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Pre‐AIDS mortality in HIV‐infected individuals in England, Wales and Northern Ireland, 1982–1996

Laurichesse, Henri A.A.1; Mortimer, Janet1; Evans, Barry G.1,3; Farrington, C Paddy2

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Author Information

1Public Health Laboratory Service AIDS and Sexually Transmitted Diseases Centre

2Public Health Statistics Unit, Communicable Disease Surveillance Centre, London, UK.

3Requests for reprints to: Barry G. Evans, Public Health Laboratory Service AIDS and Sexually Transmitted Diseases Centre, Communicable Disease Surveillance Centre, 61 Colindale Avenue, London NW9 5EQ, UK.

Date of receipt: 9 May 1997; revised 17 December 1997; accepted 7 January 1998.

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Abstract

Objective: To assess pre-AIDS mortality in HIV-infected patients in England, Wales and Northern Ireland during the period 1982–1996.

Design: Surveillance data on pre-AIDS and AIDS deaths reported to the PHLS-AIDS Centre were analysed.

Methods: Pre-AIDS mortality was estimated as the proportion of pre-AIDS deaths among all deaths in HIV-infected people. Trends over time in the number of pre-AIDS and AIDS deaths were compared using Poisson regression with logarithmic link. Causes of pre-AIDS deaths were recorded. Comparisons were made between the pre-AIDS and the AIDS death groups by logistic regression for: age, location of residence at death, year of death and risk exposure.

Results: Four-hundred and sixty-eight pre-AIDS deaths and 8574 AIDS deaths were identified. Pre-AIDS mortality accounted for 5.0% of HIV-related deaths. Trends over time in the number of pre-AIDS and AIDS deaths were not significantly different (P = 0.11). Reported causes of pre-AIDS death included pneumonia (92), liver disease (62), septicaemia (51), malignancies (49), suicide (45), cardiopulmonary causes (46), haemorrhage (42), overdose (24) and accidental causes (24). Factors positively associated with pre-AIDS death were injecting drug use, haemophilia and blood transfusion, residence outside the Thames regions, and death at an older age.

Conclusions: Pre-AIDS mortality represents a substantial proportion of HIV mortality, particularly where injecting drug use is a frequent route of HIV transmission.

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Introduction

Routine surveillance of HIV infection in developed countries is based on AIDS case reporting using the Centers for Disease Control/World Health Organization case definition adopted in 1987 [1] and modified in 1993 in the United States of America [2] and in Europe [3]. HIV-related mortality is usually considered in terms of deaths in individuals who have met the AIDS case definition (AIDS deaths). By June 1996, the HIV pandemic was estimated to have been responsible for more than 5 million AIDS deaths throughout the world [4]. However HIV-infected individuals may die before developing AIDS (pre-AIDS deaths). Since 1988, nationwide surveillance schemes and prospective cohorts have consistently identified substantial numbers of pre-AIDS deaths, particularly in HIV-infected injecting drug users (IDU) [5–12], and haemophiliacs [13–17]. By the end of December 1996, 4% of AIDS case reports (500) in England, Wales and Northern Ireland were attributed to infection through injecting drug use [18].

An earlier analysis using data to September 1990 showed 117 pre-AIDS deaths in HIV-infected persons were identified in the UK, accounting for 5.4% of all HIV related deaths reported [19]. Therefore, both the number of AIDS cases and back-calculations to provide cumulative incidence rates of HIV infection based solely on AIDS cases are likely to underestimate the extent of the HIV epidemic and the burden of the disease, particularly in areas where injecting drug use is responsible for a large proportion of HIV transmission.

There are three relevant sources of information for the routine surveillance of HIV-related mortality in England, Wales and Northern Ireland: reports of AIDS and pre-AIDS deaths from clinicians; laboratory reports of recently diagnosed HIV infections which indicate that the patient has died; and death certificates, provided by the Office of National Statistics (ONS) of England and Wales, on which HIV or AIDS was recorded by the certifier as a cause of death [20]. These data are forwarded to the Public Health Laboratory Surveillance AIDS and STD Centre at the Communicable Disease Surveillance Centre (CDSC) in London, UK.

A review of records at CDSC of HIV-infected patients who have died without a recognized AIDS-defining event has been carried out to update estimates of pre-AIDS mortality, and to identify the causes of death and risk factors associated with pre-AIDS death in England, Wales and Northern Ireland during the period 1982–1996.

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Methods

Case definitions

An AIDS case is a patient reported to the CDSC with an AIDS-defining event according to the European case definition: an AIDS death is a death known to CDSC in a reported AIDS case; a probable AIDS death is a death in an individual with evidence of HIV infection in whom the death was associated with an AIDS-defining condition, but for whom there has been no report to CDSC as an AIDS case; a possible AIDS death is a death in an individual with evidence of HIV infection whose death was reported to be associated with AIDS without giving any AIDS-defining condition, when that individual has not been reported as an AIDS case to CDSC; a pre-AIDS death is a death which is known to have occurred in the course of HIV infection in someone who had no diagnosed AIDS-defining condition before their death.

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HIV mortality reporting scheme (sources of information)

In England, Wales and Northern Ireland clinicians caring for HIV-infected patients are asked to report AIDS cases and pre-AIDS deaths on surveillance forms [20]. These ‘blue forms’ are sent directly to CDSC or, for haemophiliac patients, via the Oxford Haemophilia Centre which reports on behalf of the UK Haemophilia Centre Director's Organization. Clinicians are asked to report the death of an AIDS patient if it occurs after the AIDS case has been reported.

Copies of death certificates for which the certifier has included AIDS, HIV, Pneumocystis carinii pneumonia or Kaposi's sarcoma as a cause of death are sent to CDSC by the ONS [20]. Most of these death certificates match a prior AIDS case report form so that they supplement the clinicians' reporting of AIDS deaths. In some cases a match is made with an HIV laboratory report only and in others the copy of the death certificate is the first information about an HIV-infected person to reach CDSC. In such instances a letter is sent to the clinician certifying death to ask for a report to be completed. A minority of these requests are not responded to and the only information available to CDSC is that on the death certificate with or without a matched laboratory report of HIV infection.

Laboratory reports of HIV infection occasionally indicate that the patient was known to have died by the time the report was made [20]. If no report is received from the clinician caring for the patient, only the limited clinical information from the laboratory report will be available and it will usually be impossible to establish whether or not the patient had AIDS.

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Death ascertainment
AIDS deaths

Many AIDS deaths were identified through the ‘blue’ report form, or subsequent information from the clinician concerned or from the ONS. Periodically reporters of AIDS cases for which no information about death has been received are contacted and asked about the vital status of the patient concerned.

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Pre-AIDS deaths

Death in an HIV patient with no AIDS-defining event reported to CDSC was included in the study as a pre-AIDS death if the record provided enough information to assert with confidence that death had occurred prior to AIDS. However, the level of confidence in case ascertainment varied with the available source of information.

Reports of pre-AIDS deaths using ‘blue’ forms designed for reporting pre-AIDS deaths as well as AIDS cases, whether forwarded spontaneously or following active follow-up of a laboratory report or a death certificate mentioning HIV infection or AIDS, were all included in the study.

A few additional pre-AIDS deaths were identified without obtaining a ‘blue’ report. In these cases information provided on the clinical course prior to death and on the cause of death were sufficient to justify the assumption that the patient had died prior to AIDS. In other instances, information provided was sufficient to assume that the patient had probably or possibly met the AIDS case definition (see definitions in Methods) before or at death because AIDS or an AIDS-defining condition was recorded to have occurred by the time of death.

In the remaining cases there was no information available on the clinical course of the patient prior to or at death despite follow-up and these were excluded from the analysis.

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Data analysis

Data relating to pre-AIDS and AIDS deaths which occurred before July 1996 ascertained by the end of September 1996 were analysed. The number of pre-AIDS deaths and AIDS deaths during the study period were counted and pre-AIDS mortality was estimated as the overall proportion of all HIV-related deaths reported to CDSC. The time trends in the numbers of pre-AIDS deaths and AIDS deaths in the period 1982–1993 were analysed by Poisson regression with logarithmic link. Deaths from 1994 to 1996 were excluded as recent deaths are subject to under ascertainment. The pre-1985 deaths were included as a single group.

In most reports of pre-AIDS deaths only one cause of death was mentioned. Where several possible causes were given, we have selected the cause, from the information available, that seemed to be the main cause of death.

The characteristics of the HIV-infected patients who died before developing AIDS were compared with those of the patients reported to have developed AIDS by the time of death. Probable AIDS deaths, possible AIDS deaths and patients with undetermined status with regards to the stage of disease at death were excluded from the analysis to prevent misclassification. The variables considered in comparing the pre-AIDS death group and the AIDS death group in univariate analysis were: sex, age at death, year of death, region of death and likely route of HIV transmission. Differences in the proportions of patients dying pre-AIDS among all ascertained pre-AIDS and AIDS deaths were analysed. The covariates included in the multivariate analysis were: the routes of HIV transmission grouped into six categories (sexual intercourse between men, injecting drug use, heterosexual transmission, administration of blood products, blood transfusion or tissue transfer and vertical transmission); age at death grouped into four categories (≤ 30 years, 31–40 years, 41–50 years, ≥ 51 years) and residence of the patient at death defined as Thames regions (south-east England including London) or outside the Thames regions. A total of 132 cases (41 pre-AIDS deaths and 91 AIDS deaths) for which the route of HIV infection was not recorded were excluded from the multivariate analysis.

Univariate analysis used the χ2 test to compare proportions and Student's t test to compare quantitative variables [21]. Multivariate analysis was performed using logistic regression providing adjusted odds ratio (OR) and 95% confidence intervals (CI) [22].

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Results

Estimate of pre-AIDS mortality

During the period 1 January 1982–30 June 1996, 942 deaths in HIV-infected patients with no record of an AIDS-defining condition and 8574 AIDS deaths were identified at CDSC through the HIV mortality reporting scheme.

Case review of the 942 records identified 468 (49.7%) pre-AIDS deaths: 430 (91.8%) from a clinician's report using the ‘blue form’ and 38 (8.2%) from a record after follow-up of a death certificate or a HIV laboratory report mentioning that the patient had died. There were 131 (13.9%) probable AIDS deaths and 116 (12.3%) possible AIDS deaths. No information was available on the clinical course of HIV infection prior to death for 227 (24.1%) patients.

These 227 patients have been omitted from all analyses. The HIV mortality reporting scheme at CDSC provided an overall estimate of pre-AIDS mortality accounting for 5.0% (468 out of 9289; 95% CI, 4.6–5.4) of all remaining HIV-related deaths identified during the period study in England, Wales and Northern Ireland.

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Trend over time in the occurrence of pre-AIDS death

Numbers of ascertained pre-AIDS deaths and AIDS deaths are presented by year of occurrence in Table 1 and as trends over time in Fig. 1. On the log scale, both AIDS and pre-AIDS deaths followed an increasing trend with a significant quadratic element. The two trend lines are parallel (P = 0.11 for the interaction), and the ratio of pre-AIDS deaths to AIDS deaths remained constant. Each year there were, on average, almost 18 AIDS deaths for every pre-AIDS death.

Table 1
Table 1
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Fig. 1
Fig. 1
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Causes of pre-AIDS death

The reported causes of death in the pre-AIDS death group are summarized in Table 2. Acute pneumonia, to which 92 deaths (19.6%) were attributed, was the leading identified cause. Septicaemia was a cause of death in 51 (10.9%) patients. Sixty-two (13.2%) patients died from a liver disease: liver cirrhosis associated with hepatic failure (57), hepatic carcinoma (five). Among these patients, non-A non-B hepatitis or hepatitis C virus infection was recorded for 10 (16%), chronic hepatitis B virus infection for six (10%) and excessive alcohol consumption for seven patients (11%). Of the 62 patients, 25 (40%) were haemophiliacs, 16 (26%) were homosexual men and 15 (24%) were IDU, four (6%) had acquired infection through heterosexual contacts and two (3%) had unreported risk factors for HIV infection.

Table 2
Table 2
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Forty-nine patients died from malignancies other than hepatic carcinoma. Eight patients died from haematological malignancy: Hodgkin's disease (five), T-cell lymphoma (two), acute lymphocytic leukaemia (one). Eleven patients died from lung cancer: all were male and their mean age (± SD) at death was 59.2 (± 9.1) years. The tumour histology, available for nine patients, was adenocarcinoma (two) and other types of carcinoma (seven). Thirteen patients died from gastrointestinal cancer: carcinoma of the colon (five), carcinoma of the rectum (four), anal cancer (two), cancer of the head of the pancreas (one), and disseminated peritoneal carcinomatosis (one). Thirteen patients died from other specified malignancies: malignant tumour of the testicles (two teratoma and one seminoma), malignant cutaneous tumour (one carcinoma and one melanoma), disseminated sarcoma (two), anaplastic mediastinal cancer (two), kidney histiocytoma (one), prostate carcinoma (one), infiltrating cerebral glioma (one), and nasopharyngeal carcinoma (one). Four patients died from disseminated malignancies for which histology was not reported.

Haemorrhage, including cerebral and gastro-intestinal haemorrhage without specific cause, was reported in 42 (9.0%) further cases mainly in haemophiliac patients.

Among the 46 (9.5%) cardiopulmonary causes of death, 13 were due to myocardial infarction, five to pulmonary embolism, four to primary pulmonary hypertension and three deaths were recorded as due to an asthma attack.

In 99 (21.2%) patients, the cause of pre-AIDS death was not given as disease related: suicide (45), accidental overdose (24), road traffic accident (seven), other accidental causes (17) and homicide (five). Forty-three of the 45 patients who died from suicide were male of whom 28 were probably infected by sex with another man; four of these and 12 further individuals were IDU. Their mean age (± SD) was 31.8 ± 7.8 years. Of the patients who died from accidental overdose (21 males and three females), 13 (54.2%) were IDU, five (20.8%) were homosexual males, three (12.5%) were exposed to HIV infection through both injecting drug use and sex with another male, two (8.3%) were haemophiliac patients and one (4.1%) had undetermined risk exposure to HIV.

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Risk factors for pre-AIDS mortality

In the pre-AIDS death group there were 418 (89.3%) males and 50 (10.7%) females (sex ratio, 8:1). These proportions differed slightly but significantly (P = 0.007) from those in the AIDS death group: 7946 (92.7%) males and 628 (7.3%) females (sex ratio, 13:1). Year at death was available for 462 (98.7%) patients in the pre-AIDS death group and for 8367 (97.6%) patients in the AIDS death group. Mean age (± SD) at death in the pre-AIDS group was 40.6 (± 14.6) years (range, < 1–86 years), slightly but significantly greater than the mean age at death in the AIDS group: 38.7 (± 10.4) years (range: < 1–81 years; P <10−5).

Patients who died pre-AIDS were more likely to live outside the Thames region than patients in the AIDS group (49.3% versus 28.8%; P <10−6; OR, 2.40).

Probable routes of HIV infection in individuals in the pre-AIDS death group differed significantly (P <10−6) from those in individuals in the AIDS death group. The proportion in the pre-AIDS group was higher for IDU (15.2% versus 3.7%), haemophiliacs (22.6% versus 5.7%) and individuals who acquired HIV infection through blood transfusion (2.3% versus 0.8%) and lower for homosexual men (41.7% versus 76.4%) and heterosexual individuals (8.8% versus 11.2%). Pre-AIDS death as a proportion of all HIV related deaths reported to CDSC (excluding the 227 deaths for which there was no clinical information) is presented in Fig. 2 by exposure category. Eighteen per cent of HIV-infected IDU, 17.8% of HIV-infected haemophiliacs and 12.9% of HIV-infected blood recipients were identified as having died prior to AIDS during the period study 1982–1996.

Fig. 2
Fig. 2
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The results of multivariate analysis are presented in Table 3 which gives the numbers in the different groups along with adjusted OR and 95% CI. There were no significant interactions (χ2 test of two-way interactions: P = 0.16). The OR in Table 3 represent independent effects, jointly estimated from the multiple regression model. The risk of an HIV-infected individual dying prior to AIDS was related to, as base line, deaths among HIV-positive individuals in the following reference groups: homosexual men, residents of the Thames regions and those < 30 years of age at death. This risk was higher for haemophiliacs, IDU and blood/tissue recipients and also higher for individuals outside the Thames regions, and for individuals who died at an older age.

Table 3
Table 3
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Discussion

Surveillance of the HIV epidemic in England, Wales and Northern Ireland during the period 1982–1996 shows that pre-AIDS deaths make a substantial contribution to mortality in HIV-infected individuals. Trends over time in the number of ascertained pre-AIDS and AIDS deaths were not significantly different, the proportion of pre-AIDS deaths being constant at around 5%. Because of possible delay in reporting, pre-AIDS and AIDS deaths identified in 1994, 1995 and 1996 were not included in the time trends analysis, so that the revised AIDS case definition used from 1993 [3] would not have influenced our conclusions.

Pre-AIDS death was more likely to occur in HIV-infected IDU, haemophiliacs and blood transfusion recipients than those infected by other routes, in those reported from outside the Thames regions and in older individuals. HIV transmission by blood transfusion or administration of blood products effectively ceased in developed countries in 1985, but the use of contaminated equipment and needle sharing continue to expose IDU to HIV, as well as to hepatitis B virus (HBV) and hepatitis C virus (HCV). It is therefore likely that IDU will become the leading risk factor of pre-AIDS death in the near future, even in the UK where injecting drug use forms a small part of the total epidemic. In England, Wales and Northern Ireland during the study period, 18.4% HIV-infected IDU died prior to AIDS.

Studies reported from other countries have consistently showed higher pre-AIDS mortality rates in IDU than in other risk groups. For instance, in a cohort in Amsterdam, after 6.5 years of follow-up an estimated 43.7% of the homosexual men were diagnosed with AIDS and 0.7% died without an AIDS diagnosis, whereas 32.7% of the IDU were diagnosed with AIDS and 19.8% died without an AIDS diagnosis [11]. High pre-AIDS mortality rates lead to substantial underestimates of the HIV epidemic in these populations if the estimation relied only on AIDS reporting [11].

Pneumonia and septicaemia were leading causes of pre-AIDS death identified by the surveillance scheme. Pneumonia due to an unspecified organism became the leading secondary cause of death among individuals dying from HIV infection in the USA during the period 1987–1992 [23]. Male death rates for septicaemia, pneumonia and influenza were higher in high-AIDS-incidence states than in low-AIDS-incidence states in the USA between 1980 and 1987 [24]. In addition, bacterial pneumonia has also been recognized as more frequent in HIV-infected individuals than in the general population, particularly among those with CD4 lymphocyte counts < 0.2 × 106/l and in IDU [25–32].

Liver disease, the second most important cause of pre-AIDS deaths, accounted for 13.2%. Hepatic cirrhosis is commonly reported as the cause of death in IDU and haemophiliacs, two groups which have been recognized as at higher risk of (HBV and HCV) infection through exposure to blood and blood products [33,34]. Although co-infection by HIV and HBV or HCV was mentioned on only a minority of death certificates or death reports, it has been assumed that viral co-infection has affected most of the patients who were reported as having died from hepatic cirrhosis or liver failure. Virological studies have shown that mean HCV RNA levels are much higher in HIV-infected patients than in HIV-negative controls and that the level does not correlate with the CD4 cell count [35,36]. Liver damage, however, correlates with HCV viraemia [37]. These virological data support the likelihood of a more rapidly progressive HCV-related liver disease in HIV-infected patients resulting in cirrhosis or liver failure as likely causes of pre-AIDS death in haemophiliacs and IDU. All previously mentioned cohort studies of HIV-infected haemophiliacs and IDU identified liver failure or hepatic cirrhosis as a major cause of pre-AIDS death [9,11,13,14,17,38,39].

Several malignancies which are not classified as AIDS-defining have been identified. Among them, Hodgkin's disease and anal cancer were expected to be identified as causes of pre-AIDS death because their high incidence and their poorer prognosis has been established in HIV-infected patients [40–46]. Case series of lung cancer in HIV-infected individuals have been reported [47,48] and case-control studies have suggested that in this group the cancer would be more likely to be adenocarcinoma, to occur at a younger age, to be more advanced disease and have a shortened survival compared with all cases of lung cancer [49–50]. Small case series of solid tumours including gastro-intestinal, cutaneous and germ cell carcinoma have been reported in HIV-infected individuals [51–52].

One-fifth of pre-AIDS deaths were due to violent causes including suicides and accidental overdoses. Overdose is widely reported as a leading cause of pre-AIDS death in HIV-infected IDU [10,11,13,14,16,53–55]. We attributed pre-AIDS death to suicide by an overdose when both items were mentioned in the reports. If suicide was not mentioned then pre-AIDS deaths due to overdose were considered to be accidental.

A recent case note audit of HIV-infected individuals in London showed a bimodal distribution of suicidal acts with peaks at or around the diagnosis or infection and again at end-stage illness [56]. Death from suicide/overdose in a cohort of IDU was found to be twice as common in HIV-infected IDU than in HIV-seronegative IDU [55].

Our surveillance data on pre-AIDS mortality in England, Wales and Northern Ireland has several limitations. There were 8574 cases known to have fulfilled the AIDS case definition by the time of death, but of the 942 reports of deaths in HIV-infected individuals without ascertained AIDS initially included in this review 227 gave no clinical information on the cause of death or the clinical course prior to death. For a further 247 patients we were not certain whether or not they had fulfilled the AIDS case definition by the time of death (131 probable and 116 possible AIDS cases). The majority of these 474 cases will represent unreported AIDS cases but some of them are probably unreported pre-AIDS deaths. The 468 reports included in this study may therefore not represent all cases of pre-AIDS deaths. The estimate for completeness reporting AIDS cases is 87% for England and Wales and if the same under-reporting rate existed for pre-AIDS death, this would add an extra 70 cases.

The quality of our data also depends on how accurately and thoroughly the causes of pre-AIDS death were reported. Causes of death represent what was written on the surveillance form or the death certificate for the national register of deaths held at the ONS. No attempt has been made to verify these data with the clinicians.

Incompleteness of reporting to our surveillance scheme may have biased some of our results. It may explain, for instance, the finding that living outside the Thames regions is an independent risk factor for pre-AIDS mortality among HIV-infected individuals.

A small but constant proportion of patients are known to have died before developing AIDS. This has led to an underestimation of the burden of the HIV epidemic when it has been based on reported AIDS cases. The situation is likely to be less stable in the future as combination therapies and primary prophylaxis for opportunistic infections postpone the occurrence of AIDS-defining events [57]. These are now associated with a lower level of immunosuppression as assessed by the CD4 cell count [58]. Non-AIDS-defining events that could lead to pre-AIDS deaths such as bacterial infections, liver cirrhosis and cancer may be more likely to occur in an ageing group of treated patients. Such factors may compromise the continuing relevance of the clinical AIDS case definition to the objectives of the epidemiological surveillance of HIV infection in industrialized countries [59]. Surveillance of HIV infection should take account of the probably increasing number of pre-AIDS deaths, particularly in IDU, in assessing the development of the HIV epidemic, especially in countries where injecting drug use is an important source of HIV transmission.

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Acknowledgements

We thank the reporters to the National Surveillance Scheme at CDSC and the Oxford Haemophilia Centre who report on behalf of the UK Haemophilia Centre Directors Organisation for patients infected by blood factor treatment. We also acknowledge the help of staff in the PHLS AIDS and STD Centre with data analysis.

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Keywords:

Pre-AIDS mortality; mortality; surveillance

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