THE PENROSE INQUIRY
Final Report

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Chapter 10

Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2

Introduction

10.1 Until mid-1984, official reports of AIDS cases in the UK, as set out in the last chapter, were of 26 infected individuals, of all populations at risk, of whom two were haemophilia patients. One of the haemophilia patients had died. The diagnosis of AIDS depended on the identification of intractable AIDS-defining disease, at least moderately predictive of a defect in cell-mediated immunity, occurring in a person with no known cause for diminished resistance to that disease ('the CDC criteria').[1] The diseases included Kaposi's sarcoma (KS) and Pneumocystis carinii pneumonia (PCP), but covered a wider range for reporting purposes.[2] Evidence of impaired cell-mediated immunity was not reportable; it was not considered sufficient for classification of a case of AIDS. The lack of a requirement for reporting impaired cell-mediated immunity was due particularly to the belief that only a very small number of those so affected might progress to full-blown AIDS. Perceptions of the risk of progression to an AIDS-defining disease changed slowly over a period of two to three years.

10.2 Meantime, scientific research increased awareness of the prevalence of HIV infection in the UK and quickly demonstrated that the populations at significant risk of progressing to life-threatening disease were, in numerical terms, considerably greater than had previously been appreciated. The major developments happened in late 1984 and 1985. The science is discussed in Chapter 29, The Discovery of HIV and Development of Screening Tests. The present chapter is concerned with developing knowledge of the epidemiology and natural history of HIV/AIDS from mid-1984 but principally in the second half of the 1980s.

United Kingdom research towards testing for HTLV-III/LAV

Development of the Weiss/Tedder research assay

10.3 In early 1984, Professor Robin Weiss of the Chester Beatty Laboratories[3] and Professor Richard Tedder of the Middlesex Hospital Medical School[4] were engaged in research aimed at developing an assay for the detection of HTLV-III/LAV-1 in human blood.[5] They had available, for research purposes only, HTLV-III isolate provided in February 1984 by Mikulas Popovic and Robert Gallo of the National Cancer Institute, Bethesda, and LAV-1 provided in May by Luc Montagnier of the Institut Pasteur, Paris. Their studies showed that the two viruses, later re-designated HIV, were indistinguishable.[6] For the purposes of this chapter, the relevant part of their research related to the study of the prevalence of antibodies to HTLV-III in UK subjects using the Gallo material. They collected sera from 2000 individuals from a wide range of populations, including AIDS patients with clinically diagnosed KS or PCP; patients with PGL (persistent generalised lymphadenopathy: enlarged lymph nodes, a condition that occurs frequently in the latent period of HIV infection); sexual contacts of AIDS patients; homosexual patients positive for Hepatitis B or syphilis and symptom-free cohorts of homosexual volunteers; heterosexual subjects recruited from genito-urinary medicine clinics; intravenous drug users (IVDUs) screened for Hepatitis B; haemophilia patients undergoing regular replacement therapy with clotting factor concentrates; and 1000 randomly selected blood donors. Sera from haemophilia patients had been collected at the Oxford Haemophilia Centre from 1982 onwards and were provided by Dr Charles Rizza, the Director of the centre. Sera from IVDUs were collected in 1983 and 1984. Sera from the other groups had been collected between June 1983 and July 1984. As will be seen in Chapter 29, The Discovery of HIV and Development of Screening Tests, the research programme was an extension of earlier research into other retroviruses which expanded to include LAV/HTLV-III. The chronology is important in understanding the relationship between their work and research by others in the field. What they found and the timing of the publication of their findings are the current issues.

10.4 The results of their research were published on 1 September 1984 by Dr Rachanee Cheingsong-Popov, Professor Weiss, Professor Tedder and others.[7] They commented that there had previously been reported only limited studies of antibody prevalence in groups at risk for AIDS. All of the reports cited were published in 1984. That limitation was consistent with the previous lack of an effective assay and the focus on intractable disease as the prerequisite of an AIDS diagnosis. Attention began to shift from diagnosis of AIDS on that basis to testing for anti-HTLV-III in the course of the year and this landmark paper made a major contribution to the change. The researchers found a striking prevalence of seropositivity[8] among members of the risk groups, including a high prevalence among haemophilia patients who had received pooled clotting factor products (34%). The results for the risk groups studied fitted a pattern that strongly suggested an agent transmissible by sexual or blood contact. The opinion remained tentative, however, and views of the prognosis for those infected were qualified. The article stated:

Even if HTLV-III is causally related to AIDS and PGL, as is strongly suggested by the evidence, we should not assume that these disorders will develop in all patients infected with this retrovirus. Symptomless seroconversion or seroconversion accompanied by mild symptoms is often seen for many infections, including retroviruses. Although it is too early to draw firm conclusions, it seems possible that overt disease will not develop in at least some, and perhaps the majority, of seropositive subjects. On the other hand, the long latent period and a possible role for co-factors in determining the expression of disease make such a suggestion tentative.[9]

10.5 They commented that the risks had to be set against the relatively low incidence of disease in the haemophilia risk group (roughly 1:1000 as reported at that time) and, further, that the likelihood was that infection resulted from commercial rather than NHS concentrates. There was said to be a relatively low risk at that time of acquiring HTLV-III or AIDS from blood transfusion in the UK.

Research in Glasgow

10.6 At about the same time, a similar view was being formulated in Glasgow. In October 1983, Dr Karin Froebel and colleagues had argued against a disease vector specific to blood products from the USA after studying changes in T-cell ratios indicating cell-mediated immune dysfunction in Scottish haemophilia patients exposed to both Scottish (NHS) and commercial (US) Factor VIII concentrates.[10] On 29 October 1984, however, Dr Froebel wrote to Dr Robert Perry at the Scottish National Blood Transfusion Service (SNBTS), stating that, after checking records, she and her colleagues now thought that seropositivity for HTLV-III was in fact strongly associated with the patients having received commercial concentrate, mostly before 1981.[11] Dr Perry wrote to her on 15 November 1984 offering to cooperate in HTLV-III studies and asking for information.[12] With her reply,[13] Dr Froebel sent an abstract of a proposed paper. The full text of the paper in draft, entitled 'Evidence for Transmission of HTLV-III to European Haemophiliacs via US Imported Factor VIII Concentrate', had been prepared by a group including herself and Dr Gallo and a colleague from the US National Cancer Institute.[14] It was based on a comparative study of evidence of transmission of HTLV-III to haemophilia patients in Denmark and Scotland and presented a picture of confidence in locally-manufactured products, concluding that the data indicated that European haemophilia patients exposed to HTLV-III had been so exposed via infected imported Factor VIII concentrate from the USA.

10.7 Initial comment on the study had been published in a letter to The Lancet on 7 July 1984.[15] The final paper was published in The Lancet on 22 December 1984.[16] Dr Gallo was among the accredited authors and the Cheingsong-Popov article was cited. The relevant conclusion was that:

Our findings suggest that HTLV-III was distributed through haemophiliac populations by factor VIII concentrate made from US donor material.[17]

10.8 By the date of publication, the validity of the comments about the safety of local products had already been undermined, so far as Scotland was concerned, by the discovery of HIV infection in 16 Edinburgh haemophilia patients discussed in detail below. The comments remained at least partially correct in a UK context.

10.9 This marked the end of a period of underestimation of the risk of HTLV-III transmission in Scotland. Evolving events were soon to dispel finally the belief that the blood supplies of the UK and the domestic blood products of the NHS were free from HTLV-III infection. Meantime, however, the Cheingsong-Popov paper received wide publicity and perpetuated the belief that the risks were associated primarily with imported products. Andrew Veitch, medical correspondent, wrote in The Guardian of 31 August 1984:

Study confirms fears on spread of Aids

Fears that the Aids virus is widespread among homosexuals are confirmed today by the biggest British investigation into the disease so far.

The investigators - teams of doctors from seven centres - also found traces of the virus in a third of haemophiliacs given the blood clotting agent, Factor 8: American Factor 8 is strongly implicated.

But, the doctors stress, it seems possible that some of those infected - perhaps even the majority - may not develop the disease.

The number of Aids victims in Britain has risen from 13 in June 1983 to 51 in June this year. By yesterday the Department of Health had confirmed 61 cases, 32 of whom have died. The majority are London homosexuals.

The doctors tested 2000 people for antibodies to the Aids virus - the tell-tale sign that they had been infected. The results are published in The Lancet today.

They found the antibodies in 89 per cent of patients with the Aids-related disease, persistent generalised lymphadenopathy (PGL). It has previously been shown that hundreds of homosexuals are suffering from PGL. The symptoms include swollen glands, night sweats, and general malaise.

Antibodies were also found in 59 per cent of homosexuals with mild symptoms; 42 per cent of homosexuals who were sexual contacts of Aids or PGL sufferers; and in 17 per cent of homosexuals who were supposedly healthy or were being routinely screened for hepatitis.

The doctors say their results confirm that the virus, called HTLV-III and discovered earlier this year, is the cause of Aids and PGL. They found antibodies to it in 30 of their 31 Aids patients; the exception had an [un]usually benign form of the illness.[18]

10.10 The findings had been placed squarely in the public domain. The natural history of HIV infection was still not fully understood and the relative safety of domestic blood supplies was given emphasis.

The Weiss/Tedder research assay and early testing in the United Kingdom

10.11 Change was, however, imminent. The Weiss/Tedder research assay for HTLV-III, as reported by Dr Cheingsong-Popov and colleagues, was more widely used in the autumn. Haemophilia clinicians provided archived samples of serum from their haemophilia patients for testing and a high prevalence of HTLV-III infection was observed. For example, Dr Peter Kernoff at the Royal Free Hospital in London submitted stored samples of sera from his haemophilia patients to Professor Tedder in October 1984. More than a hundred samples tested positive. Dr Kernoff then had a further series of tests of samples carried out on stored blood samples to determine when his patients had become infected. Almost all of the patients were infected between 1980 and 1982. As no antibody was found in any sample from before 1979, it appeared that HIV had not entered the blood supply before that date. If Scotland had been dependent on imported products to the extent England and Wales had been, it is likely that the incidence of HIV infection in Scotland would have been of the same order as that in England and Wales.[19]

10.12 In submitting stored samples for testing, Dr Kernoff was following the general practice of the day.[20] His actions reflected growing apprehension among haemophilia clinicians that factor concentrate therapy might have caused widespread infection within the haemophilia population. Dr Mark Winter said that at that time a haemophilia clinician who had stored samples would submit them for testing without consulting the patients and that samples were stored in case they might be needed for such a purpose.[21] The patient would, however, have been consulted if a fresh sample was required.[22] It is understood that Dr Kernoff did not consult the patients before submitting the samples to Professor Tedder.[23] Dr Winter did not have stored samples.[24] He had to invite his patients to come specially and to explain why he wanted additional blood. Dr Winter obtained and sent 31 samples from his own haemophilia centre at Kent and Canterbury Hospital to Professor Tedder for testing. On 26 October 1984, he received the results: 30 were positive for HIV.[25]

10.13 On 23 October 1984 Dr John Craske of the Public Health Laboratory Service (PHLS), Withington Hospital, Manchester, circulated a letter to haemophilia clinicians.[26] He advised that a batch of Factor VIII concentrate from the Blood Products Laboratory (BPL), the manufacturer of NHS concentrates in England, had been found to be infected with HTLV-III. He warned of the possible risk of infection with HTLV-III and subsequent development of AIDS. The letter stated that only a proportion of those transfused with an infected batch were likely to contract HTLV-III infection. It commented:

So far 21 patients are known to me who have clinical features of AIDS or the AIDS related complex. It is likely that the proportion of patients who contract HTLV-3 infection who contract AIDS will be of the order of 1/100 - 1/500.[27]

10.14 The long-term prognosis for patients with HTLV-III infection was said to be unknown.

10.15 By the end of October 1984, among haemophilia clinicians in the UK generally, there was growing awareness that HTLV-III infection could be, and had been, contracted from Factor VIII concentrate and that transmission could be associated with domestic as well as imported products. Between the end of October and the end of the year, further intelligence emerged in Scotland.[28]

'The Edinburgh Cohort': the initial disclosure

10.16 Any residual complacency in Scotland was shattered by the discovery that a group of Edinburgh patients ('the Edinburgh Cohort') who had received Factor VIII concentrate therapy manufactured at the Protein Fractionation Centre (PFC) in Edinburgh, some exclusively and some almost exclusively, had developed antibodies to HTLV-III during 1984. In the immediate aftermath of the discovery it was thought that the infections must be attributed to products manufactured at the PFC (the Scottish equivalent of the BPL in England).[29] Evidence available to the Inquiry relating to the events surrounding the discovery was at times inconsistent and a little confused. The news clearly had a disturbing effect on those who first heard it and witnesses' recollections reflected the degree of turmoil that affected the SNBTS and haemophilia circles when the information emerged.

10.17 Dr Brian McClelland, Director of the Edinburgh and East of Scotland Blood Transfusion Service, gave an account of events in his written statement to the Inquiry. Professor Christopher Ludlam, Director of the Edinburgh Haemophilia Centre, telephoned him at home on the evening of Friday 26 October 1984 to inform him that six patients with haemophilia under his (Professor Ludlam's) care had developed antibodies to HTLV-III. The tests had been performed in a research laboratory by Professor Tedder.[30] The date, and the number of patients affected, gave rise to discussion in the course of the oral hearings of the Inquiry.

10.18 There had been a meeting of the PFC heads of department on the morning of 26 October 1984.[31] The minutes of the meeting indicate that Dr Perry was concerned that the PFC, of which he was Director,[32] might be asked, in the future, what plans had been made to reduce AIDS infection in blood products. He proposed, and it was agreed, that it would be useful to collate all information and data on heat-treated products and that further meetings should be arranged to discuss this matter.[33]

10.19 The Inquiry explored the possibility that Dr Perry and his colleagues had already been informed of the HTLV-III transmissions in Edinburgh by this stage.[34] On the written and oral evidence available, it is unlikely that they had.[35] The picture that emerged, however, was of a state of some confusion among this group as information (not always consistent or comprehensive) was exchanged and people began to respond to the events as they evolved.

10.20 Dr Bruce Cuthbertson, SNBTS, said that he remembered that it was definitely Dr McClelland who phoned him and told him that there had been evidence of infection in three Edinburgh haemophilia patients. He also remembered clearly a meeting with Dr McClelland and Dr Perry approximately a week to 10 days later where they went through the analysis that Dr McClelland had done with Professor Ludlam which showed which batches of Factor VIII had been received by the 16 infected patients identified by that time.[36]

10.21 Dr Foster's evidence was that he first learned of the infections in late October 1984, when he overheard a telephone conversation in Dr Cuthbertson's office.[37] The call was, he thought initially, from Dr McClelland, but it might have been from Dr Frank Boulton, Consultant in Haematology and Blood Transfusion at the Royal Infirmary of Edinburgh (RIE). Dr Cuthbertson said that Dr Foster had told him about the call over the years but that he could not himself remember the event. However, he said of Dr Foster:

It's certainly true that he was in an adjacent office and I'm sure when the information came from Dr McClelland, that my voice would have risen by several octaves.[38]

10.22 Steps were immediately taken to identify the batch of concentrate which was responsible for the infection of Professor Ludlam's patients. Professor Ludlam and Dr McClelland gave evidence about this period. On 29 or 30 October Professor Ludlam established from examination of transfusion records that three of the initial group of patients who had developed antibodies had received material from batch 023110090.[39] On 2 November 1984 Professor Ludlam received further data from Professor Tedder which indicated that in total 15 or 16 patients who had received that batch had tested positive for the HIV antibody. Three other patients were added on further analysis. Fourteen out of 32 patients who had received material from the batch remained uninfected. On 3 November 1984 Dr McClelland and Dr Frank Boulton contacted all Scottish and Northern Ireland Transfusion Centres and arranged for batch 023110090 to be recalled.[40]

10.23 It was to be mid-November before a written account was prepared within the SNBTS and, by then, a certain amount of clarification of the history of events had evidently occurred. However, the group of HIV-infected haemophilia patients that was to become known as 'the Edinburgh Cohort' had been discovered at the end of October.

10.24 Dr Perry stressed that it had never been established conclusively that batch 023110090 was infective but, at the time, the SNBTS proceeded on the basis that it was 'a justifiable, though unproven, assumption'[41] that the batch was responsible for the infections. He explained that the decision to recall was an example of an application of 'the precautionary principle'. His understanding of that principle was that, where there was evidence available to a manufacturer that a medical risk associated with a particular product may exist, it was incumbent upon him and the supplier to take action to mitigate that risk.[42]

10.25 On 15 November 1984, Dr McClelland wrote to Professor John Cash, Medical Director of the SNBTS:

I have had several discussions with Dr Christopher Ludlam following the discovery that some recipients of PFC Factor VIII have developed antibodies to HTLVIII during 1984 ....

As I reported to the Scottish RTDS last week, it appeared that there are, so far, 16 patients in whom seroconversion is known to have occurred during 1984 and who have received exclusively PFC factor VIII, or (in one case only) commercial factor VIII several years ago which can be discounted from the present problem.

Initial analysis by Dr Ludlam and Dr Tedder showed that one batch of product had been received by all but one of the 16 patients and therefore was highly suspect. This batch (023110090) has been withdrawn.[43]

10.26 The batch assumed to have been implicated had been identified and action had been taken. After examination of the records, it was concluded that no other recent batch stood out as being 'distinctively strongly implicated' and there was therefore thought to be no obvious basis on which to advise a selective withdrawal of any other material.

Reactions to developing knowledge in late 1984

Official reactions

10.27 Following on the media comment by Andrew Veitch and others[44] and the discovery of the Edinburgh Cohort, the incidence of disease in the Scottish population moved into the political arena. In a parliamentary answer on 28 November 1984 relating to the incidence of AIDS in Scotland, it was announced that there were three confirmed cases by 26 November.[45]

10.28 On 29 November 1984, the SNBTS and Haemophilia Centre Directors met specially to discuss the implications of the recent findings of HTLV-III infection in Scottish haemophilia patients, measures being taken by the SNBTS to prevent the spread of AIDS by blood products and the media attention associated with these developments.[46] All relevant agencies in Scotland were clearly informed of the incidence of infection as understood at that time.

10.29 At that meeting, outbreaks in three centres were discussed. Professor Ludlam discussed the Edinburgh Cohort and Professor Charles Forbes described the findings of the study of patients at the Glasgow Royal Infirmary and Danish patients.[47] Dr Brenda Gibson reported the anxiety felt by parents of children with haemophilia: five out of 10 children treated at the Royal Hospital for Sick Children, Yorkhill, Glasgow, where imported Factor VIII concentrate had been widely used, were HTLV-III antibody positive.

10.30 At a meeting of the SNBTS Directors on 11 December 1984, Dr McClelland reported that he had attended a meeting of the National Blood Transfusion Service Working Group on AIDS which had taken place on 27 November 1984.[48] He reported that Dr Marcella Contreras had run a trial of a New York Blood Center questionnaire in the West London Donor Centre, offering donors the chance to elect for their blood to be used for research if they belonged to a risk group. A small number had agreed to do so. All of the declared homosexuals followed up were HTLV-III antibody-negative on testing.

10.31 On 30 November 1984, Dr Craske wrote to Dr Ludlam providing materials for investigation of the cases of infection in Edinburgh patients. He stated that certain 'facts' might help Dr Ludlam appreciate the position. In summary, these included:

(i) Only a proportion of the patients transfused with an infected batch were likely to contract HTLV-III infection.

(ii) Some patients who had received commercial factor VIII since 1 January 1980 would already have contracted HTLV-III infection from other infected batches.

(iii) The proportion of patients infected with HTLV-III who would eventually contract AIDS was unknown but, as serum from 34% of symptomless haemophilia patients was positive for HTLV-III antibody (the Cheingsong-Popov finding), it was thought likely that a significant proportion of patients would remain in good health. He narrated that by that date 21 patients had been reported to him as having the clinical features of AIDS (four patients) or the AIDS-related complex (17 patients). He said that it was likely that the proportion of patients with HTLV-III infection who developed AIDS would be of the order of 1/100-1/500.

(iv) The long term prognosis for patients with HTLV-III infection was said to be unknown. The incubation period of AIDS, based on projection of the epidemic curve at the CDC, was from nine months to six years, with a mean of four years.

(v) There was evidence that HTLV-III infection could be transmitted by sexual contact. Therefore some sexual partners of recipients of Factor VIII contaminated with HTLV-III might be at risk.

(vi) Those patients who were likely to transmit infection, or who were likely to contract AIDS, could not yet be distinguished by means of laboratory tests.[49]

10.32 Some of these statements proved to be wrong.[50] It was not likely that a significant proportion of patients would remain in good health and it was not likely that the proportion of patients who contracted HTLV-III infection and went on to develop AIDS would be of the order of 1/100-1/500. Over a short period at the end of the year results of tests on sera were rapidly changing perceptions. Dr Craske's letter set out clearly one set of perceptions about the disease at this time and reflected some of the 'known unknowns' as then understood.

10.33 The UK Haemophilia Reference Centre Directors met on 10 December 1984.[51] By this time, some 800 UK haemophilia patients had been tested for the antibody: the prevalence in haemophilia patients overall was about 35%, but 75% in patients with severe haemophilia.[52] Professor Ludlam is reported to have 'confirmed that in Scotland, some patients who were previously antibody +ve are now -ve.'[53] Haemophilia Directors wanted to test all of their patients.

10.34 It was thought that there was a clear need for research to determine prevalence in the UK. A report of the meeting noted a view that inconsistencies in the results of the tests revealed that a study of the haemophilia population would provide invaluable material to increase knowledge of the disease. There was a wide-ranging discussion on a number of important issues but few conclusions were drawn by the haemophilia clinicians present. The prevalence of infection was far from clear and, furthermore, the likelihood of developing AIDS for those who were HTLV-III positive was unknown.

10.35 On 14 December 1984, the United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO) produced an 'AIDS Advisory Document.'[54] The background information provided included data on infection, as understood by the UKHCDO. In the USA, where there had been over 6000 cases of AIDS, 52 haemophilia patients had been infected. It was said that in the UK there had been 102 cases of AIDS with three reported haemophilia patient cases and 'no doubt other cases ... developing.'

Press reports

10.36 In the media there was more reporting. A Daily Express article dated 21 December 1984 stated:

56 are given AIDS killer blood: Alert as homosexual admits being a donor.

Blood which has been infected with the killer AIDS virus has been given to 56 people, it was revealed yesterday.

Fifteen of the recipients are Scots. Another 32, including a pregnant woman, are from England, and nine others are from Wales.

Most are haemophiliacs but none has yet contracted the disease - although it has an incubation period of up to four years.

Shocked experts at the Blood Transfusion Service made the discovery when the patients mysteriously developed antibodies to the AIDS virus, which is normally transmitted by homosexuals.

Then horrified doctors at a Bournemouth hospital discovered that a young homosexual who is seriously ill with AIDS had been a regular blood donor all over England.

His blood was used for transfusions to patients in the Midlands and the North, but mainly in the South and in Wales. The contaminated blood given to Scots patients is not thought to come from the same source. 'We are still trying to identify the donor' said a Scottish Office spokesman ....

The AIDS virus was discovered among the 15 Scots patients when recently developed tests showed up traces of antibody to the disease in their blood.

Dr Frank Boulton, deputy head of the Edinburgh Blood Transfusion Service said: 'Previously, the only way that AIDS was diagnosed was by the illness itself. But the tests have not been around long enough for us to know what degree of immunity the presence of antibodies indicates.'[55]

10.37 In The Scotsman of 22 December 1984, William Paul wrote:

AIDS 'barrier' proves illusory

With the benefit of hindsight, it is now possible for doctors to reflect on the inevitability of AIDS ... gaining a foothold in Scotland.

The disease has largely established itself in Europe and in England since originating in the U.S. and Dr Brian McClelland, director of the Edinburgh and South-East Scotland Blood Transfusion Service, admitted yesterday that it would not have been realistic to expect Scotland to be by-passed.

Even so, Scotland's self-sufficiency in blood and blood products was seen as a significant barrier and the medical profession must have experienced a sense of disappointment when routine tests on haemophiliacs at Edinburgh Royal Infirmary recently uncovered the fact that 15, or possibly 16, of them had contracted the HTLV 3 virus which can cause AIDS.

The virus was transmitted in injections of the blood-clotting agent Factor 8, used by most haemophiliacs to control their condition, which had been prepared from a particular batch of plasma, now identified and withdrawn. Its source was a blood donation given somewhere in the East of Scotland about 12 months ago.

Government scientists are now working to trace the donor but it is by no means certain that they will be successful as plasma is made up from many thousands of individual blood donations.

The balance of probability, according to Dr McClelland, is that the donor of the contaminated blood was a practising homosexual male because that is the section of the population considered to be most at risk from the disease ....

Dr McClelland prefers to think that the contaminated blood must have been donated unwittingly, but cannot rule out the possibility that the donor deliberately went ahead knowing himself to be a member of the at-risk groups ....

'If we had to be 100 per cent certain of the purity of all the blood we turn out we would have to cease operations', Dr McClelland said.

'But the risk to people from not having blood available would be far greater than the risk of AIDS being transmitted for the foreseeable future. The chances of getting AIDS virus from a transfusion are put at a million to one.'

The haemophiliacs in Edinburgh who have been told their blood has produced antibodies to fight the AIDS virus are all described as clinically very well. The odds against them actually developing symptoms of the disease proper ... are said to be 2000 to one. [56]

10.38 The quoted risk of 2000:1 against developing the disease proper was clearly very wrong indeed and, even at that time, was more optimistic than other estimates. The source of some of the information in these media reports is unclear. However, accuracy apart, the extent and tone of media comment reflected growing public concern about the spread of the epidemic.

10.39 In and after 1985, there was intense interest in the Edinburgh Cohort. The patients comprised in the group were studied by clinicians and scientists seeking more information about HIV and AIDS. Several of the articles published about this group of people emphasised the value from a research point of view of being able to study the disease in a group assumed to have had a common source of infection.[57] Several of the articles are referred to in the Preliminary Report at paragraphs 8.205-8.214. It will be appropriate to return to some of these in the context of other developments.

1984-1985

HIV in the United Kingdom: a matter of public health

10.40 With the discovery of the Edinburgh Cohort, the risk of transmission of HIV by SNBTS factor concentrate, despite the exclusive use of Scottish blood donations in its manufacture, was demonstrated and there was no longer room for differentiating Scottish patients from others at risk, so far as exposure to the epidemic by means of blood, blood components or blood products was concerned. Advice and comment took on a more general character thereafter.

10.41 An editorial in The Lancet of 22 December 1984 (the issue in which the article discussed at paragraph 10.7, above, was also published) contained discussion of 'Blood transfusion, haemophilia and AIDS'.[58] It noted that 52 haemophilia-associated cases of AIDS had been reported in the USA and three in the UK. The overall prevalence of AIDS in treated US haemophilia patients was about twice that in Europe but it was thought that in countries that used Factor VIII concentrate from the USA the number was likely to increase. This obvious inference had previously been resisted but it is difficult to understand how a product manufactured by a given pharmaceutical company for general distribution could have a higher rate of infectivity in its country of origin, the USA, than in importing countries abroad. The prevalence of HTLV-III infection in homosexuals and others seemed to be increasing rapidly in countries outside the USA. It was observed that contamination of local blood products could only be a matter of time. The editorial discussed the options for treatment of blood disorders against this background.

10.42 There was growing concern about public health. A Ministerial answer by Kenneth Clarke, MP, then Minister of State for Health, to a Parliamentary Question on 21 January 1985 reflects the position of the government at the time:

We are considering the public health implications of AIDS and what further steps might be taken to control it. We have established an expert advisory group[59] to advise the health departments in the United Kingdom, whose members will include experts on all aspects of the disease. Their advice will be valuable in assisting the formulation of a strategy for prevention and control.

There is at present no vaccine against AIDS or specific treatment, but general preventive measures and health education have a major part to play in controlling the disease ....

Internationally, we are in touch with the Centers for Disease Control in the United States and the World Health Organisation AIDS Reference Centre in Paris, which have considerable data on the disease. Research in this country is proceeding through five projects funded by the Government through the Medical Research Council. [60]

10.43 He answered further questions (i) to the effect that AIDS was not a notifiable disease under the Public Health (Control of Disease) Act 1984; (ii) relating to monitoring arrangements; and (iii) relating to the intention to make the disease notifiable and the practical implications of that:

Interim guidelines drawn up by the Advisory Committee on Dangerous Pathogens[61] on the safe handling of AIDS patients have recently been published jointly by our Department and the Health and Safety Commission. These set out the measures which should be taken to protect clinical and laboratory staff who come into contact with patients suffering from AIDS or with specimens taken from them. We are taking steps to reduce the risk of the spread of AIDS through blood transfusion and the use of blood products. We are strengthening our efforts to dissuade those in AIDS high-risk groups from donating blood, and our revised leaflet 'AIDS Important New Information for Blood Donors' will be distributed individually to all donors. We are also considering the need to screen blood donations for the HTLV III antibody. Supplies of heat-treated factor VIII for haemophiliacs will shortly be made available to the NHS from the Central Blood Laboratories Authority.[62]

Reaction in Scotland

10.44 In Scotland, steps had already been taken to protect staff at the PFC. On 31 December 1984 Dr Perry had issued a memorandum setting out the current understanding of AIDS risk and encouraging the use of safe working practices.[63] There was an understandable emphasis on staff safety but some of the information provided in the memorandum gives an insight into the impact of media comment and the understanding within the PFC at the time: the memorandum distinguished transfusion from factor concentrate therapy; and it noted that there had been no cases of AIDS in Scotland or Northern Ireland associated with transfusions of blood or blood products from the SNBTS and that some haemophilia patients had HTLV-III antibodies, evidence of exposure to the AIDS virus, but that none had symptoms of AIDS. It narrated that the patients who had been exposed to the AIDS virus all received some vials from the suspect batch and that some had also received material from a number of other batches. It was stated that the fact that these patients had evidence of exposure to HTLV-III did not necessarily mean that they would go on to develop AIDS. Employees were encouraged to work safely but they were reassured that at that time there had been no cases (worldwide) of AIDS in any centres manufacturing blood products despite the fact that the spread of AIDS in the USA was some two to three years ahead of Europe.

10.45 Dr Perry distributed a second memorandum to all PFC staff, dated 31 January 1985, discussing further the transfusion risks associated with blood components.[64] Red cells and platelets had been used normally by Regional Transfusion Centres (RTCs) and there was no evidence to date to indicate that the recipients of these products had developed HTLV-III antibodies. He provided information on attempts to identify donors who had contributed to the batch implicated in the infection of the Edinburgh Cohort and to quarantine all plasma from those individuals who had been identified and who subsequently gave donations. The memorandum narrated:

The decision to quarantine this plasma was taken to safeguard both product and staff safety in the belief that additional evidence and further investigation of repeat donations would identify the infective donation(s) and permit the remaining donations to be entered into process. As you know, a suitable test is not yet available for large scale application to individual donations with the result that it is not possible at the present time or in the foreseeable future to establish the relative infectivity of plasma pools or product batches. On this basis, the quarantined plasma was released for process. You will also be aware of the fact that plasma from these donors has inevitably entered process on previous occasions. While this does not necessarily provide comfort or reassurance, one must conclude that, at this stage, it is impossible to judge that some plasma is 'safer' than others or that one pool of plasma represents a higher risk than others either from a patient or staff safety point of view.[65]

10.46 On 4 February 1985, the Scottish Home and Health Department (SHHD) distributed the advice of the Advisory Committee on Dangerous Pathogens in the form of 'Interim Guidelines on AIDS' (dated December 1984).[66] Their interim character was emphasised but the guidelines provide a useful summary of contemporaneous knowledge of the disease and its clinical course.[67] It was noted that HTLV-III and LAV had been recovered from patients with AIDS. It was said that the two agents (in fact, it would later be discovered that they were the same) had also been isolated from patients with PGL, haemophilia patients and apparently healthy male homosexuals. The prevalence of infection in AIDS patients, haemophilia patients who had received pooled clotting factors and others was tabulated. Eighty-eight cases had been reported between The Lancet report of 12 December 1981 and October 1984 and 37 individuals had died. One patient had been diagnosed retrospectively as having been infected in 1979. The cases were grouped according to their prime recognisable condition:

Kaposi's sarcoma (KS) 30
Pneumocystis carinii pneumonia (PCP) 32
KS plus PCP 5
Other opportunistic infections 20
Cerebral lymphoma 1[68]

10.47 Of the 88 cases, over 75% were male homosexuals while the remainder were patients with direct or indirect contact with central Africa, recipients of pooled clotting factors and a small group with no recognised risk factor. The Interim Guidelines commented:

If the trend in the UK follows that seen in the USA we can expect an exponential increase in the number of cases of clinical AIDS diagnosed. Furthermore the serological studies ... seem to indicate that whereas the most severe outcome of infection with HTLV III is certainly AIDS, it cannot be assumed that all infections with this virus will necessarily lead to this disease, although the possibility cannot be ruled out.[69]

10.48 There was now a realistic official assessment of the probability of a growing epidemic in the UK. On 16 January 1985, the Department for Health and Social Security (DHSS), jointly with the Health and Safety Executive, issued a press release: 'AIDS guidelines for clinical and laboratory staff'.[70] The press release noted the publication of the Interim Guidelines and stated that a review of the measures recommended would be undertaken within the next 12 months to take into account any new knowledge or understanding of AIDS.

10.49 On 25 February 1985 Mr John MacKay, Under-Secretary of State for Scotland, told Parliament that there had been four cases of AIDS reported in Scotland.[71] One patient had died in 1982 and one in 1984. In addition a patient ordinarily resident in England had died in Scotland in 1984.

10.50 Over the next few months there was an explosion of published material. Typical examples are referred to in the Preliminary Report.[72]

Official statements

10.51 Official statements were distributed. On 1 April 1985, the Chief Medical Officer (CMO) for Scotland issued a circular letter to Chief Administrative Medical Officers and community medicine specialists,[73] together with a leaflet entitled 'Some Facts about AIDS'[74] which was then available for distribution. It was produced by the Health Education Council and reprinted for the Scottish Health Education Group. This was followed, on 17 May 1985, by a letter from the Deputy Chief Medical Officer (DCMO) to all doctors.[75] The papers sent with the letter contained a further summary of the state of knowledge of the UK government at the time entitled 'AIDS - general information for doctors', dated May 1985, and a paper dated 22 February 1985 prepared by the Communicable Disease Surveillance Centre in London giving a detailed account of the epidemiology of the condition.[76]

10.52 The paper dated 22 February 1985 and prepared by the Communicable Disease Surveillance Centre stated:

[T]here is a wide spectrum of clinical states associated with HTLV3 infection ranging from healthy antibody-negative persons to patients with fully developed AIDS. It seems probable that only a very few of the infected persons become ill ....

....

Tests for antibodies to HTLV3 have been developed but these are not tests for AIDS and are difficult to interpret.[77]

10.53 The paper 'AIDS - general information for doctors' reiterated the established criteria for reporting AIDS, following the US CDC definition,[78] and noted that they had been accepted by other countries and by the World Health Organization (WHO). It stated that, by the end of February 1985, 132 cases of AIDS had been reported within the UK and that there had been 58 deaths. Data indicated that three haemophilia patients were included and that there were no cases of infected blood transfusion recipients. The covering 'Dear doctor' letter from the DCMO gave more up-to-date data: there were four cases of AIDS registered 'to date' in Scotland and 159 cases in the UK. Doctors who had patients with AIDS under their care were invited to assist in the maintenance of a register by reporting in strict confidence to the Communicable Diseases (Scotland) Unit in Glasgow.

10.54 Further observations in the UK government's general information for doctors included:

The risk of infection as a result of blood transfusion is extremely low. Infection with HTLV-III has occurred as a result of treatment with Factor VIII and Factor IX. Heat treated Factor VIII is now available and in use and is likely to eliminate the risk of transmission.[79]

And:

HTLV-III infection is already widespread in certain groups at risk (e.g. in homosexuals with multiple sexual partners and in haemophiliacs). Estimates vary as to what percentage of infected individuals will ultimately develop AIDS, but it may be in the order of 10 per cent.[80]

10.55 The prevailing view, as published, remained that HTLV-III infection was unlikely to progress to AIDS in the majority of cases but that the risk to haemophilia patients, and a lesser risk to transfusion patients generally, was recognised. There appears to have been a conscious effort to avoid panic reactions while providing doctors generally with information and advice about AIDS and HTLV-III infection that was not otherwise available in textbooks at that stage.

10.56 Some experts thought that there were aspects of AIDS that were not adequately monitored in the UK. The Preliminary Report set out details of arguments advanced by Professor Julian Peto, Professor of Epidemiology at the Institute for Cancer Research, in a letter dated 20 May 1985 circulated to members of the Medical Research Council.[81] He thought that AIDS might already be 'catastrophic' for haemophilia patients and for homosexual men in London. His attached paper[82] was a plea for further research but it presented a more pessimistic projection of future progression of the disease than the official government position. Professor Peto suggested that many and possibly the majority of seropositive individuals might eventually die of AIDS. Even the fact that AIDS was always, or almost always, fatal was still not universally appreciated at this time as only half the individuals diagnosed with the disease had so far died. It was thought by Professor Peto that only a minority, if any, of the general population might be capable of mounting an effective immune response to initial infection and it seemed to him likely that the chronic infection that ensued constituted a permanent infective carrier state.

The Edinburgh Cohort revisited

10.57 On 23 May 1985, Professor Ludlam sent Dr Perry a copy of the final draft of the RIE study of the Edinburgh Cohort,[83] later published in The Lancet on 3 August 1985.[84] The introduction to the published paper reported as background that the virus HTLV-III/LAV was the most likely cause of AIDS and that tests carried out on stored serum samples from haemophilia patients showed that HTLV-III antibodies were first detectable in the USA in 1978 and in the UK no later than 1979. The summary stated:

Fifteen haemophiliac patients acquired antibodies to [HTLV-III] during 1984. One batch of factor VIII concentrate given to all these patients is presumed to be the cause of the seroconversion. A further eighteen patients who received the same batch did not seroconvert .... Ten other patients received a batch of factor IX concentrate from the same donor plasma; none of these patients seroconverted.

10.58 The article further commented in its introduction:

In contrast to haemophiliacs elsewhere in the UK, almost all patients attending the Edinburgh Haemophilia Centre have received factor VIII and IX concentrates prepared exclusively from locally collected plasma by the Scottish National Blood Transfusion Service (SNBTS). Until recently there were no reported cases of AIDS in Scotland and it therefore seemed possible that our patients might not be exposed to HTLV-III ...

As part of the continuing assessment of our haemophiliacs, we have now observed that sixteen of our patients acquired anti-HTLVIII during 1984; all but one of these patients had received a common batch of SNBTS factor VIII concentrate.

10.59 The study discussed 34 patients with Haemophilia A and eight patients with Haemophilia B. It reported their treatment histories and noted that samples dated up to early 1984 were all negative on testing for anti-HTLV-III. None of the infected patients was known to have risk factors for developing antibodies to HTLV-III other than replacement therapy.

10.60 The paper set out the results in some technical detail. In summary, the discussion noted:

  • The prevalence of anti-HTLV-III in Scotland among haemophilia patients at the beginning of 1984 was relatively low and where it occurred could be attributed to occasional use of commercial blood products. In contrast, in some places prevalence had risen to over 90%.
  • One specific batch had probably caused the infection in the Edinburgh Cohort: a definitive investigation would have to await a reliable test of infectivity. All but one of the 16 patients with Haemophilia A who had developed anti-HTLV-III had received the batch between March and May 1984.
  • The risk of developing HTLV-III was a function of the recipient's helper/suppressor cell ratio,[85] the number of transfused vials of presumed infected Factor VIII and the total annual consumption of Factor VIII.
  • If the study were otherwise correct in its conclusions, half of the patients who received the single suspect batch did and half did not develop antibodies to HTL-VIII.
  • Patients who received Factor IX prepared from the same pool were known. None demonstrated seroconversion when tested up to four months after infusion.

10.61 The presumed infective batch was manufactured in November 1983 from plasma collected in the autumn of the same year. Following the reports of product infectivity, attempts were made to identify the specific donation(s) which led to the product being infective but these were unsuccessful. The paper noted that the PFC had developed a programme to study possible methods of eliminating the transmission of viral infections by blood factor concentrates. The expertise developed had been put immediately into effect, following the finding of HTLV-III antibodies in Scottish patients.

The reality of risk for recipients of blood and blood products

10.62 The AIDS Information and Advisory Group at the Glasgow Royal Infirmary (GRI) met on 31 May 1985.[86] In common with others, they recognised the need for further research. In the west of Scotland, 16% of haemophilia patients were HTLV-III antibody positive.[87] All had, in retrospect, seroconverted between 1981 and 1983. The minutes of the meeting noted that the Regional Reference Laboratory was using the 'Abbott' kit,[88] confirmed by immunofluorescence testing, for HTLV-III antibody testing, with reference to Dr Tedder in London in the event of inconsistent results. Dr Robert Crawford, a Consultant at the West of Scotland Blood Transfusion Service, reported that the national HTLV-III test evaluation was progressing. The aim was to test all blood donations at major regional blood transfusion centres, with the particular aim of protecting the higher-risk pooled products, rather than the low-risk single-donor products, from infected donations. It was stated that arrangements should be made to counsel blood donors found to be HTLV-III antibody positive.

10.63 The focus was changing away from discussing whether there actually was a risk of transmission of infection: interest was now focused on the response to the reality of the risk for recipients of blood and blood products and the need for care of donors and patients. Inactivating virus contamination by heat-treatment was promoted as part of the response and Dr Crawford reported that the second generation of heat-treated Factor VIII concentrate was being clinically evaluated. Heat-treated Factor IX concentrate was still under development and had not been released for clinical evaluation at that stage.

10.64 Government agencies continued to collect data. On 20 September 1985 a note to the Private Secretary of John MacKay, Under Secretary of State for Scotland, and copied to the offices of the Secretary of State, the CMO and other senior officials, provided data on the incidence of AIDS to the end of August.[89] There were said to be 206 cases in the UK, of which 114 individuals had died. The figures for Scotland were six cases and two deaths. Comparative figures to the end of February had been 132 cases in the UK, of which 58 had died, with Scotland having four cases and two deaths.

10.65 On 26 September 1985, a press release was issued by the DHSS[90] and, in turn, a press release was drafted by the SHHD.[91] The SHHD press release was entitled 'Countering the Spread of AIDS in Scotland' and stated that, to that date, six people in Scotland had developed AIDS, of which two had died. The UK total was 206 cases of AIDS, of which 114 had died.

The prevalence of HTLV-III antibody in haemophilia patients in the UK

10.66 There was by now growing interest in the prevalence of HTLV-III antibody in haemophilia patients in the UK.[92] The need for research had been anticipated and was now in hand. Dr Rizza and Miss Rosemary Spooner of the Oxford Haemophilia Centre contacted the 109 haemophilia centres in the UK requesting information on the antibody status of their patients and on 27 September 1985, the results were circulated.[93] Eighty-one centres provided data. Of the remaining 28, four replied that they could not cooperate because of confidentiality issues and three said that they would try to provide information later. The survey was destined to be less than comprehensive.

10.67 At the time there were 4918 Haemophilia A patients, 896 Haemophilia B patients and 1725 von Willebrand's disease patients on the national haemophilia register. Of the 2970 Haemophilia A, Haemophilia B and von Willebrand's disease patients treated in the UK in 1984, 2525 had been tested.[94] The range of results as reported for those groups was as follows:

Table 10.1: UK Haemophilia AIDS Survey

Patients treated in 1984 Patients Tested for HTLV-III % of Treated Patients Tested Number HTLV-III Positive % of Tested Patients Positive
Haemophilia A 2277 1994 88 873 44
Haemophilia B 391 316 81 20 6
von Willebrand's 302 215 71 11 5
Total 2970 2525 85 904 36

10.68 In the case of severely affected Haemophilia A patients (defined for this purpose as having less than 2% Factor VIII)[95] the proportion testing positive for HTLV-III rose to 59%. The average proportion testing positive in the three groups combined was 36%.

10.69 The age profile for severely affected haemophilia patients with HTLV-III antibodies (expressed as a percentage of the total numbers tested) was:

Table 10.2: age profile for severely affected haemophilia patients with HTLV-III antibodies

Age 0 - 5 5 - 9 10 - 14 15 - 19 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69 70 +
Haem A 6 32 68 65 68 65 61 51 34 20
Haem B 0 0 0 9 15 3 6 14 20 0

10.70 The highest percentages according to age groups were in those aged 10-14 years and those aged 20-29.

10.71 On the basis of the data collected, and assuming that those patients not yet tested were at the same risk as those already tested, the authors of the report predicted that if all children with Haemophilia A up to the age of 19 (865 children) were to be tested, 320 patients (37%) might be expected to be HTLV-III positive.[96]

10.72 Tables prepared by Dr Craske dated 1 October 1985 gave data on cases of AIDS-related diseases reported to the Oxford Haemophilia Centre.[97] A total of 67 cases in patients with Haemophilia A or von Willebrand's disease had been reported along with three cases in patients with Haemophilia B.

10.73 The diseases reported were:

Table 10.3: Cases of AIDS-related diseases, October 1985

Syndrome Haemophilia A Haemophilia B
Total Deaths Total Deaths
AIDS: Pneumocystis carinii pneumonia 7 6
AIDS: opportunistic infections 3 2 1 1
'AIDS Related Complex'
(the patient who died committed suicide)

15

1
Other syndromes 3 1
Thrombocytopenia 20 1
Persistent Generalised Lymphadenopathy 12 1
Glandular fever-like syndrome 7

10.74 Seventy-five family contacts were also tested and four partners were found to be anti-HTLV-III positive.[98]

10.75 On 28 November 1985, an internal DHSS memorandum was sent to the Chief Medical Officer for England and Wales.[99] It commented on some hearsay evidence that haemophilia patients were seroconverting to become anti-HTLV-III positive despite being given heat-treated Factor VIII. This became an issue for discussion in 1986. If true, it would have indicated that the epidemic was less likely to be contained by the existing production technology employed in the manufacture of blood products for therapeutic use.

1986

Further information on prevalence

10.76 Additional information on prevalence was gathered. On 7 February 1986 there was a meeting to discuss the virological aspects of the safety of blood products at the National Institute of Biological Standards and Control (NIBSC).[100] At the meeting, Professor Forbes raised the issue of seroconversion after treatment with heat-treated concentrates, with particular reference to three specific patients.[101] The question was to attract attention for some time and cast some doubt on the effectiveness of the PFC's heat-treatment of Factor VIII concentrate. It was dealt with in official correspondence in February and March.[102] So far as concerns the spread of the epidemic, it was eventually shown to be a false trail. A general consensus was reached that the seroconversions of the three patients were related to previous treatment with untreated material of either commercial or NHS origin.

10.77 The survey data now covered 2609 UK patients from 81 haemophilia centres. Of Haemophilia A patients, 46% were positive for HTLV-III antibody. For Haemophilia B patients and von Willebrand's disease patients the figures were 6% and 5% respectively.

10.78 The source of infection in patients with coagulation defects continued to be debated. In discussion at the meeting on 7 February, Professor Tedder reported that, tests of stored samples dating from 1978 to 1984 showed that seropositivity rose rapidly from 33% in 1980 to 64% in 1982 in the case of patients who had received commercial concentrates. In the case of patients who had received NHS concentrates, samples were seronegative until 1982. Between 1983 and 1984 seropositivity rose from 1% to 11%. These rates were considerably higher than those indicated by the data on AIDS cases reported on CDC criteria down to 1984 which were discussed in Chapter 9, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 1. The Director of the NIBSC, Geoffrey Schild, asked if anyone knew the reasons for the low incidence of clinical AIDS (around 1%) in seropositive haemophilia patients. Dr Craske and Professor Forbes said that the true incidence of AIDS was probably much higher, due to a tendency to suppress reporting.[103] It has to be remembered, however, that until Professor Tedder's tests were applied data were collected only on cases meeting the CDC definition of AIDS. Under-reporting of AIDS may have been a factor but, with the benefit of hindsight, long periods of asymptomatic infection with HIV must also have contributed to the difference as the CDC criteria required the presence of intractable AIDS-associated disease for a case to be 'confirmed' as one of AIDS. The natural history of the disease was still not understood.

10.79 At a meeting of the SNBTS Directors on 25 March 1986, it was reported that the transfusion service was concentrating on following up patients who had received donations known to have been contaminated by HTLV-III.[104] Professor Tedder intended to study the epidemiology of infected donors and all recipients of implicated blood and blood products, retrospectively for five years. It is not clear that these studies progressed or produced meaningful results but they reflected growing appreciation of the need for better understanding of the natural history of the disease.

10.80 At successive conferences, new data on HIV prevalence were reported with reference to different cohorts and with inconsistent and irreconcilable results.

10.81 At a conference on AIDS held in Newcastle between 11 and 13 February 1986 and sponsored by the Haemophilia Society, Professor Tedder commented that the small number of seroconversions following the use of heat-treated Factor VIII concentrates was due to 'a long delay in the latent phase'. On this view, transmission of infection as a result of treatment had occurred but diagnoses had been made only after the change of treatment regime to include heat-treated products. The natural history of HIV infection was becoming more clearly understood and AIDS was said to present a significant problem for the future.[105] There were estimated to be about 20,000 positive individuals in the UK, spread among four groups. Dr Foster's report summarised the information available[106] as follows:

Table 10.4: UK Situation by February 1986

Group Total Number % Antibody Positive Trend
Haemophiliacs 4000 25% Down
Blood recipients 1,000,000 0.006% Down
IV drug users 20,000 5% Up
Gay people 500,000 3% Up

10.82 The percentage of antibody positive haemophilia patients was significantly lower than that reported by Dr Rizza and Miss Spooner above.

10.83 Dr Peter Jones, Director of the Newcastle Haemophilia Centre, also spoke specifically about the incidence in patients with haemophilia: he estimated, extrapolating from the limited data available, that 1200 UK haemophilia patients would already have seroconverted. In relation to treatment, he said that of those who had been treated with cryoprecipitate only, 1% tested positive for the virus; of those treated with NHS concentrate only, 10% were positive; and of those treated with commercial concentrate only, 45% had tested positive. His basic data were not consistent with the data collected by Dr Rizza and Miss Spooner but referred to a cohort of similar size and with less variance than the data reported by Dr Foster.[107]

10.84 At the 19th Congress of the International Society of Blood Transfusion in Sydney between 11 and 16 May 1986, the association of AIDS with the use of blood products was discussed.[108] Participants reported their experiences. There were differences both internationally and within and among regions.

10.85 Professor Arthur Bloom reported that 43 out of 153 haemophilia patients in Cardiff (28%) had seroconverted, compared with the rate for the UK as a whole, which he said was 44%. He said that the incidence of transfusion-associated AIDS in Australia was 10 times greater than in the UK. He also commented on the timescale of seroconversions of Haemophilia A and B patients. The time from exposure to seroconversion ranged from six days to one year and the mean timescale for developing 'full blown' AIDS was three years. He suggested that haemophilia patients might be 'lagging behind' other high-risk groups in developing AIDS.[109]

10.86 Dr Jones reported experience among people with haemophilia in Newcastle. There were eight confirmed cases of clinical AIDS and four awaiting confirmation, an incidence of eight to ten per cent.[110] In the report, written by Dr Foster, Dr Jones is said to have claimed that the degree and type of treatment in Newcastle was no different to many other centres and he was unable to postulate any reason why haemophilia patients in Newcastle should have been affected so differently. Other reports on infection among haemophilia patients, from the USA, Australia and France, gave comparative data. Dr Bruce Evatt, CDC, reported on the incidence of seropositivity in the USA. As already noted[111] prevalence values were 74% in people with Haemophilia A and 35% in people with Haemophilia B, with 15% of 'haemophilia wives' also seropositive and with the seroconversion rate still increasing. A 12-month French study reported by Professor Jean-Pierre Allain showed 58% seroconversion in the patients included. Dr Roger Garsia from Australia found 45% seroconversions among the 161 patients studied. The Congress also discussed the incidence of seroconversion in non-haemophilia patients following treatment with blood products.[112]

10.87 This was a wide-ranging conference in which doctors from around the world shared their experiences of the epidemic. It exposed the prevalence of AIDS and HIV antibody positivity over a number of countries. The advantage of heat treatment of products was a major topic. According to Dr Garsia, there had been no cases of seroconversion in Australia since the introduction of heat-treated products. Others, however, spoke of experiences of seroconversion following use of heated products. The Congress appears to have been exploratory in nature, with each participant contributing to the general understanding of the wider AIDS epidemic.

The European context

10.88 Between 28 and 31 May 1986, the Committee of Experts on Blood Transfusion and Immunohaematology met at Berne.[113] Much of the background material in the report was repeated in the Advisory Committee on Dangerous Pathogens (ACDP) guidelines issued in June and is dealt with in that context below.[114] The factual material set out the wider European understanding of the position at the time. It was observed that, prior to the screening of donated blood, many haemophilia patients had become infected, as had a few recipients of transfusions. It was said that these routes of infection had now been closed by a combination of measures - publicity to deter those in high-risk groups from donating blood, heat-treating blood products to inactivate any virus they might contain and testing all blood donations for antibody and discarding any that were found to be positive.

10.89 The report tabulated data on: AIDS cases and deaths up to various dates in 1985 and 1986; screening of blood donations; information to and counselling of donors and follow-up of patients receiving blood from antibody-positive donors; cases of positive tests for the virus and of AIDS in patients with haemophilia; and treatment of haemophilia.[115] The information provided on UK non-haemophilia patients up to March 1986 was that there had been 342 cases of people infected with AIDS, of whom 172 had died. The data relating to Haemophilia A and B patients were derived from the Oxford study discussed above with some updating. The total population remained the same: 4918 people with Haemophilia A and 896 people with Haemophilia B. The position for UK haemophilia patients was set out as:[116]

Table 10.5: Data on AIDS cases and deaths by 1986

Number of patients Number treated Anti-HLTV tested Positive % Number with AIDS/ARC[117]
Haem A 4918 2277 2025 896 44 18/20
Haem B 896 391 324 20 6 3/0

10.90 The percentages of patients testing positive had not changed and the numbers with AIDS or ARC remained broadly the same.

10.91 By way of comparison, it was reported that:

The positive rate for anti-HTLV 3/LAV in patients suffering from Haemophilia A varied considerably from 4% in Belgium and 8% in Norway to over 90% in Malta and the USA. The usual level of positivity was between 35 and 60%. The low rate of positivity in Belgium and Norway could probably be attributed to the almost exclusive use of cryoprecipitates prepared from local donors.[118]

10.92 It was further reported that, with a few exceptions, the positive anti-HTLV-III/LAV rate for patients with Haemophilia A was greater than that for Haemophilia B and that the incidence of AIDS and AIDS-related complex was also higher in Haemophilia A in most instances. Dr Albert Farrugia (Malta) suggested that the 95% incidence of anti-HTLV-III/LAV antibodies in Haemophilia A patients in Malta had almost certainly arisen because these patients had been exclusively treated with imported Factor VIII concentrate, whilst patients with Haemophilia B had been treated with Factor IX concentrate obtained from European voluntary donors.[119]

10.93 In June 1986, the ACDP issued 'Revised Guidelines' on LAV/HTLV-III.[120] It was reported that the number of cases of AIDS (in Europe) continued to double every 6 to 12 months. Detailed figures were provided for reported cases and estimated rates per million of population in 21 European countries including the UK.[121]

10.94 Rates of infection in those European countries supplying figures ranged from 1.0 per million of population (Greece) to 11.9 (Belgium).[122] The figure for the UK was 4.0 per million. Globally, it was stated:

In certain parts of Africa where LAV/HTLV III has probably been present longer than in the USA, small surveys have detected evidence of infection in as much as a fifth of the sexually active population and in some parts of the USA it now seems that a majority of male homosexuals are infected. It is not assumed that this will necessarily happen in the UK but it has to be recorded that such levels of infection have been observed elsewhere.[123]

10.95 The general hazard and risk statement commented:

[T]here are very serious consequences for a proportion of those infected, although not all will necessarily develop AIDS, which to date has invariably been a fatal disease. For this reason the intrinsic hazard of infection should not be under-estimated.[124]

10.96 By this stage, the likelihood of patients having developed antibodies to HIV from blood products produced prior to the introduction of heat-treatment was understood to be high, in severely affected Haemophilia A patients in particular. It was also appreciated that AIDS was a fatal illness, although the risk of progression to AIDS was still underestimated. The natural history of untreated HIV infection was still not well understood.

United Kingdom data updated

10.97 On 10 September 1986, Dr Craske issued an update on a retrospective study of HIV-related illness.[125] The data were incomplete: a second HIV antibody survey was in hand. By the date of the report, returns to the Oxford Centre in 1985 had identified eight batches of NHS Factor VIII and two of Factor IX that had been associated with either an anti-HIV positive donor or a donor who later developed HIV-related illness. Evidence of transmission had been identified in five of the Factor VIII batches, two were possibly associated with transmission, and there was no information on the remaining batch. There was evidence of transmission in one batch of Factor IX and information was awaited on the other batch. Quantification aside, the association between NHS factor products and the transmission of infection was clear.

10.98 The report narrated:

The total number of patients reported to Oxford with HIV related illness by 22.4.86 was 109. This was 12.9% of the total antibody positive patients identified in the Survey in August 1985 (896) .... The number of AIDS cases reported of which 15 have died is 23. Eighteen cases are known to the Communicable Disease Surveillance Centre .... Two of these had not been notified to Oxford so that the total may come to 25.[126]

10.99 The comparative number of patients with AIDS or AIDS-related conditions in the August 1985 survey had been 38. In September 1986, 109 cases were listed under three categories: (i) 'AIDS', comprising PCP (15), opportunistic infection (8) and AIDS related complex (20); (ii) 'unclassified' comprising abdominal lymphoma (1) and (iii) 'other syndromes,' comprising thrombocytopenia (28), purpura (5), PGL (30) acute glandular fever (10) and encephalopathy (2).[127]

10.100 The paper stated that a significant number of HIV-infected persons would continue to develop AIDS-related illness over a period of years, despite the efficacy of heat-treated Factor VIII and Factor IX in preventing further patients being infected.[128] The small proportion of Haemophilia B patients so far infected with HIV was said to be partly accounted for by a lower contamination rate of Factor IX concentrate as compared with Factor VIII. This was said to be confirmed by independent observations of the Edinburgh Cohort.[129]

10.101 Dr Craske advised that further study was necessary. He proposed that the next step in research should be to identify patients who were HIV-positive post-exposure and to increase the cohort for study to at least 30 or 40 patients. These patients would be followed up every six months in their usual review clinic. He emphasised that only limited additional investigations would be necessary. Dr Craske was still encountering obstacles. He wrote:

For the past 6 months there has been a lot of natural concern regarding the confidentiality of data reported to the National Survey at Oxford. Arising from this there was a noticeable drop in the rate of case reporting early this year. This had increased again in recent months, but I think it is still important to emphasise that reporting is necessary to enable us to obtain information on the size of the problem; to establish the efficiency of preventative measures e.g. safety of heat treated factor VIII, and to identify new patterns of the disease associated in the HIV infection. [130]

10.102 On 3 October 1986, Dr Rizza and Miss Spooner of the Oxford Haemophilia Centre distributed a further report on the incidence of anti-HIV in people with haemophilia in the UK.[131] In this survey, 84 out of a total of 109 haemophilia centres made returns. Confidentiality remained an issue. Thirteen centres which contributed data in 1985 failed to do so in 1986 and 14 centres which had not made returns in 1985 did return data in 1986. The report noted that this had to be borne in mind in comparing data. 40.48% of 2228 Haemophilia A patients, 6.74% of 386 Haemophilia B patients and 2.75% of 327 von Willebrand's disease patients were anti-HIV positive. Individuals present in both the 1985 and 1986 returns were 1707 Haemophilia A, 283 Haemophilia B and 161 von Willebrand's disease patients. The analysis of results by age group and severity of blood disorder showed a broadly similar pattern to the 1985 survey.

10.103 However, this was not intended to be a sample survey; rather, it was an attempt at a total survey of the whole haemophilia population. Piecemeal returns, with significant gaps, necessarily undermined the reliability of the exercise and the resulting information distributed to UKHCDO members cannot be treated as presenting a complete and valid picture of the prevalence of infection.

10.104 In Scotland, data on registered blood donors were shared by all regions. At a meeting of SNBTS Directors on 9 October 1986 the current status of HIV antibody-positive donations reported since screening was started was: Inverness one; Aberdeen none; Dundee three; Edinburgh eight; Glasgow two; Belfast two.[132] The next meeting of the SNBTS Directors was on 17 December. The current status of HIV antibody-positive donations reported at that meeting was: Inverness, one; Aberdeen, none; Dundee, three; Edinburgh, nine; Glasgow, six; and Belfast, two. [133]

1987

10.105 The minutes of the meeting of SNBTS Directors held on 3 March 1987 noted that one further donor in Edinburgh had been found to be positive.[134]

10.106 On 22 June 1987, the Scottish Office issued a press release.[135] The latest AIDS figures for Scotland up to the end of May 1987 reported a total of 20 AIDS cases, with 12 deaths; this included two haemophilia patients who had both died. The figure also included one recipient of whole blood and one recipient of a blood product,[136] both of whom had died. (The equivalent figures for the UK were 791 reported AIDS cases with 444 deaths; these included 31 haemophilia patients of whom 25 had died; one haemophilia patient, who was also an intravenous drug user, who had died; and six recipients of blood by transfusion in the UK, all of whom had died.)

10.107 When the UK Haemophilia Centre Directors met in London on 25 September 1987, AIDS had become the leading cause of death in UK haemophilia patients.[137] A third national survey of anti-HIV among haemophilia patients was under way. Three new patients had been reported as being seropositive in 1987. Amongst 314 sexual partners of anti-HIV seropositive haemophilia patients who had been treated, 18 (5.7%) had been found to be positive. Dr Craske commented that this compared with rates of up to 15% in the USA.

10.108 In October 1987, a table in the journal International Plasma News showed the percentages of HIV seroconversion among haemophilia patients in eight European geographical areas and in Canada. Scotland had the lowest percentage, at 15%; the 'UK' figure (presumably England and Wales) was 46%; Canada and Spain were 69%. For Sweden, Italy, France, West Germany and Denmark, the values ranged from 31% to 60% and averaged 50%.[138]

10.109 At the end of the year there was renewed discussion on the association between the use of heat-treated Factor VIII concentrate and HIV seroconversions in 'naïve' (otherwise 'virgin' or 'previously untreated') haemophilia patients. On 21 December 1987, following a telephone conversation with Dr Dale Lawrence of the CDC, Professor Bloom circulated information to haemophilia directors about experience in Canada.[139] There had been six initial seroconversions in the period from spring to summer 1987. The products used included dry-heated material developed by Cutter (heated at 68°C for 72 hours) and Armour (heated at 60°C for 30 hours) and possibly others. Canadian research implicated the manufacture of the Armour product and Travenol and production and distribution had been stopped.[140] Armour Factor VIII had been implicated in transmission in the USA and West Germany. The company had withdrawn its product in the USA. Professor Bloom noted that the CDC was convening an emergency meeting of manufacturers and haemophilia doctors in Atlanta on 11 January 1988. He commented that BPL's product (dry heated at 80ÂșC for 72 hours) was 'in the air', and was to be discussed, with all of the information, in the February meetings of the UKHCDO.[141] Product specification, and particularly heat-treating protocols, was entering into the discussion of factors influencing the development of the epidemic.

1988 and beyond

10.110 In and after 1988, intelligence on the prevalence of HIV in the UK and the risks of progression to AIDS continued to be published and Parliament was updated on the developing position. For example, in a Parliamentary answer on 21 December 1989, it was stated that there had been 76 HIV-positive haemophilia patients and 12 non-haemophiliac HIV-positive recipients of blood or blood products in Scotland.[142] By the end of February 1990, the total number of haemophilia patients with AIDS in the UK who had died was 118.[143] In 1990 there was a report on patients with haemophilia in Edinburgh who had acquired HIV from commercial concentrates.[144] There was highly technical Scottish research into factors possibly indicating that an individual was at increased risk of swiftly progressing to full-blown AIDS.[145] The Edinburgh Cohort provided a particular focus for research and comment.

The Edinburgh Cohort: developing knowledge

10.111 At the time of the recall of batch 023110090, no chemical or biological test was carried out to ascertain whether it was infective. Dr Perry doubted whether there was a test available that could have been used. He said that those assays 'simply didn't exist'[146] and that the test used by Professor Tedder was not validated for patient samples, let alone as part of a pharmaceutical evaluation process.[147] The first testing on batch 023110090 by SNBTS was performed in 1985 using a commercial assay. This was a first-generation antibody test and the result was negative. This early version of the test was, however, unable to pick up low levels of antibodies in samples tested.[148]

10.112 Between 1985 and 1986 further tests were carried out in a number of laboratories including the NIBSC. The tests then available would have been Enzyme-Linked Immunosorbent Assay (ELISA) tests,[149] all of which were looking for antibodies. None of the tests carried out gave any chemical or biochemical indicator that the batch contained an infectious virus or that it contained antibodies to a virus.[150] No test that was carried out indicated the presence of antibody to the virus until very much later.

10.113 Dr Perry explained that after HIV screening was introduced in October 1985, all donors found positive were studied and their previous donations were traced and library samples, where available, of their donations were tested. These investigations established that none of those donations had been used to make up batch 023110090.[151]

Publications

10.114 An article in the British Medical Journal (BMJ) of 27 February 1988 set out results obtained from testing serum from the Cohort.[152] The narrative recorded that there were 18 patients affected and that 'infection was acquired from a single batch of Factor VIII during a short period starting in March 1984'. It was also suggested that:

[T]he low prevalence of HIV 1 infection in Scotland in 1983, when blood for the batch was collected, makes it probable that the batch was contaminated by a single donation.[153]

10.115 It was reported that 32 patients had been transfused. Eighteen of those patients had undergone seroconversion.[154] Eight patients had developed symptoms before March 1987 ('the unwell group') and the other 10 remained asymptomatic in mid-1987. The symptoms included PGL, AIDS Related Complex (ARC) and AIDS. The authors tentatively suggested that there was a relationship between the amount of Factor VIII transfused and time to seroconversion. It was said that much of the variability in the course of infection was clearly the result of differences in susceptibility of the patients to infection.[155]

10.116 The progression of disease in the Edinburgh Cohort received further attention in a paper written in 1988 by Professor Ludlam and colleagues.[156] The study period ran from early 1987 to mid-1988. By the end of that period two patients had died and only seven patients remained wholly asymptomatic. It was concluded that the amount of Factor VIII transfused did not influence clinical progression or the ability of doctors to isolate HIV from a patient's serum. It was also pointed out that:

Compared with other cohorts, the rate of morbidity and mortality in this cohort is relatively high with half the HIV seropositive patients having developed serious clinical complications within 4 years .... Thus in clinical terms, the implicated viral strain appears to be particularly virulent. [157]

10.117 In an article published in The Lancet in 1988 by Dr C Michael Steel and others (including Professor Ludlam), the factual understanding of the source of infection at that time was set out:

It was ... established that a single batch of locally produced factor VIII had been contaminated with [HIV].... That batch was used by 32 previously seronegative patients between March and May, 1984.[158]

10.118 By this stage, sophisticated methods of analysis of the evolutionary relationships among groups of organisms, such as HIV, had been developed. Typically presented as 'phylogenetic trees', the findings on analysis enabled the definition of genetic relationships among samples from several sources. In 1988, Professor Peter Simmonds and associates reported on phylogenetic analyses of two regions of the env gene, a component of the 'viral envelope' of HIV, in the Edinburgh Cohort. Sequences from most of the patients studied were grouped together on phylogenetic trees with common origins.[159]

10.119 The study dealt with nine patients, eight of whom were members of the Cohort. Six were grouped closely on analysis and it was inferred that they were infected with HIV sequences from a single donor. It was suggested that three of the nine, including two members of the Cohort, may have been infected independently of the others at about the same time. The conclusion that one common batch of concentrate was implicated in the infection of the Cohort, reached previously on analysis of the transfusion records, was weakened. At that stage, however, 10 members of the Cohort had not been included in the study.

10.120 A further study reflecting results obtained from examination of the Edinburgh Cohort was published in the BMJ in 1990.[160] The study did not identify any immunological variable or clinical characteristic which distinguished the patients who seroconverted from those who did not. It reported that, within the Edinburgh Cohort, the cumulative incidence of serious HIV-related disease was 55.5% at five years. A third member of the Cohort, a patient born in 1948, had died (in 1989).

10.121 The understanding of the Cohort changed further with the publication in 1995 by Edward Holmes and others of further virological findings.[161] The study was aimed at clarifying the number and origins of the batches of Factor VIII involved in the HIV infection of the Edinburgh haemophilia patient population. It would be inappropriate in this report to enter into a detailed technical discussion of the studies carried out but some of the conclusions are material. With two exceptions, the patients studied were formed part of a single phylogenetic tree and fell into a single group. The patients were identified only by number. Patients 74 and 82 were the two patients distinguished in the 1988 study as possibly having been infected independently. In this 1995 study, patient 74 could not be separated from the main group with any confidence but there was good evidence that patient 82 was not a member of the main Cohort because his data suggested a close relationship with a patient, patient 80, who had never been exposed to batch 023110090 of the PFC's NY Factor VIII product and now appeared to have been infected by a different batch which patient 82 had also received. The similar viruses found in patients 82 and 80 must have been derived from a Factor VIII batch that they were known to have shared. Taking the results of their several studies together, the authors commented:

The most striking finding was that there are several distinct HIV variants circulating in Edinburgh. The haemophiliac patients appear to be divided into a number of distinct groups whose members were infected by at least two batches of contaminated factor VIII. This is particularly surprising since most of these patients seroconverted at about the same time (spring 1984) and were originally thought to have been infected after exposure to a single common batch.[162]

10.122 After discussing the specific findings relating to patient 74, the paper stated:

Thus, there appear to have been 2 or 3 HIV-infected donors contributing to the local plasma pool at the time these batches were prepared (1983). This shows that there was substantial viral diversity during the early stages of the HIV epidemic in Scotland...[163]

10.123 The same study discussed infected heterosexual and IVDU patients whose data had been analysed, and concluded:

The fact that the heterosexual and IVDU groups are some distance from the haemophiliac groups on all the phylogenetic trees shows that the HIV infections in these populations were independent and refutes suggestions the haemophiliacs could have been infected from the IVDU community.[164]

10.124 Two potential sources of infection had been excluded. Further inferences were avoided. It appears from this work that the original conclusion, that there was a single donor source of infection transmitted to haemophilia patients by Factor VIII concentrates, was wrong.

SNBTS investigations

10.125 On 25 January 1991, Dr Cuthbertson, then Quality Assurance Manager at the PFC, wrote to Professor Cash enclosing a final report, 'HIV Seroconversions related to SNBTS FVIII'.[165] This was an update of an earlier, interim report of 28 June 1986.[166] It reflected the information available to the PFC. The infection of 16 patients in Edinburgh was referred to, as was the infection of two patients in the West of Scotland, one of whom had seroconverted between 5 October 1984 and 25 October 1985. It was not possible to draw definitive conclusions as to the batches by which all these patients had been infected; batch 023110090 remained the main candidate for 15 of the 18 seroconversions but the other candidate batch(es) had not been identified.

10.126 The report contained the following detail:

16 Haemophiliacs in the South-East of Scotland were found to have seroconverted to HIV at some stage during 1984. Fifteen of the 16 haemophiliacs received a common batch (023110090) and it has been concluded that this batch was infective.

Follow-up of West of Scotland haemophiliacs has revealed two patients receiving SNBTS FVIII who seroconverted in 1984 and 1985 respectively.

PATIENT 1
Incomplete details available as no written report ever received from reporting clinician (Dr Maddock [sic - Madhok], GRI).
Sample 1.7.82 Negative
Sample 12.12.83 Positive.

PATIENT 2
Seroconverted between 5.10.84 and 25.10.85. At least five years since previous Commercial FVIII

The batches of product received by the ... seroconverters are summarised in Table 1. The following should be noted:

a. Neither of the West of Scotland patients received the batch (023110090) implicated in the South-East Scotland seroconversions.

b. No batch is common to the two West of Scotland seroconversions.

c. If SNBTS FVIII was responsible for each of the 18 seroconversions, then at least three infective batches must have been issued.[167]

10.127 It is possible that there were four, not three, sources of infection. One of the South-East Scotland patients did not receive batch 023110090: there had to have been at least two sources of infection in that area. Two patients were infected in the West of Scotland but neither had received batch 023110090 and they did not receive batches in common with others. A manuscript note on a copy of Dr Cuthbertson's report recovered by the Inquiry questioned whether cryoprecipitate was a source. Cryoprecipitate was a potential alternative cause of limited spread infection in the West of Scotland where it was a popular therapeutic material. The probability of a single infection from a pooled product must be relatively low and must get lower as one multiplies examples. It is not possible for the Inquiry to identify definitively the source of infection in all cases. The discussion in the quoted report is in many respects inconclusive. It was noted at the end of Dr Cuthbertson's report that polymerase chain-reaction (PCR) studies were being carried out which might define more precisely the implicated batches but that the position remained uncertain, apart from in the Edinburgh Cohort.

10.128 The final position on numerical data on the incidence of HIV infection and AIDS in those affected by blood, blood components and blood products, so far as uncovered by the Inquiry, is set out in Chapter 3, Statistics. For present purposes, it is sufficient to note that the final numbers consistently exceed the earlier estimates.

10.129 At the date of the Inquiry's hearings, it appears that 15 of the 18 members of the Edinburgh Cohort had died.

The Edinburgh Cohort: 2008 testing

The history of batch 023110090

10.130 The history of batch 023110090 was investigated in great detail by the Inquiry. Although perhaps somewhat tangential to the progress of the AIDS epidemic in the period under discussion, it illustrates many of the difficulties confronting scientists at the time in conducting research into the association of AIDS with blood product therapy. In addition there is some advantage in setting out the Inquiry's findings in the context of the foregoing discussion of the impact of the infected product on patients.

10.131 Further investigations into the history of the infection of the Edinburgh Cohort took place in 2008. The preparation of batch 023110090 was studied in some detail and Dr Perry explained that the batch had a conventional history. Collection took place between June and October 1983, with plasma collected from each of the RTCs in Scotland. A total of 940 kilograms of plasma was collected from about 4000 donations. The plasma weight delivered to the PFC would have been recorded by each RTC.[168]

10.132 At the PFC the plasma was first divided into intermediates or 'fractions', which were then stored frozen. When required they were taken out of inventory and entered into a specific batch manufacturing process, at which point a batch number was allocated. A record was kept to allow a trace back from the batch number of a product to the fraction.[169]

10.133 Dr Perry explained that there were two forms of plasma record.[170] Boxes of 12 donations were bound together in groups of four for storage purposes and each group of four boxes was given a new identifier called a 'cold storage number'. The cold storage numbers for each group of four boxes were recorded in the batch record; these records were kept down to the box number. Each box had bar-coded labels. There was a clear link between the boxes and the donations from the RTC. Although the PFC could not itself identify individual donations, the RTCs had records which identified which plasma donations had gone into an individual box. From the record, 95 cold storage units were used to manufacture batch 023110090.[171]

10.134 The batch record shows that the manufacturing process started on 7 November 1983 and produced 1070 vials of Factor VIII.[172] The batch record shows the number of vials placed at issue and entered into stock.[173] The product was cleared for issue on 10 February 1984 and the product clearance sheet showed when the batch was released for issue.[174] It was recorded that 1020 vials were sent to the South East of Scotland RTC and that fifty vials were supplied to the North East RTC in Aberdeen where they were held for the treatment of patients with haemophilia. A batch history sheet recorded the final quality release of the batch.[175] This document was used for stock control by PFC.[176]

Tracing the donations to batch 023110090

10.135 As the recording system was designed, the batch record allowed the SNBTS to trace the donations which had made up any particular batch. The cold storage numbers gave key references for the individual plasma boxes. The box number identified the RTC which supplied the box and the RTCs had records from which to identify the individual donations. From the individual donations it was then possible to identify the specific donors.[177]

10.136 It was a deliberate policy to disable the PFC from identifying specific donors from its own records. This maintained a separation between the 'greater clinical environment' at the RTCs and the PFC, which was a pharmaceutical manufacturing plant.[178] Following a meeting on 6 November 1984, it was decided that repeat donations from the donors contributing to the implicated batch should be followed up.[179] That was done but none of the subsequent donations were found to be HIV-positive. Dr Perry did not know how many repeat or returning donors there were.[180]

10.137 Subsequently, consideration was given to trying to test the donors of all 4000 donations.[181] Donation samples were available from about 50% of these donors. Having taken advice from Professor Tedder that 99.5% of the donors would be required for the exercise to be meaningful, this was not followed through and the proposal was not pursued.[182] Dr Perry referred to correspondence with Dr Tedder.[183] It was considered impossible to find the source of the donation in this way. Dr Perry accepted that as return donors came back the pool of potentially infective donors began to shrink. A chronology prepared by the SNBTS also set out the documents relevant to each event.[184]

2008 testing

10.138 Dr Perry explained that, by 2008, he personally was satisfied that batch 023110090 was the batch responsible for infecting most of Professor Ludlam's patients. He explained that after the present Inquiry was announced, the SNBTS anticipated that the question of the implicated batch would be investigated and they decided to look at the matter again. It turned out that the majority of the remaining vials of Factor VIII belonging to batch 090 had been destroyed in 1988. However a single vial was discovered in the laboratory of Professor Simmonds and it was sent for testing. The vial had been stored in uncontrolled conditions and there was concern that the contents would have deteriorated and that any virus would have degraded so that it was not detectable.[185]

10.139 The samples were sent to the NIBSC on the authority of Professor Ian Franklin who was the National and Medical and Scientific Director of the SNBTS in 2008. The testing was done at the the NIBSC to extremely high standards. The vial was first tested by nucleic acid amplification (NAT) technology for the Hepatitis C virus (HCV), a PCR test for the presence of virus. Tests for HCV would provide a positive control if the assay was working. The SNBTS knew that products in 1983-84 and 1985 were likely to contain HCV, so if the test had come back negative for HCV this would have cast doubt over a negative result for the HIV test: it would have raised the inference that the product in the vial had degraded so much over the years that any virus originally in the vial had disappeared.

10.140 In the event, the sample was positive for HCV RNA. The sample was negative, however, in a duplicate test for HIV-1 RNA by NAT, a standard commercial assay. The conclusion was that no HIV RNA could be found in the vial using that test.

10.141 Further 'in-house' tests were then done, with the result that there was evidence for the detection of HIV-1 RNA sequences at very low levels.[186] The in-house tests were very specialist, essentially research assays developed by expert virologists at the NIBSC. Dr Perry explained that the results suggested that the sample might contain a fragment of HIV RNA but that one could not be absolutely sure. The results were inconclusive because the research assay had not been subjected to the rigorous analysis needed for a routine test. However, it provided an indicative result of a fragment of RNA of HIV.[187]

10.142 The NIBSC also carried out a combination test for antigen and antibody. This result was quite clear: the sample was reactive; HIV had been detected in the sample. As it was a 'combination test', it was not clear whether the sample was reactive for the antigen or the antibody and the precise meaning of the result was that there was either HIV antibody or HIV antigen in the sample.[188]

10.143 Other tests using ELISAs came back negative and the Western Blot test was indeterminate. Dr Perry explained that these tests in 2008 were the first chemical and biological evidence that were in line with the epidemiological evidence from the patients in 1985.[189]

10.144 The level of technological sophistication that has now enabled scientists to form these views about the infectivity of batch 023110090 had not been achieved at any time during the course of the AIDS epidemic among recipients of blood, blood components or blood products. The risk that the product presented to haemophilia patients could not have been identified at the time it was administered or investigated by chemical or biological assays after the infections were first diagnosed.

Discussion

10.145 This chapter has sought to trace evidence of the growing awareness among relevant practitioners, and in particular haemophilia clinicians, of the incidence and characteristics of HIV infection and AIDS-related diseases during the critical period up to and covering the introduction of effective technology for the treatment of factor concentrates, looking at the position in the world in general but with specific reference to the UK.

The Edinburgh Cohort

10.146 Particular attention has been paid to the Edinburgh Cohort. The discovery of HTLV-III infection in that group was not an isolated event: it happened in the context of the testing of samples from Haemophilia Centres throughout the UK using the Tedder/Weiss assay. However, the infection of the Cohort was distinguished by its scale; its concentrated impact on one regional centre; the fact that infection in the Scottish domestic product was unexpected; and in the extent and intensity of the investigation that followed. The immediate confusion following the discovery has been described. The last point is most instructive of contemporaneous understanding of the implications for manufacturers, transfusionists and haemophilia clinicians alike.

10.147 The timescale for withdrawal of batch 023110090 was short. From the records, Professor Ludlam ascertained on 29 or 30 October 1984 that the three original recipients of SNBTS concentrate had received material from that batch. The additional information from Professor Tedder was received on 2 November. Dr McClelland and Dr Boulton arranged for the withdrawal of the batch on 3 November. That was clearly the correct course of action.

10.148 At the end of 1984, when the scale of infection in the Cohort was established, none of those involved in the SNBTS and in the haemophilia clinical service had the technological means to identify infective donations, or to assess the infectivity of blood products, or to find explanations for the course of events that unfolded. That continued to be the position.

10.149 Dr Perry's view that it was a 'justifiable, though unproven assumption' that batch 023110090 was implicated was valid on the information available. It left open two alternatives, however: it remained possible, on the one hand, that the batch would prove not to be infective and it remained possible, on the other, that other batches were infective.

10.150 The second of these possibilities raises the more significant questions. Unless investigations were to establish that all of the patients who were infected had received batch 023110090 and that none of those found to be infected had received SNBTS material from any other batch, it would have been logically indefensible to conclude that only the single batch was infected. By May 1985 it was known that one of Professor Ludlam's infected patients had not received material from batch 023110090. Source donations could not be identified and it was not possible by that route to limit the potential range of infected batches. Further, cases of infection were being identified at the same time in other parts of Scotland, and in particular in the Glasgow and West of Scotland Region.

10.151 Technology was not sufficiently developed at the time of the recall of batch 023110090 to test it for infectivity. Initial testing in 1985 and 1986 found no chemical or biochemical indicator that the batch contained an infectious virus or that it contained antibodies to a virus. The SNBTS staff were not surprised by the negative test in 1985 because they knew that the tests were relatively insensitive and also thought that, if the infection derived from one donation, it would have been diluted by 4000 other donations. In addition, they did not know at the time how the HIV antibody partitioned during the fractionation process.[190]

10.152 The testing of serum from patients reported in the BMJ in February 1988 led to the conclusion that 18 patients had acquired infection from a single batch and that the batch was probably contaminated by a single donation. At that stage there was some technological support for the inferences being drawn. Further scientific support was provided by Professor Simmonds and his associates in 1988. Whatever objections on strictly logical grounds might be taken to the initial inference that there was a common source of infection, there was now apparent scientific proof of the inference drawn from the information available at that time.

10.153 It was to be 1995, however, before scientific evidence was published that there were two infective batches and contributions to the local plasma pool at the time by two or three HIV-infected donors. It was 2008 before something approaching scientific proof was available of at least anti-HIV in the sole remaining sample of batch 023110090. Dr Perry explained that, in his view, putting the 2008 test results together with the epidemiological evidence, batch 023110090 was 'probably infectious'. It would always fall short of absolute proof but he thought that there was a very strong probability that batch 023110090 was the correct batch to have identified as being responsible for the transmissions. As for the putative second infective batch, the possibility that this existed was only raised in 1995. By that point it was not possible to take the matter forward, the materials (including samples of any implicated batches) having long since been used or discarded.

10.154 Details of HIV infection in the Edinburgh Cohort were widely reported. On the other hand, infections in some other affected groups were not. Dr Cuthbertson's final report of 25 January 1991 dealt with two infected West of Scotland patients only. As shown in Chapter 3, Statistics, the actual final picture would be seen to be quite different.

Wider surveillance

10.155 Throughout the UK, there were deficiencies in the reporting of instances of infection. The picture that emerges from the account of Dr Craske's surveys reflects inconsistent and incomplete disclosure of relevant information by significant numbers of Haemophilia Centres and frustrating attempts to analyse the problems related to patients and their illnesses which led to the publication of partial information when, within the relatively small group of Centres involved, comprehensive sources of information were available. The wish to protect patients' confidential personal data is understandable, as is the belief that any level of disclosure would threaten confidentiality and with it the patient-doctor relationship. The stigma surrounding HIV infection was indiscriminate and damaging. The accounts of patients and their families in Chapters 4 and 5 are eloquent of the concerns felt by clinicians at the time. However, the outcome was unfortunate in the respect that, at the time, more comprehensive data might have influenced the approach to management of infected patients and accelerated the appreciation at government level of the risks presented.

10.156 The Communicable Diseases Report Review, no 8, of 17 July 1992 stated:

The surveillance of the spread of HIV infection in the United Kingdom relies on the voluntary reporting of AIDS cases and HIV infected individuals, and on large-scale unlinked anonymous seroprevalence surveys. The distribution of currently reported cases by region and exposure category reflects the pattern of infection some years ago, because of the long incubation period of AIDS. New reports of HIV infected individuals identified through voluntary testing reflect current transmission patterns more closely but also depend on the numbers tested in each exposure category. Unlinked anonymous testing provides seroprevalence estimates for sentinel groups in the population but is limited by the extent to which epidemiological information can be related to the sera tested, and by the composition of groups that can be sampled. Moreover, serial seroprevalence data can only provide an indirect estimate of the incidence of new infections.

To extend national surveillance, a collaborative study was set up in 1986 by the PHLS to record relevant epidemiological information for both HIV antibody positive and negative individuals tested voluntarily in selected laboratories in England. The main objectives of the study are to enhance interpretation of data from HIV antibody positive reports, by providing information on the numbers tested according to exposure category; to provide an indication of seroprevalence in groups not sampled or categorised in the unlinked anonymous testing programme, and to provide direct estimates of incidence in selected high risk groups. [191]

10.157 Eighteen laboratories in England were selected. The results obtained were tabulated:

Table 10.6: Prevalence of HIV antibody by exposure category:
October 1986-September 1991

Males Females

Exposure category
Number
tested
Tested
positive (%)
Number
tested
Tested
positive (%)
Sexual intercourse
Homosexual/bisexual 17,685 1582 (8.9) 514 -
Heterosexual
lived in/visited Africa 1970 134 (6.8) 1037 109 (10.5)
lived in/visited Americas 358 4 (1.1) 197 4 (2.0)
HIV positive partner 321 14 (4.4) 634 43 (6.8)
high risk partner 1798 10 (0.6) 5317 32 (0.6)
moderate risk partner 3427 5 (0.1) 3692 2 (0.1)
many partners 11,527 21 (0.2) 14,682 10 (0.07)
Injecting drug use 7031 184 (2.6) 3017 75 (2.5)
Blood
Blood factor (eg, for haemophilia) 1022 60 (5.9) 141 -
Blood/tissue transfer (eg, transfusion) 1147 8 (0.7) 1483 9 (0.6)
Mother to infant 98 15 (15.3) 83 9 (10.8)
Other
Multiple exposure categories 2059 92 (4.5) 745 18 (2.4)
Unspecified contact with HIV positive or at-risk person
2796

16 (0.6)

3320

12 (0.4)
Household Contact/nursing/needlestick/bite 440 - 405 -
No reported risk 46,331 15 (0.03) 28,039 8 (0.02)
Total 98,010 2160 (2.2) 63,306 331 (0.5)

10.158 The table probably provides a reasonably reliable basis for comparison of the balance of infection among the groups sampled. Given its selective nature, however, it cannot present a picture of the incidence of disease generally. So far as transmission to NHS patients is concerned, it shows a very small rate of transmission by blood and tissue, as would have been expected after the introduction of anti-HIV testing. As noted above, the Oxford report of 3 October 1986 showed that 40.48% of 2228 Haemophilia A patients, 6.74% of 386 Haemophilia B patients and 2.75% of 327 von Willebrand's disease patients, almost all tested before heat-treatment of concentrates and screening of donors was commenced, were anti-HIV positive. It would be expected that the number of additional cases of infection identified after October 1986 would be much lower, again because of testing. Sixty additional cases from 1022 males tested would reflect that, though it is not clear when they were infected and the true number of additional infections may be lower still.[192]

10.159 However, it is not possible, on the basis of these figures, to express any confident view of the scale of the epidemic in England and Wales and therefore of the scale of the problem in the UK as whole. Only general impressions of the scale and development of the epidemic can be suggested.

10.160 There is inevitably a lack of certainty about the end of the epidemic so far as NHS patients are concerned - in terms of the date when HIV was last transmitted to a blood disorder patient by replacement therapy or to a patient receiving blood or blood components in the course of medical or surgical procedures. Factor VIII concentrates issued from January 1985 were heat-treated to inactivate HIV and heat-treated Factor IX was routinely issued from October that year. Meantime, routine anti-HIV screening of blood donations had been introduced on 14 October 1985. It is not possible to exclude completely the possibility that there might have been transmission of HIV to NHS patients after these procedures were in place.[193] Human error might have occurred, resulting in the clinical use in or after January 1985 of Factor VIII that had not been heat-treated but had remained in stock. There is the same transitional risk with Factor IX around October 1985 and unscreened blood or components might have been used after 14 October 1985. However, it seems reasonable to take these three events as marking the end of the period of risk for most patients.

10.161 The numbers of patients infected with HIV were not determined until later. Final numbers, so far as ascertained by the Inquiry, are discussed in Chapter 3, Statistics.

Summary

  • Throughout the period when HIV transmission was a significant threat to recipients of blood, blood components and blood products, data on the numbers of individuals infected were incomplete and generally underestimated the extent of the developing epidemic.
  • Adoption of the CDC test for AIDS, the identification of intractable AIDS-defining disease, without a requirement to report significant evidence of impaired cell-mediated immunity, inevitably had an impact on the understanding of the developing epidemic until late 1984 when testing for anti-HTLV-III became available.
  • As a result, government and NHS agencies did not have accurate information on the scale of the epidemic as a guide to policy generally and in particular as a guide to management of blood disorder patients.
  • In retrospect it is clear that the voluntary reporting system did not secure comprehensive reporting of the numbers of patients infected.
  • Neither the UKHCDO nor any other professional group had authority to require disclosure of the anonymised data which were needed properly to measure the emerging pattern of infection in blood disorder patients.
  • There were no rules of conduct prescribed by any government agency with responsibility for the administration of the National Health Service that required such disclosure.
  • This is an area in which the apparently unquestionable independence and autonomy of the medical consultant seriously inhibited the collection and analysis of information essential to a full understanding of these emerging diseases and their implications for the patient population.
  • As a result, the extent of the AIDS epidemic in recipients of blood, blood components and blood products in the UK generally has only become apparent following extensive retrospective analysis.

1 MMWR, 24 September 1982; 31(37): 507-8 [LIT.001.0540]

2 See, for example, [DHF.002.3521], a form for reporting patients with coagulation defects who met the UK Haemophilia Centre Directors Hepatitis Working Party survey criteria for AIDS.

3 Professor Weiss is currently Emeritus Professor of Viral Oncology at UCL Medical School.

4 Professor Tedder is currently Professor of Medical Virology at UCL Medical School.

5 See Chapter 29, The Discovery of HIV and Developments Screening Tests

6 Cheingsong-Popov et al, 'Prevalence of antibody to human t-lymphotropic virus type iii in aids and aids-risk patients in Britain', The Lancet, 1 September 1984 [LIT.001.0417] at 0419

7 Ibid [LIT.001.0417] at 0419

8 That is, showing a significant level of HIV antibodies indicating infection with HIV.

9 Cheingsong-Popov et al, 'Prevalence of antibody to human t-lymphotropic virus type iii in aids and aids-risk patients in Britain' The Lancet, 1 September 1984 [LIT.001.0417] at 0419

10 Froebel et al, 'Immunological abnormalities in haemophilia: are they caused by American factor VIII concentrate?' British Medical Journal, 1983;287:1091 [LIT.001.0215]

11 Letter from Dr Froebel to Dr Perry dated 29 October 1984 [SNB.004.8734]

12 Letter from Dr Perry to Dr Froebel dated 15 November 1984 [SNB.004.8739]

13 Letter from Dr Froebel to Dr Perry dated 05 December 1984 [SNB.004.8777]

14 Draft paper 'Evidence for Transmission of HTLV-III to European Haemophiliacs via US Imported Factor VIII Concentrate' [SNB.004.8779]

15 Melbye, M et al 'High prevalence of lymphadenopathy virus (LAV) in European haemophiliacs' The Lancet, 1984; 324:40-41(40-41) [LIT.001.0423]

16 Melbye et al 'HTLV-III seropositivity in European haemophiliacs exposed to Factor VIII concentrate imported from the USA' The Lancet, 1984; 324:1444-1446 [LIT.001.1702]

17 Ibid [LIT.001.1702] at 1704

18 'Study confirms fears on spread of AIDS', The Guardian 31.8.84 [SGF.001.0930]

19 Dr Winter - Day 16, pages 101-6. As noted in paragraph 9.10 of Chapter 9, Knowledge of the Geographical Spread and Prevalence Of HIV/AIDS 1, the most up-to-date data available to the Inquiry indicate that for the UK, excluding Scotland, 1310 patients with bleeding disorders tested positive for HIV by April 2012. Scotland has roughly 10% of the UK haemophilia population but only 60 patients treated in Scotland tested positive. See also Chapter 3, Statistics.

20 For more detailed discussion of the ethical issues surrounding the testing of stored samples, please see Chapters 32 and 33.

21 Day 16, pages 169-70

22 Day 16, pages 156-7

23 Day 7, pages 82-85; Evidence to Lord Archer http://www.archercbbp.com/hearing.php

24 Day 16, page 157

25 Day 16, page 157-160. See also his evidence to the Archer Inquiry, Day 7, page 86 http://www.archercbbp.com/hearing.php

26 Letter [SNF.001.4020]

27 Ibid [SNF.001.4020] at 4021. Compare Dr Craske's letter to Dr Ludlam dated 30 November 1984 referred to at paragraph 10.31.

28 See Chapter 11, HIV/Aids Aetiology, at paragraphs 11.59-11.61

29 Letter from Dr McClelland to Dr Cash dated 15 November 1984 re analysis of PFC Factor VIII batches [SNF.001.3624]

30 Dr McClelland's Witness Statement [PEN.011.0062] at 0063

31 Minutes of a Meeting of Heads of Department/Section Managers held on Friday 26 October 1984 [SNB.010.3479]. Dr Perry told the Inquiry that the heads of department meetings were held regularly on Friday mornings at this time: Day 42, pages 52-3.

32 Dr Perry had been Quality Control Inspector at the PFC from 1981-1984. He was appointed Acting Director in 1984 and the role was made substantive the following year, 1985. See Day 11, pages 93-4.

33 Minutes of a Meeting of Heads of Department/Section Managers held on Friday 26 October 1984 [SNB.010.3479] at 3481

34 Schedule to Witness Statement requests on Topic B3, Heat Treatment to 1985 [PEN.012.1531] at 1538

35 See, for example, Dr Perry - Day 45, page 106; Dr Perry's Witness Statement [PEN.012.1759] at 1777

36 Day 46, page 76

37 Dr Foster's Witness Statement [PEN.012.1438] at 1472

38 Day 46, page 78

39 Day 35, pages 97-102 and Day 40, pages 82-89; Edinburgh Haemophilia and Thrombosis Centre - Appendix to witness statement from Professor Ludlam [PEN.012.0351] at 0354; Note of a Meeting between Professor Ludlam and the Penrose Inquiry legal team [PEN.012.0774] at 0784

40 'Events Leading up to the Recall of Factor VIII Batch 023110090' [SNB.006.5996]

41 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1263

42 Day 38, pages 13-14

43 Letter from Dr McClelland to Dr Cash dated 15 November 1984 re. analysis of PFC Factor VIII batches [SNF.001.3624]; reported in The Scotsman 22.12.84 [SGH.002.6484]; Preliminary Report, para 8.102

44 See Chapter 9, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 1, paragraph 11.41.

45 Hansard 28 November 1984, column 494 [SNF.001.3313]

46 Note of Meeting of Haemophilia Directors and SNBTS Representatives on 29 November 1984 [SNB.001.5256]; Preliminary Report, paragraphs 8.104 to 8.107

47 See paragraph 10.6 above

48 Minute of meeting [SGF.001.0137] at 0139. See Dr McClelland's Note on meeting of Advisory Group on AIDS, 27 November 1984 [PEN.012.1938]

49 Summarised from a letter from Dr Craske to Dr Ludlam dated 30 November 1984 re: Suspect Batches of Edinburgh Factor VIII and Factor IX [LOT.003.4331] at 4332

50 Dr Winter - Day 16, page 116

51 Meeting of the Haemophilia Reference Centre Directors - 10 December 1984 [DHF.003.0898]; Notes of the Haemophilia Reference Centre Directors Meeting Blood Products Laboratory Elstree, 10 December 1984 [SNF.001.3850]. The Haemophilia Reference Centre Directors was a committee of UKHCDO and Drs Ludlam, Cash and Forbes were in attendance. More detail of events from this point until the end of 1984 are set out in the Preliminary Report at paragraphs 8.116-8.119

52 Meeting of the Haemophilia Reference Centre Directors - 10 December 1984 [DHF.003.0898]

53 Notes of the Haemophilia Reference Centre Directors Meeting Blood Products Laboratory Elstree, 10 December 1984 [SNF.001.3850] at 3853. From later discussion of infection in the Edinburgh Cohort, the record appears to be wrong: some patients who had been negative before receiving the implicated batch were subsequently found to be positive. Some were found to be negative before and after receiving the implicated batch.

54 AIDS advisory document [SGF.001.2388]; Preliminary Report, para 8.117

55 '56 are given AIDS killer blood', The Daily Express, 21.12.84: [SGF.001.0904]

56 'AIDS "barrier" proves illusory', The Scotsman, 22.12.84 [SGH.002.6484]

57 See, for example, Preliminary Report, para 8.205

58 'Blood Transfusion, Haemophilia, and AIDS', The Lancet, 1984; 324:1433-35 [LIT.001.0446]. See Preliminary Report para 8.119 for further details.

59 The members of the expert advisory group are listed at [SNF.001.3323]

60 Written Parliamentary Answer, 21 January 1985, columns 345-348 [DHF.001.9150]

61 Acquired Immune Deficiency Syndrome (AIDS) - Interim Guidelines [DHF.001.6071]

62 Written Parliamentary Answer, 21 January 1985, columns 345-348 [DHF.001.9150]

63 Memorandum from Dr Perry to All Staff dated 31 December 1984 re AIDS [SNB.004.8843]

64 Memorandum from Dr Perry to All Staff dated 31 January 1985 re AIDS [SNF.001.3715]

65 Ibid, [SNF.001.3715]. This conclusion led to the release of plasma for processing.

66 Interim Guidelines [DHF.001.6071]

67 The interim guidance was accompanied by a letter: an example is [SGH.001.0360]

68 Interim guidelines [DHF.001.6071] at 6077

69 Ibid, [DHF.001.6071] at 6077

70 Press release: 'AIDS guidelines for clinical and laboratory staff' [SNB.001.0124]

71 Written Parliamentary Answer [DHF.001.9389]

72 See, for example: Madhok 'HTLV III antibody in sequential plasma samples: from haemophiliacs 1974-1984' The Lancet, 1985; 325:524-525 [LIT.001.1673]; See also the Preliminary Report, paragraphs 8.146 and 8.147

73 Letter from the CMO dated 1 April 1985 [SNB.004.9328]

74 Leaflet 'Some Facts About AIDS' [SNB.004.9329]

75 Letter from the DCMO dated 17 May 1985 [SGH.004.6581]

76 'AIDS - general information for doctors' [SGH.004.6582]; CDSC Epidemiology Paper [SNB.004.9642]

77 CDSC Epidemiology Paper [SNB.004.9642] at 9643

78 See paragraph 10.1 above.

79 'AIDS - general information for doctors' [SGH.004.6582] at 6586

80 Ibid, [SGH.004.6582] at 6589

81 Preliminary Report, para 8.153; Professor Peto's Letter [DHF.002.5498]

82 Professor Peto's paper [DHF.002.5499]

83 Letter from Dr Ludlam to Dr Perry [SNF.001.3271]; Final Draft of Paper [SNF.001.3272]

84 Ludlam, C et al 'HTLV-III infection in seronegative haemophiliacs after transfusion of factor VIII' The Lancet, 1985; 326:233-236 [LIT.001.1669] Preliminary Report, para 8.154

85 Helper/suppressor ratios are discussed in Chapter 11, HIV/AIDS Aetiology, paragraph 11.86

86 Minutes of AIDS Information and Advisory Group, 31 May 1985 [SNB.004.9656]; Preliminary Report, para 8.155

87 By 1991 the rate of infection in treated haemophilia patients in Edinburgh was said to be 25%: Cuthbert et al, 'Immunological studies in HIV seronegative haemophiliacs' British Journal of Haematology, 1991; 80:364-9 [PEN.012.0405]

88 The testing kit developed by Abbott Diagnostics in the USA.

89 Note to Mr MacKay and others [SGF.001.0831]

90 DHSS Press Release: 'the fight against AIDS - more government money' [DHF.001.7916]; Preliminary Report, para 8.136

91 SHHD Press Release [SGH.002.7072]

92 Preliminary Report, para 8.164

93 Interim Report on Survey of HTLVIII Antibody in Haemophiliacs in UK [SNB.001.7593]

94 A total of 2570 patients were tested including carriers of Haemophilia A and B and other groups. Data from these cohorts (45) are not represented above.

95 See Chapter 2, Patients at Risk, paragraph 2.26 for discussion of the categorisation of haemophilia into 'mild', 'moderate' and 'severe' categories.

96 Interim Report on Survey of HTLVIII Antibody in Haemophiliacs in UK [SNB.001.7593] at 7596

97 Haemophilia AIDS Group - Cases of AIDS Related Diseases Notified to Oxford 1 October 1985 - Table 1 [SNF.001.1106]

98 Ibid, [SNF.001.1106] at 1107

99 Memo to CMO [DHF.001.8523]

100 Minutes of a meeting on the Virological Aspects of the Safety of Blood Products, held at the NIBSC on February 7th, 1986 [SNB.005.1495]; Preliminary Report, para 8.168

101 Ibid [SNB.005.1495] at 1501. This was the issue raised with the CMO, England and Wales, on 28 November 1985, noted above.

102 Dr Perry's letter [SNB.004.7776]; Dr Forbes' letter [SNB.004.7732]; Preliminary Report, para 8.171

103 Minutes of a Meeting on the Virological Aspects of the Safety of Blood Products, held at the NIBSC on February 7th, 1986 [SNB.005.1495] at 1502

104 Minutes of a Directors Meeting Held in the HQ Unit on 25 March 1986 [SNF.001.0135] at 0138-9; Preliminary Report, para 8.173

105 Report of AIDS Conference, 11-13 February 1986 [SNF.001.4215] at 4216; Preliminary Report, para 8.169

106 Ibid, [SNF.001.4215] at 4218

107 Report of AIDS Conference, 11-13 February 1986 [SNF.001.4215] at 4220. Dr Jones had data from 2025 patients compared to the 2525 reviewed by the Oxford study.

108 Dr Foster's report of the Congress [SNB.008.6547]

109 Ibid [SNB.008.6547] at 6548-49

110 Ibid [SNB.008.6547]

111 Chapter 9, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 1, at paragraph 9.65.

112 Dr Foster's report of the Congress [SNB.008.6547] at 6549-50 and 6554

113 Extract from the Report of the Committee of Experts on Blood Transfusion and Immunohaematology - Berne 28-31 May 1986 [SNB.004.8127]; Preliminary Report, para 8.180

114 Advisory Committee on Dangerous Pathogens (ACDP) - Revised Guidelines on LAV-HTLV III - The Causative Agent of AIDS and Related Conditions [DHF.002.1456]

115 Extract from the Report of the Committee of Experts on Blood Transfusion and Immunohaematology, Berne, 28-31 May 1986 [SNB.004.8127]

116 Ibid [SNB.004.8127] at 8136

117 AIDS related complex

118 Extract from the Report of the Committee of Experts on Blood Transfusion and Immunohaematology, Berne, 28-31 May 1986 [SNB.004.8127] at 8144

119 Ibid [SNB.004.8127] at 8144

120 Advisory Committee on Dangerous Pathogens (ACDP) - Revised Guidelines on LAV-HTLV III - The Causative Agent of AIDS [DHF.002.1456]

121 Ibid [DHF.002.1456] at 1464-5

122 Advisory Committee on Dangerous Pathogens (ACDP) - Revised Guidelines on LAV-HTLV III - The Causative Agent of AIDS [DHF.002.1456] at 1465. NB Several reported 0% infection rates (Czechoslovakia, Hungary, Iceland, Poland, USSR).

123 Ibid [DHF.002.1456] at 1464-65

124 Ibid [DHF.002.1456] at 1468; Preliminary Report, para 8.186

125 Update on HIV Related Illness - September 1986 [SNF.001.1114]; Preliminary Report, para 8.189

126 Update on HIV Related Illness - September 1986 [SNF.001.1114]. This appears to relate to Haemophilia A patients only: 896, the figure used in calculation, was the number of such patients who were antibody positive as at March 1986. The change of terminology within the papers from AIDS-related to HIV-related does not appear material in view of the specification of diseases given.

127 Update on HIV Related Illness - September 1986 [SNF.001.1114] at 1116

128 Ibid [SNF.001.1114] at 1115

129 Ibid [SNF.001.1114] at 1118

130 Update on HIV Related Illness - September 1986 [SNF.001.1114]; Preliminary Report, para 8.190

131 Provisional Report on 1986 Survey of Anti-HIV in Haemophiliacs in UK [SNB.001.7684]

132 Minutes of a Directors Meeting held on 9 October 1986 [SGF.001.0268] at 0269; Preliminary Report, para 8.191

133 Minutes of Directors Meeting held on 17 December 1986 [SGF.001.0189] at 0190

134 Minutes of a Directors Meeting held on 3 March 1987 [SGH.001.6653] at 6655

135 Press Release: 'Latest AIDS figures for Scotland' [SNB.004.8475]

136 Presumably a non-haemophilia patient.

137 Minutes of the 19th Meeting on the UK Haemophilia Centre Directors - 25th September 1987 [SNB.001.7768] at 7771; Preliminary Report, para 8.197

138 International Plasma News October 1987 [SNB.005.9298]; Preliminary Report, para 8.198

139 Letter dated 21 December 1987 [SNB.006.4583]

140 Ibid [SNB.006.4583] at 4584; Preliminary Report, paragraphs 8.198-8.200

141 Letter dated 21 December 1987 [SNB.006.4583]

142 Hansard, 21 December 1989, columns 379-380 [SGF.001.1248]

143 Hansard, 18 April 1990, column 876 [SGF.001.1202]

144 Zhang, LQ et al 'Detection, quantification and sequencing of HIV-1 from the plasma of seropositive individuals and from factor VIII concentrates' AIDS, 1991; 5:675-81 [LIT.001.0516]; Preliminary Report, para 8.213

145 Simmonds, P et al, 'Determinants of HIV disease progression: six-year longitudinal study in the Edinburgh haemophilia/HIV cohort' The Lancet, 1991, 338:1159-1163, [LIT.001.0279]; Preliminary Report, para 8.214

146 Day 38, page 17

147 Day 38, page 18

148 Day 38, pages 16-18

149 ELISA tests use an enzyme to detect antibodies in a sample and include various reagents which give a colour reaction. Dr Dow - Day 4, pages 85-6; Professor Weiss - Day 48, pages 161-2

150 Day 38, pages 19-20

151 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1265-6

152 Simmonds et al, 'HIV antigen and antibody detection: variable responses to infection in the Edinburgh haemophiliac cohort', British Medical Journal, 1988; 296:593-8 [LIT.001.0305]; Preliminary Report, paragraphs 8.206 and 8.207

153 Simmonds et al, 'HIV antigen and antibody detection: variable responses to infection in the Edinburgh haemophiliac cohort', British Medical Journal, 1988; 296:593-8 [LIT.001.0305] at 0306

154 Cuthbert, RJG et al 'Five year prospective study of HIV infection in the Edinburgh haemophiliac cohort' BMJ, 1990; 301:956-61 at 957, [LIT.001.0291]. As late as 1991, Dr Cuthbertson of the PFC was referring to there having been 16 seroconversions. Preliminary Report, para 8.221. Originally, 16 were reported but three further seroconversions were observed during follow-up between October and December 1984, with one of the original 16 being discounted as not having been infected by the implicated batch.

155 Simmonds et al, 'HIV antigen and antibody detection: variable responses to infection in the Edinburgh haemophiliac cohort', British Medical Journal, 1988; 296:593-8 [LIT.001.0305]

156 Cuthbert et al, 'Human immunodeficiency virus detection: correlation with clinical progression in the Edinburgh haemophiliac cohort' British Journal of Haematology, 1989; 72: 387-90 [LIT.001.0581]; Preliminary Report, para 8.211

157 Ibid, [LIT.001.0581] at 0584. A possible link with a particular genetic feature in some of the affected individuals was explored in Steel et al, 'HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease' The Lancet, 1988; 1185-8, [LIT.001.0895], this was corroborated in later American and Australian studies. Kaslow et al , 'A1, Cw7, B8, DR3 HLA antigen combination associated with rapid decline of T-helper lymphocytes in HIV-1 infection' The Lancet 1990; 335: 927-30 [LIT.001.3825]

158 CM Steel et al, 'HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease' The Lancet, 1988; 1185-8 [LIT.001.0895]

159 Balfe et al, 'Concurrent Evolution of Human Immunodeficiency Virus Type 1 in Patients Infected from the Same Source: Rate of Sequence Change and Low Frequency of Inactivating Mutations' Journal of Virology, 1990; 64:6221-6233 [PEN.012.1403]

160 Cuthbert et al, 'Five year prospective study of HIV infection in the Edinburgh haemophilic cohort', British Medical Journal, 1990; 301:956-961 [LIT.001.0291]; Preliminary Report, para 8.212

161 Holmes, EC et al 'The Molecular Epidemiology of Human Immunodeficiency Virus Type 1 in Edinburgh' The Journal of Infectious Diseases 1995; 171:45-53 [PEN.012.1679]

162 Holmes et al, 'The molecular epidemiology of human immunodeficiency virus type 1 in Edinburgh' The Journal of Infectious Diseases 1995; 171:45-53 [PEN.012.1679] at 1685

163 Ibid [PEN.012.1679] at 1686

164 Ibid [PEN.012.1679] at 1686

165 Letter from Dr Cuthbertson to Professor Cash, 25 January 1991 [SNF.001.3564]; Report 'HIV Seroconversions Related to SNBTS FVIII' [SNB.001.1243]

166 Interim Report [SNB.008.6427]

167 Report 'HIV Seroconversions Related to SNBTS FVIII' [SNB.001.1243]

168 Day 38, pages 53-58

169 Day 38, pages 46-47

170 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1264 and Day 38, page 51

171 Day 38, pages 50-2; 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1264

172 Batch Record [PEN.012.1339]; 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1263

173 Finished Product Documentation [PEN.012.1339] at 1373

174 Product Clearance Sheet [PEN.012.1339] at 1340

175 Batch Issue History sheet [PEN.012.1375]

176 Dr Perry - Day 38, page 43-44; 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1264

177 Day 38, pages 58-59; 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1263-4

178 Day 38, page 59

179 Letter from Dr Perry to Dr Brooks, 12 November 1984 [PEN.012.1378]

180 Day 38, page 61

181 Letter from Dr McClelland to Dr Tedder, 28 November 1984 [PEN.012.1423]; 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1266

182 Dr Perry - Day 38, page 63

183 Letter from Dr Tedder to Dr McClelland, 20 December 1984 [PEN.012.1424]

184 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1270

185 Ibid [PEN.016.1258] at 1263 and 1266; Day 38 pages 21-23

186 'Actions surrounding FVIII Batch 023110090' [PEN.016.1258] at 1283

187 Day 38, pages 27-28

188 Day 38, page 33

189 Day 38, pages 28-29

190 Dr Perry - Day 38, pages 40-41

191 CDR Review, no 8, 17 July 1992 [LIT.001.4789]

192 Since the earlier surveys were incomplete, it cannot be concluded that all of the 60 cases were new infections after October 1986: they may equally have been omitted from the earlier data because they were registered at Haemophilia Centres which refused to provide data.

193 One case is noted in the Preliminary Report at paragraph 8.194

11. HIV/AIDS Aetiology >