THE PENROSE INQUIRY
Final Report

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Chapter 12

HIV/AIDS: Response and Clinical Practice

Introduction

12.1 As knowledge developed in the USA, in the UK generally, and in Scotland in particular, first of AIDS and then of HIV, it inevitably had an impact on clinical practice. Chapters 9-11 set out those developments at length and are not repeated in detail in this chapter, except where necessary to provide context. Rather, this chapter of the Report discusses aspects of the response to HIV/AIDS by haemophilia clinicians over the early and middle years of the 1980s. In particular, the question to be addressed is whether clinicians in Scotland should have adapted their treatment regimes sooner than they did, in response to the threat of AIDS.

12.2 That is a difficult issue and the context in which it has to be addressed must take account of what was happening in the rest of the UK. Scottish haemophilia clinicians did not function in isolation from their counterparts in England and Wales. The constituencies represented by the United Kingdom Haemophilia Centre Directors' Organisation (UKHCDO) and, at that time, the Haemophilia Society, were UK-wide. It is likely that views expressed and attitudes communicated in their publications would have had an impact in Scotland, as information about AIDS was nationally disseminated. In discussing when Scottish practitioners should have reconsidered haemophilia therapy generally and whether such changes in clinical practice as did occur should have been made earlier, it is therefore appropriate to have regard to what was happening in the rest of the UK.

12.3 Although it is necessary to take into account developing views throughout the UK, as these formed an important part of the background for clinicians as they responded to the emerging threat of AIDS, it is also important to bear in mind the degree of independence in clinical matters afforded to individual Regional Transfusion Directors (RTDs) and Haemophilia Directors at the time. As noted in Chapter 21, Haemophilia Therapy - Use of Blood Products 1985-1987, individual RTDs of the SNBTS and Haemophilia Directors in the UK, asserted and were accorded a high degree of autonomy in their practices.^[1] This was not limited to clinical independence at the point of delivery of care to the patient; so far as is relevant to this chapter, it also included the selection and use of therapeutic products generally. There were significant regional differences in practice throughout the UK. In Scotland, the variations in clinical practice are illustrated by the analytical tables and figures in Chapter 21, Haemophilia Therapy - Use of Blood Products. These are discussed in more detail below.

12.4 The question that naturally and understandably arises from haemophilia patients who acquired HIV infection, is why they were prescribed large-pool factor concentrates when there was, as is now known, a disproportionate risk of transmission of HIV by those products as compared to treatments such as cryoprecipitate and fresh frozen plasma which might, for some patients, have represented appropriate alternative therapies.^[2] The question cannot be answered in a simple and straightforward way for all of Scotland, much less for the UK as a whole. Implicit in the question is an assumption that clinicians were, at the material time, in possession of sufficient evidence of disproportionate risk in large-pool concentrates such that they should have adapted treatment regimes sooner than they did. That assumption may not be valid, however, and it is necessary to distinguish the existence of risk in an absolute sense from knowledge of risk sufficient to instruct a reasoned decision on therapy. In addition, the therapeutic options available to clinicians differed across the country; even within a given region, different options were available to individual patients.

Key issues: the debate on the aetiology of AIDS; advances in haemophilia care; and faith in the safety of the UK blood supply

12.5 The question is complicated by a number of fundamental issues addressed in this chapter. In the first place, for much of the period before HTLV-III/HIV was identified as the infective agent causing the immune deficiencies in patients who progressed to AIDS, there were competing theories supported by bodies of influential experts on both sides of the Atlantic. The full significance of the discovery in France of LAV^[3] in May 1983 was not widely understood and those findings were resisted by many, particularly in the USA. Medical science did not resolve the fundamental question of the cause of AIDS, to the satisfaction of the majority of experts, until the spring of 1984. Even after the seminal publication in Science announcing the discovery of HTLV-III, some comments continued to be published challenging the findings that AIDS was spread by means of a virus present in blood. The history is set out in detail in Chapter 11, HIV/AIDS Aetiology, although, for the purposes of this chapter, a few key dates are important in discussing the timing of developments in clinical practice. Secondly, there was an acknowledgement that the development of large-pool concentrates had transformed the lives of haemophilia patients. Under such circumstances, many haemophilia clinicians, and others, appear to have been reluctant to accept evidence that those therapeutic materials might have transmitted infection to their patients. Thirdly, and perhaps linked to the last point, there was a long-held and strongly felt confidence in the safety of the UK blood supply. Early reports of AIDS infection were limited to the USA and, for those who might have been prepared to entertain the idea that AIDS was caused by a blood-borne infective agent, this confidence in the relative safety of NHS blood products may also have influenced thinking on the appropriate response to AIDS.

Irreconcilable views on the aetiology of AIDS

12.6 Early reports of what came to be known as HIV/AIDS infection first emerged in the USA in 1981 and the initial debate on the disease was heavily influenced by the fact that most of the earliest reports dealt exclusively with homosexual men. The major pathological features of AIDS were very profound immunosuppression (with characteristic suppression of the ratio of helper to suppressor cells) and the development of certain otherwise rare diseases such as Pneumocystis carinii pneumonia (PCP) and the vascular cancer, Kaposi's sarcoma (KS). Starting in 1982 similar, if less marked, immune phenomena were identified in homosexual men who appeared healthy and, in particular, did not have overt disease characteristics of AIDS.^[4] Also in 1982, immigrants to the USA from Haiti and intravenous drug users (IVDUs) began to present with similar immune dysfunction and, occasionally, overt disease.^[5] In July 1982, 'opportunistic infections' characteristic of AIDS were found in three US haemophilia patients who had received frequent administration of Factor VIII,^[6] and further reports followed.

12.7 Irreconcilable views on the aetiology of AIDS emerged in 1982 and were expressed clearly at a workshop in Atlanta on 4 January 1983.^[7] The 'transmissable agent' theory was supported by the American Centers for Disease Control (CDC), whose spokesman was Dr Bruce Evatt. That theory of AIDS transmission postulated that a blood-borne virus was responsible for the observed cases (including those in haemophilia patients). By contrast, the 'antigen overload' theory was supported by a body of haemophilia clinicians, whose most prominent spokesman was Dr Louis Aledort, a respected haematologist and Director of the Haemophilia Center in New York. That theory considered exposure to foreign antigens in concentrates to have caused a high degree of antigenic stimulation that wore out haemophilia patients' immune systems. Both views were strongly held and forcefully argued.

12.8 At various points in 1983 the competing theories were supported or criticised in published papers and at conferences. At this time in Scotland, Professor Christopher Ludlam (Edinburgh Haemophilia Centre) and Professor Charles Forbes (Glasgow Haemophilia Centre) conducted studies into the phenomena of immune irregularities in haemophilia patients. Of these, Professor Ludlam's studies led more positively to the view, published in The Lancet on 28 May 1983, that the immune changes identified in his patients resulted from infusion of 'foreign' proteins in the therapeutic products administered to them, or a ubiquitous virus, rather than a specific AIDS virus in Factor VIII concentrates: the antigen overload theory.^[8] These studies are referred to in more detail, in a specifically Scottish context, below at paragraphs 12.111-12.119.

12.9 By the time of the meeting of the World Federation of Hemophilia in June 1983, Françoise Barré-Sinoussi and Luc Montagnier of the Institut Pasteur, Paris, had published the results of research suggesting that they had identified an infectious agent, which they termed LAV.^[9] That was, however, not generally accepted as persuasive (especially in the USA) until 23 April 1984, when Dr Robert Gallo and his team announced the discovery of HTLV-III.^[10] Later research was to demonstrate that LAV and HTLV-III were, in fact, the same virus, later named HIV.^[11] The position until April 1984 was summed up by Professor Lever, Professor of Infectious Diseases at Addenbrooke's Hospital, Cambridge:

Up until that time I think it's a gradation. There was gradual acceptance that it couldn't just be put down to immunological-based theories and that the epidemiology looked more and more like an infectious agent.^[12]

12.10 It appears that Dr Mark Winter, Consultant Haematologist at Kent and Canterbury Hospital from 1983, accepted the infective agent theory at a relatively early date^[13] but it is not clear that, by April 1984, the 'gradation' Professor Lever described encompassed all interested parties. In this context, it is of interest to note that, in a paper detailing testing for HTLV-III that was underway in the second half of 1984, the linking of antibody-positivity to AIDS was still presented as a hypothesis, albeit one which 'strongly implicated' a transmissible agent.^[14] Even after that point, some commentators continued to publish articles sceptical of the claim that AIDS was caused by a transmissible virus^[15] although, increasingly throughout the period and certainly after April 1984, that scepticism appears to have involved finding alternative explanations for the considerable accumulating evidence supporting the transmissible agent theory. Given the gradual progress of developing knowledge, however, and the fundamental differences of opinion that prevailed throughout 1983 and into 1984, it was highly unlikely that a view common to all or most haemophilia clinicians would have emerged before April 1984 that accepted the infectious agent theory. It is clear from the evidence available to the Inquiry that the infectious agent theory did not prevail until at least then, with some continuing to defend alternative hypotheses for some months after that date. It also appears clear from the evidence that, throughout the period of uncertainty, some haemophilia clinicians at least found their assessment of the risk associated with blood products to some extent confounded by an appreciation of the significant benefits large-pool concentrates used in coagulation disorder therapy had brought to their patients.

The significance of advances in haemophilia care

12.11 Before it was recognised that the use of factor concentrates might present a risk of immune deficiencies in coagulation disorder patients, whether caused by an infective agent or by antigen overload, the development of factor products (including cryoprecipitate but particularly large-pool concentrates) had brought about a major advance in healthcare. The improvement in life expectancy, the reduction in morbidity and improvements in the quality of life of haemophilia patients achieved were little short of spectacular.^[16]

12.12 Therapy for Haemophilia A and Haemophilia B in particular had revolutionised the lives of patients. At a meeting on the Infectious Hazards of Blood Products arranged by the National Institute for Biological Standards and Control (NIBSC) on 9 February 1984, Dr Duncan Thomas^[17] noted the improvement in life expectancy which had resulted from the use of concentrates, from 37 years in 1962 to almost normal in 1984.^[18]

12.13 A significant factor in these improvements was the development of 'home therapy' treatment programmes. Prior to the introduction of factor concentrates, haemophilia patients who experienced bleeds would attend hospital for treatment, typically with cryoprecipitate. It was impractical for most patients to keep stocks of cryoprecipitate at home for self-administration as the packs required to be stored in large quantities in deep freezers^[19] and, compared with factor concentrates, were difficult to prepare, requiring to be reconstituted from the frozen state in a water bath at 37°C in a clean, or ideally sterile, environment.^[20] In addition, the potency of cryoprecipitate could not be known until the point of administration and the product was frequently associated with significant side-effects, some of which could require hospital care.^[21] By contrast, factor concentrates could be stored in a refrigerator (requiring only to be stored at 4°C), potency was more uniform and, after training, could be more easily prepared and administered by patients (or, in the case of younger children, their parents). Side-effects, at the point of administration, were less common. Patients no longer needed to attend hospital following a bleed, an experience Dr Winter described as 'harrowing' and 'a pretty dreadful experience'.^[22] A textbook on paediatric haematology written by Dr Michael Willoughby, at the time Director of the Haemophilia Centre at The Royal Hospital for Sick Children, Yorkhill, Glasgow (Yorkhill), and published in 1977 set out the advantages of factor concentrates as compared to cryoprecipitate and noted that 'home treatment is highly efficacious in reducing the morbidity of haemophilia and improving the quality of life'.^[23]

12.14 Upon taking up the post of Director of the Edinburgh Haemophilia Centre in 1980, Professor Ludlam began almost immediately to radically expand the home therapy programme, using concentrates, in that area. As discussed below, his predecessor, Dr Howard Davies, had been somewhat circumspect in relation to the use of concentrates. Although they were not infrequently used while he was Director, Dr Davies was concerned about the risks associated with large-pool products. As a result, at the beginning of 1980 only six of a total of 187 haemophilia patients registered at the Centre were established on home therapy. Professor Ludlam said he was 'continuingly being asked' to expand the programme for which there was 'a lot of enthusiasm'.^[24] By 1989, this number had grown to 47. He considered cryoprecipitate inappropriate for home therapy and was 'not prepared to take the risk' he saw in placing patients on home therapy with cryoprecipitate.^[25] Dr Boulton, who began working in Edinburgh around the same time, agreed.^[26] Professor Ludlam may have been constrained in his efforts to expand the home treatment programme due to his stated preference for locally-sourced factor concentrates.^[27] The drive towards increasing the number of patients on home therapy led him to impress upon the SNBTS his desire to have more NHS Factor VIII concentrate.^[28]

12.15 There was an obvious major benefit derived from treatment, especially with large-pool concentrates as they were developed from the early 1970s.^[29] There was a reduction in the number of school or work days lost; patients could travel more easily, whether on holiday or for business; and patients were spared frequent 'time-consuming and psychologically undesirable' visits to hospital.^[30] Professor Forbes agreed that home therapy was 'a very popular move', describing the relatively short period between the development of home therapy programmes and the emergence of non-A, non-B Hepatitis and AIDS as 'the golden age' in haemophilia care.^[31] As discussed in Chapter 21, Haemophilia Therapy - Use of Blood Products, paragraphs 21.95-21.100, the development of home treatment programmes had a significant effect on the demand for factor concentrates and production of concentrates increased accordingly to meet demand. In the absence of an alternative of proven efficacy, for many clinicians ceasing to use concentrates threatened patients' quality of life, health and even their lives.

12.16 Professor Forbes said:

For a long time after the initial cases of AIDS was [sic] reported there was great debate about the best way of treating bleeding. It was certainly not possible to stop the use of concentrate as bleeding would have resulted in death and the general reaction of most Haemophilia Directors at that time was to continuing [sic] to treat the bleeding with concentrate.^[32]

12.17 In oral evidence to the Inquiry, Professor Forbes said that he thought that the 1983 decision to continue treatment with concentrates was correct.^[33] Similar views persisted into 1984. Professor Arthur Bloom, Cardiff Haemophilia Centre, took up the theme in an article in The Lancet dated 30 June 1984. He commented:

In view of the immense benefits that haemophiliacs have derived from treatment physicians are naturally reluctant to abandon these agents, with their hypothetical dangers, in the absence of alternative concentrates which have been proven safer. This attitude may change as information accrues, and haemophilia treatment needs to be monitored world-wide.^[34]

12.18 Against this background, it is not surprising that there was a range of strongly held views. The approach of Dr Aledort at the workshop in Atlanta on 4 January 1983 reflected the position held at one extreme of that range. There were clinicians who demanded full scientific proof of an infective agent as a condition of changing from established factor concentrate therapy.^[35]

Faith in the safety of the UK blood supply

12.19 Further to the significance of advances in haemophilia care, there was faith in blood factor products, both cryoprecipitate and concentrates, produced by UK public sector facilities that strongly influenced many (but not all) practitioners throughout the UK. From the beginning of the AIDS era until 1984, this faith had at its roots a belief that, if AIDS was indeed caused by an infective agent, it had not entered the blood donor population in the UK generally and in Scotland in particular. Accordingly, for those who subscribed to the infective agent hypothesis, it was thought that Factor VIII produced in the UK was unlikely to transmit the postulated AIDS virus. Those who acknowledged that there was a risk thought it was minor. It was deeply ingrained in the psyche of haemophilia clinicians and patients, that donated blood of UK origin was much more likely to be free of viruses than blood from the USA.

12.20 The situation in Edinburgh illustrates this point particularly well. Professor Ludlam's predecessor as Director of the Edinburgh Haemophilia Centre, Dr Howard Davies, made almost exclusive use of locally-produced therapeutic materials. Professor Ludlam stated that Dr Davies avoided the use of imported materials as a matter of policy, believing those derived from Scottish donors would be safer. Dr Davies' argument in preference of locally sourced materials centred on the risks associated with hepatitis viruses, but appears to have had a more general basis: both Professor Ludlam and Dr McClelland stated that Dr Davies was reluctant to potentially introduce 'novel' viruses to the local population. Dr Brian McClelland,^[36] who worked with Dr Davies early in his (Dr McClelland's) career, said that Dr Davies' policy struck him as 'eminently sensible'. In relation to imported products, he thought the policy was grounded in 'elementary biology' and that 'the further afield the blood came from, there was a certainly incalculable but reasonable grounds to expect that something new and different and unfamiliar to the indigenous population might be in that blood'.^[37] Dr Davies also tended to avoid large-pool concentrates, preferring, where possible, to use cryoprecipitate in the belief that large pools of donations were more likely to contain transmissible viruses, whatever their source. As noted above, when Professor Ludlam succeeded Dr Davies, he quickly reversed this part of Dr Davies' policy and moved as many patients as he could to home therapy with concentrates. He continued, however, to prefer locally produced products, believing that the general population of Scotland was at the time relatively 'stable' and that the risks associated with the local donor pool were 'small'.^[38] Dr Davies' thinking on this was, he said, for its time, 'very sensible ... [o]therwise I wouldn't have continued it'.^[39]

12.21 Professor Ludlam's faith in the relative safety of the UK blood supply is perhaps most clearly demonstrated in relation to a policy he adopted towards patients under his care who might require to travel. A national system in place from the 1970s ensured that all UK haemophilia patients were given a card stating their condition, its severity and details of their local Haemophilia Centre. Professor Ludlam added to this a printed statement requesting that, if a patient was treated elsewhere than their local Centre, either cryoprecipitate or NHS factor concentrates be used in preference to commercial concentrates. He stated that he had provided his patients with the additional statement specifically so that, if they were to require treatment away from home - and particularly in England or Wales where there was considerably less NHS material available - his patients would not be exposed to commercial concentrates.^[40]

12.22 Not all clinicians favoured this approach. Dr Willoughby, until he was succeeded by Professor Ian Hann at Yorkhill, had 'what appeared to be a preference for commercially (as opposed to NHS-produced) products'.^[41] Although, as noted above, Dr Willoughby agreed that home treatment programmes were of proven efficacy, he believed commercial concentrate was a better product for that purpose, being of higher purity, resulting in fewer adverse reactions and being easier to prepare.^[42] At least part of his approach, however, appears also to have been based on the availability of locally produced materials: in a discussion with Professor Hann, Dr Willoughby expressed disillusionment with the health service throughout the UK generally and, in particular, that he felt let down with regard to supplies.^[43]

12.23 As noted below in discussion of product selection at Scottish centres, Professor Hann immediately reversed this policy upon taking up the post of Haemophilia Director at Yorkhill. Professor Hann believed that, as well as being cheaper, locally produced products would be safer because the donor pool was better. He had taken into account potential problems with this approach, including availability, but for him, 'the lower risk of infectivity was ... paramount'.^[44] Professor Hann did not, however, criticise Dr Willoughby's preference. It appears clear that Dr Willoughby had exercised his clinical judgement and that he reached his conclusions for what he regarded as good reasons. Dr Willoughby had not had to face the emerging problems of non-A, non-B Hepatitis/Hepatitis C or HIV/AIDS, however, and another part of the explanation for his preference and practice may have been a belief that what he perceived as the greatest risk to haemophilia patients, Hepatitis B, was reducing and that avoiding large-pool concentrates more effectively reduced that risk,than preferring large but local donor pools.^[45]

12.24 The selection of therapeutic materials in the three other Scottish centres (Aberdeen, Dundee and Inverness) point clearly towards a preference for NHS products. As will be seen below in discussion of the actual products administered, use of imported commercial concentrates was very infrequent throughout the material time at Aberdeen and Dundee, while Inverness used no imported products from 1974 onwards. Practice at these centres appears to have closely followed international, government and SNBTS guidance and policy that haemophilia treatment should be on a self-sufficient basis using domestically sourced products, other than in exceptional cases.

12.25 The existence of HTLV-III/HIV infection in haemophilia patients in the UK emerged with a dreadful suddenness, however, after the publication of the seminal article in The Lancet on 1 September 1984 by Dr Rachanee Cheingsong-Popov and others.^[46] The article presented strong evidence supporting the infectious agent hypothesis and gave the results of 2000 HTLV-III tests conducted in the UK. It commented that there had previously been reported only limited studies of antibody prevalence in groups at risk for AIDS, but that those studies had shown a moderately high seropositivity amongst at-risk populations such as apparently symptom-free homosexual men, haemophilia patients and IVDUs. Antibodies to HTLV-III were found in 34% of haemophilia patients studied, but the article advised caution in interpreting the results. There was perceived at that time to be a relatively low risk of acquiring HTLV-III or AIDS from blood transfusion in the UK, which was said to be regarded as a 'low-risk country'.

12.26 In retrospect, it is difficult to understand the confidence in UK blood in its most extreme form, at least among those who accepted the transmissible agent theory in the debate over the aetiology of AIDS. By 1980 international tourism was well established, both in foreign holidays for UK residents and in holidays in the UK for foreign residents. The interchange across borders of individuals with an interest in activities that exposed them to a high risk of HIV infection, whether the risk was associated with intravenous drug use or promiscuous male homosexual activity, was known from the earliest cases of AIDS in the UK to be associated with travel.^[47] An editorial in The Lancet of 22 December 1984 commented on an article by Dr Mads Melbye and others in the same edition, which noted that anti-HTLV-III seropositivity in Danish homosexual men was most strongly correlated with travel to the USA and especially New York City^[48] and noted that, of Scottish patients studied in Glasgow, of those treated with domestically sourced product only those who had travelled abroad were HTLV-III antibody positive. It observed that contamination of local blood products with HTLV-III must only be a matter of time, effectively recognising the reality that had already emerged.^[49]

Clinical practice in the United States of America; in England and Wales; and in Scotland

12.27 The chronology of the emergence of AIDS has been dealt with in detail elsewhere (see Chapters 9-10). In examining the clinical response to these developments, it is appropriate in the first instance to have regard to attitudes and actions in the USA, where the first AIDS cases were identified and where it was quickly recognised that AIDS was potentially a major public health issue. The UK presented a very different picture, however, and within the UK there were significant differences in treatment regimes for haemophilia therapy as between England and Wales on the one hand and Scotland on the other. Chief amongst these was the availability of therapeutic materials derived from UK donors: in England and Wales, these accounted for only a small proportion of the required products and the importation of commercial products was correspondingly high. By contrast, Scotland was increasingly able to produce a much greater proportion of therapeutic materials from domestically sourced blood and the importation of commercial products was considerably lower. After the discussion of the clinical response in the USA, therefore, there follows discussion of opinions and reactions in England and Wales before the clinical response particular to Scotland is considered.

Clinical response to the emergence of AIDS: The United States of America

Initial response

12.28 The initial response to the emergence of AIDS in the USA^[50] was limited to advice on clinical practice in managing patients with diseases of the 'AIDS complex'. Clinicians were advised to treat the infections identified in patients suffering from the syndrome, so far as they were treatable. In addition to managing diagnosed disease, long-term prophylaxis for PCP was suggested as a possibility.^[51] The focus was predominantly on patient care for those infected or suspected of having been infected with AIDS and those with AIDS-related conditions, rather than on preventative measures.

Haemophilia patients at risk

12.29 After it was reported in July 1982 that US haemophilia patients appeared to be at risk,^[52] a wider approach was adopted generally in the USA. The US National Hemophilia Foundation (NHF) called for action to protect patients and, in collaboration with the CDC and the Food and Drug Administration (FDA), instituted a surveillance programme to determine patterns of AIDS transmission among haemophilia patients, with a view to establishing guidelines for treatment.^[53]

12.30 In response to the threat of AIDS some haemophilia clinicians in the USA, notably Dr Oscar Ratnoff of Cleveland, proposed that haemophilia patients should suspend the use of concentrates and revert to cryoprecipitate, prepared from pools of ten donors or fewer.^[54] He was opposed by the pharmaceutical industry and by other haemophilia doctors. In December 1982, however, after a total of eight cases of haemophilia-associated AIDS had been reported, the first NHF directive was issued recommending that concentrates should not be introduced to those who had not previously been exposed to them, including newborn children and young children up to four years old; to newly diagnosed patients; and to patients with mild haemophilia. Cryoprecipitate and fresh frozen plasma were recommended for therapy in such patients instead.^[55] This was an approach that appears to have been based, in those very early days of the AIDS epidemic, on caution rather than firm scientific proof of the relative risks of transmission by cryoprecipitate and concentrates.

12.31 In January 1983, a further NHF directive recommended the use of Desmopressin (otherwise known as DDAVP, a synthetic replacement for the hormone vasopressin) for patients with mild and moderate haemophilia.^[56] The directive also recommended delaying elective surgery. This reflected considerable suspicion that AIDS was due to a blood-borne agent but, at the time, the risk of haemophilia patients developing AIDS was perceived to be very low. The use of DDAVP, where possible, was perceived as a prudent, and conceivably safer, alternative to the use of concentrate.

12.32 In US studies reported early in 1983, it was found that patients treated with cryoprecipitate did not develop impaired cell-mediated immunity.^[57] As against the practical problems associated with a switch from concentrate therapy to cryoprecipitate, those studies appeared to suggest that cryoprecipitate exposed recipients to less risk of immune deficiencies than risks posed by concentrates.^[58] Professor Ludlam noted, however, that it is now recognised that, largely due to variations in individuals' immune systems generally, immune changes such as those described were not necessarily a good reflection of HIV status.^[59] As noted at paragraphs 12.114 and 12.118, it was to transpire that many of the haemophilia patients studied in Edinburgh and Glasgow, who showed changes in cell-mediated immunity, were not in fact HIV-positive at that time.^[60] In addition, it was to transpire that in countries which used cryoprecipitate exclusively, HIV transmission still occurred, albeit to numbers of patients considerably lower than in those countries which used concentrates.^[61]

12.33 The preference for cryoprecipitate, as expressed by Dr Ratnoff, was repeated in an editorial in the New England Journal of Medicine (NEJM) of 13 January 1983 written by Dr Jane Desforges.^[62] She commented that, in view of the results from the Lederman^[63] and Menitove^[64] studies reported in that edition (noted in the preceding paragraph), current modes of treatment would have to be scrutinised and suggested that, if cryoprecipitate use reduced the risk of haemophilia patients contracting AIDS, the current home treatment programme (using concentrate) needed to be revised. This was a more radical proposal than that contained in the NHF directive. She advised physicians involved in the care of haemophilia patients to be alert to the risk and wrote that, '[p]reventing the complications of the present treatment might have to take precedence over preventing the complications of haemophilia itself'. The withdrawal of factor concentrates was mooted, though it was acknowledged that there might not be enough evidence to demand such a radical change.^[65] Professor Ludlam noted that Dr Desforges had accepted that the number of patients involved in her preliminary study was 'too small for definitive comparison of the risks of different modes of treatment' to be made.^[66]

12.34 These early responses related to haemophilia therapy suggested product selection in order to reduce risk in particularly vulnerable groups, or avoiding elective procedures so that blood product therapy would not be required. More generally, concentrate therapy was considered unavoidable, save in the more radical proposals put forward by Drs Ratnoff and Desforges. Further proposals soon emerged in the USA but, as noted above, there was controversy over the infective agent hypothesis and possible solutions based on product selection were unlikely to be persuasive while the controversy remained unresolved.

12.35 Realistically, however, the widespread use of cryoprecipitate as proposed by Dr Ratnoff and Dr Desforges had little prospect of success in the USA or elsewhere. Production facilities did not exist to provide the quantities of cryoprecipitate that would have been required, as indeed Dr Desforges had suggested in her article.^[67] Other clinicians thought that because of the cumulative effect of infusing large quantities, cryoprecipitate would ultimately be as likely as concentrates to transmit disease.^[68] Many clinicians, the blood products industry and, indeed, many patients strongly resisted switching from home therapy using concentrates to the use of cryoprecipitate, which would have ended the home therapy programme and resulted in haemophilia patients requiring to attend hospital when they experienced bleeds. Subsequently, in March 1985, Dr Ratnoff reported that of 91 patients under his care, only five had followed his advice and switched to cryoprecipitate therapy.^[69] Professor Ludlam was not aware whether Dr Desforges had acted on her 'recommendation' and changed patients under her care from concentrate therapy to cryoprecipitate.^[70]

Statements on the prevention and control of AIDS

12.36 On 4 March 1983, the US Public Health Service noted that statements on the prevention and control of AIDS had been issued by the National Gay Task Force, the National Hemophilia Society, the American Red Cross, the American Association of Physicians for Human Rights and others. There was broad agreement that steps were required to reduce the potential risks but the organisations differed in the methods proposed to accomplish that goal. The Public Health Service made a number of general precautionary recommendations. So far as clinical practice was concerned, it recommended that physicians should adhere strictly to medical indications for transfusions and that autologous transfusions (whereby, in anticipation of planned surgical intervention, the patient gives their own blood in advance for use in the operation) should be encouraged. Manufacturers were encouraged to produce safer products.^[71]

12.37 A similar point was made in the March-April 1983 edition of the journal Transfusion which published a joint statement on AIDS related to blood transfusion.^[72] The statement, which 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 Centers, with both voluntary and government assistance, recommended that physicians should be educated further regarding the importance of balancing the decision to use each blood component against the risks of infection, be they well established or, like AIDS, under investigation.

12.38 The Medical and Scientific Advisory Council of the NHF began to produce a series of guidelines for the treatment of haemophilia patients, developed in response to the latest scientific and medical knowledge. Some of the guidelines of this period were reflected in the approaches of international bodies. For example, on 21 December 1982 the World Federation of Hemophilia issued the recommendation that:

[C]ryoprecipitate be used to treat patients in the following groups except where there is an overriding medical condition: new born infants and children under 4; newly identified patients never treated with factor VIII concentrate; and patients with clinically mild haemophilia who require infrequent treatment.^[73]

12.39 It was recommended that DDAVP should be used whenever possible in patients with mild or moderate Haemophilia A. These recommendations were a close parallel of the then current US Public Health Service recommendations.

12.40 The wish of many haemophilia clinicians to maintain the status quo remained an important factor, however. In June 1983, Dr Aledort affirmed that his position on treatment was 'business as usual'. There was, in his view, no evidence that treatment with concentrates caused AIDS and no need to change therapy.^[74]

The position in the United States of America at the end of 1983

12.41 By the end of 1983, a number of strategies had emerged in professional literature and in national agency directives in the USA:

• Physicians should adhere strictly to medical indications for transfusions.
• Physicians should be educated further regarding the importance of balancing the decision to use each blood component against the risks of infection, be they well established or potential.
• Autologous transfusions should be encouraged.
• Concentrates should not be introduced to those who have not previously been exposed to such treatment, including newborn children and young children up to four years old, newly diagnosed patients, and patients with mild haemophilia.
• According to one extreme of opinion, factor concentrates should be withdrawn.

12.42 Two background factors appear to have been particularly important in influencing policy at the end of 1983:

• No transmissible aetiological agent of AIDS had been isolated or identified, to the satisfaction of leading authorities in the USA, ^[75] and there was no screening test to protect the blood supply.
• Strategies to reduce hepatitis infectivity in factor concentrates were in the course of development and it was presumed that, if the transmissible agent of AIDS were a virus, similar strategies could reduce the infectivity of other agents, including a possible AIDS agent.

Clinical response to the emergence of AIDS: England and Wales

The aetiology of AIDS: transmissible agent or antigen overload?

12.43 As noted above, the emergence of AIDS, seen at the time as a genuinely new disease with no relevant history upon which to base decisions on appropriate action, gave rise to debate as to the aetiology of the condition. This debate itself - between those who believed that an infectious agent, probably a virus, was responsible for the observed clinical signs and symptoms in AIDS patients (the transmissible agent theory) and those who believed that those signs and symptoms were attributable to the repeated infusion of foreign proteins in factor concentrates in haemophilia therapy (the antigen overload theory) - was an important factor, as guidance on the selection of therapeutic materials was developed.

12.44 Dr Peter Kernoff^[76] expressed the view in the Haemophilia Society publication The Bulletin, edition 33, No 1, January 1983, that the links between AIDS and concentrate therapy for haemophilia were 'very tenuous'. Haemophilia patients might be at increased risk of AIDS if AIDS was caused by an infectious agent and if this agent were transmitted in blood - 'and these are both big "ifs'' '.^[77] The idea that there was an epidemic of AIDS amongst haemophilia patients was dismissed as 'ludicrous'. In general, he said that AIDS was just the latest item in a long list of possible risks associated with factor therapy.

12.45 Dr Kernoff's views were noted in the media^[78] and by the Department for Health and Social Security (DHSS), where it was commented that the benefits of clotting factor concentrates 'far outweigh the possible, and as yet unproven hazards of the transmission of acquired immune deficiency syndrome'.^[79] It was still four months before the first suspected case of AIDS in a UK haemophilia patient (see paragraph 12.69 below). Though expressed in strong terms, Dr Kernoff's views were within the range of acceptable expert opinion in January 1983.

The benefits of factor concentrate therapy

12.46 Debate on the selection of therapeutic materials for haemophilia therapy appears to have been influenced, at least in part, by the appreciation of the considerable benefits of factor concentrate therapy already noted.

12.47 On 4 May 1983, the Haemophilia Society distributed a letter by Professor Arthur Bloom that has been referred to in other contexts.^[80] Professor Bloom was influential: he 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 (CBLA). He wrote that the cause of AIDS was quite unknown and that it had not been proven to result from transmission of a specific infective agent in blood products. He too supported continuing use of current therapy using concentrates and referred explicitly to the benefits of factor concentrate therapy in support of his position:

Haemophiliacs, their parents and doctors have always balanced the quality of life and the dangers from bleeding against the risks of treatment. We are no strangers to infective diseases, such as hepatitis, which can be transmitted by factor concentrates ....

....

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.^[81]

Imported commercial blood products in England and Wales

12.48 Throughout the UK at this time, practitioners were confident of the safety of the domestically produced factor concentrate products and remained confident so long as there was no evidence of infection in recipients of NHS blood products. There were significant differences between Scotland and the rest of the UK that affected discussion of risk, however, which have to be borne in mind. In particular, treatment options in England and Wales were limited by the inability of the public sector manufacturer to meet the demand for Factor VIII concentrate. Scotland had more ample supplies of concentrates manufactured at the Protein Fractionation Centre (PFC, the manufacturer of NHS blood products in Scotland) and this important distinction is explored below. In the first place, however, the position in England and Wales is discussed without reference to these differences.

12.49 In most, if not all, regions of England and Wales, Factor VIII therapy using concentrates necessarily involved the use of imported commercial products. As noted in Chapter 21, Haemophilia Therapy - Use of Blood Products, the distribution of NHS materials in England and Wales was provided for on a regional basis, with concentrates manufactured at the Blood Products Laboratory (BPL, the manufacturer of NHS blood products in England and Wales) distributed pro rata to the contributions from each region of plasma for fractionation. At all material times, NHS output was insufficient to meet total demand and the shortfall was met by commercial purchases, funded by regional health authorities.^[82]

12.50 In early 1983, the supply of NHS manufactured Factor VIII concentrate accounted for less than 30% of the demand in England and Wales. The remainder was commercial product, largely imported from the USA. As shown in Chapter 21, Haemophilia Therapy - Use of Blood Products, Figure 21.2, commercial Factor VIII was the main therapeutic product used throughout the 1980s in England and Wales and the use of imported products could not realistically be avoided if concentrate therapy was to continue.

12.51 Dr Mark Winter described the state of affairs as he found it when he became Consultant Haematologist at Kent and Canterbury Hospital in 1983. The scope for choice of therapeutic products was limited. The output from the BPL was restricted by the capacity of the plant^[83] and his centre obtained only small quantities of NHS Factor VIII concentrate. At least 90% of the concentrate available for use was commercial. This formed part of the practical background to his response to the emergence of the AIDS threat: whatever he thought of the risk, he could not discontinue the use of imported concentrates. In fact, Dr Winter said that he was convinced at a relatively early date that AIDS was caused by a blood-borne infective agent but, for him and for Haemophilia Directors with similar views, concentrate therapy was dependent on the products of US pharmaceutical companies. In time, the capacity of the production facilities in England was increased. The foundation of a new facility at Elstree, aimed at self-sufficiency, was laid on 23 March 1984. That was, however, clearly too late to make any impact on the importation of commercial concentrates while the threat of transmission of HIV/HTLV-III continued.

12.52 In the circumstances, discussion in England and Wales tended to focus on the continuing use of imported products. Support for the status quo in coagulation therapy was forcefully expressed in the article by Dr Kernoff referred to above. In addition to supporting continued use of factor concentrates generally, he wrote that it would be premature to jump to the conclusion that commercial concentrates were more dangerous than NHS concentrates. In any event, dependence on US imports was a fact of life and he saw no reason to change current practice. His final comment was that:

For particular patients, and at particular centres, there may be reasons for preferring cryoprecipitate, but these reasons have little to do with AIDS.^[84]

12.53 For Dr Winter - even though his personal assessment of the situation at the time was different - that was an understandable position to adopt, having regard to the obvious benefits derived from the use of concentrates:

He is a very respected figure looking at the data and saying it is of concern, but we are talking about a product that has revolutionised the lives of patients and there is a major obvious benefit to this treatment. We will have to look at the risk that appears to be evolving. That was the situation of the day.^[85]

Recommendations and guidance

12.54 The approach of Professor Bloom, set out in his letter of 4 May 1983, was supported at a special meeting of the UK Haemophilia Reference Centre Directors. That meeting of 13 May 1983 at St Thomas's Hospital was chaired by Professor Bloom and was convened specifically to discuss the problem of AIDS.^[86] There were noted to be ten cases of AIDS in homosexual males in the UK by that date and one haemophilia patient was reported as being 'suspected' of suffering from the disease. Concern was expressed at the definition of AIDS and it was advised that evidence of impaired cell-mediated immunity should not be regarded as necessarily leading to AIDS.^[87] The consensus reached at that meeting among the Haemophilia Reference Centre Directors in attendance was set out in a letter from Professor Bloom to the Directors, including Scottish Directors, dated 24 June 1983.^[88] Reflecting both the view that the aetiology of AIDS was as yet unknown and the appreciation of the benefits of concentrate therapy, he commented that, with the exception of some vulnerable patients:

It was agreed that there is 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 will be constantly reviewed.^[89]

12.55 General recommendations were agreed:

• For mildly affected patients with haemophilia A or von Willebrand's disease and minor lesions, treatment with DDAVP should be considered.
• It was noted that many Directors already reserved supplies of NHS cryoprecipitate and concentrates for the treatment of children, mildly affected patients and patients unexposed to imported concentrates and the recommendations suggested that it would be 'circumspect to continue that policy.' ^[90]

12.56 At this stage, the recommendations were less cautious in the case of Haemophilia A as compared with the NHF directives in the USA, noted in paragraph 12.30 above. The NHF recommendation was that DDAVP should be used for mildly and moderately affected haemophilia patients. In relation to concentrates, in addition to children and mildly affected patients or patients not previously exposed to imported concentrates, the NHF recommended that concentrates should not be introduced to newly-diagnosed patients or to patients with mild haemophilia.

12.57 Additional points were made after the meeting and reported by Professor Bloom in his letter of 24 June. The first of these related to the treatment of patients with Haemophilia B. He commented:

The evidence to incriminate factor IX concentrates in AIDS is even less than with FVIII and it seems logical to continue to use our normal supplies of NHS concentrate.^[91]

12.58 That remained the consensus view throughout the development of the AIDS crisis and it was only later that a small number of AIDS cases came to be reported in Haemophilia B patients.^[92]

12.59 Opinion on therapy was also developing in Europe. The Committee of Ministers of the Council of Europe adopted Recommendation No R(83)8 on 23 June 1983. It dealt with the prevention of the spread of AIDS as a result of infected blood donations. It recommended that Member States:

[T]ake all necessary steps and measures with respect to the Acquired Immune Deficiency Syndrome and in particular:

• To avoid wherever possible the use of coagulation factor products derived from large plasma pools; this is especially important for those countries where self-sufficiency in the production of such products has not yet been achieved;
• To inform attending physicians and selected recipients, such as haemophiliacs, of the potential hazard of haemotherapy and the possibility of minimising those risks. ^[93]

12.60 The first recommendation would have restricted the use of factor concentrates manufactured in the UK as well as imported commercial products. The qualification regarding self-sufficiency would have affected England and Wales to a greater extent than Scotland, which was closer to self-sufficiency. The emphasis on large-pool products appears implicitly to have reflected the view - clearly not yet accepted by all UK haemophilia clinicians - that AIDS was spread by infected blood products, as did the emphasis on the prevention of AIDS transmission by means of blood transfusion. To that extent, it presented a challenge to those who disagreed with the Committee of Ministers to explain their position.

12.61 In May 1983, Dr Frank Boulton^[94] wrote to Professor Bloom.^[95] Professor Bloom replied on 23 May and commented:

We have not laid down hard and fast regulations since the detail of treatment will depend upon local circumstances. I do not think that anyone is complacent about the situation but I think that we all agree that it would be counter-productive to ban the importation of blood products at this moment ... The Haemophilia Society have expressed concern that we are not expanding the home treatment programme with sufficient vigour ....^[96]

12.62 There was media comment on the views of the Haemophilia Society in the same period. On 18 May 1983 in an article with the headline 'US Gay Blood Plague Kills Three in Britain', The Sun reported that the Haemophilia Society had appealed to the government not to ban US blood products.^[97] The Society was said to have claimed that without the US imports there would be a sharp rise in the number of deaths among people with haemophilia.

12.63 On 11 July 1983, in a note on 'Factors to be considered in the Selection of Hepatitis Reduced Products for Clinical Trial - Evaluation of Residual Infectivity for Hepatitis Viruses', Dr John Craske^[98] commented that the possibility had to be considered 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.^[99] However, he said that there was, as yet, no product which was not made from sources which were likely to carry such a risk (implicitly accepting that, if the infective agent theory were to prove accurate, there was every reason to suppose that it would enter the UK blood supply in time, if it had not already done so). On his approach, there was not much that could be done to avoid the use of coagulation factor products derived from large plasma pools, whatever their origin.

Contrary views

12.64 There were, however, contrary views. Dr Spence Galbraith of the Communicable Disease Surveillance Centre supported a temporary ban on the use of certain imported products in a paper 'Action on Aids' sent to Dr Ian Field of the DHSS in May 1983. Dr Galbraith stated in his covering letter:

I have reviewed the literature and come to the conclusion that all blood products made from blood donated in the USA after 1978 should be withdrawn from use until the risk of AIDS transmission by these products has been clarified.^[100]

12.65 Dr Galbraith's reasoning was based on the transmissible agent theory. It was a powerful statement of the risk as perceived by a public health specialist but it did not ultimately lead to the change in policy advocated: his advice was rejected by the Biologicals Sub-Committee of the Committee on the Safety of Medicines on 13 July 1983.^[101] It was concluded by the Sub-Committee that withdrawal of imported products was not feasible on the grounds of supply. In addition, 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 from foreign suppliers would reduce markedly, although not eliminate, the risks to recipients. It was noted that haemophilia doctors and patients, who saw first hand the benefits of Factor VIII over cryoprecipitate, did not wish blood products from the USA to be withdrawn.^[102] It is apparent that the Sub-Committee shared the opinions of the haemophilia clinicians and the Haemophilia Society over the crucial issue of withdrawal of imported commercial products.

12.66 The conclusions rejecting Dr Galbraith's recommendations were controversial for some. According to evidence provided to Lord Archer, some experts were taken aback by the decision.^[103] Professor Christopher Bartlett, formerly of the Communicable Disease Surveillance Centre (CDSC), is reported to have said, 'I was dismayed when the Sub-Committee concluded that the risk was small, because I, like Dr Galbraith, found that the evidence was rather stronger than that ....'^[104] Dr Galbraith was 'completely bowled over' by the Sub-Committee's decision.^[105]

12.67 Dr Winter commented that this stage was, in his view, another highly critical time.^[106] He thought that everything Dr Galbraith had said in his paper was true, scientifically: in retrospect, what he proposed would have saved some lives. Clinicians and those advising them were, however, constrained by concerns about the consequences of withdrawing imported concentrates. Given the risk to patients, particularly that of exposing patients to potentially fatal cerebral bleeds, Dr Galbraith's proposal would have been met with very great reluctance by doctors and by patients.

12.68 At this stage, therefore, in the summer of 1983, Dr Galbraith, a public health specialist, favoured avoiding imported concentrates; Dr Craske, also a public health specialist, acknowledged a risk but thought it common to all Factor VIII concentrates; and the Haemophilia Society and its advisers remained committed to the use of concentrate, including imported products, though exceptions were provided for in practice guidance.

First AIDS deaths in the United Kingdom

12.69 By May 1983, there had been deaths in the UK from AIDS in the male homosexual community and AIDS was suspected in a haemophilia patient in Cardiff.^[107] By 31 July 1983, 14 cases of AIDS had been reported to the CDSC.^[108] One of the 14 was a haemophilia patient who had received Factor VIII imported from the USA.^[109] A second case of infection in a haemophilia patient, in Bristol, had apparently not been formally reported to the CDSC by this stage. The risk from blood products imported into Britain was considered by the CDSC to be 'very small' at that time: there were about 2167 patients with haemophilia then receiving treatment in the UK, the majority with imported Factor VIII concentrate. By September there were two well documented cases of AIDS in haemophilia patients in England and Wales and one had died of the disease.^[110] These events did not, however, have an immediate or significant impact on treatment policy or practice.

12.70 On 21 June 1983, the CBLA Central Committee for Research and Development in Blood Transfusion met for the first time. The Chairman, Dr Harold Gunson, outlined the problems caused by AIDS and noted that 'it appeared to be spread by blood and blood products'. However, the general feeling of the committee was reported to be that 'not enough was known about AIDS to enable any decisions to be made'.^[111]

12.71 The coordinator of the Haemophilia Society wrote to a government official on 15 August 1983 regarding a meeting arranged to take place between representatives of the Society and Lord Glenarthur, Parliamentary Under-Secretary of State, DHSS, on 8 September 1983.^[112] The issues the Society wanted to discuss included the avoidance of banning the importation of concentrates from the USA unless there was definite evidence that this was necessary. An undated file copy of a letter from Lord Glenarthur to the Society sets out the points made at the meeting.^[113] He commented that, 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.^[114]

12.72 On 10 September 1983, the UKHCDO surveillance of AIDS in coagulation disorder patients was updated. The 'Cardiff patient', reported in the CDSC bulletin of 6 May as a possible case of AIDS, remained reasonably well. The 'Bristol patient', however, had been unwell through June and July and died in August. This was considered to be the first confirmed case of death from AIDS in the UK associated with blood products. Both cases were reported to the Haemophilia Centre Hepatitis Working Party on 14 September 1983^[115] and to a meeting of the Haemophilia Reference Centre Directors on 19 September 1983.^[116]

12.73 The UKHCDO Hepatitis Working Party report for 1982-83 was produced on 28 September 1983 under the chairmanship of Dr Craske.^[117] It commented on the possible contamination of plasma by a putative AIDS-related agent as a complication. It reflected the views Dr Craske had previously expressed that, at that stage, the existence of an infective AIDS agent was considered to be unproven but, if an infective agent existed, all source material might be infected by it, as was the case for the non-A, non-B Hepatitis virus. The dilemma for clinicians prescribing therapy was expressed but not resolved.

12.74 On 17 October 1983, the UK Haemophilia Centre Directors held their 14th meeting, in Manchester.^[118] By then, information about one of the haemophilia patients, treated in Bristol, had been published in The Guardian and Dr Geoffrey Scott, from Bristol, attended the meeting. There was, therefore, first-hand information available about the patient who had died there, although the record does not disclose whether Dr Scott contributed to the meeting. Dr Morag Chisholm of Southampton raised the problem of patients refusing to take up commercial Factor VIII concentrate because of the AIDS scare and wondered whether they could revert to cryoprecipitate for home therapy. Other Directors voiced similar concerns. Professor Bloom replied to Dr Chisholm:

[T]hat he felt that there was no need for patients to stop using the 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.^[119]

Reaction to a World Health Organization Meeting on AIDS in November 1983

12.75 The World Health Organization (WHO) met in Geneva between 22 and 25 November 1983 to discuss AIDS. The draft report of the meeting contained a section on the prevention and control of AIDS. In relation to blood and blood products, it stated:

AIDS cases have infrequently occurred in both hemophiliacs receiving clotting factor concentrates and in recipients of blood and blood component transfusions who do not have other apparent risk factors. Approaches to reducing the possibility of spreading AIDS by blood and blood products include: ... 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 transmitting AIDS.^[120]

12.76 The topic was developed in the paper:

Immunoglobulin and albumin prepared by generally accepted methods have not been implicated in AIDS and are considered safe. Coagulation factor concentrates, however, have been implicated in cases of AIDS. Although additional inactivation methods have recently been developed, it will not be possible to fully establish their effectiveness until the agent of AIDS is discovered.^[121]

12.77 The association of factor concentrates with AIDS risk was acknowledged and unchallenged, so far as the draft report discloses, although continued use of concentrates was clearly envisaged. The alternative methods available for reducing risk were: reducing pool sizes; adopting process technology aimed at reducing contamination risks; and adopting specific donor/recipient practice, especially in the case of those newly diagnosed with haemophilia and requiring only infrequent therapy.

12.78 On 5 December 1983, Dr McClelland, Director of the South East Scotland Blood Transfusion Service, prepared an initial report on the conference, for the Scottish RTDs' Meeting of 8 December.^[122] He noted that the WHO meeting was chaired by Walter Dowdle and was heavily influenced by him, Dr Curran and Dr Francis, all three from the CDC. The association of factor concentrates with AIDS appeared to Dr McClelland, at the time, to have been exaggerated by them. He reported that the NIH had issued practice directions for follow-up of recipients of blood and blood products in the USA.

12.79 In his report, Dr McClelland commented on steps that might improve safety for individual recipients of therapy, such as the use of small pool concentrates and batch dedication, in particular for those who were newly diagnosed and required only infrequent therapy. The evidence adduced at the conference was primarily related to experience in the USA. Dr McClelland's observations as a Transfusion Director indicate that there was still not unqualified acceptance of the infective agent theory in the UK by the end of 1983. Publications at the end of that year appear to confirm this.

The requirement for a very high standard of proof

12.80 In an editorial published in the British Medical Journal (BMJ) of 10 December 1983, Dr Peter Jones, Newcastle Haemophilia Centre, reflected one extreme in the developing views among haemophilia clinicians of the risks associated with the therapeutic use of blood products.^[123] The introductory paragraph set the tone:

People with haemophilia, their families, and their doctors feel threatened by the deluge of speculation about the possible side effects of treatment with blood products. Two topics hold their attention: the risk of contracting the acquired immunodeficiency syndrome (AIDS) and the risk of developing hepatitis and subsequent chronic liver disease.

12.81 Characterising the risk of AIDS as a speculative possibility reflected the approach of Dr Kernoff at the beginning of the year and was not dissimilar to the DHSS view then prevailing. However, that view was becoming less sustainable in December, having regard to increasing knowledge of the characteristics of the disease and its prevalence.

12.82 Dr Jones stated that the incidence of AIDS among haemophilia patients in the UK and USA was about 0.8 per thousand. He suggested as a possibility the idea that what had been seen in haemophilia patients was an entirely different disorder from that seen in homosexuals, caused by 'repeated antigenic challenge over many years' (the antigen overload theory) rather than by a transmissible agent.^[124]

12.83 He posed the question: what risk is there of serious harm from haemophilia treatment? With limited exceptions, he considered that there was no justification for discontinuing the use of concentrates and that 'the risk of haemorrhage and its complications far outweighs the risk of developing AIDS'. Implicitly accepting the alternative aetiology - the transmissible agent theory - he said, in relation specifically to imported concentrates:

The commercial companies in the United States acted responsibly and quickly to exclude high risk donors, and similar action has now been taken in Britain ....^[125]

12.84 Dr Jones stated that, while there was anxiety about AIDS, the advice from Reference Centre Directors and the Haemophilia Society was to carry on with Factor VIII treatment.^[126] He advised that, since no Factor VIII could be guaranteed AIDS-free, cryoprecipitate should be used to treat very young severely affected children and other options (DDAVP or porcine Factor VIII) should be used for older people with mild haemophilia or von Willebrand's disease and carriers of these disorders. The comments in the editorial reflected the view already advanced by Professor Bloom that AIDS required no significant change to therapy, save for particular groups of patients.

12.85 Dr Jones' views were reported in The Guardian on 9 December 1983.^[127] There was a further comment by Andrew Veitch, medical correspondent, relating to the two cases of AIDS in haemophilia patients that had by then been confirmed.^[128] Mr Veitch reported the two cases and noted that the affected patients were thought to have contracted the disease from contaminated supplies of Factor VIII imported from the USA. He referred to emerging data from Germany on infection within the homosexual community, confirming fears that AIDS had arrived in Europe from the USA two years earlier. He quoted Dr Jones' comment that alternatives to concentrates should be used to treat very young, severely-affected children and older people with mild forms of haemophilia. Overall, the article reflected views somewhat less sanguine than those expressed by Dr Jones.

12.86 On the other hand, there was a constituency of opinion among haemophilia clinicians, represented by Dr Winter at this Inquiry, which took a more pessimistic view of the risks associated with concentrate therapy but often could not practically adapt clinical practice to reflect their opinions on risk. He thought that as information of an association between factor therapy and AIDS was published, the practical necessity of using imported products induced a state of denial in some haemophilia clinicians:

[I]f you like, the clinicians didn't want to believe any of this data, because we have just been through such a very major advancement in healthcare .... In America it was the same .... There were lots of political issues around that. So none of the related agencies wanted to know this. That's why ... I'm sure, this data took some time to really hit home.^[129]

12.87 However, as noted above, he also commented that many clinicians, even if they did accept the transmissible agent theory, thought that they could not change practice, given the benefits of factor concentrate therapy.^[130] There were fundamental practical issues relating to the choice of therapeutic product for haemophilia treatment.

12.88 There is no basis for a view that clinicians were deliberately suppressing or ignoring data on transmission in commenting on the use of concentrate therapy. It appears, rather, that those who promoted the continuing use of imported Factor VIII could not accept the conclusions resulting from those data. The problem was possibly that noted in relation to the workshop in January 1983 in Atlanta: too high a standard of proof was set. Full scientific proof according to accepted norms was impossible.^[131]

12.89 The official view of the cause of AIDS, as expressed by DHSS Ministers and officials throughout 1983 and into 1984, was essentially a negative view, that there was 'no conclusive proof' or 'no conclusive evidence' that AIDS was transmitted through blood products. That is discussed in Chapter 9, Knowledge of the Geographic Spread and Prevalence of HIV/AIDS 1, paragraphs 9.108-9.123. So far as it is possible to understand the published statements made at the time, they are consistent with what Professor Hann agreed was a requirement for a very high standard of proof.^[132] Such a high standard was not met by a contemporaneous observation in a DoH publication that AIDS was 'almost certainly' transmissible by transfusion of blood and blood products.^[133] The official government view at the end of the year was expressed in a letter dated 13 December 1983 written by Lord Glenarthur to John Maples MP, who had enquired about the government's assessment in light of recent press reports. It stated that the cause of AIDS was as yet unknown and there was no conclusive proof that the disease had been transmitted by US blood products. The practical situation was set out:

[T]he Government is committed to making this country self-sufficient in blood products .... Meanwhile, in the absence of a satisfactory alternative, we shall be dependent upon imports from the USA for an adequate supply of Factor VIII.^[134]

12.90 Professor Lever was asked to comment, with the benefit of hindsight, on the point at which there required to be a reassessment of the risk/benefit balance involved in the use of therapeutic products.^[135] In summary, he pointed to two factors of importance as triggers of reassessment: evidence of immunosuppression associated with therapy and evidence of death from immunosuppression.^[136] As far as the first of those is concerned, a haemophilia patient in Cardiff had become ill with suspected AIDS by the beginning of May 1983. Profound immunosuppression in the east and west of Scotland patients had been established by the studies carried out in 1983. A fatal outcome after immunosuppression in haemophilia was known from the middle of September 1983. The scene was set for review of current therapy.

Views of the Haemophilia Society in early 1984

12.91 On 9 January 1984, the Blood Products Sub-committee of the Haemophilia Society produced a paper reviewing blood products supply and related issues in England and Wales.^[137] While the Sub-committee is likely to have had expert help, the paper illustrates the response of one interested community to scientific developments at the time. On the topic of AIDS, the paper repeated the position that no infective agent had been identified for AIDS and that there was no reliable evidence that the disease was transmitted through blood products. However it commented that if AIDS was so transmitted:

[T]he 'Mail on Sunday' reasoning - that importation of American blood products should cease^[138] - may prove to be an over-simplification, as AIDS could still be transmitted from the British donor population. Certainly the immunological abnormalities which may be associated with AIDS are observable in haemophiliacs not exposed to commercial concentrates [e.g. in Scotland and Australia].^[139]

12.92 After discussion, it concluded that:

[T]here 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.^[140]

12.93 It is of interest that the second well-documented case of AIDS, that of a patient in Cardiff, does not appear to have been acknowledged at this point. The paper reflected a view, still held by at least some haemophilia clinicians at the time and in particular by the Society's advisers, that factor concentrate therapy for haemophilia patients should continue, including the use of imported products.

12.94 As a practical matter, with the exception of Scotland (and Northern Ireland when supplied from Edinburgh), there was no reasonable prospect of avoiding the use of imported commercial products in the UK as a whole during the first five months of 1984 if factor concentrate therapy was to continue. The Blood Products Sub-committee paper of 9 January 1984 commented on the rising trend of demand from 1975-82,^[141] which showed no sign of levelling off. The proportion of total usage represented by NHS products fluctuated over the period but the critical factor was the use of commercial products. Never less than 54%, in the last four years of the period use of commercial products was consistently over 60% and in 1982 reached 66.6%. At that stage production at BPL was near its target of 30 million units. The paper noted:

[W]e must be somewhat doubtful that NBTS could achieve the requirement, stated by the UK Haemophilia Centre Directors, of 100 million units by the middle of the present decade.^[142]

12.95 The Haemophilia Society's own projection of demand - 145 million units in 1985 rising to 178 million units in 2000 - was much higher than the Haemophilia Directors' estimate. On any view, the inevitable inference drawn by the paper was that the 'UK' - by which the Society must have meant England and Wales - would have to rely on imported Factor VIII 'for a very long time'.^[143] The situation in Scotland was quite different and is discussed below, beginning at paragraph 12.124.

12.96 The paper set out arguments in favour of imported products, covering ethical and financial factors as well as risk of infection. At that stage, there appears to have been little apprehension among those responsible for the paper that the use of imported products carried a high level of risk.

12.97 In relation to AIDS and blood products, it stated:

The AIDS scare has given us the opportunity, which we have not yet utilised, to campaign strongly for self-sufficiency in blood products. Given, however, that the original factors in our policy no longer apply or have reduced force, and that AIDS is still a great unknown, I submit that we should not undertake such a campaign. Now is not the time to ask that all our blood-product 'eggs' should be placed in one basket. Instead, without necessarily abandoning our long-term objectives, 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 seem to demand.^[144]

Developments in 1984: the impact of HTLV-III infection

12.98 As noted above, on 23 April 1984 Dr Robert Gallo and his team announced the discovery of HTLV-III.^[145] The identification of the virus is more fully discussed in Chapter 29, The Discovery of HIV and the Development of Screening Tests. Although it appears that some commentators remained of the view that the AIDS in haemophilia patients might be caused, not by the virus announced by Gallo and his team (or, indeed, that announced by Montagnier a year earlier), but by some other mechanism (such as antigen overload) it is reasonably clear that most accepted that the HTLV-III discovery pointed very clearly towards the infective agent theory. Professors Weiss and Tedder had been working on a screening assay for several months, using French virus obtained from Luc Montagnier,^[146] and a prototype assay was ready for laboratory application on 4 July 1984, allowing them to begin epidemiological studies.^[147] It took several months to develop an HIV test kit for general use, as discussed in Chapter 30, Screening of Donated Blood for HIV. In the meantime, however, many haemophilia clinicians had begun to submit samples to Professor Tedder.

12.99 As noted above, in the last three months of 1984 the reality of HTLV-III infection in a significant proportion of Haemophilia A patients was brought home to clinicians, and the wider scientific and medical community, when test results became available.^[148] By October 1984, many Haemophilia Directors, including Professor Ludlam, Dr Winter and Dr Kernoff, had already had samples tested by Professor Tedder. Professor Forbes had samples tested by Dr Gallo. Many, if not all, Directors knew that some of their patients were infected with HTLV-III. All but one of Dr Winter's patients, about 30 in total, were infected.^[149]

12.100 In a letter dated 23 October 1984, Dr Craske reported that it had been confirmed that a donor who had provided plasma used in the preparation of a batch of Factor VIII concentrate had been admitted to hospital with AIDS. The letter was concerned mainly with Dr Craske's interests as a public health doctor and discussed the need for follow-up.^[150] He referred, however, to the likelihood that any patient who had received commercial Factor VIII since 1980 had possibly already been exposed to HTLV-III.^[151]

12.101 A meeting of the UK Haemophilia Reference Centre Directors was held on 10 December 1984, chaired by Professor Bloom.^[152] He introduced the meeting by referring to recent events in Newcastle and Australia 'and the continuing work on HTLV III'. The most extensive record of discussions available indicates that this was a major strategic meeting.^[153] 'Events in Newcastle' included the death of a haemophilia patient who had contracted AIDS.^[154] Apart from a comment attributed to Dr Ludlam, the record does not disclose a report of the cases of infection in Glasgow and Edinburgh, though from subsequent events it appears that the position in Edinburgh at least must have been disclosed.^[155] After extensive discussion of HTLV-III antibody tests and their significance, Professor Bloom's summary was that HTLV-III antibody-positive haemophilia patients should be considered a risk but that it could not be assumed that those who were apparently HTLV-III antibody-negative were not, in fact, infective.^[156] That appears to have set the scene for a discussion of clinical implications.

12.102 It was anticipated that by the end of December 1984 or very early in 1985, Scotland would be self-sufficient in heat-treated concentrate. However, discussion proceeded to the availability and use of heat-treated Factor VIII more generally. It was reported that there was not a sufficient supply of NHS heat-treated concentrate to meet demand. In some circumstances the alternative to avoiding non-heat-treated concentrate would be that there would be no treatment. Professor Bloom summarised a long discussion by commenting that it was difficult to avoid the argument that non-heat-treated concentrate constituted a risk.

12.103 According to an alternative record of the meeting, after prolonged discussion it was agreed that children should be treated with cryoprecipitate or if necessary with heat-treated Factor VIII.^[157] New haemophilia patients should be treated with heat-treated Factor VIII. It was not proven that heat-treatment inactivated HTLV-III; nevertheless Directors felt that they should use commercial heat-treated Factor VIII in preference to commercial non-heat-treated Factor VIII. Dr Jones reported to the meeting that at Newcastle all concentrate used was heat-treated commercial product. There had been no other change in therapy apart from holding back on prophylaxis for children on home therapy.^[158] The Reference Directors agreed that heat-treated product should be given to all patients, if freely available.^[159] The commercial products on the market were reviewed.^[160] Most agreed to use non-heat-treated product until heat-treated product was available from BPL, although Dr Jones refused to do so, stating that all of his patients would have 'safe' heat-treated Factor VIII.^[161]

12.104 It was anticipated that this guidance would cause severe financial problems for treatment centres in England since the newly introduced US commercial heat-treated Factor VIII concentrate was more expensive.^[162]

12.105 There followed a discussion of the need to control the arrangements for the use of unlicensed products as it was felt that the rules at that time allowed companies to exploit the named patient system. In discussion of the availability and use of heat-treated Factor VIII, Professor Cash, Medical Director of the SNBTS, urged that the financial consideration be looked at seriously. Notwithstanding the small number of patients involved, the cost of imported heat-treated factor products would be high.^[163] The regulatory bodies would also need to consider applications for variation orders on existing licences 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.^[164] The meeting was concerned about the social attitudes being adopted towards AIDS patients and haemophilia patients. The situation was becoming very emotive and common sense was giving way to panic amongst donors, patients and contact groups.^[165] Guidelines on treatment were to be issued by Professor Bloom after the meeting.

12.106 The transmission of infection by the infusion of PFC Factor VIII was established in October 1984 in Edinburgh and the east of Scotland and in or about October 1984 in Glasgow and the west of Scotland. The information shared on 10 December (as summarised in the letter of 14 December referred to below) reflected acceptance of the transmissible agent theory and its association with profound immuno-suppression. Three patients with haemophilia had developed AIDS and two had died. Accordingly, the meeting on 10 December marked a further important juncture in the assessment of appropriate therapy: immunosuppression in haemophilia and its potentially fatal consequences was now definitively associated with NHS product. There was, in the event, a comprehensive reassessment of policy for the treatment of coagulation disorder patients.

12.107 On 14 December 1984, the UKHCDO produced an 'AIDS advisory document', in consultation with Drs Lane, Cash, Gunson, Mortimer, Tedder, Craske and others.^[166] The background information provided included data on infection. In the USA, there had been over 6000 cases of AIDS including 52 haemophilia patients. It was said that in the UK there had been 102 cases of AIDS with three reported cases in haemophilia patients and doubtless other cases developing. The information provided on infectivity was:

Antibody positivity probably correlates with exposure to imported concentrates but there have been two notable recent episodes concerning U.K. concentrates.

Antibody tests indicate prior infection but do not imply immunity as antibodies may not be neutralising ....

Antibody positive persons should ... be considered at risk of transmitting or developing AIDS but antibody negativity does not exclude infectivity.^[167]

12.108 The document described the tests available. It proceeded to discuss the inactivation processes currently in use and the processes used in the production of specific concentrates. It set out the options, in 'probable decreasing order of safety from AIDS for Haemophilia A' as:

1. Heated U.K. concentrate (note: still NANB hepatitis risk)

2. Single donor cryo. or FFP

3. Heated imported conc. (note: still NANB hepatitis risk)

4. Unheated U.K. conc.

5. Unheated imported conc - almost certain to be contaminated

...

RECOMMENDATIONS

1. Concentrate is still needed; bleeding is the commonest cause of disability and death.

2. Use DDAVP in mild Haemophilia A and vWd if possible.

3. For Haemophilia A needing blood products

a. 'Virgin' Patients those not previously exposed to concentrate, and children, use cryo or heated NHS factor VIII (if available)

b. Severe and Moderate haemophiliacs previously treated with factor VIII use heat treated NHS factor VIII, if available or heat treated US commercial.

4. Haemophilia B

a. Mild Christmas Fresh frozen plasma if possible (otherwise NHS Factor IX.

b. 'Virgin' Patients and those not previously exposed to concentrate use fresh frozen plasma (or NHS factor IX concentrate if essential)

c. Severe and Moderate Christmas Disease previously exposed to factor IX concentrate continue to use NHS factor IX.

In individual patients there may need to be a choice. In general heated concentrate appears to be the recommendation of virologists consulted but individual Directors may wish to make up their own minds. This is particularly true of unheated NHS material. The evidence that heated U.S. factor VIII is safer than unheated NHS is debateable and some Directors may wish to continue using unheated NHS material until all supplies are heated. This is valid for carefully selected patients but must be on individual decision based on the assumption that some batches of NHS materials will be contaminated with HTLVIII. The argument that HTLV III positive patients have already been infected and could receive unheated American material is probably scientifically true but this material would pose an additional risk to staff and families and its continued use would pose logistic problems.^[168]

12.109 In the case of haemophilia B, Professor Ludlam summed up the position in 1984:

I had a few patients with particularly moderate Haemophilia B. That was difficult. I think there was commercial heat-treated Factor IX of unproven safety from a donor pool that was likely to have many more HIV positive donors in it, versus [non-heat-treated] NHS clotting Factor IX. We knew at that stage in December 1984 that the prevalence of anti HTLV-III positivity in Haemophilia B was very much lower than in Haemophilia A, and we presumed that that was because the virus to a large extent was excluded in the manufacturing process, excluded from the final Factor IX product. So Factor IX was seen as a much safer product from the point of view of HTLV-III, even unheated. So the national recommendation was to continue to use unheated NHS Factor IX concentrate in those who had already been exposed to it and to use fresh-frozen plasma in patients who hadn't been exposed to it, if possible. If they had severe new patients with severe haemophilia, they might anyway have to be put on to the concentrate but to use UK concentrate. So it wasn't an entirely black and white issue. It was in a sense slightly easier to not use the heat-treated commercial because the epidemiology at that stage was that patients were much less likely to get infected with anti HTLV-III.^[169]

Clinical response to the emergence of AIDS: Scotland

The aetiology of AIDS: competing theories in Scotland

12.110 In common with both the USA and England and Wales, as discussed above, until at least June or July 1984 it remained a common view among commentators in Scotland, representing a broad spectrum of medical and scientific expertise, that the cause of AIDS was unknown and that it had not been established, or proved, that it resulted from transmission of a specific agent in blood products. Even after that date, a small number of commentators continued to resist the transmissible agent theory. In Scotland, as already noted, two separate studies in 1983 - led by Professor Ludlam in Edinburgh and the east of Scotland and by Professor Forbes in Glasgow and the west of Scotland - attempted to determine whether the phenomenon of immune abnormalities in haemophilia patients first noted in the USA in 1982 was also occurring in Scottish haemophilia patients.

Edinburgh research

12.111 Professor Ludlam explained that he was prompted to conduct his research following the publication of a letter in The Lancet by Dr Robert Gordon, NIH, dated 30 April 1983. The letter noted that, by March 1983, eleven cases of clinical AIDS in haemophilia patients had been reported to the CDC. It presented the two principal possible aetiologies considered at the time: the transmissible agent theory and the immune overload theory. Dr Gordon concluded by suggesting that 'the alternative hypotheses might be distinguished through a study ... among similarly treated haemophiliacs in a geographical area to which AIDS has not yet been introduced'.^[170] Professor Ludlam said:

I thought that we were studying individuals with haemophilia who were treated with blood products in what appeared to be an AIDS-free population, and therefore perhaps the results that I was beginning to gather might be able to address the question that Dr Gordon is posing.^[171]

12.112 He carried out his research in the spring of 1983 and found that many of his coagulation disorder patients who were otherwise feeling well had immune abnormalities very similar to those reported from homosexual men and haemophilia patients living in North America.^[172] As he saw it, however, it was inappropriate in mid- to late-1983 to make an assumption that the AIDS in people with haemophilia was necessarily of similar aetiology to the AIDS in the other groups. It was known that, clinically, the spectrum of AIDS-related conditions differed to some extent as between the groups and so clinicians considered the possibility that they had arisen simultaneously, or nearly simultaneously, but were of different aetiologies.^[173]

12.113 Professor Ludlam's view in 1983 was that, while his patients had immune abnormalities similar to those reported in homosexual and other populations in the USA, they could not have been infected with an AIDS virus and that, at least in Edinburgh, haemophilia patients' immune disturbances were not due to an AIDS-causing agent.^[174] In a letter to The Lancet dated 28 May 1983, reporting on his research, Professor Ludlam expressed confidence in the local blood supply and, subsequent to this, explicitly endorsed the 'antigen overload' hypothesis as a possible explanation for the immune irregularities he had observed in his haemophilia patients:

Since there are no known cases of AIDS in our blood donor population it seems likely that the immunosuppression observed in haemophiliacs ... results from infusion of foreign proteins or a ubiquitous virus rather than a specific AIDS virus in factor VIII concentrates.^[175]

12.114 In due course it emerged that there were three sub-sets among the patients with lymphocyte abnormalities in the study group: those with abnormal immune systems who were subsequently shown to be infected with HIV; those with abnormal immune systems who were not infected with HIV; and those with normal immune systems who were infected but in whom changes in the immune system had not yet begun.^[176]

12.115 Professor Ludlam noted that there was 'much speculation' as to the cause of the immune irregularities observed in haemophilia patients.^[177] In oral evidence he noted that the immune system 'has only a number of limited ways' of responding to 'provocation' and that, therefore, there were 'lots of possible reasons why you can get these immune changes'.^[178] The possibilities considered were: (i) that immune disturbance could have been a previously undescribed feature of haemophilia; (ii) that chronic liver disease (and many haemophilia patients had contracted hepatitis viruses by transfusion) had caused changes in patients' immune systems; (iii) that large amounts of proteins other than Factor VIII/IX present in blood products for the treatment of haemophilia had disordered patients' immune systems (the antigen overload theory); and (iv) that the immune changes observed could have been caused by a putative AIDS virus (the transmissible agent theory).^[179] He stated that, at the time, he and others tended to believe that the antigen overload theory was particularly convincing, although he did not dismiss the transmissible agent theory entirely:

Of the four principal causes for immune modulation in haemophiliacs there was general agreement that it was due, at least in part, to the extraneous non-factor VIII proteins in the concentrates. Some of the immune disturbances might in addition be due to the presence of a putative AIDS virus in some patients.^[180]

12.116 In oral evidence, he suggested that the results of his studies 'cast doubt over the extent of infection with a putative virus in other patients with haemophilia elsewhere in the world. That was one of the inferences from this'.^[181] Indeed, his research supporting the antigen overload theory was to receive international attention and form part of the evidence base for international debate around the aetiology of AIDS. At a joint meeting of the World Federation of Haemophilia and the International Society on Thrombosis and Haemostasis in June 1983, discussed above, the response of US delegates to the suggestion that commercial concentrates manufactured in North America might be 'bad news' (implying that they might be contaminated with an AIDS-causing virus) was 'to cite Ludlam et al' and cast doubt upon the data implicating commercial products. Dr Foster, who attended the meeting, thought at the time that there was in this 'something of an attempt to suppress AIDS "hysteria"' but that some of the arguments put forward 'did appear to make some sense'.^[182]

12.117 In oral evidence, Professor Ludlam summarised the thinking behind the antigen overload theory:

I calculated ... that in an average lifespan, you gave out a kilogramme of protein intravenously in an average severe haemophiliac. We are not designed to accept proteins in that magnitude intravenously. So one possibility was that ... maybe haemophilia as a whole was sliding into AIDS because of all the concentrate we were using. Quite separate from HIV or a putative virus.^[183]

Glasgow research

12.118 There was similar research in Glasgow, published in October 1983.^[184] Professor Forbes' research group also found an association between the administration of large amounts of Factor VIII concentrate and the immune process, which was suppressed in many patients and presumed by the research group to be caused by something in the concentrate they were given. He thought that there was a mystery, not resolved even now; as with Professor Ludlam's group, it was to transpire, when HIV testing became available, that not all of the haemophilia patients in his group with immune irregularities were HIV-positive at the time of the initial research. His comment was:

I think it was probably accurate to say that there were abnormalities but what they meant, we didn't know, and of course, some of it probably was that they were infected with the unknown virus, HIV. So we were looking for something but we didn't know what we were looking for at the time.^[185]

12.119 The report of this research suggested gradual diminution of the patients' ability to resist infections or neoplasms (tumours) as a possible consequence of repeated injection. As Professor Forbes recalled, he and his colleagues 'guessed it probably was some kind of virus that we had never encountered before'.^[186]

A spectrum of opinion

12.120 In Scotland as internationally, then, from the initial reports of immune irregularities in various cohorts of patients, there was a spectrum of opinion as to the aetiology of AIDS. Shortly before his appointment at Yorkhill, Professor Hann attended the Second International Symposium of Infections in the Immunocompromised Host, held in Stirling in June 1982. Despite not originally being included amongst the topics for discussion, AIDS was 'the talk of the meeting', although discussion was characterised by 'extreme' puzzlement. Various aetiologies for the new and alarming condition were presented at that conference, including cytomegalovirus infection alongside hereditary factors and amyl nitrate use.^[187] Professor Hann noted that the proceedings of the symposium made only passing reference to the possibility of transmission by blood and blood products^[188] but, in oral evidence, said that 'it was thought most likely that there may have been a new agent, a new viral agent, but that may well not be the only cause'.^[189] Although he adapted practice at Yorkhill upon his appointment, at least in part due to concerns about AIDS, this appears, at least in the earlier stages of the epidemic, to have been based on precaution rather than firm scientific evidence implicating blood and blood products:

My memory ... is that it was not plainly obvious at this time [early 1983], until later that year... and I would say the second half of that year ... that this was a blood product transmitted issue in haemophilia.^[190]

12.121 According to Professor Forbes, he and his colleagues guessed that the observed immune irregularities in haemophilia patients were caused by a novel virus. For much of 1983, that remained a controversial view, however; there was, he noted, 'still a lot of doubt about it and many people didn't believe it was an infective agent'. It took time for proof of a viral aetiology to emerge and he thought that 'all this was speculation at the time'. He thought, however, that as 1983 progressed, a viral aetiology for AIDS in haemophilia patients 'rapidly' became clear and that, over the course of the year, 'most people' came to accept that AIDS was caused by transmission of an infective agent.^[191]

12.122 Professor Ludlam appears to have resisted the infective agent hypothesis longer than some others: neither increasing numbers of haemophilia patients exhibiting immune irregularities (in the USA, the UK and elsewhere) nor specific cases (such as 'the San Francisco child')^[192] were, for him, 'clinching events' sufficient to prove to his satisfaction that AIDS was transmissible by blood products. Although he acknowledged the significance of these developments, he thought that the antigen overload hypothesis was 'still on the table' for much of 1983.^[193] As early as July 1982, he had accepted that a viral aetiology 'had to be a possibility'.^[194] In oral evidence, however, he agreed that for him it may have been as late as January 1984 that he fully accepted that the antigen overload hypothesis was 'increasingly less tenable'.^[195] He agreed that, following the identification of LAV in May 1983, he continued to prefer the antigen overload theory. A further article on the Edinburgh research was published in June 1984, again showing a preference for the antigen overload theory. This was, however, around the same time as Gallo and colleagues announced the discovery of HTLV-III. Asked how he had reacted to the discovery of HTLV-III, which pointed clearly towards the transmissible agent theory as being correct, undermining his previously held conviction, Professor Ludlam replied:

I had no difficulty in accepting and it was very welcome news that a virus had been identified, absolutely.^[196]

12.123 In general, it appears that, as Dr Winter (and Professor Forbes) suggested, 1983 saw a 'gradation' of opinion and 'gradual acceptance that [AIDS] couldn't just be put down to immunological-based theories and that the epidemiology looked more and more like an infectious agent'. As noted above, even the discovery of HTLV-III was not sufficient for a minority of commentators to fully accept the infective agent hypothesis, although the discovery of HTLV-III was clearly the fundamental development in the aetiology debate for a great many interested parties.

Confidence in domestic product and supply

12.124 Attitudes towards the choice of therapeutic materials for coagulation disorder patients in Scotland at this time appear to have reflected the confidence in NHS products and in the availability of supply of those domestically sourced products, particularly as compared with England and Wales. On 22 July 1983, the Edinburgh Evening News carried a report of an interview with Mr John Watt, Director of the Protein Fractionation Centre (PFC - the Scottish manufacturer of NHS blood products).^[197] It was reported that Scotland was virtually self-sufficient in blood products and that only a small percentage came from the USA.

12.125 The claim of virtual self-sufficiency was repeated in a letter to The Scotsman dated 14 July 1983, by Professor Ronald Girdwood, Chairman of the SNBTS. Contrasting the Scottish position with that in England, he wrote:

[T]he Scottish National Protein Fractionation Centre at Liberton ... is a very advanced non-commercial centre ....The staff are aware of the problems of the AIDS difficulties in the United States and have appropriately modified their processes here. Patients in Scotland should be reassured by the fact that, although the Elstree Centre has yet to be expanded, such development took place several years ago in Scotland and we are virtually self-sufficient.^[198]

12.126 Differences of opinion were to emerge as to whether these claims to self-sufficiency were accurate throughout Scotland and whether the assertion was correct that manufacturing processes had been 'appropriately' modified. Data on product use are discussed below. The comments clearly reflected attitudes at the time, however.

12.127 As will be seen, there was some change in clinical practice as heat-treated commercial products came onto the market later in 1984. In the critical period between the spring of 1983 and the end of 1984, however, Scottish haemophilia clinicians were in the relatively privileged position of having available a more or less ample supply of domestically produced concentrates for therapy which, as indicated in Professor Ludlam's letter to The Lancet quoted above, were considered to be free of the postulated AIDS-causing agent. Occasional use of imported products continued in some centres for a small number of patients with special clinical needs, for example where the patient could not tolerate the PFC product. That aside, Scotland was not confronted with the difficulties found by English practitioners,in having to use large quantities of imported concentrates because of a lack of supply of domestically sourced alternatives. Therefore, so far as Scottish practice is concerned, the issue, is whether use of PFC factor concentrates should have continued at all. The alternatives were those identified in England in Wales, or more amply in US practice: the use of cryoprecipitate or of DDAVP. In the first instance, however, it is appropriate to note the data on actual product use throughout the material time.

Use of blood products in Scottish haemophilia therapy to 1984

12.128 On 21 January 1983, at a joint meeting of the Directors of the SNBTS and the Scottish Haemophilia Directors, Professor Cash referred to recent articles in the USA, and also in The Observer and The Lancet, about the problem of AIDS.^[199] An extract from the CDC publication Morbidity and Mortality Weekly Report (MMWR) had been circulated with his paper. The SNBTS and the Haemophilia Directors were clearly aware of the situation developing in the USA. By then, however, there had already been movement in the choice of therapeutic products in those regions that had not previously used Scottish products exclusively.

The Royal Infirmary of Edinburgh

12.129 The numerical data for Edinburgh^[200] show that in 1980 and 1981, following the appointment of Professor Ludlam as Haemophilia Director, there was an initial increase in usage overall, mainly of cryoprecipitate and PFC Factor VIII but with commercial product usage rising in significance as output from the PFC failed to keep up with growing demand. In 1982, small quantities of two commercial products, Koate and Factorate, were used, representing about one half of one per cent of total Factor VIII usage. Use of cryoprecipitate continued to fall from its peak in 1980 to the end of the period. In the most critical part of the period, 1980-84, commercial product use was a minor element of the total Factor VIII prescribed.

Glasgow: Yorkhill and the Glasgow Royal Infirmary

12.130 Within Glasgow, the GRI and Yorkhill operated independently, although Dr Willoughby, Haemophilia Director at Yorkhill, referred to Professor Forbes at the GRI for advice before Professor Hann's appointment in January 1983 and Professor Hann also 'worked very closely with the adult centre' at the GRI after his appointment.^[201]

12.131 Dr Willoughby had favoured commercial concentrates for the home treatment of children with coagulation disorders on the ground of ease of use. Upon taking up the post, Professor Hann 'inherited' some residual stock of imported products. As noted above, however, Professor Hann regarded NHS materials as both more cost-effective and safer^[202] and use of commercial products fell very quickly and dramatically in 1983-84. Thereafter, products supplied by the PFC were used exclusively.^[203]

12.132 Professor Forbes was Director of the Regional Haemophilia Centre at the GRI from 1983-87. As noted in Chapter 21, Haemophilia Therapy - Use of Blood Products, his account of the use of therapeutic materials at the GRI Centre was not clear. As recorded,^[204] commercial product use at the GRI was inconsistent and without obvious pattern. From a peak in 1979, it fell to a very low level in 1982, increased in 1983, and fell again to a more or less nominal amount in 1984. Overall, a wide range of products contributed to total use, particularly Koate, Factorate, Kryobulin, Hemofil VIII and Humanate, without any apparent structured sourcing policies.

Other centres

12.133 In the rest of Scotland, use of Factor VIII and Factor IX concentrates was almost exclusively of PFC products.^[205] In these circumstances there was clearly no uniform policy relating to product selection in Scotland as a whole. Until the mid-1980s each haemophilia centre operated independently: the centres carried out more or less separate institutional roles.^[206] As matters developed, however, there was coincidentally a broad similarity of practice among Haemophilia Directors. By the spring of 1983, clinical practice in the treatment of coagulation disorder patients, with factor concentrates, was largely limited to the use of PFC products.^[207]

The production and use of therapeutic materials in early 1984

12.134 The production and use of therapeutic materials was discussed at a joint meeting of the SNBTS Directors and the Haemophilia Directors, held on 2 February 1984. Professor Cash produced a paper setting out the background and indicating the views held at that time about the materials required.^[208] Details of the amount of fresh plasma processed at the PFC for Factor VIII concentrates and the pattern of issue of concentrate were said to indicate that the production level was about right. Professor Cash said that trends over the previous five years indicated that the SNBTS production of Factor VIII concentrates might be exceeding clinical demand, in that current stocks at RTCs appeared to be increasing. It was agreed at the meeting that it was desirable to maintain the current production target and that existing stocks should be held for possible sudden demands on the service and to bridge the period when the PFC would be converting to a heat-treated product. It was noted that, if a surplus of PFC Factor VIII arose, other parts of the UK could be offered the product in preference to purchasing from other sources. No wastage was envisaged.

12.135 It was recorded that the GRI was totally satisfied with the PFC product and had intimated that it was no longer necessary to purchase commercial alternatives. Dr Hann commented that he was prepared to dispose of the 30,000 units of commercial product he had 'inherited' at Yorkhill as it was going out of date. (From the numerical data outlined above, it also appears that Professor Hann had already dramatically reduced the use of these materials.) Professor Ludlam indicated that he needed a small stock of high purity Factor VIII, which would have to be imported from commercial suppliers for a very few patients. It was noted that in Glasgow and Edinburgh children were being treated with cryoprecipitate as the preferred material and that it was recognised that, bearing in mind reports from abroad, recipients of blood could 'also' be at risk.^[209] Professor Ludlam said that cryoprecipitate was preferred in the treatment of children at that juncture because of the new danger of AIDS. Dr Hann concurred but noted that otherwise a policy seemed to be emerging to use less cryoprecipitate for Haemophilia A patients. It was agreed that a certain minimum amount of cryoprecipitate was required and Professor Cash pointed out that in emergencies Transfusion Directors could produce it themselves.^[210] It was accepted that given domestic production it was not necessary in general to purchase commercial products from abroad unless, exceptionally, a superior product was available and clinically necessary.

12.136 So far as Factor IX concentrates were concerned, it was noted that some Defix (a non-heat-treated SNBTS Factor IX concentrate) was still required and its availability would be retained. Subject to the provision of data which satisfied the Licensing Authority it was hoped to introduce Supernine (an improved SNBTS Factor IX concentrate)^[211] in 1984-85, for routine use throughout the Scottish health service. These arrangements were seen as an interim step pending the development of a heat-treated product, details of which were set out in the paper.^[212]

12.137 Other strategies were discussed, including the possibility of 'batch dedication' of Factor VIII, designed to expose patients to the lowest number of batches of concentrate in order to reduce the risk of transmission of infection. This was a major review of clinical practice and of the demands that were created for therapeutic products. There was a preference for materials produced using plasma from locally donated (that is, Scottish) blood, with cryoprecipitate and other single-donor products identified as appropriate for limited groups of recipients, in line with current practice. It appears to be clear that extending the use of cryoprecipitate beyond those groups would have involved its use in the treatment of patients other than the vulnerable groups, such as children, who were already catered for by clinical practice. That apart, the policy that emerged clearly from the discussion at this stage in early 1984 was developed around the continuing use of concentrates produced from locally collected plasma.

12.138 The purchase of commercial heat-treated products was not discussed at the joint meeting of the SNBTS Directors and the Haemophilia Directors held on 2 February 1984, so far as the minutes disclose.^[213] By then, however, the use of commercial Factor VIII products in Scotland had almost ceased.^[214] Use of cryoprecipitate had dwindled by 1983 to a very small percentage of total Factor VIII replacement therapy.^[215] With the exception of patients requiring FEIBA^[216] and a small number for whom commercial products were prescribed as a matter of clinical judgment, the product of choice in 1983 and 1984 was PFC Factor VIII concentrate. There was no general move towards imported heat-treated products until December 1984.

The development of heat-treated products

12.139 The development of heat-treated products had been in hand for some considerable time, however. Commercial heat-treated products were licensed by the FDA on various dates in and after March 1983 but in the case of most companies licences were granted during and after January 1984.^[217] Alpha Therapeutics' product, Profilate HT, was licensed in February 1984. Because of concern over AIDS, Dr Winter and doctors from St Thomas' Hospital and the Royal Free Hospital, London, and from Sheffield approached Alpha in February for supplies of their heat-treated Factor VIII to be prescribed on a named patient basis (which under the Medicines Act 1968 allowed products to be prescribed without the need for a licence). They received some Alpha heat-treated product in May 1984 and used it on a selective basis until more ample supplies became available later in that year.^[218]

12.140 On 22 March 1983, Professor Forbes agreed to trial a new heat-treated Factor VIII product then being developed at the PFC.^[219] However, it was to be December 1984 before the PFC had an effective virally-inactivated Factor VIII product available.

12.141 The effectiveness of heat treatment to eliminate HTLV-III could not be tested until the virus was isolated and cell systems for the reproduction of HTLV-III antigen had been developed. That step was not announced until May 1984.^[220] Earlier heat treatment had been directed towards eliminating NANB Hepatitis and the elimination of HTLV-III was an incidental benefit.

Developments in late 1984

12.142 The SNBTS and Haemophilia Directors held a meeting on 29 November 1984.^[221] The meeting had been arranged at short notice to discuss the implications of the finding of HTLV-III antibodies in Scottish haemophilia patients, and related topics including measures being taken by the SNBTS to prevent the transmission of AIDS by blood products. The cases of infection in Edinburgh and Glasgow were discussed. Dr Perry reported that it was anticipated that all PFC Factor VIII issued from about the beginning of January 1985 would be heat-treated.^[222]

12.143 The meeting in Scotland was, in part, preparation for the meeting of the UK Haemophilia Reference Centre Directors due to be held on 10 December 1984 (already discussed at paragraphs 12.101-12.105 above).^[223] Professor Cash, Professor Ludlam and Professor Forbes attended the UK Reference Centre Directors Meeting, which was chaired by Professor Bloom. In his evidence to the Inquiry, Professor Ludlam said the meeting was stressful: the decisions reached were not easy and had to be made on the basis of limited data.^[224] The commercial companies had kept much under wraps and there was very little published information on their work. There was apprehension that changes in treatment might make things worse for haemophilia patients. As a practical matter, Professor Ludlam would return to Edinburgh to find that (only) heat-treated product was to be available from the PFC from the end of December 1984 but he did not remember knowing that before the meeting. For him, as for Professor Cash in relation to initiating heat treatment, December 1984 was a 'terrible month'.^[225] He was coming round to the view that the product was probably safe but he continued to have reservations. He had arranged for the testing of PFC heat-treated Factor VIII product in four patients earlier in December. If they had developed inhibitors,^[226] he would not have wanted to use the product, notwithstanding the growing consensus among senior colleagues favouring heat-treated products.^[227]

Central coordination

12.144 At a meeting of the SNBTS Directors on 11 December 1984,^[228] Professor Cash expressed some of the frustration of Directors at the apparent lack of apparent central coordination:

Dr Cash said that he would make further representations to the SHHD that there should be a more effectively co-ordinated UK approach to transfusion and AIDS - this had already been recommended by the Scottish Directors. The Directors noted with regret that a second meeting of this Working Group on AIDS had not been arranged and that there appeared to be no evidence of co-ordination of the many splinter groups which existed.^[229]

12.145 As noted above, however, on 14 December 1984 the UKHCDO produced an 'AIDS advisory document' to which Professor Cash had contributed. The treatment options presented in the document were set out in 'probable decreasing order of safety' in terms of the transmission of AIDS and demonstrated a preference for heat-treated NHS concentrates, followed by single-donor cryoprecipitate, heat-treated imported concentrates and, finally, unheated NHS concentrates and unheated imported concentrates. Use of DDAVP in mild Haemophilia A and von Willebrand's disease patients was recommended, if possible.^[230]

12.146 Effective heat treatment of PFC's Factor VIII product from December 1984 put an end to the risk for Haemophilia A patients treated in Scotland. There remained a risk for Haemophilia B patients until effective viral inactivation was introduced in October 1985. Two Glasgow patients acquired HIV infection from PFC Factor IX. One patient, the date of whose last negative sample is unknown, was first positive on 15 November 1985. The second was negative on 15 October 1985 but positive on 15 July 1986.

Should clinicians in Scotland have adapted their treatment regimes sooner than they did in response to the threat of AIDS?

The significance of early research into immune abnormalities

12.147 Until Professor Ludlam's findings in the spring of 1983 and the results of the Glasgow research later in that year, there was nothing in the direct experience of Scottish clinicians (as distinct from what might have been inferred from reports of experience elsewhere) to cause a radical re-assessment of haemophilia therapy. Those research projects showed that patients receiving concentrate therapy had developed immune abnormalities that shared many of the characteristics of those identified in other patient groups at high risk of progression to AIDS and diseases of the AIDS complex. It is appropriate to consider whether the discovery by laboratory testing of alterations in patients' immune systems, attributable to the administration of concentrates, marked the beginning of a period in which the continued use of factor products should have been reconsidered.

12.148 Each of the two aetiologies postulated - the infective agent theory and the antigen overload theory - incriminated the use of concentrates in adversely affecting the immune systems of patients. As Dr Desforges commented in the NEJM of 13 January 1983, whatever the cause of AIDS, whether it was transmitted by an infective agent or was secondary to multiple antigenic exposures or some other unknown mechanism, haemophilia patients treated with concentrates were being exposed to a risk of immune system abnormalities which might progress to fatal illness. The nature of that risk and the extent to which it might affect haemophilia patients remained controversial and, as observed by Professor Ludlam, the spectrum of AIDS-related conditions differed to some extent between the groups. Kaposi's sarcoma appeared to be restricted to transmission by sexual routes and was not found in haemophilia patients.^[231] However, haemophilia patients who developed AIDS did acquire Pneumocystis carinii pneumonia and that was associated with high mortality.

12.149 The view of some haemophilia practitioners in the UK that British blood was likely to be essentially free of viruses and very safe and that British-produced Factor VIII was extremely unlikely to transmit the new disorder of AIDS, does not provide an answer to the risks associated with the antigen overload theory. If the antigen overload theory explained the development of immune disorders associated with AIDS related diseases in a significant number of haemophilia patients, with an established and increasing risk of morbidity and mortality, the continued use of concentrates in therapy would still have had to be justified on a balance of risk and benefit that took express account of the risks of progression to serious disease.

12.150 Retrospective testing of blood samples showed that only a small proportion of the patients with immune irregularities were, in fact, HIV-positive at the time of the initial study. The outcome of this later research provided partial vindication of the conclusions reached by Professor Ludlam in 1983 supporting the antigen overload theory (or at least rejecting the transmissible agent theory as the sole cause of immune irregularities in all of the haemophilia patients studied). Nevertheless, the 1983 research provides a particular focus on the question as to when there was information that might have led to a change in use of factor concentrates in haemophilia therapy. It was widely appreciated that patients were developing AIDS-like immune abnormalities associated with concentrate therapy. The spectrum of AIDS-related conditions may have differed from those associated with AIDS caused by an infectious agent, but knowledge that there were significant immune deficiencies developing in patients that were attributable to concentrate therapy was in itself of potential importance.

12.151 According to Professor Forbes, it was speculated by his group that something in the concentrates suppressed the immune system of recipient patients and that this made them more likely to be infected by the virus which was then appearing in concentrates.^[232] On his account, it became accepted by most people in the course of 1983 that AIDS was transmitted by an infective agent.^[233] He said that, as that became accepted, most people also came to think that AIDS would undoubtedly come to the UK in the course of time.^[234] Already, haemophilia clinicians were looking at their patients to see if they had any of the features that might be an early warning of AIDS.

12.152 It is important to emphasise that the 1983 research findings in Edinburgh and Glasgow included patients treated exclusively with PFC factor products produced from locally sourced plasma. The development of immune disorders in Haemophilia A patients in the main centres in Scotland was not associated with the use of Factor VIII imported from the USA to the extent that the prevalence of the disorders could be attributed solely to infective imported products: Scottish products were necessarily implicated. For those who accepted the transmissible agent theory as more likely, faith in the relative safety of UK blood could not have been supported, at least to the extent it had been until that point, in light of the 1983 research findings.

12.153 Having regard to the Scottish research alone, the earliest point at which it might be suggested that an overall assessment of therapy should have begun was the spring of 1983. The issue became irrelevant at the end of December 1984: heat treatment effective to eradicate HTLV-III/HIV from blood products, and in particular Factor VIII, was developed at the end of December and was in routine use from early 1985. There were no recorded cases of infection transmitted by PFC heat-treated Factor VIII concentrates after that development.^[235]

12.154 The actual importance of the biochemical data as an indicator of a need to review clinical practice is limited, however, as there was no evidence of serious clinical disease among the patients studied in 1983. The initial study examined biochemical data collected over one month from patients treated during the previous five years.^[236] It did not report progression in immunodeficiency and could not, without further study, have supported conclusions on future progression.

Should Scottish clinicians have elected to use cryoprecipitate in preference to concentrates?

12.155 A particular question that arises is whether Scottish clinicians should have changed to the use of cryoprecipitate for Haemophilia A patients already receiving concentrate therapy, given the results of research in Edinburgh and Glasgow in 1983. In addition, other research evidence published early in 1983 reported that patients treated with cryoprecipitate did not develop impaired cell-mediated immunity (see paragraph 12.32 above). On the other hand, some clinicians thought that large quantities of cryoprecipitate were as likely as concentrates to transmit infection. Professor Ludlam noted that impaired cell-mediated immunity was not in itself a reliable indicator of HIV infection, as retrospective studies of patients exhibiting such abnormalities later confirmed. Furthermore, it was later to transpire that cryoprecipitate was, in fact, responsible for the transmission of HIV, albeit at greatly reduced rates and not in the UK, so far as is known to the Inquiry.^[237] As against the practical problems associated with a switch from concentrate therapy to cryoprecipitate discussed below, however, contemporaneous evidence suggested that cryoprecipitate exposed recipients to less risk of immune deficiencies than concentrates. Some clinicians did advocate a switch on that basis, with limited success (resulting in few patients making the switch). It is important to note the recorded use of cryoprecipitate, as background to the discussion of the question.

Use of cryoprecipitate in Scotland

12.156 There was extensive use of cryoprecipitate in many regions of Scotland. Recorded use over the period 1981-85, so far as the Inquiry's researches have shown, is as follows:

Table 12.1: Use of Cryoprecipitate (units): Scottish Haemophilia Centres 1981-85

	1981	1982	1983	1984	1985
RIE	720,160	612,000	341,700	139,000	127,680
GRI	56,650	40,950	136,550	121,100	223,990
Yorkhill	29,200	7050	30,500	32,340	27,930
Aberdeen	86,480	20,510	10,710	9030	10,300
Dundee	48,800	1370	4240	2560	0
Inverness	0	0	1540	0	0

12.157 Inverness used almost no cryoprecipitate over that period; PFC Factor VIII was used almost exclusively. Dundee used cryoprecipitate in 1981, as the centre had in previous years. In that year and later, however, it accounted for only a small percentage of total therapy which, as noted above, was based on almost exclusive use of PFC Factor VIII. Neither centre had a case of HIV transmission. In Aberdeen, use of cryoprecipitate fell over the period and the use of PFC Factor VIII grew proportionally.

12.158 In Edinburgh, use of cryoprecipitate was reduced following Professor Ludlam's appointment. It remained high, in absolute and relative terms, however, throughout the period of maximum exposure of coagulation disorder patients to HIV. Cryoprecipitate was used in Edinburgh for vulnerable groups, including children. A change of practice would have affected older children and adults, many of whom would have been on home treatment programmes. Throughout that period, Professor Ludlam used considerably more cryoprecipitate than Professor Forbes, both absolutely and, taking into account that the GRI had a consistently higher number of registered patients than Edinburgh over this period, also as a ratio of their haemophilia patient populations.

12.159 The position at the GRI is less easy to describe. Professor Forbes thought that the use of cryoprecipitate at the GRI might explain the low prevalence of HIV infection in his patients, but his evidence on this point is not supported by the analysis of the actual use of therapeutic materials in his centre. Professor Forbes' recollection of detail had clearly suffered with the passage of time. Cryoprecipitate was indeed used at the GRI but Professor Forbes' evidence on its use was less precise and it is not possible to define sub-groups with any degree of certainty. The recorded use, based on the materials available to the Inquiry, is preferred as evidence of practice at the GRI.

12.160 The regime at Yorkhill changed after Professor Hann was appointed, reflecting both his previous interest in immunocompromised patients and his faith in the quality of the UK blood supply. Early reports of what became known as HIV infection were related to sexual behaviour and intravenous drug use but - partly through a 'corridor discussion' at the Stirling conference on immunocompromised patients in June 1982 - at an early stage Professor Hann considered it a 'possibility' that haemophilia patients would come to be affected.^[238] By late 1983, Professor Hann said that he was 'becoming more convinced that this was a blood product transmissible disease' and that he had to do everything he could to minimise that risk.^[239]

12.161 He defined a 'difficult interim period' in therapy between May 1983, when the discovery of LAV (later proved to be identical to HTLV-III) was published, and late 1984, when the HTLV-III virus had been isolated and some of the patients were found upon testing to have antibody to the virus.^[240] Although the development of tests was important, Professor Hann noted that there were still unresolved questions. The sensitivity and specificity of the tests was not clear and, more fundamentally, 'we didn't know what positivity meant'.^[241] It was not clear whether positivity was transient or permanent and it was not known what proportion of those testing positive would progress to AIDS.^[242]

12.162 Professor Hann shared the concerns of many Haemophilia Directors about the use of cryoprecipitate, discussed below, particularly as this would have affected home therapy programmes. Nevertheless, he said that cryoprecipitate treatment may have been recommended as the first option for newly diagnosed patients in that period.^[243] He believed that, in relation to a child who was already receiving Factor VIII concentrate in late 1983, he would have offered the possibility of ceasing concentrate therapy and returning to cryoprecipitate^[244] and he was almost certain that in late 1983 he did change some patients over to cryoprecipitate and continued others for longer than he would have done previously.^[245] Professor Hann's patients at Yorkhill were children, however: in due course Yorkhill patients were transferred to the GRI for treatment in their teens and as adults. He was not therefore confronted with the problem of changing the treatment regime of adults already settled on concentrate therapy and, in particular, the home therapy programme widely agreed to be advantageous.

12.163 With the exception of Yorkhill, the picture that emerges overall, is that clinicians used cryoprecipitate on a selective basis, distinguishing children and other vulnerable groups from those settled on concentrate use and doing so on a broad precautionary basis rather than because they were committed to the infective agent theory of transmission.

The decision not to switch to cryoprecipitate use generally

12.164 Dr Jones' editorial in the BMJ of 10 December 1983 provides a reference point in English practice.^[246] Against the background of a view that there was no evidence that any product, 'commercial or volunteer', was free from the risk of transmitting AIDS, he commented that, for the moment, it would be sensible to treat very young severely affected children with cryoprecipitate, and that DDAVP or porcine material should be used in mildly affected haemophilia patients, von Willebrand's disease patients and carriers of those disorders. His advice was not significantly different from that observed in Scotland and favoured a discriminating approach to product selection.

12.165 A similar approach was reflected in discussion at the Reference Centre Directors' meeting on 10 December 1984, at the end of the period. The AIDS Advisory Document of 14 December 1984 set out clearly the Reference Centre Directors' recommendations on therapy. The use of heat-treated imported concentrate was recommended after heat-treated UK concentrate and cryoprecipitate and fresh frozen plasma. Until imported heat-treated concentrates became readily available, that aspect of the advice would have had little practical effect, especially in England and Wales. Dr Winter and those of his colleagues who had no alternative to the use of commercial concentrates were in the vanguard of clinicians seeking to use heat-treated concentrates from May 1984. They were not able to obtain sufficient supplies for general use until later in the year. From a practical point of view, cryoprecipitate and fresh frozen plasma had become preferred alternative products for most clinicians and would remain so for some time, notwithstanding reservations about their use.

12.166 The Haemophilia Reference Centre Directors' recommendations comprised a turning point in guidance. Until then there was no authoritative statement in the United Kingdom favouring cryoprecipitate for general use. There was a minority view held by some clinicians, led by Dr Ratnoff in the USA and echoed by Dr Galbraith in the UK, that current therapy regimes should have been radically reviewed as soon as there was evidence of a possible association between factor concentrates and infection with a presumed agent of transmission of AIDS; that use of concentrates should have been abandoned or suspended; and that patients generally should have been prescribed cryoprecipitate.

12.167 That view received limited support from Dr Desforges' editorial in the New England Journal of Medicine of 13 January 1983.^[247] It was opposed by Dr Kernoff in his article 'AIDS and Haemophilia', in the Haemophilia Society's publication The Bulletin, edition 33, No 1, January 1983.^[248] On 17 October 1983, Professor Bloom's advice in answer to Dr Chisholm of Southampton was 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.^[249] In December 1983, Dr Jones wrote that cryoprecipitate should be used to treat very young, severely affected children. Professor Bloom repeated his views at a meeting of the UKHCDO held in December 1983. There was a large body of informed opinion that rejected the Ratnoff/Galbraith approach.

12.168 The question whether clinicians should use cryoprecipitate was discussed in these exchanges in terms of the selection of appropriate forms of therapy for specific groups of patients. One might suggest, in the light of later knowledge, that the decisions taken and the advice tendered were to the disadvantage of some NHS patients. It would, however, be impossible to criticise them as wrong decisions, either on the basis of the information taken into account or on the basis of the conclusions drawn from that information. Having regard to the published statements of leaders among the haemophilia clinicians, Professor Hann in Scotland and Dr Winter in England were very much in the minority in adopting the infective agent theory at an early stage in the AIDS epidemic and adapting their treatment programmes accordingly, so far as they were able to do so. Moreover, it is important to emphasise the extent to which cryoprecipitate was in fact used elsewhere: the advice on product selection was generally reflected in clinical practice.

The impact on home therapy programmes

12.169 The patients who would have been affected by a general switch to cryoprecipitate would be those already established on concentrate therapy, often on a home treatment basis, and those requiring frequent or heavy doses of concentrate. There was a widely held view in the UK that cryoprecipitate was not suitable for home treatment.^[250] It was also limited in supply.^[251]

12.170 Under those circumstances, haemophilia patients would have required to attend hospital for all treatment. Beyond the inconvenience that would be caused by moving patients from home treatment with concentrates to hospital treatment with cryprecipitate, there were clinical reasons for resisting such a move. Even under home treatment programmes using concentrates, cerebral bleeding was still, at the material time, the leading cause of death amongst haemophilia patients: in the UK, between 8 and 19 patients died annually from cerebral bleeds before they could attend hospital in this way. Professor Ludlam considered it inevitable that such deaths would have increased, were patients required to attend hospital for cryoprecipitate treatment. Moreover, as cerebral bleeds were often 'spontaneous', by the time a patient arrived at hospital for treatment, 'very severe brain damage ... often occurred'. Finally, the increased morbidity associated with delayed treatment at hospital would not have been limited to cerebral bleeds: haemarthroses, left untreated until admission to hospital, would result in 'excruciating and protracted pain' and bed rest for around 10 days. As a consequence of the disuse of the joint and bed rest, 'there would be atrophy of the muscles ... and the weakened muscles would predispose to further haemorrhage'.^[252] Professor Ludlam noted that patients under Dr Ratnoff's care had in fact resisted his proposal to switch to cryoprecipitate use, 'despite the apparently much higher risk in the USA of haemophiliacs developing AIDS in the early-mid 1980s'. In oral evidence he recalled that, of around 90 patients under his care, only five followed Dr Ratnoff's advice.^[253] Professor Hann noted that, principally because of the inevitable impact changing from home therapy to hospital-based cryoprecipitate therapy would have on patients and their families - a point the Haemophilia Society 'repeatedly made' during the period - the majority of families declined the offer to switch to cryoprecipitate use at Yorkhill.^[254]

12.171 There was clearly conflicting evidence. Professor Hann found that some of his patients were willing to switch to cryoprecipitate, or remain on it for longer than would have been normal. His patients were children, however, and his background had been in infections in patients with immune deficiencies and leukaemia and cancers associated with immune deficiencies. He offered his patients a choice, as Professor Ratnoff had done in Cleveland. Professors Ludlam and Forbes, along with the rest of the Scottish clinicians, did not do so and continued using concentrates for the majority of their patients. Although they had both carried out studies into immunological abnormalities, neither study reported progression in immunodeficiency and neither clinician knew what the findings of their studies meant. Due to the unstructured, preliminary character of those studies, a full research programme following up on them would have been required if reliance was to be placed upon their conclusions in instructing any changes in the approach to therapy.

Practical issues

12.172 The narrative of the evidence indicates that there would also have been practical problems if there had been an attempt to revert to more or less exclusive use of cryoprecipitate. That was the view, for example, of the Sub-Committee on Biological Products of the Committee on the Safety of Medicines on 13 July 1983 (see paragraph 12.65 above). Professor Ludlam considered that it would have been necessary to invest considerable sums of money to purchase equipment such as centrifuges and fridges.^[255] Dr Galbraith's proposal that concentrates manufactured in the USA from blood donated after 1978 should be withdrawn from use was held to be not feasible in the UK on the basis of supply.

12.173 Those were factors that clinicians and others were entitled to have regard to but it is questionable whether they would have been conclusive, or even material, if it had been understood that the relative risk of transmission of HIV infection by use of concentrates was so high that their continued use exposed patients to serious morbidity and mortality risks when an alternative - the use of cryoprecipitate - was available and could have been used notwithstanding the difficulties involved. In other words, in a question of patient safety, the decision of the Sub-Committee on Biological Products of the Committee on the Safety of Medicines was hardly credible unless the risk that was implicitly accepted was of such a low order as to be dismissed. Difficulties in process change would have been real, but those difficulties would have had to be addressed if the difference made was a real reduction in the perceived overall risk to patients.

Should Scottish clinicians have made greater use of DDAVP?

12.174 Dr Winter noted that 'a good number' of mildly affected haemophilia patients and von Willebrand's disease patients in the UK contracted HIV through contaminated blood products; he considered that switching mildly affected patients to DDAVP might have prevented this, '[o]ne wonders why they were ever treated with concentrate. Because they would have been suitable for DDAVP treatment'.^[256]

12.175 It is appropriate to consider this issue, not least because advice regarding the use of DDAVP appeared regularly in guidance on the selection of therapeutic materials in the USA, in the UK generally and in Scotland.^[257]

12.176 As noted at paragraph 12.31, Desmopressin, otherwise known as DDAVP, is a synthetic replacement for the naturally-occurring brain hormone called vasopressin. As it is not derived from human blood, it was not capable of transmitting HIV. Administered to patients with mild Haemophilia A and von Willebrand's disease, it releases Factor VIII from the lining of blood vessels, allowing normal clotting to occur. It is important to note, however, that not all such patients are responsive to DDAVP and that, while it is an important and useful drug for those patients who are responsive, it is ineffective in patients with moderate or severe haemophilia and those mildly affected patients who do not respond to it.^[258] Professor Ludlam said that, at the point of diagnosis, his practice was to give a 'test dose' of DDAVP to determine whether a mildly affected haemophilia or von Willebrand's disease patient was responsive to the drug.^[259] Professor Lowe said that the same practice applied at the GRI.^[260]

12.177 DDAVP is not generally considered useful in response to a spontaneous bleed of any real severity: more immediate treatment is usually required than DDAVP can provide. Professor Forbes stressed that DDAVP was principally used for elective procedures, such as minor operations or tooth extractions, and that it was rarely used to treat bleeds.^[261] Professor Ludlam, who had a long-term clinical and research interest in DDAVP,^[262] generally agreed but noted that DDAVP could be useful in treating some minor bleeds (giving a nose bleed as an example) or prophylactically in advance of minor operations (again, such as tooth extraction) but not for bleeding into joints.^[263] He noted that at his centre, 'it was standard practice to use DDAVP if that was suitable'.^[264]

12.178 In addition to the relatively limited number of patients for whom DDAVP was suitable, its use was also associated with side-effects and it had to be used with care. Professor Forbes noted that DDAVP is 'not without its own problems' and that 'it could not therefore be used routinely'.^[265] In oral evidence, he stated that 'we did use it but with some caution'.^[266] In particular, the therapeutic use of DDAVP is associated with fluid retention and changes in blood pressure. This did not constitute a general contra-indication for therapeutic use, as such problems as noted would only become apparent, if they arose, after administration. In his statement he noted that, at the GRI:

We were ... very aware of the possibility of using DDAVP in patients with mild disease who were having small traumas or small surgery. This we widely accepted, and was really very successful for a day or two's treatment only, for example one or two teeth or a very small procedure. During this time we also became aware of the other long term implications of DDAVP particularly fluid and electrolyte retention so it was used with some caution.^[267]

12.179 Professor Lowe agreed, stating that at the GRI '[t]he policy was to treat patients with mild Haemophilia A preferentially with DDAVP, where appropriate and tolerated'.^[268] He added that DDAVP had only a short-term effect and that its effectiveness decreased with repeated administration:

It has a short-term effect. And usually after about 48 to 72 hours, if you are giving a daily or twice daily injection, you observe a phenomenon called tachyphylaxis, which is a reduced response, and this is because you are trying to stimulate release of the patient's own Factor VIII [or] von Willebrand factor complex .... [T]here is individual variation, but usually, after four doses of desmopressin, you don't get any more bang for your buck. So you have to bear in mind that limited situation.^[269]

12.180 Professor Hann stated that, from his appointment in January 1983, Yorkhill operated a policy whereby mildly and moderately affected Haemophilia A and von Willebrand's disease patients were treated preferentially with DDAVP (where a response to its use had been demonstrated). He noted that shortly after his arrival at Yorkhill, he made these policies 'explicit' and 'spent the first few months of my job writing them down' in a specific set of protocols. He stressed, however, that this approach 'was not always feasible or appropriate' - DDAVP is not considered safe for very young children (under one year of age) and was contra-indicated in those with fluid retention or neurological problems (in whom it can cause convulsions). Like Professor Lowe, he pointed to the problem of tachyphylaxis, making it inappropriate in many surgical settings, and to the fact that some patients do not respond at all to DDAVP.^[270]

12.181 Professor Ludlam also agreed with the reservations regarding DDAVP use. Asked whether this meant that DDAVP was a drug which had to be used with great care, he replied:

With a degree of circumspection, yes. Great care in small children, and particularly if you want to give repeated doses, because of the water retention. And also in patients who have atherosclerosis ....

So, although it's a very useful drug, it is not without its contra-indications.^[271]

12.182 Professor Lowe was the lead author of a letter to The Lancet in 1977,^[272] the first to note the problem of progressive water retention associated with the use of DDAVP and which recommended that water intoxication should always be considered a potential side-effect, particularly after repeated administration. In oral evidence, he said:

I think the point I'm making is that desmopressin is not the panacea. It had a very useful place - let's not underestimate it - during the 1980s, in sparing many patients with haemophilia and von Willebrand's disease around the world from getting virus infections. So it has its place, but it's not the panacea. And you have to assess every patient individually across the whole spectrum of haemostatic agents, not only in this period of time that we are talking about, concentrates versus cryoprecipitate or fresh-frozen plasma ....^[273]

12.183 The numerical data on the use of DDAVP suggests that its use varied among Haemophilia Centres in Scotland. At Edinburgh, it is recorded as having been used in small amounts (between 6 and eleven international units) between 1984 and 1987, but not at any other time.^[274] At Yorkhill, it was used in 1989 only (20 international units).^[275] Aberdeen and Dundee used no DDAVP at all in the material period.^[276] Inverness used varying amounts (between 4 and 108 international units) beginning in 1987 but used none before that date.^[277] Glasgow Royal Infirmary was the centre which made most use of DDAVP. Although none was used in 1980, 1983 or 1984, in every other year between 1979 and 1987, use ranged between 229 and 978 international units. From 1988-1991, use ranged from 1210 to 1548 international units.^[278]

12.184 Ultimately, however, the most important point for this Inquiry to make in relation to the use of DDAVP is that, so far as the data available to the Inquiry show, no mildly affected haemophilia patient in Scotland contracted HIV from concentrate therapy. The comment made by Dr Winter in paragraph 12.174 above does not therefore apply in Scotland.

Use in Scotland of imported commercial products

12.185 Until commercial products imported from the USA were heat-treated to inactivate HIV, American Factor VIII posed a relatively high risk of transmission of infection. The experience at Yorkhill, where Dr Willoughby favoured the use of commercial concentrates until he was succeeded by Professor Hann, is persuasive evidence of the risk associated with older generations of product. Patients registered at the hospital numbered between 70 (1980) and 108 (1985). Twenty-one HIV infections in an average population of 90, just over 23%, exceeds by a considerable margin the experience elsewhere in Scotland. Excluding Yorkhill, the average for the rest of Scotland was just over 8% (39/480).

12.186 On Dr Winter's evidence, the safety of the American product changed in 1984 with the adoption of effective heat treatment. Heat-treated product manufactured by Alpha Therapeutics was obtained in May 1984 and used on a named patient basis in Kent, St Thomas' Hospital and the Royal Free Hospital, London and in Sheffield. Dr Jones moved to exclusive use of commercial heat-treated Factor VIII at Newcastle before 10 December 1984, the date of the meeting of the UK Haemophilia Reference Centre Directors at which treatment policy was widely discussed. That was, however, too late for many patients at both the Kent and Newcastle centres where seropositivity was high. On 14 December 1984, the UKHCDO 'AIDS Advisory Document' summarised recommendations on treatment options and preferences. At this point, as events were to prove, PFC was on the threshold of routine production of heat-treated Factor VIII concentrate that, as with the commercial product, was in time found to be effective in inactivating HIV.

12.187 The record of the meeting of 10 December reflects the dismay and deep uncertainty of the professional community, desperate to find a solution to a problem that had not been anticipated but which went to the very roots of their management of patients. It might suggest that more positive action could have been taken in the last quarter of 1984 to obtain US heat-treated products for all patients, as Dr Jones had done by December of that year. It is not likely that supplies could have been obtained earlier. Dr Winter, who had a long history of use of commercial products, initially had difficulty in sourcing sufficient quantities for all of his patients. Dr Jones' determination to use the products suggests that he would not have delayed in his efforts to obtain them. It remains a matter of speculation when commercial heat-treated products would have been available in sufficient quantities to meet total demand in the UK as a whole, or in Scotland in particular. It could not, however, have been earlier than late 1984.

12.188 It is reasonably clear that a switch to imported heat-treated products would have been of little advantage to Scottish patients. Early in December 1984, the PFC began distributing its first heat-treated product to haemophilia centres. The product was despatched by carrier to Belfast, Aberdeen, Dundee and Inverness around 10 December. At the same time, the PFC itself delivered heat-treated product to Glasgow and Edinburgh.^[279] In each case, the quantity delivered was about one month's supply. Full scale production of heat treated product took over from the beginning of 1985.

12.189 There is no evidence available to the Inquiry to suggest that the UK or Scottish demand for heat-treated factor VIII concentrate for haemophilia therapy could have been met at any time during 1984 wholly from American pharmaceutical companies. The Haemophilia Reference Centre Directors recommendation on 10 December was that heat-treated product should be given to all patients, 'if freely available'.^[280] The market position remained uncertain at that date, when the PFC was already issuing a domestic heat-treated product.

The ethics of medical practice

12.190 The ethics of medical practice in this field are discussed in Chapter 32, An Investigation into Systems in Place for Informing Patients about the Risks - Ethical Context. In short, prior to 1988 there were no rules, relevant to such a situation as described in this chapter, requiring clinicians to consult their patients about potential changes in therapy. Furthermore, the approach of both Professor Forbes and Professor Ludlam throughout the 1980s was consistent with the advice that was to be provided by UKHCDO in mid-December 1984.

DISCUSSION

12.191 Sixty patients with bleeding disorders acquired HIV infection from treatment in Scotland (see Chapter 3, Statistics, paragraph 3.296). The infection of all but one of these patients can be associated with specific centres: Edinburgh, 23; GRI, 12; Glasgow Yorkhill, 21; and Aberdeen, 3. The remaining patient is known to have been infected in Scotland, probably at a hospital that was not a haemophilia centre. At least 18 NHS patients are known to have acquired HIV/AIDS transmitted by blood or blood component transfusion (see Chapter 3, Statistics, paragraph 3.321).

12.192 All of the patients with bleeding disorders acquired their infection from blood factor concentrates. There is no recorded case in the UK of transmission of HIV related to the use of cryoprecipitate. The UKHCDO did not record relevant data of cryoprecipitate use, however, and it is not possible to be totally confident that transmission by infusion of infected cryoprecipitate did not happen. Transmission of HIV by cryoprecipitate certainly did occur in other countries. However it seems appropriate to proceed on the basis that, if there were any cases, they would be very few, and that cryoprecipitate generally was not responsible for transmitting HIV in the UK generally or Scotland in particular.

12.193 Leaving aside the multiple infections of the Edinburgh Cohort,^[281] there is no evidence of transmission of HIV to groups of patients in Scotland by use of SNBTS large-pool concentrates. On the evidence available to the Inquiry about the chemistry of plasma processing, the pool of plasma prepared for processing would be more or less uniformly affected by a component donation that was infected by a virus. On that basis, the pooling of plasma from the donations of many hundreds of individuals clearly created a risk that an infected donation might infect large numbers of recipients. The experience of the Edinburgh Cohort demonstrates that the risk was real. Most members of the Cohort have been shown by genetic analysis to have acquired the virus from a single source. The Inquiry has not recovered similar evidence for other infected individuals. Cryoprecipitate was pooled in general application at the point of administration: the dose for an adult patient might require 10-20 bags. An infected donation would still reach one recipient only, however. Had cryoprecipitate been used exclusively in the treatment of coagulation disorder patients throughout the AIDS period - roughly 1981-85 - then the risk of transmitting HIV infection would have been arithmetically reduced: the number of patients potentially infected could not have exceeded the number of infected donations.^[282]

12.194 In relation to risk, it is important to bear in mind that, untreated, haemophilia carries a high rate of serious and potentially fatal illness. The life expectancy data noted in this chapter provide one measure of the risk of fatal illness: bleeding was the most frequent cause of death before concentrate therapy was introduced. It is against that risk that the risks associated with therapy had to be balanced. The studies carried out by Professors Forbes and Ludlam suggested that profound immunosuppression occurred in patients treated with PFC Factor VIII. Those studies were of a preliminary nature and did not provide evidence of progression in immunodeficiency. More significantly, however, it became widely known in the autumn of 1983 that a haemophilia patient treated with concentrates had died of AIDS. Once it was apparent that immunosuppression could progress to fatal illness the risk/balance assessment changed: the risk of death from bleeding then had to be measured against the risk of death from HIV/AIDS. Decisions on therapy had to take account of a different context.

12.195 The only alternatives at this stage were to cease entirely the use of blood products in haemophilia therapy or to endeavour to switch all Haemophilia A patients to cryoprecipitate. In relation to the period from autumn 1983 to December 1984, the point when heat-treated product began to be issued in Scotland, it is not possible to conclude that a general cessation of use of blood products should have occurred. Given the uncertain state of knowledge of AIDS and the risks posed by untreated haemophilia, it was reasonable for general treatment policy to continue to include the use of blood products, provided these were used on a more discriminating basis. The advice formulated at the Reference Centre Directors meeting of 13 May 1983 appears sound - that it was circumspect to continue to reserve NHS concentrates for children and mildly affected (adult) patients, rather than using concentrates imported from the USA. More specifically, the advice contained in Dr Jones's editorial in the BMJ in December 1983 that cryoprecipitate should be used for children and other options, such as DDAVP, considered for older patients, was prudent; one might have expected similar points to have been made by Professor Bloom at the UKHCDO meeting on 17 October 1983, rather than his seemingly unqualified endorsement of concentrate therapy.

12.196 In relation to the suggestion that all Haemophilia A patients should have been switched to cryoprecipitate from around autumn 1983 onwards, several points need to be borne in mind. As with the proposition dealt with in the preceding paragraph, the general uncertainty surrounding the proportion of patients who would develop the profound immunosuppression being observed, and the proportion of that group who might not survive, was relevant. To be balanced against these unquantifiable risks were the known dangers of untreated haemophilia, as noted above. As Professor Lever put it, 'the risk-benefit ratio of being infected versus not receiving concentrates was not clear cut'.^[283] Treatment was necessary and therapy with concentrates was well established. Clinicians and patients favoured concentrates rather than cryoprecipitate for understandable reasons, a preference also strongly supported by the well respected Haemophilia Society. In addition, it cannot be concluded that a mass switch to cryoprecipitate would have been practically possible.

12.197 Cryoprecipitate appears to have been utilised for particular groups of patients; on all of the evidence available to the Inquiry, that appears an appropriate general course. Issues concerning information given to individual patients, and the choices they were offered in relation to their own treatment, are dealt with in Part 5 of this Report.

Conclusions

12.198 Professor Lever's evidence is accepted: reassessment of the risk/benefit balance in the use of factor concentrates in haemophilia therapy became necessary when evidence of two factors was present: (i) the association of profound immunosuppression in patients with infusion of factor concentrates and (ii) death from immunosuppression.

12.199 Independent of the cause of the immunosuppression in coagulation defect patients treated with factor concentrates, knowledge that there was an association between established therapy and immunosuppression in patients was a potential trigger for a reassessment of clinical practice. The studies reported in Edinburgh in May 1983 and in Glasgow in October 1983 were preliminary in nature: they demonstrated immunosuppression in patients treated with factor concentrates but did not, and could not, report progression in immunodeficiency. At that point, there had been no report of a UK haemophilia patient having died of AIDS. Nevertheless, published guidance and letters in journals at the time, as well as the records of materials used, suggest there was a general awareness of the importance of a discriminating approach to product selection in light of incomplete information.

12.200 The association of immunosuppression in patients with haemophilia treated with factor concentrates and a potentially fatal outcome was established in the UK by the autumn of 1983. The general approach to the use of blood products in haemophilia therapy was reassessed and appropriately modified, insofar as references were made to the need to protect children and mildly affected patients in particular.

12.201 The transmission of infection by infusion of PFC Factor VIII was established around the end of October 1984 in Edinburgh and the east of Scotland and in or about October 1984 in Glasgow and the west of Scotland. A further general reassessment of coagulation defect therapy was therefore necessary and took the form of the meeting and guidance issued in December 1984. The response in autumn 1984 of the Haemophilia Reference Centre Directors to emerging knowledge was appropriate and is not open to criticism.

12.202 The use of imported heat-treated products was not an issue in Scotland so long as there was no evidence that the PFC product transmitted HTLV-III infection and so long as there was no evidence that the immunosuppression found in coagulation defect patients might progress to fatal illness.

12.203 Having regard to the timing of the discovery that PFC materials transmitted infection, and the imminence of production of a safe product by PFC, the failure of Scottish practitioners to import and use US heat-treated products is not material.

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