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HEPATITIS 1982 TO 1985


Chronically elevated liver function tests in patients with Non-A Non-B Hepatitis (NANB Hepatitis) – patients often asymptomatic – reports of cirrhosis following liver biopsy – nearly all newly-treated haemophilia patients developing NANB Hepatitis, whether treated with NHS or commercial Factor VIII concentrate – debate on the seriousness of liver disease – evaluation of early heat-treated Factor VIII concentrates – reports of transmission of NANB Hepatitis by intravenous immunoglobulin – early discussions on whether to screen blood donors for surrogate markers of NANB Hepatitis (ie ALT and anti-HBc testing).


7.1 As more fully chronicled in Chapter 8, the most pressing issue in the first half of the 1980s was Acquired Immune Deficiency Syndrome (AIDS) and the steps taken to tackle that disease. This chapter sets out the events that had a direct bearing on the developing knowledge of hepatitis between 1982 and 1985.

7.2 In the early 1980s, there was an awareness that many patients with Non-A Non-B Hepatitis (NANB Hepatitis) developed chronically elevated alanine aminotransferase (ALT) levels, indicative of liver inflammation. However, most patients were asymptomatic and the author of the leading textbook at the time considered that the prognosis for those with mild chronic hepatitis was ‘uncertain but probably benign’.[1]

7.3 A number of studies were carried out between 1982 and 1985 in which liver biopsies were taken from patients with NANB Hepatitis. The studies showed that some patients developed cirrhosis.[2] These histological findings suggested that the disease might be more serious than previously thought, despite the fact that few of the patients who developed cirrhosis otherwise suffered symptoms.

7.4 In the early 1980s studies in England showed that most haemophilia patients who routinely received Factor VIII and IX blood products, whether manufactured by the National Health Service (NHS) or by commercial companies, were likely to develop NANB Hepatitis.[3]

7.5 Early heat-treated Factor VIII concentrates were developed but were found to transmit NANB Hepatitis notwithstanding heat treatment.[4]

7.6 During this period there were also reports of NANB Hepatitis being transmitted by immunoglobulin products administered intravenously.[5]

7.7 Throughout most of the 1980s the Hepatitis C Virus (HCV) had still to be identified with the result that there was no direct test for the virus. Instead, consideration was given to testing blood donations for certain indirect, or surrogate, markers in the blood of donors that studies in the United States of America (USA) had indicated might be associated with the development of NANB Hepatitis in recipients.

7.8 In particular, consideration was given to screening donors for elevated ALT and for the presence of antibody to the Hepatitis B core antigen (anti-HBc). It was known that elevated ALT levels were an indication of liver inflammation, possibly as a result of NANB Hepatitis but could also be due to other causes such as excess alcohol intake or obesity. Anti-HBc testing was considered as a screening test following an apparent association, at least in certain USA studies, between the presence of anti-HBc in blood donors and the development of NANB Hepatitis in transfusion recipients.

7.9 As at 1985, the question of whether surrogate testing of blood donors for NANB Hepatitis should be introduced remained unresolved. Surrogate testing was introduced in the USA in 1986/87. It was never introduced in the United Kingdom (UK).


7.10 In 1982, a five year study by Realdi et al (Padua, Italy) on post-transfusion hepatitis was reported.[6] Twenty one patients who developed post-transfusion hepatitis after open-heart surgery were followed up for a period of five years. Histological chronic sequelae were documented in 13 patients, five of whom developed cirrhosis and one of whom died of gastrointestinal bleeding due to cirrhosis of the liver. Progression to these chronic states was, in most cases, symptomless. The authors concluded that their results suggested that cirrhosis might develop, often with an asymptomatic course, in a significant number of patients who did not recover after acute post-transfusion NANB Hepatitis.

7.11 In 1982 an abstract of a paper by Koretz et al (Los Angeles) was published in Hepatology.[7] The authors reported on a prospective study of 66 patients with NANB Hepatitis. Of the patients studied, 21 had liver biopsies demonstrating chronic hepatitis and/or cirrhosis. The authors concluded:

(1) NANB post-transfusion hepatitis commonly results in chronic liver disease (35-53%). (2) Cirrhosis has occurred in at least 6% [i.e. 4 patients] of those developing NANB post-transfusion hepatitis (after 4-9 years of follow up) and exclusively in those with persistently abnormal ALT values. (3) Patients with NANB post-transfusion hepatitis should be followed for many years after the onset of disease if biochemical resolution fails to take place. (4) Cirrhosis develops in a clinically silent fashion and usually only after years of activity.

7.12 In 1982 Dr Gunson, National Blood Transfusion Service (NBTS), applied for a grant to carry out a study in the UK into surrogate testing for NANB Hepatitis. The application was refused.[8]

7.13 On 11 January 1982 the Oxford Haemophilia Centre wrote to all Haemophilia Centre Directors advising that at least four commercial companies were about to introduce preparations of Factor VIII, and possibly Factor IX, that had been processed in an attempt to reduce the risk of transmitting NANB Hepatitis.[9] It was thought that the products had been subjected to a heat treatment process such as pasteurisation but other methods might have been used. The Hepatitis Working Party of the United Kingdom Haemophilia Centre Directors’ Organisation (UKHCDO) was discussing plans for clinical trials of these products.

7.14 Details of the products were not given in the letter. The following table, however, summarises the first generation heat-treated Factor VIII products that were subsequently licensed by the USA Food and Drug Administration (FDA).[10]



Method of Treatment

Date applied for FDA licence

Date licence granted by FDA

Baxter (Hyland/Travenol)

Hemofil T

Dry heat,
60ºC for 72h

June 1982

March 1983


Profilate HT

Wet heat,
60ºC for 20/24h

December 1982

February 1984



Dry heat,
60ºC for 30/36h

December 1982

January 1984

Bayer (Miles/Cutter)

[not known]

Wet heat,
60ºC for 10h

August 1983

January 1984

Bayer (Miles/Cutter)

Koate HT

Dry heat,
68ºC for 72h

November 1983

February 1984

7.15 In a letter published in The Lancet on 6 March 1982, Preston et al (Sheffield) reported on a 34 year old male with von Willebrand’s disease (vWD) who received Factor VIII concentrate to cover a surgical procedure.[11] The patient developed acute Non-B Hepatitis and had consistently abnormal liver function tests in the absence of symptoms. A liver biopsy after 18 months showed a very mild chronic aggressive hepatitis with features of NANB Hepatitis viral infection. After a further two and a half years the patient continued to have abnormal liver function tests and a liver biopsy undertaken at that stage showed very severe architectural disturbance with evolving cirrhosis. Features of NANB Hepatitis infection were still present. The authors concluded that the case showed several important and disturbing features, namely, significant progression of liver disease over two and a half years in the absence of symptoms and as a result of a single infusion.

7.16 On 16 March 1982 the Scottish National Blood Transfusion Service (SNBTS) Directors met.[12] The minutes of this meeting noted that the SNBTS had previously proposed to the NBTS Directors that a UK Working Party be established on the microbial contamination of blood products. The NBTS had responded with a proposal to study post-transfusion hepatitis. The SNBTS Directors agreed to remind the NBTS that their proposal had not been confined to hepatitis. It was noted that the Medical Research Council’s Blood Transfusion Research Committee had decided recently to disband their Hepatitis Working Group because a number of groups in the UK were studying hepatitis.

7.17 The Medicines Inspectorate visited the Edinburgh and South East Scotland Blood Transfusion Service (BTS) Edinburgh on 10 -11 March and 10 -12 May 1982. A discussion on the need for Cryoprecipitate was recorded. It was noted that there was a reduced risk of contracting hepatitis from a small pool donor source and that the risk of contracting hepatitis was substantially increased when a pool exceeded 10 donations. At that time, Edinburgh BTS were using an initial pool of three donors, but that was later pooled with four other pools, ‘making a total of 12 donors involved’.[13]

7.18 On 21 May 1982 the Committee of Experts on Blood Transfusion and Immunohaematology, European Health Committee, Council of Europe held its fifth meeting. A note of the meeting records a discussion on transfusion associated hepatitis.[14] Committee members reported that it was generally recognised that the frequency of transfusion associated hepatitis was higher when using commercial plasma. In order to reduce the risk of such hepatitis, they recommended that national blood transfusion services take steps to ensure that there was an adequate supply of plasma from voluntary, non-remunerated donors in order to achieve national self-sufficiency in the production of coagulation factor concentrates.

7.19 On 25 June 1982 the European Health Committee of the Council of Europe met.[15] Dr Gunson presented a report on the control of post-transfusion hepatitis. Dr Gunson stated that the incidence of NANB Hepatitis in the UK appeared to be low in patients receiving Cryoprecipitate but high following transfusion of Factor VIII concentrates prepared from large pools. He noted 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.

7.20 On 17 July 1982 Rickard et al (Sydney) reported on a study of blood products and hepatitis in Australia.[16] Two hundred and forty three patients with haemophilia were studied over a period of four and a half years. At the time of the study, commercial blood products were not used in Australia. Cryoprecipitate prepared from blood from unpaid voluntary donors was the major treatment and only small amounts of Factor VIII and IX concentrates were used.[17] Despite the use of blood products obtained from entirely voluntary blood donors and the frequent use of single-donor packs of Cryoprecipitate, markers of viral hepatitis were common in the patients in the study. There were 66 cases (27%) of NANB Hepatitis. Antibody to Hepatitis B surface antigen (anti-HBs) was detected in 63% of the patients. The authors concluded that the risk of hepatitis already existed under the voluntary donor system in Australia and there was no longer a valid reason for prohibiting the import of Factor VIII concentrates.

7.21 In September 1982 a follow up study by Mannucci et al (Milan, Italy) on liver disease in 11 haemophilia patients was reported.[18] The authors had previously reported on liver biopsies from these patients taken in 1977. The initial study found that of the 11 patients, four had chronic persistent hepatitis, five had chronic active hepatitis, one had cirrhosis and one had alcoholic hepatitis.[19] By the time of repeat biopsies in 1980, the patient with cirrhosis had died of gastrointestinal bleeding. Of the remaining 10 patients, four continued to have chronic persistent hepatitis, two had developed chronic lobular hepatitis and there was spontaneous improvement of disease activity in three cases. The authors stated:

This study suggests that in hemophiliacs with NANB chronic hepatitis, progressive disease is not the rule … It is remarkable … that only 2 of the entire series of 91 hemophiliacs followed since 1974 have died from cirrhosis and that both were [hepatitis B surface antigen] serum positive.

7.22 The authors concluded,

Study of the serum and intrahepatic markers for hepatitis B and delta viruses suggest that chronic liver disease is non-progressive in hemophiliacs who have no intrahepatic viral markers.

7.23 In September/October 1982 an article by Gerety and Aronson (Office of Biologics, USA FDA) was published.[20] The introduction stated that, ‘Viral hepatitis is one of the most serious adverse reactions following intravenous infusions of plasma derivatives’.

7.24 Following a discussion of the risk of transmission of hepatitis through Factor VIII and IX concentrates Gerety and Aronson noted:

The chronic hepatitis in hemophiliacs shares many characteristics with chronic non-A, non-B hepatitis. It is frequently an asymptomatic acute illness with low mean peak serum aminotransferase activity and, in a high proportion of infected individuals, it progresses to a chronic hepatitis characterized by widely fluctuating serum aminotransferase levels and severe liver disease histologically.

7.25 The authors noted that in the Mannucci study reported in 1978, 63% of the haemophilia patients studied had abnormal liver biopsies and half had chronic active hepatitis or cirrhosis.[21]

7.26 On 13 September 1982 the 13th meeting of the UKHCDO took place.[22] Dr Craske of the Public Health Laboratory Service (PHLS) advised that a preliminary study in Oxford of hepatitis in mildly-affected or seldom-treated patients had provided interesting data and that the results of the study were being prepared for publication.[23] A report of the meeting by a representative from the Haemophilia Society noted that it appeared from the Oxford study that the risk of contracting hepatitis from large pool NHS concentrates was unexpectedly high.[24]

7.27 In a letter published in The Lancet on 2 October 1982,[25] Drs Ludlam and Peutherer (Edinburgh Haemophilia Centre) inferred from the Australian study carried out by Rickard et al[26] that the use of Cryoprecipitate instead of Factor VIII concentrates had no effect on the risk of hepatitis.

7.28 In a response published on 27 November 1982, Drs Gabra, Crawford and Mitchell (SNBTS, Glasgow) disagreed, stating that large pool products carried the greatest risk of exposing patients to the risk of hepatitis.[27] They argued that that was particularly so in the case of persons with mild and moderate haemophilia. The contribution of Cryoprecipitate to risk was small, even when it was the main product used in therapy. That was shown both by the Australian study and by three previous studies from Edinburgh.[28]

7.29 In December 1982 White et al (North Carolina, USA) reported on a study of hepatitis in patients with haemophilia with intermittently abnormal liver function tests.[29] In their introduction, the authors noted that repeated exposure to blood products placed individuals with severe haemophilia at high risk of developing both acute and chronic post-transfusion liver disease. Previous studies had reported on liver biopsies in haemophilia patients with continuously abnormal liver function. This study was a prospective study of liver histology in 15 haemophilia patients with intermittently abnormal liver function tests. None of the patients had symptoms of chronic liver disease. The authors reported that liver biopsies showed chronic persistent hepatitis or other mild forms of liver disease in 14 of the 15 patients. The authors continued:

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.

7.30 It was concluded:

The results show primarily chronic persistent hepatitis and milder forms of liver disease and support the continued use of concentrates in transfusion-requiring hemophiliacs. At the same time, although the results of this study indicate a predominantly benign hepatic histology in patients with intermittent enzyme abnormalities, any form of liver disease is obviously undesirable and continued efforts to prepare hepatitis-free products should remain an issue of high priority.


7.31 In 1983 the 7th edition of the standard textbook on blood transfusion medicine in the UK was published.[30] In a discussion of NANB Hepatitis, it was noted that:

This rather clumsy term is used to describe hepatitis in which both [the hepatitis A virus] and [the hepatitis B virus] have been excluded. The term hepatitis C is not used because there is evidence that there is more than one kind of non-A, non-B virus and because no specific tests have yet been developed … 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.[31]

7.32 The textbook noted the results of the USA based Transfusion Transmitted Viruses Study, reported in 1981,[32] namely, that the incidence of NANB Hepatitis in recipients of blood transfusion was directly related to the level of ALT in the relevant blood donors and commented:

Although [NANB 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.[33]

7.33 It was also noted 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%.[34] Only prospective studies were likely to give a true indication of the frequency of post-transfusion hepatitis. No such study, carried out exclusively with HBsAg negative blood, had been reported. The textbook further noted that, ‘Nevertheless, there is evidence that non-A, non-B viruses play a smaller part in the UK than in the USA’.[35]

7.34 In 1983 opinions from a number of experts were published on whether ALT screening of blood donors should be introduced with a view to reducing the incidence of post-transfusion NANB Hepatitis.[36] Aach (Baltimore, USA) had supported the introduction of surrogate testing when the results of the Transfusion Transmitted Viruses Study were published in 1981[37] and that remained his view. In Germany, ALT testing had been in place for some time and Muller (Hanover, Germany) did not feel that screening should be abandoned. In contrast, Bayer (Kansas, USA), Gerety (Office of Biologics, USA FDA), Holland (Clinical Centre Blood Bank, Bethesda, USA), McClelland (SNBTS, Edinburgh), Mitchell (SNBTS, Glasgow) and Reesink/Reerink-Brongers (Amsterdam, Netherlands) did not support the introduction of surrogate testing for NANB Hepatitis in the absence of further research into the costs and benefits of surrogate testing.[38]

7.35 In 1983 Schimpf (Heidelberg, West Germany) published the results of a study of post-transfusion hepatitis in haemophilia patients.[39] A brief English summary stated that frequent application of Factor VIII and IX concentrates, single-donor Cryoprecipitates and concentrates from large plasma pools led to transmission of Hepatitis B and NANB Serum Hepatitis. Almost all of the patients showed signs of active hepatitis or an immune response to hepatitis viruses. There was an increasing frequency of chronic hepatitis (65%). There was also an increase in liver cirrhosis which manifested itself 13 years earlier than in the normal population.

7.36 In 1983 Dienstag (Harvard) reviewed a number of studies of patients with NANB Hepatitis who had been followed for varying periods after transfusion. He concluded:

After transfusion, as many as 40%-60% of patients with acute NANB hepatitis will be left with chronic elevations of serum aminotransferase activity, often in a fluctuating pattern: histologic features of the liver in a majority of patients with transfusion-associated chronic NANB hepatitis are consistent with chronic active hepatitis, and ~10%-20% of chronic cases eventuate in cirrhosis.[40]

7.37 In 1983, under the title ‘Liver disease in haemophiliacs: an overstated problem?’, Stevens et al (Manchester) reported the results of liver biopsies carried out on 12 haemophilia patients with persistently abnormal liver function tests.[41] 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. The authors stated that the results represented a much lower incidence of severe histological liver damage than many previous reports in which chronic active hepatitis and cirrhosis had been found in between one third[42] and one half[43] of patients with haemophilia who had undergone a liver biopsy. The authors 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 Aledort et al[44] where the incidence of chronic active hepatitis and cirrhosis was 16%. The authors concluded that routine liver biopsy was not indicated in asymptomatic haemophilia patients with abnormal liver function tests. Proven therapy was not available and the natural history of those liver changes had yet to be elucidated.

7.38 On 19 March 1983 The British Medical Journal 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.[45] 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.

7.39 On 22 March 1983 the Haemophilia and SNBTS Directors Working Group met.[46] Dr Cash (SNBTS) asked members to consider the possibility of a study of liver function tests in patients with mild haemophilia and referred to a study in Birmingham. Drs Forbes and Ludlam agreed to consider the matter.

7.40 On 1 July 1983 Diane Walford of the Department of Health and Social Security (DHSS) wrote to Dr Gunson (NBTS).[47] Three chimpanzees had developed hepatitis after receiving Hyland/Travenol’s heat-treated Factor VIII.

7.41 On 26 July 1983 the Central Blood Laboratories Authority produced a paper entitled ‘AIDS: progress with heat treatment of human plasma products’.[48] The paper noted that the absence of markers for the NANB Hepatitis virus prevented screening of source material and that epidemiological evidence suggested that large-pool concentrates were universally associated with transmitting the NANB Hepatitis virus. The paper also noted that the severity of NANB Hepatitis in haemophilia patients, probably associated with the co-existent impaired immune responsiveness of these patients, had motivated plasma fractionation organisations to re-examine means whereby hepatitis viruses could be inactivated in large-pool concentrates. Heat treatment of blood products was still primarily directed at the inactivation of hepatitis.

7.42 In September 1983 the Congress of the European Society of Haematology met in Barcelona. Professor Mannucci (Milan) reported orally to a number of haemophilia doctors the results of his study of Hyland/Travenol’s Hemofil T Factor VIII concentrate (dry heated at 60ºC for 72h). The product transmitted hepatitis.[49]

7.43 By letter dated 12 September 1983, Dr Entwistle (NBTS) sent Dr Brookes (SNBTS, Dundee) what he hoped would be the final versions of ‘Guidance for the Selection, Medical Examination and Care of Blood Donors’ and ‘Notes on Transfusion’.[50] The documents had been produced by Dr Entwistle’s Working Party, of which Dr Brookes was a member, on behalf of the NBTS and SNBTS. The guidance on the selection of donors stated that individuals who had a history of jaundice or hepatitis or in whose blood anti-HBs was present could be accepted as donors, providing they had not suffered from jaundice or hepatitis in the previous 12 months, had not been in close contact with hepatitis or received a transfusion of blood or blood products in the previous six months, and providing their blood gave a negative reaction for the presence of Hepatitis B surface antigen (HBsAG) when tested by an accepted sensitive method, eg Recombinant Immuno Blot Assay (RIBA).[51]

7.44 On 27 September 1983 the UK Blood Transfusion Services’ Working Party on Transfusion Associated Hepatitis met.[52] Notes of the meeting were prepared by Drs Mitchell (SNBTS, Glasgow) and McClelland (SNBTS, Edinburgh).[53] The topics discussed included the transmission of NANB Hepatitis by intravenous immunoglobulin prepared by the Blood Products Laboratory in Elstree (BPL).[54] ALT studies in the recipients of similar Scottish material had not, at that time, shown any cause for concern.

7.45 On 28 September 1983 Dr Craske (PHLS, Manchester) produced the Annual Report for 1982/1983 of the UKHCDO’s Hepatitis Working Party.[55] The report referred to the Oxford study, started in 1981, of hepatitis in infrequently treated haemophilia patients.[56] The risk of contracting NANB Hepatitis from Factor VIII concentrates was 100% on first exposure, whether NHS or commercial Factor VIII. An internationally based trial of Hyland/Travenol’s heat-treated Factor VIII (Hemofil T)[57] had commenced and an Armour heat-treated product (Factorate HT)[58] would soon be available for evaluation. However, the problem of AIDS had overshadowed these developments. 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.

7.46 The report also noted that the German manufacturer Behringwerke had developed a heat-treated product that had undergone clinical trial in Germany. It was, however, unlikely that Behringwerke would consider applying for a UK product licence unless an approach was made to them. Since their unheated product was not marketed in the UK, that might take some time. The report attached figures for the number of cases of acute hepatitis reported by Haemophilia Centre Directors in 1980-82.

7.47 On 22 October 1983 Dr Lane (BPL) reported that all 12 patients in a clinical trial of an intravenous immunoglobulin developed by BPL had developed NANB Hepatitis.[59] In contrast, none of the patients in the control group, who had received intramuscular immunoglobulin, had any clinical or biochemical evidence of hepatitis.[60]

7.48 On 12 November 1983 Collins et al (Newcastle) reported on a prospective study of post-transfusion hepatitis in patients undergoing heart surgery.[61] Of 248 patients who received transfusion, six (2.4%) developed acute short incubation NANB Hepatitis.[62] These six patients had normal liver function tests six months after transfusion but a further two of the surviving 228 patients had raised serum transaminase levels at six months. In one of these patients, liver biopsy disclosed chronic persistent hepatitis; in the other, alcoholic liver disease was suspected. The authors considered that the incidence of post-transfusion NANB Hepatitis after cardiac surgery in their study (3.2%)[63] was low compared with similar studies in other countries, all of which used volunteer blood.[64] The authors concluded that:

non-A, non-B hepatitis after blood transfusion from a largely British blood donor group probably leads to clinically significant chronic liver disease very rarely indeed.

7.49 On 14 November 1983 the Haemophilia and SNBTS Directors Working Group met.[65] Dr Forbes (Glasgow) intimated that he was writing up his experience of hepatitis in 12 patients with mild haemophilia who had been treated with Factor VIII from the Protein Fractionation Centre, Edinburgh. He undertook to submit this data to Dr Cash.[66]

7.50 On 10 December 1983 Fletcher et al (Oxford) formally reported on their study of NANB Hepatitis due to transfusion of Factor VIII in infrequently treated patients with haemophilia.[67] In a study of 30 patients, the authors found a high incidence of NANB Hepatitis in patients treated with Factor VIII who had not previously received Factor VIII or had received it only infrequently. That was so whether the patients received commercial Factor VIII or NHS Factor VIII. The authors stated that it might be that the pool size of NHS concentrates had increased to the point where the benefit conferred by using plasma from volunteer donors had been lost.

7.51 In an accompanying BMJ editorial that also considered the risk of contracting AIDS from the use of blood products, Dr Jones (Newcastle Haemophilia Centre) stated that throughout the world the opinion of the majority of haemophilia centres was that the risk of haemorrhage and its complications far outweighed the risk of developing AIDS or chronic liver disease. However, for the time being, it seemed sensible to treat severely affected young children with Cryoprecipitate, rather than factor concentrates, and to consider alternative methods of raising Factor VIII activity (eg with desmopressin (DDAVP), danazol or perhaps porcine material) for persons with mild haemophilia, vWD and carriers of these disorders.[68]


7.52 In 1984 the International Committee on Thrombosis and Haemostasis drafted criteria for the design and performance of clinical studies intended to evaluate the efficacy of viral inactivation procedures against the risk of transmission of NANB Hepatitis.[69]

7.53 In 1984 ‘Notes on Transfusion principles and practices’ were jointly published by the DHSS, Scottish Home and Health Department (SHHD) and the Welsh Office on behalf of the NBTS and SNBTS.[70] It was noted that NANB Hepatitis viruses were transmissible by transfusion but specific laboratory tests had not been developed to identify them at that time. The incubation period was variable, extending up to 70 days or more. The clinical course could be acute or chronic leading to cirrhosis.[71]

7.54 On 9 January 1984 a report was prepared by the Blood Products Sub-Committee of the Haemophilia Society. The report reviewed the policy of the Society in relation to the supply of blood products in the UK.[72] Regarding the risk of NANB Hepatitis, the report noted that recent work suggested that UK material was no better (and might be worse) than imported material.[73]

7.55 On 9 February 1984 the National Institute for Biological Standards and Control (NIBSC) met to discuss the infectious hazards of blood products.[74] Dr Smith (NIBSC) explained that while the NIBSC was not the licensing authority in the UK, it gave scientific advice to the licensing authority and the Committee on the Safety of Medicines. In a discussion on blood products and hepatitis, it was noted that it had been shown that the first exposure to factor concentrate, from whatever source, was associated with 100% infectivity with NANB Hepatitis. Dr Craske (PHLS, Manchester) described the incidence of jaundice in persons with haemophilia in the UK from 1969 to 1979. Apart from a period in the mid-1970s when the incidence of jaundice rose to five per cent, the incidence had mostly been around two per cent a year.[75] NANB Hepatitis was very prevalent in the haemophilia population. Some 30–40% of UK haemophilia patients had abnormal liver function tests, indicative of possible chronic liver damage, although only two patients had died of liver disease in the past 10 years. Dr McClelland (SNBTS, Edinburgh) presented data which suggested that the risk of transmitting NANB Hepatitis by blood transfusion was one in 100. In a discussion on policies adopted in Scotland to minimise the risk of transmission of infection (including AIDS), the following main strategies were noted:

1) avoidance of high risk communities (such as prisons, known homosexual areas etc); 2) detection of clinical abnormalities by examination and careful questioning; 3) exclusion of the high risk donor, or his blood, always allowing an “escape route” for the donor who is deemed unsuitable.[76]

7.56 In discussion, Dr Eibl commented that it was insufficient to ask a donor if he had suffered from jaundice during the previous 12 months since some individuals could be carriers for several years. It was noted that there was much discussion about the optimal size of plasma pools, but no agreement that reduction of pool size would be either a practicable or successful way of reducing the transmission of either hepatitis or AIDS.

7.57 On 29 March 1984 the Chairmen of the UKHCDO and its Hepatitis Working Party wrote to all UK Haemophilia Centre Directors on the question of hepatitis reduced Factor VIII.[77] The Chairmen called for cooperation between the Haemophilia Centre Directors in coordinating trials of the new heat-treated blood products so that the maximum information about the relative merits of different products would become available with the most economical use of the limited number of patients available. The letter explained that there were at present eight different products in preparation or available for trial. Clinical trials had only been completed on one product, Hyland/Travenol’s Hemofil HT Factor VIII.[78] The results indicated that there was still a 63% attack rate of NANB Hepatitis on first exposure in patients who had not received Factor VIII concentrate previously. Trials were difficult to evaluate because, for ethical reasons, no control group was used. The products currently available were (1) heated products from Armour, Cutter, Travenol and Alpha, (2) NHS Factor VIII prepared from a specially selected donor panel which was monitored for abnormal liver function tests, hepatitis etc, (3) heated NHS Factor VIII (one brand was manufactured at the PFC in Edinburgh and, it was noted, would shortly be available; the second was manufactured by BPL in Elstree and was to be available later that year) and (4) a heated preparation manufactured by Behringwerke, Germany. The German product was heated at 60ºC for a period known to inactivate Hepatitis B. It was noted that the problem with the Behringwerke product was that the yield of Factor VIII coagulant activity was considerably reduced, so that the cost was likely to be at least four times higher. Trials had been carried out in Germany, but no published information was available.

7.58 By letter dated 10 April 1984, Dr Ludlam (Edinburgh Haemophilia Centre) replied to the UKHCDO’s request for cooperation in coordinating trials of the new heated Factor VIII products.[79] He stated that most of his patients had been treated exclusively with SNBTS Factor VIII and that he was very reluctant to consider using any of his patients as trial subjects for the commercial hepatitis reduced concentrates. Dr Ludlam had been testing a new higher purity heat-treated SNBTS Factor VIII concentrate and wished to reserve any patients he might have for that product.

7.59 By letter dated 25 April 1984 Dr Cash (SNBTS) advised Dr Crawford (SNBTS, Glasgow) that he was anxious that the SNBTS look at the incidence of hepatitis and transaminitis in previously untreated haemophilia patients who received SNBTS heat-treated Factor VIII concentrate and asked if Dr Crawford would coordinate such a study.[80] Dr Cash enclosed a draft protocol.[81] He explained that a prospective study in England had shown that all nine patients who had not previously received blood concentrates had contracted NANB Hepatitis after receiving their first transfusion of either USA commercial Factor VIII or English Factor VIII. It was proposed to assess the residual infectivity of SNBTS hepatitis reduced Factor VIII by means of a clinical trial in patients who had not previously been treated with large pool Factor VIII concentrates. The object of the study would be explained to patients and their consent or, if under 16 years of age, that of their parents, would be obtained.

7.60 On 23 May 1984 Dr Bell (SHHD) sent a memo to Mr Murray (SHHD) commenting on the Common Services Agency’s case for funding the production of heat-treated Factor VIII.[82] Dr Bell noted that at present nearly all newly-treated haemophilia patients became infected with NANB Hepatitis, though not usually of dramatic severity. About 40% also showed evidence of infection with Hepatitis B. The longer term effects of such infection in persons with haemophilia were not known with certainty because, until relatively recently, haemophilia patients had little prospect of living into middle or old age. However, 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.

7.61 In July 1984, Dr Follett (Regional Virus Laboratory, Ruchill Hospital, Glasgow) and Dr Dow (SNBTS, Glasgow) produced a final report on a three year research project, ‘Non-A Non-B Hepatitis in the West of Scotland’.[83] The summary stated that in the West of Scotland NANB Hepatitis was not a major problem. Cases of post-transfusion hepatitis were rare, although persons with haemophilia and drug abusers did present with unexplained jaundice episodes. In the past four years only 14 cases of Non-B post-transfusion hepatitis had been notified to the Glasgow and West of Scotland Blood Transfusion Service. Of these 14 cases, four were haemophilia patients who had been multiply transfused with Scottish and imported blood products. The authors concluded that it appeared that post-transfusion hepatitis was not a significant problem in the region, although they recognised that sub-clinical forms of post-transfusion hepatitis probably occurred but were not notified. The screening of prison populations had detected 10 times more donations with grossly elevated ALT levels compared to other sessions. The report noted that these results had discouraged the SNBTS from visiting prisons to obtain blood for transfusion purposes.

7.62 Between 22–27 July 1984 the 18th Congress of the International Society of Blood Transfusion was held in Munich. Dr McClelland (SNBTS, Edinburgh) produced an abstract entitled ‘Hepatitis – a transfusionist’s view’.[84] Dr McClelland stated that the risk of Hepatitis B following transfusion of blood or its components was extremely rare. Clinically apparent NANB post-transfusion Hepatitis was also a small problem. Although a few transfused patients developed asymptomatic elevations of liver enzymes, the importance of that remained undefined. Thus for the recipient of blood or single-donor components the benefits of improved donor testing were not quantifiable. The transfusion centre which supplied plasma for fractionation and the clinician using large pool plasma fractions, however, faced quite different problems, since coagulation factor concentrates had a very high risk of transmitting NANB Hepatitis. That might be improved by a combination of approaches including: use of small pool alternative products for suitable patients, reduction of the number of donors contributing to fractionation pools, dedication of batches for designated patients, improved fractionation technology and chemical or immunological intervention.

7.63 In October 1984, an article by Drs Barbara and Tedder (North London Regional Transfusion Centre (RTC) and University College and Middlesex School of Medicine, London) was published, ‘Viral infections transmitted by blood and its products’.[85] The authors noted that there appeared to be more than one NANB Hepatitis virus. 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. While it had been suggested that exclusion of donors with elevated ALT levels might reduce the prevalence of transfusion associated NANB Hepatitis, the cost effectiveness of ALT screening was difficult to assess because of major uncertainties about the consequences of NANB Hepatitis. It was not even certain that such a policy would necessarily reduce post-transfusion NANB Hepatitis.

7.64 The authors noted that if ALT screening was introduced in the North London RTC as many as 10 donors a day would be disqualified. The authors stated that having regard to the high proportion of ‘false positive’ and ‘false negative’ results that arose when ALT was used as an index of NANB Hepatitis infectivity, and having regard to the geographical variations in ALT levels reported in other studies, routine ALT screening was not considered feasible in North London. The additional question of appropriate advice to donors would also be enormous. Such considerations had led the American Association of Blood Banks to advise against routine ALT screening of donors. At the North London RTC there was noted to be an increased prevalence of anti-HBc in panels associated with post-transfusion NANB Hepatitis. Even so, the authors considered it questionable if the approach of using anti-HBc as a marker for high-NANB-risk donors would be generally applicable. Most patients with haemophilia developed NANB Hepatitis after their first treatment with Factor VIII concentrate and might do so more than once. The authors 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, even that was frequently self-limiting and resolved within two years in most cases.

7.65 On 10 November 1984, Lever et al (Royal Free Hospital, London) formally reported on the 12 patients who had developed NANB Hepatitis following treatment with intravenous gammaglobulin manufactured by BPL.[86] Most of the patients were symptomless but
10 months after the onset of infection 10 of the 12 patients still had abnormal liver function.

7.66 In December 1984 Stevens et al (New York and other USA centres) analysed data from the Transfusion Transmitted Viruses Study (TTVS)[87] to consider the association between the presence of anti-HBc in blood donors and the occurrence of NANB Hepatitis in transfusion recipients.[88] The authors explained that the TTVS, conducted from July 1974 through December 1979, was designed to assess the risk of post-transfusion hepatitis in transfusion recipients in four regions of the USA and evaluate factors influencing its incidence. The blood was collected from volunteer donors.

7.67 In 1981 the TTVS had reported an association between raised ALT levels in donors and an increased risk of transfusion recipients developing NANB Hepatitis. In the present study, Stevens et al analysed data from the TTVS to ascertain whether patients who received blood from donors who tested positive for anti-HBs and anti-HBc were at increased risk of developing NANB Hepatitis.

7.68 The authors did not find a statistically significant association between donors who were positive for anti-HBs and the development of NANB Hepatitis in recipients. The data suggested, however, that the incidence of post-transfusion NANB Hepatitis might have been reduced by about one third by screening for anti-HBc. Elevated ALT levels in donors had a similar association with NANB Hepatitis in recipients but would have resulted in fewer units of blood being discarded than would screening for anti-HBc (2.8% as against 5.1%). The authors considered that 21.4% of cases of NANB Hepatitis might have been prevented by screening for anti-HBc, 29.9% of cases might have been prevented by screening for ALT and 39.2% of cases might have been prevented by screening for both anti-HBc and ALT. Adjusting these figures to take into account the incidence of NANB Hepatitis in non-transfused control patients, resulted in figures of 33.3%, 47.4% and 61.2% respectively. Screening for both ALT and anti-HBc would have resulted in a loss of nearly eight per cent of donor units.

7.69 The consensus of the authors was that ALT screening of donors was favoured over anti-HBc screening. The authors emphasised that their calculations were only rough estimates of the potential impact of donor screening based on their data. Other critically important factors affecting the risk to recipients – the prevalence of NANB Hepatitis among donors and the susceptibility to infection among recipients – remained unknown in the absence of specific serologic tests and varied among both donor and recipient populations.


7.70 In 1985 Harvey J Alter (National Institutes of Health (NIH), USA), a leading authority on the subject, set out what was known about post-transfusion hepatitis at that time.[89] He noted that it was important to re-emphasise that in virtually every study comparing volunteer and commercial blood, the risk of paid donor blood was inordinately high.

7.71 Alter stated that while the majority of cases of post-transfusion NANB Hepatitis were relatively asymptomatic, the importance of the disease was not in its acute manifestations but in its chronic sequelae. An astounding number of cases progressed to chronic hepatitis, at least as judged by persistent ALT elevations. Although NANB Hepatitis was generally a clinically benign disease, there was accumulating evidence that some cases progressed to severe chronic liver disease. A composite of existing data suggested that at least 10% of patients who developed chronic ALT elevations following acute post-transfusion hepatitis progressed to cirrhosis. If these findings were validated, then the clinical implications of NANB Hepatitis were somewhat greater than previously anticipated.

7.72 Alter discussed screening blood donors for NANB Hepatitis, whether by direct or indirect tests. He noted that although there had been over 30 published reports of a NANB Hepatitis assay, and although most of these reports seemed internally consistent and appropriately controlled, none had been reproducible from laboratory to laboratory and none had withstood the test of time. There was currently no assay available that could reliably and reproducibly detect the specific agent(s) of NANB Hepatitis.

7.73 In the absence of a specific test for NANB Hepatitis, it had been suggested that indirect or surrogate tests, in particular, ALT or anti-HBc, might serve as useful interim donor screening measures. Alter noted that the question of whether or not ALT testing should be routinely adopted for donor screening was widely debated and currently remained an essentially unresolved issue. Inherent in the debate were questions as to whether the predicted efficacy could actually be achieved in clinical practice,[90] and questions relating to test standardisation, non-specificity, responsibility to the donor and the ability to sustain the donor loss which would ensue.

7.74 Alter reported on a historical study carried out by the NIH on the impact of ALT testing on post-transfusion hepatitis. In 1981 the NIH had introduced ALT testing and had excluded all blood donations with high ALT levels. The incidence of NANB Hepatitis in the following three years, both in patients and untransfused controls, was virtually identical to that in the two years prior to testing ie there was no significant decline in the incidence of hepatitis after ALT testing.

7.75 Overall, Alter was of the view that while existing data on indirect or surrogate testing was inconclusive, it was sufficiently compelling that a definitive answer must be sought and that a randomised, controlled study was long overdue and should be instituted as rapidly as possible. Such a study could be completed in one and a half years and could address both the ALT and anti-HBc issues, thus providing a definitive and rational basis for making these complex decisions.

7.76 In 1985 Kernoff et al (Royal Free Hospital, London) reported on the high risk of haemophilia patients developing NANB Hepatitis whether treated with commercial Factor VIII concentrate from the USA or with NHS Factor VIII concentrate manufactured from volunteer donors.[91] In a study of haemophilia patients who had not previously been treated with Factor VIII concentrates, all nine patients who were prescribed commercial concentrate from the USA (from three different manufacturers) developed acute NANB Hepatitis. Ten out of 12 patients who were prescribed NHS concentrate developed acute NANB Hepatitis. The authors were of the view that since clotting factor concentrates were usually prepared from pools of at least 1500 donors, it was not surprising that the overall attack rate following a first exposure to such products should approach 100%, whether they were of volunteer or commercial origin. Of five patients treated with NHS Cryoprecipitate, none developed NANB Hepatitis. The authors concluded that that probably reflected their relatively low exposure, ie none of the patients had received more than 70 donor units.

7.77 Between 11–13 June 1985 the World Health Organisation held a meeting in Munich. A report was produced, ‘Viral hepatitis in Europe – further trends and targets’.[92] It recommended that research on the identification of the agents of orally and parenterally transmitted NANB Hepatitis, and the development of specific diagnostic tests, be given a high priority.

7.78 On 29 June 1985, The Lancet published an article by Hay et al (Sheffield), ‘Progressive liver disease in haemophilia: an understated problem?’.[93] By way of introduction, the authors noted that little concern had been expressed about the long-term implications of liver disease associated with haemophilia, few clinical features of chronic liver disease had been reported in persons with haemophilia and few deaths had been attributed to it. Liver biopsy studies had shown chronic active hepatitis in most of these patients, leading various workers to conclude that liver disease in haemophilia was benign and non-progressive.

7.79 In the study by Hay et al 79 patients with haemophilia who had received clotting factor concentrates were followed for eight years. Of the 79 patients, there was evidence of chronic progressive liver disease in at least 17 patients (21%). Of these 17 patients, eight had chronic active hepatitis and nine had cirrhosis. Histological evidence suggested that NANB Hepatitis was mainly responsible. Serial liver biopsies showed progression from chronic persistent hepatitis to chronic active hepatitis and cirrhosis within a period of two to six years, leading the authors to conclude that progressive liver disease was a potentially serious problem for persons with haemophilia.

7.80 Hay et al noted that there was only one previous report of serial liver biopsies in patients with haemophilia (Mannucci et al, 1982),[94] which had reported partial resolution of chronic active hepatitis in 4 of 11 patients who had serial biopsies (although one patient with cirrhosis had died from bleeding oesophageal varices). Those findings contrasted with the findings of the Sheffield study, which had followed patients over a longer period of time. Hay et al noted that cirrhosis might take several years to develop and it was not surprising that cirrhosis was more common in their study than in earlier studies with shorter periods of follow-up. The authors noted that studies in non-haemophilia patients with NANB Hepatitis showed a prevalence of chronic liver disease and frequency of progression to chronic active hepatitis and cirrhosis comparable with the observations of their study. While few deaths attributable to liver disease in patients with haemophilia had been reported, Hay et al predicted that that would become more common and that liver disease in haemophilia patients would become an increasing clinical problem in the future.

7.81 On 6 July 1985 Colombo et al (Milan and other European centres) reported on the transmission of NANB Hepatitis by Hyland/Travenol’s Hemofil T Factor VIII concentrate (dry heat treated at 60ºC for 72h).[95] The authors noted that NANB Hepatitis had an attack rate close to 100% in haemophilia patients not previously exposed to blood or blood derivatives and remained a formidable problem. Although Hemofil T had not transmitted NANB Hepatitis when administered to chimpanzees, when administered to 13 haemophilia patients who had not previously been treated with blood products evidence of NANB Hepatitis was found in 11 patients.

7.82 On 27 July 1985 Preston et al (Sheffield) reported on their experience of heat-treated concentrates in three patients who had not previously received blood or blood products.[96] Two patients with mild haemophilia were given Armour’s heat treated product, Factorate.[97] Both patients developed NANB Hepatitis, despite the product having previously been tested in chimpanzees, without transmission of the disease. A third patient, who had vWD, was treated with dry heated, intermediate purity, NHS factor concentrate prepared from a pool of 309 regular donors. Reviewed weekly for one month and fortnightly thereafter for four months, the third patient’s hepatic indices remained persistently normal.

7.83 In August 1985 Aledort et al (New York and other international centres) reported on the largest study at the time of liver biopsies and liver disease among patients with haemophilia.[98] Liver samples and associated clinical data were collected from 155 patients from haemophilia centres in the USA and Western Europe. The purpose of the study was to determine (1) the spectrum of liver disease in persons with haemophilia, (2) whether the nature and severity of liver disease depended on the type and magnitude of prior transfusion therapy and (3) the safety of continuing to perform liver biopsies on haemophilia patients.

7.84 The authors reported that the incidence of cirrhosis (15%) and chronic active hepatitis (7%) were 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, leading 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. The risks involved in liver biopsy were relatively high: clinically significant haemorrhage occurred in 12.5% of the procedures. The authors noted that the lack of severity of the histopathological findings in the materials studied might not be entirely reassuring as some recent evidence had suggested insidious progression of NANB Hepatitis to cirrhosis,[99] although other studies suggested the possibility of reversion towards normal hepatic architecture.[100]

7.85 On 5 October 1985 Mannucci and Colombo (Milan, Italy)[101] responded to the report by Hay et al (Sheffield) which suggested that liver disease in haemophilia patients was an understated problem.[102] Mannucci and Colombo considered that the findings of Hay et al, that NANB Hepatitis in haemophilia patients often progressed to severe liver disease, contrasted with the results of the large study carried out by Aledort et al[103] in which a panel of pathologists found histological features of ‘severe liver disease’ in ‘only 22% of cases’. The findings of Hay et al also contrasted with several reports cited by Aledort et al and with the findings of the study by Mannucci and Colombo.[104] The non-progressive course of NANB Hepatitis in the patients in Mannucci and Colombo’s study was further confirmed by a third liver biopsy in 1983 (unpublished) which showed continuation of chronic persistent or lobular hepatitis in all cases, rather than progression of the disease. Mannucci and Colombo considered that the fact that the patients in their study were considerably younger than those in the Sheffield study suggested that the degree of liver damage might be inversely related to the age at which patients became infected, i.e. that younger patients had a better outcome.

7.86 Thus, by the end of 1985:

• There was increasing concern about the potential seriousness of NANB Hepatitis,

• It was known that almost all haemophilia patients who regularly received treatment with concentrates were likely to develop the disease,

• First generation heated concentrates continued to transmit NANB Hepatitis, and

• The debate over the benefits and drawbacks of screening blood donors for surrogate markers of NANBH continued.

[1] Sherlock, Diseases of the Liver and Biliary System, 6th edition, 1981, p259

[2] The following studies, and the conclusions drawn from them at the time, are more fully discussed below: Realdi (1982), Koretz (1982), Mannucci (1982), White (1982), Stevens (1983), Hay (1985), Aledort (1985)

[3] Fletcher et al, ‘Non-A non-B hepatitis after transfusion of factor VIII in infrequently treated patients’, British Medical Journal, 1983;287:1754-1757 [LIT.001.0239]; Kernoff et al, ‘High risk of non-A, non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of pooled human immunoglobulin’, British Journal of Haematology, 1984;58:174 and Kernoff et al, ‘High risk of non-A, non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin’, British Journal of Haematology, 1985;60:469-479 [LIT.001.0800]

[4] Informally reported by Professor Mannucci at a meeting of the European Society of Haematology in Barcelona in September 1983 and subsequently published by Colombo et al, ‘Transmission of NANBH by heat-treated factor VIII concentrate’, Lancet, 1985;2:1-4 [LIT.001.0369]

[5] Lane, ‘Non-A, Non-B hepatitis from intravenous immunoglobulin’, Lancet, 22 October, 1983:974 [SNF.001.1041] and Lever et al, ‘Non-A, non-B hepatitis occurring in agammaglobulinaemic patients after intravenous immunoglobulin”, Lancet, 10 November 1984:1062-4 [LIT.001.0449]. In contrast, immunoglobulin products administered intramuscularly did not appear to transmit NANB Hepatitis.

[6] Realdi et al, ‘Long-term follow-up of acute and chronic non-A, non-B post-transfusion hepatitis: evidence of progression to liver cirrhosis’, Gut, 1982; 23:270-275 [LIT.001.0528].

[7] Koretz et al, ‘Non-A, non-B transfusion hepatitis: Disaster after decades’, Hepatology, 1982 (abstract):2(5):687

[8]A v National Blood Authority (2001) 3 All ER 289, paragraph 126. The Inquiry does not have documentary evidence of the grant application or its refusal.

[10] This table has been compiled from information contained in the USA Institute of Medicine report, ‘HIV and the Blood Supply: an analysis of crisis decision-making’, page 92 and the SNBTS submission to the Scottish Executive dated February 2000, ‘Investigation concerning events surrounding the introduction of heat treatment for blood products in the mid 1980s – Additional information requested by the Scottish Executive’, page 2 [SGF.001.1439]

[11] Preston et al, ‘Blood product concentrates and chronic liver disease’, Lancet, 6 March 1982:565 [LIT.001.0398]

[16] Rickard et al, ‘Hepatitis and Haemophilia Therapy in Australia’, Lancet, 17 July 1982: 146-148 [LIT.001.0548]

[17] Prepared either by the Commonwealth Serum Laboratories, Melbourne from a pool of 1,500 donors or by the New South Wales division of the Red Cross Blood Transfusion Service from 500 donations

[18] Mannucci et al, ‘Nonprogressive course of non-A, non-B chronic hepatitis in multitransfused hemophiliacs’, Blood, Vol 60, No 3 (September), 1982; 655-658 [LIT.001.0543]

[19] Mannucci et al, ‘A clinicopathological study of liver disease in haemophiliacs’, Journal of Clinical Pathology, 1978;31:779-783 [LIT.001.1624]

[20] Gerety and Aronson, ‘Plasma derivatives and viral hepatitis’, Transfusion, 1982;22(5):347-351

[21] Mannucci et al, ‘A clinicopathological study of liver disease in haemophiliacs’, Journal of Clinical Pathology, 1978;31:779-783 [LIT.001.1624]

[23] This appears to be a reference to the paper subsequently published in 1983 by Fletcher et al, ‘Non-A non-B hepatitis after transfusion of factor VIII in infrequently treated patients’, British Medical Journal, 1983;287:1754-7 [LIT.001.0239]

[25] Ludlam, 1982, Lancet, 1982, 776

[26] Rickard et al, ‘Hepatitis and Haemophilia Therapy in Australia’, Lancet, 17 July 1982: 146-148 [LIT.001.0548]

[27] Gabra et al, ‘Factor VIII, cryoprecipitate and hepatitis risk’, Lancet, 27 November 1982:1220. In a previous letter to The Lancet, Drs Crawford and Mitchell had expressed the following, similar, view: ‘As a matter of principle, blood transfusion – and particularly the use of large pool coagulation products – should be kept to a minimum. This is one of the reasons why we have introduced small-pool dried cryoprecipitate to the UK’: Crawford and Mitchell, ‘Post-transfusion hepatitis’, Lancet, 8 August 1981:312

[28] These studies were (1) Stirling et al, ‘Liver function in Edinburgh haemophiliacs: a five year follow up’, Journal of Clinical Pathology, 1981;34:17-20 [LIT.001.0748] (2) Burrell et al, ‘Antibody to hepatitis B surface antigen in haemophiliacs on long term therapy with Scottish Factor VIII’, Journal of Clinical Pathology, 1978;31:309-312; and (3) Ramsay and Khoo, ‘A five year study of a haemophilia reference centre’, Journal of Clinical Pathology, 1975;28:696-700

[29] White et al, ‘Chronic hepatitis in patients with hemophilia A: Histologic studies in patients with intermittently abnormal liver function tests’, Blood, 1982; 60:1259-1262 [LIT.001.0535]

[30] Mollison, Blood Transfusion in Clinical Medicine, 7th edition, 1983 (Blackwell Scientific Publications)

[31] Alter, ‘The dominant role of non-A, non-B in the pathogenesis of post-transfusion hepatitis: c clinical assessment’, Clinics in Gastroenterology, 1980;9:155-170

[32] Aach et al, ‘Serum alanine aminotransferase of donors in relation to the risk of non-A, non-B hepatitis in recipients: the transfusion-transmitted viruses study’, New England Journal of Medicine, 1981;304:989-994 [LIT.001.0753]

[33] Holland et al, ‘Post-transfusion viral hepatitis and the TTVS’, New England Journal of Medicine, 1981;304:1033-1035 [LIT.001.1630]

[34] Blum and Vyas, ‘Non-a, non-B hepatitis: a contemporary assessment’, Haematologia, 1982;15:162-183 [LIT.001.1106]

[35] Mollison, supra, at pp 773-774

[36] ‘Based on your analysis of the benefits and costs of routine donor screening for ALT-GPT to reduce the incidence of post-transfusion Non-A, Non-B hepatitis in your blood services region, what action would you recommend?’, Vox Sanguinis, 1983;44:48-64

[37] Aach et al, ‘Serum alanine aminotransferase of donors in relation to the risk of Non-A, non-B hepatitis in recipients, The Transfusion Transmitted Viruses Study’, New England Journal of Medicine, 1981;304:989-994 [LIT.001.0753]

[38] While expressed more equivocally, this also appears to have been the view of Chataing et al (Lyon and Toulouse, France).

[39] Schimpf, Behring Inst Mitt, 1983;73:111-117 [LIT.001.0001]

[40] Dienstag, ‘Non-A, Non-B Hepatitis: 1. Recognition, Epidemiology, and Clinical Features’, Gastroenterology, 1983;85:439-462 [LIT.001.1239] and Dienstag, ‘Non-A, non-B Hepatitis: 2. Experimental Transmission, Putative Virus Agents and Markers, and Prevention’, Gastroenterology, 1983:85:743-768 {LIT.001.1213]

[41] Stevens et al, British Journal of Haematology, 1983;55:649-655 [LIT.001.0008]

[42] Spero et al, ‘Asymptomatic structural liver disease in hemophilia’, New England Journal of Medicine, 1978;298:1373-1378 [LIT.001.0177] and Schimpf et al, ‘Liver biopsy findings in haemophilia’, in Haemophilia, ed Seligsohm et al, 1981, pp 149-153

[43] Lesesne et al, ‘Liver biopsy in haemophilia A’, Annals of Internal Medicine, 1977;86:703-707; Mannucci et al, ‘A clinicopathological study of liver disease in haemophiliacs’, Journal of Clinical Pathology, 1978;31:779-783 [LIT.001.1624] and Preston et al, ‘Percutaneous liver biopsy and chronic liver disease in haemophiliacs’, Lancet, 1978;ii:592-594 [LIT.001.0387]

[44] Aledort et al, ‘A study of liver disease among haemophiliacs’, Blood, 1981;58, Suppl. 1, 210a

[45] Rizza et al, ‘Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976-80:report on behalf of the directors of haemophilia centres in the United Kingdom’, British Medical Journal; 286:929-933 [LIT.001.0234]

[49] Evidence of Professor Mannucci to the Lindsey Tribunal of Inquiry (noted at page 62 of the Tribunal’s Report). Travenol was part of the Baxter group. The results were published in 1985: Colombo et al, ‘Transmission of NANBH by heat-treated factor VIII concentrate’, Lancet, 1985;2:1-4 [LIT.001.0369]

[51] The origin of the policy of accepting donors with a history of jaundice or hepatitis but who tested negative for Hepatitis B surface antigen may have been a recommendation contained in the second report of the Advisory Group on Testing for the Presence of Hepatitis B Surface Antigen and its Antibody (1975), at paragraph 18 [SGH.003.0079]

[52] Drs Cuthbertson, Mitchell, McClelland, Crask, Barbara, Pollock, Lane and Thomas were present. Dr Gunson was unable to attend.

[54] Subsequently reported in The Lancet on 22 October 1983.

[56] Subsequently reported by Fletcher et al, ‘Non-A non-B hepatitis after transfusion of factor VIII in infrequently treated patients’, British Medical Journal, 1983;287:1754-1757 [LIT.001.0239]

[57] Dry heat treated at 60ºC for 72 hours.

[58] Dry heat treated at 60ºC for 30/36 hours.

[59]Lane, ‘Non-A, Non-B hepatitis from intravenous immunoglobulin’, Lancet, 22 October, 1983:974 [LIT.000.0000]. A fuller report was published on 10 November 1984 by Lever et al, ‘Non-A, non-B hepatitis occurring in agammaglobulinaemic patients after intravenous immunoglobulin’, Lancet, 1984:1062-1064 [LIT.001.0449]

[60] On 19 November 1983, Welch et al (SNBTS, PFC) reported on their work to pasteurise immunoglobulin: ‘Non-A, Non-B hepatitis from intravenous immunoglobulin’, Lancet, 1983:1198-1199

[61] Collins et al, ‘Prospective study of post-transfusion hepatitis after cardiac surgery in a British centre’, British Medical Journal, 1983;287:1422-1424 [LIT.001.0212]

[62] As defined by transaminase levels rising to over 2.5 the upper limit of normal, in the absence of any other explanation.

[63] ie the initial six patients with grossly elevated transaminase levels plus the two patients with elevated levels six months after surgery.

[64] The incidence was 14.6% in one study in the USA, in Italy 17.8%, in Sweden 18.9% and 30.4% in Japan. A study in the Netherlands had found a low incidence of post-transfusion NANB Hepatitis (3.4%) which was closely comparable with the results of the Newcastle study.

[66] By 28 March 1984 Dr Cash had still to receive the data and wrote Dr Forbes a reminder [SNF.001.2890]

[67] Fletcher et al, ‘Non-A non-B hepatitis after transfusion of factor VIII in infrequently treated patients’, British Medical Journal, 1983;287:1754-1757 [LIT.001.0239]

[68] Jones, ‘Acquired immunodeficiency syndrome, hepatitis and haemophilia’, British Medical Journal, 10 December 1983;287(6407):1737-1738

[69] The criteria were described in a review article by Mannucci and Colombo, ‘Virucidal treatment of clotting factor concentrates’, published in The Lancet on 1 October 1988 [LIT.001.0456].

[71][DHF.003.0394] At a meeting of the SNBTS Directors on 11 September 1984 it was noted that Dr Cash had recommended to Dr Bell ( SHHD) that the ‘Notes on Transfusion’ should not be issued in Scotland. This was partly because of the large number of printing, and other, errors in the text and partly for professional reasons [SGH.001.0445]. Instead, a decision was taken by the Scottish Directors Coordinating Group on 28 August 1984 to produce guidelines for local distribution [SNB.003.8411]

[73] This was a reference to the Oxford study: Fletcher et al, ‘Non-A non-B hepatitis after transfusion of factor VIII in infrequently treated patients’, British Medical Journal, 1983;287:1754-1757 [LIT.001.0239]

[75] It is now, in fact, known that only a small proportion of people infected with Hepatitis C suffer an acute attack of overt jaundice. It also seems likely that the incidence of jaundice in haemophilia and blood transfusion patients was underreported during this period.

[78] Dry heated at 60º for 72 hours.

[85]Clinics in Haematology, October 1984;13(3):693-707

[86] Lever et al, ‘Non-A, non-B hepatitis occurring in agammaglobulinaemic patients after intravenous immunoglobulin’, Lancet, 1984:1062-1064 [LIT.001.0449]. The transmission had previously been reported by Lane, ‘Non-A, Non-B hepatitis from intravenous immunoglobulin’, Lancet, 22 October, 1983:974

[87] Aach et al, ‘Serum alanine aminotransferase of donors in relation to the risk of non-A, non-B hepatitis in recipients: the Transfusion-Transmitted Viruses Study’, New England Journal of Medicine, 1981;304:989-994 [LIT.001.0753]

[88] Stevens et al, ‘Hepatitis B virus antibody in blood donors and the occurrence of [NANBH] in transfusion recipients’, Annals of Internal Medicine, Dec 1984;101(6):733-738

[89] Alter, ‘Posttransfusion hepatitis: clinical features, risk and donor testing’ in Infection, Immunity and Blood Transfusion, Alan R Liss, 1985, pp 47-61

[90] As Alter put it, ‘Efficacy cannot be reliably predicted; it must be randomly and prospectively demonstrated’.

[91] Kernoff et al, ‘High risk of non-A non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin’, British Journal of Haematology, 1985;60:469-479 [LIT.001.0800]

[93]Lancet, 29 June 1985:1495-1498 [LIT.001.0335]. The title was, presumably, in response to the 1983 publication by Stevens et al (Manchester) entitled ‘Liver disease in haemophiliacs: an overstated problem?’British Journal of Haemotology, 1983;55:649-655 [LIT.001.0008]

[94]Mannucci et al, ‘Nonprogressive course of non-A, non-B chronic hepatitis in multitransfused hemophiliacs’, Blood, Vol 60, No 3 (September), 1982; 655-658 [LIT.001.0543]

[95] Colombo et al, ‘Transmission of non-A, non-B hepatitis by heat treated factor VIII concentrate’, Lancet, 1985;ii:1-4 [LIT.001.0369]. As noted above, Professor Mannucci had verbally reported the results of his study to a number of haemophilia doctors at a European meeting in Barcelona in September 1983. The article by Colombo et al referred to the product as having been manufactured by ‘Hyland Therapeutics’, which, like Travenol, was also part of the Baxter group.

[96] ‘Non-A, non-B hepatitis and heat treated concentrates’, Lancet, 27 July 1985:213 [LIT.001.0464]

[97] Dry heated at 60º for 30 or 36 hours.

[98] Aledort et al, ‘A study of liver biopsies and liver disease among haemophiliacs’, Blood, 1985;66(2):367-372 [LIT.001.0505]. The findings of the study had been presented in part in December 1981 at a meeting of the American Society of Hematology at San Antonio, Texas. The paper for publication was originally submitted to Blood in July 1983.

[99] Koretz et al, ‘Non-A, non-B transfusion hepatitis: Disaster after decades’, Hepatology, 1982 (abstract):2(5):687

[100] Mannucci et al, ‘Nonprogressive course of non-A, non-B chronic hepatitis in multitransfused hemophiliacs’, Blood, Vol 60, No 3 (September), 1982; 655-658 [LIT.001.0543]

[101] Mannucci and Colombo, ‘Liver disease in haemophilia’, Lancet, 5 October 1985:774 [LIT.001.1656]

[102] Hay et al, ‘Progressive liver disease in haemophilia: an understated problem?’, Lancet, 29 June 1985:1495-1498 [LIT.001.0335]

[103] Aledort et al, ‘A study of liver biopsies and liver disease among hemophiliacs’, Blood, 1985;66:367-372 [LIT.001.0505]

[104] Mannucci et al, ‘Nonprogressive course of non-A, non-B chronic hepatitis in multitransfused hemophiliacs’, Blood, Vol 60, No 3 (September), 1982; 655-658 [LIT.001.0543]

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