The UKHCDO database indicated that all but 10 of the HIV-infected individuals had received high HCV risk products, as had 895 of the HIV-uninfected individuals with severe haemophilia (92% of those born before 1985), and 2497 of the HIV-uninfected individuals with moderate/mild haemophilia (64% of those born before 1985). Enquiries at haemophilia centres showed that UKHCDO treatment records were not comprehensive, and that all 10 of the remaining HIV-infected individuals and many others with severe haemophilia were also likely to have received high HCV risk products. When the analyses in Table 2 were repeated excluding those with no recorded exposure to high HCV risk products, the results were essentially unchanged: annual mortality in those with severe haemophilia was 0.9% (0.5–1.2), 0.9% (0.6–1.3), 1.0% (0.6–1.4), and 0.9% (0.6–1.3) during 1977–1978, 1979–1980, 1981–1982 and 1983–1984, whereas for those with severe haemophilia without HIV annual mortality during 1985–1986, 1987–1988, 1989–1990, 1991-1992, 1993–1994, 1995–1996 and 1997–1999 was 0.9% (0.5–1.2), 0.9% (0.5–1.4), 0.9% (0.4–1.4), 0.6% (0.2–0.9), 0.9% (0.5–1.4), 1.2% (0.7–1.7), and 0.7% (0.4–1.1), respectively. For moderate/mild haemophilia the corresponding values during 1977–1978, 1979–1980, 1981–1982, 1983–1984, 1985–1986, 1987–1988, 1989–1990, 1991–1992, 1993–1994, 1995–1996 and 1997–1999 were 0.5% (0.3–0.7), 0.5% (0.3–0.6), 0.4% (0.2–0.5), 0.5% (0.4–0.7), 0.4% (0.2–0.5), 0.4% (0.2–0.5), 0.5% (0.3–0.7), 0.4% (0.3–0.6), 0.5% (0.3–0.6), 0.4% (0.3–0.6), and 0.4% (0.3–0.5), respectively.
A strong gradient in mortality was observed with age at HIV infection: for those infected at ages 1–14 years, 57% of those alive on 1 January 1985 survived to 1 January 2000, whereas for those infected at ages 15–34, 35–54 and over 55 years, 38, 12, and 2%, respectively, survived to 1 January 2000 (Fig. 2). Some age gradient would be expected without HIV: mortality among the HIV-uninfected individuals suggests that, without HIV, survival in the HIV-infected group to 1 January 2000 in the four age-at-infection groups would have been 98, 92, 69, and 39%, respectively. When mortality in the HIV-infected individuals was corrected for deaths that would have been expected without HIV, a strong age gradient remained: relative survival to 1 January 2000 in those aged 1–14, 15–34, 35–54 and over 55 years at HIV infection was 59, 41, 18 and 4%, respectively.
Of the 788 deaths in HIV-infected individuals during 1985–1999, 610 were HIV related, and annual mortality from HIV-related causes rose from 3.0% during 1985–1990 to 8.4% during 1991–1996 and then fell to 2.9% during 1997–1999. For all causes of death the temporal pattern was similar with annual mortality at 4.0, 10.3 and 4.7% in 1985–1990, 1991–1996 and 1997–1999 (Table 3). Considering the 178 deaths not classified as HIV related, annual mortality rose from 1.0% in 1985–1990 to 1.9% in 1991–1996, then fell slightly, to 1.8%, in 1997–1999. These values are considerably higher than those for HIV-uninfected individuals, in whom annual mortality from all causes (standardized for age and haemophilia severity) was 0.8% (0.6, 1.0), 0.8% (0.6, 1.0), and 0.7% (0.5, 1.0) during 1985–1990, 1991–1996, and 1997–1999, respectively.
Among HIV-infected individuals, 59 of the 178 deaths not classified as HIV related were from liver disease, including seven liver cancers, and annual mortality from liver disease was 0.2% in 1985–1990, rising to 0.8% in 1991–1996 and remaining at 0.8% in 1997–1999. Among the deaths classified as HIV related, a further 27 were certified as being caused by liver disease: when these were included annual liver disease mortality was 0.2% (0.1, 0.3), 1.2% (0.9, 1.5), and 1.2% (0.6, 1.7) in 1985–1990, 1991–1996, and 1997–1999, respectively. In contrast, among HIV-uninfected individuals annual liver disease mortality was 0.09% (0.05, 0.13) during 1985–1999, and 0.05% (0.01, 0.08), 0.11% (0.04, 0.18), and 0.14% (0.04, 0.23) during 1985–1990, 1991–1996, and 1997–1999, respectively. The exclusion of patients with no recorded high HCV risk exposure had little effect in the HIV-uninfected group: annual liver disease mortality in this restricted group during 1985–1999 was 0.10% (0.06–0.14), whereas values during the years 1985–1990, 1991–1996, and 1976–1999 were 0.05% (0.01–0.09), 0.12% (0.05–0.19) and 0.13% (0.04–0.23), respectively.
For deaths classified neither as HIV related nor from liver disease, annual mortality in HIV-infected individuals varied little during 1985–1999, taking values 0.9, 1.1 and 1.0% during 1985–1990, 1991–1996 and 1997–1999, respectively (Table 3), whereas for HIV-uninfected individuals the corresponding values were appreciably lower, at 0.7% (0.6, 0.8) during 1985–1999, and 0.7% (0.5, 0.9), 0.7% (0.5, 0.9), and 0.6% (0.3, 0.8) during 1985–1990, 1991–1996, and 1997–1999, respectively. For the 119 deaths in HIV-infected individuals, all available information regarding cause was inspected. No common pattern was apparent, although several suggested immunodeficiency (see previous analyses of these data [1,2]). There was no evidence that death was caused by a toxic effect of HAART in the information regarding the 14 deaths occurring during 1997–1999.
The infection of 1246 UK haemophilic males with HIV-1 during the early 1980s offers unusual insight into the impact of this virus on mortality. The reasons for this are: the chance of infection depended only on how much clotting factor concentrate an individual needed , and which particular batches he received; the infections took place during a short time period and within a clearly defined total population that had a wide age-range; a reliable test for HIV antibodies had become available shortly after the infections occurred; the testing of those potentially infected was essentially complete; the previously stored blood samples enabled the seroconversion date to be estimated, and it has been possible to calculate mortality separately for HIV-infected individuals and others.
There are, inevitably, a number of limitations to this study. One is that the vital status on 1 January 2000 of 73 individuals who emigrated and 198 individuals lost to follow-up is unknown. If their subsequent mortality has been similar to the mortality among those with complete follow-up, the study results would be unchanged. However, if their mortality differs, some bias may have occurred. For HIV-infected individuals, only 10 are involved. With such a small number, the study results would scarcely be affected even if they had substantially increased or decreased mortality compared with all HIV-infected individuals. Among the HIV-uninfected individuals the numbers emigrating are also small in relation to the total and therefore, once again, the differences between their mortality and that of those who did not emigrate would make little difference. The number of HIV-uninfected individuals lost to follow-up is larger. If they had lower mortality than those with complete follow-up, then the study results would not change. Some bias might occur if they had substantially higher mortality, but this is unlikely because individuals in poor health are unlikely to lose contact with their haemophilia centre.
In the entire UK haemophilia population, annual mortality was constant during 1977–1984, at approximately 0.9% in severe haemophilia, and 0.4% in moderate/mild haemophilia. From 1985, mortality in those not infected with HIV remained essentially unchanged but, among the infected individuals, mortality rose progressively by large amounts. Among those infected, the timing of the increase was identical in the two severity groups, and in each calendar period mortality rates were similar in size in the two groups, despite the different proportions infected and their different mortality rates in the absence of infection (Fig. 1). Survival was poorer in HIV-infected individuals than in uninfected individuals at all ages (Fig. 2). However, a much larger proportion of individuals remained alive by the end of the follow-up period for those who were younger when infected, even after correcting for the mortality expected in the absence of HIV. Such an age gradient would be anticipated from the greater number of thymic cells in younger individuals, giving a greater possibility for the ongoing replenishment of the CD4 T-cell population .
This haemophilia population has a high prevalence of HCV infection, and another limitation of this study is that individuals cannot formally be classified by HCV status. Sensitive tests to detect antibodies to HCV antigens became available only in the 1990s, and serum samples for this large population were not stored systematically. There is thus no possibility of ascertaining the HCV status for many who died before this. A surrogate marker of HCV infection is, however, available, which suggests that nearly 100% of the HIV-infected individuals and almost all others with severe haemophilia and born before 1985 were infected with HCV [5,6]. Among those with moderate/mild haemophilia and without HIV, some individuals have never needed treatment with blood products and probably remain free of HCV. Nevertheless, when those without documented high HCV risk exposure are excluded, the study results scarcely change.
The impact of co-infection with HCV on mortality in HIV infection is hard to estimate precisely. Before 1997 it was probably proportionately small, because during this period liver disease was the certified cause of death for only 9% of the deaths in HIV-infected individuals. Studies comparing HIV-infected individuals in different exposure categories, some of whom would have had much lower HCV prevalence, have also found no appreciable effect of exposure category on survival before the HAART era .
During 1997–1999, mortality fell sharply in HIV-infected individuals, both in severe and in moderate/mild haemophilia (Fig. 1). A similar fall, occurring shortly after the introduction of HAART, has been reported in other groups [21–23], and clearly demonstrates the impact of HAART. However, at the end of the present follow-up period, mortality in HIV-infected individuals still remained substantially higher than in HIV-uninfected individuals. Both the large increase in mortality up to 1996 and the subsequent fall were chiefly caused by changes in mortality from HIV-related causes (Table 3). However, when mortality from other causes was examined separately, a substantial increase over time remained, with the value during 1991–1996 almost double that for 1985–1990 and no appreciable decline in 1997–1999. The increase was entirely caused by an increase in liver disease, which during 1997–1999 was the certified cause of death for over 25% of deaths in HIV-infected individuals. This tallies with findings in other studies of HIV/HCV co-infection in which liver disease has also emerged as a leading cause of death in recent years [13,24,25]. The treatment of HCV infection with a combination of IFN-α and ribavirin became widespread in the UK during 2000 . Therefore its impact on liver disease in this population is, as yet, unknown.
For deaths that were classified neither as HIV related nor from liver disease, mortality remained virtually constant during 1985–1999, albeit at a higher level than that of HIV-uninfected individuals. It seems likely that at least some of these deaths were attributable to HIV, although there was no indication that the individuals concerned had developed an AIDS-defining condition. HAART has been associated with several categories of major toxic effects , but there was no evidence of any deaths occurring as a result of HAART in this population.
UK Haemophilia Centre Doctors’ Organisation
Analysis and Writing Committee
Sarah C. Darby, Sau Wan Kan, Rosemary J.D. Spooner, Paul L.F. Giangrande, Christine A. Lee, Michael Makris, Caroline A. Sabin, Henry G. Watson, Jonathan T. Wilde, Mark Winter.
Data collection was carried out by Rosemary Spooner, Sau Wan Kan, Paul Giangrande and Sarah Darby. The statistical analysis was designed by Sarah Darby and carried out by Sarah Darby and Sau Wan Kan. All members of the Analysis and Writing Committee participated in the preparation of the report.
UK haemophilia centres contributing data to this study
Aberdeen: Grampian Area Haemophilia Centre, Aberdeen Royal Infirmary. Ashford: Haematology Laboratory, Ashford Hospital. Bangor: Haemophilia Centre, Ysbyty Gwynedd. Barnstaple: Department of Haematology, North Devon District Hospital. Basingstoke: The North Hampshire Haemophilia Centre, North Hampshire Hospital. Bath: Department of Haematology, Royal United Hospital (North). Bedford: Department of Haematology, Bedford Hospital Trust. Belfast: N.I. Haemophilia Comprehensive Care Centre, Belfast City Hospital; Royal Belfast Hospital for Sick Children. Birmingham: Haemophilia Unit, Queen Elizabeth Hospital; Department of Haematology, The Birmingham Children's Hospital NHS Trust. Blackburn: Department of Haematology, Blackburn Royal Infirmary. Bournemouth/Poole: Department of Haematology, Poole General Hospital. Bradford: Bradford Haemophilia Centre; Department of Paediatrics, Bradford Royal Infirmary. Brighton: Department of Haematology, Royal Sussex County Hospital. Bristol: Avon Haematology Unit, Bristol Oncology Centre; Department of Oncology/BMT, Royal Hospital for Sick Children. Bury St Edmunds: The West Suffolk Hospital. Camberley: Department of Pathology, Frimley Park Hospital. Cambridge: Department of Clinical Haematology, Addenbrooke's Hospital. Canterbury: Haemophilia Centre, Kent and Canterbury Hospital. Cardiff: Department of Haematology, University Hospital of Wales. Carlisle: Department of Pathology, Cumberland Infirmary. Carshalton: Department of Haematology, St Helier Hospital. Chelmsford: Department of Haematology, Broomfield Hospital. Chertsey: Department of Pathology, St Peter's Hospital. Chichester: Haematology Laboratory, St Richard's Hospital. Colchester: Department of Haematology, District General Hospital. Coventry: Department of Haematology, Walsgrave Hospital NHS Trust. Derby: Derbyshire Royal Infirmary. Dorchester: Department of Haematology, West Dorset Hospital. Dundee: Haemophilia Unit, Ninewells Hospital. Eastbourne: Department of Haematology, District General Hospital. Edinburgh: Haemophilia Centre, Royal Infirmary; Department of Haematology, Royal Hospital for Sick Children. Epsom: Haematology Laboratory, Epsom General Hospital. Exeter: Department of Haematology, Royal Devon and Exeter Hospital (Wonford). Glasgow: Haemophilia and Thrombosis Centre, Glasgow Royal Infirmary; Department of Haematology, Royal Hospital for Sick Children. Harlow: Department of Haematology, Princess Alexandra Hospital. Harrogate: Harrogate District Hospital. Harrow: Department of Haematology, Northwick Park Hospital. Hereford: Department of Haematology, County Hospital. Hillingdon: Hillingdon Hospital. Huddersfield: Department of Haematology, Huddersfield Royal Infirmary. Hull: Department of Haematology, Kingston General Hospital. Inverness: Department of Haematology, Raigmore Hospital. Ipswich: The Ipswich Hospital. Kettering: General Hospital. Kingston upon Thames: Haematology Laboratory, Kingston Hospital. Lancaster: Department of Haematology, Royal Lancaster Infirmary. Leeds: Haemophilia Unit; Department of Paediatric Haematology, St James’ University Hospital. Leicester: Haemophilia Centre, Leicester Royal Infirmary. Lincoln: Lincoln County Hospital. Liverpool: Haematology Laboratories, Royal Liverpool University Hospital; Department of Haematology, Royal Liverpool Children's Hospital, Alder Hey. London: Department of Haematology, Imperial College School of Medicine, Hammersmith Hospital; Department of Haematology, St Mary's Hospital; Department of Haematology, Great Ormond Street Hospital for Sick Children; Department of Haematology, Barts and The London Haemophilia Centre, Royal London Hospital; Haemophilia Centre, Royal Free Hospital; Department of Haematology, University College Hospital; Department of Haematology, King's College Hospital; Department of Haematology, Lewisham Hospital; Haemophilia Centre, St Thomas’ Hospital; Department of Haematology, St George's Hospital. Luton: Department of Pathology, Luton and Dunstable Hospital. Manchester: University Department of Haematology, Manchester Royal Infirmary; Department of Haematology, Royal Manchester Children's Hospital. Medway: Medway Maritime Hospital. Milton Keynes: Department of Haematology, Milton Keynes Hospital. Middlesborough: Department of Clinical Pathology, Middlesborough General Hospital. Newcastle upon Tyne: Haemophilia Centre, Royal Victoria Infirmary. Newport: Department of Haematology, Royal Gwent Hospital. Northampton: Department of Haematology, Northampton General Hospital NHS Trust. Norwich: Department of Haematology, Norfolk and Norwich Hospital. Nottingham: Department of Haematology, University Hospital, Queen's Medical Centre. Oxford: Oxford Haemophilia Centre, Churchill Hospital. Peterborough: Peterborough District Hospital. Plymouth: Derriford Hospital. Portsmouth: Central Laboratory, East Wing, St Mary's General Hospital. Salisbury: Department of Pathology, Salisbury District Hospital. Sheffield: Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital; The Roald Dahl Paediatric Haematology Centre, The Children's Hospital. Shrewsbury: Department of Pathology, Shrewsbury Hospital (Copthorne North). Southampton: South Hampshire Haemophilia Centre, South Hampshire General Hospital. Southend: Department of Haematology, Southend Hospital. St Leonards-On-Sea: Conquest Hospital. Stoke on Trent: Central Pathology Laboratory, North Staffordshire Hospital. Sunderland: The District General Hospital. Swansea: Swansea Haemophilia Centre, Singleton Hospital. Taunton/Yeovil: Department of Haematological Medicine, Taunton and Somerset Hospital. Thornton Heath: Haematology Laboratory, Mayday Hospital. Torquay: Department of Haematology, Torbay Hospital. Truro: Department of Haematology, Treliske Hospital. Tunbridge Wells: Pembury Hospital. Whitehaven: West Cumberland Hospital. Winchester: Pathology Laboratory, Royal Hampshire County Hospital. Wolverhampton: Department of Haematology, New Cross Hospital. Worcester: Department of Haematology, Worcester Royal Infirmary NHS Trust. Worthing: Haematology Laboratory, Worthing Hospital. York: York District Hospital.
The authors would like to thank the Office of National Statistics and the General Register Offices in Edinburgh and Belfast for help in establishing the vital status of the population and providing death details, Patricia Wallace of Oxford Haemophilia Centre for clerical work and Nina Keleher of the Clinical Trial Service Unit for secretarial assistance.
Sponsorship: This study was supported by the UK Medical Research Council and Cancer Research UK. Sarah Darby and Sau Wan Kan are supported by Cancer Research UK. The UKHCDO National Database was held at Oxford Haemophilia Centre and was supported by the Oxford Haemophilia Centre while this study was being carried out.
1. Darby SC, Ewart W, Giangrande PLF, Dolin PJ, Spooner RJD, Rizza CR, on behalf of the UK Haemophilia Centre Directors’ Organisation. Mortality before and after HIV infection in the complete UK population of haemophiliacs. Nature
2. Darby SC, Ewart DW, Giangrande PLF, Spooner RJD, Rizza CR, for the UK Haemophilia Directors’ Organization. Importance of age at infection with HIV-1 for survival and development of AIDS in the UK haemophilia population. Lancet
3. Darby SC, Rizza CR, Doll R, Spooner RJD, Stratton IM, Thakrar B. Incidence of AIDS and excess of mortality associated with HIV in haemophiliacs in the United Kingdom: report on behalf of the Directors of Haemophilia Centres in the UK. BMJ
4. Wilde JT, Lee CA, Darby SC, Kan SW, Giangrande PLF, Phillips AN, et al
., on behalf of the UK Haemophilia Centre Doctors’ Organisation. The incidence of lymphoma in the UK haemophilia population between 1978 and 1999. AIDS
5. Fletcher ML, Trowell JM, Craske J, Pavier K, Rizza CR. Non-A non-B hepatitis after transfusion of factor VIII in infrequently treated patients. BMJ
6. Kernoff PBA, Lee CA, Karayiannis P, Thomas HC. High risk of non-A non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin. Br J Haematol
7. Watson HG, Ludlam CA, Rebus S, Zhang LQ, Peutherer JF, Simmonds P. Use of several second generation serological assays to determine the true prevalence of hepatitis C virus infection in haemophiliacs treated with non-virus inactivated factor VIII and IX concentrates. Br J Haematol
8. Darby SC, Ewart DW, Giangrande PLF, Spooner RJD, Rizza CR, Dusheiko GM, et al
., for the UK Haemophilia Centre Directors’ Organisation. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. Lancet
9. Spooner RJD, Rizza CR. Development of a national database to provide information for the planning of care of patients with congenital blood coagulation defects.
In: Rizza C, Lowe G, editors. Haemophilia and other inherited bleeding disorders.
London: Saunders; 1997. pp. 435–453.
10. AIDS Group of the United Kingdom Haemophilia Centre Directors. Seropositivity for HIV in UK haemophiliacs. Phil Trans Roy Soc, Lond, Series B
11. AIDS Group of the United Kingdom Haemophilia Centre Directors. Prevalence of antibody to HIV in haemophiliacs in the United Kingdom: a second survey. Clin Lab Haematol
12. Ancelle Park RA. European AIDS definition. Lancet
13. Yee TT, Griffoen A, Sabin CA, Dusheiko G, Lee CA. The natural history of HCV in a cohort of haemophilic patients infected between 1961 and 1985. Gut
14. Armitage P, Berry G. Statistical methods in medical research
, 2nd ed. Oxford: Blackwell Scientific Publications; 1987.
15. World Health Organization. Manual of the international statistical classification of diseases, injuries, and causes of death
, ninth revision. Geneva: WHO; 1977.
16. Reeves GK, Beral V, Bull D, Quinn M. Estimating relative survival among people registered with cancer in England and Wales. Br J Cancer
17. StataCorp. Stata statistical software: release 6.0.
College Station, TX: Stata Corporation; 1999.
18. Sabin CA, Pasi KJ, Phillips AN, Lilley P, Bofill M, Lee CA. Comparison of immunodeficiency and AIDS defining conditions in HIV negative and HIV positive men with haemophilia A. BMJ
19. McCune JM, Loftus R, Schmidt DK, Carroll P, Webster D, Swor-Yim LB, et al
. High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J Clin Invest
20. Collaborative Group on AIDS Incubation and HIV Survival including the CASCADE EU Concerted Action. Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis. Lancet
21. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med
22. Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al.
, for the EuroSIDA Study Group. Changing patterns of mortality across Europe in patients infected with HIV-1. Lancet
23. Piot P, Bartos M, Ghys PD, Walkker N, Schwartlander B. The global impact of AIDS. Nature
24. Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, de Moerloose P, White GC, et al
., for the Multicenter Hemophilia Cohort Study. End-stage liver disease in persons with hemophilia and transfusion-associated infections. Blood
25. Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, et al
. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis
26. National Institute for Clinical Excellence. Guidance on the use of ribavirin and interferon alpha for hepatitis C. Technology appraisal guidance – no. 14.
). London: National Institute for Clinical Excellence; 2000.
27. Powderly WG. Long-term exposure to lifelong therapies. J Acquired Immune Defic Syndr
2002; 29 (Suppl. 1)
Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
Cohort study; haemophilia; hepatitis C virus; highly active antiretroviral therapy; HIV; liver disease; mortality