In most HIV-infected groups it is impossible to estimate directly the effect of infection on subsequent mortality because information is lacking on the mortality rates that would have occurred in its absence. People with haemophilia are a notable exception. In the early 1980s, they were exposed to HIV-1 infection through treatment with plasma-derived clotting factor concentrates. New infections ceased in the mid-1980s when donor screening and viral inactivation procedures during concentrate manufacture were introduced. By then, however, many patients had been infected. Mortality and disease incidence in the complete UK haemophilia population before and after infection with HIV have previously been reported [1–4]. This paper updates that evidence and reports on mortality rates since the introduction of effective treatment for HIV with highly active antiretroviral therapy (HAART) in mid-1996. Before the mid-1980s, haemophilia treatment also carried a near certain risk of hepatitis C virus (HCV) infection, and the majority of this population, including almost all those with severe haemophilia, were infected [5–8]. Data on mortality from liver disease are therefore also presented.
The UK Haemophilia Centre Doctors’ Organisation (UKHCDO) has maintained a nationwide register of individuals diagnosed with haemophilia A (factor VIII deficiency) or B (factor IX deficiency) since 1976 . The register is updated continuously using data on newly diagnosed individuals and deaths received from individual haemophilia centres. In addition, the vital status on 1 January 2000 of registered individuals was checked with the UK Office for National Statistics.
HIV-1 testing became available late in 1984, and virtually all haemophilia patients who had received potentially infected blood products were tested very shortly afterwards. Information on HIV test results and AIDS diagnoses has been collated [1–3,10,11]. Previously stored blood samples for some individuals enabled an estimation of the seroconversion date for all those infected. For over 80% the estimate was during 1981–1983, with the median December 1982. The definition of AIDS was always that currently in use in the UK .
Individual information on HCV status is not available. Information on treatment with high HCV risk products is, however, held in the database, and studies in small groups have shown that close to 100% of those treated before 1985 were infected with HCV, with a single exposure to large-pool concentrate usually causing infection [5–7,13].
For each individual, the person-years at risk were calculated from the date of registration on the database until the date of death or emigration or, for those still alive and in the UK, 1 January 2000. For the few whose vital status on 1 January 2000 could not be established, their contribution to the person-years was taken to end on the last date when they were known to be alive. Annual death rates, directly standardized for age  using the distribution of person-years in the HIV-infected individuals in age groups less than 20, 20–29, 30–39, 40–49 and over 50 years, were calculated for all causes and for individual causes by calendar year, haemophilia severity and, from 1985, HIV status. Death certificates were obtained for individuals who had died, and the underlying cause was coded to the 9th revision of the International Classification of Diseases , except if the underlying cause was described as haemophilia as a result of some other, more specific cause (e.g. AIDS, hepatitis), then the more specific cause was taken whenever appropriate. All deaths certified as being caused by AIDS or an AIDS-defining condition, or occurring in individuals reported as having developed an AIDS-defining condition shortly before death, were classified as HIV related.
For the HIV-infected group, survival from 1 January 1985 to 1 January 1987, 1 January 1989, …, 1 January 1997, and 1 January 2000 was calculated separately for those aged 1–14, 15–34, 35–54 and over 55 years at infection using the equation:
Equation (Uncited)Image Tools
where S(t) is the probability of surviving to time t; ni, O+i, and Y+i are the numbers of calendar years, observed deaths and person-years, respectively, in the ith calendar period, and summation is over calendar periods to time t. The survival that HIV-infected individuals would have experienced without infection was also calculated by replacing O+i in equation (1) by
Equation (Uncited)Image Tools
where O−j and Y−j are the numbers of observed deaths and person-years in HIV-uninfected individuals with severe haemophilia in the jth 5-year attained-age group during 1985–1999, Y+ij is the number of person-years in the jth attained-age group in HIV-infected individuals in calendar period i, and summation is over all attained-age groups. Relative survival  was calculated by considering the excess number of deaths in HIV-infected compared with uninfected individuals, i.e. by replacing O+i in equation (1) by (O+i−E+i). Calculations were completed using the computer package Stata .
Of the 7250 haemophilic men and boys living in the UK during 1977–1998 and registered on the UKHCDO database, 2262 had severe (clotting factor concentration < 1 IU/dl), and 4988 had moderate/mild haemophilia. Among those with severe haemophilia, 952 were infected with HIV (53% of those alive on 1 January 1985), whereas 294 individuals with moderate/mild haemophilia were infected (7% of those alive on 1 January 1985). The lower proportion among those with moderate/mild haemophilia reflects the lower treatment frequency in this group. Among HIV-infected individuals, 65.8% of those with severe and 59.9% of those with moderate/mild haemophilia had died by 1 January 2000, whereas for HIV-uninfected individuals the proportions who had died were much lower, at 18.3% for those with severe and 13.0% for those with moderate/mild haemophilia (Table 1).
During 1977–1984, mortality in individuals with severe haemophilia remained constant at 0.9% (Table 2). Among HIV-uninfected individuals, mortality remained at this level during 1985–1999. In contrast, among HIV-infected individuals, mortality increased progressively to 2.5, 4.3, 5.8, 8.1, and 12.7% in the years 1985–1986, 1987–1988, 1989–1990, 1991–1992, and 1993–1994, respectively (Fig. 1). In 1995–1996 annual mortality was 11.3%, before falling to 5.3% in 1997–1999, after the introduction of HAART. For individuals with moderate/mild haemophilia, annual mortality during 1977–1984 was 0.4%. This is half the corresponding value in individuals with severe haemophilia, and the difference is principally caused by the lower mortality from causes involving bleeding. For individuals with moderate/mild haemophilia without HIV, annual mortality remained at 0.4% throughout 1985–1999. For individuals with moderate/mild haemophilia with HIV, annual mortality increased progressively, to 2.5, 2.6, 5.9, 8.1, 11.5, and 13.1% in years 1985–1986, 1987–1988, 1989–1990, 1991–1992, 1993–1994, and 1995–1996, before falling to 2.9% in 1997–1999.
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.
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