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.
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.
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.
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.
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  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 . High pre-AIDS mortality rates lead to substantial underestimates of the HIV epidemic in these populations if the estimation relied only on AIDS reporting .
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 . 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 . 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 . 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 . 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 .
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 . These are now associated with a lower level of immunosuppression as assessed by the CD4 cell count . 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 . 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.
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:© Lippincott-Raven Publishers.
Pre-AIDS mortality; mortality; surveillance