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Chapter 11

HIV/AIDS Aetiology


11.1 This chapter discusses the aetiology of AIDS: the cause or causes of the Acquired Immune Deficiency Syndrome that exposed individuals to disproportionate risk of opportunistic infection, cancers and other diseases of the AIDS complex, as disclosed in public debate, professional literature and the written and oral evidence provided to the Inquiry.

Inter-disciplinary research in the 1980s

11.2 Medical and scientific understanding of the epidemiology of AIDS, as set out in Chapters 9 and 10, Knowledge of the Geographic Spread and Prevalence of HIV/AIDS 1 & 2, provided the context for discussion of the cause or causes of the disease as well as the modes of transmission of infection. It is necessary, however, to repeat a note of caution at the outset. Multi-disciplinary research and cooperation were less well-developed features of medical and scientific practice in the 1980s compared to contemporary practice. There was a lack of coordination of the research of groups working on similar problems but focusing on their own specialist interests. So, virologists and infectious diseases specialists might take one view of emerging evidence of disease while haematologists and haemophilia clinicians might take different views. Fractionators - those involved in the manufacture of blood products - responded quickly to the Barré-Sinoussi article in Science on 20 May 1983 (the seminal publication by the Montagnier group at the Institut Pasteur in Paris announcing the isolation of a putative AIDS-causing virus, discussed at paragraph 11.90, below).[1] Their approach was influenced by their apprehension that their products were already transmitting non-A, non-B Hepatitis. Professor Ian Hann, Director of the West of Scotland Paediatric Haemophilia Centre, Yorkhill, Glasgow, between 1983 and 1987, thought that one of the beneficial lessons of the HIV era was the need for multi-disciplinary teams,[2] but in the early 1980s that did not generally happen. As a consequence, what might have been known to one discipline about an emerging syndrome cannot be assumed to have been known to another and, in particular, what was published (still, at this stage, largely in paper form) in even a prestigious publication of specialist interest to one professional discipline cannot be assumed to have been read by specialists in other areas. The material years of the early 1980s were before the advent of electronic literature searches now considered routine.

11.3 In modern practice, the degree of insularity that appears to have existed would be considered inappropriate. With the benefit of hindsight, practice in the 1980s might be the subject of adverse comment but it is difficult to re-create the medical environment without imposing on it changes in attitude and developments in practice that would only be achieved later, often in the light of experience with HIV/AIDS and the Hepatitis C virus. The reality is that one cannot assume homogeneous dissemination of information or a common understanding of that information among the disparate groups of scientists and clinicians who became interested in AIDS in the early 1980s. It is particularly important to bear in mind the possibility that a fact well known to and understood by an infectious diseases specialist, for example, might have been wholly unknown to, or if known misunderstood by, a haemophilia specialist, even though each might have had an interest in patients with the same or similar infections.

11.4 Apart from differences among clinical specialists, there are likely to be differences between (i) the information and knowledge available to clinicians as a whole and (ii) the information and knowledge developed by scientists engaged in fundamental research, especially where there may be intellectual property rights to be protected. This chapter will leave the second topic for discussion in Chapter 29, Discovery of HIV and Developments of Screening Tests. Although scientific research overlapped in time with the events discussed in this chapter, and merged with them in 1984, progress in understanding of the aetiology of AIDS developed independently between the groups engaged in public debate and those pursuing confidential projects.

11.5 These factors add further difficulty to what is inevitably a complex and difficult exercise: tracing changing theories of the cause of AIDS and assessing their relevance to scientific investigation and clinical practice.

11.6 The controversies surrounding the possible cause of AIDS effectively ended by mid- to late 1984 with the confirmation that the lymphadenopathy-associated virus (LAV)/human T-cell lymphotropic virus III (HTLV-III) was the pathogen responsible for transmitting infection. The developments in thinking up to that time are recounted at some length. Tragically, the majority of individuals infected with HIV - either those with bleeding disorders or following transfusion with infected blood - acquired the virus between early 1982 and mid-1984 when there was no settled understanding of the cause or causes of AIDS. There is natural, and wholly understandable, concern that in some way AIDS was 'allowed' to happen when it could, and should, have been controlled. If that concern is to be addressed, at the very least it is necessary to have information that is as reliable as possible about events as they unfolded.

Early reports and first thoughts

11.7 Early reports of the disease are discussed in the Preliminary Report and in Chapter 9, Knowledge of the Geographical Spread and Prevalence of HIV 1. The initial debate on AIDS, as published in 1981 and 1982, was heavily influenced by the fact that most of those reports dealt exclusively with homosexual men.[3] An association with some aspect of a homosexual lifestyle or disease acquired through sexual contact was promoted as a cause of the disease. Cytomegalovirus (CMV) infection, sometimes associated with cellular-immune dysfunction, was prevalent among male homosexuals and there was speculation at the end of 1981 that there was a causal link. Michael Gottlieb and colleagues reported that four young previously healthy homosexual men, whose clinical manifestations were similar to the group originally reported in June 1981,[4] all had CMV infection and this was suggested as a major factor in the pathogenesis (causation and development) of the immunocompromised state.[5] Other possibilities canvassed included abnormal responses to Epstein Barr virus (EBV) or Hepatitis B virus.[6] It was thought that seminal fluid might be an important vehicle of CMV transmission. This suggested the possibility that common exposure predisposed male homosexuals to opportunistic infections.[7]

A genuinely new disease

11.8 AIDS seemed to be a genuinely new disease.[8] At the International Symposium on Infections in the Immunocompromised Host held in June 1982, a lecture on AIDS in homosexuals and drug addicts was 'the talk of the meeting'. Professor Hann said that after the lecture there was an atmosphere of extreme puzzlement. He explained:

[A]lthough we knew some viruses, like Epstein Barr virus, the glandular fever virus, other Herpes viruses like cytomegalovirus, could cause immune deficiencies, nothing remotely like this had ever happened before.

So we needed to prospectively study apparently normal gay people at that time, intravenous drug abusers et cetera, and see what it was that was making them immune deficient.[9]

11.9 In relation to the cause of this syndrome, he said that the preferred belief among the experts present at the symposium was that it was most likely that a new viral agent or that several viruses might be involved.

11.10 When the first cases were reported at the beginning of the 1980s, HTLV-III appeared to be a unique infection.[10] AIDS was considered to have no relevant history. It is now thought that HIV is a zoonosis - a pathogen transmitted from another species and in this case a descendant of a Simian Immunodeficiency Virus (SIV).[11] There are two types. HIV-1 is the more predominant, probably causing more than 98% of the human infections. It is believed that it was passed from chimpanzees to humans in West Africa in the early part of the twentieth century. HIV-2 has a different structure that is very closely related to a virus found in the sooty mangabey monkey species. Professor Andrew Lever, Professor of Infectious Diseases at Addenbrooke's Hospital, Cambridge, explained:

[T]he evidence is that HIV-2 crossed into humans from the sooty mangabey, whereas HIV-1 crossed into humans from the chimpanzee. Both of these, almost certainly - as I think it's well understood now - came into the human race, as far as we can tell, through the bush meat trade, where wild monkeys are caught and slaughtered and butchered and sold for food, and since both viruses are blood-borne and in fact in the monkey population they're transmitted predominantly by blood - by fighting, by biting and scratching - then it's relatively easy to think of how a virus may have been transmitted from fresh meat into someone who was handling that.[12]

11.11 Once passed to humans, SIV mutated to become HIV.[13] Over time, HIV spread from Africa to the West and, in particular, to the USA.[14]

11.12 In the early 1980s, comment focused on the novelty of the emerging features of the disease, such as Pneumocystis carinii pneumonia (PCP) or Kaposi's sarcoma (KS), in apparently healthy homosexual males who had not previously had clinically apparent immunodeficiency. There was also speculation that homosexual men contracted the disease because their immune system was not working properly, having been compromised by so-called 'recreational' drugs taken for stimulation.

Risk factors

11.13 By mid-1982, the mix of homosexual and heterosexual patients, intravenous drug abusers and haemophilia patients suggested that risk factors might be different for different groups. At this stage, in the first half of 1982, a blood-borne virus, spread by sexual relations, had been postulated but there was great uncertainty.[15] Other mechanisms were suggested, especially in the case of haemophilia patients, and it has become clear with the passage of time that some haemophilia patients did indeed develop different immune disorders, not dissimilar to those associated with HIV but without a viral agent of transmission of infection and with apparently different outcomes.[16]

11.14 Professor Lever said that information about infection in drug users was an additional piece of the jigsaw:

Until that time there were plausible arguments that what was being seen, which was effectively confined to the gay, homosexual population, might have had a number of causes and ... people initially started looking for things they could find, which was why cytomegalovirus and Hepatitis B came up, and the fact that these populations were almost uniformly positive for these viruses, whereas the general population has a much lower incidence overall, made them potential candidates. But there was also an uncovering of information about the gay lifestyle at the time, about sexual promiscuity and about drug abuse, which also distinguished that population to some extent, certainly in the level of it, from most other populations. So there was room for a lot of speculation as to what might be triggering the immunodeficiency.[17]

11.15 It was speculated that abnormal exposure to pathogens in the rectum and in the gut associated with male homosexual practices was significant. However, intravenous drug users, as a population, did not characteristically indulge in homosexual practices: heterosexual transmission affected the range of speculation related to homosexual behaviour and pointed to something that was probably common to both types of sexual conduct. As put by Professor Lever, it would have been logical to be looking for the common element: what was going wrong with the patients' immune systems.[18]

11.16 Other heterogeneous theories were discussed and were explored by different specialist groups. One, relating to retroviruses, was to become important but in retrospect it appears to be clear that there was as yet, in the first half of 1982, a lack of cross-fertilisation of ideas among those taking an interest in this new phenomenon.

A widening constituency and the infective agent theory

A widening constituency

11.17 Reports of opportunistic infections among Haitian immigrants to the USA and additional cases of PCP in haemophilia patients in July 1982, and of intravenous drug abuse as a risk factor in September 1982, marked a further material change in context away from an exclusive focus on sexual behaviour.[19] The initial hypothesis linking the condition only to sexual behaviour could not be sustained: it was no longer possible to focus exclusively on such behaviour and theories related exclusively to homosexual conduct and lifestyle were largely discarded.

11.18 Three US haemophilia patients who reported with opportunistic infections in July 1982 had all received frequent administration of Factor VIII concentrate.[20] No two had received concentrate from the same batches. PCP had not previously been reported among haemophilia patients who had no other underlying disease and who had not had therapy associated with immunosuppression.[21] Possible transmission of an agent through blood products was suggested.

Dr Bruce Evatt and the infective agent theory

11.19 The report of these cases reflected the findings and views of Dr Bruce Evatt of the US Centers for Disease Control (CDC). The CDC had a supervisory function relating to off-licence use of certain drugs. At the material time, pentamidine, an antibiotic with certain conventional applications, was used for the treatment off-licence of PCP. Controlled issue allowed the CDC to build up a national epidemiological map of putative diagnoses of the disease, hitherto extremely rare and, where it did occur, almost always confined to immunosuppressed patients such as those undergoing chemotherapy.[22] In early 1982, Dr Evatt had received a report of PCP in a haemophilia patient and similar reports relating to Haitian patients, although previously haemophilia had not been among the underlying disorders of patients for whom pentamidine had been requested for PCP.[23] His organisation began surveillance of requests for pentamidine for haemophilia patients who were contracting PCP and several applications were received in quick succession in June and July.[24] It was inferred within the CDC that a new form of immune suppression was occurring in the haemophilia community.[25] Dr Evatt was convinced that AIDS had reached haemophilia patients.[26] Dr Mark Winter, who became Consultant Haematologist at Kent and Canterbury Hospital in 1983, said that Dr Evatt was the doctor who identified the haemophilia patients in 1982 with what became known as AIDS.[27]

11.20 Dr Winter commented:

Prior to July 1982 the disorder was known as GRID, Gay Related Immuno-Deficiency, and it was these reports of July 1982 that really changed the favoured aetiological agent, obviously enough towards a virus. The fact that here were this small number of patients with a blood disorder, treated regularly with blood products, here were they with the same disorder, that made viral aetiology very much more likely than the previously favoured theories, and then obviously we only had to wait a few more months before there was much clearer evidence that it was likely to be a viral disorder even though the virus had not at that time been identified.[28]

11.21 Not everyone was convinced and Dr Evatt's views were not generally accepted at the time. Opinion that the disease was likely to be due to a blood-borne transmissible agent hardened to some extent after July 1982 but unanimity was not achieved. There remained considerable divergence of views on the aetiology of the disease. Dr Evatt's views met with particular resistance among haemophilia clinicians.

11.22 Specialists in infectious diseases also saw difficulties. Professor Lever told the Inquiry that, at that time, there were hints that this new illness might be an infection but that it did not have the usual characteristics of an infection. With chronic infections such as hepatitis, the immune system would be activated to try to clear the infection. One of the mysteries with AIDS was the apparent deterioration of the immune system: 'It was almost like a degenerative disease, things were failing, and there was no obvious evidence before testing came along that the body was doing anything about it.'[29]

11.23 Professor Lever thought that individual physicians and the people at the CDC whose job it was to study the epidemiology would have been looking for a common element causing suppression of the immune system, taking into account the unusual infections and malignancies that were affecting different groups.[30]

11.24 Epidemiological studies, begun shortly after the initial reports of the disease, confirmed that the constellation of symptoms seen in homosexual men was also seen in the additional groups found to be infected and in heterosexuals with multiple partners. The need for a more broadly-based hypothesis was reinforced by the report in December 1982 of four more cases of heterosexual haemophilia patients with opportunistic infections in the USA[31] and, in the same month, the report (by Dr Arthur Amman and others) of a possible transfusion-related case of AIDS in a 20-month-old child from San Francisco.[32] The child had been treated with an infusion of platelets from a donor who subsequently died of PCP. This case, and another of a child under 10 years of age, suggested that an association with sexual conduct was unlikely.

The 'San Francisco child' debate

11.25 There was, however, considerable divergence of opinion on the case of the infant from San Francisco. As noted in Chapter 9, The Geographical Spread and Prevalence of HIV 1, paragraph 9.32, the Morbidity and Mortality Weekly Report (MMWR) editorial of 10 December 1982 advised caution. Professor Christopher Ludlam, Director of the Edinburgh Haemophilia Centre during the reference period, commented that it was not a definite case of AIDS. He speculated that the child could have had a congenital immune deficiency, notwithstanding that there was an infected donor.[33] He agreed that it was a significant event, although not a 'clinching' one.[34] Professor Lever said that the case was 'compelling but not absolutely conclusive'. He also pointed out that the genetic background of the child was unknown, as was his particular susceptibility to illness which could have made him more prone to an infection. He thought that, taken with other knowledge at this time, it was 'more and more suggestive of an infectious agent and a transmission by blood products. But it doesn't close the door'.[35] Later, when discussing the differing hypotheses emerging around this time, Professor Lever returned to this case and commented that a very young child, months old, was not something to hang a whole case on because 'some two per cent of children are born with some oddity about them, some minor difference from the average'.[36]

11.26 On the other hand, Dr Winter's view was that the report of infection in the San Francisco infant was a critical point in the developing history.[37] After that, it was no longer possible, in his view, to support the theory that the disease was related to the lifestyle of homosexuals rather than that it was caused by an infectious agent. He expressed his view strongly:

By December 1982 ... [a]ny clinician looking at this data would have to believe that AIDS was a transmissible disorder and that it could have been transmitted by blood and blood products. It was the only clinical interpretation of the data that was available.[38]

11.27 On the evidence as a whole, however, Dr Winter was ahead of other opinion in arriving at this conclusion. It was inconsistent with Dr Peter Kernoff's reported views at the time and with the views of Professor Lever and Professor Ludlam, expressed in retrospect, among others. It is clear that a further major split in opinion was to develop, as Dr Winter indicated, but that was to come later.

Koch's postulates

11.28 At a workshop convened on 4 January 1983 in Atlanta there was a hostile reaction to Dr Evatt's argument.[39] As he reported it, there were calls to 'Show us the agent ... subject it to Koch's postulates.'[40] At the end of the workshop it was said that the biggest question of all remained what caused AIDS. In relation to the infective agent theory, Dr Louis Aledort, Director of the Haemophilia Center at New York and a respected US haematologist, was and remained for some time a prominent sceptic. He was one of a group of clinicians who found it particularly difficult to accept that blood products were transmitting an infectious agent.[41] Dr Aledort favoured the idea that haemophilia patients were exposed to a great number of foreign antigens in the course of treatment and experienced a high degree of antigenic stimulation that effectively wore out their immune systems: the 'antigen overload theory'.

11.29 The resort to Koch's postulates by the CDC's opponents perhaps reflected the full extent of the divergence of opinion at the time. Robert Koch was a 19th-century German physician who set out criteria that he thought necessary to prove that an infectious agent (at the time typically bacteria) was the cause of a particular illness when transmitted from one person to another.[42] Professor Ludlam outlined the requirements:[43]

  • The bacteria must be present in every case of the disease.
  • The bacteria must be isolated from the host with the disease and grown in pure culture.
  • The specific disease must be reproduced when a pure culture of the bacteria is inoculated into a healthy, susceptible host.
  • The bacteria must be recoverable from the experimentally-infected host.

11.30 If Koch's postulates were satisfied, that demonstrated to a satisfactory standard that a particular disease was caused by an infectious bacterial agent.[44] The postulates did not supply proof to the standard of a mathematical or scientific certainty, however, that the specific bacterial agent caused the specific disease. It remained a test of probability according to Dr Winter.[45] Consistent with Dr Winter's evidence, Professor Lever said that Koch's postulates were valuable as a guide but they were not the final definition of whether something was an infection. He also explained that the postulates were much more difficult to apply to viruses:

[B]ecause viruses only grow within living cells and if one doesn't have the appropriate cells in culture in which that virus can grow, or one cannot keep the appropriate cells alive, one cannot fulfil the second of Koch's original postulates.[46]

11.31 In early 1983 the agent of transmission, HIV, had not been identified. It could not be known that, if there were an agent of transmission, it would necessarily share common characteristics with bacteria that would enable the postulates to be satisfied. Furthermore, AIDS was not a 'specific' disease. The disease manifestations of AIDS included PCP and KS but the full spectrum ranged from cases of proven cell-mediated immune deficiency without symptoms to non-specific symptoms associated with laboratory evidence of immune deficiency. The CDC definition for reporting purposes by this stage identified AIDS as a 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. Koch's postulates would have required adaptation for application to the identification of an infective agent for the transmission of AIDS.

11.32 There are other reasons for concern that Koch's postulates may have been relied upon. Fully developed AIDS, as understood from the earliest stages of the epidemic, was associated with high mortality. Leaving aside the first two postulates, the infusion of blood from a known AIDS patient into a susceptible, healthy host - another human being - with an inherent risk of causing potentially fatal disease could not have been justified. By the time it was accepted that HIV was probably the agent of transmission, so that the first two postulates might have been tested, the risk of incurable and potentially fatal disease was so well established that it would have been unthinkable to expose a healthy, susceptible human host to infection to test the postulates.

11.33 So far as the UK is concerned, Professor Ludlam stated that he had no recollection of Koch's postulates featuring in the discussion around this time (in 1983). He emphasised that in clinical medicine one worked the whole time with incomplete data and information, making assumptions that may not be backed up by scientific evidence.[47] In relation to the infant who had received a transfusion of platelets (reported in the MMWR of 10 December), Dr Winter thought that 'because you had ... three parts of the equation - the donor, the recipient and the blood transfusion - it could have been said to have fulfilled Koch's postulates.'[48] Professor Lever said that some clinicians took the approach that if most of the postulates were satisfied, it was more likely than not an infectious agent but that other clinicians did not agree with this approach.[49] Controversy reigned.

11.34 By the end of 1982 and in to 1983 the aetiology of AIDS remained, technically, unknown so far as Koch's postulates were concerned: the full requirements of the postulates had not been fulfilled.[50] At the Atlanta conference the opponents of Dr Evatt's views regarded his evidence as anecdotal in the absence of proof to that standard. The CDC was dismayed by the outcome of the Atlanta conference.[51]

11.35 Koch's postulates were an impossible test at the time. The demand for proof to that standard demonstrates the resistance among highly respected US clinicians to the infectious agent theory but leaves open the question whether that resistance was based on scientific grounds or reflected wider concerns about the implications for haemophilia therapy if the theory was given credibility.

Altered immunological states in haemophilia patients

11.36 On 29 January 1983, Dr Margaret Ragni and others reported altered immunological states in two multiply-transfused patients with severe haemophilia.[52] They commented:

The lymphadenopathy and immunological features in these two haemophiliacs bear a striking resemblance to the acquired immunodeficiency syndrome (AIDS) of homosexuals, intravenous drug abusers, and Haitian immigrants. These findings may represent a prodromal [early, often asymptomatic] phase or forme fruste [atypical manifestation] of AIDS. Transmission of an infectious agent in blood products seems likely.[53]

11.37 Professor Ludlam commented that at this time it was unclear whether individuals with the features reported by Dr Ragni and her colleagues were likely to get AIDS but that the study provided further evidence for AIDS in haemophilia patients being caused by an agent transmissible in Factor VIII concentrate.[54]

11.38 By the summer of 1983 there was continuing doubt in some segments of the haemophilia community, in the blood banking industry, and among physicians and the Food and Drug Administration (FDA) in the USA that AIDS was a blood-borne infection.[55] There was no consensus that the disease was transmitted by a virus and, until Robert Gallo's announcement in 1984, no generally accepted evidence of a candidate for transmission.[56]

11.39 There were similarly differing views in the UK. Dr Winter was asked whether there was particular resistance to the transmissible agent theory, on the part of at least some haemophilia clinicians in the UK, because of the advantages of using concentrates. He said:

I think ... that was the case. The initial - if you like, the clinicians didn't want to believe any of this data, because we [had] just been through such a very major advancement in healthcare. So that would have been the mindset originally and then they are looking at this American data and the next thing is, okay, these patients - they are a very small number and there were no British ones and there were no German ones, so I'm just going to keep on looking at the situation, and now you have a situation, December 1982/January 1983, I can't ignore this any more. These patients must have a disorder that's caused by blood transfusion in the forms of the concentrates. So maybe in Britain things will be fine if we now just switch or do all we can to use British concentrate.

In America it was the same ... the clinicians didn't want to believe it, the commercial companies didn't want to believe it, the blood transfusion services didn't want to believe it because they were particularly sensitive about excluding certain risk groups as donors. There were lots of political issues around that. So none of the related agencies wanted to know this. That's why, if you like, I'm sure, this data took some time to really hit home.[57]

11.40 He continued:

So deeply engrained in the psyche of haemophilia clinicians, as in the patients ... was the concept that British blood was likely to be much freer from viruses than American blood. So here we were in 1982, we already knew about hepatitis, we already knew about the increased risk from commercial donors. Here was now what looked like a transmissible disease that also appeared to be occurring in these same unsavoury American blood donors. This reaffirmed the view that these things weren't likely to happen in British blood donors.[58]

11.41 On the evidence now available to the Inquiry there was, on one view, ample circumstantial evidence by early 1983 of an association between some blood products and transmission of infection. Infected patients had received large amounts of concentrate; none had prior opportunistic infections; their personal and environmental histories were different; and two were 10 years of age or less. It would have been open to infer that the whole group of infected patients would not fall within any of the other known at-risk categories of promiscuous homosexuals, heroin addicts and immigrants into the USA from Haiti. However, the proponents of the several theories were divided on a more basic level reflecting interests that were not wholly scientific in origin. The resistance of the haemophilia clinicians appears to have reflected their wish to continue to use factor concentrates of proven efficacy in treating their patients. The pharmaceutical industry had commercial interests to protect. Human nature rather than the strict application of scientific theory probably contributed to the persisting differences of opinion.

Competing theories in 1983

11.42 While a common cause was postulated in the haemophilia population and in homosexual and other groups by some commentators, there were unresolved issues. In particular, once it was established that AIDS was occurring in the haemophilia population as well as in other risk groups, there was an apparently inexplicable difference in the pattern of disease. The haemophilia patients did not develop KS, whereas this was common in homosexual AIDS patients. The difference in the pattern of disease presentation probably contributed to the belief that there were different aetiological agents behind the diseases in the two groups.[59]

11.43 It is now reasonably clear that there are likely explanations for the difference. Professor Lever told the Inquiry that it is now thought there are two or three possible explanations for the absence of KS in haemophilia patients with HIV infection. One is that HHV8 (otherwise KSHV, the herpes virus responsible for KS) may be very poorly transmitted by blood-borne routes. Transmission does occur by these routes, but it is certainly less easily transmitted than HIV. The amount of HHV8 virus present in the blood may be far less than the many millions of copies of HIV that one finds. Second, it may be far more easily transmitted by the sexual route and that would also be plausible because other herpes viruses are transmitted by mucus membrane contact. Classically, herpes simplex type 1, which causes the cold sore, is transmitted mouth to mouth or by saliva. EBV, another herpes virus, causes glandular fever and is sometimes known as 'the kissing disease'. So it is quite likely that sexual transmission of HHV8 is far more efficient than any other route. The third possibility is that a preparation technique might have been effective to inactivate in blood products what is a large and also relatively fragile, complex virus. Or the explanation might be a combination of the above.[60] These possible explanations of the differences in disease profile were, however, quite unknown in the 1980s.

11.44 There were other uncertainties at that time. Professor Lever told the Inquiry that there were many people who from the beginning thought there was an infectious cause and many who did not. He thought that the issue was that there was no physiological appearance of an infection. He continued:

The fact that you get a rash with measles is probably only there to tell the rest of the population that you are infectious and should be kept away from. The fact that you get a very high fever in some diseases doesn't actually do you very much good but it tells other people that you are ill. That's how mothers know their babies are ill because they feel hot.[61]

11.45 The geographical spread was also unusual, although not unprecedented. Professor Lever advised that some infections could spread very rapidly but in this case there was no continuity or explosion of a cluster in one particular area.[62] In the period 1982-83 these and other uncertainties led to a more broadly-based study by virologists of immune deficiencies in cases of AIDS infection.

Haemophilia research

11.46 The publication of cases of AIDS in haemophilia patients, first in June and then November 1982, had prompted several groups of researchers in the USA to carry out immune studies in groups of asymptomatic haemophilia patients. It was known that the absolute number of certain cells ('helper' cells known as T4 or CD4 cells) and the ratio of those cells to another group ('suppressor' cells known as T8 or CD8 cells) provided a measure of cell-mediated immunity, the effectiveness of the immune system. The researchers found widespread depression of T4/T8 ratios in their subjects and also found that depressed T4 counts were very closely related to exposure to US commercial Factor VIII concentrates. The 'immune overload', or 'antigen overload', theory developed as an alternative to a transmissible agent theory as an explanation of these immune disorders: the fact that immune abnormalities occurred in asymptomatic haemophilia patients receiving single or multiple-donor products suggested that immunological defects might arise from blood product treatment alone.[63] It was also relevant to the view developed at the time that there was uncertainty about what did constitute AIDS.[64]

11.47 The major pathological feature of AIDS was very profound immunosuppression, with characteristic suppression of T4/T8 ratios and hyperglobulaemia (an excess of globulin in the blood). Researchers began to explore ideas based on the hypothesis that there was a relationship between these immune phenomena and the aetiology of AIDS. During 1982 and into 1983 immune studies of homosexual men with no symptoms of AIDS showed similar, if less marked, immune phenomena (notably suppressed T4/T8 ratios) to those with overt diseases characteristic of AIDS.

11.48 On 13 January 1983, the New England Journal of Medicine (NEJM) published an article by Michael Lederman and others entitled 'Impaired cell-mediated immunity in patients with classic hemophilia'.[65] They studied 19 patients and 19 controls and, within the haemophilia group, distinguished those who had received Factor VIII concentrates from those who had received only cryoprecipitate.[66] The T4/T8 ratio results for the latter group did not differ from the controls. The results for the group who had received Factor VIII concentrates were similar to those reported among populations of apparently healthy homosexual men. The authors thought that genetic haemophilia factors were unlikely to explain their findings. They stated:

A more likely possibility is that the immune dysfunction is acquired. Active infection with hepatitis B virus is probably not responsible, since none of the 11 patients in the group [treated with concentrates] had demonstrable hepatitis B surface antigenemia. The cause of the immuno-suppression in this population is not known ....[67]

11.49 They commented that, among AIDS patients, epidemiological evidence would implicate a blood-borne pathogen as the cause of immunosuppression but offered no view as to whether this explained their findings.

11.50 In the same issue of the NEJM, Jay Menitove and others also published immunology studies on apparently healthy haemophilia patients, differentiating those treated with cryoprecipitate obtained from volunteer blood donors and those treated with commercially prepared Factor VIII concentrates and further distinguishing groups according to dosage.[68] They set out to test the hypothesis that AIDS might be transmitted through Factor VIII infusion. They found that none of the cryoprecipitate users had abnormal T4/T8 ratios while 57% of the users of commercial concentrates did have abnormal ratios. They noted that there had been speculation that AIDS might be transmitted to haemophilia patients through Factor VIII infusion. The article noted that the epidemiology of AIDS was suggestive of a blood-borne transmissible agent but it was not yet clear whether the abnormalities in cell-mediated immunity in patients with haemophilia and, in particular, in those who had also developed opportunistic infections were due to the putative blood-borne pathogen. The authors advised caution in the interpretation of the findings. They noted that the proposed explanations for AIDS included CMV infection, inhaled nitrates and exposure to foreign antigens, such as spermatozoa, and concluded:

Our data are consistent with the possibility that commercially prepared lyophilized factor VIII concentrates can induce an AIDS-like picture, but a large number of patients must be studied before a definite conclusion can be drawn. In addition, we cannot hypothesize about the emergence of this apparently new syndrome at this time. Whether the abnormalities found in our patients will evolve into clinical disorders remains to be determined, but we urge those involved in the care of patients who use factor VIII concentrate to follow them carefully for stigmata of AIDS and changes in immunologic status.[69]

11.51 The opinions in these two articles in January 1983 were carefully qualified. Neither paper used the term 'immune overload' or any of the alternative expressions carrying the same meaning. However, to a greater or lesser extent each explored the underlying idea while not excluding a largely infective blood-borne cause of AIDS in haemophilia patients.

The 'immune overload' hypothesis

11.52 The hypothesis was that immune cellular dysfunction might be brought on by an 'overload' of normal immune responses, either by repeat introduction of foreign proteins contained in sperm or the repeated infusions of concentrates, or repeat infections with organisms such as CMV or EBV, leading to a state of immune suppression and presumably 'priming' the individual for an infection or other event leading to overt AIDS disease. Until early 1984, this theory gained support and, until the publication by Gallo of his identification of HTLV-III, was favoured by haemophilia specialists, some virologists and some immunologists.

11.53 In an editorial in the same issue of the NEJM, Dr Jane Desforges commented that it was not yet known whether AIDS was secondary to multiple antigenic exposures, to a specific transmitted agent or to some other mechanism. The options were open.[70]

Antigen overload or a transmissible agent?

11.54 As indicated at paragraph 11.28 above, at the Atlanta meeting on 4 January 1983, Dr Evatt and his colleague, Dr James Curran, reported the findings and views of the CDC linking AIDS to a transmissible agent in blood products and noting that the risk for non-haemophiliacs was unknown but apparently small. The alternative theory was laid out. The hypothesis underlying Dr Aledort's theory was that prolonged exposure to foreign proteins had an impact on the immune system similar to that found in homosexual men and that AIDS was an end-stage development of these abnormalities.

11.55 Both theories received media attention. There was comment on the issue in The Observer of 16 January 1983 in an article entitled 'Mystery Disease Threat'. The article commented on the infective agent theory. On the alternative point of view, the article quoted Dr Peter Kernoff from the Royal Free Hospital in London as saying:

"Assessing the risk is not a straightforward matter: we need much more hard evidence .... Factor VIII is a very valuable product and the advantages far outweigh the disadvantages."[71]

11.56 Dr Winter thought that Dr Kernoff's comment reflected the position at the time:

He is a very respected figure looking at the data saying it is of concern, but we are talking about a product that has revolutionised the lives of patients and there is a major obvious benefit to this treatment. We will have to look at the risk that appears to be evolving. That was the situation of the day.[72]

11.57 In the Department of Health and Social Security (DHSS), someone (name redacted) expressed the official view that:

[T]he value to severe haemophiliacs of clotting [Factors VIII and IX] far outweigh the possible and as yet unproven hazards of the transmission of acquired immune deficiency syndrome.[73]

11.58 At the 19th Congress of the International Society of Haematology and 17th Congress of the International Society of Blood Transfusion in Budapest in August 1982, Dr Aledort discussed his experience with the cases of three haemophilia patients in the USA who had died from pulmonary infections characteristic of AIDS (as reported in the July MMWR - see paragraph 11.18 above). The theory was taken up by some haemophilia clinicians in the UK. On 15 January 1983, simultaneously with the two NEJM papers mentioned above, there was a report in The Lancet of altered immunology in English haemophilia patients.[74] The article, by Dr Peter Jones and others, Newcastle upon Tyne, noted that transfusion was immunosuppressive, in an as yet unidentified way, in renal transplantation and commented that an immunosuppressive syndrome associated with T-cell subset reversal had been noted in a small population of multiply-transfused, heterosexual haemophilia patients in New York. They commented on their own findings:

The alterations in T cell subsets in our survey may simply reflect temporary altered immune status in multitransfused individuals. But half our patients without T cell ratio reversal had been exposed to equally large quantities of blood. It could be that T cell ratio reversal is a normal defence mechanism to antigenic load, and that the patients without reversal show an abnormal lack of response.

None of our patients, who have all been exposed to commercial blood products of American origin, shows features of AIDS ....[75]

11.59 The article by Dr Jones followed in date, but must have been submitted before, the workshop convened by the CDC in Atlanta on 4 January 1983.[76] At the date of its preparation, the antigen overload theory had a certain currency among other haemophilia clinicians in the UK. Professor Ludlam commented that this report of low T4 counts and T4/T8 ratios suggested that the changes might be a response to antigenic load.[77] In his case, this initiated a research interest that came to have considerable importance for a time. Commenting later on a draft paper prepared for litigation in England and Wales 20 years ago,[78] he said:

[It was] possible that AIDS was arising in haemophiliacs because during the 1970s there was increasing use, massive increasing use of Factor VIII concentrates.

I mean, I calculated that at least using SNBTS concentrates, that in an average lifespan, you gave out a kilogramme of protein intravenously in an average severe haemophiliac. We are not designed to accept proteins in that magnitude intravenously. So one possibility was that actually - as we hinted earlier - maybe haemophilia as a whole was sliding into AIDS because of all the concentrate we were using. Quite separate from HIV or a putative virus.[79]

11.60 In March 1983, Jonathan Goldsmith and others wrote an article published in The Annals of Internal Medicine in which they considered the similarities in T-helper/T-suppressor cell ratios in haemophilia patients and in homosexual men, Haitian refugees and narcotics addicts.[80] They noted that a characteristic feature of the altered cellular immune functions in homosexual men was reduced T4/T8 ratios and that it had been suggested that these abnormalities were the result of continued exposure to sexually transmitted viral infections, particularly CMV infection. They studied 12 apparently healthy haemophilia patients to ascertain if they had similar abnormalities in their lymphocyte sub-populations. The similarities in biometric abnormalities were striking in 9 of the 12 patients studied. However, none of the haemophilia patients had been exposed to nitrates and all had stable antibody titres to CMV.

11.61 The conclusion relating to the haemophilia patients was that:

The presence of an abnormal ratio of helper to suppressor T-cells in these patients is of uncertain significance, and this observation needs to be confirmed .... In addition, since the establishment of the ... Regional Haemophilia Centre ... in 1976, no cases of pneumonia or chronic infection have occurred in our patients .... Whether patients with these T-cell defects are at increased risk for development of malignancy has yet to be substantiated. Reports from the literature, however, suggest that patients with congenital bleeding disorders have a prevalence of malignant disease similar to the general population. At this time there is insufficient evidence to advocate a change in therapeutic practices in these patients. However, additional patients with hemophilia need to be evaluated to ascertain if the magnitude of exposure to clotting factor concentrates is associated with an increased incidence of malignancy or opportunistic infections.[81]

11.62 In early 1983 the antigen overload theory was supported by haemophilia clinicians on both sides of the Atlantic. Professor Lever explained that it was a compelling theory at that stage.[82] He suggested that the theory had probably originated in New York amongst the physicians looking after patients with HIV and amongst the gay population in New York itself. He thought that 'a physician in New York' (a description that Dr Aledort would have fitted) had put the antigen overload theory forward as an alternative, less stigmatising theory. With the benefit of hindsight, it could be speculated that they felt that if it was perceived that there was an infectious cause the gay population might be more stigmatised for transmitting agents which caused disease. The stigma was very real. Professor Lever described the scenes that occurred during the first Canadian conference on AIDS held in Montreal in May 1985.[83] The stage was taken by different pressure groups protesting about what had been seen to be media perceptions or medical professional perceptions. The prostitute population complained that being referred to as 'vectors of disease' was very demeaning. In South Africa it was deemed to be politically better for there not to have been a virus originating in Africa which caused the infection. These reactions would have established themselves in the minds of people who had vested interests in there not being a virus.

11.63 Professor Lever was anxious, however, to put the issue in context. As already noted, he emphasised that the initial manifestations of HIV did not look like a normal infection. They looked like something that was leading to degeneration or deterioration in the immune system. There had not been another infection which clearly did that. That was why theories of protein overload and theories of abuse of specific drugs like amyl nitrate were brought up. The disease could have been a toxic effect in the immune system. All of the theories were as plausible as each other. None of them had a majority view at the very beginning. Professor Oliver James, Medical Assessor to the Inquiry, had a similar impression of the early development of these theories. [84]

11.64 The antigen overload theory persisted in parallel with the transmissible agent theory and remained competitively tenable until the virus was isolated.[85] Various agents were considered as possible causes of the new disease.

Scottish research

11.65 In Scotland, interest in the topic developed in Edinburgh and in Glasgow. In the context of haemophilia therapy, Professor Ludlam began a series of tests, described by him as 'screening' tests, in about the beginning of 1983.[86] His studies started after the first three cases of AIDS in haemophilia patients had been reported in the USA in July 1982 and followed the course of research into clinical immune deficiencies in homosexual men with AIDS. As already noted, a characteristic feature of these immune deficiencies was a reduction in blood CD4 lymphocyte numbers and a decrease in CD4/CD8 ratios. Similar decreases in CD4 numbers and CD4/CD8 ratios were found in intravenous drug users. Professor Ludlam explained that it was uncertain whether these were due to viral infection, chronic antigen stimulation or another aetiological factor. This stimulated his research into the position in asymptomatic haemophilia patients.[87]

11.66 Professor Ludlam studied a large number of patients and found a pattern of suppression that seemed to have at least some parallels with the New York studies. Professor Lever explained that in the absence of an illness that looked like conventional infection one would look around for competing theories.[88] To ensure control of the tests, Professor Ludlam had the forms for samples labelled 'AIDS study'.[89] This was later to give rise to suspicion on the part of some patients that he was carrying out experiments on his patients. In the view of this Inquiry that suspicion was without foundation. Professor Ludlam explained that by the spring of 1983, it was becoming clearer that strange things were happening to the immune systems of patients with haemophilia who were otherwise feeling well.[90] He explained what he was doing:

In 1982/83 in the absence of any patient with an AIDS-defining illness, the only way to potentially investigate individuals to assess their possible susceptibility to developing AIDS was to assess their immune function by laboratory testing. By 1983 it therefore seemed important, as it did to many other haemophilia physicians, to investigate the immune status of patients under my care....

I was surprised to observe that many patients had immune abnormalities very similar to those reported from homosexual men and haemophiliacs residing in North America.[91]

11.67 He said in oral evidence:

It was - the interpretation that you could put upon those was puzzling us. I would say that similar abnormalities were shown in gay men who were otherwise feeling well. And the question is in fact: were all these patients or all these individuals in the United States actually already infected with a latent, if you like, AIDS virus?[92]

11.68 While his patients had immune abnormalities similar to those reported in homosexual and other populations in the USA, it was inferred that they could not have been infected with an AIDS virus and that, at least in Edinburgh, patients' immune disturbances were due to a non-AIDS-causing agent.[93] This raised the possibility that haemophilia patients in the USA and elsewhere might not be infected with an AIDS virus.[94] In the event, his oral evidence was that there were three groups: those with abnormal immune systems who were subsequently shown to be infected with HIV; those with abnormal immune systems who were not infected with HIV; and those with normal immune systems who were infected but in whom changes in the immune system had not yet begun.[95]

11.69 A letter to The Lancet of 30 April 1983 by Robert Gordon of the US National Institutes of Health (NIH) put the antigen overload theory in a way that provoked a response from Professor Ludlam. Having noted that observations of altered distribution of T-lymphocyte sub-populations in haemophilia patients with AIDS was consistent with the hypothesis that the disease was caused by a transmissible agent, presumably a virus, in blood products, Dr Gordon continued by saying that the observations were:

[A]lso compatible, however, with the possibility that repeated administration of factor VIII concentrate from many varied donors induces a mild disorder of immune regulation by purely immunochemical means, without the intervention of an infection.[96]

11.70 A response from Professor Ludlam and others appeared in The Lancet of 28 May 1983. It referred to Dr Gordon's letter and to the ongoing study of haemophilia patients in south east Scotland. By this stage in Dr Ludlam's continuing research programme, 23 patients who had received exclusively SNBTS Factor VIII in the past five years, most of whom had never received commercial concentrate, had been studied. In the majority of these patients, the T4/T8 ratios were reduced. The letter stated:

Since there are no known cases of AIDS in our blood donor population it seems likely that the immunosuppression observed in haemophiliacs, as reflected by reduced T lymphocyte helper/suppressor ratios, results from infusion of foreign protein or a ubiquitous virus rather than a specific AIDS virus in factor VIII concentrates.[97]

11.71 Professor Ludlam's letter to The Lancet was published at or about the time that the results of Montagnier's work were coming into circulation.

11.72 The course of study of immune abnormalities amongst haemophilia patients involved a number of projects and teams and continued into 1984 with many published papers, including Professor Ludlam's own work. The work demonstrated a range of immune disturbances similar to those observed in other risk groups: a reduction in CD4 counts, disturbed CD4/CD8 ratios and other immune abnormalities. In a summary of the position as he saw it at about this time, Professor Ludlam observed that there were several candidate viruses in the field, some known and some unknown or mutations of known viruses. In the case of homosexual men, 'antigen overload' from semen in the rectum and 'recreational drugs', such as amyl nitrate and isobutyl nitrate, were candidates. Proteins other than Factor VIII/IX in clotting factor concentrates used to treat haemophilia were another.[98] On his approach, it was inappropriate in mid to late 1983 to make an assumption that the AIDS in people with haemophilia was of similar aetiology to the AIDS in the other groups. It was known that, clinically, the spectrum of AIDS-related conditions differed to some extent as between the groups and so clinicians considered the possibility that they had arisen simultaneously, or nearly simultaneously, but were of different aetiologies.[99]

11.73 At the Glasgow Royal Infirmary (GRI), Professor Charles Forbes was interested in the same phenomenon. His group's research on immune disorders was published in October 1983.[100] He said:

It was quite apparent that there was an association between the administration of large amounts of Factor VIII concentrate and the immune process, which was suppressed in many patients. A variety of other investigators were finding the same kind of abnormalities using a range of biochemical tests and the real question was what did this mean? Was there something in the Factor VIII or IX concentrates that did suppress these tests of immunity?[101]

11.74 He explained:

We became interested because of the ability to measure so many of the factors in blood. And we were kind of thrown off the scent at this time by finding that a lot of our patients who had been highly treated, a lot of protein given to them, had abnormalities of various kind[s], not all the same kind, and we thought that it must be that their immune system was being suppressed by something in the plasma that they were given, and that was a view we took and explored for several years. And I think it was probably accurate to say that there were abnormalities but what they meant, we didn't know, and of course, some of it probably was that they were infected with the unknown virus, HIV. So we were looking for something but we didn't know what we were looking for at the time.[102]

11.75 So far as he was concerned, the mystery has not been resolved even now.[103] His evidence about the state of knowledge in the early 1980s was not clear.[104] He thought, however, that there was a lot of doubt and argument at the time: knowledge was not hard and fast.[105]

The infective agent theory

11.76 As noted in paragraph 11.55, an article was published in The Observer in January 1983 commenting on the competing theories. In relation to the infective agent theory, it stated:

A commercial blood product imported into Britain from the United States, may pose a grave threat to the health of haemophiliacs who inject it to encourage clotting ....

[I]t is being been linked in America with a devastating and mystifying disease previously associated with homosexuals, which causes a serious breakdown in the body's immunity system.

Officials at the Government's Center for Disease control ... have described the spread of the disease as 'an impending epidemic' among haemophiliacs ....

In the past 10 months the disease has spread from the homosexual community to include haemophiliacs, Haitian immigrants, drug abusers, a handful of heterosexuals and some children. The cause remains baffling. One theory is that an infection agent is transmitted directly, either sexually or through contaminated blood products, in a similar manner to hepatitis B ....

Although no cases of AIDS have been reported from British haemophiliacs, the deaths of at least 10 American haemophiliacs, are now known to be caused by the disease following a survey of nearly 6000 haemophiliacs.[106]

11.77 An article in the New Scientist of 3 February 1983 commented that there was a risk that AIDS was transmitted by blood products. It stated that the hunt for the cause of the disease:

[H]as now labelled as a prime suspect some unknown blood-borne virus.


In the last year, a task force under Dr Harold Jaffe at the Center for Disease Control in Atlanta, Georgia, has found seven cases of AIDS among haemophiliacs .... Jaffe believes that the spread of the disease may be connected with new preparations of factor VIII concentrate - the blood-clotting agent given to haemophiliacs - which are made up from blood from large numbers of donors, rather than one individual.

If this is correct, any patient in hospital who is given a blood transfusion could be at risk if one of the donors of the blood carries the virus.

No cases of AIDS among British haemophiliacs have been reported so far - even though 50 per cent of the factor VIII used in Britain comes from the US.[107]

11.78 On 1 March 1983, a paper on AIDS was produced by the UK Haemophilia Centre Directors' Hepatitis Working Party.[108] It was sent to the DHSS on 11 April 1983. This paper summarised the position to that date, based on information from the CDC at Atlanta. Aetiology was explored, with the infectious agent theory being favoured as the most likely cause. The concluding paragraph stated that it was likely that batches of Factor VIII concentrate which might contain the AIDS agent had been in use since the beginning of 1980. The CDC had therefore requested the UK Haemophilia Centre Directors to report cases of AIDS which might be related to transfusion of US concentrate. A detailed list of possible symptoms, diseases and signs associated with AIDS formed part of the survey sent to all centre directors.[109]

11.79 Dr Winter told the Inquiry:

I think by that stage all haemophilia clinicians were signed up to the infectious theory because of the evidence of the San Francisco child. There was no other construction you could put on that evidence. So I think these minutes are just reflecting - they are setting out the other theories and discounting them because of the new haemophilia data.[110]

11.80 Despite Dr Winter's view, it is clear that in fact there was not unanimity by this stage. However, the view of the UK Haemophilia Centre Directors' Hepatitis Working Party can be taken to be broadly representative of opinion in the profession.

11.81 In The Annals of Internal Medicine of March 1983, an editorial and a series of articles discussed the evidence available up to that time and lent further support to the transmissible agent hypothesis.[111] Dr Evatt and Dr Curran were two of the three authors of the editorial. It gave further information about the preparation of concentrates. In the US, plasma pools contained up to 22,500 individual donations and approximately 500,000 international units of anti-haemophilic factor. The average patient with severe haemophilia received 30,000 to 50,000 units per annum from 5 to 10 separate lots and was thereby exposed to tens of thousands of donors each year. Haemophilia patients receiving blood products were said to be at the highest risk of contracting AIDS. Substantially the same material was contained in the UK Haemophilia Centre Directors' Hepatitis Working Party report referred to in paragraph 11.78, above.

11.82 In March 1983, Dr Peter Foster of the PFC (the Protein Fractionation Centre, the manufacturer of NHS blood products in Scotland) gave a series of presentations to haemophilia clinicians and haematologists in Edinburgh and Dundee.[112] He was somewhat guarded in expressing his opinion. He mentioned that AIDS might be caused by transmission of an infectious agent. In evidence, he said that at that time his perception of the risk had been somewhere between a possibility and a probability. He was not definitive, but thought that the risk should be taken into account by the PFC.[113] As an SNBTS scientist, that was a reasonable position to adopt at the time. An infectious aetiology was still not settled. The editorial in The Lancet of 2 April 1983, 'Acquired Immunodeficiency in Haemophilia', commented that the links with blood or blood products must be regarded as not proven.[114]

11.83 The UK public health view as reflected by Dr Spence Galbraith, Director of the Communicable Disease Surveillance Centre (CDSC) in England and Wales, was set out in a letter to the DHSS in May 1983. He enclosed a paper setting out his views in support of the transmissible agent theory.[115] His view, which he supported by detailed discussion, was that the AIDS epidemic in the USA was probably due to a transmissible agent and that the agent was probably transmitted by blood and blood products.

The comparative position in mid-1983

11.84 Professor Lever commented on the competing theories at this time:

There were competing hypotheses as to what was causing the immunodeficiency, some of which had quite powerful advocates. I think ... the balance of opinion or the balance of evidence was in favour of an infectious agent at that stage. However, as one knows, the amount of distress and concern and worry, sometimes unnecessarily, that you can induce in people by raising the fear of an infectious agent in something like a blood product would be undesirable unless it was absolutely certainly the case, or as near certain as you could be that that was the case.

I think people would not necessarily have been very understanding had this turned out to be a false alarm and individuals had either bled or died by withdrawal of the clotting factors and then it having been found that there was not the threat which had been assumed.[116]

11.85 Professor Ludlam said that the inferences in his studies in 1983 were confirmed when anti-HTLV-III (HIV) testing became available in late 1984 and all but two of the patients in the 1983 study were found to have been negative for HIV in 1982 and in 1983.[117]

11.86 Professor Ludlam's work was to receive attention in June 1983. When Dr Foster reported on the World Federation of Haemophilia (WFH) and International Society on Thrombosis and Haemostasis (ISTH) meeting in June 1983, he recorded that some participants had attempted to make a number of points regarding features of haemophilia patients with T-cell abnormalities: in essence, North American studies correlated lowered helper-suppressor ratios with lifetime exposure to Factor VIII or with age, whereas European studies correlated the lowered ratios with use of imported concentrates and not with local concentrates. Many European participants were implying that USA products were 'bad news'. The North American response had been 'to cite Ludlam et al'' and then to attack the validity of the data. The general feeling appeared to be that a low CD4/CD8 ratio in haemophilia patients would not necessarily indicate a pre-AIDS condition. Dr Foster's own feeling had been of an attempt to suppress AIDS 'hysteria', although some of the more scientific criticism of the T-cell situation did appear to him to make some sense. He was at a disadvantage, as were others, in one respect: Dr Evatt had not submitted an abstract and delegates were left to make their own notes of his address.[118] He noted that Dr Evatt had explained that none of the known haemophilia cases had any other risk factor.

11.87 There was a clash between Dr Evatt and Dr Aledort that reflected the depth of feeling at the time. Douglas Starr, in Blood: An Epic History of Medicine and Commerce, commented:

Bruce Evatt had been invited to speak, but he felt himself set up in a way. Though Aledort was supposed to give a brief introduction, instead he swung into a lengthy discourse on how little scientists knew about the disease. Evatt, when his turn came, felt he had to defend how much they did know.[119]

11.88 The WFH was an influential body, comprising scientists, doctors, nurses and patients.[120] It concluded that there was insufficient evidence to cause changes in the treatment of haemophilia. Once more, however, the question appears to have turned on whether there was transmission by an infective agent to the exclusion of the risks inherent in the antigen overload theory.

11.89 Professor Lever was asked when the early theories began to be disregarded. He responded that until the infectious agent had been found, theories like that would always have some degree of credibility. Once Montagnier and Barré-Sinoussi had identified something and 'certainly by the time Gallo had published', there was only a small fraction of individuals who still clung on to a theory of anything other than infection. He continued:

Up until that time I think it's a gradation. There was a gradual acceptance that it couldn't just be put down to immunological-based theories and that the epidemiology looked more and more like an infectious agent.[121]

May 1983: Identification of LAV

11.90 The continuing controversy in early summer 1983 initially paid little regard to the work of Montagnier and Barré-Sinoussi in France that was to become of real importance as the middle years of the decade passed. On 20 May 1983, an article appeared in Science reporting that the team of scientists at the Institut Pasteur in Paris had isolated a retrovirus, which they named lymphadenopathy-associated virus (LAV), from cultures of T-lymphocytes derived from the lymph nodes of a patient with signs and symptoms thought to precede AIDS.[122] There is more detailed discussion of this development in Chapter 29 The Discovery of HIV and Development of Screening Tests.

11.91 The full significance of the French discovery was not widely understood in 1983 and later Montagnier was to recognise that the results remained controversial until Gallo and his group announced their discovery of HTLV-III in the spring of 1984.[123] Nevertheless, it seems likely that the article was known to Scottish scientists by 15 June 1983 and hardened opinion in favour of an infective agent, at least as a working hypothesis.[124]

11.92 Reports of cases led to the identification of products possibly associated with transmission. Dr Foster's report from the WFH and ISTH meetings stated that of the 16 US cases one was a mildly affected Haemophilia B patient who also received two units of New York blood.[125] Of the 14 cases of AIDS reported to the UK CDSC by 31 July 1983, one was a haemophilia patient and it was noted that he had received Factor VIII imported from the USA.[126] There was growing apprehension that the disease was associated with commercial blood products from the USA. Dr Foster's report of the contribution of Dr Evatt included comments relevant to the present chapter. In summary, Dr Foster noted:

  • The June 1983 figures at CDC showed that the total number of USA confirmed cases was marginally higher than would be predicted from an exponential growth, consistent with the view that AIDS is caused by a transmissible agent.
  • Epidemiology strongly suggested a transmissible agent (AIDS had been found in spouses, male and female, siblings etc.)
  • AIDS fell into two categories: those who developed KS and those who developed opportunistic infections.
  • Haemophilia patients were in the group which developed opportunistic infections.
  • AIDS was still located mainly in key urban areas in the USA (New York, San Francisco, Los Angeles) but the haemophilia cases were generally located in non-AIDS areas. This was strong evidence for transmission by Factor VIII.
  • Common lots of Factor VIII concentrate seemed to be 'rare or non-existent'. Haemophilia patients who received material from two known Factor VIII lots prepared from plasma containing two AIDS donations had been followed for two years with no signs of AIDS at that stage.
  • The haemophilia patient with AIDS in Cardiff received products from Armour and Immuno as well as NHS concentrates. Other suspected cases had received products from Hyland (reported from Israel) and Hyland and Immuno (reported from Sweden).[127]

11.93 On 23 June, the recital of a Council of Europe resolution noted that AIDS 'may be caused by an infectious agent transmissible by blood and blood products'.[128]

11.94 On 13 July 1983, Dr Galbraith's paper of May[129] was discussed at a meeting of the Biological Products Sub-Committee of the Committee on Safety of Medicines.[130] It was minuted that the cause of AIDS was unknown but that an infectious aetiology seemed likely. The minute proceeded:

A previously unrecognised or new agent may be responsible, but repeated exposure to, or reactivation of, known agents, (eg CMV, EBV) may be involved. Heightened susceptibility may be an important factor, e.g. immunological deficiencies induced by unusual sexual practices or exposure to blood products. Based on the clinical evidence, transmissibility of the supposed agent(s) appears to be low, requiring intimate contact or introduction into the tissues.

Patients who repeatedly receive blood clotting-factor concentrates appear to be at risk, but the evidence so far available suggests that this risk is small. The risk appears to be greatest in the case of products derived from the blood of homosexuals and IV drug abusers resident in areas of high incidence (eg New York and California), and in those who repeatedly receive concentrates in high dosage.[131]

Developments during the remainder of 1983

11.95 Over the remainder of 1983, there were reports of increasing numbers of infections.[132] On 28 September, there was a meeting of the Central Blood Laboratories Authority.[133] It was noted that the Medical Research Council (MRC) had set up a working group on AIDS. The working group first met on 10 October 1983.[134] In their discussion of aetiology, there was a 'passing allusion' to the antigen overload hypothesis. The 'more widely held view' noted was that AIDS was due to a novel 'AIDS agent'. Retroviruses were considered and it was noted that HTLV was a possible candidate on the basis of its known tropism for T-helper cells.[135] The comment proceeded:

However a critical evaluation of the data led to the view that it was more probably an opportunist was unlikely [sic - likely][136] to be the aetiological agent. The assumption that the agent was necessarily a virus was challenged and the need to keep an open mind on organisms such as protozoa was stressed.[137]

11.96 The group was careful to reserve its opinions. It was said that the 'best and brightest' in the UK (at the MRC) were still very confused as to the causal agent. It was suggested that systematic antimicrobial therapy might provide leads on such agents. It was noted that blood product associated cases could enable some of these alternative hypotheses to be tested. Specifically in relation to epidemiology, but probably more generally, there was a lack of confidence in US studies which were thought to be insubstantial and not of the highest quality.

11.97 Meantime, as events were to prove, UK patients were being infected with HIV. It is of interest to note the reasons for casting doubt on US epidemiological research:

The erasure of patients' names from the records held at the Centres for Disease Control in Atlanta as a result of political pressure would limit the ability of CDC to conduct proper epidemiological studies. The organisation of epidemiology in the United Kingdom was well suited to studying this problem. The importance of establishing such studies early in the emergence of disease was again stressed. Further emphasis was given to the concept of identifying early phases of the disease for testing aetiological hypotheses. It was emphasised that at this stage national collaboration was possible and indeed essential on items such as an AIDS case-control study and active surveillance ... The close liaison between clinical and laboratory medicine in the UK was again stressed as an important background for such work. Blood transfusion policy was discussed in relation to the possibility of using 'clean' donor panels for blood products.[138]

11.98 This rather optimistic view of the situation in the UK is challenged by the difficulties in obtaining comprehensive data, not least caused by the insistence of haemophilia directors on the confidentiality of patient details (discussed in Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2, paragraph 10.101). This Inquiry has found no objective support for the MRC's relative lack of confidence in the CDC's epidemiological research.

11.99 On 14 October 1983 the UK Central Blood Laboratory Authority's central committee for research and development in blood transfusion Working Group on AIDS in Relation to Blood Transfusion first met. The record of the meeting noted:

Epidemiological Features of HTLV infection

The epidemiological features of AIDS suggest that an infectious agent is responsible for the condition but as yet no aetiological factor has been unequivocally associated with the disease.[139]

11.100 The paper proceeded to comment on evidence of HTLV infection in homosexuals and in AIDS patients, among other topics, and continued:

Recently two variant viruses have been found in association with a few AIDS patients. Cherman et al have described a retrovirus isolated from a French homosexual .... Recent evidence suggests that this virus is distinct from HTLV ... (Montagnier.Pers.Comm). A virus related to HTLV but distinct from HTLVI and HTLVII has recently been demonstrated in proviral form in a few AIDS patients.

The inherent difficulty in interpreting the significance of HTLV infection in AIDS patients is that these individuals are highly susceptible to a wide range of opportunistic infections, a category into which HTLV might fall. Furthermore the establishment of infections requiring intimate contact is likely to be favoured in populations with a high degree of sexual promiscuity, a social feature which appears to be common in AIDS victims.[140]

11.101 In the British Medical Journal of 15 October 1983, Karin Froebel and others (Professor Forbes' Glasgow group) reported on a study of changes in T-cell ratios in Scottish haemophilia patients exposed to Scottish and US Factor VIII concentrates.[141] They carried out a 'controlled' experiment to compare the cellular immunity of patients who had received solely Scottish product and a comparator group who were administered Profilate (Alpha) Factor VIII. Their conclusion was that:

Our results ... argue against a disease vector that is specific to American blood products. In terms of lymphocyte abnormalities, Scottish patients with haemophilia yield results that are consistent with those seen in the acquired immune deficiency syndrome and in acute viral infection. Whether these abnormalities in the T cell ratios ... are sufficient to render the patients immunodeficient and therefore, possibly, in a prodromal stage of the acquired immune deficiency syndrome, will become apparent as the patients are followed up clinically.[142]

11.102 The paper was mentioned in The Guardian of 14 October 1983 in an article by Andrew Veitch, medical correspondent. He noted the findings and commented that, on the basis of the research, US Factor VIII appeared to be no more dangerous than the Scottish version. The headline and opening comments were:

Aids 'not imported in blood'

Fears that more haemophiliacs may contract Aids from contaminated US supplies of the blood clotting factor VIII will be calmed, at least temporarily, today.[143]

11.103 The tone of the article was somewhat sceptical. Mr Veitch noted, without comment, emerging evidence in England that implicated US Factor VIII in the infection of haemophilia patients.

11.104 The Glasgow paper appeared to accept the hypothesis that immunodeficiency might be diagnostic, in itself, of a prodromal state of AIDS. In that sense it was less cautious than Professor Ludlam's published views at this stage.

11.105 The first World Health Organization (WHO) European conference on AIDS, entitled 'AIDS in Europe, Status Quo 1983', was held in Aarhus, Denmark between 19 and 21 October 1983.[144] The press release for the conference, dated 30 September 1983, noted that the AIDS epidemic continued to 'baffle' scientists.[145] It stated that the epidemiological evidence showed clearly that AIDS was contagious and that it was probably transmitted by blood contact. No infectious agent had so far been identified but a strong candidate was a C-type retrovirus.[146] Latency periods were thought to range from a few up to 18 months. It was still not clear what symptoms preceded fully-developed AIDS. Neither was there precise information about the number of AIDS victims who harboured the putative infectious agent. In any case the very poor prognosis for AIDS victims made it essential to gather as much information as possible in a co-ordinated way, in order to help contain the disease through preventative measures and to set up international research projects.

11.106 The fact that the meeting aimed to summarise the available information about the nature of prodromal (early) symptoms of AIDS and the effectiveness of the different therapeutic strategies reflected a low level of accepted knowledge of the fundamentals of the epidemic and the aetiology of the disease.

End of 1983

11.107 Dr Brian McClelland and Mr John Watt represented the SNBTS at a WHO Conference in Geneva between 22 and 25 November 1983.[147] Others attending included representatives from the CDC and Professors Montagnier, Leikola and Zuckerman. The draft report of the meeting was distributed on 14 December with a request for comments by 6 January 1984.[148] The aetiology of the disease was said to be unknown but the epidemiological pattern was said to be most consistent with a transmissible agent. Transmission appeared to occur by blood sharing; the most likely cause was a virus. Coagulation factor concentrates had been implicated and methods of inactivation were being developed but these could not be evaluated until the causative agent was discovered.

11.108 The only new observation recorded was that an aetiological role for retroviruses had been considered because they were known to be capable of causing immunosuppression and neoplastic diseases (such as tumours) in animals after long latency periods. HTLV was suggested as a possibility.[149]

11.109 There appear to have been two clear schools of thought at the end of 1983. There was no settled consensus as to the cause of AIDS or the diagnostic significance of the cellular abnormalities identified in laboratory tests. For many, the almost simultaneous appearance of acquired immune deficiencies in homosexuals, IV drug abusers and haemophilia patients pointed to a single transmissible agent. For others, there were cohort differences that distinguished the patient groups and suggested that different pathologies might be involved.

11.110 The factors that were adduced in support of the antigen overload theory at this stage were:

  • The low absolute and relative numbers of haemophilia patients with signs and symptoms of overt disease.
  • The apparent absence of recorded disease in populations with a high exposure to imported commercial Factor VIII (notably in Germany).[150]
  • Uncertainty whether there was one single cause of AIDS.
  • The clinical differences between haemophilia patients and others with severe immune abnormalities.

11.111 There are several problems with this position. By no means all homosexual men contracting AIDS had KS and some developed PCP. Lack of evidence of KS in haemophilia patients did not distinguish them from the group of infected homosexuals as a whole. Further, to exclude KS from the constellation of conditions to which haemophilia patients might be exposed at this stage would have been speculative. The most that one could have said was that no cases had been diagnosed. Many individuals in both groups had PCP.

11.112 The epidemiological evidence inevitably depended on the reliability of reports. But whereas by January 1983 there had been only eight cases out of a total haemophilia population in the USA of about 20,000, the total number increased during the year to 21.[151] The rate was increasing as it had in the case of homosexual men.

11.113 Professor Ludlam thought that the antigen overload theory was still on the table but, increasingly, that appears to have depended on finding alternative explanations for emerging evidence favouring the transmissible agent theory.[152]

January to mid-May 1984

11.114 It appears that the picture became clearer still in early 1984. There was a report in The Annals of Internal Medicine for January 1984 of AIDS in the elderly wife of a haemophilia patient.[153] Her husband had received Factor VIII concentrate and subsequently died from PCP and probable AIDS.

11.115 The same issue of The Annals of Internal Medicine noted the case of the San Francisco child in a report of an NIH conference entitled 'Acquired Immunodeficiency Syndrome: Epidemiologic, Clinical, Immunologic, and Therapeutic Considerations'.[154] One of the contributors, Dr Edward Gelmann, commented on the arguments for and against the hypothesis suggesting that a retrovirus might be involved in the aetiology of AIDS. His conclusion was that:

The significance of the association between human T-leukemia virus and the acquired immunodeficiency syndrome is not known. There are no data to disprove that there may be an etiologic role for this virus in the syndrome. The elucidation of this role is hindered by the low levels and transient nature of the virus expression. Molecular analysis of the cloned viral genome from one of the patients described may shed further light on the significance and pathogenic potential of this isolate. On the other hand, human T-leukemia virus may represent another new or reactivated opportunistic infection in persons predisposed by the underlying immunodeficiency.[155]

11.116 The evidence of T-leukemia virus infection in AIDS cases had come in particular from Dr Gallo's laboratory. So far as published, it was clearly not considered to be conclusive at this stage. However, by this time at least 11 possible cases of transfusion-associated AIDS, together with cases of sexual partners of risk group members and certain infants connected with risk group members, had been identified in addition to the groups previously described. The previous, erroneous assumption that there was something intrinsic to homosexuality itself or other forms of sexual behaviour that was causally related to the syndrome had effectively been dismissed but this had not resolved the issue of aetiology.

11.117 On 9 January 1984, the Blood Products Sub-Committee of the Haemophilia Society produced a paper reviewing blood products supply and related issues in the UK. On the topic of AIDS, the paper stated:

No discussion of blood products can be complete at present without referring to AIDS. Unfortunately facts are in very short supply. No infective agent has been identified for AIDS, and there is no reliable evidence that the disease is transmitted through blood products (although this still seems the most popular theory) ....

Certainly the immunological abnormalities which may be associated with AIDS are observable in haemophiliacs not exposed to commercial concentrates (e.g. in Scotland and Australia) ....

There is also a theory that the AIDS agent is closely associated with Hepatitis, the AIDS agent being in some way harboured by the hepatitis virus.[156]

11.118 The letter to The Lancet by Professor Ludlam and others already referred to in paragraph 11.70 was cited in support of the reference to Scotland. The letter had noted that it seemed likely that immunosuppression observed in haemophilia patients resulted from infusion of foreign protein or a ubiquitous virus rather than a specific AIDS virus in Factor VIII concentrates. It did not say expressly that the abnormalities were those which might be associated with AIDS and Professor Ludlam was characteristically cautious in expressing his views. However, in general the paper reflected the continuing uncertainty about the aetiology of AIDS that was prevalent at the time among haemophilia doctors.

The balance of opinion

11.119 The approach adopted in the opinions of leading public health and transfusion doctors and blood product scientists was different. There were protagonists for and against an infective agent aetiology but the balance of opinion was, in general, in favour of an infective agent.

11.120 On 12 January 1984, the NEJM published the results of a study by Curran and others of patients in the USA with AIDS and no recognised risk factors.[157] Patients who appeared to have been infected by blood transfusion were identified. At least one high-risk donor was identified for each of the seven cases in which investigation of the donors was complete. The authors concluded that their findings strengthened the evidence that AIDS might be transmitted in blood.

11.121 An editorial in the same issue, by Joseph Bove, Yale University School of Medicine, advised caution in assessing the conclusions in the Curran paper. Having recited the data, he stated:

The apparent conclusion, and the one favoured by Curran et al., is that some cases of AIDS are caused by a blood-borne agent that is transmitted by transfusion. This conclusion also requires that there is a carrier state during which a person with infectious disease is healthy enough to be accepted as a blood donor. Although other epidemiological studies have also suggested such a carrier state, these transfusion-associated cases provide an opportunity to evaluate it more carefully and to study the critical aspect of recipient susceptibility.[158]

11.122 The comment noted that the paper did not provide information about what happened to the recipients of other blood components from the suspect donors, whose donation would normally be channelled into component production. It proceeded:

If recipients of other components from the suspected donation remain healthy, one must either postulate an agent of low infectivity and assign major importance to host factors or question the basic assumption of blood-borne spread.[159]

11.123 In the UK, a meeting was arranged by the National Institute for Biological Standards and Control (NIBSC), scheduled for 9 February 1984, to examine the infectious hazards of blood and blood products, with particular reference to hepatitis and AIDS.[160] The outcome of the discussion can only be regarded as inconclusive. Professor Tedder of the Middlesex Hospital Medical School posed the question whether AIDS could be caused by transmission of an infectious agent in blood and blood products. He commented that one possible explanation for the occurrence of AIDS in recipients of blood and blood products was due to a filterable agent, 'presumably a virus', but he noted that another possible explanation was 'an overwhelming of the immune system by repeated infusion of foreign (and possibly altered) proteins', concluding that 'the true explanation may lie between the two extremes'.[161] Dr Geoffrey Schild (NIBSC) suggested the possible importance of genetic susceptibility.[162] While some of the contributions appear to have proceeded on the hypothesis that AIDS could be transmitted by blood products, the record does not disclose an agreed answer to Professor Tedder's question.

Growing concern

11.124 There was growing concern in Scotland. By letter dated 15 February 1984 Professor John Cash, Medical Director of the SNBTS, wrote to Dr Albert Bell at the Scottish Home and Health Department (SHHD). He suggested that a UK group should be formed for coordinating research into blood transfusion and AIDS. He said:

[T]here should be formed a single UK group responsible to the Departments of Health for co-ordinating research in the area covering the interface between blood transfusion and AIDS. This group should have representatives of existing smaller groups already in existence - haematologists and haemophilia centre directors and of the SNBTS Directors.[163]

11.125 The major areas of research proposed were listed and Professor Cash asked Dr Bell to bring those matters to the attention of the appropriate authorities.

11.126 Meanwhile events were proceeding apace. Dr Evatt and others (including Dr Curran) returned to the subject in The Annals of Internal Medicine in April 1984.[164] In all but two of the 22 haemophilia cases examined by this time the standard risk factors had been excluded. The common factor was exposure to Factor VIII or Factor IX concentrates and all but one had also received other blood components. The discussion commented that the hypothesis that AIDS developed in the patients as a result of an infectious agent transmitted by blood products seemed logical. That had been Dr Evatt's view from early 1982. It seems unlikely that it would have been sufficient of itself to overcome the reservations of others. At this point, before publication of Gallo's work, the issue was clearly unresolved to general expert acceptance, at least in the haemophilia community.[165]

11.127 The views of adherents of the 'antigen overload' theory among haemophilia clinicians at this time were reflected in a paper prepared by Professor Ludlam in 1990.[166] It contained a comprehensive analysis of the competing theories, and served to underline the state of uncertainty among haemophilia clinicians, as seen by Professor Ludlam, about the aetiology of AIDS until Gallo's publication. The paper was prepared for pending litigation in England and Wales.[167] However, it reflected Professor Ludlam's published research and he confirmed that it reflected the way of thinking at the time. In summary, as an alternative to a viral aetiology, immune abnormalities observed in asymptomatic haemophilia patients might be due to the following:[168]

  • A previously undescribed feature of haemophilia.
  • Chronic liver disease.
  • Large amounts of foreign proteins in plasma preparations.

11.128 Professor Ludlam summarised the evidence for the immune abnormality being due to blood products and not a virus and the contrary proposition that the immune changes could have been due to a putative AIDS virus, repeating the discussion already dealt with that had evolved over time, particularly as reflected in his own research. He said:

I think one of the things that we were just wondering ... was that maybe the AIDS in people with haemophilia was actually of a different aetiology from that in gay men ....


[M]aybe haemophilia as a whole was sliding into AIDS because of all the concentrate we were using. Quite separate from HIV or a putative virus.

Q: Just looking on AIDS almost as an end stage, as it were, in the progressive demolition of the immune system?

A. From Factor VIII concentrate per se or the proteins, the contaminant.[169]

11.129 This answer is revealing. It suggests that, as an adherent of the antigen overload theory, Professor Ludlam had in mind that there was no significant clinical difference between the acquired immune deficiency syndromes in haemophilia patients and other groups and that each might be a progressive and potentially fatal complication in haemophilia. Fundamental to the theory was the hypothesis that factor concentrates by themselves were contributing to the development of serious acquired immune deficiency.

11.130 Professor Ludlam was pressed on the question whether physicians examining the problem could have thought that antigen overload was the whole explanation of immune abnormalities in haemophilia patients. He said:

I think that became increasingly less tenable with the unfortunate case reports of a spouse and a child of a haemophiliac developing AIDS ... Because that was evidence of a presumed sexually transmissible agent, furthermore, sadly being passed to the child.[170]

11.131 Professor Ludlam was referred to an article by Drs Barbara and Tedder published in October 1984.[171] The article suggested that 'little significance should be attached to reports of abnormal lymphocyte profiles in haemophiliacs'. He ultimately accepted that 'by October 1984, there was little doubt that HTLV-III was the cause of AIDS', including in people with haemophilia.[172]

The 'antigen overload' theory in retrospect

11.132 In retrospect it appears that the antigen overload theory was not a satisfactory answer to the question whether there was AIDS associated with haemophilia. On the face of it, Dr Aledort's view, and the development of the antigen overload theory generally, led to the conclusion that heavy and prolonged use of factor concentrates, and in particular Factor VIII, could be expected, in some cases, to damage the blood disorder patient's immune system in a way similar to the damage found in homosexual men who were exposed to the risk of progression to AIDS. That had to include the possibility of a fatal prognosis in some cases at least. It provided an explanation for the development of immune abnormalities in some patients, due solely to the administration of factor concentrates, but implicit in it was a risk of progressive damage. That process might result in an immune deficiency state indistinguishable from that in asymptomatic homosexual patients who were at risk of AIDS. Without evidence of relative rates of progression, the outcome for the patient might be the same whatever the aetiology of the cellular immune deficiency.

11.133 Further, the possibility of antigen overload as a causative factor could not exclude the concurrent possibility of infection transmitted in blood and blood products, with a fatal prognosis in some cases. The two aetiologies postulated were not mutually exclusive. The positive risk could not exclude the increasing probability that haemophilia patients might also develop AIDS due to viral transmission. At best it was an additive risk. At worst it was an aggravating feature that could increase the threat to the patient exposed to an infective agent.

11.134 Less than three years had passed from publication of the first cases of AIDS, however. Despite intensive research and debate, there was no consensus as to the cause of the immune abnormalities observed in the haemophilia community, where they affected patients with severe Haemophilia A in particular. There was ample scope for continuing research and debate. How that might have developed would be a matter of pure speculation, however, as there was about to be a major change in direction.

May to October 1984: identification of HTLV-III

11.135 Dr Gallo and his group announced the discovery of HTLV-III on 23 April 1984 at a press conference in Washington.[173] As described in Chapter 29, The Discovery of HIV and the Development of Screening Tests, they concluded that HTLV-III might be the primary cause of AIDS and found antibodies to HTLV-III in a majority of patients with AIDS, thus opening the way to future testing of those infected by the virus.

11.136 With the development of HTLV-III testing, following US research based on Dr Gallo's work, further cases of infection emerged and the discovery laid the basis for the general consensus that has prevailed ever since.

11.137 Gallo's finding that HTLV-III caused AIDS is discussed in more detail in Chapter 29, The Discovery of HIV and the Development of Screening Tests. Confirmation of his findings was provided by Jay Levy and others, writing on the recovery of retroviruses from Factor VIII concentrates and processes to inactivate them.[174] Levy's findings on virus inactivation were, in turn, referred to in the US CDC update on AIDS in persons with haemophilia published in the MMWR of 26 October 1984.[175] For present purposes, the ability to infect Factor VIII concentrate with the AIDS virus, freeze dry it and thereafter heat it to reduce residual virus titre to an undetectable level were important stages in proof of a viral aetiology for AIDS. Nine patients were discussed. They had no risk factors for AIDS other than haemophilia therapy. The Editorial Note in the MMWR stated:

[T]he occurrence of nine cases with no known risk factor or exposure other than the use of factor VIII preparations implicates these products as potential vehicles of AIDS transmission.[176]

11.138 These were significant findings. As a practical matter, after Gallo, work in the USA turned towards identification of infection in individuals and virus inactivation in manufacture.

The view in the UK in 1984

11.139 Even after the reports from Montagnier and Gallo, there continued to be comments published in the UK suggesting that immunological compromise in patients with haemophilia might be due to the repeated challenge of the immune system inherent in administration of Factor VIII concentrates manufactured from large pools. On 30 June 1984 The Lancet published an article by Dr Robert Carr and others (Professor Ludlam's Edinburgh group), related to a study of 47 patients with haemophilia who had been treated exclusively with SNBTS Factor VIII and Factor IX concentrates.[177] In Haemophilia A patients, the number of T-cells was depressed, resulting in a reduction of the helper/suppressor ratio in about half the patients. In Haemophilia B, the helper/suppressor ratio was also depressed, attributable to a slight increase in the suppressor number and a slight decrease in the helper number. It was suggested that these immunological abnormalities resulted from transfusion of foreign proteins in blood products rather than from an infective agent in the blood products giving rise to AIDS. It was also commented that at least a year had passed since the most recent batch of plasma used to prepare these concentrates had been collected.

11.140 The final comment in the article was:

Furthermore, the relation between the lymphocyte subset abnormalities in symptomless haemophiliacs and the likelihood of eventual frank AIDS remains unclear although it may be connected with HLA status.[178]

11.141 The article must have been written and presented for publication some months earlier than its date (30 June) and Gallo's discovery would not have been known to the authors. It forms an important bridge between Professor Ludlam's earlier 1983 letter and the discovery in late 1984 of the infection of the Edinburgh Cohort (a group of Edinburgh haemophilia patients infected by NHS products, discussed in Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2). Briefly, at this date it remained an acceptable view among certain experts in the UK that full-blown AIDS in haemophilia patients might be the end-stage of progressive immune compromise caused by something other than a specific AIDS infective agent, an unidentified component of concentrates or a non-specific effect of foreign proteins.

11.142 Therefore, at least until June 1984 some haemophilia clinicians clearly remained sceptical of the claims that AIDS was caused by a transmissible virus. Some in the scientific community took a different approach and researched the development of a laboratory test, as had happened in the USA.

11.143 On 7 July 1984 The Lancet published a letter by Mads Melbye and others.[179] A study of 22 haemophilia patients from Denmark who had been treated with Factor VIII concentrate purchased from US and European commercial sources demonstrated a high prevalence of antibodies to LAV: 14 of the 22 were positive.[180] Clinicians caring for haemophilia patients were advised to consider alternative forms of therapy for new patients not yet exposed to 'Cryoprecipitate concentrate', factor concentrate in UK nomenclature. The authors stated that, until screening tests or inactivation techniques were in widespread use, commercially available cryoprecipitate products should be considered as 'probably contaminated'.

11.144 This was followed by a letter in The Lancet dated 18 August 1984 by Rosemary Ramsay and others (including Dr Evatt) of the CDC giving additional information about a number of US cases. They argued that the serological data described, indicating a high risk of exposure to LAV for heavy users of Factor VIII concentrate, supported the contention that LAV was transmitted by some blood products. They studied 25 Haemophilia A patients and four with Haemophilia B, none of whom had symptoms associated with AIDS:

Haemophilia A patients who were seropositive for LAV had used significantly more factor VIII concentrate than had patients sero-negative for LAV. This association would be expected if factor VIII concentrates contain LAV or its proteins. In contrast, the haemophilia patients with AIDS had a significantly lower antibody prevalence, perhaps because patients with AIDS have a declining antibody response to antigen despite paradoxically higher levels of circulating immunoglobulins. 4 patients with haemophilia B were negative for LAV antibody and had normal cellular immunity. Patients with haemophilia B, in general, have not been found to have the degree of immune abnormalities seen in haemophilia A.

These serological data, indicating a high risk of exposure to LAV for heavy users of factor VIII concentrate, support the contention that LAV may be transmitted by some blood products.[181]

11.145 Although not published until October 1984 in Clinics in Haematology, the transfusionist John Barbara and virologist Richard Tedder had written in about May or June that:

The characteristics of agents lending themselves to transmission by blood or blood products centre around their presence in blood, or its components, which has been taken from apparently healthy donors. Thus these agents often will have a combination of a long incubation period with a prolonged and high-level viraemia.[182]

11.146 It was inferred that agents transmitted by blood and blood products must have a 'silent period' because the donor appeared healthy when blood was given. In relation to HTLV-III, the paper noted the cases of possible transmission of AIDS by transfusion and continued:

The transmission of AIDS by pooled clotting factor concentrates is less controversial. Since, as a group, haemophiliacs are well studied, it is unlikely that there should have been an illness like AIDS unrecognized before 1980. Little significance should be attached to reports of abnormal lymphocyte profiles in haemophiliacs; nevertheless there is no doubt that there have been deaths of haemophiliacs due to AIDS in the absence of other established risk factors and that, unlike those associated with transfusion, these cases were scattered throughout the USA. In addition there is a report which seems to have identified the transmission of AIDS from a haemophiliac (asymptomatic at that time) to his wife.[183]

11.147 The paper went on to note the isolation and characterisation of LAV/HTLV-III and the likely aetiological link to AIDS.

11.148 Professor Ludlam was asked to comment on the statement that little significance should be attached to reports of abnormal lymphocyte profiles in haemophilia patients. He said:

They are virologists and until the virus was identified and the antibody test developed, there was no other way of studying this condition other than by immune tests. These were patients who presented, when they developed AIDS, with profound immune deficiency and they were therefore investigated for immune deficiency with laboratory investigations.


Q. Yes, but I suppose the point they seemed to me to be making was that, firstly, this is plainly being written after the work by Gallo in the earlier part of 1984, which had linked AIDS and HTLV-III, and they seem to be saying, firstly, that, as far as they are concerned, the hunt is over, and the agent which is causing AIDS in people of homosexual orientation and also people with haemophilia, the hunt is over. Is that what they are saying?

A. I think by October 1984 there was little doubt that HTLV-III was the cause of AIDS ... I'm very happy to accept that. However, we don't know or we didn't know until the antibody test was produced, just how many people might have been infected. We don't know whether everyone was equally susceptible. It may be those who had abnormal immune tests were more susceptible to the virus when exposed to it. So I'm happy - very happy to agree.


Q. I can certainly understand, professor, the point you make, that there were many unanswered questions, and indeed even today there seem still to be unanswered questions, but your acceptance that you indicated a moment ago that by the autumn of 1984 that this virus, HTLV-III, was the cause of AIDS, including in people with haemophilia; does your acceptance extend to that?

A. Yes.

Q. Right. The point that Drs Tedder and Barbara make in this paragraph however, about it being unlikely that there should have been an illness like AIDS in people with haemophilia caused by some other phenomena, that was a valid point even in 1983, was it not?

A. Yes.[184]

Autumn 1984: a viral aetiology

11.149 Given Professor Ludlam's prominence in the development of alternative theories, the autumn of 1984 can be seen as the point at which a viral aetiology for AIDS was established, notwithstanding that there remained unanswered questions. It followed that some patients receiving factor concentrate therapy for haemophilia and other coagulation deficiencies were known at that stage to have been exposed to the risk of transmission of HTLV-III/HIV. Attention began to focus on the progression of disease from infection.

11.150 On 1 September 1984, The Lancet published the article by Dr Rachanee Cheingsong-Popov and others (including Professor Tedder). HTLV-III and LAV-1 were indistinguishable. The high incidence of HTLV-III antibodies in haemophilia patients found in this and other studies had to be set against the relatively low incidence of overt AIDS in this risk group so far - roughly one per thousand haemophilia patients in the UK.

11.151 The article defined the hypothesis for the cause of AIDS in these terms:

Recent evidence has strongly implicated newly identified retroviruses as the cause of AIDS and PGL.[185] These viruses have been termed lymphadenopathy-associated or immunodeficiency-associated virus (LAV/IDAV) and human T-lymphotropic virus type III (HTLV-III), and they seem to have more similarities than differences. To date the evidence implicating them aetiologically comprises a high frequency of virus isolation from AIDS and PGL patients and high prevalence of specific antibody in these subjects. A notable feature of these retroviruses is their tropism for the T "helper" (T4+) lymphocytes, which typically are depleted in AIDS patients.[186]

11.152 The detection of HTLV-III antibodies in all but one of the AIDS patients studied was said to strengthen the evidence for an aetiological relationship to AIDS. The prevalence of HTLV-III seropositivity in PGL patients was said to confirm the notion that HTLV-III was not the cause only of AIDS but was also the cause of PGL in epidemiologically related risk groups.

11.153 The authors commented that even if the causal relationship with AIDS and PGL was established, as the evidence strongly suggested:

[W]e should not assume that these disorders will develop in all patients infected with this retrovirus .... 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.[187]

11.154 An apparent carrier state was also described.

11.155 The article made reference to an accompanying paper by Professor Brian Gazzard and others. That paper referred to earlier US research relating to sexual contacts of AIDS patients, the recent discovery of LAV/HTLV-III and the accompanying paper supporting the aetiological association with AIDS/PGL. The main object of the study was explained as being:

[T]o observe the clinical spectrum of disease in men who had had sexual contact with AIDS or PGL patients, and to correlate development of symptoms with HTLV-III positivity.[188]

11.156 They reported that several of the group's findings were consistent with the hypothesis that HTLV-III was the sexually transmitted agent responsible for both AIDS and PGL and that it might be associated in certain cases without symptoms. It was a very early description of the natural history of the disease.

11.157 On 11 September 1984, the SNBTS Directors met.[189] Dr McClelland reported that Professor Tedder had acquired a significant quantity of reagents from the USA and was establishing anti-HTLV-III assays.[190] The work of the English scientists was intimated to all of the Directors in Scotland at this stage.

11.158 Within Scotland, there was active exchange of data and other information between the SNBTS in Edinburgh and scientists in Glasgow following a letter from Dr Perry to Dr Froebel at the GRI on 15 October 1984 in which Dr Perry asked for information about Glasgow data on HTLV-III and offered samples of Factor VIII for screening purposes.[191] Scottish scientists were also collaborating actively with colleagues abroad in developing knowledge of the disease and its prevalence.

October to December 1984: growing awareness

11.159 Knowledge of AIDS among haemophilia patients, of its prevalence and aetiology, continued to accumulate in this period, in the USA and in the UK. Evidence of transmission became more clearly focused in the UK on 23 October 1984. Dr Craske of the Public Health Laboratory Service (PHLS), Withington Hospital, Manchester, circulated a letter advising that a batch of Factor VIII concentrate produced by the Blood Products Laboratory (BPL, the English manufacturer of NHS blood products) 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.[192] Professor Cash, Professor Ludlam and Dr Perry, amongst others, received copies of the letter.[193]

11.160 Dr Craske's letter of 23 October 1984 provided a direct sequential link between infection in donated blood included in a plasma pool and transmission of AIDS to haemophilia patients and was, at least, highly persuasive evidence of a causal relationship. He stated:

You will have already heard that one of the donors who contributed to the plasma pool used in the manufacture of the batch of factor VIII ... was recently admitted to hospital with clinical features consistent with the diagnosis of AIDS. I am afraid that this has now been confirmed. The patient has developed Pneumocytosis carinii pneumonia and two specimens of serum collected in September and October 1984 have been found to be positive for antibody to HTLV-3 by competitive radioimmunoassay (RIA).


From studies already underway on recipients of batches of factor VIII transfused to the two haemophilia A patients who contracted AIDS in 1983, we have already provisionally identified one batch of factor VIII which was transfused to one of the AIDS patients and was associated with seroconversion to HTLV-3 antibody positive in seven out of thirteen recipients. One of the patients who acquired HTLV-3 infection subsequently developed AIDS, a second developed thrombocytopenia, and the other five have remained symptomless.[194]

11.161 Dr Craske commented that further research was required to confirm the association of HTLV-III infection and transfusion. However, against the background of earlier published work, this letter was significant in giving wide publicity within the medical and scientific community in the UK to the risk of transfusion-transmitted HTLV-III in haemophilia patients. It helps to identify a time from which there was, or should have been, general acceptance of risk associated with factor concentrates. There were, in addition, other contemporaneous sources of information pointing in the same direction and medical practitioners began to consult scientists to investigate the incidence of infection in their own patients (see Chapter 10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2, paragraphs 10.3-10.5). The results of testing by Professor Tedder and his colleagues of samples submitted by clinicians demonstrated the association of HTLV-III infection with the transfusion of factor concentrates.

Developments in 1985

11.162 In January 1985, '[AIDS] - an overview' by James Gracie and others was published in the Scottish Medical Journal.[195] The authors, Dr Gracie, Dr Froebel, Dr Madhok, Professor Lowe and Professor Forbes, practised at the Regional Haemophilia Centre, GRI. The article presents a picture of the generally held views at that Centre at the time of its preparation (December 1984). Overall, the authors stated that it seemed certain that a specific transmissible agent was responsible for AIDS. Other theories were dismissed.

11.163 Emerging data on AIDS in patients who did not belong to any at-risk group but who had received blood transfusions were commented on as having serious implications. It had become necessary to look at the safety procedures used in obtaining blood and blood products.[196] The article made no mention of the Edinburgh Cohort. It cannot be taken to reflect the opinion among experts throughout Scotland but it does show a level of understanding of the wider context. The exposure of haemophilia patients to risk was clearly documented.

11.164 The MMWR dated 11 January 1985 published provisional public health recommendations on screening donated blood. By way of background, it stated:

Evidence has shown that a newly recognised retrovirus is the cause of AIDS. Although this virus has been given several names ... it is referred to as HTLV-III in this discussion.


Epidemiologic data suggest that the virus has been transmitted through intimate sexual contact; sharing contaminated needles; transfusion of whole blood, blood cellular components, plasma, or clotting factor concentrates that have not been heat treated; or from infected mother to child before, at, or shortly after the time of birth.[197]

11.165 In the public health context in the USA, AIDS was unequivocally held to be caused by HTLV-III.

11.166 On 9 February 1985, a letter written by Professor Arthur Bloom was published in The Lancet.[198] It was concerned primarily with clinical practice and relative risks associated with the use of concentrates but it acknowledged finally and expressly the infection of British Factor VIII with HTLV-III and the risk of transmission.

11.167 On 3 August 1985 The Lancet published the Royal Infirmary of Edinburgh (RIE) preliminary study of Edinburgh haemophilia patients ('the Edinburgh Cohort') referred to in Chapter 10 Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2, paragraphs 10.57-10.60. This was a milestone document. The authors of the report were Professor Ludlam, Dr Tucker, Dr Steel, Professor Tedder, Dr Cheingsong-Popov, Professor Weiss, Dr McClelland, Ms Philip and Dr Prescott. The article stated:

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.[199]

11.168 The text acknowledged that substantial evidence had accumulated that the most likely cause of AIDS was HTLV-III/LAV infection. Re-testing stored samples had demonstrated that the patients' sub-set irregularities (identified in the spring of 1983) prior to transfusion of the infected batch were not associated with HTLV-III infection. This demonstrated that the abnormal T lymphocyte subsets reported in 1983 were a result of the intravenous infusion of Factor VIII and not HTLV-III infection but it also suggested a relationship between CD4/CD8 ratios and the exposure of patients to HTLV-III infection: the lower the ratio, the greater the incidence of HTLV-III antibodies.[200] The absence of apparent seroconversion in a substantial number of patients was thought to be due to a range of factors including the concentration of antibodies; the immunological status of the individuals; the absence of viral infection; or replication of the lymphocyte cells.[201]

11.169 The paper acknowledged the reality for Scottish clinicians and patients: HTLV-III was the most likely cause of AIDS and was transmitted by blood products. Information about these cases and contemporaneous English experience put the issue of risk to patients beyond question, as Professor Bloom's letter in The Lancet of February 1985 shows.

11.170 More widely, there was further evidence. The NEJM of 21 February 1985 published an article by Dr Evatt and others describing research into the incidence of antibodies to HTLV-III/LAV in haemophilia patients in California, Georgia, New York and Texas by testing stored serum samples from several centres. There were no seropositive patients in the 1968 and 1969 samples and there was only one seropositive patient in 1978 in California. They also found that a seropositive response was related to the amount of Factor VIII used.[202]

1986 and beyond

11.171 Between 11 and 13 February 1986 there was a conference in Newcastle on AIDS sponsored by the Haemophilia Society. The introduction to a paper presented (by Dr Philip Mortimer, PHLS)[203] at the conference stated that:

There is convincing evidence available from studies involving donor-recipient pairs that the HTLV-III/LAV virus can be transmitted by the transfusion of infected blood and blood products.[204]

11.172 It was also narrated that during 1984 the causative virus for AIDS was recognised as HTLV-III/LAV and that there was a significant correlation between the antibody to HTLV-III/LAV and patients with AIDS.[205] In his paper, Dr Mortimer said that of 4000 haemophilia patients in the UK, 25% were positive for antibodies to HTLV-III.[206] Only 0.006% of transfusion recipients were positive for antibodies to HTLV-III.[207] Blood donor screening had shown that one in 45,000 donors was positive.[208]

11.173 It is clear that by this date there was general acceptance of a causal association between some infected blood products and the development of HTLV-III/LAV and AIDS in haemophilia patients.

11.174 Between 14 and 16 April 1986, the WHO held a meeting in Geneva, on the safety of blood and blood products in relation to AIDS. A report on the meeting was prepared by the World Hemophilia AIDS Center.[209] Prior to the meeting, WHO officials and plasma fractionators met to discuss current LAV/HTLV-III inactivation methods. Thirty-three countries were represented at this meeting, principally by staff from blood banking or blood transfusion facilities and a large staff of participants from the secretariat of the WHO under the direction of John Petricciani, Chief of Biologicals.

11.175 The meeting began with an overview of infection with LAV/HLTV-III virus, in which information was presented regarding the recognition and identification of two new retroviruses termed LAV-2 and HTLV-IV. The speaker representing Professor Montagnier stated that the AIDS virus was the first human lente virus (otherwise 'lentivirus') and was comparable to the visna virus in sheep.[210] The envelope gene in the visna virus is highly variable. The two new viruses had been termed LAV-II (isolated from two patients in West Africa) and HTLV-IV (isolated in Kakar, also in West Africa). These two viruses were not identical, although they had some cross-reactivity with LAV-1 and HTLV-III respectively. The new terminology apparently would be HIV-1 (human immunodeficiency virus 1), which was equivalent to LAV-1, to HTLV-III, and to ARV (AIDS retrovirus). HIV-2 was equivalent to LAV-2 (from West Africa). HTLV-IV remained to be classified. The phylogenetic tree (see Chapter10, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 2) of the human immunodeficiency viruses was being described by amino acid homologies. There was a long discussion on the clinical safety of immune globulins. Genetic analysis had now begun to dominate scientific thought: there was little or no scope for doubt about the cause of AIDS transmission more generally.[211]

The modern view

11.176 As discussed in Chapter 8, Knowledge of HIV/AIDS Now, the modern view of the aetiology of AIDS is heavily influenced by the findings of geneticists of some fundamental characteristics of the virus. Before the identification of the first retroviruses, first in other animals and then in humans (in the form of HTLV-I), it was believed that there was a single direction of flow of information in the replication of pathogens, from DNA to RNA to protein. Then retroviruses were identified. When viruses in this group were first identified, it appeared that the genetic material within the virus particle was made of RNA but it was eventually established that when the virus entered a cell the RNA was converted backwards into DNA material. That DNA material was then inserted into the DNA of the cell so that it looked like part of the cell's own DNA. Because of that apparent reversal of the flow of genetic information from RNA back to DNA, this family of viruses came to be called retroviruses. This family includes Hepatitis B, which also goes through a DNA intermediate. The term 'retro' comes from that original observation that the flow of genetic information went backwards. When cell replication begins, the flow of genetic information goes in the normal direction again because that DNA is made into an RNA copy and into protein which, in addition to normal cell products, also produces the virus, since the instructions are now encoded into the cellular DNA.[212]

11.177 Professor Lever emphasised some of the common characteristics of the natural history of virus infection generally.[213] On general principle, the more often a person is exposed to virus infection or the bigger the 'dose' of viral particles, the more likely is the chance of infection.[214] More often than not, the patient mounts an appropriate immune response, clears the infection and is then immune from further infection by the same agent: the immune system remembers the infection and prevents recurrence. Mumps and rubella were taken as typical examples. At the start of the AIDS epidemic, it was known that in the case of some chronic infections, such as Hepatitis B, while some people were relatively poor at clearing the virus and a proportion of these became chronic carriers, the majority of healthy individuals did appear to be able to clear it and develop immunity from re-infection. This experience informed the common notion at the time that exposure to infectious agents gave a level of protection against further infection by the same virus. A perception had arisen that, having been exposed to a virus, the individual would not be harmed by being exposed to the same virus again because either the immune system would have developed sufficient immunity to protect the individual completely or it would somehow help to suppress the second exposure. However, almost without precedent at the time, it was to emerge that, in the case of HIV, prior exposure to the virus gave no protection against infection on further exposure.[215]

11.178 As already noted, a similar discovery was later to emerge in the case of Hepatitis C. Immunity from further infection does not follow from clearance of infection with the virus.


11.179 With the identification of AIDS in 1981, scientists and clinicians were confronted by a phenomenon, unique at that time in modern medicine: a disease of no known aetiology that was rapidly progressive and fatal. Initially it appeared to affect a small set of vulnerable individuals whose known behavioural characteristics suggested that the scope of the disease was limited to promiscuous male homosexuals. Evidence undermining that hypothesis was soon to emerge in 1982 but alternative hypotheses as to the cause of AIDS, especially alternatives that depended on an agent of transmission, could not be proved in the absence of evidence that such an agent existed. There was a period of intense research and a virus was found that provided the answer to general, though not universal, satisfaction. It is important to stress that proof of a viral aetiology was provided, in France and the USA, within about three years of the first reported cases, and within two years of the initial evidence supporting the transmissible agent hypothesis. This was a remarkably short period.

11.180 Success was achieved against the background of controversy. The CDC, and Dr Evatt in particular, became convinced by about July 1982, by evidence of infection in haemophilia patients, that AIDS was a blood-borne disease, though there was no direct proof. As late as 4 January 1983, at the advisory committee meeting convened in Atlanta, there was a hostile reaction to Dr Evatt's arguments.[216] By the summer of 1983 there was continuing doubt in some segments of the haemophilia community, the blood banking industry, physicians and the FDA in the USA that AIDS was a blood-borne infection.[217]

11.181 The publication in Science by the Institut Pasteur of the isolation of LAV did not resolve the controversy. It would be February 1984 before those results were presented to the CDC. The position changed with the publication of Dr Gallo's findings in April. However, that was dramatic progress from a state of total ignorance of the disease and its viral aetiology to convincing proof.

11.182 This chapter has set out, at some length, the evolving discussion of the alternatives, especially in the case of haemophilia patients, as the position would have been understood to clinicians and as discussed in professional literature as well as in evidence to the Inquiry.

11.183 The pace of development of knowledge of the disease, and the concentrated effort made within a very short time to deal with the problem presented by its sudden and unanticipated appearance are particularly remarkable. As will appear from Chapter 29 The Discovery of HIV and the Development of Screening Tests, the public debate among haemophilia clinicians and others referred to in this chapter was for the most part irrelevant to that progress. The scientists responsible for cutting edge research and technological progress were convinced at an early stage of the viral aetiology of AIDS and were largely untouched by the debate. In contrast, doubt concerning a viral or otherwise infectious aetiology was strongest amongst haemophilia clinicians, some of whom sought other explanations (notably 'immune overload') for as long as such explanations remained tenable. This debate was fundamental to clinical practice in the treatment of haemophilia and other coagulation defect patients.

1 Barré-Sinoussi et al, 'Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS)', Science, 20 May 1983 [LIT.001.0058]

2 Day 21, page 57

3 Evatt 'The tragic history of AIDS in the hemophilia population 1982-1984', Journal of Thrombosis and Haemostasis, 2006; 4/11:2295-2301, (reprint) [PEN.016.1183] at 1185

4 See Chapter 9, Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 1, paragraph 9.18

5 Gottlieb et al 'Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men', New England Journal of Medicine, 1981; 1425-1431 [LIT.001.0779]

6 Professor Hann - Day 21, pages 43-44

7 'Pneumocystis pneumonia - Los Angeles', MMWR 5 June 1981; 30(21):1-3 [LIT.001.1026] at 1027

8 Dr Winter - Day 15, page 111

9 Day 21, pages 43-44

10 Professor Lever's Report [PEN.015.0517] at 0518

11 Zoonosis, or 'spillover', is relatively frequent, with up to 60% of known human diseases estimated to be zoonotic in origin. SARS (Severe Acute Respiratory Syndrome) is another, more recent example. 'Viral chatter' - tracing the emerging 'incursions' of zoonotic diseases - is an important part of virological research.

12 Day 26, page 27

13 (1) Gao et al, 'Origin of HIV-1 in the chimpanzee pan troglodytes troglodytes' Nature, 1999; 397:436 [LIT.001.1178]; (2) Bailes et al, 'Hybrid origin of SIV in chimpanzees', Science, 2003; 300:1713 [LIT.001.1184]; and (3) Wolfe et al, 'Naturally acquired simian retrovirus infections in Central Africa hunters', The Lancet, 2004; 363:932 [LIT.001.1185].

14 For a relatively recent (and technical) discussion of the spread of HIV/AIDS using sophisticated phylogenetic, molecular, historical and epidemiological techniques see Gilbert et al 'The emergence of HIV/AIDS in the Americas and beyond' Proceedings of the National Academy of Sciences, 2007; 104(47):18566-18570 [LIT.001.4483]

15 For example in editorial comment in the MMWR of 16 July 1982 [LIT.001.0559]

16 See the discussion of the 'antigen overload theory' later in this chapter.

17 Day 26, pages 32-33

18 Day 26, pages 36-37

19 See Chapter 9, Knowledge of the Geographic Spread and Prevalence of HIV/AIDS 1, paragraphs 9.20-9.22

20 'Epidemiologic Notes and Reports - Pneumocystis Carinii Pneumonia Among Person With Haemophilia A', MMWR, July 16 1982; 31:365-7 [LIT.001.0559] at 0560; Preliminary Report, para 8.12

21 All three had died by December 1982.

22 Dr McClelland - Day 21, pages 138-39

23 'Epidemiologic Notes and Reports - Pneumocystis Carinii Pneumonia Among Person With Haemophilia A', MMWR, July 16 1982; 31:365-7 [LIT.001.0559]

24 Dr Winter - Day 16, page 23; Evatt 'The tragic history of AIDS in the hemophilia population 1982-1984', Journal of Thrombosis and Haemostasis, 2006; 4:2295-2301 (reprint), [PEN.016.1183] at 1185-6

25 Dr McClelland - Day 21, pages 138-39

26 Evatt, 'The tragic history of AIDS in the hemophilia population 1982-1984' Journal of Thrombosis and Haemostasis, 2006; 4:2295-2301 (reprint) [PEN.016.1183] at 1186

27 Day 15, pages 112-113

28 Day 15, page 114. Similar views were later reported by Dr Margaret Ragni: 'AIDS and treatment of hemophilia patients', Plasma Therapy and Transfusion Technology, 1988; 9:173 [SGF.001.1314]

29 Professor Lever - Day 26, page 35

30 Day 26, pages 37-38

31 'CDC Update on acquired immune deficiency syndrome (AIDS) among patients with haemophilia A', MMWR, 1982; 31:644-652 [LIT.001.0576]

32 'CDC Possible transfusion-associated acquired immune deficiency syndrome [AIDS] - California', MMWR, 1982; 31:652-654 [SGH.008.5105] at 5108. Dr Amman and others reported the case in April 1983 in The Lancet: 'Possible Transmission by Means of Blood Products' [LIT.001.0405]

33 Day 18, page 117

34 Day 18, page 117

35 Day 26, page 50

36 Day 26, page 101

37 Day 16, page 7

38 Day 16, page 8

39 Research News: 'Health Officials Seek Ways to Halt AIDS' [LIT.001.1589]

40 Evatt, 'The tragic history of AIDS in the hemophilia population 1982-1984' Journal of Thrombosis and Haemostasis, 2006; 4:2295-2301, (reprint) [PEN.016.1183] at 1188. For competing views, see Marx, 'Health Officials Seek Ways to Halt AIDS', Research News, 21 January 1983 [LIT.001.1589]

41 Professor Ludlam - Day 18, page 115

42 Dr Winter - Day 16, page 5. (Koch is widely regarded as the founder of modern bacteriology and discovered the aetiological agents of anthrax, cholera and tuberculosis.)

43 Day 19, pages 8-9

44 Professor Lever - Day 26, pages 57-58

45 Dr Winter - Day 16, page 6

46 Day 26, page 55

47 Day 19, pages 11-12

48 Day 16, page 6

49 Day 26, pages 57-58

50 Dr Winter - Day 16, pages 4-5.

51 Evatt, The tragic history of AIDS in the hemophilia population 1982-1984, Journal of Thrombosis and Haemostasis, 2006; 4:2295-2301 (reprint) [PEN.016.1183] at 1188

52 Ragni et al, 'Acquired immunodeficiency-like syndrome in two haemophiliacs', The Lancet, 29 January 1983, 213 [SNB.007.3455]. See also Dr Ragni's comments in 'AIDS and Treatment of Hemophilia Patients', Plasma Therapy and Transfusion Technology, 1988; 9:173 [LIT.001.0598]

53 Ragni et al, 'Acquired immunodeficiency-like syndrome in two haemophiliacs', The Lancet, 29 January 1983, 213 [SNB.007.3455]

54 Historical Summary of AIDS in Haemophilia 1981-1985 [PEN.015.0468] at 0468-9

55 Evatt, 'The tragic history of AIDS in the hemophilia population 1982-1984', Journal of Thrombosis and Haemostasis, 2006; 4:2295-2301 (reprint) [PEN.016.1183] at 1189

56 It is interesting to compare the development of thought in relation to hepatitis. See Chapter 15, Knowledge of Viral Hepatitis 2, 1975 to 1985 paragraph 15.24. Alter et al applied the postulates, only to set them aside as research proceeded and the realities of the disease required a more flexible approach.

57 Day 16, pages 28-29

58 Day 16, pages 29-30

59 Professor Lever's Report [PEN.015.0517] at 0520. HHV8/KSHV, the cause of Kaposi's sarcoma, was finally identified in 1994.

60 Professor Lever - Day 26, page 76

61 Day 26, page 43

62 Professor Lever - Day 26, page 43

63 Ragni, 'AIDS and treatment of hemophilia patients', Plasma therapy and transfusion technology, 1988; 9:173 [SGF.001.1314] at 1317

64 'Update on Acquired Immune Deficiency Syndrome (AIDS) among Patients with Hemophilia A', MMWR, 10 December 1982 [SGH.008.5105] at 5108-10

65 Lederman et al, 'Impaired cell-mediated immunity in patients with classic hemophilia', New England Journal of Medicine, 1983; 308/2:79-83 [PEN.012.0263]

66 That is, in this case, 19 age-matched, apparently healthy people without haemophilia.

67 Lederman et al, 'Impaired cell-mediated immunity in patients with classic hemophilia', New England Journal of Medicine, 1983; 308/2:79-83 [PEN.012.0263] at 0266

68 Menitove et al, 'T-lymphocyte subpopulations in patients with classic haemophilia treated with cryoprecipitate and lyophilized concentrates' New England Journal of Medicine, 1983; 308:83-86 [LIT.001.0031]

69 Ibid [LIT.001.0031] at 0033. They did not comment on the lack of fit between volunteer donors and commercial donor populations.

70 Desforges, 'Aids and Preventive Treatment in Haemophilia', New England Journal of Medicine, 1983; 308/2 [LIT.001.0040]

71 'Mystery Disease Threat', The Observer, 16.01.83 [DHF.001.7108]

72 Day 16, pages 13-14

73 Memo dated 18 January 1983: 'Factor 8 and the Observer Article' [DHF.001.7111]

74 Jones et al, 'Altered immunology in haemophilia', The Lancet, 1983; 120 [DHF.001.7107]

75 Ibid, [DHF.001.7107]

76 'Health Officials Seek Ways to Halt AIDS', Research News, 21 January 1983 [LIT.001.1589]

77 Historical Summary of AIDS in Haemophilia 1981-1985 [PEN.015.0468] at 0469

78 Appendix 2 to Professor Ludlam's statement [PEN.015.0385] at 0400 onwards

79 Professor Ludlam - Day 18, page 150

80 Goldsmith et al , 'T-lymphocyte subpopulation abnormalities in apparently healthy patients with hemophilia', The Annals of Internal Medicine, March 1983 [LIT.001.0055]

81 Ibid [LIT.001.0055] at 0057

82 Day 27, pages 29-30

83 The Conference was held with a view to bringing together the ideas and proposals for strategy held by affected groups. It led to the formation of the Canadian AIDS Society in July 1986.

84 Day 27, pages 39-40

85 Professor Lever - Day 27, page 30

86 Professor Ludlam's Statement [PEN.015.0445] at 0448; Day 19, page 13

87 'Human Immunodeficiency Virus Infection in Haemophiliacs' [PEN.015.0385] at 0400-0401

88 Day 27, page 40

89 Day 35, page 19

90 Ibid, page 21

91 Professor Ludlam's Statement [PEN.015.0445] at 0448

92 Day 35, page 21

93 Day 19, pages 18 and 21

94 Day 19, pages 16-18

95 Day 19, pages 18-20. It was later found, in 1985, that those who were infected with HIV had the same abnormal T lymphocyte subsets after as they had had before transfusion of material infected with the virus, confirming to the satisfaction of Professor Ludlam and his colleagues that the abnormal T lymphocyte subsets were a result of the intravenous infusion of Factor VIII concentrates per se and not HIV infection: Ludlam et al, 'human T-lymphotropic virus type III (HTLV-III) infection in seronegative haemophiliacs after transfusion of Factor VIII', The Lancet, 3 August 1985 [SNB.008.3434] at 3436

96 Gordon, 'Factor VIII products and disordered immune regulation' The Lancet, April 30 [LIT.001.0911]

97 Ludlam et al, 'Disordered immune regulation in haemophiliacs not exposed to commercial Factor VIII' The Lancet, 28 May 1983 [LIT.001.0416]

98 Professor Ludlam - Day 18, page 105

99 Professor Ludlam - Day 18, page 109

100 Froebel et al, 'Immunological abnormalities in haemophilia: are they caused by American Factor VIII concentrate?', British Medical Journal, 1983; 287:1091-1093 [LIT.001.0215].

101 Amended Witness Statement of Professor Charles Forbes [PEN.015.0254] at 0256-7, para 9

102 Day 17, pages 89-90

103 Day 17, pages 90-91

104 Amended Witness Statement of Professor Charles Forbes [PEN.015.0254] at 0257

105 Day 17, pages 96-97

106 'Mystery Disease Threat', Observer, 16.01.83 [DHF.001.7108]

107 'AIDS - transfusion patients may be at risk', New Scientist. 03 February 1983 [DHF.001.7119]

108 'The Acquired Immune Deficiency Syndrome (AIDS)' [DHF.001.7178]

109 UK Haemophilia Centre Directors' Hepatitis Working Party - Acquired Immune Deficiency Syndrome Survey [DHF.001.7183]

110 Day 16, page 34

111 Curran, Evatt and Lawrence, 'Acquired Immunodeficiency Syndrome - The Past as Prologue', Annals of Internal Medicine, 98/3, March 1983 [LIT.001.0047]

112 Preliminary Report, para 11.113

113 Dr Foster - Day 23, pages 10-11

114 'Acquired Immunodeficiency in Haemophilia', The Lancet, 2 April 1983 [LIT.001.0408]

115 Letter [MIS.001.0001]. Re-typed letter [MIS0010005]. See also Chapter 9, Knowledge of the Geographic Spread and Prevalence of HIV/AIDS 1, for further discussion of this letter.

116 Day 26, page 92

117 Day 19, page 40 (Of the two patients positive for HIV at that time, one died of AIDS, the other from bleeding.)

118 Dr Foster's Witness Statement [PEN.015.0101] at 0109

119 Starr D, Blood: An Epic Hitory of Medicine and Commerce, 1998, Harper, London, pages 281-282 [LIT.001.2936] at 2951 (emphasis in original)

120 Dr Winter - Day 16, page 61

121 Day 26, page 41

122 Barré-Sinoussi et al, 'Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS), Science, 1983; 220: 868-871 [LIT.001.0058]

123 'A History of HIV Discovery', Science, 2002; 298:1727 [LIT.001.3767] at 3768; Preliminary Report, para 8.83

124 The Barré-Sinoussi article may have been the 'recent work' showing an association between AIDS and a human t-cell leukaemia virus referred to at a meeting on 15 June 1983 of the Factor VIII safety sub-committee: Minutes of FVIII Safety Sub-Committee Meeting held on 15th June 1983 [SNF.001.3730]. An alternative possibility is a different article in the same issue of Science: Gallo et al, 'Isolation of human T-cell leukemia virus in [AIDS]', Science, 1983; 220: 865-867

125 Dr Foster appears to have prepared two reports: [SNF.001.3714] and [SNF.001.3712]; the one referred to is the latter of these.

126 Haemophilia Centre Directors AIDS Investigation - Surveillance of AIDS Cases in Patients With Blood Coagulation Disorders [SNB.001.7556]. See reference to this case in Dr Craske's update in September 1983. The case was also highlighted in a letter to The Lancet of 19 November, 1983 [LIT.001.0413]

127 Dr Foster's Memo [SNF.001.3712]

128 Recommendation No R(83)-B of the Committee of Ministers to Member States on Preventing the Possible Transmission of Acquired Immune Deficiency Syndrome (AIDS) from Affected Blood Donors to Patients Receiving Blood or Blood Products [DHF.002.2149]

129 Action on AIDS [MIS.001.0001]; Re-typed letter and paper [MIS.001.0005]

130 Committee on Safety of Medicines - Sub-Committee on Biological Products, Minutes of the Meeting held on 13 July 1983 [MIS.001.0291]

131 Ibid [MIS.001.0291] at 0292

132 Dr Craske's report of 10 September 1983 [SNB.001.7556]; his report to the UK Working Party on Transfusion Associated Hepatitis on 27 September [SNF.001.1039], as noted by Dr McClelland and by Dr. Mitchell [SNB.001.3443]; and Dr Craske's report to the UKHCDO Hepatitis Working Party for 1982-83 [SNF.001.0948]

133 Minutes of the Eighth Meeting of the Central Blood Laboratories Authority held on 28 September 1983 [DHF.001.4807]

134 Minutes [SNF.001.3759]; Preliminary Report, para 8.54

135 Tropism is the response of an organism to an external stimulus by growth in a direction determined by the stimulus. At this stage HTLV-III had not been discovered, but HTLV-I had been and was the subject of study.

136 Notwithstanding the approval of the Minutes at the next meeting the Inquiry considers that the word 'unlikely' should read 'likely'

137 Minutes [SNF.001.3759] at 3761

138 Ibid [SNF.001.3759] at 3762-3763

139 Minutes [DHF.002.4834] at 4838

140 Ibid [DHF.002.4834] at 4839

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

142 Ibid [LIT.001.0215] at 0216

143 The Guardian, 14.10.83 [SGF.001.0948]

144 'International Notes Acquired Immunodeficiency Syndrome (AIDS) - Europe', MMWR, 1983; 32(46):610-611 [LIT.001.0555]. See also cutting from Daily Telegraph, 20 October 1983 [DHF.001.4959]

145 Press Release [SGF.001.0949]

146 The class of 'C-type retroviruses' include avian leukosis virus and salmon lymphoma virus. It was later thought that HIV belonged to a different class of retroviruses, 'lentiviruses'. See Chapter 29 The Discovery of HIV and Development of Screening Tests at paragraph 29.4, footnote 6, for Professor Lever's view that more recent research suggests that, while certainly a retrovirus, HIV may not properly belong to the lentivirus genus, either.

147 Dr McClelland was Director of the Edinburgh and East of Scotland Blood Transfusion Service. Mr Watt was Director of the PFC. See Preliminary Report, para 8.65 for a more extensive summary of the meeting.

148 Draft Report [SNF.001.2575]; Covering Letter [SNF.001.2574]

149 Dr McClelland's initial report for the Scottish Regional Transfusion Directors' meeting on 8 December 1983 [SNF.001.0552] contained no new data on transmission.

150 Draft Report [SNF.001.2575] at 2609. It appears frequently to have been overlooked that Germany had reported a few cases of AIDS in haemophilia patients to the WHO by this time.

151 Professor Ludlam's Statement [PEN.015.0385] at 0398-0399

152 Day 18, page 119

153 Pitchenik et al, The Acquired Immunodeficiency Syndrome in the Wife of a Hemophiliac', Annals of Internal Medicine, 1984; 100:62-65 [LIT.001.0681]

154 Fauci et al, 'Acquired Immunodeficiency Syndome: Epidemiologic, Clinical, Immunologic, and Therapeutic Considerations', Annals of Internal Medicine, 1984; 100:92-106 [LIT.001.1573]

155 Ibid [LIT.001.1573] at 1585

156 Blood products Sub-Committee Paper [DHF.001.5151] at 5154

157 Curran et al, 'Acquired Immunodeficiency Syndrome (Aids) Associated with Transfusions', New England Journal of Medicine, 1984; 310(2):69-75 [LIT.001.0695]

158 Bove, 'Transfusion Associated Aids - A Cause for Concern', New England Journal of Medicine, 12 January 1984 [LIT.001.0702]

159 Ibid [LIT.001.0702]

160 Draft Minutes [SNB.004.8628]; Preliminary Report, para 8.75

161 Ibid [SNB.004.8628] at 8630

162 Ibid [SNB.004.8628] at 8635

163 Letter [SNB.004.8639]; Preliminary Report, para 8.77

164 Evatt et al, 'The Acquired Immunodeficiency Syndrome in Patients with Hemophilia', Annals of Internal Medicine, 1984; 100:499-504 [LIT.001.0689]

165 Dr McClelland's Witness Statement [PEN.015.0307] at 0324

166 Professor Ludlam - Human Immunodeficiency Virus Infection in Haemophiliacs [PEN.015.0385] 30 October 1990

167 Day 18, page 20

168 Day 18, page 143, Professor Ludlam - Human Immunodeficiency Virus Infection in Haemophiliacs [PEN.015.0385] at 0401-0402

169 Day 18, pages 149-150

170 Day 18, page 155. Ragni et al, 'Acquired immunodeficiency syndrome in the child of a haemophiliac', The Lancet, 19 January 1985 [LIT.001.5042]

171 Day 19, page 1. Barbara and Tedder, 'Viral Infections Transmitted by Blood and Its Products', Clinics in Haematology [LIT.001.3739]

172 Day 19, pages 5 and 7

173 Preliminary Report, para 8.84

174 Levy et al, 'Recovery and inactivation of infectious retroviruses added to factor VIII concentrates', The Lancet, 1984; II:722-23 [LIT.001.0434]

175 'Update: Acquired Immunodeficiency Syndrome (AIDS) in Persons with Hemophilia' MMWR, 1984; 33(42):589-591 [PEN.013.0186]

176 'Update: Acquired Immunodeficiency Syndrome (AIDS) in Persons with Hemophilia' MMWR, 1984; 33(42):589-591 [PEN.013.0186] at 0187

177 Carr et al, 'Abnormalities of circulating lymphocyte subsets in haemophiliacs in an AIDS-free population', The Lancet, 1984; 1431-1434 [LIT.001.0425]; Preliminary Report, para 8.86

178 Carr et al, 'Abnormalities of circulating lymphocyte subsets in haemophiliacs in an AIDS-free population', The Lancet, 1984; 1431-1434 [LIT.001.0425] at 0428. HLA, human leukocyte antigen, is the immune system's recognition protein. It is discussed in more detail, in the context of HCV, in Chapter 13, Knowledge of Viral Hepatitis Now.

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

180 Interestingly, when the research was published in December, it was said that 59% of the Danish patients were infected. 59% of 22 would be 13, not 14.

181 Ramsey et al, 'Antibody to Lymphadenopathy-Associated Virus in Haemophiliacs With and Without AIDS', The Lancet, 1984 [LIT.001.0421] at 0422

182 Barbara and Tedder, 'Viral Infections Transmitted by Blood and its Products', Clinics in Haematology, October 1984; 13/3 [LIT.001.3739] (emphasis in original)

183 Ibid [LIT.001.3739] at 3749

184 Day 19, pages 4-7

185 Persistent generalised lymphadenopathy: enlarged lymph nodes, a condition that occurs frequently in the latent period of HIV infection.

186 Cheingsong-Popov et al, 'Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain', The Lancet, 1984; 477-480 [LIT.001.0417]; Preliminary Report, para 8.92

187 Cheingsong-Popov et al, 'Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain', The Lancet, 1984; 477-480 [LIT.001.0417] at 0419

188 Gazzard et al, 'Clinical Findings and Serological Evidence of HTLV-III Infection in Homosexual Contacts of Patients with AIDS and Persistent Lymphadenopathy in London', The Lancet, 1984; 480-483 [DHF.002.5914]

189 Minutes [SGH.001.0445]

190 Ibid [SGH.001.0445] at 0446

191 Letter [SNB.004.8715]

192 Letter [SNF.001.4020] See also Chapter 10 Knowledge of the Geographic Spread and Prevalence of HIV/AIDS 2, paragraph 10.13 for discussion on Dr Craske's discovery of HTLV-III infected concentrate.

193 Circulation stamp dated 13 November [SNF.001.4020]

194 Letter [SNF.001.4020]

195 Gracie et al, ''Acquired Immune Deficiency Syndrome - An Overview', Scottish Medical Journal, January 1985; 30/1 [LIT.001.0829]

196 Ibid [LIT.001.0829] at 0833

197 'Provisional Public Health Service Inter-Agency Recommendations for Screening Donated Blood and Plasma for Antibody to the Virus Causing Acquired Immunodeficiency Syndrome', MMWR, 11 January 1985 [SNB.004.9195] at 9195-6

198 Bloom, 'Haemophilia and AIDS', The Lancet, 9 February 1985 [LIT.001.1029]

199 Ludlam et al, 'Human T-Lymphotric Virus Type III (HTLV-III) infection in seronegative haemophiliacs after transfusion of Factor VIII', The Lancet, 3 August 1985 [LIT.001.1669]

200 Ibid, [LIT.001.1669]

201 Ibid, [LIT.001.1669] at 1671

202 Evatt et al, 'Coincidental appearance of LAV/HTLV-III antibodies in hemophiliacs and the onset of the AIDS epidemic' New England Journal of Medicine, 1985; 312:483-486, February 21, 1985

203 See Dr Foster's report of the meeting [SNF.001.4215] at 4217-9

204 AIDS Conference Newcastle - 11-13 February 1986 [DHF.002.0816] at 0817

205 Ibid, [DHF.002.0816] at 0818

206 Report of AIDS conference [SNF.001.4215] at 4218

207 Ibid, [SNF.001.4215] at 4218

208 'Outline Protocol of an Epidemiological Study of the HTLV III - LAV Virus by the Blood Transfusion Service' [SNB.012.9478] at 9479.

209 Report on the World Health Organization Meeting - Safety of Blood and Blood Products in Relation to AIDS, April 14-16 1986 [DHF.002.1524]. Unredacted version of first two pages is [SNB.004.7796]. The World Hemophilia AIDS Center (WHAC), Pasadena, California, was established by the World Federation of Haemophilia during its annual congress in Stockholm in July 1983 to facilitate the collection and dissemination of data on HIV/AIDS.

210 See Chapter 29 Discovery of HIV and Development of Screening Tests at paragraph 29.4, footnote 6 for Professor Lever's view, based on further study, that HIV does not properly belong to the lentivirus genus.

211 See Chapter 10 Knowledge of the Geographic Spread and Prevalence of HIV/AIDS 2 at paragraphs 10.118-10.120 for an illustration of the application of genetic analysis in tracing the source(s) of infection of batch 023110090, for example.

212 Professor Lever - Day 26, pages 10-12

213 Day 26, page 60

214 Day 26, page 62

215 Day 26, pages 60-61

216 'Health Officials Seek Ways to Halt AIDS', Research News, 21 January 1983 [LIT.001.1589]

217 Evatt, 'The tragic history of AIDS in the hemophilia population 1982-1984', Journal of Thrombosis and Haemostasis, 2006, 4/11: 2295 - 2301, (reprint) [PEN.016.1183] at 1188

12. HIV/AIDS: Response and Clinical Practice >