HIV AND AIDS
First reports, USA June 1981 - AIDS in Europe - Theories of causation - Concentrates possibly involved - Initial UK response - Increasing concern spring 1983 - Developing theories of causation - Action in UK summer 1983 - Leaflets - Retrenchment on blood products - Increasing activity in autumn 1983 - Death from AIDS of UK haemophilia patient - WHO conference Geneva November 1983 - First documented Scottish AIDS case - Heat-treated commercial products appear - Identification of virus causing AIDS - Testing of patients begins - Positive tests in Scotland - Early NHS heat treatment - Establishment of EAGA - Development, assessment and implementation of large-scale tests of blood - PFC refining heat treatment - International conferences 1985 and 1986 - Further cases in Scottish patients with haemophilia - Further study of Scottish patients - UK concern about continuing new cases in haemophilia and blood transfusion - The Edinburgh cohort - Financial supports and medical treatment.
8.1 In this chapter, the period 1981–1985 is dealt with. The most serious issue to emerge during this period for people with haemophilia and for those involved in treating them, or preparing products for their use, was HIV/AIDS. Non-A Non-B Hepatitis (NANB Hepatitis) remained a problem both in relation to blood products and transfusion of whole blood; events relating to it during this period are dealt with separately in chapter seven.
8.2 Key issues for this Inquiry regarding AIDS are:
• the recognition of the new syndrome internationally and in Scotland;
• the emerging realisation that there appeared to be transmission by a blood-borne agent, posing risk to those undergoing blood transfusion or treatment with blood products;
• the identification of the virus;
• approaches to the need to :
1) minimise the risk of those who were HIV positive donating blood,
2) treat blood products to inactivate the virus,
3) test donated blood for the virus,
4) provide information to those involved.
8.3 The problems encountered were common to many countries, and this chapter therefore explores issues from an international perspective as well as examining the position in Scotland from time to time. The stage during which awareness of the nature of the condition was increasing also overlaps with the beginning of the stage where precautions began to be taken - as would be expected. Awareness of the emerging condition and responses to it are not therefore always treated as discrete topics.
8.4 The Morbidity and Mortality Weekly Report (MMWR) for 5 June 1981 published a report of pneumocystis carinii pneumonia (PCP) in five young men, all active homosexuals. They had been treated for biopsy confirmed disease at three different hospitals in the Los Angeles area. Two had died. All five had laboratory-confirmed previous or current cytomegalovirus (CMV) and candidal mucosal infection. The authors reported as follows:
The patients did not know each other and had no known common contacts or knowledge of sexual partners who had had similar illnesses. They did not have comparable histories of sexually transmitted disease.
The editorial note commented that the fact that all five were homosexuals suggested, at that stage, an association with some aspect of homosexual lifestyle or disease acquired through sexual contact.
8.5 It is possible, in retrospect, to identify deaths from AIDS occurring prior to this report, and the virus itself is thought to have moved from chimpanzees to humans, probably via the bushmeat trade in the Congo area, in the first half of the twentieth century. This aspect is more fully discussed in chapter two. The MMWR report, however, is generally regarded as the first recognition by a public health body of what became characterised in the 1980s as ‘the AIDS epidemic’.
8.6 The MMWR of 4 July 1981 reported 26 patients with Kaposi’s sarcoma (KS) in the United States of America (USA) over the previous 30 months. All these patients were homosexual men. Twenty of them were in New York and six in California. Six of these patients also had PCP. All 12 of those tested for CMV were positive. This report referred back to the MMWR of 5 June, and added that another 10 cases of PCP had now been identified in homosexual men in California. Two of those men also had KS. The editorial note commented:
It is not clear if or how the clustering of KS, pneumocystis and other serious diseases in homosexual men is related. What is known is that the patients with pneumocystis pneumonia described in the previous report showed evidence of impaired cellular immunity and previous or current CMV infection. Physicians should be alert for Kaposi’s sarcoma, PC pneumonia and other opportunistic infections associated with immunosuppression in homosexual men.
8.7 The MMWR of 28 August 1981 reported an additional 70 cases of KS and PCP
in previously healthy homosexual men. On 19 September 1981, The Lancet published
a report of eight cases of KS in young homosexual men in New York. All eight had had a variety of sexually transmitted diseases and all who had been tested for CMV and Hepatitis B surface antigen (HBsAG) gave positive results.
8.8 On 10 December 1981, an article appeared in the New England Journal of Medicine (NEJM) concerning ‘a new acquired cellular immunodeficiency’. Four patients treated at University of California Los Angeles medical centre were referred to: all were previously healthy homosexual men who had developed PCP and, in one case, KS as well. The authors speculated that a high level of exposure to CMV might account for the occurrence of the immunodeficiency. The same edition also carried an article dealing with 11 New York patients who had all acquired PCP; seven were drug abusers and six were homosexuals (two were both). The authors suggested that drug abusers and homosexuals were at high risk for PCP. The Lancet of 12 December 1981 published a letter from physicians at Duke University North Carolina, referring to the ‘newly recognised syndrome of opportunistic infections and/or KS in homosexual males’. Because of the severe immunocompromise involved, the term ‘Gay Compromise Syndrome’ had been coined. The same edition also carried a letter from physicians at the Brompton Hospital in London and the Royal National Hospital in Bournemouth detailing the case of a 49 year old man who had reported to the Brompton Hospital with a three month history of weight loss, general malaise and increasing breathlessness. He was homosexual and travelled to Florida regularly.
He had been diagnosed with PCP and CMV, but had no underlying immune deficiency. The journal asked in its editorial ‘What is the cause of this outbreak of bizarre infections and a rare tumour in these young homosexuals?’
8.9 On 13 February 1982, the British Medical Journal (BMJ) carried an article entitled ‘Human cancers and human viruses’ by A P Waterson, Professor of Virology at the Royal Postgraduate Medical School in London. This article referred to the recent cases of KS in the USA:
occurring at what is, for the United States, an unusually early age in an unusually generalised form with an unusually rapid progression, together with pneumocystis caused by organisms which behave as pathogens only in immunosuppressed patients. Is there a common cause for the immunosuppression and the neoplasm?...Almost to a man, homosexuals show evidence of past or present infection with CMV. The presence of CMV might therefore explain both the immunosuppression and the oncogenesis. This is a tidy concept, but it may be by no means the whole picture: some drugs, euphemistically dubbed ‘recreational’, may have an immunosuppressive role in what has been termed the ‘gay compromise syndrome’.
8.10 On 11 June 1982, MMWR reported that, up to 28 May 1982, the Centers for Disease Control and Prevention (CDC) had received reports of 355 cases of KS and/or serious opportunistic infections, especially PCP, in previously healthy persons between 15 and 60 years of age. Of those, 281 were homosexual or bisexual men, 20 were men of unknown sexual orientation, 41 were heterosexual men and 13 were heterosexual women. The proportion of heterosexuals was higher than previously described.
8.11 On 9 July, 1982, opportunistic infections and KS were reported in Haitians living in the USA.
8.12 On 16 July 1982, MMWR carried a report of PCP in three persons with Haemophilia A but no other underlying disease. All were male and two had died. All were from geographically distant parts of the USA and were heterosexual males, with no history of intravenous drug abuse. All had received frequent administration of Factor VIII concentrate; their usage of these products had been reviewed and no two had received concentrate from the same lots. The editorial note commented:
The clinical and immunological features these three patients share are strikingly similar to those recently observed among certain individuals from the following groups: homosexual males, heterosexuals who abuse IV drugs and Haitians who recently entered the US. Although the cause of the severe immune dysfunction is unknown, the occurrence among the three hemophiliac cases suggests the possible transmission of an agent through blood products …. CDC has notified directors of hemophilia centres about these cases and, with the National Hemophilia Foundation, has initiated collaborative surveillance. A Public Health Service advisory committee is being formed to consider the implications of these findings.
8.13 The BMJ of 3 July 1982 carried an article entitled ‘Severe Acquired Immunodeficiency in European Homosexual Men’, which described the cases of four Danish men who had developed KS or opportunistic infections. Three of the men had never been to the USA.
8.14 At the joint meeting of the 19th Congress of the International Society of Haematology and the 17th Congress of the International Society of Blood Transfusion in Budapest in August 1982, Dr Aledort reported that the most recent problem to surface in the treatment of haemophilia in the USA had been the three deaths from pulmonary infections. This had been linked to the development of AIDS. Dr Peter Foster attended this meeting on behalf of the Protein Fractionation Centre, Edinburgh (PFC), and recorded this information in his report of the proceedings.
8.15 It can therefore be observed that by autumn 1982:
• there had been a succession of reports, mainly but not exclusively in the MMWR, indicating the existence of a seemingly new syndrome which affected the immune system and which led to serious and often fatal illnesses in those affected;
• it was apparent that the syndrome was occurring in the United Kingdom and elsewhere in Europe;
• the presence of the syndrome in people with haemophilia had been reported;
• the use of concentrates by people with haemophilia had been considered as a possible explanation for their acquisition of the syndrome; and
• both through attendance at an international conference and through dissemination of published articles, there will have been an awareness of these issues in those working in the field of blood transfusion in Scotland.
Initial United Kingdom Response
8.16 The UK Haemophilia Centre Directors met in Manchester on 13 September 1982. The meeting was chaired by Professor Arthur Bloom of Cardiff. Those present from Scotland were: Dr F E Boulton, Edinburgh Blood Transfusion Service; Dr C D Forbes, Glasgow Royal Infirmary (GRI); Dr C A Ludlam, Edinburgh Royal Infirmary; Dr R J Perry, Scottish National Blood Transfusion Service Protein Fractionation Centre (pm only); Dr C R M Prentice, GRI; Dr R A Sharp of Ninewells Hospital, Dundee; and Dr Vosylius of Raigmore Hospital, Inverness. On page 10 of the minutes, in the section dealing with ‘Any Other Business’ and under the heading ‘The acquired immune deficiency syndrome’ it is noted that:
The Directors had asked Dr Craske to look into the report from the United States of this syndrome, mainly in homosexuals but including three haemophiliacs. It appeared that there was a remote possibility that commercial blood products were involved. Dr Craske asked the Directors to let him know if they had any cases of the syndrome. The [Hepatitis] Working Party was considering the implications of the reports from the USA.
The finalised minutes of this meeting were sent out on 5 May 1983.
8.17 None of the minutes of the meetings of the Scottish National Blood Transfusion Service (SNBTS) Directors in 1982 includes any discussion of AIDS. The Directors of the SNBTS and the Haemophilia Directors met at St Andrews House on 21 January 1983. The previous joint meeting had been on 30 January 1981. Item six of the meeting on
21 January related to AIDS. The minutes read as follows:
6 (a) Acquired Immune Deficiency Syndrome (AIDS)
Dr Cash drew members’ attention to recent articles in the United States, and also in the Observer and the Lancet, about this problem. An MMWR extract (CDC, Atlanta) had been circulated with his paper. Dr Ludlam informed members that in the UK a letter and questionnaire had been sent out to haemophilia directors.
The next joint meeting was arranged for February 1984.
8.18 On 24 January 1983, a meeting chaired by Professor Bloom was held at Heathrow Airport with a Dr Eibl, a representative of the drug company Immuno. There were at least 24 doctors present. Almost all the discussion related to the company’s current research into possible methods of reducing or eliminating the risk of transmission of NANB Hepatitis in Factor VIII and Factor IX concentrates, and to introduction of these products into the UK. The Immuno note of the meeting only mentions AIDS very briefly:
13. The possibility of reducing the risk of AIDS was not known at this stage. In any case it is not known if AIDS is caused by a virus or an attacker inimical to T cells.
8.19 However, according to the other note of the meeting there was discussion of AIDS in the afternoon, with an update being given by Dr Craske. The note summarises this update as follows:
The basic lesion appears to be intractable and to be caused through impaired cellular-mediated immunity. The population groups affected include promiscuous homosexuals, heroin addicts, immigrants into the US from Haiti (these are not necessarily homosexuals or addicts, and one such individual may well have acquired his disease outside the US) …
Up to 10 December 1982, some 800 people had been reported as suffering from AIDS, and there was a 45% mortality.
Ten haemophiliacs in the US have been affected and five have died. The youngest was aged 7. All cases have had prolonged treatment with Factor VIII, but there is no specific implication of one particular product or batch. Other cases involving blood and blood product transmission have included platelets transfused in three cases. In one of these cases, one of the donors was a young New York man in his twenties. A second case was a 20 month old child with Rhesus HDN who had received several units, including platelets known to have come from a homosexual donor who was asymptomatic at the time, but who later died. The child has developed autoimmune haemolytic anaemia and a possible AIDS state….
In the UK, so far only one or two cases have been reported from the communicable diseases centre.
Spring 1983 - increasing concern
8.20 An article in the New Scientist of 3 February 1983 recognised the risk that AIDS was transmitted by blood products. It stated that the hunt for the cause of the disease:
has now labelled as a prime suspect some unknown blood-borne virus….In the last year, a task force under Dr Harold Jaffe at the Center for Disease Control in Atlanta, Georgia, has found seven cases of AIDS among haemophiliacs….Jaffe believes that the spread of the disease may be connected with new preparations of Factor VIII concentrate – the blood-clotting agent given to haemophiliacs – which are made up from blood from large numbers of donors rather than one individual. If this is correct, any patient in hospital who is given a blood transfusion could be at risk if one of the donors of the blood carries the virus. No cases of AIDS among British haemophiliacs have been reported so far - even though 50 per cent of the Factor VIII used in Britain comes from the US.
8.21 In the USA, the idea that specific precautions needed to be taken was gaining ground. In January 1983, the withdrawal of factor concentrates had been mooted in an editorial in the NEJM, ‘even though [there might not be] enough evidence to demand such a radical change.’ The same edition of the NEJM carried articles concerning impaired immunity in patients with haemophilia and the T-lymphocyte populations in patients with classic haemophilia. The former article noted that the epidemiology of AIDS was suggestive of a blood-borne transmissible agent; whether the abnormalities in cell-mediated immunity in patients with haemophilia and, in particular, in those who had also developed opportunistic infections, were due to the putative blood-borne pathogen was not yet clear. The latter article found abnormal T4/T8 ratios in 57% of the users of commercial concentrates in their study and none in the users of Cryoprecipitate. In The Lancet of 29 January 1983, an article narrating the cases of two multiply transfused haemophilia patients concluded that ‘transmission of an infectious agent in blood products seems likely’. In March 1983, the American Association of Blood Banks published an information leaflet for donors entitled ‘An important message to all blood donors’. It asked donors to refrain from donating blood if they were in any of a number of identified groups. On 4 March 1983, the US Public Health Service recommended that, although the cause of AIDS remained unknown, as a temporary measure, members of groups at increased risk of AIDS should refrain from donating plasma and/or blood, centres collecting such material should
inform potential donors of that recommendation, physicians should adhere strictly to medical indications for transfusions, autologous transfusions should be encouraged and work should continue towards safer blood products for haemophilia patients. On
22 March 1983, recommendations to similar effect were issued from the US National Centre for Drugs and Biologics.
8.22 The March-April edition of Transfusion published a joint statement on AIDS related to transfusion. The statement was dated 13 January 1983, and had been developed by the American Association of Blood Banks, the American Red Cross and the Council of Community Blood Centres, with both voluntary and government assistance. It recommended that physicians should be further educated regarding the importance of balancing the decision to use each blood component against the risks of transfusion be they well-established or, like AIDS, under investigation. Donor screening should include questions to detect possible AIDS or exposure to patients with AIDS. Although efforts to recruit donors should not be targeted towards groups which might have a high incidence of AIDS, direct or indirect questions about a donor’s sexual preference were inappropriate. The presently available evidence that AIDS could be spread by blood components remained incomplete.
8.23 On 2 April 1983, an editorial in The Lancet entitled ‘Acquired Immunodeficiency in Haemophilia’ referred to reports from the USA of haemophiliacs who had received Factor VIII concentrates developing AIDS. The editorial also stated that the links must be regarded as not proven; whilst careful surveillance must continue, the reported cases did not constitute a strong argument for a change in treatment policy. On 30 April, letters in The Lancet reported AIDS in 11 haemophilia patients in the USA and three in Spain who had received commercial concentrate. Dr Spence Galbraith, Director of the Communicable Disease Surveillance Centre (CDSC) in England and Wales, contacted the health authorities in Spain and discovered that the three cases in Spain had all received Factor VIII from the USA.
8.24 On 9 May 1983, Dr Galbraith sent a paper ‘Action on Aids’ to Dr Ian Field of the Department of Health and Social Security (DHSS). He stated:
I have reviewed the literature and come to the conclusion that all blood products from blood donated in the USA after 1978 should be withdrawn from use until the risk of transmission by these products has been clarified.
This paper was considered at a meeting of the biological sub-committee of the Committee on the Safety of Medicines on 13 July 1983, and rejected.
8.25 In May 1983, the Haemophilia Society took steps to reassure members about AIDS. Professor Bloom, who was chairman of the Haemophilia Centre Directors, a senior member of the Society’s own medical advisory panel and a member of the Central Blood Laboratories Authority, was contacted by the Society and provided a letter dated 4 May containing the following passage:
The cause of AIDS is quite unknown and it has not been proven to result from transmission of a specific infective agent in blood products. The number of cases reported in American haemophiliacs is small and in spite of inaccurate statements in the press we are unaware of any proven case in our own haemophilic population.
Neither have any cases been reported from Germany where massive amounts of American concentrates have been used for many years. Nevertheless the situation is being closely monitored by the Haemophilia Centre Directors and in a more general way by the Communicable Disease Surveillance Centre in London. In addition the importation of licensed blood products has always been strictly monitored and controlled. Thus whilst it would be wrong to be complacent it would equally be counter-productive to alter our treatment programmes radically. We should avoid precipitate action and give those experts who are responsible a chance continually to assess the situation.
This was distributed by the Society.
8.26 On 13 May 1983, there occurred a special meeting of the UK Haemophilia Reference Centre Directors at St Thomas’s Hospital, chaired by Professor Bloom. This was arranged specifically to discuss the problem of AIDS. On 17 May, the Haemophilia Society wrote to an official at the DHSS recording their wish to meet a minister as soon as possible after the election, with one of their concerns being ‘No ban on the importation of American concentrates meantime’.
8.27 On 20 May 1983, there appeared an article in the journal Science reporting that scientists at the Institut Pasteur in Paris had isolated a retrovirus from a patient with pre-AIDS symptoms. This virus came to be known as LAV (Lymphadenopathy Associated Virus) and was later recognised as identical to that isolated by Dr Robert Gallo and his team at the National Institute of Health in the USA in 1984. The significance of the French discovery was not generally appreciated in 1983; the topic of the isolation of the virus and identification of its role in the causation of AIDS is dealt with later at paragraphs 8.81 to 8.85.
8.28 On 24 May 1983, AIDS was discussed at a meeting of the SNBTS coordinating group. The minutes read as follows:
Dr Mitchell reported that he had introduced into the health questionnaire to donors a question inviting those who were worried about AIDS to consult the doctor at the session. It was understood that the AABB’s advice to blood banks in the USA was that individual donors should sign a statement to the effect that they had read the literature and understood that certain groups of donors had been asked to refrain from donating.
Dr Urbaniak had decided, after consideration, not to do anything locally, his view being that once a donor had entered the session it was too late to make an approach and the problem was minor in NE Scotland.
Dr McClelland had prepared a leaflet (which he tabled) which explained through questions and answers the background to the recent publicity and detailed those donors who should refrain from donating blood. He intended to consult some of the organisations representing the ‘gay’ community through which his leaflet might be circulated. It might go also to VD clinics and possibly also to drug abuse centres.
There was discussion about the transmission of AIDS through needle-stick injuries and it was agreed that it was important to assure staff that management were striving to deter possible carriers from donating blood.
8.29 In May 1983, Dr Boulton wrote to Professor Bloom. Professor Bloom replied on
23 May, apparently having found Dr Boulton’s suggestions of limited use, since the issues raised by Dr Boulton had been discussed several times amongst ‘those concerned with haemophilia treatment’ and had been the subject of a special meeting of the Haemophilia Reference Centre Directors recently. Professor Bloom commented that it would be counter-productive to ban the importation of blood products at that moment.
8.30 On 28 May, a letter from doctors at Edinburgh Royal Infirmary appeared in The Lancet. It referred to a study of haemophiliacs in South East Scotland. Twenty three patients, who had received exclusively SNBTS Factor VIII in the past five years and most of whom had never received commercial concentrate, had been studied. In the majority of these patients, the T4/T8 ratios were reduced. The letter suggested that it seemed likely ‘that the immunosuppression observed in haemophiliacs … results from infusion of foreign protein or a ubiquitous virus rather than a specific AIDS virus in the Factor VIII concentrates’.
8.31 On 30 May 1983, Dr FE Boulton sent a memorandum to Dr DBL McClelland to say that he had been in touch with Dr Peter Jones of Newcastle, who had reported that there should be no discrimination against anyone who wished to donate blood and, in particular, there should be no questions into their sex lives, although literature should be provided, ‘to include definition of high risk categories etc’. Dr Jones also claimed that there was a lot of doubt about the diagnosis of all the AIDS cases in the UK, and in particular the haemophiliacs.
8.32 Thus, by the end of May 1983:
• there had been articles in the UK regarding a possible link between blood transfusion and blood products and the development of the syndrome;
• in the USA, there had been recommendations about precautions to be taken in the collection of blood to reduce the risk of the causative agent entering the blood supply;
• in the UK, the possibility of withdrawal of US blood products had been mooted;
• there was no specific focus on the risk of the causative agent being in the UK blood supply;
• there was a body of medical opinion that immunological abnormalities in patients with haemophilia were due to the repeated infusion of foreign proteins rather than contamination of concentrates;
• the idea that steps required to be taken to deter donors perceived to be ‘high risk’ from donating blood had been mentioned in Scotland.
Summer 1983 - action taken in United Kingdom
8.33 On 14 June 1983, at a meeting of the SNBTS Directors, there was discussion of AIDS. Dr Gunson, who attended the directors’ meetings as a representative of the National Blood Transfusion Service (NBTS), referred to leaflets and questionnaires prepared for donors in England with a view to excluding certain groups from donating blood, namely homosexual men (especially those with multiple partners), drug addicts and anyone who had had sexual contact with a sufferer from AIDS. He reported that there was pressure for leaflets to be given to every donor rather than simply being made available. Dr McClelland had amended his leaflet following discussions with SHRG. They were to issue a press statement and to distribute the leaflet within their own organisation. There was discussion of how to deter certain donors without causing offence to others. It was also noted that the DHSS were closely involved in England and that the Scottish Home and Health Department (SHHD) should be similarly involved in Scotland. Dr Cash agreed to circulate copies of a Council of Europe paper on the subject of AIDS. In June 1983, Edinburgh and South East Scotland produced a leaflet ‘AIDS and Blood Transfusion’. The leaflet asked those in certain high-risk groups not to give blood until there was a suitable screening test. It appears to have commenced circulation around 15 June 1983.
8.34 On 15 June 1983, there was a meeting of the Factor VIII safety sub-committee, one of the sub-committees of the SNBTS Factor VIII concentrate study group formed by
Dr Cash in December 1981. The minutes of the meeting on 15 June record that:
The putative AIDS virus must be considered as a potential hazard in F VIII concentrates….
Although not proven to be a virus, this apparently infectious agent has been found in haemophiliacs in the UK. It would seem wise to try somehow to encompass AIDS inactivation along with HBV and NANB inactivation schemes. In this regard, it reinforces the choice of heat or irradiation as opposed to antibodies, adsorbents or detergents which were likely to be more specific to a particular class of virus….
Taking a pessimistic view, some viruses are known with heat resistance up to 80ºC, so 70ºC may not be sufficient…. Recent work has shown some association between AIDS and human T-cell leukaemia virus, an (RNA) retrovirus. In view of this, model virus systems including these viruses are to be set up in tissue culture if possible….’
8.35 On 21 June, the Central Blood Laboratories Authority, Central Committee for Research and Development in Blood Transfusion, first met. It was minuted that AIDS was an issue for the committee, ‘since it appeared to be transmitted through blood and blood products’. The general feeling ‘seemed to be that … not enough was known about AIDS to enable any decisions to be made’. The committee set up an ad hoc working group on AIDS in relation to blood transfusion to consider the problem of AIDS in relation to the transfusion of blood and blood products.
8.36 On 24 June, Professor Bloom and Dr Rizza wrote to Dr Ludlam at Edinburgh Royal Infirmary summarising the discussions at the meeting of Haemophilia Reference Centre Directors on 13 May 1983 at St Thomas’s Hospital. In view of the risk of AIDS, recommendations for treatment had been agreed. For mildly affected patients with Haemophilia A, treatment with Desamino-D-Arginine-vasopressin (DDAVP) should be considered. For treatment of children and mildly affected patients or patients unexposed to imported concentrates, many directors already reserved supplies of NHS concentrates (Cryoprecipitate or freeze-dried) and it would be circumspect to continue with this policy. There was as yet insufficient evidence to warrant restriction of the use of imported concentrates in other patients in view of the immense benefits of therapy, but the situation would be constantly reviewed. Use of the specified donor-recipient approach for persons with newly diagnosed haemophilia requiring only infrequent therapy should be explored. As far as Haemophilia B was concerned, the evidence to incriminate Factor IX concentrates in AIDS was even less than with Factor VIII; it seemed logical to continue to use the normal supplies of NHS concentrate.
International Conference; further responses
8.37 Between 27 and 29 June 1983, Dr Foster attended a WFH and ISTH meeting at the Karolinska Institute. Dr Foster appears to have prepared two memoranda for Mr Watt of PFC on his return. In the first, he recorded that participants had attempted to make a number of points regarding features of haemophilia patients with T-cell abnormalities: in essence, North American studies correlated lowered helper-suppressor ratios with lifetime exposure to Factor VIII or with age, whereas European studies correlated the lowered ratios with use of imported concentrates and not with local concentrates. Many European participants were implying that USA products ‘were bad news’. In response, the North American response had been ‘to cite Ludlam et al’ and then to attack the validity of the data. The general feeling appeared to be that a low ratio in haemophiliacs would not necessarily indicate a pre-AIDS condition. Dr Foster’s own feeling had been of an attempt to suppress AIDS ‘hysteria’, although some of the more scientific criticism of the T-cell situation did appear to make some sense. In the second memorandum, Dr Foster noted that:
• the epidemiological evidence strongly suggested that AIDS was caused by a transmissible agent;
• that there was a latent period of up to a year after the point of infection and then a period (which could be from 1 – 2 years) with various early symptoms not themselves specific for AIDS;
• that infected persons could transmit the disease from the point of infection; that there was predicted mortality of 100% once AIDS had developed;
• that there was strong evidence for transmission by Factor VIII;
• that surrogate donor screening tests (circulating immune complexes and anti-HBc) would identify a very high proportion (98.4%) of all AIDS cases, but would restrict the plasma pool by 10%;
• that the message from America was that the risk was remote.
The figure of one in a million as the risk had been mentioned a number of times although, Dr Foster commented, simple arithmetic suggested one in a thousand. The message (from US delegates) had been to keep on taking concentrates.
8.38 Dr Foster’s impression was that there had been a concentrated attempt from the US delegates to play down the situation and an attempt to suppress the AIDS hysteria. He also had reservations about what he described as the ‘T-cell situation’. He concluded ‘With the 1st haemophiliac case only 12 months ago and a possible incubation period from 1-3 years a number of delegates (mainly European) were clearly uneasy and felt that we may be still only seeing the tip of the iceberg’. The medical board of the WFH reached agreement on two issues. Their resolutions were:
1. There is insufficient evidence to recommend at the present any changes in treatment; therefore present treatment of haemophilia should continue with whatever blood products are available according to the judgement of the individual physician;
2. Longitudinal studies are urgently needed on the questions already mentioned, as well as better definition of the relative risk/benefit ratios of various treatment regimens.
8.39 On 30 June 1983, a document containing guidelines for handling blood and blood products was issued in south east Scotland, by Dr Smith the donor consultant. It contained information for, and instructions to, staff on the handling of donors. High-risk groups for AIDS were listed as: men with multiple male partners; intravenous drug users; Haitian immigrants to the USA; haemophiliacs; recipients of contaminated blood products; and sexual contacts of any of the above groups. The note stated that these people in high risk groups were asked to refrain from volunteering to give blood. A policy and procedures for handling those who nevertheless presented was set out.
8.40 On 11 July 1983, Dr Craske as chairman of the UK Haemophilia Centre Directors’ Working Party prepared a ‘Note on Factors to be considered in the Selection of Hepatitis Reduced Products for Clinical Trial - Evaluation of residual infectivity for Hepatitis Viruses’. He recorded that there were five cases of AIDS resulting from blood products in Europe. The infective theory for the causation of this disease was still the one that fitted all the known facts about AIDS. Consideration must, therefore, be given to the possibility that Factor VIII concentrate prepared from plasma donations obtained in the USA might be contaminated with a putative infectious agent associated with the cause of AIDS. He said that there was, as yet, no product which was not made from sources which were likely to carry a risk of a putative virus associated with AIDS being present in the plasma pool from which the Factor VIII was fractionated and which was heat-treated.
8.41 On 13 July, the biological sub-committee of the Committee on the Safety of Medicines considered a paper from Dr Galbraith suggesting the withdrawal of concentrates manufactured in the USA from blood donated after 1978. In the first place, the committee discussed withdrawing clotting factor concentrates altogether, and replacing them with Cryoprecipitate. It concluded that this was not feasible in the UK on the grounds of supply. The separate possibility of withdrawing US preparations was also discussed. Again, it was concluded that this was not feasible on the grounds of supply. Moreover, the perceived level of risk did not ‘at present justify serious consideration of such a solution’. It was anticipated that the efforts being made to secure UK independence of foreign suppliers should reduce markedly, although not eliminate, the risks to recipients.
8.42 On 22 July 1983, the Edinburgh Evening News carried a report of an interview with Mr John Watt of PFC. It was reported that Scotland was virtually self-sufficient in blood products and that only a small percentage of blood products came from the USA. As regards AIDS, the facts of the scare were reported as real, but the risk was a small one. Perhaps the people most at risk from blood infections were the staff at his centre. The case for a link between the infection and blood products was no more than strongly circumstantial. The major cause of death among haemophiliacs was still haemophilia.
8.43 On 26 July 1983, the Central Blood Laboratories Authority produced a paper headed ‘AIDS’. The paper dealt with progress with heat treatment of human plasma products, viral transmission in haemophiliacs, AIDS and means of heat treatment of blood products. It noted that AIDS was likely to include in its aetiology transmission of an infective virus; and that, in limited numbers, AIDS sufferers had included individuals receiving human blood-based fractions. That aetiological observation had prompted more activity in the area of blood products pasteurisation on the empirical view that a virus was involved and, as with hepatitis virus, was likely to be partially or completely inactivated by heat. Heat treatment was the most favoured route of viral inactivation at that time. It could take place during the process of blood product purification, ie during a wet process step or, alternatively, heating a finished freeze-dried product could be attempted. Heat transfer in the wet state was more homogeneous and efficient and, to satisfy reliability in manufacture, was to be preferred. However, wet treatment was associated with more molecular damage of heat-unstable proteins than occurred with the dry-heat route.
The majority of commercial manufacturers were using dry-heat treatment of finished Factor VIII to reduce the infectivity of the product relative to transmission of hepatitis. There were associated claims (said to be entirely unfounded in scientific terms) that the heat process would inactivate the putative virus causing AIDS.
8.44 By 31 July 1983, 14 cases of AIDS had been reported to the UK CDSC; six were cases of KS without PCP, five were cases of PCP without KS and three involved other opportunistic infections. Five patients had died: they were all adult homosexual men. One of the 14 patients was a haemophiliac who had received Factor VIII imported from the USA. The risk from blood products imported into Britain was considered at present by the CDSC to be ‘very small’; there were about 2167 patients with haemophilia receiving treatment in the UK at that time.
8.45 Thus, by the end of July 1983:
• in the UK, the principal risk was thought to come from US blood products;
• the possibility of withdrawal of US blood products had been considered and rejected;
• there had been a move away from the unrestricted use of blood products for all patients with haemophilia;
• steps in the form of the drafting and issue of leaflets had been taken to attempt to deter those in perceived ‘high risk’ groups from donating blood;
• attention had been paid to the possibility of inactivating the causative agent by heat treatment of blood products;
• self-sufficiency was seen as part of the answer to the problem;
• the possibility that the agent was already present in the UK blood supply had not been specifically acknowledged.
Autumn 1983 - increasing activity
8.46 A meeting was arranged between representatives of the Haemophilia Society and Lord Glenarthur to take place on 8 September 1983. On 15 August, the coordinator of the society wrote to a civil servant regarding the meeting. The issues to be discussed were: the need to move towards self-sufficiency; the avoidance of banning importation of concentrates from the USA unless there was definite evidence that this was necessary; and the need for research into AIDS in the UK. An undated copy of a letter from Lord Glenarthur to the society records points made at the meeting. In considering whether the import of blood products from the USA should cease, it was deemed necessary to weigh the possible risks of infection from AIDS against the obvious risks arising from inadequate supplies of Factor VIII. Furthermore, the Food and Drug Administration (FDA) in the USA had introduced new regulations for the collection of plasma, designed to exclude donors at high risk of AIDS. All future supplies of Factor VIII were to be manufactured in
accordance with these new regulations; however, there was still a considerable quantity of pre-March stock, both in the UK and in the USA awaiting export. The FDA had decided not to ban the use of this stock, since doing so would cause a crisis in supply, in both the UK and the USA.
8.47 On 1 September, a leaflet ‘AIDS and how it concerns blood donors’ was published by the UK health departments. The leaflet asked ‘Can AIDS be transmitted by transfusion of blood and blood products?’ and answered ‘Almost certainly yes …’. The accompanying Scottish Office press release stated that no cases of the disease had been confirmed in Scotland and that there was no conclusive proof that the disease could be transmitted in blood or blood products.
8.48 On 10 September, Dr Craske issued an update for the ‘United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) AIDS investigation’ on surveillance of AIDS cases in patients with blood coagulation disorders. He reported that the first patient notified to the Oxford Haemophilia Centre as a possible case of AIDS remained in reasonable health. In July, he had had herpes labialis, but had been treated with acyclovir and had recovered. Nine suspect batches of Factor VIII transfused to this patient between 1 January 1980 and 1 March 1983 were being followed up. Another patient, a mild haemophiliac, had been largely maintained on Cryoprecipitate but in 1976 and 1978 had received NHS Factor VIII concentrate. In 1981, he had received concentrate from the USA after surgery, and had contracted NANB Hepatitis three weeks later. He had suffered other illness, and laboratory investigations in May 1983 had revealed a significant reduction in T-helper cells. His was considered to be a mild or prodromal case of AIDS. He had remained unwell through June and July and died in August. A post-mortem had revealed PCP. This was considered to be the first confirmed case of AIDS possibly associated with transfusion of blood products in the UK. The three batches transfused to him in 1981 were being investigated. Three patients with autoimmune type thrombocytopenia had also been reported and the centre was looking at cases of this disorder in people with haemophilia since 1980.
8.49 On 13 September, there was a meeting of the SNBTS Directors. The UK leaflets were discussed - they were either on display, or available on request in the west area. The position in Edinburgh was not known, as Dr McClelland was not at the meeting. Dr Wagstaff reported that in England there was still pressure to give the leaflet to every donor, but this had been resisted as there was a trial going on with different methods. Information was to be sought from Dublin on practice there. There was a note that the DHSS wanted a report in three months on the efficiency of distribution. Dr Urbaniak intended to distribute the leaflet at sexually transmitted disease (STD) clinics, an approach which was commended. Illness notices had only been amended to refer to AIDS in the west area.
8.50 On 27 September, the UK Working Party on Transfusion Associated Hepatitis met at Blood Transfusion Service, Edgware (BTS). Drs Mitchell and McClelland were present. Dr Craske reported on the two cases of AIDS discussed in his update of 10 September. Dr Craske explained that, for material involved in these cases, batches of Factor VIII and Cryoprecipitate back to January 1980 would be traced and attempts would be made to identify all other recipients of these. It appeared that no additional resources had been made available for this tracing activity. The working group expressed the view that a common policy on the distribution of an AIDS leaflet was highly desirable but failed to reach any agreement what that policy should be. Dr McClelland was of the view that serious consideration should be given to stepping up the approach and mailing the leaflet with an explanatory note to all donors.
8.51 On 28 September, there was a meeting of the Central Blood Laboratories Authority. The membership of the central committee for research and development in blood transfusion working group on AIDS was now complete, and its first meeting had been arranged for 14 October. The meeting noted that the Medical Research Council (MRC) had also set up a working group on AIDS.
8.52 The report of the UKHCDO Hepatitis Working Party for 1982–83 was produced on 28 September 1983 under the chairmanship of Dr Craske. AIDS had been discussed at the group’s meetings, and a surveillance system for the reporting of cases had been set up.
8.53 There was a meeting of the council of the Haemophilia Society on AIDS on 8 October; they were addressed by a medical expert.
8.54 On 10 October 1983 the MRC Working Party on AIDS first met. Its terms of reference were:
(1) to review scientific knowledge and research on AIDS in the UK and abroad;
(2) to encourage contact and cooperation between research workers in this field; and
(3) to advise the Council on the current state of knowledge in the field and topics for research.
8.55 The working party was chaired by Dr David Tyrrell. Dr WM Prentice of SHHD was present as an observer. The current position on AIDS was reviewed, and the varying and considerable period of incubation (one to four years) was noted. While the laboratory markers for disease were well established for AIDS itself, it was said that their relevance in screening and in a possible precursor state was not established. The problems of definition and interpretation of these so called precursor syndromes were outlined by several members. The special features arising in relation to haemophilia were discussed and the possibility of identifying the role of imported Factor VIII concentrate used for UK patients was outlined. The UK figure of 24 cases indicated that there had been a recent increase almost conforming to a six-month doubling time. In their discussion of aetiology, the group mentioned the antigen overload hypothesis as well as the ‘more widely held view that AIDS was due to a novel ‘AIDS agent’. Retroviruses were considered and it was noted that HTLV was a possible candidate on the basis of its known tropism for T-helper cells. However a critical evaluation of the data led to the view ‘that it was more probable an opportunist was unlikely to be the aetiological agent.’ The assumption that the agent was necessarily a virus was challenged and the need to keep an open mind on organisms such as protozoa was stressed. There was no reference to the Barré Sinoussi work. The fact that the epidemic in the UK was lagging three years behind the USA offered particular opportunities for research, with the potential to enhance the ability to detect emergence of AIDS in high risk groups. The UK system for haemophilia treatment and for blood product organisation would allow detailed study of cases associated with haemophilia.
8.56 On 14 October 1983 the CBLA’s central committee for research and development in blood transfusion working group on AIDS in relation to Blood Transfusion first met.
It was noted that Professor Bloom was a member of the MRC group which had met on
10 October; he was also a member of the research and development committee of the CBLA. Liaison between the two bodies seemed necessary and Professor Bloom was considered an appropriate link. So this working group decided that he should be invited to their next meeting. The chairman commented that issuing the leaflet ‘AIDS and how it concerns blood donors’ was at present the only practical step being taken by the transfusion service. The view was expressed (by the group) that a uniform system of distribution would be a good idea. Special clinics should be included and ‘gay societies’ should be contacted. The group also discussed surrogate testing, with anti-HBc being seen as preferable to TPHA. Outline proposals for a study were to be prepared for the next meeting. There was a short discussion on the importance of human T-cell leukaemia virus (HTLV) in relation to AIDS. An appended paper set out the current thinking on the epidemiological features of HTLV infection, the significance of HTLV infection in AIDS patients and the importance of screening in the UK. An inherent difficulty was that AIDS patients were susceptible to a wide range of opportunistic infections, a category into which HTLV might fall. There was discussion of the use of plasma pools containing small numbers of donors, with recognition that this would affect the plasma supply for self-sufficiency.
8.57 Between 19 and 21 October 1983 the first World Health Organisation (WHO) Europe conference on AIDS, entitled ‘AIDS in Europe, Status Quo 1983’, was held in Aarhus, Denmark. The press release for the conference, dated 30 September 1983, noted that the AIDS epidemic continued to baffle scientists. It stated that the epidemiological evidence showed clearly that AIDS was contagious and that it was probably transmitted by blood contact. No infectious agent had so far been identified but a strong candidate was a C-type retrovirus. The aims of the meeting were said to be:
1. to compile, for immediate publication, the available information concerning AIDS in Europe so as to give a picture of the initial years of the occurrence of the epidemic in this part of the world;
2. to summarise, for immediate publication, the available information concerning two pressing clinical problems, namely the nature of early prodromal symptoms of AIDS and the effectiveness of the different therapeutic strategies;
3. to draw up a set of recommendations concerning preventative measures, for the use of European health authorities and WHO; and
4. to establish a permanent international monitoring system in Europe and to develop research projects on the disease that should be carried out on a collaborative basis by countries in Europe and other parts of the world.
8.58 Thus, by October 1983:
• one person with haemophilia who had received blood product concentrates in the UK had died of AIDS;
• the viral theory as to the causation of AIDS was the most popular, but there were those who did not accept it and at least one competing theory had support from some doctors;
• the growth of the outbreak of AIDS in the UK was being charted, and the long incubation period had been noted;
• there had been considerable activity in relation to leaflets for blood donors but neither in Scotland nor in England was there consensus about the best method of distribution;
• several working groups had been set up, including one which focused specifically on AIDS in relation to blood transfusion and blood products;
• practice in relation to importation of blood products from America and in relation to their use had apparently changed little.
Further recognition of immunological abnormalities in Scottish haemophilia patients
8.59 On 15 October 1983, a paper was published by Froebel and others who were based at Glasgow Royal Infirmary, ‘Immunological abnormalities in haemophilia: are they caused by American Factor VIII concentrate?’ The authors had conducted a study of 19 Scottish patients with severe haemophilia. Seventeen patients had received American Factor VIII concentrate at some point in the last six years, but 14 had not received any in the past two years, being treated only with NHS product in that time. The Scottish patients had immunological abnormalities similar to those in their American counterparts - that is, a reduced proportion of T-helper cells, an increased proportion of T-suppressor cells and a reduced response to concanavilin A. It was also noted that addition of both commercial concentrates and NHS ones inhibited the lymphocyte response to non-specific mitogens, that is the potential for immune response. The authors commented that ‘patients with haemophilia may be assaulting their immune system every time they inject themselves’. They asserted that these results argued against a disease vector specific to American blood products.
Activity in the UK to end of 1983
8.60 On 17 October 1983, the advisory committee on the NBTS met. Dr Bell from the Scottish Home and Health Department attended as an observer. In their discussion of AIDS, they suggested that the UK could anticipate between two to four deaths among haemophiliacs from the disease. There was, as yet, no conclusive proof of a link between AIDS and blood products, but the department had produced a leaflet aimed at reducing the risk of transmission by blood donation. The two groups set up were referred to and also the fact that ACDP would be producing guidelines for staff.
8.61 On 17 October 1983, the UK Haemophilia Centre Directors held their 14th meeting, in Manchester. Those attending from Scotland were: Dr Adamson (Inverness); Dr Boulton (SNBTC); Dr Brookes (Dundee); Dr J F Davidson (Glasgow); Dr Hann (Yorkhill); Dr Ludlam (Edinburgh); Dr R J Perry (PFC). Those who sent apologies were: Dr Bennett (Aberdeen); Dr Cash (represented by Dr Boulton); Dr Dawson (Aberdeen); Dr Forbes (Glasgow);
Dr MacDonald (Glasgow) (represented by Dr Davidson); Dr Tudhope (Dundee) (represented by Dr Brookes) and Mr Watt (represented by Dr Perry).
8.62 Dr Chisholm of Southampton raised the problem of patients refusing to take up commercial Factor VIII concentrate because of the AIDS scare. She wondered if they could revert to Cryoprecipitate for home therapy. Other directors voiced similar concerns. Professor Bloom was of the view that there was no need for patients to stop using commercial concentrates because at present there was no proof that the commercial concentrates were the cause of AIDS. After discussion, ‘it was agreed that patients should not be encouraged to go over to Cryoprecipitate for home therapy but should continue to receive the NHS or commercial concentrates in their usual way’. There was some discussion of the two cases of AIDS in haemophiliacs in the UK - Dr Craske’s paper had been pre-circulated.
8.63 On 14 November, in answering a parliamentary question, Kenneth Clarke, then Secretary of State for Health, stated that there was no conclusive evidence that AIDS was transmitted by blood products, although haemophilia centres had been advised in relation to the possible risks of AIDS from blood products. On the same day a working group of SNBTS met. The SNBTS Directors and Haemophilia Directors met annually, but it had been decided to establish a working group to discuss matters of continuing interest during the year. The first meeting had been on 22 March 1983 and the second was on 14 November. The only specific discussion in relation to AIDS concerned the effectiveness of a leaflet, although progress in relation to heat treatment was also covered. On 28 November,
Dr Ray Brettle accepted an offer from Dr McClelland of appointment as Honorary Consultant in Infectious Diseases to the South East Scotland Blood Transfusion Service. Meanwhile in the USA, on 2 December 1983, the CDC advised that, as of 30 November 1983, a total of 21 AIDS cases among haemophilia patients had been reported.
8.64 The directors of the SNBTS met on 8 December and discussed AIDS. The leaflets had been available at donor sessions for some time and it was felt that now each donor should receive a copy and be asked in the health questionnaire if they had read it.
Dr McClelland was to produce a revised leaflet. He had also prepared a report on the WHO meeting in Geneva on AIDS, which he and Mr Watt had attended. An official draft report of the conference was to be issued in January 1984 and the topic was to be discussed at a subsequent meeting. As at 9 December in the UK, a total of 26 cases of AIDS had been reported to Dr Galbraith of the CDSC in London. The number of affected haemophiliacs was still reported as two. The following day, a leader article in the BMJ by Dr Peter Jones asserted that the incidence of AIDS among haemophiliacs in the UK and US was about 0.8 per thousand. He mooted as a possibility the idea that what had been seen in haemophiliacs was an entirely different disorder from that seen in homosexuals, caused by repeated antigenic challenge over many years rather than a transmissible agent. He pointed out that the median life expectancy for people with severe haemophilia had risen from 37 in 1962 to near normal in 1980. This rise was due entirely to the widespread introduction of concentrates and to comprehensive care for patients. But since no Factor VIII could be guaranteed AIDS free, Cryoprecipitate should be used to treat very young severely affected children and other options used for older people with mild haemophilia or Von Willebrand’s Disease and carriers of these disorders.
WHO Conference in Geneva, 22 – 25 November 1983
8.65 Dr McClelland and Mr Watt represented the SNBTS. The draft report of the WHO meeting in Geneva is of some length; it is not clear that a final report was ever prepared, although Walter Dowdle in his letter of 14 December to Mr Watt did request comments by 6 January for a final report to be written by WHO. There were draft conclusions and recommendations on a number of matters relating to AIDS, including surveillance, prevention and control. In the USA, diagnosis had been by the use of certain ‘marker’ conditions. It was recognised that the extent of the problem was being underestimated, both because of the technique used and because of the time lag between diagnosis and reporting. It was now recognised that cases had been diagnosed as early as 1978. The fatality rate was high – under 20% of those with AIDS were alive two years after diagnosis. In the USA, 0.7% of cases were in persons with haemophilia and no other known risk factor, and 1% of cases were in those who had received a blood transfusion in the previous five years. There were in addition paediatric cases linked with blood transfusion. The cases diagnosed were concentrated in five urban areas of the country. For Europe, 4% of cases were said to be in persons with haemophilia. The aetiology was not known but the epidemiological pattern was most consistent with a transmissible agent. Transmission appeared to occur by blood sharing; the most likely cause was a virus. The report contains a section on blood and blood products. Approaches were noted to include: educating the general public and donor groups; excluding donors belonging to high-risk groups; avoiding non-essential use of blood and blood products; and preparing and using blood and blood products in such a way as to reduce the risk of transmission of AIDS. Voluntary self-exclusion of donors required good communication with donor groups and continuous effort. It was likely to be more effective with volunteer donors and the report noted that the WHO had recommended voluntary systems in 1975. Donor screening might also be used, but since, in the absence of a specific screening test, this would be done by surrogate testing, the sensitivity and specificity of any marker would have to be assessed for the area in which it was to be used. Coagulation factor concentrates had been implicated and methods of inactivation were being developed, but these could not be evaluated until the causative agent was discovered. There were two approaches to minimising the risk from processed plasma fractions from large pools. Firstly, the number of donors per pool could be reduced - at present products could be prepared from a single donor sample or from a pool of plasma from up to 20,000 donors. Secondly, process technology aimed at reducing contamination risks could be employed (this was not further specified). The specified donor/recipient approach should be explored for those who were newly diagnosed and required only infrequent therapy. The report recommended sharing scientific information and collaboration on experiments. Patients with haemophilia and their doctors should also be informed of the potential hazards of Factor VIII and IX products including the risks related to AIDS. WHO should regularly review its specifications for blood
and blood products. An appended table listed all known AIDS cases in Europe as at
20 October 1983, a total of 268: France had 94, Germany 42, Belgium 38 and the UK 24.
8.66 Dr McClelland prepared an initial report dated 5 December 1983 on the Geneva meeting for the Scottish Regional Transfusion Directors’ meeting on 8 December 1983. As matters of direct relevance to SNBTS, he noted that there had been the following recommendations:
12.3 It was recommended that any non-specific tests considered for donor exclusion must be assessed in the relevant donor population of actual or potential donors.
12.4 The importance was emphasised of blood collecting organisations working, preferably together, with national advisory groups, to provide relevant information about AIDS to the general public and to donors, with the aim of promoting voluntary self exclusion.
8.67 Thus, by the end of 1983:
• there continued to be differing views about the aetiology of AIDS in general and, specifically, in patients with haemophilia;
• the statistics referred to when the problem of AIDS in patients with haemophilia was discussed suggested that the absolute number of persons affected was low;
• there were assessments of the likely future extent of the problem in patients with haemophilia which were to prove serious underestimates;
• there appears to have been no formal discussion in the UK of the risk to surgical patients receiving blood transfusions.
Early 1984-Further study-first Scottish AIDS case
8.68 In January 1984, an article appeared in Annals of Internal Medicine entitled ‘The Acquired Immunodeficiency Syndrome in the Wife of a Hemophiliac’. The case supported the theory that AIDS in haemophiliacs was due to an infectious agent ‘that could be transmitted heterosexually as well as parenterally’.
8.69 In 1984, the Haemophilia Society’s publication, The Bulletin (edition 32, number 1), contained an article on blood products by KE Milne. The article stated:
We have no evidence as yet [as] to whether AIDS may be acquired more readily from commercial Factor VIII than from the NHS product but, of course, if AIDS becomes established in the UK then NHS blood and plasma supplies are just as likely to transmit AIDS as commercial concentrates. All things considered, haemophiliacs have no reason to be worried about using commercial concentrates.
8.70 On 9 January 1984, a report was prepared by the blood products sub-committee of the Haemophilia Society. The report set out the annual use of Factor VIII between 1975 and 1982. After discussion, it concluded that:
there are no grounds for favouring NHS Factor VIII over commercial materials in the respects we have in the past considered relevant. In addition, of course, the marginal factors of stability and more convenient presentation favour commercial material.
8.71 It was also noted that, concerning AIDS, the facts were in very short supply. No infective agent had been identified and there was no reliable evidence that the disease was transmitted through blood products (although that seemed the most popular theory). It was recognised that, assuming the disease could be transmitted through blood products, AIDS could still be transmitted from the British donor population. In the Society’s view, the NBTS approach so far compared very unfavourably with the measures taken by the commercial companies. The AIDS scare had provided the opportunity, which had yet to be utilised, to campaign strongly for self-sufficiency in blood products. Given that the original factors in the Society’s policy no longer applied or had reduced force and that AIDS was still a great unknown, it was submitted that such a campaign should not be undertaken. It was not the time to ask that all blood product ‘eggs’ should be placed in one basket, ‘Indeed, without necessarily abandoning our long term objective, we should take
Mr Asquith’s advice ‘Wait and see’. When more facts emerge about AIDS we would then be in a better position to press for whatever action these facts seemed to demand.’
8.72 On 12 January 1984, the New England Journal of Medicine published the results of a study by Curran and others of patients with AIDS and no recognised risk factors in the USA. Patients who appeared to have been infected by blood transfusion were identified. At least one high-risk donor was identified for each of the seven cases in which investigation of the donors was complete. The authors concluded that their findings strengthened the evidence that AIDS might be transmitted in blood.
8.73 In 1984, heat-treated commercial products started to come through in the USA but were not licensed in the UK (Koate (Bayer); Profilate (Alpha)).
8.74 At the SNBTS Directors/Haemophilia Directors meeting on 2 February, Dr Cash expressed his desire to phase in (NHS) heat-treated Factor VIII for routine clinical use. A difficulty in the way of the SNBTS product was that a patient of Dr Ludlam had had an adverse reaction. (Previously, Dr Ludlam had said that he had received a supply of concentrate which had been used to treat one haemophiliac patient on three occasions spaced over a period of one to three weeks. The results compared favourably with other products used before with 8½-13 hours’ half-life and a recovery of about 80%. However the patient experienced minor adverse reactions on each occasion and had become anxious. It was not clear whether or not the product was the only cause of his upset.) There was apparently a general acceptance of the non-necessity of purchasing commercial products from abroad, given the domestic production, but one or two reasons were given why some commercial material was still required. In Glasgow and Edinburgh, children were being treated with Cryoprecipitate, given the new risk of AIDS and it was recognised that, standing reports from abroad, recipients of blood could ‘also’ be at risk. The leaflet addressed to blood donors must be given to all prospective donors.
8.75 On 9 February 1984, there was a meeting arranged by the National Institute for Biological Standards and Control (NIBSC) to examine the infectious hazards of blood and blood products, with particular reference to hepatitis and AIDS. Dr Cash and
Dr McClelland were present. Dr Thomas of NIBSC prefaced his narration of the use of blood and blood products in the UK with the observation that life expectancy for people with haemophilia had risen from 37 in 1962 to virtually normal in 1984. But the undoubted therapeutic benefit of Factor VIII concentrates was clouded by a well-recognised side-effect, namely hepatitis and, more recently, AIDS. The most recent information indicated that two UK patients with haemophilia had contracted AIDS. A recent report from the CDC had also identified 31 people in the USA who had contracted AIDS and who had been recipients of a blood transfusion. Maximum pool sizes for Factor VIII production were said to be 30,000 donors (commercial products) and 5000 (NHS product) within the past five years. Dr Cash appears to have been referred by Dr Thomas to the Scottish study in the BMJ showing that patients who had received commercial products and NHS products had similar immunological changes. Dr Tedder (Middlesex Hospital) explained that the aetiology of AIDS (in recipients of blood and blood products) was either a virus or repeated infusions of foreign proteins, or a combination of both. American strategies for excluding high risk donors were explained by Dr Petricianni of the FDA; some companies were now avoiding plasma from centres in high risk areas. Dr McClelland gave similar explanations for Scotland. He advised that the three main strategies in Scotland to minimise the risk of infection were (1) avoidance of high risk donor communities (such as prisons, known homosexual areas etc), (2) detection of clinical abnormalities by examination and careful questioning and (3) exclusion of the high risk donor, or his blood, always allowing an ‘escape route’ for the donor who is deemed unsuitable. Dr McClelland also presented data showing that the risk of acquiring AIDS by blood transfusion was about one in a million but for haemophiliacs treated with blood products was much greater. As far as laboratory tests screening for AIDS were concerned, it was generally agreed that, on present evidence, only the test for Hepatitis B core antibody was thought likely to be of value. However, there was no general agreement that such testing should be part of the routine screening carried out on all donors. The meeting also had representatives from commercial organisations: Dr H. Eibl of Immuno and Dr Ashworth of Cutter were present. There was noted to be much discussion about the optimal size of plasma pools, but no agreement that reduction of pool size would be either a practicable or a successful way to reduce the transmission of AIDS. It was agreed that, following a diagnosis of AIDS in a donor, products from pools to which that donor had contributed should be withdrawn. If a donor was only suffering from lymphadenopathy, which was associated with incipient AIDS but neither diagnostic nor specific, recall was not justified. It was recognised that the scientific rationale for this course of action left much to be desired, but that no other action could be taken which would not imperil the supply of Factor VIII.
8.76 On 11 February 1984 the BMJ contained a report of what appears to have been the first reported case of AIDS in Scotland. The report, by doctors at Glasgow Western Infirmary, concerned a male who had returned to the UK after working in East Africa for many years, and who fulfilled the criteria for AIDS.
8.77 By letter dated 15 February 1984 Dr Cash wrote to Dr Bell, SHHD. He suggested that there should be formed a single UK group responsible to the departments of health for coordinating research into blood transfusion and AIDS. Representatives should include haematologists, haemophilia centre directors and SNBTS Directors.
8.78 On 13 March 1984 the SNBTS Directors met. In their discussion on AIDS, they noted a previous agreement that the current leaflet should be sent to donors with the call-up letter. Dr McClelland was to revise it, and his revised draft had been circulated. Comments were to be sent to him. As at 26 March 1984, a leaflet by Edinburgh BTS, ‘Giving a donation of blood’ stated that donations would not be taken from those who had had infective hepatitis (jaundice) within one year or from those who had symptoms which could suggest AIDS or were in a group with an increased risk of AIDS.
8.79 On 23 May 1984, Dr Bell of SHHD expressed the view within the Scottish Office that failure on the part of SNBTS to pursue heat treatment of Factor VIII at this stage would be regarded as very difficult to defend in public, though it was acknowledged that it was too early to claim that the product would prevent the transmission of AIDS.
8.80 Thus, by May 1984:
• apparent heterosexual transmission of AIDS had been documented;
• the first report of a Scottish case of AIDS had been published;
• the number of UK patients with haemophilia who had contracted AIDS was still thought to be two;
• commercial manufacturers had begun to market heat-treated products;
• SNBTS was also pursuing the goal of heat-treated products;
• some in the haemophilia community were equivocal as to whether commercial products or NHS products were to be preferred.
Identification of the virus; development of tests
8.81 On 20 May 1983, in the journal Science, Montagnier and others at the Institut Pasteur in Paris reported the isolation of a retrovirus from cultures of T-lymphocytes derived from the lymph nodes of a patient with signs and symptoms thought to precede AIDS. They described the propagation and the characteristics of the virus:
We report here the isolation of a novel retrovirus from a lymph node of a homosexual patient with multiple lymphadenopathies. The virus appears to be a member of the human T-cell leukaemia virus (HTLV) family.
8.82 It came to be called LAV (Lymphadenopathy-Associated Virus) from the patient’s condition. The expression does not appear in the Science article. Rather, the article dealt with the differentiation of the new virus from HTLV-I and HTLV-II. But the tentative conclusion was that it belonged to a family of T-lymphotropic retroviruses that were horizontally transmitted in humans and might be involved in several pathological syndromes, including AIDS:
The role of this virus in the etiology of AIDS remains to be determined. Patient 1 (the extremely active homosexual) had circulating antibodies against the virus, and some of the latter persisted in lymphocytes of his lymph node (or nodes). The virus-producing lymphocytes seemed to have no increased growth potential in vitro compared to the uninfected cells. Therefore, the multiple lymphadenopathies may represent a host reaction against the persistent viral infection rather than hyperproliferation of virus-infected lymphocytes. Other factors such as repeated infection by the same virus or other bacterial and viral agents may, in some patients, overload this early defence mechanism and bring about an irreversible depletion of T cells involved in cellular immunity.
8.83 Montagnier later explained in A History of HIV Discovery:
Our results were still controversial, however, and we had difficulty in obtaining the funding needed to better characterize the virus and develop a blood test. The tide only turned in France when Robert Gallo and his group in the US made a similar discovery.
8.84 On 23 April 1984, at a press conference in Washington, Dr Robert Gallo of the National Institute of Health announced that he had isolated the virus that caused AIDS. Details were published in Science on 4 May 1984. Retroviruses belonging to the HTLV family and collectively designated HTLV-III had been isolated from a total of 48 subjects, some with AIDS, some with pre-AIDS and some without symptoms but in risk groups. The virus had been found to be not dissimilar to the Hepatitis C virus in that, after infection there could be a period of time, usually many months, or even years, when the patient appeared perfectly well, but was an infectious carrier of the virus. The authors concluded that HTLV-III might be the primary cause of AIDS.
8.85 Controversy, which is not of immediate relevance to this Inquiry, developed over the discovery and its attribution.
8.86 Even after these reports, there continued to be published articles suggesting that AIDS in patients with haemophilia might be due to the repeated challenge of the immune system inherent in administration of Factor VIII concentrates manufactured from large pools. On 30 June 1984 The Lancet published an article by Carr and others, Edinburgh. The article related to a study of 47 patients with haemophilia who had been treated exclusively with SNBTS Factor VIII and Factor IX concentrates, described as products from a population apparently free from AIDS. In Haemophilia A patients, the number of T cells was depressed, resulting in a reduction of the helper/suppressor ratio in about half the patients. In Haemophilia B, the helper-suppressor ratio was also depressed, attributable to a slight increase in the suppressor number and a slight decrease in the helper number. The authors concluded that these observations suggested that the immunological abnormalities resulted from transfusion of foreign proteins in blood products rather than from an infective agent in the blood products giving rise to AIDS. It was also commented that at least a year had passed since the most recent batch of plasma used to prepare these concentrates had been collected.
8.87 The same edition of The Lancet published an article by Professor Bloom of Cardiff. A survey of European haemophilia centres in 18 countries, together with previous data, pointed to 11 cases of AIDS in 13,000 treated haemophiliacs. No haemophilia patient with AIDS definitely related to transfusion of blood products was reported from Germany where very large amounts of American Factor VIII concentrates had been used for many years. Thus, in Professor Bloom’s opinion, the role of American concentrates in the causation of AIDS in European haemophiliacs must be regarded as not proven. 23 out of 135 haemophilia physicians had reduced their prescribing of American blood products and only seven had stopped using them altogether. In view of the immense benefits that haemophiliacs had derived from treatment, physicians were naturally reluctant to abandon these products, with their hypothetical dangers, in the absence of alternative concentrates which had been proven safer. That attitude might change as information accrued. Haemophilia treatment required to be monitored worldwide.
8.88 On 14 June 1984, the journal Nature reported that the companies selected by the US federal government to manufacture a blood test for AIDS were expected to be announced that week. The selected companies were to be provided with Dr Gallo’s method for mass-producing HTLV-III in return for a royalty to the government.
8.89 By August 1984, a laboratory test for AIDS, suitable at this stage for research use, had been developed by Dr Richard Tedder, Middlesex Hospital, London and Dr Robin Weiss of the Chester Beatty Institute, London. The UKHCDO made an arrangement with
Dr Tedder that they could send him samples from patients with haemophilia for testing. Dr Tedder’s work was also discussed at the SNBTS Directors’ meeting on 11 September.
Early test results
8.90 On 7 July 1984 The Lancet published a letter by Melbye and others. A study of 22 haemophiliacs from Denmark who had been treated with Factor VIII concentrate purchased from US and European commercial sources demonstrated a high prevalence of LAV: 14 of the 22 were positive. LAV was very similar to, if not identical with, the HTLV-III virus isolated from many AIDS cases in the US. Clinicians caring for haemophiliacs should consider alternative forms of therapy for the care of new patients not yet exposed to Cryoprecipitate concentrate. Until screening tests or inactivation techniques were in widespread use, commercially available Cryoprecipitate products should be considered as probably contaminated.
8.91 In August 1984 the US National Haemophilia Foundation issued the first in a series of directives to haemophiliacs to decrease the risk of transmission of HIV to their sexual partners and future offspring, including the use of condoms, and deferral of pregnancy.
8.92 On 1 September 1984, The Lancet published an article by Cheingsong-Popov and others. Two thousand persons in the UK were tested for antibodies to HTLV-III. Testing was undertaken using a competitive radioimmunoassay (RIA) and a membrane immunofluorescence assay (IFA). The assays were simple, reliable and specific. HTLV-III and LAV-1 were indistinguishable. Of 184 haemophiliacs who had received pooled clotting factors, 63 (34%) tested positive for HTLV-III. The high incidence of HTLV-III antibodies in haemophiliacs found in this and other studies had to be set against the relatively low incidence of disease in this risk group so far - roughly one per thousand haemophiliacs.
In the authors’ opinion it would be unwise to presume that AIDS would necessarily develop in seropositive subjects.
8.93 On 11 September 1984, the SNBTS Directors met. Dr Bell, SHHD, advised that it was hoped to establish a UK working party on AIDS related to the transfusion service to which Scotland would be invited to nominate a representative. Dr McClelland reported that Dr Richard Tedder (Middlesex Hospital) had acquired a significant quantity of reagents from the USA and was establishing anti-HTLV-III assays.
8.94 On 23 October 1984, Dr Craske, Public Health Laboratory Service (PHLS), circulated a letter advising that a batch of Factor VIII concentrate produced by BPL Elstree had been found to be infected with HTLV-III. One of the donors to the plasma pool had been admitted to hospital and had been found to be positive for antibody to HTLV-III. From the two cases of AIDS in haemophilia patients in 1983, they had already identified one batch of Factor VIII which was transfused to one of the AIDS patients and was associated with seroconversion to HTLV-III antibody positive in seven out of 13 recipients. It was stated that only a proportion of those transfused with an infected batch were likely to contract HTLV-III infection. Moreover, it was likely that the proportion of patients who contracted HTLV-III infection and went on to contract AIDS would be of the order of 1/100-1/500. The long-term prognosis for patients with HTLV-III infection was unknown. The incubation period of AIDS based on projections from the US CDC was from nine months to six years, with a mean of four years. There was evidence that HTLV-III infection could be transmitted by sexual contact. Preliminary information suggested that HTLV-III was readily inactivated by heat at 60ºC. An appendix dated 29 October 1984 on ‘Ethical problems associated with HTLV-III infection in haemophiliacs’ set out two strategies as to whether to tell patients of the risks where they had received a batch of Factor VIII from plasma collected from a donor subsequently shown to have HTLV-III infection or AIDS.
Dr Craske considered that the only tenable strategy on moral and ethical grounds was to tell patients.
8.95 On 26 October 1984, the US CDC published an update on AIDS in persons with haemophilia. A total of 52 cases had been reported of haemophilia-associated AIDS in the US, of whom 30 had died and only three diagnosed more than a year ago were still alive. The CDC had studied over 200 recipients of Factor VIII and 36 recipients of Factor IX concentrates containing materials from US donors. AIDS virus antibody rates of prevalence were 74% for Factor VIII recipients and 39% for Factor IX recipients. Recent research suggested that the virus was inactivated by heat treatment at 68°C. Reference was made to the paper by Levy and others discussed at paragraph 8.97 below.
8.96 In October 1984, Dr Kernoff of the Royal Free Hospital tested stored blood samples from his patients with haemophilia. Of his 100 patients who had HIV, nearly all had had the virus for a number of years, although none before 1980.
Heat inactivation of the AIDS virus
8.97 On 29 September 1984, The Lancet published a preliminary communication by Levy and others. Using mouse retroviruses, the authors had ascertained that they were not inactivated by the procedures used to concentrate Factor VIII. Thereafter, however, the retroviruses had been inactivated by prolonged heating at 68ºC in the lyophilised state. Adoption of this procedure in the manufacture of Factor VIII concentrates should result in materials free of these infectious viruses.
8.98 In studies done at CDC, in cooperation with Cutter Laboratories, USA, AIDS virus was added to Factor VIII concentrate and the factor was lyophilised and heated according to commercial manufacturers’ specifications. Infectious virus was undetectable with these regimens. Preliminary data were presented to the advisory council at the CDC in September 1984, and formed the basis of their recommendation that heat-treated lyophilised concentrates be used in the treatment of haemophilia.
8.99 On 1 and 2 November 1984, there was a conference on plasma fractionation in the Netherlands. Dr Foster attended. Results of experiments indicated that heat inactivation was effective against HIV.
8.100 Thus, by the end of October 1984:
• Researchers had found the virus that caused AIDS;
• There were still those who maintained that AIDS in patients with haemophilia might not be caused by contamination of blood products;
• Testing had begun, showing a high prevalence of antibody positivity in haemophilia patients;
• There were still those who hoped that some people with the virus might not go on to develop AIDS;
• Contamination of a batch of NHS product had been discovered in England;
• There was evidence that the AIDS virus could be inactivated by heat treatment.
Scotland - test results and responses
8.101 On 31 October 1984, Professor Eyster at the Milton S Hershey Medical Centre, the Pennsylvania State University, wrote to Dr McClelland enclosing an abstract of part of her work on HTLV-III antibodies in haemophiliacs. Professor Eyster indicated that she would be happy to exchange data with Dr McClelland on their different populations once available. By letter dated 13 November 1984, Dr McClelland advised Professor Eyster that his colleagues at the haematology department were currently studying HTLV-III antibody prevalence in a group of haemophiliacs treated largely with Factor VIII concentrates produced in Scotland and would be happy to let Professor Eyster have the information when it was assembled.
8.102 On 15 November 1984, Dr McClelland wrote to Dr Cash following the discovery that recipients of PFC Factor VIII concentrate had developed antibodies to HTLV-III during 1984 ‘which must, at present, be attributed to infusions of PFC product’. Initial analysis by Dr Ludlam and Dr Tedder showed that one batch of product had been received by all but one of the patients and was therefore highly suspect. This batch (023110090) had been withdrawn. Other batches used over the relevant period had also been looked at to determine whether any of them should also be considered for withdrawal or should be set aside for further investigation. It was concluded that no other recent batches stood out as being ‘distinctively strongly implicated’. There was therefore no obvious basis on which to advise a selective withdrawal of one or more of the other batches. Dr Ludlam had requested that the information relating to the batch associated with seroconversion be treated in confidence.
8.103 On 21 November 1984, the Blood Transfusion Service sub-committee convened by Mr R Wallace met at Trinity Park House, Edinburgh. A letter had been received from Professor Girdwood expressing concern over a misleading impression given by a recent article in the Scotsman on AIDS, which implied that Factor VIII supplies would continue to be imported from the USA, while in fact in Scotland there was self-sufficiency in the product. The minutes contain no record of any discussion regarding the recent discovery that PFC Factor VIII concentrate appeared to have transmitted HTLV-III.
8.104 On 29 November 1984, the SNBTS and Haemophilia Centre Directors met at a specially convened meeting to discuss the implications of the recent findings of HTLV-III antibodies in Scottish haemophiliacs, measures being taken by the SNBTS to prevent the spread of AIDS by blood products, and the media attention associated with these developments.
8.105 At that meeting, outbreaks in three centres were discussed. Dr Ludlam explained that 16 haemophilia patients treated exclusively with SNBTS Factor VIII had developed antibodies to HTLV-III. Dr Forbes described the findings relating to HTLV-III antibody seroconversion in a comparative study of haemophilia patients in Glasgow and Denmark. (The Glasgow research was subsequently included in an article published in The Lancet on 22 December 1984. It was a study by Melbye, Froebel and others of HTLV-III antibody in 77 Scottish haemophiliacs and 22 Danish haemophiliacs. Since 1979, the Scottish patients had been treated largely with Factor VIII concentrate produced in Scotland, whereas most of the Danish patients had received both locally prepared concentrate and commercial concentrate made from US donor material. Testing was undertaken by an enzyme-linked immunosorbent assay (ELISA). 16% of the Scottish patients (12 patients) and 59% of the Danish patients were antibody positive. All but two of the Scottish patients were known to have received commercial factor concentrate in the period 1979–84. The authors suggested that HTLV-III was distributed through haemophilia populations by Factor VIII concentrate made from US donor material).
8.106 Five out of 10 children treated at RHSC, Glasgow with imported concentrates were HTLV-III antibody positive. (It has since been asserted that a total of 18 children with haemophilia treated at Yorkhill acquired the virus from blood products).
8.107 Dr Perry explained that it would be some months before there would be routine wet heat treatment of all PFC product. Having regard to the established sensitivity of retroviruses to heat and corresponding reports of the efficacy of heat treatment at 68ºC in countering HTLV-III activity, PFC had commenced, as a short-term measure, heat treating lyophilised Factor VIII at 68ºC for two hours. Clinical trials were already in progress. Assuming these trials revealed no unexpected problems, all PFC Factor VIII being issued from about the beginning of January 1985 would be heat-treated in this way. The licensing authorities were aware of, and did not take exception to, this procedure. The possibility of batch dedication of Factor VIII was being considered but difficulty was foreseen.
Dr McClelland explained that all donors now had to sign a statement saying they had read the AIDS leaflet. Screening of donations for HTLV-III could probably not be introduced until well into 1985. Views were exchanged on the very difficult ethical problems which had arisen, including whether patients and patients’ relatives should be informed and perhaps subjected to needless worry.
8.108 On 29 November 1984, Dr Cash sent a letter to the transfusion directors summarising the actions required regarding the AIDS donor leaflet, including that each donor, prior to blood withdrawal, would be asked to sign a statement that they had read the SNBTS AIDS leaflet and that they confirmed that, to the best of their knowledge, they were not in one of the defined transfusion-related risk groups.
8.109 On 30 November 1984, Mairi Thornton of SNBTS produced a note, ‘AIDS, action taken in SEBTS to endeavour to make blood transfusion safe’, setting out steps taken between May 1983 and 30 November 1984.
8.110 On 6 December 1984, Dr Perry sent a letter to all transfusion directors. The first infusions of dry-heated Factor VIII had been successful in Edinburgh. The first batches of Factor VIII were to be dispatched to certain regional treatment centres. Continuous supply of heated product should be available after 10 December. In the New Year, non-heated products would be collected from regional treatment centres.
8.111 On 11 December 1984, the SNBTS Directors met. Dr McClelland reported a number of matters including that there was a British cell line available which would permit the growth and propagation of HTLV-III. There had been unanimous agreement to test all donors once an antibody test was available. Disappointment at the outcome of the first meeting of the NBTS working group on AIDS was recorded. There appeared to be ‘no evidence of coordination of the many splinter groups which exist(ed).’ Dr Cash would make further representations to the SHHD that there should be a more effectively coordinated UK approach to transfusion and AIDS, as already recommended by the directors. There was discussion of (PFC) Factor VIII batch 023110090, the batch implicated in the infection of the patients in Edinburgh. It was agreed that directors should continue to hold the plasma of donors who had contributed to the pool, releasing the red cells and platelets for clinical use, until the result of Dr Tedder’s test on a sample from a donor to that pool. This donor was in Dr Mitchell’s region, was presumed to be a homosexual and had given one donation ‘which was weakly positive for VD.’ Leaflets were discussed again, including the possibility of further re-drafting. Dr McClelland undertook to circulate a leaflet produced by the Terence Higgins Foundation giving to homosexuals a clear explanation that they should not give blood.
8.112 On 20 December 1984, the Scottish Office issued a news release ‘New measures to counter AIDS’, advising that the SNBTS had announced that day that all Scottish produced supplies of Factor VIII had now been heat-treated to counter HTLV-III, the virus that could cause AIDS. The move followed the recent discovery that 15 Scottish haemophiliacs who had received a particular batch of Factor VIII had developed antibodies to HTLV-III. A revised leaflet was being issued to blood donors, who were being asked to sign a statement that they had read the leaflet and were not in one of the risk groups.
8.113 A meeting to which all haemophiliacs in Scotland were invited was held just before Christmas to explain the position. It appears that media pressure led to the meeting being arranged: the Yorkshire Post wanted to run a story revealing that a number of patients in Edinburgh had become infected but agreed to hold off until the patients had been informed.
Developments in the rest of the UK to end of 1984
8.114 In the autumn of 1984, another working group was formed, this time with a focus on AIDS in relation to blood transfusion. On 26 September 1984, Dr Bell, SHHD, wrote to Dr ME Abrams, DHSS, accepting an invitation to join that group, the working group on AIDS of the advisory committee of the NBTS, and recommending the appointment of Dr McClelland as an expert member. (At the meeting of SNBTS Directors on 11 December, Dr McClelland reported that he had attended a meeting of the NBTS working group on AIDS and had found the outcome disappointing; a second meeting does not appear to have been arranged.)
8.115 By letter dated 28 November 1984 to Lord Glenarthur, the Haemophilia Society noted concern at the time gap while the supply of a UK heat-treated Factor VIII product caught up with product demand and urged that heat-treated commercial concentrates be introduced forthwith. A meeting took place on 7 December, and on 12 December 1984 Lord Glenarthur wrote to the Reverend Tanner of the Haemophilia Society confirming some of the points from the meeting. He advised that BPL would start heating their product in April 1985. Since commercially available heat-treated products were not licensed in the UK, the Committee on the Safety of Medicines had suggested that existing commercial product licence-holders be asked to make an early application for variations in their licences to allow introduction of heat-treated products. In the meantime, health care practitioners were allowed to continue to prescribe unlicensed heat-treated Factor VIII concentrates on a named-patient basis only. The choice of treatment, including prescribing unlicensed heat-treated Factor VIII, remained a matter for the judgment of the clinician responsible and the cost would be borne by the health authorities. The same suggestion regarding commercial heat-treated products was made in a letter of 29 November 1984 from
Dr RD Mann of the DHSS to Professor Bloom.
8.116 On 10 December 1984, the UK Haemophilia Reference Centre Directors met. The chairman, Professor Bloom, explained that the publicity surrounding events in Newcastle and Australia, and the continuing work on HTLV-III had precipitated the meeting. At this time, some 800 haemophiliac patients had now been tested for the antibody: the prevalence in haemophiliac patients overall was about 35%, but 75% in patients with severe haemophilia. There was a wide-ranging discussion on a number of important issues. As regards HTLV-III antibody screening, Dr Tedder advised that the Gallo cell line was available for investigation although the USA had made the isolates difficult to obtain. There were problems in obtaining the antigen. The testing of donors for HTLV-III antibody required either mass commercialisation of a British test or application of a current commercial test. It was thought that testing would be introduced at two centres in 1985 prior to widening availability to the rest of the NBTS. Dr Cash expressed concern that no central organising body was being contemplated for the test programme. Considerable concern was expressed over the lack of financial support from the DHSS.
Dr Ludlam confirmed that in Scotland some patients who were previously antibody positive were now negative. There was a long discussion on whether persons found to be positive should be informed. Several differing views were expressed. It was agreed that each clinician would decide for each case depending on the facts of the case but, in general, information would be provided if asked for. It was agreed that heat-treated Factor VIII products, if freely available, should be given to all patients, to include those found to be antibody positive. In the case of antibody negative patients, it was agreed that from now on, treatment must be with heat-treated material. Guidelines on treatment would be issued after the meeting by Professor Bloom. In a discussion on the availability and use of heat-treated Factor VIII, Dr Cash urged that the financial consideration be looked at seriously. The implications for the cost of treatment of haemophilia were enormous for the small number of patients involved. BPL’s current product had been dry-heated at 60ºC. This material had been available since March 1984 on a limited basis in solution. Current work was directed to making available limited supplies of a heat-treated product to April 1985, when it was expected that all batches would be heat-treated. Three ovens were required. One was already in use, and two were expected in March. A new product of higher specific activity was already being prepared which would withstand more severe heat treatments and other treatments designed to inactivate hepatitis viruses as well as HTLV-III. There was a discussion of the need to control the arrangements for the use of unlicensed product. Current rules allowed companies to exploit the named patient system. The regulatory bodies would also need to consider applications for variation orders and to determine whether the products were new formulations requiring new licence applications. Commercial companies were being asked to reapply for licences for heat-treated products. The meeting was concerned about the social attitudes being adopted towards AIDS patients and haemophiliacs. The situation was becoming very emotive, and common sense was giving way to panic amongst donors, patients and contact groups.
8.117 On 14 December 1984, the UKHCDO produced an ‘AIDS advisory document’, in consultation with Drs Lane, Cash, Gunson, Mortimer, Tedder, Craske and others. It was said that in the UK there had been 102 cases of AIDS with three reported haemophiliac cases, and doubtless other cases developing. HTLV-III positivity probably correlated with exposure to imported concentrates but there had been infection of at least one BPL and one Scottish batch of Factor VIII. From now on all Scottish Factor VIII would be dry heated to supply Scotland and Northern Ireland. The recommended options, in probable decreasing order of safety from AIDS, for Haemophilia A were:
(1) heated UK concentrate (which still carried a risk of NANB Hepatitis);
(2) single donor Cryoprecipitate or fresh frozen plasma;
(3) heated imported concentrate (which still carried a risk of NANB Hepatitis);
(4) unheated UK concentrate;
(5) unheated imported concentrate (almost certain to be contaminated).
8.118 Recommendations for each category of patient were set out. It was recommended that patients be HTLV-III antibody tested and patients informed, reassured and counselled regarding transmission to spouses etc if the tests were positive.
8.119 The Lancet of 22 December 1984 contained an editorial on ‘Blood transfusion, haemophilia and AIDS’. The main immediate spin-off from the virological advances reported in 1984 was that there would be large scale development of antibody tests to exclude donors who were HTLV-III antibody positive. Five American commercial firms were competing to provide test kits. There were confident predictions of success despite a high rate of false positives at present. Tests for viral antigens would also be needed, because donors were presumably infective before seroconversion occurred. The overall prevalence of AIDS in treated American haemophiliacs was about twice that in Europe, but in countries that used Factor VIII concentrate from the USA the number was likely to increase. The prevalence of HTLV-III infection in homosexuals and others seemed to be increasing rapidly in countries outside the USA; contamination of local blood products must only be a matter of time. The previous findings from Glasgow, that the Scottish haemophilia population still exhibited the abnormal lymphocyte subsets seen in other populations at risk, had to be reconciled with the current finding that no patients treated only with domestic product were antibody positive. Since HTLV-III was relatively heat labile, heat treatment of concentrates (as developed for serum hepatitis) was a step that could rapidly be introduced. Dry heat had been used for the first generation of heat-treated concentrates. While a first generation dry-heated concentrate had transmitted NANB Hepatitis (Mannucci, unpublished), the serious nature of AIDS justified a pragmatic approach and it was reasonable to switch to heat-treated Factor VIII concentrate for Haemophilia A. The position regarding heat treatment of Factor IX concentrate was less clear. Various recommendations for treatment were set out. The editorial ended by reminding readers that by far the commonest cause of deaths in haemophiliacs remained bleeding. These views were reiterated in a booklet AIDS and the Blood - a practical guide, written by Dr Jones and published and distributed by the Haemophilia Society in February 1985. Only a minority of patients who were challenged by the AIDS virus developed AIDS. The present evidence was that the great majority of people exposed to the HTLV virus were not harmed by it. Patients should not stop their haemophilia treatment as bleeding caused more crippling and premature death in haemophilia than AIDS had or was ever likely to do.
8.120 Around the turn of the year, steps were taken by the government to establish a new working group: the Expert Advisory Group on AIDS (EAGA). The group was established with the purpose of providing ‘advice on such matters relating to HIV/AIDS as may be referred to it by the Chief Medical Officers of the Health Departments of the United Kingdom’. It first met on 29 January 1985, with its existence and membership being announced in the House of Commons on 20 February 1985. Drs Cash and McClelland were members.
8.121 Thus, towards the end of 1984:
• Testing of patients for HTLV-III had begun for audit and research, and it had been discovered that at least 33 Scottish haemophilia patients were positive for the AIDS virus;
• Both NHS product and commercial products were implicated in this infection;
• All Factor VIII produced by the NHS in Scotland was now heat-treated before issue;
• Most medical experts considered that the HTLV-III virus could be transmitted by Factor VIII concentrate;
• There was still dissatisfaction at a perceived lack of coordination in the responses to the problem of AIDS in the context of blood transfusion;
• The prognosis for patients infected with HTLV-III was uncertain – a number of experts considered that such patients would not necessarily develop AIDS;
• Some haemophilia clinicians believed that only a minority of those with the virus would develop AIDS;
• The Haemophilia Society continued to press for the supply of imported heat-treated products.
Screening of blood donations
8.122 By the end of 1984, it was known that five American commercial firms were competing to develop kits for testing individual donations. On 11 January 1985, the MMWR in the USA published provisional public health service inter-agency recommendations for screening donated blood and plasma for antibody to the virus causing AIDS. All donors should be told that their blood would be tested for the virus and that they would be notified if the test was positive.
8.123 Scientists in the UK were also trying to develop tests. In order to do so, they needed an isolate of the virus. Dr Gallo had provided an isolate of HTLV-III for research purposes, but when the DHSS asked if the isolate could be used to assist in developing a test for the UK market, permission was refused. The Pasteur Institute in France were also known to be developing an antibody test based on the LAV isolated by Dr Montagnier.
8.124 By 3 December 1984, Dr Richard Tedder of the Middlesex Hospital and Professor Robin Weiss of the Chester Beatty Institute had prepared a local, independent isolate. A radioimmunoassay (RIA) from this isolate was also developed at the Middlesex. In order to develop a test kit for use by the blood transfusion services, the RIA required to be scaled up and then further work carried out to develop the actual test. The Centre for Applied Microbiology and Research at Porton Down (CAMR) was enlisted to help with the scaling up and Wellcome Diagnostics (Wellcome) were to carry out the research and development necessary to achieve the test kit. The involvement of Wellcome was said to have arisen at the instigation of Professor Weiss and Dr Tedder, who had patented the British isolate and certain aspects of their test method. They had asked all likely UK firms in this field if they were interested in becoming involved and Wellcome were ‘the most enthusiastic and quickest off the mark’. There was clear support for the principle of a UK test: for example at the 16th meeting of the Central Blood Authority on 1 February 1985, the subject was discussed. The minutes record:
The Chairman stressed that revenue sparing was as important as saving. X emphasised that the enzyme assay was a United States test and if the United Kingdom needed to be converted for enzyme testing it would pose a serious problem for the continuance of RIA testing. It was therefore considered vital that a British test be developed.
8.125 Meanwhile, the DHSS had decided that an evaluation of all the competing kits (including any developed in the UK) was necessary, so that the blood transfusion services could be advised as to which test was most suitable for them. It was seen as important that the most suitable test was chosen for NHS use, and that it was introduced uniformly throughout the NBTS. The intention behind the assessment was described as being to ‘inform the NHS through suitable media of those products which were worthy of consideration. Thereafter the would-be purchasers could make a decision based on price and the results of appraisal with local circumstances in mind’. The kits would not need a licence under the Medicines Act 1968, but such an evaluation was envisaged as helpful
in the making of choices as to which kit to purchase, although it was recognised that the DHSS had no statutory authority to force manufacturers to have their products evaluated before sale to the NHS was permitted. There was some consideration of introducing a requirement that tests have the approval of the US FDA before they were introduced in the UK, but this proposal was rejected, one of the reasons being that it ‘might not act in Wellcome’s best interests in the short term’.
8.126 The perceived need for assessment of the kits coincided with concerns expressed about the high rate of false positives from some of the kits. On 21 February 1985, Dr Cash and others from the SNBTS and NBTS sent a letter to The Lancet. There was concern that the current commercial kits for HTLV-III antibody tests were likely to give a high rate of false positive results. The effect on donors could lead to a sizeable drop in the supply of blood and blood products. While the authors strongly supported the screening of all blood donors for HTLV-III antibody, that should be delayed until test systems had been appropriately evaluated and efforts made to give the public access to HTLV-III antibody testing. The EAGA also endorsed the principle of introducing screening tests for
blood donors as soon as possible. At a meeting of regional transfusion directors on 17 April 1985, it was stressed that uniformity of action was essential among Regional Transfusion Centres.
8.127 There was recognition that the commercialisation of what was described as the BTS test (presumably the Wellcome test) and the evaluation programme for all the tests should be regarded as separate. Initially, Dr Tedder and Professor Weiss had applied for funding both to develop their own test and to assess the commercial kits, but this part of the proposal was dropped since it would ‘not be proper’. The assessments were to be coordinated by Dr Philip Mortimer of the Public Health Reference Laboratory. EAGA had a sub group considering various aspects of screening tests for AIDS. Later, an ad hoc working group to monitor progress with the assessment process was also established. The first meeting of the former group was on 15 February 1985.
Dr Tedder was a member of the former group. The proposed membership of the latter group raised concern about conflict of interest; due to redaction it is not possible for the Inquiry team to identify to whom the concern related.
8.128 The expectation appears to have been that this joint venture between academic researchers and a drug company would lead to a test developed in the UK about the same time as the American tests would become available. In fact, however, the first American test, that of Abbott Laboratories Limited (Abbott), was licensed by the United States’ FDA on 2 March 1985. A second American test, the Virgo test, manufactured by Electro Nucleonics Inc (ENI), was licensed on 7 March. Testing of blood donations was then introduced in the USA in April 1985. The DHSS was anxious that all blood transfusion authorities should wait until the results of the evaluation process were available, although the Chief Medical Officer (CMO) was concerned to monitor what was happening in other countries. Not only was there monitoring of developments elsewhere, there was also pressure being brought to bear concerning the completion of the evaluation exercise. It is also apparent that, during the process, two of the companies whose kits were involved in the evaluation withdrew material in order to replace one or other of the agents originally supplied. The preference for having a British test evaluated as a possible candidate was referred to in a briefing note for the private office of the minister of state on 30 May.
8.129 Professor Bloom was anxious that one of the FDA-licensed kits should be introduced immediately and wrote to the DHSS to convey that view. With others, he also wrote to the BMJ to similar effect, his letter being published on 22 June 1985. Three commercial HTLV-III screening kits had been approved by the US FDA. Although there might be a small number of false positives, Professor Bloom said that it was unreasonable to delay testing until that possibility was eliminated. In light of his position, the option of immediate introduction of kits from the USA appears to have been considered within the DHSS, but not followed. At the meeting of the screening test sub-group of EAGA on 10 June, there was a proposal to allow the three commercial kits due to have been evaluated by the end of June to proceed to the field test stage. However, the counter view - that it was better to wait until the PHLS had evaluated more tests, including that of Wellcome - appears to have prevailed. The paper from PHLS Colindale of June 1985 presents a slightly different picture of how far the assessment process had progressed: the first stage evaluation had begun and three companies, Abbott, ENI and Wellcome had demonstrated their assays. The summary of the paper refers to the ideal position of having one UK kit (Wellcome) and one US one.
8.130 The need to introduce testing was also raised in the House of Commons: on 27 June 1985 Kenneth Clarke, Secretary of State for Health, gave a written reply to a parliamentary question. He said that it was important that tests were accurate and could be trusted. A number of test kits were available and in use abroad but reports from those countries suggested that the tests were not entirely reliable. No test should be introduced in the UK until its reliability had been established. An evaluation programme was being undertaken by the PHLS and NBTS experts as a matter of urgency. It was hoped to introduce a test within four to five months. There was also a background note by the Chief Medical Officer on ‘Screening blood donations for HTLV-III antibody’ explaining the need to evaluate the screening tests.
8.131 At a meeting of the central committee for research and development in blood transfusion on 9 July 1985, the then chairman of Haemophilia Centre Directors said that, whilst he appreciated the need for a proper evaluation of the tests, his immediate priority, as a representative of ‘users’, was the protection of recipients of Factor VIII. He therefore considered that any undue delay in introduction of the tests would be unreasonable.
8.132 On 11 July 1985, the working party of the Regional Transfusion Directors’ Committee produced a report, ‘Screening of blood donations for anti-HTLV-III in regional blood transfusion centres’. The content of the report had been agreed with the SNBTS. The first version of the report stated that routine screening tests for HTLV-III should not be introduced until the proposed evaluation in the NBTS of different tests had enabled satisfactory system(s) to be selected. A revised version altered this: the evaluation should take place but urgency precluded the completion of the evaluation of kits prior to arrangements being undertaken for the introduction of routine screening.
8.133 Both versions stated that the other steps necessary before the commencement of screening were: that reference centres had been established to carry out confirmatory tests on sera giving positive results, and that alternative venues for non blood donors to obtain testing had been established. The last point reflected a widely shared concern that the introduction of testing would lead to those who suspected that they might have the virus trying to donate blood simply in order to be tested. In communications about the introduction of testing, health authorities were therefore asked to make provision for testing outwith blood transfusion centres.
8.134 On 30 July 1985, it was announced that the first round of the evaluation was complete, with the tests made by Wellcome and by Organon deemed most suitable for use in a blood transfusion context and, therefore, the tests which should pass on for second stage evaluation. The fifth meeting of EAGA was held that day; they considered a paper, EAGA(5)11, which would be issued to health authorities as a report on the evaluation of the kits. The kits had been tested against a panel of sera from unselected
blood donors, from groups of patients with AIDS or AIDS-related diseases, and from
groups of patients in whom false positive results were a possibility. The kits recommended as most suitable for use in diagnostic laboratories were Vironostika anti-HTLVIII (Organon Teknika Ltd), Wellcozyme anti-HTLVIII (Wellcome Diagnostics) and BTL.VIII BioEnza Bead (Ortho Diagnostic Systems Ltd). These kits provided a clear distinction between positive and negative results, had a low rate of false positives, and gave reliable results with heat-treated sera. Wellcozyme anti-HTLVIII and Vironostika anti-HTLVIII were considered to be particularly suitable for use in blood transfusion centres and were easy to use. Both these kits would be the first to be investigated in the second stage of the evaluation which was designed to investigate performance in large-scale screening of blood donors. The chairman congratulated all those concerned with the development of this work, particularly for the speed with which it had been achieved.
8.135 There was some controversy in the media at that time as to whether the process had been delayed deliberately in order to allow Wellcome to catch up with the US companies. On 8 August 1985 the New Scientist reported that the UK government had recently approved three AIDS virus test kits for use in diagnostic laboratories and two, made by Organon and Wellcome Diagnostics, had been chosen to enter the second phase of assessment for daily use at blood transfusion centres in Edgware and Manchester. According to the New Scientist, Abbott Laboratories accused the government of delaying approval until a British test was available. Abbott later wrote to the editor to deny that they had made any such accusation. The internal response of the DHSS, rebutting most of the points in the original article, is evident from a memo of 16 August. On
22 August 1985 the New Scientist published a letter by JAF Napier, medical director, NBTS, Cardiff, defending the policy in respect of the introduction of testing. Dr Barbara and Dr Hewitt of the blood transfusion service in Edgware also wrote to the New Scientist on
29 August, to similar effect. A press release of 23 August 1985 intimated the introduction of testing by mid-October and the availability of new facilities for testing elsewhere.
8.136 The third meeting of the ad hoc working group on evaluation was on 25 September; the conclusion then, after the further evaluation at Manchester and Edgware, was that both kits were suitable for the routine screening of blood donations. Some reservations were expressed about the operation of each. A minute of 29 September records a meeting between Organon, Wellcome and certain individuals in the DHSS on 27 September to discuss preparedness to meet demand for their products. Organon thought that Scotland would ‘probably go with Wellcome’, although they might secure Aberdeen. A further press release on 1 October announced the screening of all blood donations from mid-October and emphasised how important it was that those who believed themselves at risk refrain from donating blood in order to be tested.
8.137 In Scotland, although Dr Cash appeared to favour an integrated UK approach, he also had a number of reservations about the manner in which certain aspects of the AIDS problem were being handled, including the move to testing of blood donations. The Scottish Office appears to have been kept informed of the DHSS position on screening in 1985. On 21 January, Dr Bell of SHHD gave his response to a DHSS submission regarding the introduction of screening. Although the matter was for the SNBTS, Dr Bell apparently envisaged that Scotland would follow the same approach as the rest of the UK. Others in SHHD had reservations as to the necessity for screening: a draft minute of 21 February suggesting that policy in Scotland should avoid the early introduction of testing became a final recommendation to that effect of 21 March 1985. Within SNBTS, it was agreed at a meeting of the coordinating group on 19 February that no transfusion centre in Scotland would unilaterally commence routine testing of donations for HTLV-III antibody under any circumstances and whatever pressures might be applied. It was hoped there would be a ministerial statement to the effect that testing of blood donations would not be introduced until the tests were likely to yield more accurate results. At the meeting of SNBTS Directors on 27 February, it was agreed that no testing centre would commence testing unilaterally. On 6 March, Dr Bell thanked Dr Cash for confirming that the SNBTS would hold off validation of kits until protocols had been agreed through the expert working group. At the directors’ meeting on 20 June, it was minuted that the SNBTS were awaiting the evaluation of tests arranged by the expert working group. On 20 September 1985 SM Liddle, St Andrew’s House, distributed a minute on AIDS. The availability of HTLV-III antibody tests for NHS patients and the screening of blood donations were due to commence in mid-October. The commercially available test kits had been evaluated by a panel of experts from the PHLS and a summary of the results had been made available to health boards. Confirmatory testing of positive donations would be carried out at Ruchill Hospital, Glasgow and the Clinical Virology Laboratory, Edinburgh. On 2 October 1985, the SNBTS Directors met. All four regions represented had chosen the Wellcome test; the minutes do not record which test had been chosen in the West area. At PFC, all finished product and plasma was being screened.
8.138 The Inquiry team is not aware of any person in Scotland acquiring the virus from a blood transfusion between the date when testing was introduced in the USA and
14 October 1985, when it was introduced in the UK.
8.139 The points which emerge from this survey of the process leading to the introduction of testing of donated blood are:
• the process of developing a test in the UK necessitated isolation in the UK of the virus, as it was not permissible to utilise for production purposes isolates which had been provided from the USA for research purposes;
• a decision was taken around the end of 1984 or beginning of 1985 that it was necessary to evaluate all available test kits in the UK to ascertain which were the most suitable for use in testing blood donations;
• the prospect of a test being developed in the UK as a result of cooperation between UK science and UK industry was viewed favourably in the DHSS and also by at least some working in the field of blood transfusion;
• the first tests available for the testing of blood donations for the virus were manufactured by US companies and were available in March 1985;
• there was no legal impediment to sale of such testing kits in the UK;
• there was concern in the blood transfusion field in the UK about perceived high rates of false positives with some of the early kits;
• it was accepted in Scotland in 1985 that it was necessary to await evidence and advice from the Expert Working Group and to introduce testing at the same time as the rest of the UK;
• testing was introduced in the UK in October 1985.
AIDS, January to June 1985 – increasing knowledge
8.140 In January 1985, ‘[AIDS] – an overview’ by Gracie and others was published in the Scottish Medical Journal. It was now clear that 80% of the earliest diagnosed patients with AIDS had died. There had been an exponential growth of the outbreak in all countries. The authors commented that in Scotland the AIDS virus did not seem to have affected the donor pool as yet, but a test for the HTLV-III antigen would be valuable in screening for virus contamination. The risk of a donor with a pre-clinical infection giving blood which was then processed into a pool of Factor VIII concentrate or blood products was recognised.
8.141 On 31 January 1985, Dr Perry sent a memorandum to all staff at the PFC on the subject of AIDS. In accordance with the decision of the directors in December, all donors (4000 in total) who had contributed to the pool of Factor VIII that had been implicated in infection of the Edinburgh haemophiliacs had been identified, and plasma from those individuals who subsequently gave donations had been quarantined. The decision to quarantine this plasma had been taken to safeguard both product and staff safety in the belief that additional evidence and further investigation of repeat donations would identify the infective donation(s) and permit the remaining donations to be processed.
But a suitable test was not yet available for large scale application to individual donations, with the result that it was not possible at the present time or in the foreseeable future to establish the relative infectivity of plasma pools or product batches. On this basis, the quarantined plasma was released for process.
8.142 On 5 February 1985, John MacKay, Minister for Health and Social Security, Scottish Office, answered two parliamentary questions. The first answer advised that donors were required to sign a statement that they had read the revised leaflet for blood donors and that they were not in one of the risk groups. The second stated that there was evidence that a batch of Factor VIII produced in Scotland was made from a pool of plasma containing a contribution from an apparently healthy donor who must have been exposed to HTLV-III. This batch was used for the treatment of a number of haemophiliacs, some of whom had developed antibodies to HTLV-III. It did not follow that they either had or would go on to have AIDS. On 25 February 1985, Mr MacKay told Parliament that there had been four cases of AIDS reported in Scotland and that two of the patients had died.
8.143 On 14 February 1985, a consultant virologist at the Public Health Laboratory at the Withington Hospital, Manchester, wrote to unidentified recipients regarding a recent finding that some patients with Haemophilia B were positive for HTLV-III antibody. There appeared to be no common batch of concentrate. Further testing was needed.
8.144 On 19 February 1985, there was a meeting of the AIDS group of Haemophilia Centre Directors. The meeting discussed testing, mainly in relation to the testing of haemophiliacs for the virus. Some of the concerns which had been articulated in the context of the introduction of donor screening were expressed, including that there were many false positives from use of the tests developed in the USA but that there were technical difficulties in developing a UK test. A view was expressed that centre directors should not rush into using unvalidated test systems. Another participant preferred an antigen test to an antibody test. There was also discussion of family studies, with Professor Bloom expressing the view ‘that quite a lot of families would like it’.
8.145 On 20 February 1985, in a reply to a parliamentary question, Kenneth Clarke, Secretary of State for Health, detailed the current measures being taken to control the spread of AIDS. Among other steps, he advised that imported heat-treated Factor VIII was already available for prescription on a ‘named patient’ basis. A number of abridged applications for product licences were being considered urgently. It was hoped that by April all of the Factor VIII made by BPL would be heat-treated. On 12 March 1985, in answer to a further parliamentary question, Kenneth Clarke stated that all seven applications made since November 1984 for product licences for heat-treated Factor VIII had been granted earlier in the year. 
8.146 The Lancet of 2 March 1985 contained a letter from Madhok and others. The results of testing of stored sera in the 12 Glasgow haemophilia patients who were HTLV-III positive (referred to in the paper published in 1984) showed that the earliest seroconversion occurred in 1981.
8.147 On 9 March 1985 The Lancet published a letter from Tucker and others reporting the case of a 14 year old boy who had developed antibodies to HTLV-III after being given PFC Factor VIII following a knee operation. The boy was said in the letter to be one of a group who had developed antibodies, which group was said to number 15.
8.148 On 1 April 1985, the Chief Medical Officer for Scotland issued a circular letter to chief administrative medical officers and community medicine specialists, together with a leaflet ‘Some Facts about AIDS’ which was now available for distribution.
8.149 An international conference on AIDS, sponsored by the United States Department of Health and Human Services and the WHO, was held in Atlanta, Georgia, on 15 to 17 April 1985. It was attended by over 2000 participants from 50 countries, and was followed on 18 to 19 April by a WHO consultation to review the information presented at the conference and to assess its international implications. The group of consultants concluded that the information available at that time was sufficient to permit health authorities to take action which might reduce the incidence of AIDS among certain risk groups.
8.150 The following were the main conclusions and recommendations of the consultation:
For Member States:
• The public should be informed that LAV/HTLV-III infection is acquired through heterosexual and homosexual intercourse; needle-sharing by intravenous drug users; transfusion of contaminated blood and blood products; transmission by infected mothers to their babies; and probably through repeated use of needles and other unsterile instruments used for skin piercing. Information should be provided about the risk of LAV/HTLV-III infection and AIDS, especially to those persons, both men and women, who may be at increased risk because of multiple sexual partners. There is currently no evidence of the spread of LAV/HTLV-III by casual social contact, or within households. Countries which have yet to recognize AIDS should know that provision of timely and accurate information on this point is often necessary to allay inappropriate public concern.
• Countries should ensure that health care workers are informed about AIDS and LAV/HTLV-III infection, modes of transmission, clinical spectrum, available programme of management including psychosocial support, and methods for prevention and control.
• Each country should assess the risk that AIDS poses to its population and establish methods of diagnosis through surveillance and laboratory testing, including specific tests for LAV/HTLV-III.
• Since LAV/HTLV-III infection precedes AIDS in an individual or a community, early recognition will require serological studies in groups with potential risk of infection. WHO should encourage and assist in periodic serological studies in countries where AIDS has yet to be recognized and should ensure the collection of comparable data and a representative selection of sera.
• Where feasible, potential donors of blood and plasma should be screened for antibody to LAV/HTLV-III, and positive units should not be used for either the transfusion or the manufacture of products where there is a risk of transmitting infectious agents. Potential donors should be informed about the testing in advance of the donation.
• Risks of transmission of LAV/HTLV-III by Factor VIII and IX concentrates can be reduced through treatment by heat or other proven methods of inactivation. The use of such products is recommended.
• Potential donors of organs, sperm, or other human material should be informed about AIDS and groups at increased risk of infection should exclude themselves from donating. Whenever possible serological testing should be performed before these materials are used. This is particularly important when donor material is collected from an unconscious or deceased patient on whom relevant information may be lacking.
• Individuals with positive tests for antibody to LAV/HTLV-III should be referred for medical evaluation and counselling. Such people should inform their health care attendants of their status.
• Health authorities should develop guidelines for the total care of patients and handling of their specimens in hospitals and other settings. These guidelines should be similar to those which have been effective for care of patients with Hepatitis B.
• Countries should be aware of the importance of confidentiality of information about the results of serological testing and the identity of AIDS patients. Serological testing should be undertaken with the informed consent of the subject.
8.151 The Expert Advisory Group on AIDS met for the third time on 22 April 1985. Those members who had attended the conference in Atlanta each gave a report on those aspects pertaining to their spheres of interest. There was also discussion of the problem of irresponsible media reporting, and the need for public education.
8.152 On 17 May 1985 a letter was sent by the Deputy Chief Medical Officer for Scotland to chief administrative medical officers and community medicine specialists. He enclosed a letter for distribution to all doctors, with two papers to be enclosed with it. The first was a paper of May 1985, ‘AIDS-general information for doctors’, which had been prepared with the help of the expert advisory group and the second was a paper dated 22 February 1985 prepared by the CDSC in London giving a detailed account of the epidemiology of the condition. The first paper stated that estimates varied as to what percentage of infected individuals would ultimately develop AIDS, but it might be of the order of 10%. As at 28 February 1985 there were 62 haemophiliacs with AIDS in the US and three haemophiliacs with AIDS in the UK; in total, 132 cases of AIDS had been reported to the Communicable Disease Research Centre in the UK. The covering letter from the Deputy Chief Medical Officer (DCMO) gave more up to date statistics: there were four cases of AIDS registered ‘to date’ in Scotland and 159 cases in the UK.
8.153 On 20 May 1985, a letter was sent round the MRC working party on AIDS by Julian Peto, CRC Professor of Epidemiology at the Institute of Cancer Research, regarding aspects of AIDS not adequately monitored in the UK. The letter stated that the situation (regarding AIDS) might already be catastrophic for haemophiliacs and for homosexual men in London, but advocated effective action to limit further spread. In a paper which Professor Peto enclosed, he suggested that many and possibly the majority of seropositive individuals might eventually die of AIDS. A systematic international collation of these results should be organised to attempt to project the eventual prognosis by conventional actuarial analysis. The estimates as to the progression of the epidemic indicated the scale of the research effort required. Even the fact that AIDS was always, or almost always, fatal was still not universally appreciated, as only half the diagnosed cases had so far died. Only a minority, if any, of the general population might be capable of mounting an effective immune response to initial infection, and it seemed likely that the chronic infection that ensued constituted a permanent infective carrier state. Information regarding the spread of AIDS in the heterosexual community could be gained through the Haemophilia Society, with heterosexual contacts of unmarried haemophiliacs being even more informative. Every opportunity to study sexual and family contacts of seropositive heterosexual individuals should be exploited. These included haemophiliacs, heterosexual seropositive Sexually Transmitted Disease (STD) clinic patients, and of course all heterosexual AIDS patients. As far as the organisation of research was concerned, the present system, under which separate laboratories, clinics and haemophilia groups conducted limited studies with individual, uncoordinated and usually inadequate grants was not satisfactory.
8.154 On 23 May 1985, Dr Ludlam sent Dr Perry a copy of the final draft of the Edinburgh Royal Infirmary (ERI) study of Edinburgh haemophiliacs. The article was published in The Lancet on 3 August 1985. Fifteen haemophiliac patients had acquired HTLV-III, presumed to be from a batch of SNBTS Factor VIII concentrate administered between March and May 1984. One other patient became seropositive but had not received that batch.
8.155 On 31 May 1985, the AIDS information and advisory group at Glasgow Royal Infirmary met. A range of issues was covered. Of Glasgow haemophilia patients tested to date, those treated with commercial Factor VIII had the highest incidence of positive tests. All seroconverted between 1981 and 1983. Dr Lowe reported that 16% of West of Scotland haemophiliacs were HTLV-III antibody positive, the lowest incidence reported amongst haemophilia centres. Dr Crawford reported that the national HTLV-III test evaluation was progressing.
8.156 On 22 June, the BMJ published a letter from Professor Bloom, and Drs Forbes and Rizza. The authors no longer considered that the use of Cryoprecipitate or other non-heat-treated concentrates was justified. Moreover, the risk from ordinary blood transfusion was increasing. The risk of HTLV-III infection in patients receiving whole blood or other products from 50 or more donors in a short space of time could be as high as one in 20 in certain areas of Britain. A response was published on 20 July 1985 by Mitchell and others, Leicester Royal Infirmary, in which the authors raised concern at the recommendations that Cryoprecipitate no longer be used and the implications for those with mild and moderate haemophilia for whom DDAVP was not appropriate. One implication of the earlier letter was that there would be use of large donor-pool Factor VIII concentrates, albeit heat-treated, but ‘recurrent treatment with blood products is hazardous’. The best approach was a treatment policy designed to reduce as much as possible all the risks associated with blood products, and tailored to the needs of each individual patient. Until screening of blood donations was adopted, one helpful step would be to prepare Cryoprecipitate from the plasma of female donors only.
8.157 In The Lancet of 22 June was a letter from Levy and others stating that heating lyophilised Factor VIII for 72 hours at 68°C or the liquid product for 10 hours at 60°C would eliminate infectious ARV (AIDS associated retrovirus) if it was not present in the plasma at more than 106 infectious particles per ml.
8.158 On 28 June 1985, MMWR published a revision of the case definition of AIDS for national reporting, following resolutions agreed by the conference of state and territorial epidemiologists at the beginning of the month.
8.159 Thus, by the end of June 1985:
• There was a realisation that the mortality rate for AIDS was very high;
• There were still doctors who believed that only around 10% of infected individuals might develop AIDS;
• Others considered that it was possible that the majority of seropositive individuals might die;
• It had been ascertained that some patients with haemophilia had seroconverted much earlier than had been appreciated;
• Kits for screening donated blood were being evaluated in the UK and had been licensed and introduced in the USA;
• NHS producers in Scotland and England were routinely issuing heat-treated Factor VIII;
• Some commercially produced heat-treated products were being imported;
• There was a widespread desire for further research on AIDS, its transmission and prognosis.
1985 to 1986 - Consolidating Knowledge
8.160 In July 1985, a memo was sent within the DHSS commenting adversely on the fact that there was duplication of research and development in blood transfusion within the UK and the resultant waste of money and loss of central coordination to exploit any commercial opportunities. Greater coordination was required; within England, there should be a working group to examine the possibility of joining together to form one service.
8.161 On 4 July 1985, the Chief Medical Officer for England and Wales received a memo informing him that since 19 December 1984, all imported Factor VIII ‘cleared by NIBSC’ had been heat-treated, all Elstree material received since April had been heat-treated and all Scottish supplies had been heat-treated since 23 January 1985. The handwritten response of the CMO was that he wanted to give the secretary of state an assurance that no haemophiliacs would be infected from now on.
8.162 On 13 September 1985, the EU Committee of Ministers adopted a recommendation in relation to combating the threat of AIDS.
8.163 On 26 September 1985, a press release was issued by the DHSS and, in turn, a press release was drafted by SHHD. It was entitled ‘Countering the spread of AIDS in Scotland’. To date six people in Scotland had developed AIDS, of whom two had died. The UK total was 206 cases of AIDS, of whom 114 had died. From mid-October all blood donations would be screened by the regional transfusion centres for antibody to the AIDS virus.
8.164 On 27 September 1985, Drs Rizza and Spooner of the Oxford haemophilia centre circulated the results of a survey of patients with HTLV-III antibodies. Eighty one out of 109 haemophilia centres in the UK responded to the survey. A total of 2570 patients were tested. Of Haemophilia A patients tested, 44% were found to have HTLV-III antibody (in severely affected patients, the proportion rose to 59%). The highest percentages according to age groups were in those aged 10-14 years and those aged 20-29. The prevalence of HTLV-III antibody in Haemophilia B patients tested was 6% and in Von Willebrand’s patients 5%. Tables dated 1 October 1985 by Dr Craske gave data on AIDS related cases reported to the Oxford haemophilia centre. A total of 67 cases in patients with Haemophilia A or Von Willebrands Disease had been reported, with three cases in patients with Haemophilia B.
8.165 On 28 November 1985, a memorandum was sent to the Chief Medical Officer for England and Wales. There was ‘some hearsay evidence’ that haemophiliac patients were seroconverting to become anti-HTLV-III positive despite being given heat-treated Factor VIII. One explanation was that certain heat-treated products were not being subjected to sufficient heat treatment. PFC heated product from the period when it was treated with a very quick method might be among those implicated. BPL were rather late starters in heat treating their Factor VIII but were ‘probably now producing the safest product in the world’. The need for exactitude in stating only that heat-treated product ‘should’ inactivate HTLV-III was emphasised.
8.166 On 10 December 1985, the SNBTS Directors met. Dr Cash reported an expectation that a paper would be published by Montagnier expressing the opinion that dry heat at 68ºC for 24 hours might not eliminate the HTLV-III virus in Factor VIII concentrates. PFC were preparing experiments to determine the facts. Their long-term aim was to heat blood products at 80ºC for 72 hours. PFC had a nine month supply of Factor VIII in stock. The first Factor VIII from plasma tested for HTLV-III antibody would be issued in February 1986. A proposed study of confirmed seropositive donors and of recipients of blood subsequently shown to be antibody positive was also discussed. Dr Tedder had provided a protocol for this study, which the MRC were anxious to see proceed. After discussion of the considerable ethical problems which required to be addressed, it was agreed to support this proposal.
8.167 SNBTS has stated that, following the introduction of HIV screening, archive samples of earlier donations of any donor found to be HIV positive were tested and the fate of their previous donations was then traced. The date at which this information became
available depended on the dates on which these individuals returned to donate blood following the introduction of HIV screening, and ranged from 29 January 1986 to
7 December 1988. Products found to have been prepared using an HIV positive donation were recalled immediately this information was available. No haemophilia patient who was treated with any of these batches was infected with HIV as a consequence (the ‘infected’ batches were heat-treated between November 1984 and June 1985 and were issued for use between December 1984 and September 1985).
8.168 On 7 February 1986, there was a meeting on the virological aspects of the safety of blood products at the National Institute of Biological Standards and Control (NIBSC). There was a review of relevant virology, of viral inactivation generally and inactivation of the HTLV-III virus in particular. Dr Perry gave an overview of the Cohn fractionation process and the possible virus load in the various products. More data were needed on the effects of the individual stages of the process on virus inactivation. There was discussion of the safety of immunoglobulin products. A virus resembling HTLV-III had been isolated from two patients given commercial intravenous immunoglobulin. One of those had a definite AIDS syndrome, but he had had evidence of cellular immunodeficiency before treatment.
There had been no other clinical reports of AIDS during the last two years in patients treated all over the world with intravenous immunoglobulin. Dr Forbes presented data on HTLV-III in patients with haemophilia. The meeting was interested in whether any patients had seroconverted after treatment with heated concentrates; three recent seroconversions were referred to but these could be the effect of a long incubation period. The various test kits available and their performance were also discussed, as was the experience of screening blood donations so far. Thirteen donations out of more than 600,000 tested had been confirmed to be positive, an incidence of one in 46,000 donations, which was very low in international terms. Possible reasons for this were examined. There was consensus on a number of points at the meeting, including that there should be closer scientific liaison among BPL, PFC and NIBSC. There was also a recommendation of the establishment of a working group from these bodies.
8.169 Between 11 and 13 February 1986 there was a conference in Newcastle on AIDS sponsored by the Haemophilia Society. Dr Foster attended and produced a report. The broad base of the conference attendees had lowered the usefulness for those already working at the forefront of their subject. Dr Tedder had expressed the opinion that the small number of seroconversions following the use of heat-treated Factor VIII were due to a long delay in the latent phase of infection and not to the Factor VIII. The incidence of HTLV-III positive tests in blood donors in the USA was almost twenty times greater than in the UK. Dr Jones had spoken about the incidence in patients with haemophilia: of those who had tested positive for the virus, one per cent had been treated with Cryoprecipitate only, 10% had been treated with NHS concentrate only and 45% had been treated with commercial concentrate only. A paper on the blood transfusion service was also presented; this generated correspondence between Dr Mitchell and Dr McClelland regarding the effectiveness of the Wellcome and Abbott kits in comparison with each other.
8.170 On 5 March 1986, the SNBTS Directors, Haemophilia Directors and SHHD met. Dr Cash advised that dry heating at 68ºC for 24 hours may not inactivate HTLV-III and NANB Hepatitis. Dr Perry advised that PFC had recalled all residual stock of material heated at 68ºC for two hours for testing. No seroconversions had resulted from its use. Current information indicated that the HTLV-III virus was inactivated when dry heated at 80ºC for 72 hours; the current PFC goal was to introduce an intermediate purity product which had been treated in this manner. Details of seroconversions in patients with haemophilia and the average time to seroconversion were discussed.
8.171 On 13 March 1986, Dr Perry wrote to Dr Rotblat at the DHSS. Dr Perry had been told by Dr Cash that the DHSS had no details of Scottish seroconversions following the use of heat-treated Factor VIII, and he was therefore sending Dr Rotblat a copy of a letter from Dr Forbes on the subject. The cases were equivocal. Dr Forbes’s letter listed three patients, in each of whom HTLV-III seropositivity could have resulted from the use of SNBTS concentrates; that they had been heat-treated concentrates could not be ruled out.
8.172 On 15 March 1986, a letter by a group of physicians from North America to
The Lancet gave an account of probable HIV seroconversion following treatment with heat-treated Factor VIII concentrate.
8.173 On 25 March 1986 the SNBTS Directors met. The current status of antibody positive donations was reported as: Aberdeen nil; Belfast one; Dundee three; Edinburgh four; Glasgow two; Inverness one. The Blood Transfusion Service (BTS) were concentrating on following up patients who had received known contaminated (HTLV-III) donations. There was an update on Dr Tedder’s research: the intention was to study the epidemiology of donors and all recipients of blood/blood products retrospectively for five years. The Directors met again on 25 June. The DHSS were seeking information on virus inactivation in the manufacture of immunoglobulin by 1 July. Dr Foster listed the PFC products in stock in SNBTS centres and informed the meeting whether they were manufactured from screened or unscreened plasma. He advised that the Factor VIII material currently issued was ‘derived from unscreened plasma but it was anticipated that the position would change fairly soon.’ Most of the Factor IX products were now derived from screened plasma. A follow up study of anti-D recipients to assess HIV status was ‘not a practicable or justifiable proposition’. A table of purchases of commercial blood products by hospital pharmacies prepared by Dr Forrester of SHHD had been circulated.
8.174 On 5 April 1986, a letter was published in The Lancet from Van Den Berg and colleagues from the Netherlands giving an account of probable HIV seroconversion following treatment with heat-treated Factor VIII concentrate of American origin. According to the manufacturers, one of the donors whose plasma was included in one of the transfused batches had developed AIDS.
8.175 On 14 June 1986, in The Lancet, there was a letter from Ralph Rousell of Cutter Laboratories protesting at the failure to specify the heat treatment protocol followed
in the March and April 1986 papers by White and Van Den Berg. An editorial note stated that the heat treatment, in both cases, was 60ºC for 30 hours in a lyophilised (freeze-dried) state.
International conferences, 1986
8.176 Between 14 and 16 April 1986, the WHO held a meeting at the World Haemophilia AIDS Centre, Geneva on the safety of blood and blood products in relation to AIDS. Prior to this meeting, WHO officials and plasma fractionators met to discuss current LAV/HTLV-III inactivation methods. Thirty-three countries were represented at this meeting, principally by staff from blood banking or blood transfusion facilities, and a large staff
of participants from the secretariat of WHO, under the direction of Dr Petricciani, Chief of Biologicals.
8.177 The subjects covered at the meeting included: infection with LAV/HTLV-III virus, the discovery of two new retroviruses LAV-II and HTLV-IV, the clinical safety of immunoglobulins, donor exclusion, notification of antibody status, inactivation methods and ELISA testing. New terminology was noted, principally the use of the term ‘HIV’ (human immunodeficiency virus). There was one presentation by Dr James Allen of the CDC on transmission of AIDS by blood and blood products and another by Dr Shelby L Dietrich on patients with coagulation disorders. World Haemophilia AIDS Cause (WHAC) survey data were presented which indicated the international scope of the problem.
A review of plasma fractionation methods was followed by a summary of the discussions of the earlier meeting devoted to viral inactivation methods and testing. The salient features that emerged were that heat inactivation methods varied greatly from manufacturer to manufacturer and were sometimes confidential. Additionally, test methods used to measure viral inactivation differed and made it impossible to directly compare one method with another.
8.178 The writer of an apparently anonymous report of the conference commented that his or her overall impressions included the following:
1. WHO has recognized LAV/HTLV-III infection as a major problem in blood transfusion medicine and is mobilizing (albeit slowly) to offer technical assistance and advice to those member countries interested in and capable of taking steps to prevent LAV virus transmission and to improve the safety of blood supplies.
2. The special problems of patients with coagulation disorders were presented. The worldwide extent and number of AIDS cases in haemophiliacs seemed to be a surprise to many persons in attendance.
8.179 Between 11 and 16 May 1986, the 19th Congress of the International Society of Blood Transfusion took place in Sydney. Dr Foster produced a report in August 1986. The conference had reviewed the incidence of disease among persons with haemophilia and noted the high incidence in Newcastle. The rate for the UK as a whole was said to be 44%. The incidence of transfusion AIDS in Australia was ten times greater than in the UK. Cases of seroconversion in non-haemophiliac patients following treatment with blood products were also discussed. It was reported that the incidence of seropositivity in the USA was 74% in persons with Haemophilia A and 35% in persons with Haemophilia B. 13% of ‘haemophilia
wives’ in the USA were seropositive, with the seroconversion rate still increasing. As far as AIDS in general was concerned, retrospective screening in Kinshasa had shown a twelve-fold increase in antibody positivity between 1970 and 1980. Extrapolation backwards in time suggested that the disease first appeared in Africa in 1940. As far as treatment was concerned, Professor Bloom proposed that ‘virgin haemophiliacs’ should be treated with ‘second generation’ heated concentrates while severe haemophiliacs should continue to be treated with ‘first generation’ heated products. Professor Bloom also reported that timescales from exposure to seroconversion varied from six days to one year. The mean timescale for developing full blown AIDS was three years. The US National Haemophilia Foundation was not recommending recall of product lots containing positive donations. The sale of non heat-treated products was continuing in some parts of the world. From an Australian report, there had been no cases of seroconversion there since the introduction of heat-treated products.
8.180 Between 28 and 31 May 1986, the Committee of Experts on Blood Transfusion and Immunohaematology met at Berne. Their report was submitted to the 19th meeting of the European Health Committee of the Council of Europe at Strasbourg on 24-26 June 1986. The report tabulated data on: AIDS cases and deaths made up to various dates in 1985 and 1986; screening of blood donations; information to and counselling of donors and follow-up of patients receiving blood from antibody positive donors; cases of positive tests for the virus and of AIDS in patients with haemophilia; and treatment of haemophilia. The information on UK non-haemophiliacs at March 1986 was 342 cases of people infected with AIDS of whom 172 had died. Of 4918 people with Haemophilia A, 896 (44% of those tested) were positive. Of 896 people with Haemophilia B, 20 (6% of those tested) were positive. Mandatory screening of blood donations for anti-HTLV-III/LAV had commenced in all member countries except Spain. Only eight out of 25 countries surveyed were recorded as having introduced a comprehensive look-back programme.
8.181 In June 1986, the American Association of Blood Banks, the American Red Cross and the Council of Community Blood Centres issued a joint statement recommending that all blood banking establishments should trace recipients of blood components previously donated by persons now found to be positive for HIV, because some individuals who had a confirmed HIV antibody positive test in 1985 could have been infectious at the time of a previous untested donation. The American Association of Blood Banks issued guidelines for the notification of recipients of blood or blood components from donors who had a confirmed test for HIV.
8.182 Between 8 and 13 June 1986 the 17th Congress of the World Federation of Haemophilia took place in Milan. There was discussion in the medical community about the possible association between an AIDS seroconversion and Armour dry-heated Factor VIII (protocol: heating at 60ºC for 30 hours in a lyophilised state). Armour were recommending that all their heat-treated Factor VIII manufactured from plasma collected prior to donor screening be returned.
8.183 Thus, by the middle of 1986:
• Screening of donated blood in the UK was revealing very low numbers of donations positive for antibodies to HTLV-III;
• Rates of infection with the virus among patients with haemophilia continued to be monitored:
• There was concern about possible seroconversions related to the use of heat-treated product;
• There were suggestions that the first generation heat-treated product manufactured by PFC might be responsible for seroconversions, but these do not appear to have been substantiated;
• Heat-treated Factor IX was being issued;
• It had been recognised that the timescale between exposure to the virus and seroconversion could be as long as a year.
June to December 1986 - information and advice
8.184 In June 1986, the Advisory Committee on Dangerous Pathogens issued revised guidelines on LAV/HTLV-III, the causative agent of AIDS and related conditions. The purpose of the guidelines was to
[S]et out the measures to be taken to safeguard the health and safety of people who, because of their work, come into direct contact with AIDS or other LAV/HTLV-III infected patients or specimens from them.
But it was also recognised that the Guidelines contained a great deal of information of interest to a wider audience.
8.185 The preface commented that the number of individuals infected with the virus who had progressed to AIDS during the study period (approximately a year and a half) were in a minority. In the introduction, a summary designed for the general reader, it was observed that the International Committee on the Taxonomy of Viruses had very recently proposed the term Human Immunodeficiency Virus, but that the proposal had yet to receive general acceptance. The following comment was also made:
The majority of those infected with LAV/HTLV-III have so far remained well but the proportion of LAV/HTLV-III infections which lead to clinical disease is still uncertain. In the UK it is currently estimated that one in three seropositive individuals may become ill and one in ten develop AIDS.
It was also observed that, prior to screening of donated blood, many haemophiliacs had become infected as had a few recipients of transfusions. These routes of infection
had now been closed by a combination of measures – publicity to deter those in the risk groups from donating blood, heat-treating blood products to inactivate any virus they might contain and testing all blood donations for antibody discarding any that are found to be positive.
Rates of infection in European countries supplying figures ranged from 1.0 per million of population (Greece) to 11.9 (Belgium). The figure for the UK was 4.0 per million.
8.186 The general hazard and risk statement in the guidelines contained the following observation:
The increasing range of clinical conditions resulting from infection with LAV/HTLV-III…shows that there are very serious consequences for a proportion of those infected, although not all will necessarily develop AIDS, which to date has invariably been a fatal disease. For this reason the intrinsic hazard of infection should not be under-estimated. Estimates of the proportion of those infected who progress to AIDS over a maximum observation period of 5 years vary between 1% and 15% depending on the risk group examined. Amongst infected haemophiliacs, for example, the incidence of AIDS in a 3 year follow-up study has been approximately 1% while the higher figure is associated with the homosexual group.
8.187 On 17 July 1986 the Guardian reported the withdrawal of certain batches of Armour Factor VIII (Factorate) which had been made from plasma not screened for the virus. David Watters, coordinator, Haemophilia Society, urged haemophiliacs to continue with treatment, on the basis that the chance of infection was now very small and the dangers of bleeding episodes outweighed any other risk. Dr Peter Jones commented that the Department of Health had been warned five months ago of the possible danger, and criticised the delay in response. The relevant batches had been manufactured before January 1986. It appears to the Inquiry team to be likely that those infected by Armour product in Scotland include children with haemophilia who were treated at Yorkhill hospital in Glasgow.
8.188 On 25 July 1986, the Secretary of State for Social Services, Mr Hayhoe, responded to a parliamentary question about the safety of blood products. Since January 1986, all Factor VIII commercially available in the UK had been produced from plasma obtained
from donors who had been screened for antibodies to AIDS, Factorate had been manufactured from (plasma from) tested donors since the end of 1985, UK products had been heat-treated, and all manufactured batches commercially available in the UK were tested by the National Institute of Biological Standards before marketing.
8.189 On 10 September 1986, Dr Craske issued an update on a retrospective study of HIV-related illness. The results related to eight batches of unheated Factor VIII and two of Factor IX used between 1981 and 1985. A very high percentage of these were associated with infection. Since HIV testing had been started in the autumn of 1984, this meant that the pre-exposure anti-HIV status of many patients was not known. The small proportion of Haemophilia B patients infected with HIV was due to a lower contamination rate with Factor IX concentrate. By 22 April the total number of patients reported to the Oxford Centre with HIV related illness was 109. Twenty-three cases of AIDS had been reported; 15 of those had died. The comparative number of patients with AIDS or AIDS-related conditions in the August 1985 survey was 38.
8.190 On 3 October 1986, Drs Rizza and Spooner (Oxford Haemophilia Centre) reported on the incidence of anti-HIV in the UK based on a 1986 survey. From returns made by 84 out of a total of 109 haemophilia centres, 40.48% of Haemophilia A patients, 6.74% of Haemophilia B patients and 2.75% of von Willebrand’s patients were anti-HIV positive.
8.191 On 9 October 1986 the SNBTS Directors met again. Dr Perry summarised progress with model virus studies and differing heat treatment protocols. All the work was being incorporated in a report of the work to date, to be circulated to directors when available. The current status of HIV antibody positive donations was Inverness one; Aberdeen 0; Dundee three; Edinburgh eight; Glasgow two; Belfast two. The matter of autologous transfusion was still under review. A revised DHSS AIDS leaflet, containing donor self exclusion criteria, was circulated, but there was criticism of it.
8.192 On 12 December 1986, Mr Newton answered a parliamentary question in which he explained that the safety of the blood supply in the UK was maintained by (i) those who may have been exposed to known particular risks of infection being asked not to donate blood, and (ii) testing of all donations. No cases of HIV transmission through blood transfusion had been reported since testing was introduced.
8.193 The next meeting of the SNBTS Directors was on 17 December. An interim report of the studies referred to by Dr Perry at the previous meeting was now available. The current status of HIV antibody positive donations was Inverness one; Aberdeen nil; Dundee three; Edinburgh nine; Glasgow six; Belfast two. It was agreed to withdraw AIDS leaflets with effect from 31 December 1986, except in the west where withdrawal by that date was not practicable. The SNBTS Directors expressed concern that Scotland and England had issued different self-exclusion criteria, and considered that this should be avoided in future, preferably by the formation of a joint group to advise the DHSS on messages to donors. It was agreed that it would be necessary to consider the implementation of some form of autologous transfusion programme in the UK.
Events in and beyond 1987 - the effects of infection
8.194 On 5 January 1987, Ms PA Cox, SHHD, prepared a ministerial briefing which was copied to a number of recipients in the Scottish Office and the DHSS. There had been media coverage of the case of a leukaemia patient who had acquired HIV following a blood transfusion in August 1986 - almost a year after screening had been introduced. The donation was tested and found to be seronegative in August; when the donor gave blood again in October 1986, however, he was found to be infected. Because of the ‘window’ period, when a donor could be infected but antibody negative, it was vital that those in risk groups refrain from donating blood. The donor in this case strongly denied being a member of a risk group for HIV infection. The other patient who had received blood from the donation concerned had also developed HIV infection, but had since died from pneumonia, thought to be unconnected. There were known to be six patients in Scotland who developed HIV infection from blood donations before screening was introduced. This was thought to be the first case in the UK since the introduction of screening.
8.195 On 1 April 1987 a new antiviral drug for the treatment of AIDS, Zidovudine, became available in Scotland.
8.196 On 22 June 1987, the Scottish Office issued a press release. The latest AIDS figures for Scotland up to the end of May 1987 were a total of 20 AIDS cases, with
12 deaths; this included two haemophiliacs, who had both died. The figure also included one recipient of whole blood and one recipient of blood product, both of whom had died. (The figures for the UK were 791 AIDS cases, with 444 deaths; these included
31 haemophiliacs of whom 25 had died; one haemophiliac and intravenous drug user, who had died; and six recipients of blood in the UK, all of whom had died.)
8.197 On 25 September 1987, the UK Haemophilia Centre Directors met in London. AIDS was now the leading cause of death in UK haemophiliacs. The third national survey of anti-HIV among haemophiliacs was under way; only three new patients had been reported as being seropositive in 1987. So far, the findings strongly supported the safety, as regards risk of HIV transmission, of currently available therapeutic products. Amongst 314 sexual partners of anti-HIV seropositive haemophiliacs who had been treated,
18 (5.7%) had been found to be positive. Dr. Craske commented that this compared with rates of up to 15% in the USA. The Haemophilia Society was to launch ‘a campaign to obtain recompense for haemophiliacs infected with HIV’ on 13 December 1987.
8.198 In October 1987, there appears to have been a table in International Plasma News, showing the percentages of HIV seroconversion among haemophiliacs: Scotland had the lowest percentage, at 15%; the ‘UK’ was 46%; Canada and Spain were 69%.
8.199 On 16 November 1987, the government announced the setting up of the Macfarlane Trust to administer funds made available by the government for provision of hardship payments to people with haemophilia infected with HIV through treatment with infected blood or blood products.
8.200 On 21 December 1987, following a telephone conversation with Dr Dale Lawrence of the CDC, Professor Bloom circulated information on HIV seroconversions in virgin haemophiliacs who had received heat-treated FVIII. All had received ‘material from screened and (?unscreened) donors’. The materials seemed to have included dry heat Cutter (68°C for 72 hours) and Armour (60°C for 30 hours). Canadian research implicated the Armour product. Travenol had stopped manufacture.
8.201 On 11 January 1988, CDC held an emergency meeting at Atlanta of manufacturers and USA haemophilia doctors to discuss seroconversions to HIV positive in naïve haemophiliacs in North America who had been treated with heat-treated Factor VIII (Armour, dry heated at 60ºC for 30 hours).
8.202 On 14 March 1988, Dr Perry wrote to Prof Cash enclosing a ‘Summary of SNBTS response to HIV contamination of PFC Coagulation Factors’ and a document by
Dr Peter Foster, ‘Some notes on PFC/SNBTS strategy for eliminating the risk of infection from coagulation factor concentrates’ which also included a timeline showing the dates of issue of the different SNBTS leaflets and donor questionnaires.
8.203 On 8 August 1988, the General Medical Council issued to all doctors a statement on the ethical considerations relating to HIV infection and AIDS covering the basic duties and responsibilities of doctors, obtaining consent, especially in relation to testing for HIV, and confidentiality. The question of informing the spouse or other sexual partner of a patient who was HIV positive was specifically addressed.
The Edinburgh Cohort
8.205 The Edinburgh patients with haemophilia who had been infected by NHS Factor VIII (‘the Edinburgh Cohort’) were studied by clinicians seeking more information about HIV and AIDS. Several of the articles published about this group of people emphasise the value from a research point of view of being able to study the disease in a group with a common source of infection. The following passage, from an article in 1988, is typical:
While there have been several longitudinal studies of HIV infection extending over three years or more and including much larger numbers of subjects, the Edinburgh Cohort study is unique in at least three aspects. The patients had all been assessed before exposure to the virus; the period of exposure to infection has been defined with some precision; and, since no other risk factor has been identified in any of the members of the cohort, all are presumed to have been infected from the same source (probably representing a single virus strain). Information on the subsequent clinical course of these patients is thus of special value. 
8.206 An article in the BMJ of 27 February 1988 set out results obtained from testing serum from the group. The narrative records that there were eighteen patients affected and that ‘infection was acquired from a single batch of Factor VIII during a short period starting in March 1984’. It was also suggested that
the low prevalence of HIV 1 infection in Scotland in 1983, when blood for the batch was collected, makes it probable that the batch was contaminated by a single donation.
8.207 Thirty-two patients had been inadvertently transfused. Eighteen of those patients had undergone seroconversion. One patient had undergone seroconversion after leaving Edinburgh, and so serum samples from him could not be tested and he had been omitted from the study. Serum samples were taken from the other patients, for unrelated reasons, from before transfusion to the time of writing, although no samples were available for three patients after the first year of infection. Eight patients had developed symptoms before March 1987 (‘the unwell group’) and the other ten remained asymptomatic in mid 1987. The symptoms included persistent generalised lymphadenopathy (‘PGL’), AIDS Related Complex (‘ARC’) and AIDS. The number of units transfused ranged from 9-109; the two patients at opposite ends of this range were in the unwell group. The authors tentatively suggested that there was a relationship between the amount of Factor VIII transfused and time to seroconversion. Were that so, it would emphasise the association found previously with the amount of the contaminated batch used by these 18 patients, which was larger than that used by the other 14 patients, who remained seronegative. The incubation period ranged from 35 days to over 160 days. It was possible that similar amounts of antibody in the well and unwell patients indicated a poor prognosis for patients even if they remained asymptomatic.
Much of the variability in the course of infection was clearly the result of differences in susceptibility of the patients to infection.
8.208 Although primarily concerned with matters of genetics, an article in The Lancet in May 1988 reveals further details about these 18 patients.
8.209 The youngest patient, a boy aged 14 at the time of infection, had died in 1987. He appears to have developed AIDS in 1985, with initial symptoms of weight loss, fever, malaise and diarrhoea. Later, he suffered from PCP, cryptococcal meningitis and AIDS encephalopathy. At the time of his death, he was suffering from Hodgkin’s Disease.
8.210 The oldest patient in the group was born in 1941. One other patient had died in 1987, aged around 42.
8.211 The progression of disease in the Edinburgh cohort is further evidenced by a paper written in 1988. This paper recorded that in most centres at least 60% of severe haemophiliacs had developed antibodies to HIV; this related ‘to the predominant use of commercial Factor VIII concentrates’. The infected batch for the patients in the Edinburgh cohort had been transfused between March and May 1984, and 18 patients were found to have developed antibodies between April and November 1984. They had received a common batch of NHS Factor VIII concentrate between March and May 1984. The study period was from early 1987 to mid 1988. By the end of that period, only seven patients remained wholly asymptomatic, with two having died. The amount of Factor VIII transfused did not influence clinical progression or the ability of doctors to isolate HIV from a patient’s serum. It was also pointed out that
Compared with other cohorts, the rate of morbidity and mortality in this cohort is relatively high with half the HIV seropositive patients having developed serious clinical complications within 4 years….Thus in clinical terms, the implicated viral strain appears to be particularly virulent.
In so far as the 14 HIV negative patients were concerned,
[T]hey received significantly lower doses of this batch of Factor VIII…and therefore may have received no virus or only very low doses which were unable to establish infection. Alternatively, small amounts of HIV genomic material may have been incorporated into host DNA without stimulating an immune response and without causing T-cell destruction.
8.212 A further study reflecting results obtained from examination of the Edinburgh cohort was published in the BMJ in 1990. This study was directed towards identifying HIV positive individuals with a poor prognosis for HIV disease. The group of 18 was divided into those ‘with symptoms’ at any point up to mid 1989 (10 patients) and those ‘without symptoms’ (8 patients). All 18 patients had previously had evidence of chronic persistent hepatitis, although none had symptomatic liver disease before exposure to the infected batch. The study did not identify any immunological variable or clinical characteristic which distinguished the patients who seroconverted from those who did not. But once infection was established, several markers correlated with the rate of the progression of the disease. Within the Edinburgh cohort, the cumulative incidence of serious HIV disease was 55.5% at five years. A third member of the cohort, a patient born in 1948, had died (in 1989).
8.213 As at February 1990, there were also patients with haemophilia in Edinburgh who had acquired HIV from commercial concentrates; a published study refers to eight such patients. Researchers later detected HIV-1 in two batches of commercial Factor VIII distributed in the UK between 1981 and 1983.
8.214 Further research was undertaken into factors possibly indicating that an individual was at increased risk of swiftly progressing to full blown AIDS. This research showed that the extent of host immune reactivity, which may be genetically determined, was a powerful factor in the pathogenesis of HIV-associated disease.
[T]he pattern of specific IgM and IgA responses in the very early stages of infection distinguishes individuals in whom the disease is likely to run a rapidly progressive course from those who remain symptom free for a long time.
8.215 At present, the Inquiry team has no other information from or about this group of people. Much will have happened to them since the early 1990s.
1989 and beyond
8.216 On 7 November 1989, in answer to a parliamentary question, details were given of the number of haemophiliacs reported to the CDSC as being HIV antibody positive since 1985. The cumulative total for England, Wales and Northern Ireland was 1020. For Scotland, the cumulative total to 1989 was 76 haemophiliacs who were HIV antibody positive. The cumulative number of haemophiliacs with AIDS known to have died in the UK by 30 September 1989 was 102.
8.217 In a parliamentary answer on 21 December 1989, it was stated that there had been 76 HIV positive haemophiliacs and 12 non-haemophiliac HIV positive recipients of blood or blood products in Scotland. By the end of February 1990, the total number of haemophiliacs with AIDS in the UK who had died was 118.
8.218 On 28 January 1990, in a Sunday Times article by Michael Durham, the case of
a 26 year old Scottish man was referred to. He was said to be suing the SNBTS for £200,000, alleging he was given HIV contaminated blood during an operation in 1985. A 37 year-old Edinburgh woman was considering similar action after contracting HIV in hospital in 1984.
8.219 On 31 October 1990, a note was issued for distribution to government back bench MPs. The note recorded that 1216 haemophiliacs had been reported with HIV in the UK; 212 had been reported with AIDS of whom 143 had died.
8.220 On 12 December 1990, an article in the Scotsman reported that, both through the MacFarlane Trust and by settling some current litigations, the government was offering more money to haemophiliacs who had contracted HIV. That day, Fred Tyler, Balfour and Manson, chairman of the Scottish Haemophilia/HIV Litigation Group wrote to the Secretary of State for Scotland requesting clarification of how the offer made in England affected similar litigation in the Court of Session.
8.221 On 25 January 1991, Dr B Cuthbertson, Quality Assurance Manager, PFC wrote to Professor Cash, enclosing a final report, ‘HIV Seroconversions related to SNBTS FVIII’. This was an update of an earlier, interim report of 28 June 1986. The infection of
16 patients in Edinburgh was referred to, as was the infection of two patients in the
West of Scotland, one of whom had seroconverted between 5 October 1984 and
25 October 1985. It was not possible to draw definitive conclusions as to the batches by which all these patients had been infected; batch 023110090 remained the main candidate for 15 of the 18 seroconversions but the other candidate batches had not been identified.
8.222 On 21 April 1991, there was published in the Observer an article ‘Scandal of the forgotten NHS AIDS sufferers’. One hundred and seventy patients in the UK (12 in Scotland) had received HIV through blood transfusions, yet they were excluded from the compensation arrangements announced for those with haemophilia. A case of a leukaemia patient from Edinburgh who had acquired the virus during treatment in 1986 was referred to.
8.223 On 27 May 1991, David McIntosh, general manager, SNBTS wrote to Mr JT Donald, general manager, Common Services Agency (CSA), expressing concern at media reporting of patients infected with HIV by transfusion and seeking to initiate settlement of the cases. He wrote also to the directors regarding the line to be taken in comment on the cases.
8.224 On 5 November 1991, Dr Peter Foster wrote to Prof Cash. Dr Foster had been taken aback at a number of negative comments about SNBTS products made by Dr Ludlam at a meeting of the Edinburgh HIV discussion group. He also wrote to Dr Ludlam, confirming that there had been a total of four heat-treated Factor VIII batches issued for clinical use which were prepared from plasma pools retrospectively known to have contained an
HIV-antibody positive donation. Dr Ludlam replied to Dr Foster on 11 November. He had been aware of two batches containing an HIV-antibody positive donation, but unaware of the two further batches. He requested batch numbers ‘so we can confirm just who received them’.
8.225 In 1993, the government established the Eileen Trust (for non-haemophiliacs infected with HIV from blood/blood products).
 Pneumocystis pneumonia – Los Angeles: MMWR 1981; 30, 250-252. MMWR is published by the Centers for Disease Control and Prevention (CDC), a US government public health agency with its headquarters in Atlanta, Georgia. It was a publication which the Protein Fractionation Centre (PFC) received. [LIT.001.1026]
 Articles commenting on PCP and/or KS in homosexual men began to appear in a number of medical journals from this point onwards. It is not necessary to list them all here.
 Ibid, 1325.
 Public Health Laboratory, Withington Hospital (Manchester)
 There were further significant reports from the USA in the MMWR of 10 December 1982. The 3 haemophiliacs referred to in the July publication had died, ‘children with haemophilia must now be considered at risk …the illness may pose a significant risk for patients with haemophilia.’ (31(48) 644 – 6, 652). At 652 – 4, the same edition reported that a 20 month old infant appeared to have developed the syndrome after transfusions which had included platelets from a male subsequently found to have AIDS. It was commented that these reports ‘raise serious questions about the possible transmission of AIDS through blood and blood products.’ [LIT.001.0576]
 There were 2 Dr Eibls working in this area of medicine: Dr H Eibl of Immuno and Dr M Eibl of the University of Vienna.
 Ibid, 79 – 83
 There were 3 main blood collection agencies in the USA: the American Association of Blood Banks, the American Red Cross and the Council of Community Blood Centres.
 The Inquiry team has not yet been able to trace this leaflet.
 The Inquiry team has not yet been able to trace this statement.
 Dr Galbraith’s paper, discussed below.
 American Association of Blood Banks
 The Inquiry team has not yet been able to trace this letter.
 These views mirrored the views of researchers in Glasgow published in October 1983 – see below at 8.59.
 It was subsequently rejected (on 13 July).
 This was a (competing) theory re the cause of immunological abnormalities in patients with haemophilia. The debate is discussed in an article by Barbara and Tedder ‘Viral Infections Transmitted by Blood and its Products’ in ‘Clinics in Haematology’ Vol 13, no 3, October 1984: ‘Since, as a group, haemophiliacs are well studied, it is unlikely that there should have been an illness like AIDS unrecognised before 1980. Little significance should be attached to reports of abnormal lymphocyte profiles in haemophiliacs ...there is no doubt that there have been deaths of haemophiliacs due to AIDS in the absence of other risk factors…’.
 The National Blood Transfusion Service was the comparable English and Welsh organisation.
 Scottish Homosexual Rights Group
 Summary, page 1
 This statement is assumed to be based on information available about the two cases in England and Wales (see paragraph 8.48).
Page 5. The reference to “recent work” is probably an article by Gallo in Science in May, describing the isolation of the HTLV-1 virus from a person with AIDS.
 Who were, respectively, the Chairman and Secretary of the Haemophilia Centre Doctors’ Organisation.
 By this time, Glasgow and Edinburgh had been recognised as HRCs. They do not appear to have been represented at this meeting. On 8.8.85, Glasgow and Edinburgh were described in DHSS correspondence as ‘perhaps... regarded more as centres of excellence than Reference Centres’: [DHF.001.7665]
 World Federation of Haemophilia and International Society for the Treatment of Haemophilia
 The Karolinska Institute is just outside Stockholm, and is one of Europe’s largest medical universities.
 Who was Joint Parliamentary Under Secretary of State at the DHSS.
 At the meeting of the Biological Sub Committee of the CSM on 13 July, it had been commented that concentrates from the USA to be used in the UK should be derived from plasma complying with those regulations, provided supply could be assured. See [DHF.002.8865].
 Reduced platelet cells in the blood.
 Which alerted donors to symptoms or illnesses they should mention to staff.
 Collection of blood from prisons was also discussed.
 Although Dr Mitchell’s note records a feeling that RTDs should have freedom to decide in their area how best to publicise the leaflet, it is not clear if this feeling was at the meeting or prior to it.
 The report states that AIDS will be considered separately ‘at the meeting’. This must have been the UKHCDO meeting of 17 October. (see [SGH.008.5132] ).
 This appears to have been Professor Bloom. See letter of thanks [DHF.002.8919]. See also Guardian of 28.9.83 [DHF.001.4806] recording quote from Haemophilia Society – ‘risk of AIDS is tiny compared to risks from untreated bleeding episodes’.
 This hypothesis was supported by doctors in Glasgow and Edinburgh: see references in footnotes 39 and 40, and references to Froebel paper and to Carr article, infra.
 The response of an organism to an external stimulus by growth in a direction determined by the stimulus.
 See paragraph 8.81.
 A test for antibody to Hepatitis B.
 A test for syphilis (treponema pallidum)
 A higher proportion of AIDS patients had HTLV than control patients. In due course, it would be demonstrated that the virus involved was not this HTLV virus.
 A protein which triggers cell division in lymphocytes
 A similar study in Australia (Rickard and others, letter in The Lancet July 2, 50 – 51) analysed haemophiliacs who had received no commercial products. Most of these patients had reduced T4/T8 ratios; none had had any signs of AIDS. [LIT.001.0414]
 Presumably DHSS
 Advisory Committee on Dangerous Pathogens
 Underlining as in original
 See above at paragraph 8.48
 See below
 Information about the use of commercial products is discussed in Chapter 10: Trends in Demand and Use of Blood products
 Re surrogate testing – ‘Surrogate tests for AIDS are non-specific and unlikely to be helpful in screening blood donor units’ Sion and Bankhurst, Transfusion 1984, Vol 24 No 5 pp 373 - 8
 One leaflet current in 1984 was ‘Important message to blood donors’. As at the next meeting on 12 June, the leaflet was still being revised.
Science, 2002, 298(5599):1727-8
 ‘Frequent detection and isolation of cytopathic retroviruses (HTLV III) from patients with AIDS and at risk for AIDS’ Science 1984; 224:500–503.
 See, for example, ‘AIDS: Sharing out the Spoils’, New Scientist 10 October 1985 [DHF.001.8154]. In 2008, the Nobel Prize for Medicine was awarded to Luc Montagnier and Françoise Barré-Sinoussi for their discovery of the virus that causes AIDS.
 Letter from Dr Gunson to Dr Smithies at DHSS anticipating this development is [SNB.006.5978] The assay is described in an article ‘Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain’, The Lancet, 1984;477-480 (1 September 1984) [LIT.001.0417]
 Interestingly, when the research was published in December, it was said that 59% of the Danish patients were infected. 59% of 22 would be 13, not 14.
 It is not entirely clear if the batch identified as ‘suspect’ following the AIDS case in 1983 was the same batch as had been identified as a result of the donor becoming ill with AIDS as described in paragraph 1 of the letter.
 Evidence of Dr Mark Winter to the Archer Inquiry, day 7, page 94.
 This topic is considered more fully in Chapter 11.
 60°C for 20h and 68°C for 24h.
 The full results were published in August 1985: McDougal and others, ‘Thermal inactivation of the acquired immunodeficiency syndrome virus, human T lymphotropic virus-III/lympadopathy virus, with special reference to antihemophilic factor’, J Clin Invest, 1985;76(2):875-7 [LIT.001.0826]
 The batch was manufactured in November 1983 from plasma collected in Autumn 1983. Attempts to identify the specific donation which led to the product being infective were unsuccessful: [SNF.001.0445] (report of March 1988)
 Of the Scottish National Blood Transfusion Association
 Patients from the Glasgow HRC
 Thus, at that time at least 33 patients with haemophilia in Scotland were known to be positive for the HTLV-III virus.
 Letter is [SGH.002.6506]. The policy of total change to heat-treated product was criticised – see letter in The Lancet 19 January 1985 from Bird and others (page 162 - 3) [SNB.008.5887]. These criticisms appear to have been accepted by Dr Cash at that time [SNB.001.5357] but to some extent refuted in a later letter in The Lancet by Allain and others ‘The case for heat treated products’, April 6, 1985, 814 – 5 [LIT.001.0376].
 See discussion at paragraph 8.114 below
 Such a UK wide group had been suggested by Dr Cash in his letter of 15.2.84 to Dr Bell [SNF.004.8639]
 In Australia, 3 babies had died. Times, 19 November 1984, [DHF.001.5973]. In Newcastle, a transfusion recipient had died: Guardian, 19 November, [DHF.001.5990]. See also [DHF.001.5978] re World this Weekend programme.
 In fact, the research appears to indicate that a few patients treated only with local product were infected: The Lancet, 1984; 1444-46
 A group which continues to exist at the time of writing this report: .
 The number of seroconversions in Edinburgh among recipients of the implicated batch was 18, as explained in note 353.
 See The Lancet p 478 of 1984 (note 141 above), regarding ascertainment of prevalence of the virus in patients with haemophilia. Montagnier and others had provided LAV for the research.
 See position paper ‘Aids and its prevention in the United Kingdom’ (undated and without appendices) [DHF.002.0431], para 4. Date is probably 31.12.84 – see [DHF.002.0430]. See also letter from Department of Health and Human Services (‘DHHS’) to Chester Beatty Institute 19.12.84 [DHF.001.8858]
 In fact, the three tests attracting the most favourable evaluation reports in July 1985 were all enzyme tests, including that of Wellcome. The Inquiry is not aware of the reasons for the switch by Wellcome from an RIA test, nor at what point it occurred.
 A different point of view was expressed in the same edition by Carlson and others of California who advocated using a test with high sensitivity, followed by confirmatory testing to minimise disruption in the supply of blood and the loss of future donors – [SNF.001.3355].
 Letter of 31 May [DHF.002.5510]
 Professor Bloom; confirmed by DoH June 2010.
 [DHF.001.7660]. At the Conference on AIDS in Newcastle in February 1986, it was stated that the evaluation at Edgware and Manchester had revealed several interesting findings but was still to be finalised. [DHF.002.0816]
 The Inquiry does not know if any similar request for virus was made to France.
 This must have been written by a contributor unaware of events in Edinburgh.
 See paragraph 8.105.
 As at 1991, the rate in treated haemophilia patients in Edinburgh was said to be 25%: Cuthbert, Ludlam and others, British Journal of Haematology, 1991, 80, 364 - 9
 See description of evaluation process at paras 8.122 to 8.138.
 As far as the Inquiry can ascertain, the suspicion directed at the PFC product was unfounded. – see ‘Efficacy of heat treatment of Factor VIII concentrate’ Vox Sanguinis 54: 199 – 200: [LIT.001.0664]. Unheated product was recalled in January 1985 – [SNF.001.3898].
 These appear to be the data from the Rizza and Spooner report (note 292), with one or two discrepancies.
It appears to the Inquiry that it may have been possible to rule this out in one of the cases.
 Enzyme linked immunosorbent assay
 Actual figures redacted
 Inverted commas as in original.
 The highest recorded percentages for virus infection among patients with Haemophilia A were in Malta (95%) and the USA (90%)
 Report of Lindsay tribunal pp 138 – 9.
 This appears to relate to Haemophilia A patients only: 896, the figure used in calculation, was the number of such patients who were antibody positive as at March 1986 (see paragraph 8.180).
 Presumably, then, a non-haemophiliac recipient of blood product.
 Previously untreated patients
 ‘HLA Haplotype A1 B8 DR3 as a risk factor for HIV-Related Disease’ Steel, Ludlam and others: The Lancet, 28 May 1988 1185 – 8 at 1187.
 As late as 1991, Dr Cuthbertson of PFC was referring to there having been 16 seroconversions. See paragraph 8.221. Originally, 16 were reported but three further seroconversions were observed during follow-up between October and December 1984, with one of the original 16 being discounted as not having acquired his infection from the implicated batch: BMJ, 1990;301:956-61 at 957 [LIT.001.0291]
 This article read with ‘HTLV III infection associated with glandular fever like illness in a haemophiliac’, The Lancet, 1985:585.
 Cuthbert, Ludlam and others, ‘Human immunodeficiency virus detection: correlation with clinical progression in the Edinburgh haemophiliac cohort’, British Journal of Haematology, 1989;72:387-90 [LIT.001.0581]
 A possible link with a particular genetic feature in some of the affected individuals was explored in ‘HLA Haplotype A1 B8 DR3 as a risk factor for HIV-Related Disease’ Steel, Ludlam and others, The Lancet, 28 May 1988 1185 – 8 [LIT.001.0895]; this was corroborated in later American and Australian studies (The Lancet 1990; 335: 927 – 30 and 1591 – 2.).
 These categories were based on the CDC classification of HIV disease.
 Dalgleish and others ‘Failure of ADCC to predict HIV-associated disease progression or outcome in a haemophiliac cohort’ Clin. Exp. Immunol (1990) 81, 5 – 10.
 Detection, Quantification and Sequencing of HIV-1 from the plasma of seropositive individuals and from factor VIII concentrates’ Zhang, Simmonds and others, AIDS 1991, Vol 5 No. 6 pp 675 – 81 [LIT.001.0516]
 Simmonds (Cuthbert, Ludlam) and others, ‘Determinants of HIV disease progression: six-year longitudinal study in the Edinburgh haemophilia/HIV cohort’, The Lancet, 1991:338:1159-1163. [LIT.001.0279]