hepatitis B virus.

The theoretical danger of exposure to infection increases with the number of donations contributing to the doses of treatment material used….[11]

6.10 By the date of publication, (1974) the benefits of improved testing and screening for HBV, had led to the realisation that more than one blood-borne virus was responsible for PTH. Of 1837 patients, 62 were said to have had 64 episodes of clinical jaundice during the three years of the study. The diagnostic features identified were identical to those reported at the Haemophilia Centre Directors’ meeting on 5 April 1971, and related to the acute illness.

6.11 The discussion in the paper reflects the understanding at the time:

The clinical value of early treatment of haemophilic patients in the saving of life and the prevention of crippling is now well established. This treatment is known to carry two main hazards: (1) the transmission of viral hepatitis; (2) the development of specific antibodies against coagulation factors.

The data on hepatitis suggest that severely affected and multi-transfused patients with coagulation defects do not have a high incidence of clinical illness associated with jaundice. Present calculations suggest that if all of the patients were exposed to virus contained in pools of plasma 4 – 5% of them might develop clinical illness. The proportion of patients exposed to virus is likely to decrease in future rather than to increase since donations grossly infected with Hepatitis B antigen will be excluded by universal donor screening….

6.12 It was thought that patients developed some immunity to the virus from multiple transfusions. It also suggested that large donor pools might be a positive advantage because the virus would be diluted and would also contain Hepatitis B antibodies.

6.13 Donor screening was introduced following the identification of the Hepatitis B surface antigen (HBsAg). The antigen against the virus that was to become known as HBV was known from about 1963, when it was identified by Blumberg et al in the serum of an Australian Aborigine. It was initially called ‘the Australian Antigen’. The discovery would revolutionize the understanding of viral hepatitis and change radically the direction of research of the disease.[12] Four years later Blumberg’s group recognised that the appearance of this antigen was related to type B hepatitis, serum hepatitis.[13] Following their work, methods of detection of the antigen were developed, of which, at the time, radio-immunoassay (RIA) was the most sensitive, and the best method available for blood screening and for general use.[14]

6.14 The danger of clinical hepatitis following blood transfusion was thought to be small in the UK at this time. However, once testing had become available in about 1970, the high incidence of anti-HBs (the antibody to the surface antigen of the HBV virus) in haemophilia patients suggested that a high proportion did become infected by HBV.

6.15 The identification of the Australian Antigen led to research that demonstrated a clear association between the presence of HBsAg in donor blood and the development of Hepatitis B or the antigen and its antibody in the recipient.[15] The study also led to the conclusion that Hepatitis B accounted for a relatively small proportion of cases of PTH, of the order of 20–25%. Further research followed in the United States of America (USA). Research led by Alter, Aach, Knodell and Seeff confirmed that HBV was responsible for a low proportion only of PTH.

6.16 In addition, research in the USA had distinguished risk relative to the source of blood. The wider historical context is set out by Alter and Seeff:

Prior to the advent of hepatitis serological assays, by far the most important hepatitis risk factor identified was the origin of the donor blood. As early as the 1960s, investigators had noted that paid (commercial) blood was much more likely to be associated with subsequent hepatitis in the recipient than was blood that had been voluntarily donated…Even stronger support for this observation emerged during the 1970s…In every study in which this risk was investigated, the frequency of hepatitis was found to be far greater in recipients of commercial blood than in recipients of volunteer donor blood.[16]

6.17 The UK’s volunteer system of blood donation did not hamper the development of testing for HBsAg. The early stages in the study were summarised in the third report of the Department of Health and Social Security (DHSS) Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody.[17] The Advisory Group was appointed jointly by the DHSS, the Scottish Home and Health Department (SHHD) and the Welsh Office to study the organisation of and responsibility for testing blood donations and other specimens of blood in the hospital service. A meeting was convened by the DHSS on 20 July 1970 to discuss the problems. It recommended that the department should give any assistance it could in the institution of testing blood donations for the presence of the Australian Antigen and its antibody.

6.18 In May 1972, the group published a revised report.[18] The report recommended that Regional Transfusion Centres (RTCs) should start testing all blood donations for the presence of the Australian Antigen and its antibody at the earliest possible date, using, initially, an immunoelectro-osmophoretic method of testing. The group pointed out, however, that knowledge of all aspects of the Australian Antigen was accumulating very rapidly and that its recommendations should therefore be regarded as interim and subject to modification at a later date.

6.19 Tests to screen for the Hepatitis B antigen were pioneered in 1971, and were introduced for all blood donations in the UK from December 1972. Confidence in the tests was high but not unqualified. Dr Biggs’ observations in 1974 relating to the incidence of jaundice in patients treated for Haemophilia A and B (Christmas disease) in the period 1969–1971 have been quoted above, along with her reservations on the efficiency of the screening tests available.[19] However, developments were in hand.

6.20 During 1974 the screening of blood donations with third generation tests for HBsAg significantly reduced HBV infection among blood transfusion recipients. However, it did not lead to its effective eradication. Although many haemophilia patients receiving Cryoprecipitate or Factor VIII concentrate had already become infected with HBV by 1974, subsequent studies were to show that the vast majority of these individuals did not sustain long term liver damage from HBV.

6.21 Meantime, developments in the knowledge of the Hepatitis A Virus (HAV) had not progressed so far. In 1972, J Garrott Allen attributed PTH to one or other of two viral agents: Hepatitis A or Hepatitis B.[20] His use of the term ‘Hepatitis A’ was misleading. In about 25% of his subjects the infection diagnosed was of Hepatitis B infection, demonstrated by the presence of the Hepatitis B surface antigen. But, as he used it, ‘hepatitis A’ was a diagnosis by default, in the absence of any immunological test for its agent at that time.

6.22 HAV, an enteral, not a blood-borne virus, was identified in 1973 by Feinstone et al.[21] In 1973, there were still no blood tests to detect either its presence or the fact that an individual had been exposed to the virus. That development would come in 1974–1975. At the beginning of the reference period, in 1974, scientists were approaching a critical change in understanding that would lead to the identification of forms of hepatitis that were neither form A nor form B, but that stage had not been reached.

6.23 The Feinstone article in Science represented a significant advance in published information in the UK, but does not appear to have made an immediate impact.[22] By way of comparison, a report of the (then) Medical Research Council (MRC) Working Party on Post-Transfusion Hepatitis to the MRC Blood Transfusion Research Committee was published in the Cambridge Journal of Hygiene.[23] The report was received for publication on 21 February 1974. It related to the extensive and long-term study already reported in part in the paper by Maycock and others and in the reports of the DHSS Advisory group referred to above. Members of the working party included Professor Sheila Sherlock and Professor AJ Zuckerman. The chairman was Dr W d’A Maycock. As well as the general objective of collecting information about the incidence of PTH, the specific objectives of the study were related to Hepatitis B, Cytomegalovirus (CMV) and Epstein-Barr virus (EBV). One hundred and fifty eight patients developed raised serum alanine aminotransferase (ALT) values after transfusion. Two groups, amounting to six patients, had histological or clinical features consistent with viral hepatitis. Thirty five had conspicuous or sustained serum ALT rises without symptoms or physical signs suggestive of viral hepatitis and were put into an indeterminate class. The remaining 115 patients were thought not to have viral hepatitis. A very low prevalence of viral hepatitis was recorded - overall about one per cent.

6.24 The MRC report implicitly showed that not all cases of PTH could be ascribed to HBV, but few conclusions were drawn from this. [24] In the analysis of none of the groups studied by the MRC Working Party was the possibility of viral hepatitis that was neither A nor B considered. The date of the study, which was submitted for publication in February 1974, may be relevant, as may the period over which patients were identified for participation, 1 July 1969 to 20 June 1971. Commenting on the results, Alter and Seeff later stated that NANB Hepatitis in fact accounted for 80% of the cases studied.[25] The same position on the incidence of hepatitis appears from a contemporary article in the (American) Journal of Paediatrics.[26]

1974–1975

6.25 As noted already, American research into the incidence of Hepatitis B had concluded that a relatively small proportion of cases of transfusion associated hepatitis were of Hepatitis B. At first, the origin of non-B cases of hepatitis appeared obscure. Some workers, such as J Garrott Allen, thought these cases to be associated with HAV. It had been recognised that factor concentrates were associated with a risk of transmitting hepatitis,[27] at first generally, but then in the case of Hepatitis B specifically.[28] The view that there were only two relevant hepatitis viruses was reinforced in the UK by Professor Sherlock in the 5th edition of her book, Diseases of the Liver and Biliary System, published in 1975. The book can be taken to provide an authoritative description of the state of knowledge available to the medical profession in the UK generally from 1974–1975.[29] HAV was not identified as a separate cause of concern: despite her observation that the disease might be transmitted parenterally,[30] it was not thought to be associated with transfusion. Hepatitis B was described as a ‘long incubation disease’. It was spread classically by therapeutic administration of blood and blood products, but it could also be spread orally, and sexual transmission was likely.[31] The 5th edition contained no reference to the NANB Hepatitis virus.

6.26 Professor Sherlock’s description of the clinical course of viral hepatitis included the following:

Hepatic involvement, particularly to the extent of jaundice, is an infrequent complication of rather a common virus infection. The picture varies widely, ranging from slight malaise to a severe and fatal disease culminating in hepatic coma…

In general, type A and type B hepatitis run the same clinical course. Type B tends to be more severe and may be associated with a serum sickness-like syndrome. The relationship of type B to chronic liver disease has been established…

The severity is very variable. The mildest attack is without symptoms and marked only by a rise in serum transaminase levels. If it is of type B there is transient HBAg positivity. Alternatively, the patient may still be anicteric but suffer gastro-intestinal and influenza-like symptoms…

The usual icteric attack in the adult is marked by a prodromal period usually about 3 or 4 days but even up to 2 or 3 weeks…

The prodromal period is followed by darkening of the urine and lightening of the faeces. This heralds the development of jaundice and symptoms decrease…Appetite returns and abdominal discomfort and vomiting cease. Pruritis may appear transiently for a few days…

The adult loses about 10 lb weight. A few vascular spiders may appear transiently.

After an icteric period of about 1 – 4 weeks the adult patient makes an uninterrupted recovery...After apparent recovery lassitude and fatigue persist for some weeks. Clinical and bio-chemical recovery is usual within 6 months of onset.[32]

6.27 Professor Sherlock noted the possibility of prolonged jaundice, also followed by complete recovery, and commented on post-hepatitis syndrome as a condition leaving the patient feeling ‘below par’ for weeks or months. She commented that chronic persistent, chronic active hepatitis, post-hepatitic scarring and cirrhosis could all develop.[33] Of these, the author described chronic persistent hepatitis as benign. She continued:

Chronic active hepatitis often proceeds to or is associated with cirrhosis. Chronic active hepatitis also has many causes. The mechanism by which hepatocellular necrosis proceeds in any individual to chronic active hepatitis and finally to the irreversible stage of cirrhosis is in most instances unknown. Knowledge of the factors determining this course would give the key to the development of cirrhosis.[34]

6.28 On epidemiological grounds, doubts grew whether HAV could account for the majority of cases of PTH. In 1974 Prince et al suggested that a substantial proportion of cases of PTH were caused by neither HAV nor HBV and they suggested the existence of an additional hepatitis virus or viruses.[35] The work of Feinstone et al, published in 1973, was not cited.[36] The authors relied on incubation periods; the lack of intra-familial transmission; and the failure of gamma-globulin to modify the results to support the inference that Hepatitis A infection was not relevant. Two hundred and ninety nine patients were involved in the research. They had undergone surgery (mostly cardiovascular surgery) at New York University Hospital between May 1969 and August 1972. The authors were able to demonstrate that the condition they described was probably not Hepatitis A or Hepatitis B, and inferred that the cause was some other, unidentified, virus. This additional virus became known as ‘Non-A, Non-B Hepatitis’. This agent proved to be elusive and defied many wide-ranging efforts to identify it.

6.29 The identification of the specific HAV by Feinstone et al provided a basis for proof of Prince’s hypothesis.[37] Serological analysis in 1975 of stored sera from the earlier studies revealed that none of the cases of PTH could be attributed to HAV. While, in retrospect this may not appear to be surprising since HAV was thought to be almost exclusively water-borne, not blood-borne, previous failure to infer the existence of a NANB Hepatitis virus or viruses underlines the importance of the work of Feinstone and Prince.

6.30 Two other points made by Prince et al in the 1974 article are to be noted. The authors suggested, albeit tentatively, that there were long-term risks associated with Hepatitis B and Non-B viruses.

Long-term complications of acute hepatitis-B infection, such as chronic hepatitis, cirrhosis, and hepatoma, have been reported to follow mild anicteric infections more frequently than severe icteric cases;[38] consideration must thus also be given to the possibility that non-B hepatitis may play a role in the aetiology of some forms of chronic liver disease.

6.31 Secondly, they reported that, in their series, the risk of Non-B Hepatitis was ten times higher among recipients of blood obtained from commercial sources than among those given blood from volunteer donors. The data, drawn from unpublished material provided by Brotman, Prince, Kuhns and others, incidentally provided support for the findings in 1960’s studies referred to earlier of the higher risk of PTH from blood collected from commercial donors.

6.32 In 1974 sensitive and accurate tests for HAV and HBV were beginning to be widely available, and several groups reported in the following year that the majority of patients with clinically diagnosed PTH were negative for infection with HAV and HBV.[39]

6.33 Meantime, the DHSS Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody (a slightly amended title) was reconvened on 6 December 1973. In this phase of its operations, serological assays were being developed and applied routinely in the UK. The Group recommended that Reverse Passive Haemagglutination (RPH) should be adopted by RTCs in place of Counterimmunoelectrophoresis (CIE) to screen every blood donation for the presence of HBsAg. In its second report published in September 1975, it recommended that the practice of excluding donors with a history of jaundice be discontinued provided that HBsAg was not detected and the donor had not suffered from hepatitis or jaundice during the previous 12 months.[40] It appears that there was growing confidence in the effectiveness of the screening process to reduce, if not totally eliminate, the risk of transmission of HBV. The inference appears to be that, provided one excluded HBV by the HBsAg test, one could ignore other factors, such as a history of hepatitis more than a year previously.

6.34 In 1975 Harvey Alter and colleagues described a prospective study of PTH using repeated liver function tests, in 204 cardiac surgery patients.[41] They identified 51 cases (by elevated ALT measurements) of possible transfusion hepatitis and found no serological explanation (by exclusion of HBV) for this in 34 (71%) cases. They concluded:

The data suggest that a large proportion of long incubation post transfusion hepatitis is unrelated to hepatitis B and that control of post-transfusion hepatitis will require identification of a hepatitis virus(es) type C.

6.35 Following this work, and that of Prince already described, the term ‘non A, non B hepatitis’ was coined as a collective term for hepatitis in which, at that time, HAV and HBV, CMV and EBV had been excluded as causal agents.[42] Much later, further research led to the identification of the Hepatitis C Virus (HCV)[43] as the predominant cause of the condition described, though not the exclusive cause.[44] The inability to identify NANB Hepatitis viruses had, as a necessary corollary, the inability to develop any screening test or assay that would enable infected donations to be excluded from the source materials used as whole blood and blood components or in the manufacture of blood products. In time, a major debate would take place over the use of ‘surrogate’ tests. As at 1974, knowledge of HBV and NANB Hepatitis infection was not developed. Awareness of the risk of viral infection from blood and blood products was unrefined and unsophisticated.

6.36 Knowledge of Hepatitis in 1974 – 1975

• Recognition that HBV accounted for a relatively small proportion only of cases of PTH was beginning to be reported.

• HAV was discounted as a cause of PTH following Feinstone’s characterisation of the virus and the development of serological tests for the virus.

• The term NANB Hepatitis was coined for hepatitis in which, at that time, HAV and HBV, CMV and EBV had been excluded as causative agents.

• Routine (fairly sensitive) testing of HBsAg in all donor blood meant that, from this time, new cases of PTH caused by HBV would be very rare in the UK.

• The fact that at least 20% of haemophilia patients, treated with clotting factor, had markers of past infection with HBV was recognised.

• Serum markers of HBV in routine use were still confined to HBsAg-correctly thought to be an indicator of potential infectivity, and anti-HBs-correctly thought to indicate past infection with HBV, and to indicate immunity from further infection as well lack of infectivity.

• Understanding of the natural history of HBV infection, and particularly of the groups at risk of developing chronic HBV infection, was still poorly developed. But Prince and colleagues had already reported that long term complications of acute Hepatitis B infection, such as chronic hepatitis, cirrhosis and hepatoma, appeared to have followed mild anicteric infections more frequently than severe icteric cases.[45]

• Factor therapy had become more and more popular with haemophilia sufferers and their doctors[46] and there was a consequent significant increase in demand for blood from which these factors were extracted.[47]

• There was a slow realisation that factor therapy almost always resulted in hepatitis infection. But the severity of the risk was under-estimated. When NANB PTH was identified, it was assumed to be a relatively benign condition.[48]

Events in 1975

6.37 On 6 January 1975, Dr J Garrott Allen of the Stanford University Medical Centre wrote to Dr William Maycock, Director of the Blood Products Laboratory, Elstree.[49] He expressed concern about obtaining blood from paid and prison donors particularly in the USA. He asked a number of questions about the processing of blood donations in the UK. He mentioned that the pharmaceutical company, Cutter, had produced a product called Konyne which was ‘extraordinarily hazardous’ – 50–90% of the recipients had developed icteric hepatitis half of which had proved fatal. He suggested that half or more of the cases of PTH were caused by an agent other than the Hepatitis A or B viruses. His intention in writing appears to have been to persuade the UK to stop buying commercial blood products from American companies on the basis that this adversely affected American attempts to set up a volunteer donation programme.

6.38 On 26 March 1975, Major General HC Jeffrey, National Medical Director, Scottish National Blood Transfusion Service (SNBTS) wrote to Dr John Wallace, Regional Director, Glasgow and West of Scotland Blood Transfusion Service. He discussed hepatitis, indicating that, despite all precautions taken in the light of current knowledge, a few cases of PTH were ‘bound to arise’ and making reference to the 1974 Prince publication.[50] The letter was copied to Dr McIntyre at SHHD.

6.39 On 10 April 1975, Feinstone et al published the results of research into 22 patients who had an episode of PTH that was not positive for the Hepatitis B antigen.[51] Their findings suggested the possibility of a viral agent other than Hepatitis A or B which was commonly transmitted by blood transfusion.

6.40 In May 1975, the World Health Organisation (WHO) produced the World Health Assembly Resolution 28.72 entitled ‘Utilization and Supply of Human Blood and Blood Products’.[52] This resolution recommended that member states should develop national blood transfusion services based on voluntary non-remunerated regular blood donation. It stated that each country should be able to supply sufficient quantities of its own blood and blood products to meet clinical needs. It also stated that efforts should be made to stop the practice of commercial collection of blood.

6.41 At this time, prior to the full commissioning of the Protein Fractionation Centre at Liberton (PFC), Scotland was in part dependent on imported products for the treatment of haemophilia. On 11 June 1975, at a meeting of SNBTS Directors, the purchase of commercial blood products was discussed as a procurement matter.[53] The live issue was whether commercially produced blood fractions which might be required should be purchased by SNBTS or by health boards. On 30 September 1975, at a subsequent meeting of SNBTS Directors, it was decided that, because of the comparatively minor nature of the problem, it should be left to directors to purchase and distribute human blood products should this prove necessary, pending full commissioning of the PFC.[54]

6.42 From 27 July to 1 August 1975, a symposium, organised by the World Federation of Haemophilia and the International Society of Blood Transfusion, took place in Helsinki.[55] The reports of proceedings at the symposium showed that concentrates were frequently associated with side-effects which might be of clinical relevance, including hepatitis. However the view was that the side-effects did not justify withdrawal or limitation of replacement therapy as this would result in a significant deterioration in the quality of life of haemophilia patients. Dr Cash also gave a paper at the symposium, ‘Factor VIII Concentrates, Transfusion and Immunology’.

6.43 A paper by Mannucci et al, ‘Asymptomatic liver disease in haemophiliacs’, reported that 45% of haemophilia patients had raised ALT levels possibly caused by one or more NANB Hepatitis viruses.[56] The data suggested that, in persons with haemophilia, the repeated contact with the NANB Hepatitis agent might cause chronic liver damage not associated with overt illness.[57] This appears to have been the first suggestion that NANB Hepatitis, in respect of persons with haemophilia, was more than just a benign condition.

6.44 In August 1975, Dr Craske of the Public Health Laboratory, Dorset, published data on an outbreak of jaundice following the infusion of commercial Factor VIII in the Bournemouth haemophilia centre, ‘An outbreak of hepatitis associated with intravenous injection of Factor VIII concentrate’.[58] There was a 50% incidence of hepatitis after treatment. There was a pronounced increase in risk when commercial concentrates (all imported from the USA) were used. He proposed that concentrates should be prepared from volunteer donors in the UK who had been tested for Hepatitis B by RIA. He suggested restrictions on the use of concentrates. There was a further reference to this study in Dane et al, ‘Factor VIII concentrate and Hepatitis’.[59]

6.45 In September 1975, the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody (previously called the Advisory Group on Testing for the Presence of Australia (Hepatitis-Associated) Antigen and its Antibody), produced its second report[60]. The group recommended that donors who tested positive for HBsAg should be excluded from the donor panel and that the practice of excluding donors with a history of jaundice should be discontinued unless they tested positive for HBsAg[61].

6.46 On 19 September 1975, the Royal College of Physicians and Surgeons of Glasgow, held a symposium on haemophilia.[62]

6.47 On 20 September 1975, the editorial in the British Medical Journal (BMJ) adopted a position about transfusion associated hepatitis which relied heavily on the findings of Feinstone and Prince et al.[63]

6.48 A World in Action television programme about self-sufficiency was broadcast on 8 December 1975. Dr Maycock, Director of the Blood Products Laboratory, was interviewed in the programme. He said that he did not think the UK had been complacent about the risks outlined in the Allen letter. On 24 January 1976, Dr Cash wrote to the BMJ commenting that the editing of the material in the programme gave a misleading impression and suggesting that patients should be advised that the £500,000 injection into the blood transfusion services would not eliminate the need to purchase Factor VIII concentrates from 1977.[64]

1976

6.49 Initially the diagnosis of NANB Hepatitis was made on the basis of excluding other causes of hepatitis - the Hepatitis A virus, the Hepatitis B virus and other agents such as CMV and EBV.[65] In 1976 it was noticed that an interesting feature of chronic NANB Hepatitis was episodic alterations in serum transaminase levels, namely the levels of ALT and aspartate transaminase (AST), (both liver enzymes). Cyclic patterns with increased levels alternating with near normal levels were described.[66] Other causes for these alternating levels were excluded.

6.50 In 1976 the Health Circular (76)4 and associated Family Practitioner Notice 105 set out the arrangements for the care of persons suffering from haemophilia and related conditions. The concepts of Haemophilia Centres, Associate Centres and Reference Centres were described and the circular specified the criteria for designation as the different kinds of centre.[67]

6.51 In 1976, PFC developed the Mark II version of Supernine, a Factor IX product.[68] The aim of Supernine was to replace DEFIX, PFC’s standard therapeutic product for Haemophilia B, with a concentrate which was three to five times more potent and which had reduced HBsAg content. Supernine also had a reduced infusion volume and a reduced risk of side-effects such as hepatitis, thrombogenicity and allergic reactions. The Mark I product was used in clinical trials in 1973 and in 1976 scaled up production of Mark II was initiated.[69]

6.52 On 16 March 1976, TE Hutton, DHSS, sent a memorandum to Dr Waiter about ‘Testing for Hepatitis B Surface Antigen and its Antibody’.[70] The memorandum recorded that the second report of the Hepatitis B Advisory Group had been approved by the Minister of State in October 1975 and endorsed by The Standing Medical Advisory Council (SMAC) at their meeting on 11 November 1975. Outside bodies were consulted about the terms of an accompanying circular. Concern was expressed by some directors of RTCs about opening the donor panel to persons with a history of jaundice but the majority were in favour of admitting them from a given date.

6.53 On 22 June 1976, Dr Wallace, Glasgow & West of Scotland Blood Transfusion Service, wrote to Dr AD McIntyre, SHHD, about the merits of the Radioimmunossay (RIA) and Reverse Passive Hemagglutination Assay (RPHA) tests for screening of donations for Hepatitis B.[71]

6.54 On the basis of a study conducted by Dr Wallace to assess the sensitivity of RIA and RPHA tests, it was established that, in a nine month period using RPHA, seven HBsAg positive donations had not been detected. He referred to a Fatal Accident Inquiry involving transmission of Hepatitis B. Dr Wallace appears to have been concerned about the lack of sensitivity of the RPHA test which he implied might lead to further deaths. He referred to the possibility of informing the Scottish Legal Office or his own Defence Society if a way could not be found to maintain a sensitive method of testing donations. On 28 June 1976, Dr McIntyre, sent a memorandum to Dr Scott.[72] In it he referred to ‘professional blackmail’ in the letter from Dr Wallace. He stated that Dr Wallace knew of the problems of hepatitis and knew that ‘hepatitis B is only the tip of the ice-berg’. It seems that
Dr McIntyre interpreted Dr Wallace’s letter as containing a veiled threat that, if he was not given funding to continue with his study, he would report his misgivings to the authorities. On 26 July 1976, Dr Wallace duly wrote to the Chief Administrative Medical Officers, District Medical Officers and the Consultant Haematologists to Area Health Boards in the West of Scotland, advising them of the results of his study and the implication that in the course of one year between 9 and 16 donors who were chronic carriers of Hepatitis B would not be detected by RPHA.[73]

1977

6.55 On 13 January 1977, a meeting of the UKHCDO proposed the formation of a Hepatitis Working Party.[74] The setting up of a Hepatitis Working Party was subsequently agreed at a meeting of Reference Centre Directors held on 26 May 1977[75] and its constitution was officially approved at a meeting of the UKHCDO on 24 October 1977.[76]

6.56 On 12 March 1977, Dienstag et al produced a report: ‘Non-A, Non-B post-transfusion hepatitis’.[77] Thirty two patients were monitored for this report.[78] These were the 22 patients from the Feinstone report, together with 10 more cardiovascular patients, who had been multiply transfused. It concluded that there was adequate data to support the existence of NANB Hepatitis virus(es). They excluded Hepatitis A as the agent responsible for Non-B PTH, and added to the ‘growing evidence for the existence of one or more non-A, non-B hepatitis viruses’. This paper did not address the clinical effect of NANB Hepatitis infection.

6.57 In April 1977, Mannucci et al and others reported on the use of 1-Deamino-8-D-Arginine Vasopressin (DDAVP) to promote Factor VIII properties in patients with moderate and mild haemophilia and von Willebrand’s disease undergoing surgery, without use of plasma concentrates.[79] In his review of this period in the paper ‘AIDS, hepatitis and hemophilia in the 1980s: memoirs from an insider’ Professor Mannucci stated that the advantages of DDAVP in reducing the risk of blood-borne infection in mild haemophilia were immediately appreciated in Italy[80]. He stated that the early use of DDAVP led to a significantly lower rate of infection in Italian patients with mild Haemophilia A when compared to patients with mild Haemophilia B who were unresponsive to DDAVP.

6.58 In July 1977, Meyers (Dienstag) et al, published ‘Parenterally transmitted Non-A, Non-B hepatitis: an epidemic reassessed’.[81] This was a retrospective study in which stored blood was re-examined using up-to-date tests for Hepatitis A and Hepatitis B. The report concluded that most cases of PTH were not caused by HAV or HBV, but by one or more NANB Hepatitis viruses. This paper did not address the clinical effect of NANB Hepatitis infection.

6.59 In July 1977, Biggs & Spooner, produced the ‘Haemophilia Centre Directors’ Annual Statistics for 1975’.[82] The proportion of Factor VIII concentrate used (as against plasma and Cryoprecipitate) had increased from 13% in 1974 to 20% in 1975.

6.60 ‘Liver Biopsy in Hemophilia A’ by Lesesne et al[83] was a study of six haemophilia patients who had persistent raised serum transaminase values over a period of six months. Liver biopsies were taken and approximately half of the patients were found to have chronic active hepatitis. This was the first study in which liver biopsies were taken from haemophilia patients. Liver biopsy studies on persons with haemophilia were very difficult to organise due to the risk of bleeding from the liver biopsy site. Patients were given prophylactic clotting factor concentrates prior to the biopsy.

6.61 By the end of 1977 the medical community had concluded that Hepatitis A was not transmitted by a parenteral route.

1978

6.62 In 1978 Rosemary Biggs, the Director of the Oxford Haemophilia Centre, published the 2nd edition of The Treatment of Haemophilia A and B and von Willebrand’s Disease. One of the four complications that was said to arise from treatment with plasma fractions was the transmission of an infective organism, in particular hepatitis, to the patient (pages 181–2). It was suggested that mildly affected patients who had never or rarely been transfused should not receive large pool commercial concentrates. They should be given Cryoprecipitate or small pool concentrates. There was no mention of DDAVP. However Biggs concluded that treatment should not be withheld from severely affected patients because of the danger of hepatitis since ‘the danger of death from haemorrhage and crippling’ was of ‘more immediate importance’ (pages 186–7). There was no mention of NANB Hepatitis in the book.

6.63 In 1978, an information leaflet provided with Koate, a Factor VIII product produced by Cutter Biological, contained the warning that the presence of the 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.[84]

6.64 In 1978, Alter et al, summarising data concerning PTH from a number of countries, first demonstrated that NANB PTH accounted for 63%–93% of all cases.[85] But with no diagnostic viral blood markers, NANB Hepatitis remained a diagnosis of exclusion.

6.65 In 1978 a significant association between the ALT levels of a donor and the likelihood of subsequent recipient hepatitis was reported.[86]

6.66 The Lancet published an article by Alter et al, ‘Transmissible agent in NANB Hepatitis’ on 4 March 1978. In the study reported, chimpanzees were inoculated with serum from patients with NANB PTH. The study showed that there was a transmissible agent in the serum. This strongly suggested that the agent remained infectious for long periods.

6.67 In May 1978, Biggs & Spooner published a report prepared on behalf of the Haemophilia Reference Centre Directors, ‘National Survey of Haemophilia and Christmas Disease Patients in the United Kingdom’.[87]

6.68 On 22 June 1978, Spero et al published ‘Asymptomatic Structural Liver Disease in Hemophilia’.[88] The study considered liver biopsies from 14 haemophilia patients who had received many transfusions. The patients had no symptoms of liver disease other than raised ALT. It concluded that a large number of asymptomatic haemophilia patients who had received numerous transfusions must have histologic liver disease. The paper also suggested that a major effort was necessary to develop rapidly a ‘clean’ product for the next generation of haemophilia patients.

6.69 In August 1978, Mannucci et al published ‘A clinicopathological study of liver disease in haemophiliacs’.[89] In this study, 11 haemophilia patients who had three years of raised liver function enzymes had liver biopsies taken. The results showed that half of the patients had chronic active hepatitis. The results could not be easily predicted by liver function tests. The results were similar to the Lesesne study in 1977. The pathological features of chronic active hepatitis ranged from minimal to cirrhosis. It was suggested that the general incidence of significant liver disease was too small to justify withdrawal or limitation of factor therapy given the likely deterioration in the pattern of life of persons with haemophilia and the uncertainty of the natural history of chronic active hepatitis. A benign history could not be ruled out. It concluded that biopsy was advisable in patients who had persistent liver function test abnormalities.

6.70 On 20 August 1978, the Haemophilia Centre Directors’ Hepatitis Working Party, chaired by Dr Craske, produced a report which discussed a pilot project to investigate the incidence of chronic liver disease in patients treated with Hemofil in 1974–75.[90] It expressed doubts about screening tests for HBsAg. It also referred to a visit by Dr Craske to the Department of Medicine at the University of North Carolina. A study had been carried out of a group of patients who had been treated for a number of years with Factor VIII concentrates of different brands. One hundred liver biopsies had been carried out on the patients with chronically elevated serum transaminases and nearly 50% had histological changes compatible with cirrhosis, chronic active or chronic persistent hepatitis.

6.71 On 16 September 1978, Preston et al (Sheffield) published ‘Percutaneous liver biopsy and chronic liver disease in haemophiliacs’.[91] Their study involved the first use of liver biopsy in the UK to be reported. Forty seven persons with haemophilia were screened and 77% were found to have abnormal liver function test results. Biopsy was carried out on eight patients who were symptom free. A wide spectrum of chronic liver disease was found including chronic aggressive hepatitis and cirrhosis. It was not possible to differentiate between the different liver diseases on the basis of biochemical abnormalities (liver function tests). Three of the patients were likely to have been infected with NANB Hepatitis. The study concluded that a histological liver disease was common in haemophilia patients. It was noted that two of the haemophilia patients with cirrhosis had mild haemophilia and required only occasional Factor VIII transfusion. Citing Mannucci’s paper on DDVAP it was suggested that such patients might benefit from DDVAP.

6.72 On 11 November 1978, Craske et al published ‘Evidence for existence of at least two types of factor VIII associated non-B transfusion hepatitis’.[92]

6.73 At this stage, eminent researchers continued to develop hypotheses to explain NANB Hepatitis which were later disproved. In October 1978, Shirachi et al published: ‘Hepatitis “C” antigen in non-A, non-B post-transfusion hepatitis’.[93] They claimed to have found evidence for a new hepatitis-specific antigen in sera obtained from patients with NANB PTH. They proposed the designation ‘hepatitis C (HC) antigen’. It was a false trail.

6.74 The papers by Lesesne, Spero, Mannucci and Preston added significantly to the debate about concentrates and hepatitis. All of these papers were based on the results of liver biopsies which was new evidence. The natural history of chronic active hepatitis was still not known. However, by the end of 1978 a consensus had emerged that:

• most haemophilia patients had some liver inflammation and damage to the liver;

• there was no obvious relationship between blood tests and liver biopsy appearance;

• most patients with NANB Hepatitis had no symptoms;

• pharmacological companies acknowledged the likelihood of infection;

• the illness could be benign and, as there had been no apparent deaths from this liver disease, it was reasonable to carry on with concentrates given the immense enhancement of quality of life which they brought; and

• the appropriate response was to try harder to eliminate the viral risk in the course of processing concentrates. There was also the beginning of a suggestion that it would be prudent to use DDVAP for mild haemophilia patients, to reduce or eliminate the need to use factor concentrates in their case.

1979

6.75 In 1979, Iwarson et al reported two cases in which there was a well documented progression to serious liver disease, ‘Progression of hepatitis non-A, non-B to chronic active hepatitis’.[94]

6.76 The Haemophilia Centre Directors’ Hepatitis Working Party report for 1979 set out the results of surveillance for 1978 and 1979. It suggested that most of those with severe haemophilia were immune to Hepatitis B, but that cases of Hepatitis B infection were still being regularly reported. The vast majority of these were acute and self-limiting.[95]

6.77 On 8 January 1979, X, of the School of Pathology, Middlesex Hospital, wrote to the DHSS advising that the stimulus for reconvening the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen was to ‘upgrade’ the ‘viral safety’ of UK Factor VIII concentrates.[96]

6.78 On 7 February 1979, a letter was sent out by the MRC inviting individuals to an ad hoc meeting to be held on 12 February 1979 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.[97] 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. The letter also said that the Chief Scientist of the DHSS had advised the MRC that NANB Hepatitis was being given a ‘high priority’ by the DHSS. On 12 February 1979, the MRC hosted the ad hoc meeting on NANB Hepatitis.[98]

6.79 On 10 March, Wyke et al (including Zuckerman) published ‘Transmission of NANBH to chimpanzees by factor IX concentrates after fatal complications in patients with chronic liver disease’.[99] The chimpanzees were infused with batches of Factor IX (from commercial and non-commercial sources) which were associated with NANB Hepatitis. All had developed hepatitis. It was suggested that, until there was a screening test for the NANB Hepatitis agent, concentrates should be restricted to life-threatening situations. Throughout this period a debate was taking place in the medical community. On one side the view was held (mainly by virologists and public health doctors) that haemophilia patients should not be given concentrates because it was not known what viruses were being transmitted to them. The contrary view (mainly held by the Haemophilia Society and haemophilia doctors) was that concentrates should continue to be given because they transformed the lives of haemophilia patients and hepatitis appeared to be a relatively benign condition.

6.80 On 5 May 1979, Galbraith et al (including Dienstag) published ‘NANB Hepatitis associated with chronic liver disease in a haemodialysis unit’ in The Lancet.[100] This was a retrospective study based on examination of serum samples. The study concluded by saying that more and more data pointed to NANB Hepatitis agents being the cause of a substantial proportion of cases of PTH.

6.81 At this stage, post-transfusion NANB Hepatitis was thought to be rare whereas NANB Hepatitis was very common in people with haemophilia.

6.82 In July 1979, Berman et al (including Alter), published ‘The chronic sequelae of NANBH’.[101] This reported the results of a study of NANB Hepatitis in patients followed prospectively after open-heart surgery. The results showed that chronic active hepatitis was a common sequel of acute NANB Hepatitis, but that it might have a better prognosis than chronic active hepatitis from other causes. Chronic active hepatitis meant that there was on-going inflammation and damage in the liver which had been occurring for a period of time. There was no suggestion that this would inevitably lead to cirrhosis.

6.83 At the 7th International Congress of Thrombosis and Haematology, in mid-July 1979, Foster, Paterson, A J Johnson & Middleton gave a presentation on polyethylene glycol (PEG) precipitation for the removal of Hepatitis B surface antigen from a concentrate of Factors II, IX and X of intermediate purity. Various fractions were assessed for potentially thrombogenic materials, and the results were reported. The topic was written up fully in Thrombosis Research.[102]

6.84 On 24 July 1979, X sent a memorandum to Y submitting a paper proposing the setting up of an advisory group on viral hepatitis.[103] The paper supported the proposal under reference to risks to staff, and patients, and hazards associated with the use of contaminated apparatus and contaminated blood and blood products.[104]

6.85 On 11 August 1979, an article entitled ‘The price of factor VIII’ by John Watt was published in The Lancet.[105] This article considered in detail the cost of producing factor concentrates. It stated that the facilities for fractionation were adequate if the raw materials were available. PFC depended on supplies of plasma from RTCs that were adequate in quantity and of acceptable quality.

6.86 In September 1979, Ware, Luby, Hollinger and others published a paper entitled ‘Etiology of Liver Disease in Renal transplant patients’.[106] This was a study of liver disease in 162 renal transplant patients. They concluded that it was likely that infection with the NANB Hepatitis virus accounted for much of the ‘serious, often fatal complication of renal transplantation.’

1980

6.87 On 2 February 1980, Follett et al from Glasgow, published ‘Viral Hepatitis markers in blood donors with a history of jaundice’.[107] Selected blood donors, antenatal patients and hospital patients with a history of jaundice were investigated for evidence of prior exposure to HAV and HBV. This report concluded that a history of jaundice was more likely to be attributed to Hepatitis A as opposed to Hepatitis B infection. Therefore, there was no reason to treat donors with a history of jaundice as a special group who were more likely than the general population to transmit Hepatitis B infection.

6.88 On 14 February 1980, the Blood Transfusion Research Committee of the MRC Working Party on PTH had its first meeting. There was a discussion of inactivation of hepatitis viruses in blood derivatives.[108]

6.89 Bamber et al reported on the ‘Clinical and Histological Features of a Group of Patients with Sporadic non-A, non-B Hepatitis’.[109] Their findings had previously been disclosed to the Post-Transfusion Hepatitis Working Party on 14 February 1980. Their conclusions were that, while there was on-going liver inflammation in some of the patients, their condition had not deteriorated and the long term prognosis was unclear.

6.90 On 5 March 1980, a patent application concerning the pasteurisation of Factor VIII was filed by Bayer (Cutter Laboratories), based on discoveries made in their research laboratory during 1978/1979. The final version of the patent was published on 3 April 1984 and the product (Koate HS) was later approved for clinical use by the USA Food and Drug Administration (FDA).[110] This is explored in more detail in Chapter 11.

6.91 On 15 March 1980, The Lancet published a letter by Hopkins et al from Edinburgh, ‘Blood donors with history of jaundice’ adding to the findings of Follett et al from Glasgow. While acknowledging the different incidence recorded in other reports, it was stated that tests on patients in the South East of Scotland suggested that a history of jaundice was not associated with an increased risk of HBsAg carriage, but that viruses of NANB Hepatitis ‘may be a significant cause of jaundice in this population’.[111]

6.92 On 30 April 1980, the Council of Europe, Council of Ministers, made a number of recommendations including No R(80) ‘concerning blood products for the treatment of haemophiliacs’.[112] The recommendations stated that member states should pursue the goal of self-sufficiency in anti-haemophilia products and in blood plasma for their preparation. The recommendations acknowledged the fact that both the geographical origin and type of donor population had a significant effect on the risks of infectious diseases, although they did not specifically mention NANB Hepatitis.

6.93 In 1980 Peter Jones, Director of the Newcastle Haemophilia Reference Centre, Royal Victoria Infirmary, published Haemophilia Home Therapy. The purpose of the book appears to have been to promote safe home treatment of haemophilia patients.

6.94 In 1980, the third annual report of a three year study (project no J/S240/78/7) was produced by the Oxford Haemophilia Centre on behalf of the UK Haemophilia Centre Directors.[113] The report covered a series of cases of Factor VIII and IX related hepatitis in the UK which had been reported to the Oxford Haemophilia Centre. It also referred to two proposed publications.

6.95 On 23 August 1980, a letter by Dr Cash, ‘Factor VIII supply and demand’, was published in the BMJ. He stressed that, in order to maintain self-sufficiency, it was important to secure the availability of plasma.[114]

6.96 On 1 September 1980, a three year research project commenced, under Dr Follett, Regional Virus Laboratory, Ruchill Hospital, Glasgow and Dr Dow, Glasgow and West of Scotland BTS, Law Hospital into ‘Non-A, non-B hepatitis in the West of Scotland’. As discussed in Chapter 7, the final report on the project was produced in July 1984.[115]

6.97 On 15 September 1980, a memorandum was produced by X of MED SM4, Room 919 HAN H, Blood Products Laboratory, Elstree, England (BPL), on the proposed take over of BPL by Beechams. The possibility of privatisation provoked an assessment of risks. In particular, the fact that Beechams intended to import plasma was thought to be likely to cause infection of domestic plasma if it was not fractionated in separate premises. In the end this proposal was not carried into effect.[116]

6.98 On 17 September 1980, the reconvened Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody held its fifth meeting. X discussed the main findings contained in an extract of the paper which he had prepared for the MRC Research Committee. X reported that there were thought to be two distinct NANB Hepatitis viruses. Infection with these agents was a major problem in all countries and the MRC were involved in extensive research on the subject. NANB Hepatitis was not sexually transmitted. There was a 20 - 30% incidence of NANB Hepatitis infection in adults. The question of the development of the RIA test was discussed. There was a defence of the role of BPL in the production of reagents for RIA testing. There was strong opposition to the idea that medical considerations were being disregarded in favour of what ‘seemed’ to be ‘political ones’. There was strong disapproval voiced about BPL being prevented from developing the RIA test.[117]

6.99 On 30 September 1980, the UK Haemophilia Centre Directors met in Glasgow. A report was produced on work at Sheffield and the Royal Free Hospital involving liver biopsy studies of hepatitis. Data was provided on the incidence of HBV infection and NANB Hepatitis for various products from 1974–79; for Factor VIII associated Hepatitis in 1977 generally, and trends in haemophilia patients 1977–79. It was reported that Ministers had approved capital expenditure of £1million to improve BPL. At the same meeting there was extensive discussion of demand for blood products.[118]

6.100 On 1 and 2 October 1980, an International Symposium was held at the Royal College of Physicians, Glasgow, on ‘Unsolved Problems in Haemophilia’. It was decided to set up a ‘Hepatitis Advisory Group’ to meet in October 1980 for the first time. The need arose from the diverse problems associated with NANB Hepatitis. Dr Craske stated at the Glasgow symposium in October 1980, and in his paper ‘The epidemiology of Factor VIII and IX associated hepatitis in the UK’, that the acute illness of NANB Hepatitis was ‘clinically mild’ and clinically ‘indistinguishable from hepatitis A and B’. The paper also stated that it seemed likely that some patients with haemophilia who were on regular Factor VIII therapy would develop severe chronic liver disease over the next 10 years. The paper concluded by stating that there was a high risk that patients would contract NANB Hepatitis from the use of Factor VIII and IX concentrates and a 20-30% chance of resultant chronic hepatitis. Until tests were available the use of small pool concentrates or a wider use of Cryoprecipitate should be considered for patients with mild coagulation defects.[119]

6.101 In November 1980, Dr Craske, in a report to the Department of Health, ‘Studies of the epidemiology and chronic sequelae of Factor VIII and IX associated hepatitis in the United Kingdom at 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.[120]

6.102 In December 1980, the continuation of the ‘Studies of the Epidemiology and Chronic Sequelae of Factor VIII and IX Associated Hepatitis in the United Kingdom’
(project J/S240/78/7) was supported within the DHSS.[121]

6.103 In November 1980, Dr Gerard Vaughan, Minister of State at the DOH, announced that £21million had been allocated to the building of a new fractionation facility at BPL. It was envisaged that this would result in increased production and lead the UK to self-sufficiency in blood products.[122]

6.104 On 16 December 1980, Koretz et al published the results of research on ‘The Long Term Course of NANBH post-transfusion hepatitis’.[123] Patients who had contracted NANB Hepatitis had been followed from 1972 for up to five years. At the time this was the longest defined follow-up then available. Liver biopsy had revealed persistent and chronic active hepatitis in a small number of the patients, but most had remained asymptomatic. The conclusion was that NANB PTH often resulted in chronic biochemical liver disease. However, if the disease progressed to liver failure, it did 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.

6.105 In 1980, Heimburger et al published a paper entitled ‘Factor VIII concentrate – now free from hepatitis risk: progress in the treatment of haemophilia’.[124] This was a study by a group of employees of Behringwerke in Germany. 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 6–12 months and there had been no evidence of hepatitis infection. This was the first heat-treated concentrate produced.

6.106 Published SNBTS research at this time dealt with developments in processing of concentrates. Publications included:

• Foster et al, ‘Intermediate purity factor VIII concentrate: changes in antigen and coagulant activity during production’ which discussed ways of improving the yield of Factor VIII concentrates;[125]

• Foster et al, ‘Thrombogenicity of factor IX concentrates and polyethylene glycol processing’ which described PFC processing;[126] and

• Prowse et al, ‘Changes in factor VIII complex activities during the production of a clinical intermediate purity factor VIII concentrate’, which dealt with the loss of Factor VIIIC in processing.[127]

6.107 In 1980, the risk of NANB Hepatitis transmission influenced Scottish researchers in their efforts to produce safe Factor VIII and IX products through process modification and development.

6.108 In the second half of 1980, the design and construction of the second unit at PFC was completed.

1981

6.109 By the start of 1981, the Advisory Committee on Dangerous Pathogens had been established.[128]

6.110 In 1981, the 6th edition of Diseases of the Liver and Biliary System by Professor Sheila Sherlock was published. It explained that NANB Hepatitis was largely spread by blood and, citing the papers by Dienstag and Ware, that it accounted for about 75% of PTH. Haemophilia patients receiving factor concentrates obtained from commercial sources were said to be particularly at risk.[129] It also noted that the NANB Hepatitis agent had not been ‘conclusively identified’ and its identity remained uncertain. In terms of the clinical course of the disease, it indicated that a ‘mild, chronic hepatitis’ develops in about a quarter of patients but this usually improved with time although cirrhosis could develop.[130] Professor Sherlock said that the basic liver pathology of virus A, B and NANB Hepatitis was virtually identical.[131]

6.111 Professor Sherlock’s comments on the clinical courses of the three types included the following:

In general, type A, type B and non-A, non-B hepatitis run the same clinical course. Type B tends to be more severe and may be associated with a serum-like syndrome….[132]

6.112 With the exception of the rare cases of fatal, fulminant, hepatitis, Professor Sherlock described the outcome of infection in adult patients as ‘uninterrupted recovery’, or ‘complete clinical recovery’, depending on the type of hepatitis involved. She identified Hepatitis B as the commonest cause of fulminant viral hepatitis.

6.113 In relation to Hepatitis B, she wrote:

The high carriage rate of serum HBsAg and anti-HBs in those who give no history of an acute attack of hepatitis suggests that subclinical episodes must be extremely frequent.

6.114 Her comments on NANB Hepatitis were:

The elimination of hepatitis A and hepatitis B from transfused blood did not eliminate post-transfusion hepatitis. Some of the cases were due to cytomegala infection, but the majority were due to another virus or viruses termed non-A, non-B. This infection now accounts for about 75% of post-transfusion hepatitis and possibly 15–20% of sporadic hepatitis, depending on the geographic location….[133]

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

6.115 In 1981, a study from the University of Gothenburg, Sweden, was reported by Norkrans and others.[134] This was a retrospective study of clinical cases of hepatitis in patients with bleeding disorders. It concluded that NANB Hepatitis was almost five times as common as Hepatitis B in these cases. It also concluded that Factor VIII preparations obtained from large plasma pools carried a high risk of transmitting NANB Hepatitis. The NANB Hepatitis attack rate with concentrates from large plasma pools (2000 donors) was 40%. The attack rate with concentrates from small plasma pools (100–250 donors) was 8%.

6.116 In March 1981, Dr Cash prepared a brief report for discussion by SNBTS Directors entitled ‘Hepatitis and the Transfusion Service’.[135] He anticipated the publication of the ‘Jenkins Report’. He proposed that the West of Scotland Centre should be nominated as the Haemophilia 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. Dr 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 HBs-Ag carriers.

6.117 On 2 April 1981, a paper was submitted for publication by Bamber et al ‘Short incubation NANB transmitted by Factor VIII concentrates in patients with congenital coagulation disorders’.[136] This paper was produced by the leading UK liver unit at the Royal Free Hospital in conjunction with the Royal Free Hospital Haemophilia Unit. 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. The paper concluded that the failure of these patients to recover within the period of study (6–45 months) suggested that NANB Hepatitis was an important cause of liver disease in patients with coagulation disorders.

6.118 On 23 April 1981, Aach et al published ‘Serum Alanine Aminotransferase of Donors in Relation to the Risk of Non-A, Non-B Hepatitis in Recipients: The Transfusion-Transmitted Viruses Study’.[137] To evaluate the incidence of PTH and factors influencing its occurrence, 1513 transfusion recipients in a USA donor population had been studied from 1974–1979. The attack rate for PTH was 10%. The incidence of hepatitis was related to the ALT levels of the blood donors. In lower ALT levels the attack rate was 6% or less. At higher levels the attack rate rose to 45%. The authors expressed the opinion that screening blood for ALT levels would reduce the incidence of NANB PTH and concluded that ‘the high correlation between an elevated ALT level and infectivity of transfused blood products provides a compelling argument that such screening should be instituted’.

6.119 In the same edition of the New England Journal of Medicine Holland et al (from the Clinical Centre Blood Bank, National Institute of Health) argued against the immediate introduction of ALT testing until the effects had been ‘thoroughly considered’.[138] Together, these papers were influential in laying the ground for a subsequent lengthy discussion as regards surrogate testing of blood donors.[139]

6.120 In 1981, a study was produced by Stirling et al (Biochemistry Department of Edinburgh Royal Infirmary) entitled ‘Liver function in Edinburgh haemophiliacs: a five-year follow up’.[140] In this study, liver function was assessed in 38 Edinburgh haemophilia patients. Results before the introduction of NHS intermediate Factor VIII concentrate from 1974 onwards were compared with values in 1979. Deterioration over the five year follow-up period was seen only in patients on home treatment using large amounts of Factor VIII concentrate. The report concluded that ‘The nature and permanence of liver damage in these patients remains obscure’.

6.121 The SNBTS Directors met on 23 June 1981.[141] Dr Cash presented his paper recommending the establishment of an SNBTS quality assurance (hepatitis) reference centre and advisory group. Dr McClelland reported that he had prepared a protocol for presentation to the MRC on 25 June for a two-centre study, at South East Scotland and Manchester, on the transmission of NANB Hepatitis by transfusion. The directors agreed that similar studies might be made in Scotland.

6.122 On 4 July 1981, an editorial in the BMJ set out the risk to haemophilia patients in clear terms.[142] Despite advances in screening donors and in blood fractionation, PTH remained the major complication of the modern treatment of haemophilia. It noted that early death from liver disease might prove to be the price paid by haemophilia patients for the improved quality of life afforded by concentrates. It noted that considerable thought was being given to reducing the risks by focusing on: (i) collection of plasma from volunteer as opposed to paid donors; (ii) the optimum size of the plasma pool; and (iii) attempts at removing hepatitis viruses from blood products. It also provided evidence of a material change in risk when a hospital changed from commercial to volunteer blood. It concluded by predicting that hepatitis-free blood products would become available and referring to recent reports dealing with heat-inactivation.

6.123 On 11 July 1981, an editorial in The Lancet, ‘Screening of Blood Donors for Non-A Non-B Hepatitis’ stated that, when NANB Hepatitis was first recognised, many members of the British medical profession seemed to regard it as a purely American problem but that, lately, it had been accepted in the UK that NANB Hepatitis was a serious hazard of treatment with Factor VIII and Factor IX concentrates, prepared from very large pools of donor plasma.[143] It also indicated that, while no-one in the UK had paid much attention to NANB Hepatitis following transfusion of blood or platelets, more had been done in the USA in that regard. However, the results of screening tests in the USA, though encouraging, needed to be looked at very carefully before any decision was made to introduce ALT testing as part of routine screening elsewhere.

6.124 In July 1981, the DHSS Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody distributed its third report.[144] It stated that NANB Hepatitis viruses were a common cause of PTH in the USA and were thought to have been responsible for cases of PTH in the UK. Hepatitis due to these viruses was common among persons with haemophilia and followed the administration of imported, and occasionally British, concentrates. The report recommended that research should be undertaken in the UK to determine the extent and severity of PTH due to NANB Hepatitis viruses. Regional transfusion directors should encourage hospital haematologists to report all cases of post-transfusion jaundice and where these could be due to NANB Hepatitis, the facts should be reported to the appropriate person at the DHSS or SHHD.

6.125 At this stage, the difficulty in assessing the frequency of PTH was that there was no marker to show who had contracted it and most cases were asymptomatic.

6.126 The SNBTS Directors met on 22 September 1981.[145] The third DHSS report was discussed. It was seen as providing guidelines on the best procedures to be adopted, within the finance available. Dr Cash asked the SNBTS Directors to consider if SNBTS quality control was ‘satisfactory’. It was noted that none of the groups at NBTS was looking at hepatitis testing. It was agreed that Dr Cash should write to Dr Wagstaff with a proposal that a Post Transfusion Hepatitis Working Group be established.

6.127 On 24 September 1981, the Hepatitis Working Party of the UKHCDO issued its report, written by Dr Craske (Manchester, Public Health Laboratory) for 1980–1981, the third and final year of a retrospective study financed by the DHSS.[146] There had been a total of 283 episodes of hepatitis in 253 patients. Of these, 197 were thought to be episodes of NANB Hepatitis. The incidence of NANB Hepatitis infection associated with USA commercial concentrates was 4–20 times higher than that associated with the NHS product. The episodes of acute hepatitis were described as mild. The question of the significance of chronic hepatitis was described as ‘still unanswered’. The natural history of the disease was still unknown. Further hepatitis surveillance and research into the NANB Hepatitis viruses was recommended. This report was very significant because it implied that, by 1981, the vast majority of severe and moderately severe haemophilia patients already had NANB Hepatitis.

6.128 The SNBTS Directors met on 8 December 1981.[147] The recent meeting of the Working Group of Scottish Haemophilia and Transfusion Directors was discussed. There had been a successful clinical trial in West Scotland of freeze-dried Cryoprecipitate. Dr Cash would seek the views of the Medicines Inspectorate about developing freeze-dried Cryoprecipitate as a ‘product’. There was discussion of the current target of 2.75million i.u. Factor VIII/million population per annum. The BTS in England and Wales had adopted a target of 2million. It was decided to retain the Scottish target. A document was tabled showing the known purchases of commercial blood products for NHS use.

Knowledge of NANB Hepatitis in 1981

6.129 In the 6th edition of Diseases of the Liver and Biliary System, published in 1981, Professor Sherlock described the current knowledge of NANB Hepatitis in 1980, as summarised above. By the end of 1981 there had been further advances. But, 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:

• Some studies, including Lesesne’s, the first to be based on liver biopsy data, suggested that at least a proportion of persons with haemophilia infected by NANB Hepatitis virus(es) might go on to develop significant chronic liver disease.

• Other members of the medical profession, including haemophilia clinicians, recognised that a substantial proportion of haemophilia patients developed prolonged, mild elevation of serum transaminases, but relied on the evidence that morbidity and mortality from chronic liver disease in persons with haemophilia were very low in concluding that the prognosis of mild chronic hepatitis was, at that stage, uncertain but probably benign. Serious chronic liver disease and its complications were rare among haemophilia patients.

6.130 These differences reflected the fact that, by 1981, there was still very little evidence of the natural history of NANB Hepatitis - whether arising post-transfusion, or among persons with haemophilia.

6.131 The incidence of NANB PTH varied substantially according to the population of blood donors used, adding to the complexity of the issues. However, positive developments included:

• The beginning of discussion of ways of reducing PTH by using possible surrogate markers to identify blood carrying a high risk of transmitting NANB Hepatitis virus(es).

• The first attempts at viral inactivation of 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.

• Recognition that there was a problem, ie that the vast majority of severe and moderately severe haemophilia patients receiving replacement therapy already had been exposed to NANB Hepatitis virus(es) and that many had chronic, although probably usually mild and asymptomatic, liver disease.

[1] Beeson PB, Jaundice occurring one to four months after transfusion of blood or plasma, JAMA, 1943 121:1332

[2] Whittaker, JA., Brown, MJ. ‘Serum hepatitis in a haemophiliac’, British Medical Journal, 1969; 3: 597 [LIT.001.0248]

[3] Del Duca & Eppes New England Journal of Medicine, 1966; 275: 965

[4] W.d’A Maycock et al, Further Experience with a Concentrate Containing Human Antihaemophilic Factor, Brit J. Haem, 1963: 9: 215 [LIT.001.0063]

[5] Col 195, No 1166 (August 1965) pp 184 – 5

[6] Biggs, ‘Jaundice and antibodies directed against factors VIII and IX in patients treated for haemophilia or Christmas disease in the United Kingdom’, Br J Haematol, 1974; 26: 313 – 329 [LIT.001.0099]

[7] Buchholz, ‘Blood Transfusion: Merits of Component Therapy’, The Journal of Paediatrics, February 1974; 84(2): 165 [LIT.001.0141]

[8] A powerful statement of the balancing of interests and the need to continue use of concentrates was set out in a letter by Kasper and Kipnis: ‘Hepatitis and clotting - factor concentrates’, JAMA, 1972; 221(5): 510 [LIT.001.0098]

[10]See footnote 6 for full reference [LIT.001.0099]

[11] The report also covered the development of inhibitors of Factor VIII: jaundice was one of two disturbing factors

[12] Zuckerman, AJ. and Thomas HC. (eds) (1993) Viral Hepatitis: Scientific Basis and Clinical Management page 470

[13] Blumberg, et al ‘A serum antigen (Australia antigen) in down’s syndrome, leukaemia and hepatitis’, Ann. Intern. Med, 1967; 66: 924 – 931

[14] Sherlock, S. (1975) Diseases of the Liver and Biliary System, 5th edition, Blackwell, Oxford, page 311

[15]Viral Hepatitis: Scientific Basis and Clinical Management page 470

[16]Viral Hepatitis: Scientific Basis and Clinical Management page 473

[17] [DHF.003.0037] This report was published in 1981.

[18] ‘Revised Report of the Advisory Group on Testing for the Presence of Australia (Hepatitis-Associated) Antigen and its Antibody‘: 1972 DHSS This was in fact the first report. [DHF.001.1980]

[19]See footnote 6 for full reference [LIT.001.0099]

[20] Garrott Allen, J. (1972) The Epidemiology of Post transfusion Hepatitis, Stanford, page 16

[21] Feinstone et al, ‘Hepatitis A; detection by immune electron microscopy of a virus like antigen associated with acute illness’, Science, 1973; 182: 1026

[22] Cf, in America: Alter and others, ‘Post transfusion hepatitis after exclusion of commercial and hepatitis-B antigen-positive donors’ Ann Intern Med 1972; 77(5): 691 - 699; Hollinger and others, ’Limitations of solid-state radioimmunoassay for HB Ag in reducing frequency of post-transfusion hepatitis’ N Eng J Med 1973; 289(8): 385 - 391

[23]J. Hyg., Camb., ‘Post transfusion hepatitis in a London hospital: results of a two-year prospective study’, 1974, 73: 173 - 188 [LIT.001.0116]

[24]See footnote 23 for full reference [LIT.001.0116]

[25]Viral Hepatitis: Scientific Basis and Clinical Management page 472, table 29.2. It is possible that the MRC approach was influenced by the views held by Professor Zuckerman at the time. The textbook expresses the widespread surprise that, following the identification of HAV by Feinstone et al, analysis of stored sera from certain US studies showed that none of the cases of PTH could be attributed to HAV.

[26]See footnote 7 for full reference [LIT.001.0141]

[27] See footnote 6 for full reference [LIT.001.0099]

[28]Viral Hepatitis: Scientific Basis and Clinical Management page 470. See also Craske et al , ‘the outbreak of hepatitis associated with intravenous injection of Factor VIII concentrate’ The Lancet, 1975; 2:221-233 [LIT.001.0360]

[29] Later editions remained authoritative and Professor Sherlock was the sole author until and including the 8th Edition (1989)

[30] Sherlock: Diseases of the Liver and Biliary System , 5th edition, page 250

[31] Sherlock Diseases of the Liver and Biliary System , 5th edition, page 306

[32] Sherlock: Diseases of the Liver & Biliary System, 5th ed p 321-2

[33] Sherlock: Diseases of the Liver & Biliary System, 5th ed p 333

[34] Sherlock: Diseases of the Liver & Biliary System, 5th ed p 390

[35] Prince et al, ‘Long incubation post transfusion hepatitis without serological evidence of exposure to Hepatitis-B virus’, The Lancet 1974; 2: 241-6 [LIT.001.0363]

[36] See footnote 21 for full reference

[37] Though published first, Feinstone’s work is said to have been later in date: Viral Hepatitis: Scientific Basis and Clinical Management. But this must be questioned in view of the citation in the Prince paper of one paper read at the 6th symposium of the American Red Cross in May 1974

[38] Prince, Gastroenterology 1971; 60, 913

[39] Alter H J., Purcell R H., Holland P V., Feinstone S M., Morrow A G. and Moritsugu Y. ‘Clinical and serological analysis of transfusion-associated hepatitis’, The Lancet 1975; 2: 838 - 841

[40] Second Report of the Advisory Group on Testing for the Presence of Hepatitis C Surface Antigen and its Antibody: 1975 DHSS [SGH.003.0079]

[41] See footnote 39 for full reference

[42] By December 1989, CMV and EBV were also excluded as causal agents: [SNF.001.1180]

[43] Identified by Chiron Corporation in spring 1988 and announced on 10 May 1988: A v National Blood Authority (No. 1) 2001 3 All ER 289 at para 8

[44] A letter to The Lancet of 16 November 1974 by Fiala and others of California, and two Abbott workers, Overby and Ling, in response to Prince, suggested that more work was required on the possible role of cytomegalovirus in hepatitis

[45] Prince, Gastroenterology, 1971; 60: 913 cited in The Lancet article of 1974 [LIT.001.0363]

[46] In 1974, Peter Jones, a haemophilia specialist published Living with Haemophilia (Lancaster: Medical and Technical Publishing Co. Ltd). This was written as an introductory guide to haemophilia for haemophilia patients and their families, and reflected the views of contemporary haemophilia groups

[47] Spencely & Cash, ‘Factor VIII replacement in the treatment of haemophilia A – a simple illustration of a need-supply-demand spiral’ British Journal of Preventative Medicine, 1974; 28:71 [LIT.001.0149]

[48] Koff, RS (1978) Viral Hepatitis, Wiley, page 37

[51] ‘Transfusion-Associated Hepatitis not due to viral hepatitis Type A or B’: The New England Journal of Medicine, 1975;292:767-770 [LIT.001.0137]

[54] Cf Points of Clarification document in respect of a debate in the Scottish Parliament on 22 December 2005, prepared by an unnamed individual in the SNBTS on 1 February 2006 [SNF.001.2449]. Central contracts for the purchase of commercial Factor VIII were held by the Department of Health from 1972-1979. These were discontinued on 30 April 1979 and individual health authorities were advised to purchase commercial products locally thereafter. Detailed information on the use of commercial products was collected by UKHCDO and is held in its archive

[55] [DHF.001.2292] and [SNB.003.4064] (references to Symposium)

[56]J Clin Path, 1975;28(8):620-4 [LIT.001.0132]

[58]The Lancet, August 2 1975;2:221-223 [LIT.001.0360]

[59]The Lancet, 16 August 1975; 328 - 329 [LIT.001.0358]

[63] ‘The several viruses of post-transfusion hepatitis’ BMJ 1975; 3: 663 [LIT.001.0254]

[65] Koff: Viral Hepatitis, page 41

[66] Purcell R H, ‘Alter H J, Dienstag J L, Non-A, Non-B Hepatitis’, Yale J Biol and Med; 1976; 243 - 250

[69] [SNB.001.5107]. Production of Supernine later stalled

[77]The Lancet, 1977;1:560 -562 [LIT.001.0492]

[79] Mannucci et al, ‘1-Deamino-8-D-Arginine Vasopressin: A new pharmacological approach to the management of haemophilia and von Willebrand’s disease’ The Lancet, 1977; i: 869–72 [LIT.001.0354]

[80]Journal of Thrombosis and Haemostasis, 2003; 1: 2065 - 2069 [LIT.001.1101]

[81]Ann Intern Med. 1977;87(1):57-9 59 [LIT.001.0183]

[82]Br J Haematol, 1977;36:447-449 [LIT.001.0186]

[83]Annals of Internal Medicine 1977; 86:703-707

[84] ‘Examples of warnings issued with coagulation factor concentrates’ at [http://www.scotblood.co.uk/publications.asp]

[85] Alter, HJ, Purcell RH, Feinstone SM, Holland PV, and Morrow AG. In: Vyas, GN, Cohen SN, and Schmid, R (eds), Viral Hepatitis. Philadelphia, The Franklin Institute Press, 1978, pp 359-369

[86] Aach R D, Lander J J, Sherman L A, Miller W V, Kahn R A, Gitnick G L, Hollinger F B, Werch j, Szmusness W, Stevens C E, Kellner A, Weiner J M, and Mosely J W. In Vyas G N, Cohen S N, and Schmid R (eds), Viral Hepatitis, Philadelphia, The Franklin Institute Press, 1978, pp 383-396

[87]The Lancet, 1978; i:1143-1144 [LIT.001.0352]

[88]New England Journal of Medicine, 1978;298:1373-1378 [LIT.001.0177]

[89]Journal of Clinical Pathology, 1978; 31 779-783 [LIT.001.1624]

[91]The Lancet, 1978; ii: 592-594 [LIT.001.0387]

[92]The Lancet, 1978;2:1051-1052 [LIT.001.0392]

[93]The Lancet 21 October 1978: 853 - 856 [LIT.001.0383]

[94]Journal of Clinical Pathology 1979; 32: 351 - 355 [LIT.001.0196]

[99]The Lancet, 1979:520- 524 [LIT.001.0378]

[100]The Lancet, 1979; 951-953 [LIT.001.0395]

[101]Ann Intern Med, 1979;91:1-6 [LIT.001.0189]

[102]Thrombosis Research, 1980; 17; 273 -9

[103] The document supplied by the Department of Health has been redacted to delete all means of identification, including identification of the department(s) involved

[106]Annals of Internal Medicine, 1979; 91: 364 - 371 [LIT.001.1052]

[107]The Lancet, 1980; 246 - 249 [LIT.001.0430]

[109]J Clin Path 1981; 34: 1175 - 1180 [LIT.001.0759]

[111] The Lancet, 1980; 596 [LIT.001.0429]

[114]BMJ, 1980; 565 [LIT.001.0226]

[116] See: [DHF.002.1974], [DHF.002.2521], [DHF.002.2524] and [DHF.003.0794] The author of the last document noted that 90% of all post-transfusion (and blood product infusion) hepatitis in the USA and elsewhere was caused by NANBH viruses, which could not be detected by testing donor blood, and that ‘This form of hepatitis can be rapidly fatal (particularly when acquired by patients with pre-existing liver disease) or can lead to progressive liver damage.’

[122] [DHF.001.0519] [DHF.001.0537] [DHF.003.0931] at page 0959

[123]Gastroenterology 1980; 79:893-898 [LIT.001.0201]

[124]Die gelben Hefte, (the Golden Notebook) 4, 165-174. [SGF.001.1761]

[125]British Journal of Haematology, 1980; 46: 334: and more fully in Thrombosis & Haemostasis 1981

[126]Thrombosis Research, 1980;17:273-279 [LIT.001.0208]

[127]Thrombosis & Haemostasis, 1980; 46: 597-601 [SGF.001.1947]

[129]Sherlock S. (1981) Diseases of the Liver and Biliary System, 6th edition, Blackwell, Oxford, page 257

[130]Ibid

[131]Ibid

[132]Ibid

[133]Ibid

[134] Norkrans et al, ‘Acute Hepatitis Non-A, Non-B following administration of factor VIII concentrates’, Vox Sang, 1981; 41:129-133, [LIT.001.0743]

[136]Gut 1981, 22; 854-859. [LIT.001.0483]

[137]New England Journal of Medicine, 1981; 304: 989-994 [LIT.001.0753]

[138] Holland et al, ‘Post-transfusion Viral Hepatitis and the TTVS’, 1981; 304: 1033 - 1034 [LIT.001.1630]

[139] Alter et al, ‘Donor Transaminase and Recipient Hepatitis’, JAMA, August 7 1981, volume 246, No. 6 - which is a study by the
U.S. National Institute of Health that supports the association found by the TTVS between elevated ALT in donors and NANBH in recipients.

[140]J Clin Pathol 1981; 34: 17-20 - see [LIT.001.0748]

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