The Penrose Inquiry

CHAPTER 9

HEPATITIS 1986 TO DATE

Synopsis

Growing awareness of potential seriousness of Non-A Non-B Hepatitis (NANB Hepatitis) – high prevalence of NANB Hepatitis in haemophilia patients – further consideration given to surrogate testing of blood donors for NANB Hepatitis – isolation of genome of Hepatitis C in 1988 – publication in 1989 of scientific details of the isolation of Hepatitis C and details of a test for detecting antibodies to the virus – creation in 1989 of the Advisory Committee on the Virological Safety of Blood (ACVSB) – consideration given to screening donors for Hepatitis C – evaluation of first and second generation ELISA (enzyme-linked immunosorbent assay) tests – evaluation of confirmatory tests – introduction of routine testing of blood donors for Hepatitis C in September 1991 – Hepatitis C ‘look-back’ exercise carried out between 1995 and 1998 – investigations by Scottish Executive

Introduction

9.1 From about 1985 onwards there appears to have been a growing awareness that Non-A Non-B Hepatitis (NANB Hepatitis) was a potentially serious and progressive disease which could lead, over time, to cirrhosis of the liver, hepatocellular cancer and death.[1]

9.2 There continued to be discussion, internationally, on whether to introduce testing of blood donors for surrogate markers of NANB Hepatitis. The two main surrogate markers considered were raised alanine aminotransferase (ALT) levels and the presence of antibody to the Hepatitis B core antigen (anti-HBc). Surrogate testing was introduced in the United States of America (USA) in 1986/1987 and was introduced in some other countries,[2] but was never introduced in the United Kingdom (UK). Reasons for not introducing surrogate testing in the UK were stated to include the unreliability (ie the poor sensitivity and specificity) of surrogate tests, a low prevalence of NANB Hepatitis in the blood donor population, uncertainty (due to a lack of research and, therefore, evidence) as to the extent to which surrogate testing would reduce the incidence of post-transfusion NANB Hepatitis in the UK, the loss of falsely positive donors from the donor pool and the cost of testing and counselling donors.

9.3 The main breakthrough in the understanding of NANB Hepatitis was made when a genome of the Hepatitis C virus was isolated by an American company, Chiron Corporation (Chiron). That discovery was announced in May 1988.[3] Scientific details of the discovery were published in April 1989.[4] In April 1989 details were also published of an
enzyme-linked immunosorbent assay (ELISA) to detect antibodies to the Hepatitis C virus.[5] The test had been developed by Ortho Diagnostics Incorporated (Ortho), in conjunction with Chiron.

9.4 In April 1989 the Advisory Committee on the Virological Safety of Blood (ACVSB) was set up. The ACVSB advised the UK government, among other things, on surrogate testing of blood donors for NANB Hepatitis and screening of donors for Hepatitis C.

9.5 In November 1989 the US Food and Drug Administration (FDA) granted an export licence to Ortho, permitting their ELISA test for detecting antibodies to Hepatitis C (anti-HCV ELISA) to be exported to various countries, including the UK.

9.6 In May 1990 the FDA granted Ortho a licence for use of their anti-HCV ELISA within the USA. At that time a recombinant immunoblot assay (RIBA) test (which also detected antibodies to Hepatitis C) had been developed to confirm samples found positive on ELISA testing.

9.7 From around May 1990, screening of blood donors for Hepatitis C was routinely carried out by blood banks in the USA. Other countries introduced Hepatitis C screening from 1989 onwards.[6]

9.8 In the UK, between 1989 and 1991, the blood transfusion authorities evaluated the first generation, and then the second generation, anti-HCV ELISA and RIBA tests.

9.9 In September 1991, following advice from the ACVSB, routine testing of blood donations for Hepatitis C was introduced throughout the UK using second generation anti-HCV ELISA and second generation RIBA tests.

9.10 Reasons given for not introducing Hepatitis C screening of blood donors earlier in the UK included concerns regarding the reliability (ie the sensitivity and specificity) of the first generation ELISA tests, the absence of a true confirmatory test, a desire to evaluate second generation tests when they became available and uncertainty over whether persons who tested positive for antibodies to Hepatitis C were infectious.[7]

9.11 Between 1995 and 1998 a ‘look-back’ exercise was carried out throughout the UK to trace patients who had received blood and its components from donors found to be Hepatitis C positive following the introduction of routine screening in September 1991. The ‘look-back’ exercise commenced in 1995, following advice from the ACVSB, on the basis that by that time treatment for Hepatitis C had become available (Interferon) and a Scottish pilot study had shown that such a ‘look-back’ exercise was feasible.

9.12 In 1999 the Scottish Executive carried out an investigation into the infection of haemophilia patients with Hepatitis C through treatment with blood products.

1986

Publications

9.13 There was extensive publication of information about NANB Hepatitis in 1986. While understanding of the disease was incomplete, studies generally reported that:

• up to 60% of those with NANB Hepatitis developed chronically elevated ALT readings (indicating chronic ongoing hepatitis); and

• following liver biopsy of small numbers of patients, between 10–20% of patients with elevated ALT readings had cirrhosis of the liver.

9.14 In a review article published in 1986, two leading USA authorities; Dienstag (Harvard Medical School) and Alter (National Institutes of Health, USA) stated:

More than a decade has elapsed since [NANBH] entered our lexicon. After all this time, after the publication of hundreds of articles, after the emergence and maturation of now stalemated controversies over the agents and the disease, our understanding of NANB hepatitis is still unsettled and evolving … Strikingly clear is just how much we do not know about NANB hepatitis … In the decade since its discovery, the concept of NANB hepatitis has evolved from that of a benign elevation of aminotransferase activity to that of a serious disease with significant long-term consequences. The longer patients are followed, the more obvious it becomes that [chronic active hepatitis] and cirrhosis are a very real part of the natural history of NANB hepatitis … one decade after the classification of NANB hepatitis as a distinct form of viral hepatitis, collected observations indicate that biochemical evidence of chronic hepatitis develops in approximately 50% of cases related to transfusion; that among those with chronic ALT elevations who are biopsied, approximately 60% have chronic active hepatitis, cirrhosis, or both; that overall, 10 to 20% of those with chronic ALT elevations have cirrhosis on initial or repeat biopsy; and that among cases described in published reports, of 20 patients in whom cirrhosis was documented to have developed after transfusion, five have now died of liver failure.[8]

9.15 Dienstag and Alter noted that the Aledort study[9] of liver biopsies from persons with haemophilia found that cirrhosis had developed in 15% of patients. Dienstag and Alter commented that that was:

an alarming percentage and one similar to that obtained in non- hemophiliac transfused populations … While there is a divergence of opinion as to the progressive nature of … histologic abnormalities in hemophiliacs, a substantial proportion of these patients end up with cirrhosis, an unequivocal histologic diagnosis that leaves little room for argument’.

9.16 The authors noted, furthermore, that indirect evidence for an association between NANB Hepatitis and hepatocellular carcinoma was beginning to accumulate.

9.17 Dienstag and Alter discussed the detection of the NANB Hepatitis agents and noted that, while there had been more than 40 published reports of specific NANB Hepatitis assays,

Not a single test … has been reproducibly and independently confirmed, not a single test has successfully distinguished proven NANB hepatitis infectious sera from control sera when tested under independent code, and not a single test has moved from the research laboratory to the point of practical application.

9.18 There was discussion of surrogate testing by ALT and anti-HBc. Both of the indirect assays had disadvantages, namely relatively low sensitivity and specificity, a very low positive predictive value, loss of non-infective donations, cost and time.

Despite these negative features, however, the accumulating data that chronic NANB hepatitis leads to cirrhosis in 10 to 20% of cases has served as compelling evidence for the need to rely on indirect assays as an interim measure until such time as specific NANB hepatitis assays are developed … increasing documentation of the chronic sequelae of NANB hepatitis and the continued high incidence of this disease after transfusion has tipped the balance in favour of adopting indirect assays for NANB hepatitis carrier detection …. Specific therapy for either acute or chronic NANB hepatitis is not available …. In the absence of effective treatment, the need for prevention assumes even greater importance.

9.19 On 8 February 1986 The Lancet published a letter by Schimpf (Heidelberg, West Germany)[10] in which the author agreed with the report by Hay et al in 1985[11] that progressive liver disease in haemophilia patients was an understated problem. In Schimpf’s study 52 biopsies were carried out on 45 patients between 1972–1985. There were signs of subsided hepatitis in 24%, chronic persistent hepatitis in 27% and progressive liver disease in 29% (16% chronic active hepatitis, 13% cirrhosis). Schimpf also noted that the multi-centre study by Aledort et al[12] had come to a similar conclusion regarding the frequency of cirrhosis.

9.20 The 8 February 1986 edition of The Lancet also contained an update on the condition of 12 patients who developed NANB Hepatitis after treatment with a new intravenous gammaglobulin preparation produced by the Blood Products Laboratory, Elstree (BPL).[13] At least half of the patients had evidence of progressive liver disease, with cirrhotic changes in three.

9.21 On 20 June 1986, Morbidity and Mortality Weekly Report (MMWR), the journal of the USA’s Centres for Disease Control, reported 13 cases of NANB Hepatitis among patients who had undergone cardiovascular surgery and had received Factor IX produced by Alpha Therapeutic Corporation because of bleeding during surgery.[14] The report noted that clotting factor preparations had frequently been linked to the transmission of NANB Hepatitis. In haemophilia patients who routinely received commercial factor preparations, episodes of NANB Hepatitis were common; as many as 50% may develop signs of chronic liver disease. Studies in first exposed haemophilia patients and in surgical patients who received clotting factor preparations suggested that the risk of NANB Hepatitis might be close to 100%. The methods currently used to treat clotting concentrates did not appear to inactivate the causative agents of NANB Hepatitis. Because of the high risk of viral hepatitis, recommended use of clotting factor products had been limited to persons with known clotting factor deficiencies. In other settings, single donor products were preferable as they carried a lower risk of hepatitis transmission.

9.22 On 2 August 1986 The Lancet published an editorial, ‘Safer Factor VIII and IX’[15] The editorial stated:

The risk of contracting [NANB Hepatitis] from factor VIII and IX concentrates was first recognised ten years ago. The requirement for large pools of plasma, of up to 7000 donations in the UK … and even larger pools with some commercial preparations has produced attack rates approaching 100% in recipients after first exposure to unheated factor VIII. The acute illness was often mild …. Unfortunately, it is now clear that there is a substantial long-term risk of chronic sequelae, such as chronic active hepatitis and cirrhosis of the liver. Reports of serial liver biopsies in patients regularly treated with factor VIII and IX suggest that the risk of serious chronic liver disease may be as high as 16%.[16]

Other events in 1986

9.23 On 21 February 1986 the American Association of Blood Banks (AABB) reported that the US FDA would recommend that both ALT and anti-HBc testing be performed on donated blood to reduce the incidence of NANB Hepatitis through transfusion.[17]

9.24 On 4 March 1986 Dr Gerald Sandler (American Red Cross) wrote to Dr Cash (National Medical Director, SNBTS), advising that the American Red Cross would not be making changes in donor testing directives in respect of ALT and anti-HBc testing, but would be reviewing the matter on 7 March.[18]

9.25 On 25 March 1986 the SNBTS Directors met.[19] There was discussion of surrogate testing for NANB Hepatitis. The US FDA’s recommendation on surrogate testing had been circulated. Dr John M Forrester, (Scottish Home and Health Department (SHHD)) thought it highly unlikely that the Department of Health and Social Security (DHSS) would fund testing based on data from the USA. It was noted, however, that Hepatitis B surface antigen and HIV antibody testing had both been introduced without prior UK research. Certain clinicians and haematologists in the country had felt that the transfusion services had been slow to commence HIV testing and others had similar views in relation to NANB Hepatitis surrogate tests. Dr McClelland (SNBTS, Edinburgh) stated he would be able to provide data about raised ALT levels in blood donors by the Autumn of 1986, following a successful ethics committee proposal. Dr Forrester would be glad to hear of any research but could not guarantee funding. After a full discussion the Directors agreed to give consideration to funding someone to undertake research. Dr Cash would think about the possibilities in association with Dr Ian D Fraser (Bristol Blood Transfusion Centre (BTC)), and make proposals to the Directors.

9.26 The Directors of the National Blood Transfusion Service for England and Wales (NBTS) met on 24 and 25 April 1986. The minutes recorded:

Should the NBTS carry out a study on NANBH?

The Chairman reported that this had been discussed by the Scottish Directors and that he had agreed to raise it with RTD’s. [redacted] reminded Directors of two previous attempts, one by the MRC and one by the Transfusion Associated Hepatitis Working Party, to study this problem. After discussion it was agreed that this should not be pursued because of the lack of time and resources.[20]

9.27 In May 1986 Dr Brian C Dow (SNBTS, Glasgow) prepared a special report to Regional Transfusion Directors on ‘Surrogate tests for non-A, non-B hepatitis’.[21] Reference was made to Dr Dow’s 1985 doctoral thesis in which three strategies were investigated to reduce the number of post-transfusion NANB Hepatitis cases, namely the exclusion of donors with a history of jaundice, anti-HBc or raised ALT testing. Exclusion of donors with a history of jaundice would lead to a loss of around 2–3% of blood donors in the West of Scotland. The introduction of anti-HBc tests could be useful in identifying those donors who may be NANB Hepatitis carriers. If such a donor testing strategy was introduced in the West of Scotland, between 1–2% of donors would be excluded. If ALT testing was introduced in the West of Scotland, depending on the cut off point, 0.75% of West of Scotland donors would be excluded. Sixty five donors had been implicated in 18 cases of post-transfusion NANB Hepatitis. Assuming that the described strategies correctly identified NANB Hepatitis infective donors, a maximum of eight (44%) of the 18 NANB post-transfusion Hepatitis cases would have been prevented using all three strategies. That would result in a loss of approximately 5% of donors and considerably increased testing costs. Even if the combination of anti-HBc and ALT tests was shown to be 100% effective the economics involved in conducting these tests would greatly outweigh the costs of hospitalisation of the few reported post-transfusion NANB Hepatitis cases.
Dr Dow concluded:

The present UK policy of accepting donors with raised ALT levels (ie not routinely ALT testing), anti-HBc or histories of jaundice would appear to be correct. It would appear from the study that the introduction of such surrogate screening procedures would have little impact on reducing the already low level of NANB [post-transfusion hepatitis] cases at present reported within the West of Scotland region.

9.28 In response to a request by Dr Forrester (SHHD) for information on NANB Hepatitis,[22] Dr Dan Reid (Communicable Diseases (Scotland) Unit, Ruchill Hospital, Glasgow) replied on 4 June 1986, enclosing a copy of Dr Dow’s 1985 doctoral thesis on NANB Hepatitis in the West of Scotland. Dr Forrester later produced a note dated 12 June 1986, ‘Transmission of non-A, non-B hepatitis by blood and blood products: Is it practicable to reduce or prevent it by introducing ALT testing of donations?’[23] Dr Forrester noted that Dr Reid and Dr Follett did not recommend the introduction of ALT testing of Scottish blood donations.

9.29 The SNBTS Directors met on 25 June 1986.[24] There was discussion of surrogate testing for NANB Hepatitis. It was noted that there was increasing evidence that the USA and several European countries were introducing anti-HBc and/or ALT testing of blood donors in an effort to minimise the risks of NANB Hepatitis transmission through blood and blood products. Dr Cash believed that the SNBTS would soon come under pressure from clinicians to introduce testing. A limited study involving follow-up of donors with abnormal liver function tests (LFT) was about to take place in Edinburgh[25] and Dr Urbaniak (SNBTS, Aberdeen) had been in touch with a gastroenterologist who had expressed an interest in investigating post transfusion NANB Hepatitis infection, but he had not yet received a response. Dr Ian Fraser (Bristol BTC) had advised Dr Cash that he (Dr Fraser) and Dr Marcela Contreras (North London BTC) were keen to set up a small group to explore the feasibility and practicability of this development and that it was their hope that a Scottish Regional Transfusion Centre (RTC) would contribute. The Directors agreed to await the outcome of Dr Fraser and Dr Contreras’ joint deliberations and to discuss the matter again at that time.

9.30 On 28 August 1986 Dr Cash wrote to Dr Ian Fraser (Bristol BTC) on surrogate testing for NANB Hepatitis:

I have a feeling that as the drums are beating louder and louder in other parts of the world on this topic the Brits remain fast asleep. I may be wrong but I would like to be better briefed on the matter.[26]

9.31 While the suggestion of setting up a UK prospective trial had been raised, and rejected, at a meeting of NBTS Directors in England and Wales,[27] Dr Cash stated that he could not leave the matter as it was and wished to plan with Dr Fraser a consensus meeting to look at the issues associated with NANB Hepatitis.

9.32 On 4 September 1986 Dr Fraser replied to Dr Cash.[28] Dr Fraser was keen that something should be done and if Drs Fraser, Contereras and Cash ‘rowed hard enough we could get our colleagues to move in the same direction’.

9.33 On 4 September 1986 Nature published an article, ‘Hepatitis screening extended’, summarising the position in the USA in relation to the introduction of surrogate testing for NANB Hepatitis.[29] The debate over whether to use one or both of the ALT and anti-HBc surrogate tests had been raging for years. The American Association of Blood Banks (AABB) had recently announced that it expected its members to implement surrogate testing (seemingly by raised ALT) of all donated blood by 30 November 1986. The American Red Cross was also implementing ALT testing at its blood banks. Its programme had begun on 7 July and was expected to be completed by 1 October 1986. A third organisation, the Council for Community Blood Centres, had not officially declared a position on ALT testing but its President was reported as saying that ‘most members would go ahead with ALT testing’. The article stated that the use of anti-HBc testing was far more contentious. A major concern for all blood centres was the loss of donors from false positives in both surrogate tests and the cost of testing. Notwithstanding these concerns, the President of the AABB considered that the tests were ‘essential to increase the safety of the blood supply’.[30]

9.34 On 9 October 1986 the SNBTS Directors met.[31] There was discussion of surrogate testing for NANB Hepatitis. Dr Gunson reported that three English centres (Edgware, Bristol and Manchester) were to study the incidence of raised ALT and anti-HBc in their donor populations. Dr Fraser (Bristol BTC) indicated that it would be helpful if an SNBTS centre could be included in the study. Dr Gunson had recommended to the DHSS that a group should be established and this had been agreed. It was agreed by the SNBTS Directors that the UK Working Party on Transfusion Associated Hepatitis was the most appropriate body to pursue the issue of implementing surrogate testing in RTCs and Dr Cash should write to Dr Gunson on behalf of SNBTS Directors formally requesting that this Working Party be reconvened, with a view to making proposals to the DHSS.[32]

9.35 On 16 October 1986 Dr G A Scott (Depute Chief Medical Officer, Scotland) sent an internal memorandum to Dr Forrester and Mr A Murray on NANB Hepatitis screening.[33] The memorandum stated:

I should like to know where this stands. CMO DHSS is worried that if we go ahead England and Wales will have to follow suit. I think there must be consultation with DHSS before we agree to provide funds for this screening.

9.36 Dr Forrester advised, by memorandum dated 17 October 1986, that there seemed no justification for introducing hepatitis screening without gathering further British evidence, because the American experience of frequent post-transfusion hepatitis did not seem to be duplicated in Britain.[34] Dr Forrester wrote a letter dated 17 October 1986 to Dr Alison Smithies of the DHSS advising that he had no reason to think that Scotland was imminently about to adopt surrogate testing.[35] Dr Forrester hoped that the message in both Scotland and England would be ‘research first, action later’. In a memorandum dated 21 October 1986, Mr A Murray (SHHD) advised Dr Scott that the bid he was making to Finance colleagues for money for the SNBTS in 1987/88 made no provision for NANB Hepatitis screening.[36]

9.37 On 24 November 1986 the reconvened UK Blood Transfusion Services’ (BTS) Working Party on Transfusion Associated Hepatitis met for the first time. The view of the group was that:

…the USA experience did not relate to the UK. The [hepatitis B] rates in the USA were higher, and any NANBH viruses prevalent in one country were not necessarily going to be equally prevalent in the other … limited UK data did not of itself warrant introduction of anti-HBc/ALT screening at this time.[37]

9.38 Dr J M Forrester (SHHD) attended the meeting of the Working Party and produced a note.[38] He reported that the meeting felt that a prospective study to discover the present burden of transfusion associated NANB Hepatitis was impracticable on grounds of cost and huge sample size. Instead, a study was proposed in three centres (including one Scottish centre) to identify donors positive for ALT or anti-HBc, and to search for other risk factors in them. There was some discussion of the cost of screening all donations (perhaps £8million). Dr Forrester asked Dr Gunson whether he would advise screening if it were cost free and Dr Gunson replied that he would not. Dr Forrester stated in his note that the position explicitly reached at the meeting was to recommend research of no great significance or scientific interest because the prospect of research would serve to counter pressure from, for example, haemophilia patients and Haemophilia Directors to embark on an indirect and largely ineffective form of screening, which would lose a certain amount of perfectly harmless blood. Figures were produced at the meeting for the total number of NANB Hepatitis cases encountered annually among patients with haemophilia and with von Willebrand’s Disease (vWD). The average UK total was 35 over the previous six years, although in 1985 there was sharp decline to 11 in all. A proportion of these cases among haemophilia patients and similar patients were asymptomatic.

9.39 At the end of 1986 a preliminary report by Hoofnagle et al (USA National Institutes of Health) was published which suggested that long term, low dose alpha interferon therapy might be effective in controlling disease activity in some patients with chronic NANB Hepatitis.[39] A prospective controlled trial was required to confirm the role of interferon therapy in treating the disease.

1987

9.40 In 1987 the eighth edition of the standard UK textbook on blood transfusion was published.[40] The book set out understanding of NANB post-transfusion Hepatitis (PTH) at that time.[41] Post-transfusion NANB Hepatitis was stated to be diagnosed when, between 2—26 weeks after transfusion, two consecutive blood samples showed a two-fold rise in ALT levels. That method of diagnosis was ‘most unsatisfactory’, and led to ‘a great deal of uncertainty about the true incidence of NANB PTH’. It had been estimated that 20—42% of sporadic cases of hepatitis in the USA were caused by NANB agents[42] compared with 13% within the UK.[43] The book went on:

NANB PTH is usually mild and asymptomatic during the acute phase … However, prospective studies in the USA have shown that the chronic sequelae of NANB PTH may be serious. Over 50% of patients develop chronic hepatitis as judged by persisting or fluctuating rises in [ALT] levels lasting for at least
1 year after onset of the disease and in most for more than 3 years … Although the chronic phase of NANB PTH, like the acute phase, tends to be mild,[44] some patients develop severe chronic liver disease and 10% of these patients progress to cirrhosis which is generally milder than alcoholic cirrhosis.[45]

9.41 It was noted that the available data was based on biopsies in very small numbers of patients.

9.42 Mollison et al set out the main studies on the use of indirect or surrogate markers to detect carriers of NANB Hepatitis. While the American Association of Blood Banks had recommended testing of all blood donations for ALT and anti-HBc, no randomised controlled trials on the effect of testing blood donors for these surrogate markers had ever been performed in the USA. Blood bankers were faced with the prospect of having to reject large numbers of donors, most of whom were not carriers of NANB Hepatitis agents. Small prospective studies in countries outside the USA had not found the same direct relationship between donor anti-HBc and NANB post-transfusion Hepatitis as had been found in the USA Transfusion-Transmitted Viruses and National Institutes of Health studies. It was noted that in the UK the incidence of post-transfusion hepatitis seemed to be substantially lower than in the USA, although no large prospective studies had been carried out since the introduction of screening for Hepatitis B surface antigen (HBsAg).[46]

9.43 On 22 January 1987 the reconvened UK BTS Working Party on Transfusion Associated Hepatitis met for the second time. Dr Forrester (SHHD) was present and wrote a note of the meeting.[47] The following individuals were also present: Dr H Gunson (Chairman, NBTS), Mrs Janet Mortimer (Communicable Diseases Surveillance Centre), Dr Ruthven Mitchell (SNBTS), Dr Jack Gillon (SNBTS), Dr J Barbara, Dr Susan Lader (DHSS), Professor A J Zuckerman, Professor Howard Thomas and Dr J Craske. There was discussion on the proposal for research into ALT and anti-HBc screening. It was hoped that the research might start on 1 April, subject to funding.

9.44 On 26 January 1987, Dr Forrester, produced a note, ‘Material for PMO Report’.[48] He made the following comments on blood transfusion and NANB Hepatitis:

This ‘hepatitis’ is a residual rag-bag when hepatitis B and hepatitis A are excluded and consequently no specific test can detect it. It is relatively benign. But US blood banks have noted that the combination of a liver function test and a test for the core (not the surface) antigen of hepatitis B distinguishes perhaps a third of blood donations which would convey [NANBH] and allows them to be excluded. Exclusion is far from complete, and besides, some 2% of “innocent” donations may also be excluded. Nevertheless, US blood banks are evidently about to adopt this pair of tests and shoulder the expense. Here, it is intended instead to enquire into the number of relevant donations and the characteristics of the donors, before taking any further step.

9.45 On 9 February 1987 the SNBTS and Haemophilia Centre Directors met at St Andrew’s House.[49] Dr Forrester (SHHD) reported on the recent meeting of the Working Party on Transfusion Associated Hepatitis. In the USA, between 5% and 25% of transfusions led to the recipient contracting NANB Hepatitis. In the UK the figure was approximately 2.5% and, in Scotland, during the last decade, there had only been one to five cases per annum. NANB Hepatitis appeared to be relatively benign, despite some link to cirrhosis of the liver in the long-term, unless the recipient was pregnant when the effects could be very serious. In the USA screening by a combination of a liver function test and assay of Hepatitis B core antibody removed between 30%–40% of cases for the loss of 1% of donations.[50] In the UK it was proposed to set up a study based on four centres, one of which would be in Scotland. The purpose of the study would be to discover the number of donations affected, what a positive test meant about the donor, the effect of giving blood positive on this screening and the cost of screening. Dr Cash noted that commercial products, if derived from screened plasma, might enjoy an advantage over products derived from unscreened plasma. The cost of screening in Scotland would be approximately £750,000 per annum.

9.46 On 5 February 1987 Dr Susan Lader (Medical Officer, DHSS) wrote to Dr Forrester (SHHD) on the proposal for a multi-centre study of ALT and anti-HBc in blood donations.[51] Dr Forrester replied by letter dated 10 February 1987.[52] He thanked Dr Lader for her constructive comment and advised that he would ‘tip off’ the Chief Scientific Officer (CSO) for Scotland. On 10 February 1987 Dr Forrester wrote a memorandum to Dr Moir of the CSO’s office on Scottish participation in the UK research project on transfusion associated NANB Hepatitis.[53] In contrast to the position in the USA, UK evidence on surrogate testing for NANB Hepatitis was that the advantages might be outweighed by loss of ‘innocent’ blood and problems of counselling donors. While SNBTS had sought approximately £600,000 to institute screening and conduct it for a year, the request stood declined. Instead of blindly adopting American practice, research should be conducted and a project involving three English and one Scottish transfusion centres was being planned. Funding for the Scottish component of the research was sought from the CSO, to be determined in cooperation with the Research Management Division, DHSS. Dr Moir replied in a memorandum dated 17 February 1987.[54] He had very strong reservations about funding a research project including a Scottish transfusion centre. That would appear to simply repeat the study carried out over a three year period by Drs Follett and Dow, reported two years earlier, and funded by the CSO. If the SNBTS wished to formulate a research proposal for funding from the CSO it should be submitted as an application for formal review by the Biomedical Research Committee.

9.47 On 14 February 1987 The Lancet published a letter by Drs J Gillon and D B L McClelland (SNBTS, Edinburgh) on the subject of autologous blood transfusion.[55] The authors noted that only one study of the long-term sequelae of post-transfusion NANB Hepatitis had been reported.[56] Of the 50% of cases which became chronic, as evidenced by raised ALT levels persisting for more than six months, 10–15% might be expected to show evidence of clinically important liver disease. The figures were almost certainly an overestimate as they made no allowance for the proportion of recipients who died of their original disease (over 50% in most retrospective studies). In addition, the incidence of post-transfusion NANB Hepatitis was probably much lower in the UK than in the USA, having been found to be between 2–4% in coronary bypass patients in the only recent study.[57] The true figure might well be even lower as groups at high risk of HIV infection had been excluded from donation.

9.48 The SNBTS Directors met on 3 March 1987.[58] It was minuted that a proposal for a study of surrogate testing which initially included both Glasgow and Edinburgh transfusion centres had been modified and no Scottish centre was now being asked to participate.[59] It was noted that some commercial plasma collectors and non-profit blood collectors in the USA had begun surrogate testing in 1987 and that in the UK the Haemophilia Society might adopt a position which put pressure on the Blood Products Laboratory (BPL) to ensure surrogate testing was introduced. The Directors discussed the options open to Scotland and agreed to recommend to SHHD that surrogate testing for NANB Hepatitis should be implemented with effect from 1 April 1988 as a national development requiring strictly new funding. Each Director was to let Dr Cash know what funds would be required in their region, assuming that both ALT and anti-HBc screening would be undertaken.

9.49 On 6 April 1987 Dr A D McIntyre (SHHD) sent a memorandum to Dr Moir, Dr Forrester and others.[60] The memorandum noted SHHD’s reasons for refusing SNBTS’s request for annual expenditure of £810,000 to screen for NANB Hepatitis, namely: the Follett/Dow research in the West of Scotland had indicated that the impact there of NANB Hepatitis was not great; indirect screening would be expensive and could not abolish the transmission of NANB Hepatitis; there would be a loss of a perceptible amount of ‘innocent’ blood which failed to pass the screen; and the SHHD wished to await DHSS thinking on the subject. The DHSS had now invited their Transfusion Associated Hepatitis Working Party, which included two Scottish members and an SHHD observer, to consider the issue and the Working Party had advised that instead of embarking at once on expenditure on a UK basis of perhaps £6–8million, research should be commissioned to expand the previous Scottish research. The SNBTS Directors were unanimous and were pressing fairly strongly that screening should be instituted. Before embarking on such an expensive programme, Dr McIntyre was of the view that it would be logical to participate in the proposed UK research study and to delay any further action until the results were known. If that was considered to be the correct line to adopt then the Edinburgh BTS would be asked to prepare a detailed proposal along similar lines to their English counterparts. The memorandum contained a handwritten note by an unknown author as follows:

Mr Macniven, Advise please. My initial reaction is (a) it would not make sense to screen all blood for [NANBH] as benefits appear out of all proportion to the risks, (b) we should therefore participate in the research, (c) CSO should be encouraged to fund it.

9.50 On 18 April 1987 a letter was published by Anderson et al (North London BTC): ‘Surrogate testing for non-A, non-B hepatitis’.[61] The authors noted that while surrogate testing had been introduced in the USA, there were various problems, including the lack of data in the UK upon which to come to an informed decision as to its introduction. The authors argued that a national study was required to assess the incidence of raised ALT levels and anti-HBc in donors in different parts of the country; the incidence of acute post-transfusion NANB Hepatitis; and how many of those affected developed evidence of chronicity and serious clinical sequelae. The authors concluded:

If the true incidence of post-transfusion NANB hepatitis and its serious clinical sequelae are at a much lower level than reported from the USA, then screening of donations to reduce the incidence of NANB hepatitis may not be cost effective in the UK.

9.51 By letter dated 21 April 1987 Dr Gunson wrote to Dr Cash commenting on that part of the minute of the Scottish Directors’ meeting on 3 March recommending the introduction of surrogate testing for NANB Hepatitis.[62] Dr Gunson enclosed a copy of the proposals for research submitted by the UK Working Party on Transfusion Associated Hepatitis. Edinburgh was included as a participating RTC (contrary to what was stated in the minutes of the meeting on 3 March that there were no participating Scottish RTCs). Dr Gunson was ‘further dismayed’ to see that the Scottish Directors had agreed to put forward proposals for the funding of surrogate testing for NANB Hepatitis from 1 April 1988. That appeared to go against the Working Party’s research proposals and an indication previously given by Dr Cash to Dr Gunson that Scotland would not take unilateral action in this matter without consultation with regional transfusion directors in England and Wales.

9.52 Dr Cash replied to Dr Gunson by letter dated 27 April 1987:

I don’t think you should take the content of [the] minute … with regard to the introduction of surrogate testing for NANB too seriously at this stage. I think it would be appropriate to say that it was a decision made with our PESC submission in mind and, I suspect, a view that we have often expressed – that the results of the UK study are unlikely to have a material effect on future operational practice.[63]

9.53 On 14 May 1987 Dr Forrester (SHHD) sent a memorandum to Dr McIntyre, Dr Scott and Mr Macniven.[64] The outcome of Dr Gillon’s discussions with Dr W Forbes was that the Scottish component of the UK NANB Hepatitis research project was being abandoned. Dr Gillon’s Director, Dr McClelland, was unlikely to press it as his current view was that the SHHD had better simply institute screening.

9.54 Between 26—28 May 1987 an International Symposium on Viral Hepatitis and Liver Disease was held in London.[65] Dr Harvey Alter delivered a paper, ‘Transfusion-Associated Non-A Non-B Hepatitis: the First Decade’.[66] He noted that ‘NANBH has become a confusing conglomerate of terms and diagnostic entities’. He went on:

Although there is still considerable scepticism regarding the significance of chronic NANBH, evidence continues to accumulate that, in at least a proportion of cases, this is a significant and sometimes fatal illness.

9.55 On the question of surrogate testing Alter stated:

Given the magnitude of these chronic consequences, the absence of a specific marker and the absence of a proven therapeutic intervention, attention must focus on means to prevent transfusion-associated NANBH. In the past 2 years, considerable controversy has centered on the adoption of surrogate tests to interdict the NANBH carrier blood donor … The predicted efficacy for [anti-HBc] testing was 28% …. Based on … three studies, on prior data relating to ALT, and on the evidence for significant chronic liver disease following NANBH, the major blood organisations in the United States have elected to adopt both the ALT test and the [anti-HBc] test as routine screening measures for all blood donations. Although I am in agreement with this decision, I wish to stress again that these are predicted efficacies, not proven efficacies, and that, in countries that can do so, an effort should continue to be made to perform a controlled, prospective study to demonstrate whether such costly measures are truly indicated.

Alter concluded:

In summary, NANB remains a frustrating and perplexing dilemma. Nonetheless, we know a little more about its physical properties, we know considerably more about its clinical outcome, and we know of multiple ways in which it can be inactivated. What we do not know exactly is where to go next, or what can be done to create the breakthrough that will allow progress with NANBH to parallel that with hepatitis B and hepatitis A. Some sophisticated approaches to this long-standing dilemma are under study, and, despite repeated past failure, I am optimistic that the resolution to this problem will be found in the not-too-distant future.

9.56 On 2 June 1987 a paper by Mijovic et al (North London BTC) reporting on a study of ALT testing in 2000 North London blood donors was accepted for publication.[67] The percentage of the total donor population with raised ALT levels (4.6%) was greater than that found in earlier studies at the same centre in 1973 (2.8%) and 1982 (3.1%). The increase in donors with raised ALT values had occurred despite the intensification of donor education and subsequent self-exclusion of donors in high risk groups for HIV. The authors considered that that confirmed that many other factors, apart from NANB Hepatitis, affected ALT activity, including high alcohol consumption, obesity, medication, strenuous activity and inhalation of solvents etc. The authors stated:

Before we even consider testing blood donors for ALT, a well designed prospective trial is needed to compare the incidence of hepatitis associated with transfusion in patients who received blood only from donors with normal ALT activities with those receiving untested blood … even in the United States the predictive value of ALT testing of blood donations for NANB hepatitis is very poor. The costs of testing and discarding donor blood would need to be examined as well as the costs of informing and counselling donors found to have ALT values repeatedly above the normal, or donors with excessively high values at any one time. Extrapolating data from the United States to this country without knowing the magnitude of the problem or its preventability would be ill advised.

9.57 On 10 June 1987 the SNBTS Directors met.[68] The correspondence between Drs Cash and Gunson on surrogate testing was noted. Dr McClelland would probably apply to the next meeting of the Chief Scientist’s Organisation for a research grant in respect of the cost of participation by the Edinburgh centre in the proposed UK research into surrogate testing. The Directors noted the need for synchrony with England and Wales.

9.58 On 13 June 1987 The Lancet published a letter on surrogate testing by Drs Dow and Mitchell (SNBTS, Glasgow) and Dr Follett (Head of the Hepatitis Reference Laboratory, Ruchill Hospital, Glasgow).[69] Like the North London BTC, the authors had found a very low incidence of reported cases of NANB Hepatitis in the West of Scotland, with only 23 cases in the past eight years. If ALT and anti-HBc tests had been done routinely for the past eight years, at an estimated cost of £1million and with a loss of around 4% of the blood supply, only five of the reported cases might have been prevented (assuming that the donors with surrogate markers were indeed the source of NANB Hepatitis infection). The authors concluded that it would be prudent to undertake a UK study to assess the real incidence of acute post-transfusion NANB Hepatitis and to assess the proportion of those chronically affected, before considering following the USA surrogate testing policy.

9.59 The same edition of The Lancet contained a letter by Drs J Gillon and others (SNBTS, Edinburgh and the University of Edinburgh), reporting on a study of surrogate testing carried out at the Edinburgh centre between April and November 1986.[70] ALT testing had been carried out on 1742 regular blood donors and 708 plasmaphereris donors. 2086 donors were also screened for anti-HBc (the 1742 regular donors plus all first-time donors attending the same sessions). Gillon et al reported that their findings confirmed the doubts expressed by Mijovic et al on the wisdom of introducing surrogate testing for NANB Hepatitis in the UK. The Edinburgh group found a strong association between a raised ALT and both obesity and alcohol ingestion, which two factors alone, the authors considered, might account for 82% of the abnormal ALT levels found. The authors pointed out that of the four small prospective studies carried out (two using ALT screening and two using anti-HBc testing), three had failed to demonstrate any reduction in post-transfusion NANB Hepatitis as a result of donor screening[71] and only one had found an apparent association between the presence of anti-HBc in donors’ blood and the development of hepatitis in recipients.[72] Gillon et al concluded that:

… the introduction of ALT/anti-HBc screening tests as an indicator of NANB hepatitis carrier status in blood donors cannot at present be justified.[73]

9.60 On 19 June 1987 Dr McIntyre (SHHD) wrote to Professor Cash on the question of Scottish participation in the proposed UK research project on transfusion-associated NANB Hepatitis.[74] Dr McIntyre noted that there appeared to have been some confusion on the subject. On 22 April application forms for funding had been sent to the Edinburgh and South East Scotland RTC. For reasons Dr McIntyre had not fully understood, it was decided by the RTC not to proceed with the application. Following a telephone conversation on
15 June between Dr McIntyre and Professor Cash, Dr McIntyre understood that the SNBTS did now wish to proceed with the research project and would submit an application to the CSO for funding. The application would be considered at the meeting of the Biomedical Research Committee on 25 September. The outcome of the research had considerable implications as it was unlikely that funds would be made available for the routine screening of blood donations for NANB Hepatitis unless it could be clearly shown that such screening was practical and worthwhile.

9.61 Between 29 June and 1 July 1987 the European Health Committee of the Council of Europe held its 21st meeting. An extract of a report of the 10th meeting of the Committee of Experts on Blood Transfusion and Immunohaematology between 19–22 May 1987 at Rome was circulated.[75] The report noted the following discussion on the issue of surrogate testing for NANB Hepatitis.

9.62 Dr Gunson had presented a synthesis of replies from a number of countries to a recent questionnaire. The issue was in general being given careful consideration by most blood transfusion services. The general impression was that the incidence of NANB Hepatitis was rather low, but varied widely between different regions. The value of surrogate tests such as ALT and anti-HBc had been studied by different groups but there was doubt about their cost effectiveness. Dr Gunson reported on the proposed study of ALT and anti-HBc testing in four centres in the UK.

9.63 Dr B Habibi of the International Society of Blood Transfusion reviewed the available literature. There was a wide variation in the prevalence of NANB Hepatitis,[76] ranging from 1.6% in an Australian study to 18.2% in a French study, with an overall incidence of 8.34% in patients who had received a transfusion compared with 1.85% in patients who had not received a transfusion. Dr Habibi emphasised that decision-making on the issue could not be carried out uniformly as between different countries or based on clear-cut scientific data. Among arguments supporting the introduction of ALT and anti-HBc testing, he stressed the following issues: based on American and some French studies, a significant proportion of transfusion related hepatitis should apparently be prevented; no specific test was currently available to identify virus carriers; ALT testing in blood donors might represent a valuable contribution by blood transfusion centres to public health through counselling of donors; the evidence already published of the efficacy of such screening policies raised ethical issues on the initiation of additional randomised studies; and the reduction in health costs of treating chronic hepatitis might well balance those generated by the costs of screening.

9.64 After discussion, it was agreed that a working group, comprising Professor Van Aken, Dr Gunson, Dr Habibi and Dr Leikola, would prepare a brief report and, if possible, set out recommendations on surrogate testing.

9.65 In due course the working group reported. They concluded:

1. The use of [a] non-specific test for the purpose of reducing the incidence of transfusion associated NANB Hepatitis and its possible value as a public health measure remained controversial issues.

2. If a stance were taken that blood should have maximum safety then the tests would be introduced, but the benefits derived from this testing would not be uniform throughout every country. Also, there was no guarantee that, in a given country, there would be a significant reduction in the transmission of hepatitis.

3. The introduction of non-specific tests could lead in some countries to a severe depletion of blood donors which might compromise the blood supply and this was a factor which must be taken into account.

4. When non-specific testing was introduced in a country, provision must be made for the interviewing, counselling and further medical examination and treatment which might be required for donors found to have a raised ALT or who were anti-HBc positive.

5. The committee could not give a general recommendation on the introduction routinely of non-specific tests for evidence of NANB Hepatitis infectivity of blood donors. Individual countries would have to assess the situation locally and decide on the appropriate action to take.

9.66 On 4 July 1987 a letter was published by Dr McClelland (Edinburgh), the other Directors of the SNBTS,[77] Professor Cash and RJ Perry (Director, PFC), ‘Testing blood donors for non-A, non-B hepatitis: irrational, perhaps, but inescapable’.[78] While the authors accepted that the benefit from surrogate testing could not be accurately established until a prospective controlled study had been carried out in the UK to find out how many cases of post-transfusion hepatitis would be prevented, the letter stated that:

the time for this study has already passed. Starting now will give us an answer in 3-4 years – and that is probably 3 to 4 years too late. The introduction of surrogate marker testing for NANBH is now virtually inescapable.

9.67 The authors considered that the introduction of surrogate testing of blood donations for NANB Hepatitis was virtually inescapable for three reasons. Firstly, new product liability legislation was due to come into force in the UK in 1988 and would impose strict liability on the producer of a therapeutic product for any harm caused by the product unless the producer could demonstrate having used all known methods to avoid the risk. A patient who contracted NANB Hepatitis via transfusion of blood or a blood product would, therefore, have a claim against the supplier if the harmful blood or blood product had come from a donor who had not been tested for both raised ALT and anti-HBc. Secondly, while it was hoped that pooled plasma fractions would soon be made safe by heating or other antiviral treatment, these processes remained to be validated in large-scale trials. Meantime, even if surrogate marker screening would only modestly reduce the level of infectivity in these products, many would argue that some improvement was better than none. Thirdly, the UK transfusion services would be under pressure from consumers and clinicians to introduce surrogate testing as commercial suppliers had introduced such testing and would claim that their products were safer. The authors also compared the costs and benefits of surrogate testing for NANB Hepatitis with the costs and benefits of HIV and Hepatitis B screening and concluded that the cost of preventing morbidity by surrogate marker testing for NANB Hepatitis may be no greater, and could be less, than existing screening programmes.

9.68 On 21 July 1987 Dr McIntyre (SHHD) sent a memorandum to Mr Macniven and others on the subject of surrogate testing for NANB Hepatitis in blood donations.[79] The memorandum referred to the recent letters in The Lancet and the possibility that the SNBTS might start surrogate testing unilaterally, without reference to England and Wales. The DHSS were concerned at that prospect and were reassured that that was not official SHHD policy. It was noted that the SNBTS had been given the opportunity to engage in a research programme to evaluate the need for testing but had withdrawn as they felt that the time for this study had already passed.[80]

9.69 On 1 August 1987 a letter was published by Drs Contreras and Barbara (North London BTC) taking issue with the case for surrogate testing as argued by the SNBTS Directors.[81] The authors argued that the impact of transfusion transmitted AIDS was not comparable with that of transfusion-transmitted NANB Hepatitis, whose consequences seemed minor. They said:

The significance of [hepatitis B] and HIV infection are well known; the clinical importance of NANBH has to be sought. Transfusion services must not bow to irrational pressure for measures whose efficacy is unproven. In the UK, transfusion centre directors resisted commercial pressure for premature introduction of unsatisfactory screening tests for anti-HIV; they should show the same resolution with NANBH.

9.70 Contreras and Barbara argued that it was vital to extend the few available studies of transfusion recipients with more complete follow-up of un-transfused patients to find out what role sporadic NANB Hepatitis had in the hepatitis attributed to transfusion: ‘before we accept that 50% of cases of NANB post-transfusion Hepatitis progress to chronicity and that 10% of chronic cases progress to liver cirrhosis, larger studies must be done’.

9.71 In the same edition of The Lancet, Donnellan et al (Irish Blood Transfusion Service) reported on an Irish study in which 4136 donors were ALT and anti-HBc tested.[82] The introduction of ALT screening in Ireland would result in a deferral/rejection rate of 2.7%, the introduction of anti-HBc screening would result in a deferral of 1% of donors and the introduction of both ALT and anti-HBc screening would result in a deferral rate of about 3.45%.

9.72 On 20 August 1987 Dr Forrester (SHHD) sent a memorandum to Dr W Forbes and others, responding to Dr McIntyre’s memorandum of 13 August about the research proposal from Drs Gillon and McClelland.[83] Dr Forrester set out that the Department required to make a well informed decision on whether to support surrogate testing of blood donations for NANB Hepatitis. The benefits of such testing were not clearly established and there were drawbacks. The study by Dr Dow was not in itself a sufficient guide at present for a number of reasons. In view of the interest of the SHHD, Dr Forrester or Dr McIntyre would welcome the opportunity to be present at the meeting of the CSO’s Biomedical Research Committee on 25 September.

9.73 On 25 September 1987 the CSO for Scotland’s Biomedical Research Committee rejected the research proposal by Drs Gillon and McClelland for Scottish participation in the UK study into surrogate NANB Hepatitis testing. The DHSS was still to determine the English application.

9.74 On 25 September 1987 the United Kingdom Haemophilia Centre Directors’ Organisation (UKHCDO) held its 19th annual meeting.[84] Dr C D Forbes (Haemophilia Director, Glasgow Royal Infirmary) resigned as Chairman and was replaced by Dr CR Rizza. Dr Craske distributed copies of his report, dated 15 September 1987, ‘UK Haemophilia Hepatitis Working Party Report for 1986/87’.[85] The report contained a table setting out provisional figures of the number of patients with haemophilia who had contracted hepatitis that year and the particular products implicated.

9.75 On 1 October 1987 Dr Forrester (SHHD) sent a memorandum to Mr MacNiven and others on the subject of screening donations for NANB Hepatitis.[86] Dr Forrester summarised the position on testing as follows: while agreeing that the scientific evidence was incomplete, the SNBTS maintained that their general obligation to the recipients of blood and blood products required screening to start now, despite its recognised drawbacks and cost; the Health Departments, along with the NBTS, pressed for more scientific evidence before any decision to screen; the gathering of the evidence, at least in Scotland, was obstructed by the inadequacies of the research proposal. These inadequacies meant that the results of the proposed research could prove inconclusive, which was a serious objection to mounting it.

9.76 On 6 October 1987 the SNBTS Directors met.[87] In relation to surrogate testing, it was noted that the SNBTS/NBTS Microbiological Validation Group chaired by Dr Cuthbertson of the PFC were due to make a proposal to the Directors concerning ALT and anti-HBc testing.

9.77 On 19 November 1987 Drs Gillon and McClelland (SNBTS, Edinburgh) were advised in writing that their application for funding for their study into surrogate testing had been refused.

9.78 On 8 December 1987 the SNBTS Directors met.[88] The SNBTS Microbiological Validation Group was to reconsider to what extent it was necessary for every centre to be involved in evaluating the technology for ALT testing and would report on the matter by 31 March 1988. It was agreed not to consider anti-HBc testing until the report on ALT testing had been received and discussed by the Scottish Directors.

9.79 On 17 December 1987 Dr Forrester (SHHD) sent a memorandum to Mr Tom Macdonald and others.[89] A commercial producer of blood products was being allowed by the DHSS to include in their product insert a statement that the product was derived from donations which had been ALT tested. That was likely to stimulate pressure for the introduction of surrogate testing.

Summary

9.80 Thus, by the end of 1987:

• The issue of whether to test UK blood donors for surrogate markers of NANB Hepatitis remained controversial.

• Discussions had been ongoing in the UK for almost two years on the need, feasibility and funding for a large multi-centre study on the issue.

• Views as to whether a Scottish centre should be included in the study had gone back and forth.

• The Chief Scientific Officer for Scotland appeared reluctant to fund the inclusion of a Scottish centre in the study.

• While the SNBTS Directors had recommended that surrogate testing of blood donors should be introduced, that view was not shared throughout the SNBTS.[90]

• The transfusion directors in England and Wales did not support the introduction of surrogate testing and considered that further research was required.

1988

9.81 In 1988 fuller details of the study into surrogate testing by Gillon et al (SNBTS, Edinburgh) were published.[91] There was no overlap between donors with raised ALT and those with anti-HBc. Combined screening would lead to the loss of at least 4.4% of donations. The authors concluded:

In view of the medical and economic implications of the introduction of these screening tests, and the poverty of data on the clinical significance of post-transfusion non-A, non-B hepatitis … such a screening programme cannot be justified at present. Further studies are required, including a prospective controlled trial of the effects of screening.

9.82 In 1988 Kitchen et al (Brentwood BTC) reported on a study to determine the incidence of anti-HBc in donors at the North East Thames Regional Transfusion Centre.[92] 1893 donors were screened for anti-HBc. Thirty-five (1.85%) were found to be repeatedly positive. None of the donors involved in the study were subsequently reported as having been implicated in any case of post-transfusion hepatitis. The authors concluded:

The apparent low incidence of reported cases of PTH in the United Kingdom is demonstrated by the fact that during the last 12 months, in the area served by the North East Thames [RTC], approximately 120,000 units of blood were transfused and only three cases of PTH were reported for follow-up of the implicated donors. In the light of the findings of this study, and the very small number of cases of PTH reported in the United Kingdom, we believe … that at the present time there is likely to be very little benefit in the introduction of anti-HBc screening of blood donors. The loss of approximately 2% of available donors because of deferment would cause problems for those transfusion centres facing shortages of donors, especially those serving the Greater London Area. The costs of testing donations for the presence of anti-HBc is high and in the current financial climate would be hard to justify. A further consideration is the need to counsel those donors found to be anti-HBc positive. Although the introduction of surrogate testing may eventually be unavoidable, we believe that only a controlled prospective study would provide the necessary information to determine the significance of donor anti-HBc levels in relation to PTH, especially NANB, in the United Kingdom.

9.83 On 20 January 1988 a paper was produced: ‘Screening of NBTS blood donors’
(CBLA 88/10), proposing that the BPL come into line with all other major fractionators of human plasma by including ALT testing in the specification of source plasma collected by blood donor centres.[93] The paper noted that the scientific basis for introducing ALT screening of donors was far from satisfactory. The drive for ALT testing was strongly augmented by manufacturer’s liability and the demands of patients to eliminate NANB Hepatitis as a sequel to treatment, with the development of severe liver disease in up to 60% of sufferers.[94] As regards Factor VIII, BPL were distinguished from the remaining field by the use of dry-heat virus inactivation and the use of plasma unscreened for ALT.
To that extent, BPL operated outside the ‘state of the art’ practised in the USA and Europe.
An estimated 2 to 5% of donations would be unnecessarily rejected by ALT testing.

9.84 On 14 April 1988 Dr Forrester (SHHD) wrote a memorandum to Mr T Macdonald and Dr McIntyre on surrogate screening for NANB Hepatitis.[95] The CSO for Scotland had applied exacting scientific criteria to the proposal for funding the Scottish limb of the UK research project and had declined to fund it. Meantime, DHSS research funds had very recently become available for the English limb of the project. The English data was expected to be sufficient statistically, without the Scottish input originally planned. While Scotland risked being left behind, there might not be drawbacks to that.

9.85 On 15 April 1988 Dr Moir (DHSS) sent a memorandum to Dr McIntyre and
Dr Forrester.[96] The DHSS Research Management Division also had reservations as to whether the English part of the UK study could achieve its stated objectives and was not providing funding. Instead, the relevant DHSS policy division appeared to have taken the view that these reservations should be set aside and the study funded. The funding was to be provided from a policy resource and not the research budget. While there was some Scottish data on the prevalence of the problem (due to the study in the West of Scotland), there was no comparable study relating to England and Wales. Dr Metters (DHSS) felt that a substantial part of his policy colleagues’ interests in funding the study was that it would allow them to play for time in the hope that instead of ALT a more suitable screening assay could be found which would act as a marker for NANB Hepatitis.

9.86 On 5 May 1988 the SNBTS and Haemophilia Centre Directors met.[97] As regards screening for NANB Hepatitis, Dr Forrester (SHHD) advised that a research project was being mounted in England and that a decision whether to introduce screening would probably wait upon its outcome. Dr McClelland and Professor Cash were noted to consider the delay unjustifiable.

Breakthrough

9.87 In the event, the controversy over screening blood donors for surrogate markers of NANB Hepatitis was largely overtaken by events, namely, the isolation by Chiron Corporation of a genome of what would become known as the Hepatitis C virus, which enabled, for the first time, the development, and eventual introduction, of a direct test for the virus.

9.88 The first breakthrough in the search for the cause of NANB Hepatitis had come about in 1978 when two investigative groups independently produced the disease in chimpanzees by injecting them with serum or plasma from patients with hepatitis or from donors whose blood had previously been shown to transmit the disease to other humans.[98] The transmission of NANB Hepatitis to chimpanzees provided important impetus to the research of this virus. It ultimately led to the discovery by molecular cloning in 1988 of the virus associated with most cases of NANB Hepatitis - the Hepatitis C virus.

9.89 The isolation of the virus was announced in a news release by Chiron on 10 May 1988 which stated:

Scientists at Chiron Corporation have identified, cloned and expressed proteins from a long-sought blood borne hepatitis non-A, non-B virus and have developed a prototype immunoassay that may lead to a screening test for hepatitis non-A, non-B antibodies.[99]

9.90 Scientific details of the discovery were not published at the time.[100] The American Association of Blood Banks (AABB) reported that while there remained some scepticism about the results, a leading expert in the field, Harvey Alter (US National Institutes of Health) was of the view that the data he had seen looked very good.[101] The AABB further reported that health experts were agreed that further testing still needed to be performed because the protein identified might be one of several capable of causing NANB Hepatitis.

9.91 Identification of the Hepatitis C virus was, in the end, a work of inventive genius and persistence that threatened the financial viability of Chiron where Dr Houghton and his collaborators worked. The response of peer group commentators was later set out as follows:

The pathway leading to the identification of the causative agent of NANB hepatitis has been long and tortuous. In retrospect, the length of this process can be explained by the low levels of infectivity and the weak and delayed humoral immune response of the host. For these reasons, attempts using conventional virological methods produced only deep frustration for many years. Instead, it was through an unconventional approach, taking advantage of the increasingly refined techniques of molecular biology, that success was eventually achieved…It was from a chronically infected chimpanzee that large amounts of pooled plasma with an unusually high titre of infectivity were obtained for the molecular cloning of the viral genome … By using overlapping clones, the entire sequence of the HCV genome was subsequently obtained. Thus, HCV represents the first virus in the history of virology that has been characterized primarily by molecular means before it was visualized by electron microscopy or isolated in culture.[102]

9.92 As more fully set out below, Choo and others, led by Dr Houghton, were to publish a series of papers between 1989 and 1991 in which they described the isolation of the DNA clone and the organisation and diversity of the Hepatitis C virus. Their work transformed the diagnosis of NANB Hepatitis from one based merely on exclusion into that of a specific disease, Hepatitis C, and provided the best evidence that that virus was the major aetiological agent of post-transfusion hepatitis.[103] For their work Chiron were granted a patent, and lengthy and complex litigation followed. So far as is material, the challenge of the patent failed.[104]

9.93 Returning to events at the time, in July 1988 the SNBTS contacted Chiron to enquire about the availability of the Chiron test and were advised that a test might be available towards the end of 1989.[105]

9.94 On 14 July 1988 Dr E L Harris (Deputy Chief Medical Officer, England and Wales), sent a memorandum to various individuals, including Dr Forrester (SHHD) proposing the creation of an Advisory Committee on the Virological Safety of Blood (ACVSB).[106] As set out below, this group was duly set up and met for the first time on 4 April 1989. This group became the main advisory committee to the UK Government on whether surrogate testing of blood donors for NANB Hepatitis and screening of donors for Hepatitis C should be introduced.

9.95 On 26 August 1988 Mr J Hamill (SHHD) sent a memorandum to the Chief Medical Officer for Scotland (copied to Dr Scott and Mr Macniven) in relation to proposed discussions between the SNBTS and their Dutch and Finnish counterparts.[107] Mr Hamill stated that, coming new to the subject, he could not understand why the top priority should not be ensuring that there were adequate links between the SNBTS and its English counterpart and, in particular, between PFC and BPL. After speaking to Dr Perry (Director, PFC), Mr Hamill understood that collaboration between the two establishments was not all that it might be. Mr Hamill wondered whether there was a risk that these foreign contacts would lead down a road towards greater ‘independence’ from England when what should be being considered were ways in which to maximise the return to Scotland from England’s research and product testing efforts.

9.96 On a separate matter, Mr Hamill attached a letter from Mr Donald of the Common Services Agency (CSA) advising that there was a risk involved in the use by Lothian Health Board of Factor VIII supplied by Alpha Therapeutic UK Limited.[108] The product was manufactured using a solvent chemical method and ‘relatively gentle heat’ and was understood to be capable of transmitting NANB Hepatitis to possibly 20% of recipients. Mr Hamill noted that some of the patients to whom the product was being or had been supplied might already be infected.[109]

9.97 On 30 August 1988 Dr Forrester (SHHD) sent a memorandum to the Chief Medical Officer responding to the points in Mr Hamill’s memorandum.[110] Formal attempts to forge proper research and development (R&D) links between Scotland and England had been made and collapsed into acrimony. A DHSS minute of 10 June 1987 saddled Scotland with the blame.[111] Only coercion from above and some resolute decisions about R&D funding would get SNBTS and the Central Blood Laboratories Authority to make common cause. Dr Forrester observed, however, that the picture of the two bodies at blows was only what was presented to the Department of Health (DOH)[112] and SHHD. Behind the scenes the two bodies were in bed with each other; for instance PFC were now conducting virus elimination research for BPL by mutual arrangement.

9.98 Dr Forrester made a number of observations on the risk of NANB Hepatitis from the commercial Factor VIII made by Alpha, including that the product had been licensed and the risks found to be tolerable. He doubted whether Mr Donald of the CSA had been served a dispassionate view. One PFC product (an intravenous immunoglobulin) was presently under suspicion of transmitting NANB Hepatitis to several recipients.[113] The memorandum concluded:

We cannot prudently make much of the point, but this particular hepatitis is so benign, at least in the short term, that evidence of transmission has to be specially sought, the patient not being ill at all in the ordinary sense.

9.99 The reference in Dr Forrester’s memorandum of 30 August 1988 to a PFC intravenous immunoglobulin (IV IgG) product transmitting NANB Hepatitis to patients appears to be a reference to a letter by Williams et al published in The Lancet on 27 August 1988.[114] The background to the letter was that preparations of intramuscular gammaglobulin (IM GG) had not been associated with transmission of NANB Hepatitis but that there had been several reports since 1984[115] of transmission of NANB Hepatitis by intravenous gammaglobulin (IV GG) prepared by different manufacturers.[116] In their letter, Williams et al reported the transmission of NANB Hepatitis to four recipients of a single batch of IV immunoglobulin (IgG) manufactured by the SNBTS. The product was administered in late 1987. Thirty other patients who received the same batch did not show ALT elevations consistent with NANB Hepatitis. The safety of SNBTS IV IgG had previously been reported.[117] More than 2000 doses from over 100 batches had been administered. Every recipient had been followed up and the four cases reported were the only cases of NANB Hepatitis associated with the product. The four cases were all associated with a single batch. No departures from the standard manufacturing procedure had been identified. Although every batch was manufactured from about 20,000 donations, the authors considered it possible that there was an exceptionally high level of NANB Hepatitis virus in the starting plasma used to manufacture the batch in question and that that exceeded the capacity of the process to inactivate the virus. Procedures to increase the margin of safety of the product were under development. The authors stated that the cases demonstrated the importance of continued close surveillance of recipients of IV IgG, even if symptom-free, by careful monitoring of liver function and recording of all batches received.[118]

9.100 The SNBTS Directors met on 27 September 1988.[119] Surrogate testing for NANB Hepatitis was discussed. The Microbiological Validation Group’s[120] proposals on anti-core testing were not ready. The Microbiological Validation Group had undertaken a multi-centre evaluation of an ALT test produced by BDH (a pharmaceutical company). A tripartite study of ALT testing was being undertaken in England and Wales. The NIBSC/UK BTS Working Group was recommending that ALT testing of blood donation should begin in England and Wales. The SNBTS were awaiting reaction to a request for funds in the public expenditure survey bid for 1989–90. There was discussion of the Ortho anti-HCV test. The ELISA test which Ortho were developing in association with Chiron had been the subject of a workshop at the International Society of Blood Transfusion Conference in July 1988. The test was not imminent and the data presented had been inconclusive. The antibody was a late developing one which would present similar problems in relation to the ‘window‘ as HIV did. ALT remained the earliest indicator available of infection. It was agreed not to plan any medium term policy on the successful introduction of Chiron technology and that ALT would remain the test of choice meantime.

9.101 On 13 December 1988 the SNBTS Directors met.[121] On the question of surrogate testing, the Microbiological Validation Group had not done any significant work since the last meeting as the anti-HBc project had a low priority. The Directors agreed that the group had more important matters to fulfil. As regards ALT testing, Dr Wagstaff now had the Scottish details. The DOH had funded three centres to do a study of ALT and anti-HBc and Dr Gunson would send the details to Professor Cash. Dr Gunson advised that Ortho/Chiron had agreed to test one thousand randomly selected samples from the NBTS study by their anti-HCV test. Dr Gunson would report to the next meeting. Professor Cash confirmed that Scottish Directors would not commence surrogate testing until the DOH and SHHD supported and funded the project, which would be a task for the national advisory body (ie a group proposed to be established by the UK Blood Transfusion Services to advise the Departments of Health on policies).[122]

9.102 On 24/31 December 1988 an editorial was published in The Lancet summarising the recent history of ‘Chronic liver disease and haemophilia’.[123] The editorial noted that while acute post-transfusion hepatitis and chronic increases in liver enzyme concentrations had long been associated with both Factor VIII and IX infusion, those caring for haemophilia patients were slow to accept chronic progressive liver disease as an important complication. Few haemophilia patients had any signs or symptoms of liver disease, deaths from hepatic failure were rarely reported, and raised ALT levels were attributed to chronic persistent hepatitis rather than chronic active hepatitis. The results of early series of patients undergoing liver biopsy were generally reassuring in that most of them showed either chronic persistent hepatitis or mild chronic active hepatitis, with little to suggest severe liver damage.[124] In a seven year follow up study, Hay et al (1985) had documented a significant progression from chronic persistent hepatitis to chronic active hepatitis to cirrhosis.[125] Their cumulative figure of 35% of patients with chronic active hepatitis/cirrhosis was echoed by data from West Germany (Schimpf, 1986).[126] Similar figures were provided in a recent report from Dr Miller and colleagues in London (1988).[127] The Lancet editorial stated:

The evidence that chronic progressive liver disease is an important complication of haemophilia treatment is therefore becoming increasingly persuasive. Furthermore, experience with other types of viral hepatitis suggests that cirrhosis and hepatocellular carcinoma may first appear decades after infection.

Summary

9.103 Thus, by the end of 1988:

• There was an increased awareness of the potential seriousness of NANB Hepatitis.

• The name NANB Hepatitis continued to be used, rather than Hepatitis C, reflecting, presumably, the continuing uncertainty at the time regarding the significance of Chiron’s discovery (in particular, against the background that scientific details of the discovery and the test developed by Chiron/Ortho were not published until April 1989).

• While consideration continued to be given to whether surrogate testing for NANB Hepatitis should be introduced, attention had turned to the need to obtain and evaluate the Ortho/Chiron test.

• Steps were in hand to set up the Advisory Committee on the Virological Safety of Blood (ACVSB), with a proposed remit, among other things, of advising the government on the screening of blood donations for NANBH/HCV.

1989

9.104 In 1989 the eighth edition of Sherlock’s, “Diseases of the Liver and Biliary System” was published. NANB Hepatitis was still ‘ill defined’.[128] As regards the parenteral type of NANB Hepatitis, Sherlock stated:

The causative agent has not hitherto been identified … [although] a viral genomic clone has been isolated from infected plasma and liver. This encodes the antigen associated with non-A, non-B viral hepatitis in man and chimpanzees.[129]

9.105 As regards the clinical picture of the disease:

60% of patients will have raised serum transaminases one year later. In 68% the disease becomes chronic and in 20% cirrhosis develops. Hepato-cellular carcinoma … is a rare complication. Marrow aplasia may be fatal.[130]

9.106 Later, the author stated:

[Prognosis] is very variable. In some, the diseases are benign with spontaneous biochemical improvement over one to three years. In others, chronic persistent hepatitis and chronic active hepatitis can convert to more serious disease and even go on to cirrhosis. In general, however, in spite of biochemical disease, the patient is asymptomatic and the development of hepatic failure is rare. Hepato-cellular cancer has been recorded but is exceedingly rare.[131]

9.107 Sherlock commented on surrogate testing for NANB Hepatitis as follows:

If blood with an alanine transaminase level exceeding 50 is discarded 30% of [NANB Hepatitis] would be prevented with a donor loss of 1-3%. The usual cause of the raised transaminase is obesity or alcohol abuse and only 20% are presumptive carriers of [NANB Hepatitis]. Serum hepatitis B core antibody can also be used for screening. Those exposed to hepatitis B are likely to have been exposed to [NANB Hepatitis]. This test would reduce post-transfusion hepatitis by 37% with a donor loss of 4-8%.[132]

9.108 It was also noted that: ‘A radioimmunoassay test which will diagnose, and hopefully prevent, at least one type of transfusion related [NANB Hepatitis] will shortly be available’.[133]

9.109 On 24 February 1989 the UK BTS Advisory Committee on Transfusion Transmitted Diseases, chaired by Dr Harold Gunson, held its first meeting.[134] The Committee’s terms of reference were agreed as follows:

1. To consider the epidemiological, clinical and laboratory aspects of diseases which may be transmitted by the transfusion of blood and blood products.

2. To determine the appropriate policy which should be implemented by the UK Blood Transfusion Services for the control of transfusion transmitted diseases, and

3. To advise the Departments of Health accordingly.[135]

9.110 Dr Gunson introduced the meeting by saying that he had, about a year ago, discussed with Drs McClelland and Pickles the forming of a UK group to determine policy with respect to transfusion transmitted diseases. The DOH were in the process of forming such a group but its brief would be wider than blood transfusion medicine, embracing transplantation and other aspects of disease transmission.[136] The present Committee had been formed to discuss transfusion transmitted diseases and to provide advice to the Departments of Health. There was discussion of NANB Hepatitis. Dr Contreras (North London BTC) outlined the results of the study in England and Wales. Dr Mitchell (SNBTS, Glasgow) reported that in a Glasgow study of 5000 donations, 2.8% of donors had elevated ALT levels. With respect to anti-HBc tests, in a separate study 17 out of 2000 donations were found positive, of which 15 were reproducible. Professor Cash reported that in Scotland the methodology for ALT testing had been examined and a standardised method had been agreed upon. This was available at the RTC’s if ALT testing was agreed. It was agreed that there should be no recommendation to institute ALT testing until the current study was completed in England. It was noted, however, that there was a degree of inevitability about the introduction of the test which was required by regulatory authorities in other countries to determine the acceptability of fractionated plasma products. That would be discussed with BPL in the near future. Dr Gunson reported that Ortho had approached him with respect to trials of the Ortho anti-HCV test in the UK. He would report on that later when further details were available.[137]

9.111 In a letter of 8 March 1989, Dr E L Harris (Deputy Chief Medical Officer, England and Wales) noted that the UK Health Ministers had agreed to set up the ACVSB.[138] Ministers believed it was of the utmost importance that the UK Blood Transfusion Services act in unison on this subject, and with the benefit of the best advice available. The terms of reference of the ACVSB were: ‘To advise the Health Departments of the UK on measures to ensure the virological safety of blood, whilst maintaining adequate supplies of appropriate quality for both immediate use and plasma products’.[139] A paper for the first meeting noted that the Committee’s concern was:

matters of major policy, not the detailed implementation of policy. The intention is that any proposed changes in requirements or practices of one of the main groups (transfusion service, fractionators, regulators) that has major implications for the others are brought to this group first for discussion.[140]

9.112 Terms of reference of related groups were noted as follows:

• the UK Advisory Committee on Transfusion Transmitted Diseases (ACTTD): a new UK group that would be considering many of the same issues as the ACVSB, but only from a transfusion viewpoint,

• a BTS/National Institute for Biological Standards and Control (NIBSC) group formed between the NBTS/SNBTS and the NIBSC to formulate scientific guidelines for the standardisation and safety of blood and blood products, and

• the Advisory Group on Hepatitis, which provided ‘medical advice to the Chief Medical Officers of the Health Departments on all aspects of communicable hepatitis’ and had the appropriate technical expertise for detailed consideration of the technical aspects of screening donors and plasma for various forms of hepatitis, leaving the ACVSB to consider the wider policy issues.

9.113 The first meeting of the ACVSB took place on 4 April 1989 under the chairmanship of Dr E L Harris.[141] The minutes recorded that the issues which required early attention were Creutzfeldt-Jakob Disease, the European Community Directive on Blood Products and testing for HTLV1. These were the main items of business for the meeting. The intention was that the next meeting would concentrate on viral hepatitis.

9.114 At a meeting on 29 March 1989, Drs Gunson, Contreras, Barbara and others discussed how trials were to take place of the newly developed Ortho anti-HCV test.[142]

9.115 On 21 April 1989 Choo et al (Chiron and US Centres for Disease Control) published scientific details of the isolation by Chiron of the genome of the Hepatitis C virus.[143] At the same time, Kuo et al (Chiron, US National Institutes of Health and others) published details of the test developed by Ortho/Chiron to detect antibodies to the Hepatitis C virus.[144] The test, an enzyme-linked immunosorbent assay (ELISA), used a polypeptide (C100-3) synthesised in recombinant yeast clones of the Hepatitis C virus to capture circulating viral antibodies. The anti-HCV ELISA was evaluated in four separate panels of known/suspected NANB Hepatitis infected sera with, on the face of it, impressive results. Kuo et al concluded:

These data suggest that HCV is a major cause of chronic NANBH throughout the world. The advent of the specific, sensitive test for HCV antibody described here should improve the safety of the world’s blood supply as well as provide an important clinical diagnostic tool.

9.116 On 19 May 1989 the ACTTD held its second meeting. Dr Barbara reported on the Ortho anti-HCV assay.[145]

9.117 On 22 May 1989 the second meeting of the ACVSB took place.[146] There was discussion of hepatitis. A study at Central Middlesex Hospital had shown the incidence of post-transfusion hepatitis to be one per cent[147] although the general incidence might be underestimated as General Practitioner reporting of jaundice was poor.

9.118 A paper by Professor Zuckerman, (Professor of Microbiology, Royal Free Hospital School of Medicine, London) was circulated for the second meeting of the ACVSB. The paper, ‘Unresolved issues in NANBH’, had been delivered at an international conference in December 1988.[148] The paper set out that NANB Hepatitis was the most common form of hepatitis occurring after blood transfusion in countries which screened for Hepatitis B. Although, in general, the illness was mild and often subclinical, or anicteric, severe hepatitis with jaundice did occur and the infection was a significant cause of fulminant hepatitis. There was considerable evidence that the infection might be followed in many patients by prolonged viraemia and the development of a persistent carrier state. Studies of the histopathological sequelae of acute NANB Hepatitis infection revealed that chronic liver damage, which might be severe, might occur in as many as 40–50% of the patients. An RNA virus had been cloned successfully in the USA and independently in another laboratory in Japan. Professor Zuckerman’s paper considered the question of surrogate testing. Surrogate testing for anti-HBc seemed more promising that testing for HBsAg. ALT levels varied with age, sex, alcohol use and geographical region and would not be useful as a surrogate marker of NANB Hepatitis.

9.119 Another paper was circulated for the second meeting of the ACVSB, discussing a number of matters in relation to NANB Hepatitis.[149] The paper set out that the current position of the UK licensing authority was that surrogate testing by ALT was not a licensing requirement for blood or blood products. A study of surrogate testing in the UK was being co-ordinated by Dr Gunson on behalf of the UKBTS. It was too early to report as yet, but all of the samples had been collected and screened for ALT and anti-HBc. It was hoped that in June a review of the study would take place although conclusions could not be drawn until the results of the Chiron/Ortho test were known. Although there was no UK experience of the Chiron/Ortho test, arrangements had been made by the UKBTS for 10,000 tests, to allow testing of the donors in the NANB Hepatitis study. The paper noted the April 1989 articles by Choo et al and Kuo et al in Science publishing the details of the isolation of what Chiron had termed the Hepatitis C virus and the development of a test to detect antibodies to the virus. The paper noted that although Hepatitis C was a major cause of chronic NANB Hepatitis, the assay might not identify other forms of NANB Hepatitis, transmitted either by blood or other routes. The paper stated:

At present there does not appear to be any urgent need to introduce routine surrogate testing for NANB hepatitis among voluntary blood doors in the UK in respect of public health. The position should be reconsidered by this Committee when the results of the UKBTS NANB study are available.

9.120 The paper stated that the results of the study should give an indication of the effect of testing for surrogate markers of NANB Hepatitis on donor panels, the costs involved and an indication of its value in the UK. The Ortho anti-HCV ELISA test would help with interpretation of the data obtained. That test might also make surrogate testing obsolete, providing that the UKBTS and other studies confirmed the promising results so far reported, and assuming that the cost benefit analysis was satisfactory.

9.121 The minutes of the second meeting of the ACVSB noted that although some experts in the USA considered only one virus caused NANB Hepatitis, there might be two or more. The Ortho test was estimated to pick up approximately 50% only and there was a need for caution. There had been enormous progress and once the sequence was published it would be possible to test without recourse to Chiron.

9.122 At their second meeting, the ACVSB concluded that NANB Hepatitis testing should not be introduced prior to the results of the UKBTS NANB Hepatitis trial. Anti-HBc testing was not without problems. The DOH would keep the issue of testing under review. The use of the Ortho anti-HCV test or surrogate testing would be influenced by the Chiron data, once released. The Medical Research Council might be asked to consider matters. Members of the ACVSB regarded the issue to be a priority.

9.123 In June 1989, Professor Cash arranged with Ortho to obtain kits of the anti-HCV ELISA test for SNBTS to evaluate.[150] It was agreed that the West of Scotland BTS would carry out the evaluation. Meetings were held with Professor Cash, Dr R Mitchell, Dr B C Dow, Mr A Barr and Dr J Gillon to select appropriate categories for inclusion in the trial. Regional transfusion centres were asked to select samples from their libraries for testing. An initial evaluation of the test appears to have been completed by July 1989. By the start of August all RTCs had sent their contributions to the West of Scotland RTC and testing commenced on 2 August 1989 using the manufacturer’s protocol. A total of 2745 random blood donations from three SNBTS regions (North East, East and West) were tested. As noted below, a Preliminary Report was prepared on 5 October 1989.

9.124 On 13 June 1989 the SNBTS Directors met.[151] It was noted that Chiron were funding and organising an international meeting in Rome in September 1989 to summarise the experience from users of the Ortho anti-HCV test. Chiron had asked for a representative from Scotland and Dr Mitchell would attend. Dr Mitchell explained that the SNBTS would receive 1000 Ortho tests which would be used to examine samples of special interest. Directors agreed to submit interesting library samples to Dr Mitchell.

9.125 On 3 July 1989 the third meeting of the ACVSB took place.[152] Dr Jeremy Metters was to succeed Dr Harris as the Deputy Chief Medical Officer for England and Wales, and as Chairman of the ACVSB. Papers had previously been circulated on NANB Hepatitis. Those papers included a May 1989 paper by Dr Gunson, on behalf of the Council of Europe’s Committee of Experts in Blood Transfusion and Immuno-haematology, analysing replies from ten countries to a questionnaire on NANB Hepatitis.[153] Of those countries, routine ALT testing of donations was carried out in four countries, namely, Germany, France, Malta and Switzerland. France also routinely performed anti-HBc testing. Denmark Norway, the UK and France were undertaking studies to determine their policies. Several countries were planning to conduct trials of the Ortho anti-HCV test.

9.126 A preliminary report was produced on the results of a study of the anti-HCV test at the North London, Bristol and Manchester RTCs.[154] Of 3282 donations tested, 22 (0.67%) were initially reactive and 14 (0.43%) were repeatedly reactive.

9.127 The minutes of the third meeting of the ACVSB noted that a Council of Europe paper had stated that anti-HCV testing alone was not sufficient to eradicate post-transfusion hepatitis, and members supported that view. The minutes further noted that the NBTS ALT and anti-HBc study had shown raised ALTs in 25%[155] of the donors sampled. Members were concerned that this type of study revealed nothing of specificity. They also cautioned against the overly commercial stance of test manufacturers. The Ortho anti-HCV test had been used in first time recipients of Factor 8Y.[156] Preliminary results had shown no positives, while most recipients of earlier concentrates were positive. Further study of stored sera from haemophilia patients was advocated. Dr Mortimer (Public Health Laboratory Service (PHLS)) had attended a recent conference, and he considered the findings represented a persuasive case that the Ortho test results were reliable.[157] The Chairman considered that a compilation of all the data should be given to the Committee for consideration at the next meeting.

9.128 On 28 July 1989 Professor Cash wrote to Dr McIntyre (SHHD) to confirm the terms of their recent telephone conversation.[158] Professor Cash noted that Dr McIntyre had indicated that the decision to commence routine donation testing using the Ortho test would be made by SHHD and that it would not be appropriate at that time for senior SNBTS managers to liaise with Ortho with respect to arranging supplies of tests for routine donation testing. Such discussions were not to take place until instructions were received from SHHD.

9.129 On 28 July 1989 Professor Cash wrote to Dr Gunson.[159] He noted that the SNBTS would not move unilaterally on the introduction of the Ortho anti-HCV test unless instructed by SHHD, thus close collaboration seemed certain. He had taken a very hard line with Ortho and had indicated that he was unable to discuss contracts for supply etc until instructed to do so by SHHD.

9.130 On 2 August 1989 Dr AD McIntyre (SHHD) replied to Professor Cash’s letter concerning the introduction of the Ortho anti-HCV test.[160] Dr McIntyre advised that the ACVSB was meeting regularly and was considering testing. If it was considered desirable to introduce a further routine screening test for blood donors, that would be done simultaneously throughout the UK.

9.131 On 3 August 1989 Professor Cash wrote to the SNBTS Directors providing an update on the Ortho anti-HCV test.[161] Professor Cash believed that it was only a matter of time before the SNBTS commenced the new testing programme. While he did not have a start date he predicted the test would be introduced some time after April 1990. The decision to commence testing, and the start date, would be UK decisions and would be made by the UK Health Departments. The test would probably be positive for 0.5%–1% of donations. Professor Cash had started a battle with Ortho on confirmatory testing. Ortho’s current proposal (to send sera to Ortho in the USA) was not acceptable and Professor Cash intended to take the matter as high as he could within the Departments of Health.

9.132 On 5 August 1989 The Lancet published an editorial, ‘Will the real hepatitis C stand up?’,[162] commenting on the results of studies of the Ortho anti-HCV test in Spain,[163] the Netherlands[164] and Germany.[165] The editorial explained that the Spanish and Dutch workers had used the prototype radio-immunoassay originally developed by the Chiron researchers whereas the two German groups had used an ELISA test marketed by Ortho. The antigen was the same for both assays. The editorial stated:

In general, the results support the sensitivity and specificity of the test system, and underline both the urgency of making the test system available for blood donor screening, and the importance of depositing the sequence of the viral genome in the GenBank database where it would be available to the wider scientific community. There are many questions yet to be settled. How many other agents are involved? Is there a short-incubation agent? What is the cause of the negative sporadic NANB in the community? … Meanwhile, this new test system represents a clinically important advance in the detection of one of the causal agents of NANB hepatitis … It would be logical to confer the title of hepatitis C on the newcomer.

9.133 On 23 August 1989 a meeting was held in London between representatives from Ortho and Drs Gunson, Contreras and Barbara of the NBTS and Drs R Mitchell and E Follett of the SNBTS.[166] Dr Mitchell produced a report of the meeting for Professor Cash.[167] Ortho had been advised that Ministers would come to a decision on testing after taking advice from the ACVSB. It was emphasised that a confirmatory test was required and Ortho indicated that that would be available in time for the Rome meeting in September. Ortho advised that the US Food and Drug Administration (FDA) had not yet given approval to the test and such approval was expected to be given within the first 60 days of 1990. Thereafter, the USA would start testing on an individual blood bank basis. Dr Mitchell presented some of the figures for Glasgow and Scotland, which indicated a prevalence of repeatable positive results using the Ortho anti-HCV test in the order of 1 in 150/1 in 200 blood donors ie between 0.5–0.67%.

9.134 On 23 August 1989 Mr G W Tucker (SHHD) sent a memorandum to Mr Forsyth, Secretary of State for Scotland: ‘Testing of blood donations – test for hepatitis C’.[168] The memorandum referred to an article in The Guardian of the same date: ‘Dilemma on virus blood test’.[169] The memorandum noted that Ortho had offered a number of tests free of charge for evaluation. Other countries were also trying the Ortho test, but it was understood that it was not in routine use in any other country and it did not have a product licence in the USA. A pilot study had been carried out on volunteer donors in Scotland and England who had agreed to have their blood screened for NANB Hepatitis. The samples obtained were also tested using the Ortho anti-HCV test and, of those, 0.5%–1% were positive. Those donors who proved positive were being recalled for medical assessment and further tests, to check on the consistency between the tests.

9.135 The memorandum stated that only a minority of those infected with Hepatitis C displayed any symptoms either in the short or long term. The statement in The Guardian article that ‘6000 people last year may have received blood transfusions contaminated with hepatitis C’ was stated to be unnecessarily alarmist as it assumed that one per cent of all donations were from donors who were infectious (ie not just carriers), and that they passed on the antigen, and not just the antibody in their donation. Reference was made to the meeting on 23 August with Ortho noted above, which was stated to be one of several discussions with Ortho to obtain further information about the product; such as cost and other practicalities, and to report results of the pilot study. The members of the ACVSB would be discussing the test at their next meeting on 17 October. The accuracy of the test had not yet been fully established and it was felt to be essential to have confirmatory assays to eliminate the possibility of cross-reactivity with other antigens before policies for generalised screening of blood donations were implemented.

9.136 The memorandum further noted that the prevalence of Hepatitis C in the population had not been established nor had the role of blood in its transmission. The UK Health Departments, along with the UK blood transfusion services, were examining all the available data before making any decision about generalised testing. The memorandum noted that this was a UK issue and that the DOH would be taking the lead, subject to the SHHD being represented in any meeting and Ministers being consulted before any decision was taken.

9.137 On 24 August 1989 Dr McClelland (SNBTS, Edinburgh) issued a short statement to donor staff on the question of testing for Hepatitis C.[170] The statement noted that the newly developed test for antibody to Hepatitis C might prove to be an effective way of reducing the small risk of transmitting hepatitis through transfusion and was, therefore, a matter of great importance for the transfusion services. Preliminary tests showed that in the UK about 0.5–0.8% of the population had antibody to Hepatitis C. Present knowledge suggested that the great majority of people with the antibody were entirely healthy although a very small proportion might develop liver conditions. The new test was still undergoing extensive evaluation in many countries and in UK transfusion centres.

9.138 On 26 August 1989 The Lancet published a letter by Drs Contreras and Barbara (North London BTC) on screening for HCV antibody.[171] The authors agreed that the Ortho anti-HCV assay was specific for the major agent causing post-transfusion NANB Hepatitis, that it was clearly superior to all previous attempts at an assay for NANB Hepatitis virus and that it provided a welcome advance over surrogate markers for infection with NANB Hepatitis:

However, in the context of donor screening, precipitate action should be avoided. As in any other assay, the predictive value of a positive result hinges on the prevalence of the marker in a given population.[172] While the test scores well in panels of well-characterised NANB hepatitis sera and in samples from patients with a diagnosis of NANB hepatitis, we do not know the predictive value of the test in low prevalence populations, such as UK blood donors. We must have confirmatory assays to eliminate, for example, cross-reactivity with yeast antigens before sensible policies for generalised screening of blood donations can be implemented.

9.139 Contreras and Barbara had evaluated the Ortho anti-HCV ELISA test on behalf of the NBTS and had found that 0.5%–1% of donations were repeatedly reactive. While excluding such donors might not be a problem, there were 2.5million blood donations annually in the UK and contacting and counselling 12,500–25,000 donors would be an enormous undertaking, especially when the significance of a positive test in a healthy person was as yet unknown. The test took at least three hours to perform and its introduction in routine donor screening would be logistically difficult. The authors concluded: ‘Testing time and the need for a confirmatory assay should be considered when evaluating the cost-effectiveness of routine donor screening’.

9.140 The 26 August 1989 edition of The Lancet also contained a letter by Professor Cash and Drs McClelland, Urbaniak, Brookes and Follett on the subject of screening for Hepatitis C.[173] The authors shared the views set out in the editorial of 5 August[174] on the importance of the new anti-HCV test, especially in the context of screening blood donations. Professor Cash and his colleagues stated that the apparent absence of a confirmatory test would cause serious problems for blood transfusion services, which were likely to bear the brunt of donor counselling. A repeatably reactive ELISA test was suggestive but not definitive for antibody. The authors accepted that the difficulty with the existing confirmatory test (ie use of the same antigen as the ELISA screening test) was scientifically less than satisfactory, but were of the view that it was better than nothing. Ortho should make available, as a matter of urgency, appropriate reagents and/or tests so that even when an identical antigen was used, assay systems that were fundamentally different from the marketed ELISA screening tests could be used for confirmation testing. In addition, Ortho and/or Chiron should deposit the sequence of the viral genome in the GenBank database. These matters were so important that they should be taken up by Government Health Departments.

9.141 In September 1989 a paper was produced by Dr Jack Gillon and Mr A Barr (SNBTS, Edinburgh): ‘Implications for SNBTS of introduction of anti-HCV testing’.[175] Assuming a repeat reactive rate (ie a prevalence) of 0.5% in Scotland, it was anticipated that that there would be 1600 positives in Scotland a year. The paper emphasised that an urgent decision was required on whether there should be delay in informing donors until more was known about the significance of a positive antibody test. The two most important questions to be answered were: (1) was the donor infectious and (2) what was the likelihood of chronic liver disease? The answers would come from look-back studies and large scale clinical studies respectively. On the question of look-back, the authors favoured a system whereby a standard letter was sent to the clinicians of all patients identified in the look-back exercise. Assuming each test cost £2, the estimated total cost of testing to the SNBTS would be approximately £640,000 per annum plus additional staffing costs.

9.142 The 2 September 1989 edition of The Lancet included a letter from Ludlam et al (Haemophilia Centre, Edinburgh) on the prevalence of anti-HCV in patients with haemophilia who had received blood products manufactured by the SNBTS exclusively from blood donors in Scotland and in recipients of commercially prepared Factor VIII.[176] Forty-eight patients who had developed NANB Hepatitis had received non-heat treated Factor VIII/IX concentrate (before 1985) and 41 were seropositive for anti-HCV. Of the seven who received only heat-treated concentrates (and a few donations of cryoprecipitate) none were positive. Six patients received only small amounts of cryoprecipitate or red cells and were all anti-HCV negative. Forty-one out of 48 patients (85%) who had a history of NANB Hepatitis were anti-HCV positive. The authors queried whether the remaining seven patients who had a history of NANB Hepatitis but were anti-HCV negative might have possessed antibody but at a level below the detection level of the ELISA, or whether they might be HCV antigenaemic in the absence of specific antibody.[177]

9.143 An international meeting on the Hepatitis C virus, organised by Ortho, was held in Rome on 14–15 September 1989. Dr Ruthven Mitchell (SNBTS, Glasgow) attended and produced a report.[178] The Chiron test was now being evaluated in a large number of blood transfusion laboratories throughout the world (albeit no country, at that time, had introduced the test for the routine screening of blood donations). Dr Mitchell was struck by the rapidity of its introduction; either it was an example of good marketing or, quoting one delegate, ‘It is the test that we have been waiting for for many years in the investigation of alleged cases of NANBH’. It seemed, in most workers’ hands, that the results that were achieved were crisp and without too many grey or indeterminate zones. Dr Mitchell reported that the following matters were discussed at the conference. About 10% of persons being transfused developed NANB Hepatitis, which could be of two forms, an acute form and a chronic form. The incubation time varied from a few weeks to months. About 90% of post transfusion hepatitis was due to NANB Hepatitis virus or viruses. About 50% of these would become chronic and, of these, 20% would develop cirrhosis or some long term liver impairment. Prevalence of the Hepatitis C marker antibody varied between different countries. Patients in the highest risk categories had the highest prevalence of anti-HCV. Persons with haemophilia had an anti-HCV prevalence of 60-80%. The majority of repeatedly reactive samples did not have any surrogate markers such as elevated ALT or anti-HBc. In the screening of normal donor populations there did not seem to be any significant correlation between anti-HCV results and the presence of anti-HBc or ALT values.

9.144 Dr Mitchell considered that the impact of introducing anti-HCV testing in Scotland, so far as patient morbidity was concerned, was likely to be low, although it was recognised that there would be individuals in the population who might progress to advanced liver failure and/or heptatocellular carcinoma as a result of acquiring HCV infection. Dr Mitchell ended his report by noting that the newer heat-treated and solvent detergent Factor VIII preparations did not appear to transmit Hepatitis C and that the low frequency of anti-HCV among female contacts of haemophilia patients indicated that Hepatitis C was not easily transmitted by heterosexual contact or that it did not persist in spouses as long as it did in their partners with haemophilia.

9.145 Around 22 September 1989 the British Blood Transfusion Society met in Durham. On the last day of the meeting, Drs Gunson, Contreras, Barbara, R Mitchell and
Mr A Barr attended a separate meeting with representatives from Ortho. Dr Mitchell produced a note of the meeting.[179] The note disclosed that Dr Gunson indicated that, in his view, the likely recommendation of the ACTTD to the meeting of the ACVSB on 6 November would be that testing should be introduced in the UK, probably within the financial year 1990 ie sometime after 1 April 1990. A meeting of the ACTTD was being held in Manchester on 9 October 1989 to finalise details of the report to the ACVSB. Ortho advised that whatever date was chosen, they would require a minimum lead in period of 90 days. They indicated that France, Japan and Denmark were three major countries that had decided to adopt the test in the near future. Dr Contreras was hesitant at the speed of the proposed introduction of the test, especially since no account had been taken of how donor counselling would be carried out. She still felt that some of the data presented at Rome and elsewhere was imprecise and that there were many grey areas in the interpretation of results. Reference was made to the need for a confirmatory test.

9.146 On 29 September 1989 the SNBTS Directors met.[180] Dr Follett was due to produce a paper on accepting blood donors who had suffered from jaundice 12 months previously and recommending that anti-HBc testing should be performed before reinstatement. Dr Mitchell tabled a report on the Ortho anti-HCV test and a table of preliminary data. It was recalled that Scotland had not been invited to participate in the UK evaluation group but the SHHD had asked that they should, and so West and South East Scotland BTS had obtained kits for evaluation. Dr Mitchell’s data would now be submitted to the UK Advisory Group. It was noted that any routine testing would be on a UK basis, on a date to be determined by the DOH, following the advice of the ACVSB, due to meet next in November. Meanwhile the ACTTD would meet in early October and would transmit the views of the Blood Transfusion Services to the November meeting of the ACVSB. In discussion among the SNBTS Directors a number of points were made, including the crucial importance of a satisfactory confirmatory test.

9.147 On 30 September 1989, Sansonno and Dammacco (Bari, Italy) reported the results of an Italian study of the Ortho anti-HCV test.[181] The Ortho assay was used to evaluate the prevalence of HCV antibodies in non-Hepatitis B virus associated liver disease. Eleven out of 12 patients (92%) with post-transfusion chronic liver disease and 38 of the 48 (74%) with cryptogenic[182] liver disease had HCV antibodies. The data showed that HCV was the main cause of both post-transfusion NANB Hepatitis and cryptogenic chronic liver disease in Italy. The close association between HCV antibodies and chronic liver disease supported the notion that they were not virus neutralising antibodies.[183]

9.148 On 5 October 1989 Dr B C Dow, Mr A Barr and Dr R Mitchell (SNBTS, Glasgow), produced a Preliminary Report, ‘SNBTS Evaluation of the Ortho HCV Antibody ELISA Test System’.[184] The purpose of the evaluation was to determine the prevalence of anti-HCV in the Scottish donor blood population and to ascertain the relevance of surrogate markers such as ALT and anti-HBc. A total of 2745 random blood donations from three SNBTS regions (Aberdeen, Dundee and Glasgow) had been tested. Fifteen (0.55%) positive results were obtained on initial screening and 13 (0.47%) were repeatedly reactive. All 2745 donations had been tested for ALT levels in 1987 and 1988. Only one of the 15 donations that were positive on initial screening had an abnormal ALT level. The donations from Dundee and Glasgow that were anti-HCV positive on initial screening were tested for the presence of anti-HBc. None were reactive for anti-HBc. The report concluded that in the study approximately 1 in 200 (0.5%) random blood donors were shown to be anti-HCV positive, albeit that only a proportion of anti-HCV positive donations might be actually infective. One hundred and eleven donor samples implicated in 28 cases of post-transfusion NANB Hepatitis were tested. Only six donors were repeatedly anti-HCV reactive leading the authors to conclude that the Ortho test would only have prevented 21% (ie 6/28) of the cases of post-transfusion NANB Hepatitis; a somewhat lower figure than reported elsewhere. The report queried whether that might be due to these cases of post-transfusion NANB Hepatitis being caused by another agent(s). From the limited evaluation carried out, the Ortho anti-HCV ELISA test had been shown to have an acceptable specificity. The apparent diminution in the sensitivity of the HCV kit when compared to the Dev[185] kit was worrying. That underlined the need to check the sensitivity and specificity of kits before routine use. As noted below, a further Report was prepared on 13 December 1989.

9.149 On 7 October 1989 the British Medical Journal published an article by Professor Zuckerman, ‘The elusive hepatitis C virus: a cause of parenteral non-A, non-B hepatitis’.[186] Referring to the Spanish, Dutch and German studies of the anti-HCV assay published in The Lancet on 5 August 1989,[187] Professor Zuckerman commented that:

the most recently published seroprevalence studies of anti-HCV antibodies using the assays developed by the Chiron laboratories confirm the apparent specificity and (relative) sensitivity of the assays … The ability to detect anti-HCV antibodies, generally only several months after acute infection, is an important advance that is expected to provide not only a clinical diagnostic test but also a screening procedure for blood donations. Such a test would substantially improve the safety of the transfusion of blood and blood products. Preliminary serological surveys of healthy blood donors indicate average rates of anti-HCV antibodies in 0.5 to 1% in … Britain, with a similar rate in several other industrial countries that use a voluntary blood donation system.

Professor Zuckerman also noted:

Nevertheless, important problems remain. Many of these serological findings should be interpreted with some caution in the absence of a confirmatory test, sufficient independent testing, and more extensive testing, which is limited by the apparent lack of availability of reagents and test kits and the high cost of reagents. The urgent and important problem is the lack of confirmatory assays for repeatedly reactive or borderline reactions by the commercial [ELISA] in blood donations … We also need wider application of the tests to determine whether there is more than one type of bloodborne non-A, non-B hepatitis – for which there is much epidemiological, clinical, and experimental evidence.

9.150 On 9 October 1989 the ACTTD held its third meeting. Dr Gunson’s report of the Rome symposium was submitted in draft to this meeting of the ACTTD and, after a number of changes, was approved for submission to the ACVSB.[188] The original draft of Dr Gunson’s report stated:

it will be difficult not to introduce routine screening of blood donations for [anti-HCV] since there is, even from the earliest studies, the possibility that the incidence of transfusion-transmitted NANB Hepatitis will be significantly reduced. Although this disease is usually mild with recovery, some patients may develop cirrhosis of the liver.[189]

9.151 In the report submitted to the ACVSB, that wording was replaced with the following passage:

routine screening of blood donations … should be introduced when practical, since there is, even from the early international studies, the probability that the incidence of transfusion-transmitted NANBH will be reduced.[190]

9.152 Nevertheless, the primary conclusion remained the same, namely, that the ACVSB was

asked to approve the routine testing of blood donations for [anti-HCV] in principle, and request the National Directors in England and Scotland to arrange for the simultaneous introduction of the tests at an appropriate time when a policy for counselling and management of seropositive donors has been identified.

9.153 On 9 October 1989 the UK Haemophilia Centre Directors met.[191] The Hepatitis Working Party had been discontinued and a new Chronic Hepatitis Working Party had been set up under the Chairmanship of Professor F E Preston.

9.154 On 6 November 1989 the fourth meeting of the ACVSB took place.[192] A paper was tabled, summarising the results of ALT and Anti-HBc screening of blood donations from North West Thames, South Western and North Western RTCs.[193] The following conclusions were noted: taken overall, 3.2% of donors would have been rejected for raised ALT and 0.63% for anti-HBc seropositivity. However, if the policy of the Swiss Red Cross had been operated (namely, only donors with a raised ALT on two successive samples were rejected), the number would have been reduced to 1.1%. A disturbing finding was the variability of ALT testing in the three centres; there were some donors in Manchester who had normal levels of ALT who would have been rejected in Bristol or North London. It was difficult to conclude how many of the donors with raised ALT or who were seropositive for anti-HBc would have transmitted NANB Hepatitis. A prospective study would require to be performed to determine that. However, it was evident that the ALT test was non-specific since the correlation with alcohol intake and obesity was striking. Similarly, the significance of a positive anti-HBc result was unknown. Following the introduction of the anti-HCV test the only justification for performing ALT and anti-HBc tests routinely was (i) the possibility that, in particular, ALT would identify a ‘window’ of infectivity prior to seroconversion for anti-HCV and (2) the possibility that anti-HCV only identified one of a number of viruses which caused NANB Hepatitis. The introduction of other specific viral markers and increased sensitivity of the anti-HCV test might render the subject of surrogate testing of academic interest. Meanwhile, the desirability of introducing these tests remained an issue of ‘health economics’.

9.155 Dr Gunson spoke to a paper summarising the September meeting in Rome on the Ortho anti-HCV test.[194] The conclusions of the paper were as follows:

• It seemed certain that the anti-HCV test detected a viral marker associated with NANB Hepatitis.

• It seemed that anti-HCV positivity meant that the blood of the person might be infectious for NANB Hepatitis, although not in all instances.

• Evidence presented suggested that routine anti-HCV tests on blood donations would reduce the incidence of transfusion transmitted NANB Hepatitis, the clinical impact of which would depend on the incidence of transfusion transmitted NANB Hepatitis in a particular country.

• Anti-HCV positivity in a blood donor might not necessarily mean that the seropositive donor transmitted NANB Hepatitis.

• An unknown proportion might also be false positive; a confirmatory test was not yet available.

9.156 Dr Gunson reported that Chiron had indicated that they were pursuing feasibility studies of a Recombinant Immunoblot Assay (RIBA) confirmatory test and that further information would be provided as soon as it was available.

9.157 The minutes of the fourth meeting of the ACVSB noted the conclusions of the ACTTD as follows: the test would detect a viral marker to NANB Hepatitis; a positive test might mean blood was infected (but not always); routine testing for anti-HCV would reduce NANB Hepatitis, but estimates of the extent of the reduction ranged from 20%–60%. The problems that were identified were a lack of a confirmatory test and a question mark hanging over the status of ALT and anti-HBc testing. The recommendations of the ACTTD were that anti-HCV screening of blood donors should be introduced only after a confirmatory test was available, the US FDA had approved the test and urgent pilot studies had been carried out in the UK.[195]

9.158 During the discussion that followed, members of the ACVSB voiced their concerns that the test did not appear to be suitable for testing UK pooled plasma, that test results varied from kit to kit and that diluting a positive sample (by 1:10, in Scotland’s experience) resulted in a negative result. Dr Tedder gave the Committee a summary of the history of the Ortho anti-HCV test, and explained that its development used only small proteins (middle section of the RNA), whereas there were better tests on the way which tested for structural proteins. Dr Metters explained that although the DOH must bear in mind the possible litigation that could arise from a prolonged delay in the introduction of general anti-HCV screening, the NHS Management Executive would want to know more facts and figures before backing a move to testing. Dr Gunson advised that based on the North London BTC’s experience, 1:200 patients (0.5%) might go on to develop chronic hepatitis. Other members felt that the figure (taking account of asymptomatic seroconversion) could be higher. A full discussion followed.

9.159 The feeling of the ACVSB, as summed up by the Chairman, was that the test represented a major step forward, but that the Committee needed to know a great deal more about it, and acknowledged the need for a confirmatory test. It was agreed that while the UK would not want to go in advance of an FDA decision, it could prove difficult if the FDA did not decide in favour of the test. Nevertheless, it was felt that if the UK did put the test into general use RTCs would need to have had experience with it, therefore, pilot studies should proceed in Brentwood, Sheffield and Birmingham (ie North East Thames, Trent and West Midlands RTCs) to show the feasibility of adding the test to routine practice.[196] The Committee’s feeling was that there was no case for using surrogate tests for NANB Hepatitis. The Committee would support the general introduction of the Ortho anti-HCV test if the FDA approved it and the pilot study showed it to be feasible and non-problematic. For these reasons it was felt that the Committee should be developing an economic case (ie the percentage of NANB Hepatitis that would be prevented and any other supporting data) for the Department to fund the routine use of the test (at a cost of some £5-6million per annum).

9.160 On 22 November 1989 the ACTTD held its fourth meeting.[197] The outcome of the meeting of the ACVSB was reported back as follows:

It was agreed that the anti-HCV test was a major step forward in identifying those who could potentially transmit HCV. The ACVSB had noted the need for a confirmatory test either before or shortly after any routine testing of donations. They also agreed that routine screening should not commence until the FDA had granted a licence, which may be June/July 1990.

9.161 The minutes of the meeting of the ACTTD note that the DOH had agreed to fund three English centres to purchase 15,000 Ortho anti-HCV tests to undertake a multi-centre study to evaluate the performance of the test in the routine operations of the RTCs.

9.162 On or around 27 November 1989 Professor Cash and Dr Gunson received letters from Ortho’s product development manager advising that the Ortho anti-HCV ELISA test had received an Export Permit from the FDA which allowed supply of the test for ‘in vitro diagnostic use’ instead of ‘research use only’.[198] The change in status would be effective from December 1989.[199]

9.163 On or around 27 November 1989, Professor Cash was informed by the group vice-president and general manager of Ortho that an RIBA confirmatory test was being evaluated.[200] The letter advised Professor Cash of the completion of prototype RIBA tests, upon which Ortho were seeking feedback from several laboratories throughout the world, ‘so that we can use this information to introduce our confirmatory tests during the first quarter of next year’.[201]

9.164 On 30 November 1989 an important paper by Alter et al (USA National Institutes of Health and Chiron) was published, ‘Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis’.[202] Following a study of patients in the USA, the authors reported that Hepatitis C virus was the predominant agent of transfusion associated NANB Hepatitis and that screening of donors for anti-HCV could prevent the majority of cases of the disease.

9.165 Alter et al also reported that surrogate testing for anti-HBc and ALT would have detected approximately half of the anti-HCV positive donors identified as being involved in the transmission of hepatitis.

9.166 In December 1989 Dr Barbara (North London RTC) set out his views on screening for Hepatitis C in an editorial in the newsletter of the International Society of Blood Transfusion:

The recently available assay for anti-HCV developed by [Chiron] and marketed by [Ortho] undoubtedly provides a marker for the major aetiological agent of [NANBH] … In general, most authors observe clear associations of anti-HCV in donors and/or recipients and post-transfusion NANBH, but these associations are by no means complete. This may be for several reasons: some cases of apparent [post-transfusion hepatitis] may not be viral, or may be caused by an agent other than HCV. There may also be a long delay before antibody develops after infection (sometimes as long as 12 months) and antibody levels may fall in relatively short periods of time. All these factors must be taken into account when considering the question of routine anti-HCV screening of blood donations prior to transfusion. The predictive value of the assay in low prevalence populations such as blood donors may well be less than in high prevalence populations … Some form of supplementary assay for “confirmation” of screen-positive reactions is therefore essential. [Ortho] will soon have Western blot assays available and their evaluation is eagerly awaited.[203]

9.167 On 12 December 1989 the SNBTS Directors met.[204] In respect of the ACVSB, in the absence of Mr Panton (SHHD), there was nothing to report. In respect of the ACTTD, Dr Mitchell had been asked to establish a group to consider a counselling programme for donors found to be Hepatitis C positive. Ortho had responded positively to the Directors’ request for access to confirmatory testing. Directors were to send to Drs Follett and Mitchell well validated samples for confirmatory testing with the new RIBA kits due to be issued from Ortho on 18 December. It was also noted that the West of Scotland BTS were due to receive Abbott tests for evaluation.[205] Professor Cash asked Directors to submit estimated costs for Hepatitis C testing.

9.168 On 13 December 1989 Dr Dow, Mr Barr and Dr Mitchell (SNBTS, Glasgow) produced their Report, ‘SNBTS Evaluation of the Ortho HCV Antibody ELISA Test System’.[206] The conclusions were largely as set out in the Preliminary Report dated 5 October 1989 noted above.[207] On the finding that the Ortho test would only have prevented 21% of the NANB post-transfusion Hepatitis cases, a lower figure than reported elsewhere, the authors stated that that finding might have been due to the unavailability of the actual implicated samples in many cases and their substitution with later samples or, alternatively, that the cases of NANB post-transfusion Hepatitis might have been due to another agent(s). The final report again concluded that from the limited evaluation carried out, the Ortho HCV ELISA test had been shown to have an acceptable specificity but that the apparent diminution in the sensitivity of the HCV kit when compared to the Dev kit was worrying.

Summary

9.169 Thus, by the end of 1989:

• Scientific details had been published by Chiron of their discovery of a genome of Hepatitis C and a test to detect antibodies to the virus.

• It seemed likely that Hepatitis C was the main agent of NANB Hepatitis.

• The ACVSB had been formed, whose remit included advising the DOH on whether, and, if so, when, anti-HCV screening of blood donations should be introduced by the UK blood transfusion services.

• An initial evaluation of the first generation Ortho anti-HCV ELISA test had been undertaken by the UK blood transfusion services which disclosed that between 0.5–1% of blood donors tested positive for antibodies to Hepatitis C.

• While the reliability of the Ortho anti-HCV ELISA appeared relatively satisfactory when testing known NANB Hepatitis sera, there were concerns about the number of false positive reactions that might occur when screening large populations with a low prevalence of Hepatitis C, such as blood donors.

• In the UK there were approximately 2.5million blood donations annually which, at a detection rate of 0.5–1%, would lead to between 12,500–25,000 donors testing positive. It was not known what proportion of these donors were positive for Hepatitis C antigen and were, therefore, infectious.

• It was considered necessary for there to be a satisfactory confirmatory test available before anti-HCV screening was introduced.

• Ortho had promised that a confirmatory RIBA test would soon be available for evaluation.

• While the US FDA had granted an export licence for the Ortho anti-HCV ELISA, a licence had still to be granted permitting the test to be used in the USA.

• The availability of a direct test for Hepatitis C had, or would shortly, render the whole issue of indirect, or surrogate, testing for NANB Hepatitis (using ALT and anti-HBc markers) largely academic.

1990

9.170 In 1990 a review article by Dr PL Yap (SNBTS, Edinburgh) was published.[208] The author stated that while there remained a number of unresolved problems that might influence the effectiveness of anti-HCV screening, it was hoped that such screening would be routinely introduced in the second half of 1990 in the UK.

9.171 On 4 January 1990 the Special Management Committee of the NBTS met. As regards the absence of a confirmatory HCV test, Dr Gunson was noted as having advised the Committee that

the ACVSB did not necessarily see this as a barrier to the introduction of routine screening, but the ACVSB would insist that any test for routine use must be licensed by the FDA.[209]

9.172 On 17 January 1990 the fifth meeting of the ACVSB took place.[210] Dr Gunson spoke to a paper giving details of the three centre anti-HCV pilot trial (at Brentwood, Sheffield and Birmingham RTCs).[211] Approximately 5000 anti-HCV tests were performed at each of the three centres. The problems which caused the most concern were the number of tests (0.5–1%) that were in the ‘grey zone’ having a higher optical density than most of the negatives, but below the cut-off for positives and weaker reactions observed with plasma as compared to sera. This was of importance in blood donations as Directors needed samples from the actual donation. The time taken to complete the test was also seen to be a disadvantage in relation to emergency release of products. These were some of the aspects that would have to be discussed with Ortho.

9.173 The ACVSB noted that Ortho were holding a symposium on Hepatitis C in London in February, on the same day that Abbott (who were expected to produce a test shortly) would be holding one in Chicago. Members of the Committee would be attending both symposia.

9.174 There was a discussion under the heading ‘NANBH cost benefit analysis’. Dr Pickles (DOH) spoke to a paper, ‘Cost-benefit of hepatitis C screening of blood donors in the UK’.[212]

9.175 The Chairman, Dr Metters, invited the Committee to address the question of whether the time had now come for the introduction of routine Hepatitis C testing. Professor Zuckerman spoke to a letter he had written setting out his views on whether HCV screening should be introduced.[213] He expressed the view that while the projected cost of the screening test was, at least initially, very high; considering the overall morbidity of chronic NANB Hepatitis (including apparently autoimmune liver disease and hepatocellular carcinoma), and litigation which would be indefensible, the introduction of screening could not be delayed much beyond approval by the FDA. At the meeting of the Committee he emphasised the problems posed by the lack of a confirmatory test and the apparently high number of false positive reactions obtained when the test was applied to samples which had been frozen and then thawed. He advised that both in the USA and Japan it had been found that some donors who showed positive with the test had passed on disease. In attempting to give an indication of the number of possible cases of chronic liver disease that could be prevented by the introduction of routine testing, Professor Zuckerman emphasised that his figures would represent gross assumptions and estimates. On that basis, he offered a figure of 5000 members of the donor population who could be excluded from donating, but 50% could be false negatives. He also gave the Committee details of work that had been carried out in Japan which suggested that there was another Hepatitis C, which was a further complicating factor. Professor Zuckerman felt that this strengthened the argument that an open mind must be kept about other tests, which should be available within the next 12 months. He felt that it was unlikely that the FDA would license the Ortho test in the absence of a confirmatory test, and it would be difficult for the Committee to approve a test which was not approved in its country of origin. The proposed Abbott test would not really be an independent test. Dr Rotblat (DOH) added that it was also her understanding that the FDA was unlikely to approve the test at this stage.

9.176 Dr Tedder stated that it was very difficult to make any recommendations based on scientific criteria at that time, as so little was known about the virus and its antibody markers.

9.177 Professor Zuckerman added that he understood that the Japanese and USA total sequences had now been published, and they were not the same. The virus had not been visualised yet and there were few published epidemiological details, as compared with what had been produced, for example, at an early stage with Hepatitis B.

9.178 Dr Mortimer (PHLS) felt that as the perceived risk was higher than that of HIV, it would be inconsistent in the UK’s screening procedure not to introduce routine testing. If routine use of the test was begun, there should soon be a better test to move onto.

9.179 Dr Ruthven Mitchell discussed the potential problem of handling donors. He felt that it was possible to deal with donors who proved positive to the test without causing undue alarm.

9.180 Dr Gunson explained that the transfusion services were under a great deal of pressure, not just from Ortho but from the press, and increasingly from the clinicians in the field. He felt that each centre must now consider how to set up the test and what extra resources they would need to do so. He also highlighted the fact that as further tests were introduced the potential for labelling mistakes would increase to a point where the time might have come to introduce automation. Dr Tuddenham explained that, to date, donors who had shown as positive had not been recalled, but would be retested on their next appearance.

9.181 In answer to questions about funding for the additional testing and counselling, the Chairman explained that funding would have to be found from the existing health allocation.

9.182 The Chairman summed up the general consensus of the ACVSB as follows: routine testing should not be introduced in advance of the FDA decision; scientifically, not enough was known yet, but there was agreement that the test did detect some people who would transmit; the overall prevalence figure of NANB Hepatitis following blood transfusion in the UK might be 10,000 per annum, subject to very wide margins of error. The Chairman asked members for their opinions as to what action should be taken. Dr Tedder wanted it to be noted that he would not give an opinion before more scientific data had been generated.

9.183 After further discussion, the members of the ACVSB agreed: the costs should be looked at now, with regions being called upon to consider the financial implications; Professor Zuckerman’s figures would be further refined, to present as close an estimate of cases of potential infection as possible. This would undoubtedly be called for by Ministers; the Committee could give no further scientific advice at this point, but would discuss the matter further at their next meeting (in April) which would be after the international hepatitis meeting in Houston.[214]

9.184 Dr Ruthven Mitchell produced a note for his Scottish colleagues on the fifth meeting of the ACVSB.[215] Dr Mitchell noted that, in respect of anti-HCV testing:

[The] majority view was that [there was] sufficient evidence of test positive/infectivity correlation to justify implementation – overriding factor was question of product liability.

9.185 Dr Mitchell further noted that the DOH had indicated that new money would be made available for introduction of the test if and when it was agreed to do so. Therewas evidence that the USA FDA would recommend implementation for testing of cellular/single donor products but not for fractionated products. It was important to have a policy decision on the fate of pre-existing plasma stocks before implementation of the testto avoid a repeat of the HIV story. Dr Mitchell noted that it was: ‘Agreed not to introduce the test in advance of FDA approval but very compelling reasons to implement quickly following US decision’. There was no recommendation yet to Ministers to implement the test. Dr Tedder believed that there was data (from North London BTC) suggesting that
the majority of Hepatitis C positive donations were non-infective and tended to support the argument that removal of Hepatitis C positive donations from plasma pools might not be a good idea.

9.186 In February 1990 Ortho sent the first generation RIBA test, which had been developed to provide confirmation of anti-HCV ELISA positive results, to Drs Barbara, Mortimer and Follett, for evaluation.[216] The first generation RIBA test (‘RIBA 1’) detected antibodies for hepatitis C using a recombinant antigen c-100 expressed in yeast (as did the ELISA anti-HCV test) plus a sub-sequence of c-100 (5-1-1) expressed in Escherichia coli.

9.187 On 8 February 1990 the American Association of Blood Banks, the American Red Cross and the Council of Community Blood Centres issued a joint statement ‘Guidelines for planning the implementation of anti-HCV testing of blood and components for transfusion’.[217] The publication stated that available information indicated a strong correlation between anti-HCV in blood donors and the transmission of NANB Hepatitis to blood recipients. All blood and components collected for transfusion should be tested for Hepatitis C virus antibody. The recommendation should be implemented as soon as feasible after ELISA tests were licensed by the FDA and adequate supplies became available. The statement recommended that ALT and anti-HBc screening of blood donations should continue until it could be demonstrated that NANB Hepatitis agents other than Hepatitis C virus were not a significant cause of transfusion associated hepatitis. On the question of ‘look-back’, the US Public Health Service had recommended against an effort to identify and notify all past recipients of blood components from donors now found to be reactive for antibodies to Hepatitis C. The USA blood bank organisations endorsed that position. Professor Cash sent a copy of the statement to Dr MacIntyre (SHHD) by letter dated 19 February.[218] There is a handwritten note on the letter, apparently by an official in SHHD, that the statement had been copied to Dr Hilary Pickles (DOH), and had stirred up a ‘hornet’s nest’. Dr Pickles had asked for further information, including whether the statement had been issued.

9.188 On 13 February 1990 the SNBTS Directors met.[219] It was reported that the ACVSB had deferred a decision about commencing Hepatitis C testing on the advice of its microbiologist members. Dr Tedder and Professor Zuckerman had been asked to report following forthcoming international conferences and there would be a further meeting in April. Meanwhile, the UK transfusion services should consider the cost and equipment needs if testing were introduced. Dr Watt explained that SHHD would have to await a formal recommendation from the ACVSB before offering advice to Ministers. On the question of ALT testing, it was noted that there would be a problem if ALT testing commenced in England and Wales but not in Scotland. Mr D McIntosh (General Manager, SNBTS) advised that Dr McIntyre (SHHD) had reported to him by telephone the reasons why ALT testing should not be commenced in Scotland. Dr McIntyre had undertaken to contact the DOH for a corporate British stance.

9.189 On 15 February 1990 Dr McIntyre (SHHD) sent a memorandum to Dr Calder, ‘ALT donation testing: plasmapheresis donations’.[220] He noted that it looked likely that testing for Hepatitis C antibody would be introduced in the summer.

9.190 On 10 March 1990 Van der Poel et al (Red Cross, Amsterdam) reported on a study which, in the absence of a confirmatory test for Hepatitis C, considered certain co-factors in donors as a means of confirming infectivity of blood samples found to be positive using the Ortho anti-HCV ELISA test.[221] The authors stated that post-transfusion NANB Hepatitis was an important complication of blood transfusion and strongly recommended blood donor screening for anti-HCV.[222]

9.191 On 12 March 1990 Mr McIntosh (SNBTS) wrote to Dr McIntyre (SHHD) on the subject of ALT donation testing.[223] Subject to advice from the ACVSB, Mr McIntosh’s understanding was that neither the SNBTS nor the NBTS would be introducing ALT testing for the time being and that neither the SHHD nor the DOH recommended that such testing should be introduced. Equally, however, it was anticipated that there would be a need to start new testing procedures, probably including ALT testing, in conjunction with another/other test(s). There was a possibility of having to take pretty rapid steps during the course of the summer.

9.192 On 16 March 1990 the ACTTD held its fifth meeting.[224] It was noted that the ACVSB had deferred the decision to introduce routine screening of blood donations for anti-HCV. The next meeting of the ACVSB was to be held at the end of April 1990 and they were hoping, at that meeting, to receive further advice on which a decision could be reached. The DOH were carrying out a cost benefit exercise. Dr R Mitchell presented a flow chart (attached to the minutes of the ACTTD) for the handling of donors who were found to be anti-HCV positive.[225]

9.193 On 21 April 1990 Ebeling et al (Red Cross, Finland) reported on their evaluation of the Ortho RIBA 1 test.[226] The paper noted that the test was available for research use only. The ELISA and RIBA tests were applied to a frozen panel of donor and patient samples from a study of patients who had undergone open heart surgery. Six hundred and eighty-five patients received blood components from over 1000 donors. Of 11 patients who acquired post-transfusion NANB Hepatitis, seven had received a donation from an anti-HCV (ELISA) positive donor. Six of the seven donors also tested anti-HCV positive using the RIBA test. The seventh donor had a weakly positive ELISA reading and was negative on RIBA testing. Of 1029 donor samples not associated with the development of NANB Hepatitis in patients, six tested anti-HCV (ELISA) positive. On RIBA testing, while five remained positive for the c-100 antigen, all were negative for the 5-1-1 antigen (ie all were negative for the additional antigen used in the RIBA test). The authors concluded:

The RIBA may offer help in differentiating infective from non-infective blood donors. Reactivity for both antigens, and 5-1-1 especially, is associated with infectivity.

9.194 On 24 April 1990 the sixth meeting of the ACVSB took place.[227] A paper was tabled on the Ortho symposium in London on 8 February.[228] At the meeting of the ACVSB, Dr Rejman (Senior Medical Officer, DOH) stated that the overall impression was that the Ortho anti-HCV ELISA test was not sensitive or specific enough for reliable testing. A confirmatory test and more information about the significance of positive test results were needed before the Ortho ELISA could be used for the routine screening of healthy donors. Dr Mortimer (PHLS) thought there had been an underlying feeling against screening because of the lack of a confirmatory test. He thought confirmatory testing would become available within a reasonable time and that the routine screening of blood donors could not be delayed for a long time. Professor Zuckerman was disappointed at the outcome of the symposium and said that non-specificity and sensitivity of the test had been the main talking points.

9.195 A paper was tabled on the Abbott symposium in Chicago.[229] Dr R Mitchell advised the Committee that following this symposium the American Association of Blood Banks had directed that testing for Hepatitis C antibody should be introduced as soon as the FDA had approved the test. FDA approval had not yet been given. Concern about litigation was the main influence on the US Blood Banks. Dr Mitchell thought there would be problems counselling donors in view of the state of knowledge about the significance of a positive reaction to the test.

9.196 A paper was tabled on the International Viral Hepatitis and Liver Disease Conference in Houston.[230] Professor Zuckerman advised that wide geographical differences had been found and there was evidence of different strains of Hepatitis C virus. These observations would have serious implications for diagnosis and the development of vaccines. He drew attention to the main findings of the Transfusion Transmitted Viruses (TTV) study in the USA. This showed the predictive level of anti-HCV positivity for infection to be about 77%. The TTV group recommended that positive donors should be deferred. The RIBA test had confirmed positivity in 33% of ELISA positive donors who were not implicated in a hepatitis incident but among ELISA positive recipients of blood and implicated donors the rate of confirmation by RIBA was 88%. Professor Zuckerman was of the opinion that the RIBA was not good enough to use routinely as a confirmatory test.[231]

9.197 Dr Tedder presented a paper on a Polymerase Chain Reaction (PCR) test that he and his colleagues had developed, in collaboration with Wellcome, for the detection of Hepatitis C RNA sequences.[232] The PCR test, unlike the ELISA and RIBA tests, detected Hepatitis C antigen, rather than antibody, and confirmed, therefore, whether an individual was still infected with the virus. Of 1100 blood donations tested during a prospective study of post-transfusion NANB Hepatitis, six (0.55%) were repeatedly reactive using the Ortho anti-HCV ELISA test. Only one of the six donations transmitted NANB Hepatitis to a recipient.[233] Hepatitis C virus RNA sequences were detected in the serum of the transmitting donor by the PCR test. No such sequences were detected in the other five donors who were positive using the Ortho anti-HCV test. The authors considered that the reactivity in the five donors using the Ortho anti-HCV test but not the PCR test might be explained either by ‘convalescent’ antibodies in donors who had had a self-limiting Hepatitis C virus infection in the past or by non-specific reactivity due to antibodies against yeast cell contaminants of the C100 antigen preparation used in the test or against an unrelated protein which happened to share an epitope or epitopes with C100. The paper stated that while the development of the Ortho anti-HCV test represented a significant advance over the use of surrogate markers (such as anti-HBc and ALT), its introduction as a routine screening test for blood donors would create problems. Firstly, from the findings of the present study it appeared that only a small proportion (1 of 6, 17%) of anti-HCV ELISA positive donations constituted a risk of transmitting post-transfusion NANB Hepatitis. That finding was supported by a recently published prospective study of blood donors in Amsterdam in which only 17% (6 of 35) of anti-HCV positive blood products were found to be associated with post-transfusion NANB Hepatitis.[234] Based on these findings, it followed that approximately 10,000 donations a year in the UK would be unnecessarily discarded. Secondly, in the absence of any confirmatory tests, counselling of the large numbers of donors found to be reactive in the anti-HCV ELISA test would pose considerable problems, both ethical and logistical. Thirdly, the anti-HCV ELISA would not detect all potentially infectious donors because there was a prolonged delay (mean 22 weeks) between infection and seroconversion and because 40% of acute NANB Hepatitis cases failed to develop antibody to this protein at all. Finally, the financial implications of introducing the anti-HCV ELISA test for donor screening required to be considered. The reagent costs alone would amount to £6.25million per year and the additional costs resulting from donor counselling, withdrawal of blood and its products, replacement of donors and confirmatory testing would be considerable. The PCR technique described in Dr Tedder’s paper was stated to represent a significant step forward since it promised the accurate identification of the small proportion of anti-HCV positive donors who were carriers of the virus. Although the PCR assay in its present form was not suited to mass screening, recent modifications in PCR technology indicated its potential for large scale testing.

9.198 At the meeting of the ACVSB Dr Tedder added that the PCR test was found to be a useful confirmatory test for viraemics and showed that true positivity of Hepatitis C antigen was close to 1 in 1100 blood donors (0.09%) compared with the 1 in 200 (0.5%) shown positive by anti-HCV screening.

9.199 Before opening up the subject of testing for general discussion the Chairman reported that France, Belgium and Luxembourg had introduced routine screening of blood for HCV antibody. Italy had introduced the test on a voluntary basis. The Chairman also remarked that, from the reports, the science seemed to have advanced little from the time of the previous meeting. There were still questions whether the anti-HCV test was reliable and a useful step forward or created too many problems at this stage.

9.200 Dr Mitchell mentioned a report from Harefield Hospital that six of the seven Hepatitis C positive donors identified in a study did not transmit infection and four had been found not to be positive after a year. He was concerned that screening might result in 1 in 200 donors being deferred perhaps unnecessarily. Professor Zuckerman was concerned that the Ortho test had a false positive rate of 50% but that litigation might force its use. He recalled, though, that in the early days of HIV testing the UK had been prepared to accept a high false positive rate. He thought that viraemic testing could be developed with recombinant proteins being developed. A field trial could be run in RTCs using the prototypes and they could be introduced generally when they were sufficiently developed. He was still a little concerned that the FDA had not approved the Ortho test. Dr Gunson found the USA data about eliminating positive donors, in some series leading to a 50% reduction in post transfusion NANB Hepatitis, persuasive, but he recognised that there were problems in what to tell donors. He suggested a further study with selected RTCs using both the Ortho and Abbott tests, with repeat positives being referred to laboratories with access to recombinant proteins. Dr Tedder advised that the technology was already available to test which of the positives were reactive but irrelevant, which had other markers and which were viraemic. Dr Mortimer considered that the argument now was not whether the blood transfusion services should test for Hepatitis C but whether the tests were adequate. He thought the Ortho and Abbott tests should be run together in some RTCs and the positive samples referred for PCR testing.

9.201 The Chairman summed up the discussion as follows: there was inadequate scientific data to support the introduction of the Ortho test for routine screening; a confirmatory test was needed which could be used in the RTCs and not just specialised laboratories; the FDA had not yet approved the test and it would be reassuring if the regulatory authority in the country of origin had done so; there was a need to learn more about the donor panels and the significance of a positive reaction to the HCV antibody test; a prospective study involving 25—50,000 donors would generate sufficient positives for confirmatory testing. It was agreed that a sub-group of Drs Gunson, Mitchell, Mortimer and Tedder would prepare a protocol for the pilot study. The Chairman remarked that the paper by the Economic Advisor’s Office reflected the lack of data.[235] A note would be prepared for Ministers advising them of the outcome of the discussion.

9.202 Dr Perry (Director, PFC) prepared a note of the sixth meeting of the ACVSB which he sent to Professor Cash by letter dated 2 May.[236] Dr Perry noted that the subject of HCV testing had been the main agenda item and had been ‘dominated by reports and discussion by academic virologists’. Dr Gunson and Dr Perry felt that there was sufficient data to justify testing now (based on USA data suggesting a 50% reduction in post-transfusion hepatitis) but a majority of the committee members, and the DOH, preferred a more cautious approach.

9.203 On 1 May 1990 J Canavan, (DOH), sent a memorandum to Dr J S Metters and others advising Ministers of the outcome of the ACVSB discussions on the screening of blood donations for Hepatitis C. The Committee was of the view that the introduction of routine screening was not yet justified (in light of the lack of FDA approval and unresolved difficulties concerning the tests) and that a pilot study should be carried out to learn more about the significance of a positive reaction to the test and the extent to which it predicted infectivity which could be transmitted in blood.[237]

9.204 On 2 May 1990 the US FDA licensed the Ortho anti-HCV ELISA test for use in the USA. In an announcement on 4 May 1990 Ortho advised that kits were being shipped to USA blood centres and screening of the USA blood supply would commence immediately.[238] The announcement stated that Ortho was supplying anti-HCV test kits to Europe, Japan, Canada and Australia for blood screening.

9.205 On 11 May 1990 the marketing manager of Ortho announced the availability of the RIBA 1 supplementary test for HCV.[239]

9.206 On 12 May 1990 Makris et al (Sheffield) reported on a study of Hepatitis C antibody and chronic liver disease in haemophilia patients.[240] The Ortho test was used to detect anti-HCV in 154 patients with haemophilia. Prevalence of anti-HCV was associated with exposure to clotting factor concentrates. Thirty-five patients with chronic liver disease underwent liver biopsy. Histological examination showed features associated with post-transfusion hepatitis in 24, all of whom were anti-HCV positive; of the other 11 patients with no histological features of NANB Hepatitis, five were anti-HCV positive. The authors concluded that Hepatitis C appeared to be the major predisposing factor for most NANB Hepatitis and chronic liver disease in haemophilia patients.

9.207 On 23 May 1990 Dr A B Young (Deputy Chief Medical Officer for Scotland) sent a memorandum to Dr McIntyre.[241] Members of the Common Services Agency Management Committee had asked for a position paper on Hepatitis C testing for their June meeting. They were concerned at the legal liability aspects and wished to take a firm grip on how the issue was handled. Dr Young asked Dr McIntyre to brief him and to discuss what kind of paper should be produced.

9.208 On 2 June 1990 Dr Skidmore (Regional Virus Laboratory, Birmingham) reported on her experience of the Ortho RIBA test.[242] While supplies of the test were limited, she was of the view that the RIBA test might be just the test needed to confirm a positive Ortho anti-HCV ELISA result.

9.209 On 6 June 1990 Dr A D McIntyre sent a memorandum to Dr A B Young (Deputy Chief Medical Officer).[243] He reported that things were moving very fast on the Hepatitis C front. The FDA had now approved the Ortho anti-HCV test. Dr McIntyre had that morning received a letter from Dr J S Metters (DOH) indicating that recent developments might render the further study agreed at the last meeting of the ACVSB inappropriate.[244] The proposed meeting of the ACVSB on 24 July had been advanced to 2 July. Dr McIntyre was of little doubt that for a variety of reasons, many of them non-scientific, it would be decided that there was no alternative but to recommend the introduction of the test. Dr McIntyre’s understanding was that it was likely that one in 250 blood donors (0.4%) would be found to have Hepatitis C antibodies in their blood but that only a fraction of these would be infectious; also that for most of them it would be of no clinical significance. That raised the question of what to tell donors. If all those positive for Hepatitis C were referred for expert consultation that was likely to constitute a very large workload. There was the possibility of litigation, like the HIV litigation, as to whether testing had been introduced as early as possible. The whole issue was something of a minefield. Dr McIntyre suggested that further action be delayed until the meeting of the ACVSB on 2 July.

9.210 On 12 June 1990 the SNBTS Directors met.[245] There was discussion of Hepatitis C testing. Dr Mitchell reported that the sub-group of the ACVSB had agreed to undertake a study of the Abbott and Ortho tests in three centres, including Glasgow, plus the appropriate confirmatory tests which were now available. The protocol would be presented to the main Committee with possible implementation in October or December 1990. There were still severe problems relating to accuracy which might mean withdrawing a large number of donations. Dr McIntyre (SHHD) had advised Mr McIntosh (General Manager, SNBTS) that Ministers might approve a start without the above study (following a meeting of the ACVSB to be held on 2nd July).

9.211 On 14 June 1990 Mr Canavan (DOH) produced a memorandum. It stated:

I am returning to the cost/benefit question as it seems likely the ACVSB will recommend [anti-HCV] screening at its specially convened meeting of 2 July. You will see from the draft minutes of the last meeting that a pilot study was the preferred next step at that time. However our experts now seem to think advances in knowledge about the [anti-HCV test] and the means of confirming the result make it very difficult to resist the introduction of screening. A number of countries have already done so.[246]

9.212 On 16 June 1990 The Lancet published an editorial, ‘Hepatitis C virus upstanding’.[247] The editorial stated: “

The most important decisions to be faced now are when to begin testing blood donors for evidence of HCV infection and what tests should be used. Many countries are already committed to testing and excluding positive donors.[248]

9.213 By letter dated 21 June 1990 Professor Cash asked Dr Gillon (SNBTS, Edinburgh) to chair a small group to draft guidelines on the counselling of HCV positive donors following the introduction of anti-HCV screening.[249]

9.214 On 26 June 1990 Professor Cash distributed draft notes of a meeting of the Council of Europe’s Committee of Experts on Blood Transfusion which had taken place in May.[250] Consensus opinion on Hepatitis C was noted as follows:

Routine screening of blood donations for anti-HCV will increase the safety of the blood supply. There are indications that a suitable confirmatory test for general use will be available soon. It is recognised that not all units of blood or plasma which are anti-HCV positive with the screening tests presently available are infective for hepatitis C.

9.215 Sometime in 1990 (possibly July) the SNBTS submitted a revenue bid of £1.2million to finance HCV testing in 1991–92.[251] While revenue bids to introduce ALT and anti-HBc screening were also included, it was considered highly unlikely that these tests (ie ALT and anti-HBc tests) would be introduced into routine practice in the forthcoming financial year with the result that these costings were carried forward to the next year.

9.216 In July 1990 the members of the UK Regional Haemophilia Centre Directors Working Party on Chronic Liver Disease in Haemophilia met. A report was produced.[252] During the past three years 128 deaths were reported from 44 Centres. Of the 42 patients on whom autopsies were performed, liver disease was found to be present in 16 ie 38%. Recommendations were set out for surveillance of Hepatitis C liver disease in haemophilia patients.

9.217 On 1 July 1990 Brettler et al (Massachusetts and other centres) reported on the prevalence of the Hepatitis C virus antibody in a group of haemophilia patients in the USA.[253] Of 131 patients, 100 (76.3%) were anti-HCV positive. The data confirmed the previous impression that NANB Hepatitis was a major sequel to the use of pooled coagulation factor concentrates. It appeared that the presence of anti-HCV generally denoted chronic infection:

Hence, a large segment of the hemophilia population is chronically infected with an agent that induces cirrhosis, and that more recently has been associated with hepatocellular carcinoma (HCC).[254] The interval to the clinical presentation of cirrhosis and HCC has been found to be prolonged. Because many hemophilic patients have been infected since the early 1970s when factor concentrate was first widely used, the incidence of severe, overt liver disease may soon increase in this population.

9.218 The authors noted that recombinant factor concentrates were now in widespread clinical trials.

9.219 On 2 July 1990 the seventh meeting of the ACVSB took place.[255] Papers circulated for the meeting included a document setting out the basis on which the Ortho anti-HCV ELISA test had received approval by the US FDA.[256] Of 9998 volunteer donors tested, 55 (0.6%) were repeatedly anti-HCV reactive. Of those 55 donors, 39 (70.9%) had normal ALT levels and were non-reactive for anti-HBc. Of 10,523 commercial donors tested, 703 (6.7%) were repeatedly reactive. Of 63 recipients who had chronic transfusion-associated NANB Hepatitis, 51 (81%) were repeatedly anti-HCV reactive. Of another group of 61 patients with NANB Hepatitis, there was an overall rate of anti-HCV reactivity of 88.5%.[257]

9.220 Another paper circulated for the meeting set out a draft protocol by Drs Mitchell and Gunson for a comparative study of anti-HCV testing using the Ortho and Abbot test systems (the Abbott test was due to be available from 1 July 1990).[258]

9.221 Dr Rejman of the DOH summarised events since the last meeting of the ACVSB as follows: the FDA had decided to approve Hepatitis C screening, America had already introduced screening and other countries were following. More studies had been carried out confirming that Hepatitis C testing reduced infection and RIBA was now available as a supplementary test. It was now felt that a study along the lines of those talked about in April was no longer viable and the meeting had therefore been brought forward so that a decision on the introduction of Hepatitis C testing in the UK could be reached.

9.222 The Chairman, Dr Metters, advised that the main purpose of the meeting was to reconsider the principle of Hepatitis C screening. The secondary purpose was to look at the draft protocol comparing the Abbott and Ortho tests and to decide which tests to use.

9.223 Professor Zuckerman advised that, overall, he felt that the screening test should be introduced as a public health measure. Dr Gunson advised that there was scanty information but there appeared to be only a 60% overlap of positive results for the two tests.

9.224 After further discussion the Committee concluded they should recommend to Ministers that Hepatitis C testing should be introduced in the UK, but that first a pilot study using the Ortho and Abbott tests was necessary to decide which was the better test for the regional transfusion centres. The pilot study would be carried out at three RTCs (North London, Newcastle and Glasgow) each of which would perform 3500 tests. Any initial positive results would be identified and repeated against both the Ortho and Abbott tests. Repeatedly positive results would be sent to Drs Mortimer, Tedder and Follett for supplementary testing by the Ortho RIBA and the Abbott confirmatory test procedure, followed by PCR. The overall timescale for the study would be approximately four months, after finance had been agreed.

9.225 Dr Gunson advised that Wellcome were also developing a test which would be ready in September/October. The pilot study would go ahead without delay and frozen library samples would be kept so that donations could be retested later against other tests, such as Wellcome’s, as these became available. It was agreed that any donations found to be infected with the HCV antibody would not be used. Consideration of any look-back procedure was postponed. After discussion, it was agreed that plasma, as well as whole blood, should be tested for anti-HCV antibodies.

9.226 The Chairman summed up the recommendations of the seventh meeting of the ACVSB as follows: the UK should introduce Hepatitis C testing. While this would not abolish NANB Hepatitis, it would reduce the number of cases; the public relations aspect needed to be handled very carefully; blood found to be positive in the pilot study would not be used, and there would be no look-back at recipients of previous donations from donors found to be positive in the pilot study; the decision as to which Hepatitis C test to use would be made after the results of the Ortho and Abbott tests were known; there was general support for the protocol. The working group would continue to co-ordinate the study and decide upon the procedure for counselling Hepatitis C positive donors; frozen serum could be used for any other tests coming on to the market; the same test should be applied to plasma; a submission would be put to Ministers; consideration would be given to the funding.[259]

Summary

9.227 Thus, by the middle of 1990:

• The US FDA had licensed the use of the first generation Ortho anti-HCV ELISA test in the USA.

• A first generation RIBA confirmatory test was available.

• The USA and some other countries had introduced routine screening of blood donors for antibody to Hepatitis C.

• The UK blood transfusion services had evaluated the first generation Ortho anti-HCV ELISA test (and, seemingly, the first generation Ortho RIBA confirmatory test).

• The ACVSB had decided (at their seventh meeting on 2 July 1990) to recommend that Hepatitis C testing be introduced in the UK, subject to further evaluation (by way of a pilot study of the Ortho and Abbott tests in three transfusion centres) of what would be the most suitable test or tests to use.

9.228 By letter dated 9 July 1990 Professor Cash advised his fellow SNBTS Directors that he had discussed the question of HCV look-back with Dr Gunson and they had both agreed that it would not be appropriate, after anti-HCV donor screening was introduced, to introduce a systematic look-back programme on previous recipients, as had been done following the introduction of HIV screening.[260] It would, however, be appropriate, in the period before routine anti-HCV donation screening commenced, to examine the anti-HCV status of donors who had been implicated in a case of reported post-transfusion hepatitis.

9.229 On 21 July 1990 Van der Poel et al (Red Cross, Amsterdam) reported on their evaluation of the Ortho RIBA 1 confirmatory test.[261] They concluded that while it was not a true confirmatory test, a RIBA positive result was a very specific co-factor for infectivity of anti-HCV ELISA positive blood.[262]

9.230 On 23 July 1990 the product manager of Abbott Laboratories advised that the FDA had approved the marketing of an Abbott anti-HCV test.[263]

9.231 On 10 September 1990 the marketing manager of Ortho enquired if trials could be carried out of the second generation Ortho anti-HCV ELISA test at North London RTC.[264]

9.232 On 15 September 1990 Weiner et al (Chiron/Ortho) reported on anti-HCV testing in a low-risk population.[265] 9998 volunteer donors were screened with the anti-HCV ELISA test. Reactive samples were subjected to RIBA and PCR testing. The authors concluded:

Since 70% of the ELISA/RIBA reactive samples have HCV RNA and are most likely to transmit HCV and only 4% (1/28) of ELISA reactive/RIBA non-reactive samples had HCV RNA, it seems that the ELISA and RIBA … tests are specific for identifying individuals with HCV in a low risk population.

9.233 On 27 September 1990 the marketing manager of Ortho advised that a second generation RIBA test would be sent to the UK confirmatory laboratories.[266] The second generation RIBA test was a four antigen test, in which two additional HCV recombinant antigens (c33c and c22) had been added to the first generation RIBA test (containing the c100-3 and 5-1-1 antigens).

9.234 On 6 October 1990 Garson et al (Professor Tedder’s group, working with Wellcome) reported on their improved PCR assay to detect Hepatitis C virus RNA.[267] Serum samples from 20 haemophilia patients treated repeatedly with unheated commercial Factor VIII concentrate were tested with both the original PCR test and the improved test. The original PCR test detected HCV RNA in seven samples (35%), whereas the improved PCR test detected HCV RNA in 17 (85%) samples.

9.235 On 29 October 1990 the marketing manager of Ortho advised that clinical trials would soon commence on their second generation anti-HCV ELISA test.[268] The first generation ELISA test detected antibodies to recombinant HCV c100-3 antigen. The second generation ELISA test detected antibodies to structural (c22-3) and non-structural (c200) HCV antigen.

9.236 In November 1990 the second international symposium on the Hepatitis C virus took place at Los Angeles.[269] Dr J Gillon (SNBTS, Edinburgh) attended and produced a report.[270] The report appended two short papers by Lee at al (Chiron/Ortho) on the second generation Ortho anti-HCV (c200/c22) ELISA test. The first paper assessed the sensitivity and specificity of the second generation ELISA in cases of acute and chronic NANB Hepatitis.[271] The authors concluded that the second generation test provided improved sensitivity for the detection of antibodies to HCV in cases of parenterally transmitted NANB Hepatitis. The second paper assessed the sensitivity and specificity of the second generation ELISA in a variety of clinical populations.[272] The authors concluded that the second generation test provided an improvement in assay specificity (ie there were less false positives) when used to screen low risk populations for the presence of anti-HCV antibodies.[273] The authors further concluded that use of the second generation ELISA to screen normal volunteer blood donors would result in the detection of additional individuals with anti-HCV antibodies (ie the second generation test was more sensitive than the first generation test).

9.237 The eighth meeting of the ACVSB took place on 21 November 1990.[274] After the previous meeting a note had gone to Ministers advising that the ACVSB was in favour of introducing routine HCV testing. A further submission was awaiting the decision of this meeting as to which test would be the most suitable.

9.238 Dr Gunson introduced his paper on the results of phase one of the pilot study of the first generation Abbott and Ortho ELISA test kits at the North London, Newcastle and Glasgow RTCs.[275] The repeatable positive rate was similar with both tests at Newcastle and North London RTCs. The repeatable positive rate for Abbott tests at Glasgow was higher than that for Ortho. Further testing of reactive samples was undertaken by Dr Tedder and Dr Mortimer.[276] Overall there seemed little to choose between the two screening kits. Of a total of 10,633 donations, there were a total of 68 repeatable positive results using the two tests, of which six were shown to be positive using PCR.[277] The two ELISA tests did not identify the same donors as being positive. The Ortho RIBA test was preferable to Abbott’s neutralisation test as a supplementary test.

9.239 The minutes of the meeting note that Professor Zuckerman stated that studies in France and Germany, where the anti-HCV screening tests had been used extensively in combination with surrogate tests, only identified 30% of post-transfusion hepatitis.[278]

9.240 The Committee agreed that it was important to start screening as soon as practicable as a measure which would further enhance the safety of the blood supply. It was noted that better tests were about to be issued. Ortho had brought out a second generation test and had offered 2500 free test kits for use on frozen samples at the North London RTC. Abbott had brought out a third generation test and Dr R Mitchell would ask for 1000 tests to be supplied to be used in the same way.

9.241 The Chairman summed up the discussion by saying that there was agreement that the UK should introduce Hepatitis C testing as soon as practicable. RTC’s would decide individually whether to use the Ortho or Abbott test. The blood from any repeat positives would be set aside. Test samples would then be sent to the reference centre where both the Abbott and Ortho tests, followed by the RIBA test, would be performed. At this stage, some cases would no longer need to be deferred and the reference centre should inform the transfusion centre of these cases. The repeat positives would then be subjected to PCR. The transfusion centre would be informed which samples were confirmed positive and which were negative. The reference centres would determine a common protocol for supplementary testing and would revise this in light of developments in the testing field. A submission would go to Ministers regarding this significant policy decision and the NHS Management Executive would consider the funding aspect.

9.242 It was also noted at the meeting that some centres had asked for a six month period in which to set up testing. Dr Gunson thought that to be excessive, but would need to consult with other transfusion directors. The Chairman of the ACVSB stressed the importance of a common date of introduction throughout the UK. The ACTTD would be meeting to discuss the problems of counselling positive donors and the question of look-back in relation to donor screening.

9.243 Dr AD McIntyre (SHHD) produced a note of the eighth meeting of the ACVSB.[279] The note recorded that it was decided that a start should be made as soon as practicable to introduce routine testing of all blood donations for Hepatitis C. Some wanted to start forthwith but the Chairman suggested that 1 April 1991 might be more realistic.

9.244 By letter dated 22 November 1990, Professor Cash wrote to Dr J S Metters (Deputy Chief Medical Officer, England and Wales and Chairman of the ACVSB) stating that in anticipation of the commencement of HCV blood donation testing throughout the UK in the foreseeable future, the SNBTS Directors requested that a policy of look-back be considered by the ACVSB.[280] A copy of the letter was also sent to the SNBTS representatives on the ACVSB, to Dr McIntyre (SHHD) and to Dr Gunson.

9.245 On 6 December 1990 an Abbott anti-HCV test was launched.[281]

9.246 On 15 December 1990 Simmonds et al (Edinburgh) reported on the use of a PCR test to detect specific Hepatitis C RNA sequences in plasma from haemophilia patients and intra-venous drug users.[282] Fifteen of 21 haemophilia patients tested positive (only 12 had been anti-HCV antibody positive). HCV RNA was detected in all batches of commercially available Factor VIII tested and in low concentrations in some pools of plasma donations from volunteers. Factor VIII manufactured from volunteer donations was uniformly negative by PCR. There was considerable sequence diversity of Hepatitis C in different patient groups: one sequence was associated with intravenous drug users and the other with haemophilia patients infected with Scottish Factor VIII preparations. Both were distinct from sequences found in commercially available Factor VIII. Three of five Edinburgh haemophilia patients were infected with a Hepatitis C variant which was also found in one of the Scottish blood donations. The paper noted that these three patients were aged 20–30 years and were probably first infected in the 1960’s with locally collected fresh frozen plasma or Cryoprecipitate.

9.247 On 21 December 1990 J Canavan (DOH) produced a note seeking Ministers’ approval to commence screening in the NBTS as a public health measure in line with the unanimous advice of the ACVSB that screening should be introduced as soon as practicable.[283] The note stated that in view of the operational matters that needed to be discussed and finalised, it was unlikely that routine screening could be introduced before 1 April 1991.

Summary

9.248 By the end of 1990:

• Second generation anti-HCV ELISA and RIBA tests were available, or would shortly become available, for evaluation.

• The ACVSB, at their eighth meeting on 21 November 1990, had decided that routine screening should be introduced as soon as practicable.

• Ministers’ approval to commence screening in the NBTS as a public health measure was sought.

• A tentative target date of 1 April 1991 had been suggested for the introduction of HCV screening.

1991

9.249 On 8 January 1991 the ACTTD held its sixth meeting.[284] There was discussion of the anti-HCV testing action chart prepared by Dr Mitchell and the procedure to follow for positive tests. A paper prepared by Dr Gillon (SNBTS, Edinburgh) on counselling of donors was also discussed. It was agreed that there might be an ethical obligation to inform patients who might have received transfusions in the past from anti-HCV positive donations. That would involve considerable additional work including testing of library samples and would require to be funded. Extension of that to epidemiological investigations should be the subject of separate research studies.

9.250 On 21 January 1991 Ministerial approval was given for the introduction of anti-HCV screening.[285]

9.251 On 22 January 1991 Dr Gunson sent a memorandum to the regional transfusion directors of England and Wales (a copy was sent to Professor Cash), advising that the DOH had agreed that routine testing for anti-HCV could be put into operation.[286] Testing was to start simultaneously in RTCs in England and Wales and was to be co-ordinated with the commencement of testing in Scotland. Dr Gunson asked to be advised of the earliest date directors considered they could commence testing.

9.252 In February 1991 the SNBTS Working Party on Donor Counselling for HCV
(Drs J Gillon, R Crawford, G Galea and J Davidson) produced the fourth draft of their report.[287] The report set out that there were thought to be at least two NANB Hepatitis viruses but that Hepatitis C was almost certainly the most common form, thought to be responsible for around 70% of post-transfusion hepatitis. Most persons with NANB Hepatitis would be asymptomatic, but some would go on to develop long-term liver damage. Around 10–15% of persons with post-transfusion NANB Hepatitis might eventually develop significant liver disease. The prevalence of carriage of NANB Hepatitis in the general donor population was not known. The prevalence of confirmed anti-HCV in UK donors was likely to be around 1 in 1,000 (0.1%). Preliminary studies on Scottish blood donors showed that approximately 0.5% were repeatedly positive. The majority of these repeatedly positive donors were likely to have a negative confirmatory test. While, at present, a totally acceptable confirmatory test was lacking, it was expected that a suitable test would be available by the time testing was introduced. It was important for individual donors to receive further medical assessment, since they might well be at risk of chronic liver disease. Appropriate referral for investigation of those with abnormalities of liver function was essential, particularly since there was some hope that treatment with Interferon might be effective. Suggested procedures for informing and managing anti-HCV positive donors were set out. A ‘look-back’ exercise would be undertaken to identify patients who had previously received donations from donors found to be HCV positive after the introduction of screening.[288]

9.253 On 9 February 1991 Van der Poel et al (Red Cross, Amsterdam) reported on their evaluation of the second generation (4-antigen) Ortho RIBA test.[289] The authors stated that only 17–25% of anti-HCV ELISA positive blood products transmitted Hepatitis C.[290] Most of the anti-HCV ELISA positive samples might, therefore, represent non-specific ELISA reactivity. Although the first generation (2-antigen) RIBA had improved specificity, that assay did not give independent confirmation and was merely a supplementary test. While HCV infection could be confirmed by amplification of HCV sequences with PCR testing, such techniques were not routinely available. After evaluating the second generation Ortho RIBA test, the authors concluded that it was a candidate confirmation test to discriminate between infective and non-infective anti-HCV ELISA positive blood donors.[291]

9.254 On 15 February 1991 Dr Gunson wrote to regional transfusion directors in England and Wales advising that routine screening of blood donations for HCV antibody would commence on 1 July 1991.[292]

9.255 On 25 February 1991 the ninth meeting of the ACVSB took place.[293] Papers were presented on the results and conclusions of the three centre pilot study into the first generation Ortho and Abbott anti-HCV ELISA screening tests and proposed further studies.[294] The Committee discussed the likely availability of second generation anti-HCV ELISA tests and operational factors which might influence the decision by RTCs as to which screening test to choose. Licensing of the tests by the US FDA had not yet been finalised. Members agreed it was important for proper evaluation of the Ortho and Abbott first and second generation tests to be carried out before RTCs decided which test to adopt. The Committee agreed that all 10,000 archived samples should be tested using the second generation tests to ensure that any new test was at least as good as the tests already evaluated. The Ortho and Abbott first and second generation tests should, in principle, be available, among others, from 1 July for RTCs to choose. The Committee[295] discussed the problems of look-back and recommended that it should not be undertaken as a service, leaving the option for those carrying out research. However, all cases of post-transfusion hepatitis should continue to be investigated.

9.256 By letter dated 12 March 1991, Professor Cash advised Dr Gillon that the Medical and Scientific Committee of the SNBTS, at their meeting on 19 February 1991, had considered the final draft report of Dr Gillon’s group on recommendations for counselling HCV positive donors and had found it to be excellent.[296] Professor Cash stated, however, that ‘in the light of national events with regard to the implementation of look-back’, the question ‘What about my previous donations?’ and the answer (that there would be a ‘look-back’) should be omitted from the final document.[297]

9.257 On 21 March 1991 the marketing manager of Ortho advised that the second generation ELISA test was to be introduced, replacing the first generation test.[298] A product leaflet dated March 1991 set out how the test should be undertaken.[299]

9.258 On 25 March 1991 the ACTTD held its seventh meeting.[300] The proposed starting date of 1 July for the introduction of screening presented difficulties since it was considered essential that the second generation tests from both Ortho and Abbott should be evaluated prior to the commencement of routine testing. Only pre-production batches of the second generation Ortho test had been made available and it was known that there were procedural differences between the pre-production and production batches. The production batches should be available within 10 days to two weeks. The situation with Abbott was uncertain since they had not yet given an official date for launching their second generation test. The preliminary results obtained by Dr Barbara on the test kits from three manufacturers were reviewed and it was agreed that further testing at all three RTCs was essential. Dr Gunson was asked to contact Abbott and, from the information he received, recommend a starting date for the commencement of tests. It was agreed that testing of blood and plasma donations would commence on a specified date. There would not be retrospective tests carried out on donations collected prior to that date. There had been discussion of confirmatory testing at a meeting of virologists on 12 February at University College and Middlesex School of Medicine.[301] There was discussion of an information leaflet to be given to donors and revised guidelines by Dr Gillon on the counselling of donors.[302]

9.259 On 27 March 1991 Professor Cash wrote to Mr D McIntosh, (General Manager, SNBTS).[303] He advised that the NBTS in England and Wales was struggling, on a number of accounts, to meet the 1 July deadline for the introduction of HCV testing, as had previously been discussed and, as Professor Cash thought, agreed. Professor Cash believed the fundamental problem to be one of financial resources. At the recent meeting of the ACTTD it was agreed that Dr Gunson would advise DOH that the 1 July start date should be delayed until such time as an evaluation of the new HCV screening tests had been completed. If that was accepted it could push the start date to September. Both Professor Cash and Dr Mitchell had supported that proposal.

9.260 On 30 March 1991, Contreras et al (North London BTC) reported the results of a study on the incidence of post-transfusion NANB Hepatitis at their centre.[304] The study was carried out between 1987 and 1990. Three hundred and eighty seven patients undergoing operations, who each received blood or blood components from an average of three donors, were tested for anti-HCV. Samples were taken every two weeks for three months and then each month for a further three months. Two hundred and twenty nine patients also provided a sample at 12 months. Repeatedly positive samples were submitted for supplementary HCV assays (ie RIBA and PCR testing). One of the 387 patients developed HCV that was confirmed by RIBA and PCR testing. Anti-HCV reactivity, likely to be false positives (ie negative by both confirmatory tests and no adverse effects in recipients), was seen in six of 1283 donors. The authors concluded that the study, despite it being carried out in the part of the UK with the highest frequency of infectious markers in blood donations, showed a very low incidence of post-transfusion NANB Hepatitis. Given the cost of introducing screening tests and the number of false positives generated in a low prevalence population, the study highlighted the need for more specific screening tests and for less expensive confirmatory assays of greater definition.

9.261 On 3 April 1991 Dr Hilary Pickles, (Principal Medical Officer, DOH), wrote to
Dr Lane (BPL) advising that plasma collected prior to the introduction of HCV testing by the NBTS could be used for fractionation.[305]

9.262 On 3 April 1991 Dr Gunson wrote to regional transfusion directors in England and Wales advising that it would not be possible to introduce anti-HCV screening by 1 July because it had not yet been possible to commence the evaluation of the second generation Ortho and Abbott tests at Newcastle, North London and Glasgow RTCs.[306] One of the tests would not be available until later that month. RTCs should aim to commence routine screening for anti-HCV by 1 September 1991.

9.263 On 8 April 1991 Abbott’s product manager announced the launch of Abbott’s second generation anti-HCV ELISA test.[307]

9.264 On 19 April 1991 the US Public Health Service Inter-Agency[308] published guidelines for the screening of donors of blood and plasma etc for evidence of Hepatitis B and Hepatitis C.[309] The FDA currently recommended testing donations of whole blood and components for antibody to Hepatitis C virus. The sensitivity and specificity of the currently available tests for anti-HCV were not well defined.

9.265 The guidelines set out procedures for carrying out screening. If a donation tested repeatedly positive (after initial ELISA testing and re-testing by ELISA in duplicate) the donation should not be used for transfusion and the donor should be indefinitely deferred from donation.

9.266 When further information about HCV serology became available, and if highly sensitive confirmatory tests were developed and licensed, a procedure for re-entering donors repeatedly reactive for anti-HCV might be developed. It was recommended that donors with repeatedly reactive results should be notified of their results and their indefinite deferral from donation.

9.267 The guidelines stated that when the anti-HCV ELISA test was used to screen populations with a low prevalence of HCV infection the proportion of positive results that were falsely positive would be high. Licensed confirmatory tests were currently not available. Supplemental tests for specificity were available as a testing service for research purposes performed by the manufacturers of licensed screening tests, or for distribution on an investigational basis. When such tests were used, research studies indicated that their results might be of value in the interpretation of a repeatedly reactive screening test.

9.268 The guidelines stated that targeted look-back (tracing recipients of blood products from donors who tested positive for anti-HCV) or general screening programs for populations at an increased risk of HCV infection were not recommended because (a) currently available screening tests could not distinguish between ongoing infection and recovery and thus the meaning of a reactive test result in any one individual was not clear, (b) available knowledge about routes of transmission for HCV other than parenteral was limited and (c) only selected persons were eligible for therapy for chronic liver disease and the potential long-term benefits of such therapy was unknown. In addition, screening programs aimed at prior transfusion recipients were not recommended as they were likely to be ineffective for several reasons: (1) most HCV-infected former donors self-deferred or were excluded as a consequence of earlier screening policies, (2) few hospitals had transfusion records prior to the early 1980s, thus most recipients at risk would not be traceable and (3) based on the look-back programs for HIV, response by prior recipients to notification was poor. Recommendations were set out for the medical evaluation and counselling of anti-HCV positive individuals.

9.269 In May 1991 Mr MC Malone-Lee (Director of Operations and Planning, NHS Management Executive) wrote to regional general managers in England and Wales advising that while no date for the introduction of Hepatitis C antibody screening had been fixed, it was likely to be 1 September 1991.[310]

9.270 On 21 May 1991 the tenth meeting of the ACVSB took place.[311] Professor Zuckerman confirmed that the percentage of post-transfusion hepatitis cases identified by HCV screening in combination with surrogate tests in France and Germany was approximately 70%.[312] Dr Gunson reported on the progress of trials of second generation Ortho and Abbott anti-HCV tests and first generation UBI and Organon tests. Organon, which had failed to react to a known positive, was to be withdrawn from the trial by its manufacturers due to patent litigation. Trials on the other three kits were continuing.

9.271 The Committee noted that they were not due to meet again before the introduction of routine HCV screening. It was decided that three tests could be used for initial screening, namely, the second generation Ortho and Abbott tests and the UBI test. Individual RTCs would decide which was the most appropriate and would be guided by the results of the trials. The results would be available by the end of June/early July.[313]

9.272 It was noted that Newcastle BTC had begun routine testing of donated blood for HCV antibody in April (using second generation Abbott test kits). While this unilateral action was regretted, it could be used as an extension of the trial. Dr Gunson presented a paper on an extension of the trial, a main objective of which was to evaluate RIBA and PCR confirmatory tests on positive donations.[314]

9.273 Dr Mortimer reported on the meeting of virologists on 12 February 1991.[315] There was no firm basis for conclusions on the value of PCR in confirmatory testing. More information was needed on the correlation between RIBA and PCR and further evaluation should ideally extend into the early days of routine screening.

9.274 There was consideration of a paper from the ACTTD on testing.[316] It had been suggested that ALT tests be carried out on all repeatable anti-HCV donations, but the Committee agreed that ALT tests were not specific for HCV and there was poor correlation between HCV antibody and ALT. After discussion, it was agreed that ALT testing should not be carried out in the extended trial. It was noted that nothing would be said to donors who tested HCV positive at any stage until the ACVSB met again to consider the matter further.

9.275 On 10 June 1991 the ACTTD held its eighth meeting.[317] There was discussion on the procedures to follow for donations found to be ELISA anti-HCV positive. All donors who were positive using the second generation RIBA test would have to be regarded as infectious and referred for consultation. Dr Gillon’s paper on counselling was appended to the minutes and was agreed, with amendments.[318] The amended paper was to be issued to RTCs to be used as guidance for the preparation of their local standard operating procedures. It was agreed that plasma sent for fractionation should be anti-HCV negative.

9.276 On 11/12 June 1991 a meeting of the SNBTS Management Board agreed that routine testing for anti-HCV would begin on 1 September 1991.[319]

9.277 On 10 July 1991 Dr A D McIntyre (SHHD) sent a memorandum to Mr Panton commenting on the document prepared by Dr J Gillon’s group on recommendations for counselling HCV positive donors.[320] Dr McIntyre was concerned about a recommendation that, where a donation was found to be positive

In the case of regular donors, the fate of previous donations is determined and ‘look back’ initiated in accordance with SNBTS policy.[321]

9.278 The memorandum set out that in the present state of knowledge, donors who were only anti-HCV seropositive, without evidence of antigen, might not be infectious. Dr McIntyre asked what purpose was to be served by going back. It might cause the recipient of the blood (the 50% who were still alive after two years) unnecessary worry and possibly distress. In certain circumstances it could also give rise to litigation. Dr McIntyre advised that Mr Panton might wish to take legal advice before the policy was put into effect. In addition, Dr McIntyre considered that the guidance was a little woolly on the risk of transmission by sexual intercourse. Reference was made to a paper by Dr Tedder stating that spread in that way was a definite possibility.[322]

9.279 On 26 July 1991 Mr Derek Bearhop wrote a memorandum to Mr Tucker advising that Mr Forsyth, Minister of State, was content to endorse the recommendation that routine testing of blood donations for Hepatitis C antibody should be introduced in Scotland from 1 September 1991.[323]

9.280 In August 1991 the ACTTD produced a compendium of recommendations in respect of anti-HCV testing of blood donations.[324] The recommendations were not to be interpreted as Government policy but were intended as guidance for use by staff in RTCs. The date of 1 September 1991 had been agreed for the commencement of tests. The recommendations stated that ‘The question of look-back has still to be defined for England and Wales. In Scotland it is initiated in accordance with SNBTS policy’.[325]

9.281 On 8 August 1991 R Panton (SHHD) wrote to J T Donald (General Manager, Common Services Agency), to advise formally that the Minister of State had agreed to the routine testing of blood donations for antibody to the Hepatitis C virus from 1 September 1991 and requested that arrangements were made to begin testing from that date.[326]

9.282 On 13 August 1991 the ACTTD held its ninth meeting.[327] There was discussion of the results of the various anti-HCV trials. It was noted that the question of look-back had been discussed by the Committee in the past, but the minutes did not indicate that any decision had been made. It had not been considered either, as far as could be determined, by the ACVSB. It was agreed that look-back might have legal implications and that the matter should be considered. It was noted that look-back, at least to a point in time when it could be stated that a satisfactory test was available, might be advisable. In that context, it was agreed that an ad-hoc group[328] should be formed to consider the implications of an article by Simon Denison in the Independent on 7 August 1991, ‘Patients may sue over hepatitis C in blood’.[329]

9.283 On 14–15 August 1991 the SNBTS Medical and Scientific Committee met.[330] Members were asked to note that 1 September 1991 was the official start date for HCV testing. The Committee agreed that all RTC products would be HCV tested by 5 September 1991. The Committee noted that plasma for fractionation which had been bled from donors before 1 September 1991 and not tested for HCV antibody would still be accepted by PFC after that date. However, plasma collected from donors after 1 September that was destined for PFC required to be HCV negative.

9.284 On 1 September 1991 the UK introduced screening for Hepatitis C antibodies of all blood donations using second generation ELISA and RIBA assays.[331]

9.285 Crawford et al (SNBTS, Glasgow) later reported that in the first six months of testing in Scotland (ie between September 1991–February 1992) 180,658 donors were tested, 609 samples were repeatedly reactive on initial ELISA screening and 159 donors were found to be infected with HCV on confirmatory testing by RIBA and PCR, giving a prevalence of HCV infection among Scottish blood donors of 0.088%.[332] Among positive donors, intravenous drug use was the most common risk activity (39%) followed by previous blood transfusion (15.2%), other parenteral exposure (ie tattoos, ear-piercing and needlestick injuries) (11.2%) and heterosexual contact with a parenterally infected partner (8.6%). A history of jaundice was infrequent (8.6%). The risk factor in 29.1% of donors was unexplained ie they gave no history of exposure. ALT levels above the upper limit of normal were found in 59% of donors infected with HCV. Many of those donors shown to be infected had been donating regularly and the prevalence of HCV in the donor population could be expected to fall as they were excluded from further donation. Nevertheless, extrapolating these figures to the whole of the UK would suggest that around 3000 infected donors would be identified in the first year of testing.

9.286 On 7 September 1991 an article by E Fagan (Royal Free Hospital, London) was published on testing for the Hepatitis C virus.[333] The author noted that while the routine testing of blood donors for antibodies to components of the Hepatitis C virus had recently begun, doctors who wished to make a firm diagnosis of Hepatitis C virus infection still lacked a single laboratory test that was entirely satisfactory. The anti-HCV ELISA test lacked specificity for infection with Hepatitis C virus and there was no confirmatory test that was easy to use and widely available. The author considered that the reluctance to begin widespread testing of blood donors in the UK before the introduction of the second generation antibody tests seemed justified in view of the poor correlation between anti-HCV positivity based on first generation ELISA tests and results using second generation ELISA tests and PCR. Screening of blood donors, even with the newer antibody tests, would create ethical problems, such as counselling apparently seropositive people. There would also be practical problems of management, even though confirmatory testing using PCR would be available in reference centres.

9.287 On 13 September 1991 the ACTTD held an ad-hoc meeting to consider the implications of anti-HCV testing of blood donations.[334] Dr Gunson, Professor Cash, Dr R Mitchell and Professor Tedder were present. It was agreed that in order to answer questions which might arise in the future with respect to the timing of the introduction of anti-HCV screening, the facts and decisions taken should be set out in chronological order in the minutes of the meeting. A detailed narrative of events between 1 September 1989, when the Ortho tests became available for research purposes, and the introduction of testing on 1 September 1991 was accordingly set out in the minutes.

9.288 On 19 October 1991 a letter by Follett et al (Regional Virus Laboratory, Ruchill Hospital, Glasgow) was published on confirmatory testing for Hepatitis C.[335] While the second generation (4-antigen) Ortho RIBA provided a method for identifying genuine anti-HCV reactivity, a problem arose in interpreting indeterminate results. After carrying out a study of 42,498 blood donations in the West of Scotland, the authors concluded that it was important to subject indeterminate RIBA samples routinely to PCR testing, since that might allow a definitive identification of chronic Hepatitis C infection, permitting counselling of the donor with full assessment of his or her liver disease and treatment if necessary.

9.289 On 29 October 1991 the 11th meeting of the ACVSB took place.[336] Reference was made to the Compendium of Recommendations on HCV testing made by the ACTTD. The results of the first HCV test trials were reported fully in the compendium. Dr Gunson advised that no decision had been taken as to a look-back study. Dr Mitchell reported that in Scotland senior medical staff were interviewing donors who had tested positive and were informing their GPs. In response to press articles, Dr Gunson advised that the ACTTD was drawing up a paper showing the chronological steps that had been taken from the appearance of the first HCV testing kits in September 1989 to the introduction of routine screening in the UK in September 1991.[337]

9.290 On 7 November 1991 Aach et al (New York and other USA centres) reported on Hepatitis C infection in post-transfusion hepatitis, using first and second generation assays.[338] The authors concluded that nearly all cases of NANB Hepatitis were caused by the Hepatitis C virus. The first generation assays detected one or more units of blood from anti-HCV positive donors administered to 81% of the patients who seroconverted and for whom all donors units were tested. The use of the second generation assays increased that rate to 93%. Among the cases of HCV identified in the study, 73% (43 of 59) were associated with the presence of surrogate markers in the donors, a rate similar to that predicted before HCV was identified, leading the authors to conclude that the use of surrogate markers in the USA since 1986 appeared to be well justified.[339]

Summary

9.291 To summarise matters in 1991:

• Ministers approved the introduction of routine screening of blood donations for Hepatitis C in January 1991.

• Such testing was introduced throughout the UK in September 1991, using second generation ELISA and RIBA tests.

• Following the introduction of testing, under 0.1% of blood donors in the UK were found to be positive for antigen to Hepatitis C and were, therefore, infectious.

• It was decided not to undertake a look-back exercise when screening was introduced to identify patients who had previously received a donation from donors who tested positive for Hepatitis C after the introduction of screening.[340] However, all cases of post-transfusion hepatitis continued to be investigated.

1992

9.292 On 21 February 1992 the 12th meeting of the ACVSB took place.[341] After discussion of the question of ALT testing of blood and plasma, members agreed that taking into account the potential loss of healthy donors, there was insufficient reason to justify a recommendation to Ministers that ALT screening of donated blood should be introduced in the UK.[342]

1993

9.293 In 1993 the ACVSB was replaced by a new expert committee, the Advisory Committee on the Microbiological Safety of Blood and Tissues for Transplantation (ACMSBT).[343] The new committee was to advise on a much wider range of microbiological safety issues that affected blood, tissues and organs for transplantation. Membership was drawn from the existing ACVSB and, to reflect the widened remit of the ACMSBT, two microbiologists were substituted for two virologists, and two transplant surgeons were added to the membership. Dr R Mitchell (SNBTS, GLasgow) and Dr R J Perry (Director, PFC) remained members of the new committee. There continued to be an SHHD observer.

1994

9.294 As noted above, in 1994 Crawford et al (SNBTS, Edinburgh) reported on the prevalence of HCV infection in blood donors in Scotland in the first six months of screening from September 1991.[344] The paper noted that no systematic attempt was being made to trace recipients of previous donations from infected donors, and the numbers of infected recipients still alive and potentially in need of assessment or treatment could not be estimated. Further work was required to define the scale of that problem and to define strategies for identifying such patients.

Hepatitis C “Look-Back”

9.295 In 1994 Dr J Gillon’s group (SNBTS, Edinburgh) reported on their study into the tracing and testing of recipients of blood from donors found to be HCV positive following the introduction of screening in September 1991.[345] The main aims of the study were to determine the numbers of such recipients who were still alive and traceable and to determine their infection status. The feasibility and workload of such a look-back procedure were also assessed. In the first six months of routine testing 42,697 donors were tested. Of 20 confirmed to be HCV positive, 15 were regular donors. Eighty-three components were prepared from 63 HCV positive donations from these donors. Of the 83 components, 35 had not been made available for transfusion (eg because they were out of date etc). The recipients of nine of the 83 components were not identified. Of the remaining 39 components, 27 recipients were dead, there was no further information for three recipients and nine recipients were still alive. Of the nine recipients still alive and who were traceable, all were HCV positive. The authors concluded:

Our experience confirms that the identification of [infected recipients] is a daunting task, but the availability of potentially efficacious treatment for chronic hepatitis C, in the form of alpha-interferon, compels us to suggest that we have a clear ethical responsibility to these patients to identify them and offer counselling, testing and, if necessary, treatment. Many of these patients will be old and most will have only mild liver disease, but it is our view that this problem should not be ignored on logistical grounds when, in each case, there is an overwhelming responsibility to the individual patient.

9.296 On 23 September 1994 Mr D B McIntosh (General Manager, SNBTS) prepared notes on a Hepatitis C look-back exercise.[346] The overall position on the introduction of a formal Hepatitis C look-back programme remained much as it was in Mr McIntosh’s report in July 1994.[347] Pilot studies continued to assess the impact for SNBTS. There was liaison with colleagues in England. The DOH were understood to be involved and it was still hoped to reach an agreed position on full UK implementation before the end of the year. The SNBTS would anticipate being able to complete their programme within weeks rather than months following the go ahead. Based on the pilot studies already undertaken in Edinburgh the number of living recipients of HCV compromised infusions would probably be approximately equal to the number of donors involved. Dr Gillon believed that the worst case scenario for Scotland was that up to 3000 patients could be found to have been infected by blood transfusion. However, a more realistic estimate was 150. The SNBTS costs of look-back were not expected to exceed a total of £50,000, for which funds had been set aside from non-recurring sources.

9.297 In November 1994 a licence was granted for Alpha Interferon to be used in the treatment of chronic Hepatitis C.[348] This was regarded as the first ‘effective’ treatment to eliminate Hepatitis C, although it was only successful in a relatively small proportion of patients (20-30%).

9.298 On 23 November 1994, Mr McIntosh noted that following encouraging results of Dr Gillon’s study on Hepatitis C look-back, a larger pilot scheme was now under way in the Glasgow and West of Scotland RTC.[349]

9.299 On 15 December 1994 the ACMSBT met. The Committee decided to recommend to Ministers that a UK wide look-back exercise be introduced to identify those blood transfusion recipients infected with Hepatitis C prior to the introduction of Hepatitis C screening in September 1991. A draft Interim Report on the look-back exercise prepared for Ministers around January 1996[350] stated that the reason for no action in that regard before December 1994 was as follows: part of the reason for the lack of any follow up action was a concern that it would be impossible to identify all recipients of infected blood and even if it were possible there was a lack of accepted treatment which would be beneficial. It was accepted that if no effective treatment was available, informing those patients who were unaware of their situation could not be justified, since that would cause further distress and anxiety without any benefit. Two factors had led to the ACMSBT’s recommendation to introduce look-back, namely, the feasibility of a look-back had been demonstrated by a study in Scotland[351] and Interferon, a drug which was useful for some patients infected with Hepatitis C, became licensed in the UK.[352]

1995

9.300 On 11 January 1995 UK Ministers announced the look-back exercise and explained that its aim was to trace, counsel and treat those identified as being at risk.[353] In a news release of the same date, the SNBTS welcomed the announcement. Professor Cash stated that

Over 5million patients have undergone surgery in Scotland in the last 10 years. Only a small proportion of these will have had a transfusion and it is estimated that fewer than 300 will have been exposed to the Hepatitis C virus.[354]

9.301 An ad-hoc Working Party was set up under the chairmanship of Dr Metters of the DOH, drawing on membership of the Advisory Group on Hepatitis, to draw up guidance on procedures for undertaking look-back, protocols for counselling and options for treatment, together with any other action which should be taken to satisfy the NHS’s duty of care, including whether additional research should be undertaken.[355] The Working Party met on 20 January, 24 February and 14 March.[356] An action plan was formed.[357] It was agreed that the look-back exercise should be concentrated in the first instance upon donors who had given blood prior to September 1991 and been found to be Hepatitis C antibody positive after the introduction of testing in September 1991. The services would not try to trace donors who had not come back to a transfusion centre since then, the work involved in doing so would be disproportionate to the benefit. The Working Party considered the testing of serum samples stored from before September 1991 and agreed that Ministers should be advised that the testing of such samples would also be disproportionate, although a legal view on this should be obtained and the subject would be considered again following the results of the current look-back exercise. However, where an individual who had been given blood requested a test this should be made available, particularly where there had been multiple transfusions. The Working Party also advised that the look-back should not be extended to other blood products.

9.302 On 3 April 1995 Dr Kenneth Calman, Chief Medical Officer, England and Wales, sent a letter to doctors enclosing guidance on the look-back procedures and separate guidance on counselling and treatment.[358]

9.303 The guidance noted that transfusion of blood or fresh components (ie platelets, fresh frozen plasma or cryoprecipitate) prior to the introduction of routine screening on 1 September 1991, or of clotting factor concentrate prior to the use of virus inactivation procedures in 1984, carried a risk of infection.[359] Other blood products which were not virally inactivated had transmitted Hepatitis C more recently. Patients were described as anti-HCV positive when a screening test was positive and the result had been confirmed by RIBA.

9.304 Following infection with Hepatitis C virus the natural history varied widely. Some patients recovered spontaneously and completely. Some went on to develop liver damage, often without symptoms. Cirrhosis could develop in 10%–20% of those infected but that might take 20–30 years to develop and might be unrecognised clinically. A much smaller number might then go on to develop hepatocellular carcinoma. Sexual transmission occurred, but the frequency was controversial, most studies indicated infection rates of less that 5% in sexual partners. Vertical transmission (mother to baby) appeared to be of a similar order. Use of barrier contraception should be discussed with each couple. Regular sexual partners should be counselled and offered testing. Anti-HCV positive individuals should not donate blood, tissue or semen, should not carry an organ donor card and, notwithstanding the estimated low risk of sexual transmission, the same advice should be given to their regular sexual partners regardless of their HCV status.

9.305 The guidance stated that all Hepatitis C positive patients should be referred to a specialist with an interest in the condition for further assessment. That would usually involve a period of observation and, in most cases, a liver biopsy. Patients considered to be at risk of progressive liver disease might be offered treatment with Interferon. Effective viral therapy given early in the disease process would reduce the chance of the more serious long-term sequelae of chronic Hepatitis C such as cirrhosis and the development of hepatocellular carcinoma. Although 40–80% of patients responded initially to Interferon with normalisation of ALT values, only 50% of the responders (ie 20–40% of those treated) had a sustained response after cessation of treatment. Response rates depended upon the particular genotype of Hepatitis C; patients infected with type 1 (and particularly type 1b) responded less well than patients with types 2 or 3. In the UK around 60% of infections were due to Genotype 1. Patients with minimal disease would be kept under review. It was important to diagnose cirrhosis in patients with chronic Hepatitis C as these patients required regular monitoring of their liver function and regular imaging to detect hepatocellular carcinomas. Transplantation might be a life saving option for patients with end stage disease, although HCV was likely to recur in the patient despite a successful operation.

1996

9.306 A draft Interim Report on the look-back exercise was prepared for Ministers around January 1996.[360] There had been over 12,000 calls to a helpline set up to answer patients’ queries. It was estimated that in the UK there might be about 3000 haemophilia patients alive who were Hepatitis C positive and were not also HIV positive. It was estimated that it was likely that 3000 blood transfusion recipients were alive who would be identified by the look-back exercise. A table was produced showing the current status of the
look-back exercise in the UK.[361] In Scotland, as at 15 December 1995, 340 donors had been identified who were positive for Hepatitis C and who had given blood prior to 1991. 1504 donations from those donors had been identified. It was estimated that there might have been 1574 transfusions. 1516 donations had been notified to hospitals. 378 recipients had been identified by hospitals, 40 recipients had been followed up, of whom 35 had been counselled and tested and 30 had tested positive for HCV. 225 recipients had died. The Interim Report noted that the look-back exercise had been slower in achieving its objectives than had been predicted. The blood transfusion services were being encouraged to work better and faster on the project.

9.307 By letter dated 11 March 1996, K J Guinness (Head of Operational Policy Unit, DOH) advised J Adey (Chief Executive, National Blood Authority), that Ministers had considered the views of the ACMSBT.[362] Ministers had agreed that the current look-back strategy should continue but that where there were particular problems, the blood transfusion services should communicate further with the hospitals concerned and offer assistance in overcoming the bottlenecks in those hospitals which had major blockages.

9.308 Around April 1996 a further draft of the Interim Report on the look-back exercise was produced.[363] There had been further meetings of the ad-hoc look-back Working Party on 25 May and 13 October 1995. Members of the ACMSBT considered why the exercise was taking longer than initially envisaged. They identified two particular bottlenecks, one was tracing medical records for recipients identified in hospital blood banks and, secondly, a shortage of counsellors available to see patients before and after testing. The ACMSBT accepted that if both these areas of difficulty were overcome, it was likely that the hepatology services for specialist assessment and, where appropriate, commencement of treatment, would probably not be able to cope. Various alternative ways forward were considered by the ACMSBT, including abandoning the look-back entirely and offering Hepatitis C tests to anyone who had been transfused. The Committee unanimously concluded that it was important to continue with the present strategy. It was felt that communications between the blood transfusion services and hospitals where there were particular problems was the best way forward, supplemented by the offer of assistance to overcome bottlenecks in tracing hospital records and a shortage of suitably trained counsellors. In respect of testing/counselling, it was noted that there were difficulties with some GPs, who did not wish to be involved in additional work, and there were some criticisms of the blood transfusion services. Further follow up on the look-back exercise would be carried out by the ACMSBT. It was noted that a number of letters had been received asking for ‘ring fencing’ for treatment of Hepatitis C. A response had been issued that the resources of the NHS were finite and that it was for doctors and managers to make local decisions as to what forms of treatment and what drugs should be made available based on the needs of the local population. A further version of the table dated 15 December 1995 was produced.[364]

1998

9.309 On 28 April 1998 Professor Ian M Franklin (National Medical and Scientific Director, SNBTS) wrote to Dr A Keel (Scottish Office Health Department (SOHD)).[365] Over the past months, progress with the look-back exercise had been virtually static. A summary sheet prepared by Dr Gillon was enclosed showing the numbers identified by the look-back exercise.[366] Professor Franklin stated that there were a number of patients that had not been traced and it would not be possible to trace these patients without additional resources from the SOHD. There was also an issue of RIBA indeterminates. The SNBTS confirmatory test algorithm for HCV had always included PCR. The National Blood Authority protocol did not have PCR and so they proposed that the look-back be extended to RIBA indeterminates. The SNBTS had followed up over half of their RIBA indeterminate cases (20 of 37). All had remained PCR negative and all recipients of their donations had been traced and tested and were PCR negative. The remainder that required following up were in the West of Scotland and, once again, the SNBTS would not be able to trace these recipients without additional resources. It was, therefore, the view of the SNBTS Medical and Scientific Committee that the current HCV look-back should be considered to be closed unless the SOHD felt that it should resource one final effort to conclude every possible case. The SNBTS would continue to investigate any new seroconversions in donors or recipients as they came to light.

9.310 On 8 May 1998 Dr A Keel (SOHD) sent a memorandum to Mr John Aldridge (Head of Health Care Policy Division, SOHD) enclosing a copy of Professor Franklin’s letter.[367] Dr Keel was of the view that from the available information the SNBTS had probably done all that could reasonably be expected of them. If Mr Aldridge agreed, Dr Keel would write to Dr Jeremy Metters of the DOH asking him if the matter required to be put to the ACMSBT before a final decision was made.

9.311 Mr Aldridge replied to Dr Keel by memorandum dated 12 May 1998.[368] He agreed that the steps taken by the SNBTS to identify those affected through the look-back exercise seemed sufficient and that Dr Keel should write to Dr Metters.

9.312 On 10 June 1998 Dr Keel (SOHD) wrote to Professor Franklin.[369] The ACMSBT had met on 4 June and the issue of whether the SNBTS should draw a line under the look-back exercise had been discussed. There was general agreement that all reasonable measures had been taken to trace components and recipients in Scotland and that the tracing exercise could, therefore, stop. However, it was also agreed that the look-back exercise could not be considered formally closed until reasons for non-traceability of components or recipients had been logged in the look-back Register. Ministers would need to be satisfied that the reasons for non-follow up of components and recipients were clearly documented and justifiable. Dr Keel requested that the SNBTS continue their efforts to provide that information to the Register as the look-back exercise could not be considered complete until that had been accomplished. There had also been some discussion at the ACMSBT meeting about the latest figures provided from Scotland which did not appear to add up.

9.313 A final report on the HCV look-back exercise in Scotland was produced in
June 1998.[370] The final figures for the look-back exercise were reported as follows: 360 Hepatitis C positive donors who had given blood before 1991 were identified; these donors had given 1,658 donations; 2,026 components had been prepared from these donations (of which 1,356 components were traced and 670 were untraced); 880 recipients were identified by hospitals; 536 of the identified recipients were deceased; 78 were not traceable; of the remaining 226 recipients, 133 were counselled and tested positive for HCV, 70 were counselled and tested negative and the infection status of the remaining 63 was uncertain (because they had declined testing, were not appropriate for testing or their results were not reported back to the SNBTS).

Summary

9.314 Thus, by the middle of 1998 the HCV look-back exercise in Scotland was complete. In Scotland, 880 recipients of blood from donors found to be HCV positive after the introduction of screening in 1991 had been identified (of whom 226 who were still alive had been traced). As noted below, it appears that the look-back exercise only identified a small percentage of the total number of patients who contracted HCV as a result of transfusion in the 1970s and 1980s.[371]

Investigations by the Scottish Executive

9.315 The remainder of this chapter is largely concerned with the investigations carried out by the Scottish Executive into Hepatitis C and the infection of patients with haemophilia.

1999

9.316 In the late summer of 1999 Susan Deacon MSP (Minister for Health and Community Care), instructed Scottish Executive officials to ascertain the facts surrounding Hepatitis C and the heat treatment of blood products for haemophilia patients in the mid 1980s.[372]

9.317 In late 1999 the Scottish Executive requested Haemophilia Centre Directors to provide certain information relating to haemophilia patients and Hepatitis C.[373] The Haemophilia Centre Directors provided the following information in response to that request.

Edinburgh

9.318 There were about 130 persons with haemophilia in the East of Scotland who were alive and had evidence of current or previous infection with Hepatitis C. Since 1980, 42 patients registered in Edinburgh had died.[374]

Glasgow

9.319 There were 133 adult haemophilia patients alive in the West of Scotland known to be Hepatitis C antibody positive.[375] Professor Lowe believed that Dr Liz Chalmers currently had about six Hepatitis C positive children at Yorkhill Haemophilia Centre (and it was possible that some children had died since 1985). Of the 50 haemophilia patients who died from 1986 to date while attending Glasgow Royal Infirmary, 13 were known to have died of liver disease (ie cirrhosis and/or hepatocellular carcinoma).[376]

Dundee

9.320 On viewing previous Oxford annual returns, it was possible to identify eight individuals with Haemophilia A or B who had died prior to 1992. Currently there were 34 patients with Haemophilia (A or B) attending the Dundee centre on a regular basis. Thirteen were HCV antibody negative and 21 antibody positive. Two of the antibody positive patients were PCR negative. There were also three patients with vWD who were HCV positive.[377]

Inverness

9.321 There were seven patients under the care of Dr W Murray who were Hepatitis C positive.[378]

2000

9.322 In 2000, Harris et al (Communicable Disease Surveillance Centre, Public Health Laboratory Service, London) reported on the results of the UK Hepatitis C look-back exercise and the establishment, in 1998, of the HCV National Register to study the natural history of Hepatitis C infection in the UK.[379] By 31 December 1999, 996 transfusion patients infected with Hepatitis C had been traced through the look-back exercise. The details of 871 (87%) patients had been registered on the HCV National Register, on an anonymised basis, with a view to studying the natural history of the disease in these patients. Registered cases were followed up annually using a standard form sent to each patient’s clinician.

9.323 On 10 February 2000 a meeting took place between officials from the Scottish Executive and Haemophilia Directors.[380] Dr Ludlam provided the following information.

9.324 The number of HCV positive haemophilia patients currently alive in Scotland was 125 for the East Coast Centres (ie Inverness, Aberdeen, Dundee and Edinburgh; the figure included 18 patients with vWD) and 127 in Glasgow.[381]

9.325 The total number of HIV negative haemophilia patients who had died in Scotland of liver disease since 1 September 1985 to date was three in the East of Scotland and 12 in the West of Scotland. It was stressed that not all deaths were solely related to HCV.

9.326 The number of people treated for the first time in Scotland with a blood product during the period from 1 September 1985 to 30 June 1987 was as follows: 18 in the East of Scotland[382] and 13 in the West of Scotland.[383]

9.327 The following points arose from a discussion of the use of commercial products during the period 1 September 1985–31 December 1988: Dr Cachia and Dr Murray confirmed that only SNBTS products had been used at Dundee and Inverness. Dr McColl was unaware of any commercial products having been used at Yorkhill. Dr Ludlam advised that the following commercial products had been used, namely, Profilate and Monoclate, both from the USA. Professor Lowe and Dr Watson advised that checks had not yet been completed for Glasgow and Aberdeen.

9.328 Miss Teale (Head of Health Care Policy Division, Scottish Executive Health Department (SEHD)) advised that the following additional information would be required from the Haemophilia Directors: a definitive list of products used in the period in question; the statistics broken down by centre; details of the staffing levels at each of the centres between 1985–1988; copies of the guidelines issued to Haemophilia Directors; and the number of patients treated prior to 1985.

9.329 In October 2000, the SEHD published its report ‘Hepatitis C and Heat Treatment of Blood Products for Haemophiliacs in the mid 1980’s’.[384]

2002

9.330 In 2002, Soldan et al (PHLS)) reported on their estimate of the number of transfusion patients in England infected by blood and its components.[385] The authors estimated[386] that approximately 13,500 patients were infected with HCV as a result of a transfusion of blood or its components between 1 January 1980 and the introduction of HCV donor testing on 1 September 1991.[387] Over 60% of these patients were either known or estimated to have died by the end of 1995. The authors estimated that the HCV look-back programme identified about 5% of the total number of HCV infections transmitted by transfusion between 1 January 1980–1 September 1991, and over 13% of infected recipients who survived to 1995. It was noted that only two transfusion-transmitted HCV infections had been reported from anti-HCV tested components during the past six years (up to the end of 2001) and that the risk of infection by transfusion had been reduced further by nucleic acid testing of blood donations. The authors concluded:

Transfusion-transmission of HCV in the United Kingdom is therefore largely a thing of the past, although the extent of continuing secondary transmission has not been established, and investigation of the burden of disease amongst infected recipients is ongoing.

9.331 On 24 July 2002 Dr Brian McClelland (SNBTS, Edinburgh) wrote to Mr Bob Stock (SEHD) enclosing an estimate prepared by Dr Kate Soldan (PHLS) in July 2002 of the number of individuals in Scotland infected with Hepatitis C by blood transfusion.[388] Dr Soldan estimated that 3498 patients in Scotland had probably been infected with Hepatitis C by blood transfusion between 1 January 1980 and 31 August 1991. 1,886 patients were ‘known/expected to be dead’ and 1,612 were ‘not known to be dead’ as at 1995. Dr McClelland commented that of the estimated 1,612 individuals possibly surviving in 1995 with HCV due to transfusion, about 50% ie about 800, might still be alive in 2002.[389]

2006

9.332 In 2006 Harris et al (PHLS) reported on the natural history of HCV in 924 transfusion recipients on the HCV National Register when compared with 475 control patients, who had received a transfusion of blood or its components but were not infected with HCV.[390] The results showed that ‘all-cause’ mortality was not significantly different between patients on the register and control patients but that the risk of death directly from liver disease was higher (2.71 times greater) in patients on the Register than in control cases. It was noted that nearly 30% of those HCV infected patients who died directly from liver disease were known to have consumed excess alcohol.

9.333 Preliminary survival analysis of the HCV National Register to the end of 2007 (mean 19 year follow up after exposure) showed liver related mortality to be 4% in HCV positive cases compared to 1.5% in HCV negative controls (transfused around the same time as the HCV positive cases). Dr Harris noted that “Overall, while survival was found to be poorer in cases rather than controls, this difference was not [statistically] significant”. Dr Harris suggested that “HCV infection did not have a great impact on all-cause mortality after 19 years of infection”.[391]

2007

9.334 In February 2007 a review of the Advisory Committee on the Microbiological Safety of Blood, Tissues and Organs for Transplantation (MSBTO) by Dr Jon Bell was published. The report recommended that MSBTO should be replaced by an independent scientific risk assessment committee, the Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO). Responsibility for deciding on risk management options, taking account of any advice that the committee might give, should reside with the Health Departments. SaBTO held its first meeting on 23 January 2008 and continues in existence.