Causes of morbidity and mortality among patients with HIV in Singapore, from 1985 to 2001

Richard Bellamy

MRCP DPhil MSc MMEd, Consultant in Infectious Diseases and General Medicine, The James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW.

Email: richard.bellamy@stees.nhs.uk

Key words: AIDS, clinical database, cohort study, HIV, morbidity, mortality.

Summary
The major causes of morbidity and mortality among adult patients with HIV seen at the national HIV referral centre in Singapore were ascertained by a retrospective observational cohort study. Data were extracted from health care records by ten trained health care workers. AIDS-defining conditions were established using predefined criteria. For each patient a single principal cause of death was identified and confirmed by an infectious diseases specialist. Among 1504 patients, 834 had experienced a total of 1742 AIDS-defining disease episodes and 504 patients had died. 318 deaths (63.1%) were attributed to an AIDS-defining disease. The most frequent causes of the initial AIDS-defining episode were Pneumocystis carinii pneumonia (35.7%), Mycobacterium tuberculosis (22.7%), and herpes simplex (7.4%). The most frequent overall causes of any AIDS-defining disease episode were Pneumocystis carinii pneumonia (25.1%), Mycobacterium tuberculosis (16.2%), and cytomegalovirus retinitis (9.5%). The most frequent principal causes of death were Mycobacterium avium (17.5%), M. tuberculosis (9.7%), and Cryptococcus neoformans (6.7%). Mycobacterium avium infection is a more frequent cause of death among HIV patients in Singapore than has been observed in other countries.

Introduction
Cohort studies have provided valuable information on the clinical course of HIV infection in patients from Europe, North America, South America and Africa. This data is useful for health care workers caring for patients and for managers who must plan for future service requirements. Relatively few data are available on the course of HIV infection in Asian populations.
We have produced a detailed clinical database of all adult Singaporean nationals and permanent residents with HIV seen at the Communicable Diseases Centre (CDC) in Singapore since 1985. CDC is Singapore’s national referral center for adult patients with HIV. Nationwide 94.9% of all Singaporean adult residents, who have ever been diagnosed with HIV, have been referred to CDC. Underreporting of HIV does not occur as reporting occurs automatically from the reference laboratory. Therefore our database contains almost the entire country’s HIV experience. In two previous papers we have described the changes which have occurred over time in the initial AIDS-defining diagnosis and in the cause of death for the patients in this

cohort (1, 2). In this article we compare the causes of morbidity and mortality among adult patients with HIV in Singapore.

Methods
The details of the Singapore HIV Observational Ccohort Study (SHOCS) have been described previously [1, 2]. The SHOCS cohort consists of all adult Singaporean nationals or permanent residents infected with HIV who were seen on one or more occasion(s) at CDC. Data were extracted by ten trained qualified healthcare workers using a standard form. Data extraction was supervised on a daily basis by an infectious diseases (ID) physician to ensure consistency. Data were entered into a computer database (Microsoft Access™) and checked for errors and inconsistencies.

Probable and confirmed criteria were developed for the diagnosis of AIDS-defining conditions, based on the 1993 guidelines of the United States’ Centers for Disease Control and Prevention (3). Diagnoses were not included if they did not fulfill the specified criteria even if there was a strong clinical suspicion of a particular condition. If there was insufficient evidence to satisfy the criteria for a specific diagnosis, a more general diagnosis was assigned, for example cerebral lesion (cause unknown) would be used if there was insufficient evidence to support a diagnosis of toxoplasmosis of the brain or primary cerebral lymphoma. Each new or recurrent AIDS-defining condition counted as one event (i.e. a patient with three diagnoses would contribute three events). An AIDS-defining condition was counted as a separate additional event if it recurred six or more months after the initial diagnosis or in the case of tuberculosis, six or more months after treatment completion. Median CD4 counts were calculated based on the sample taken nearest the time of diagnosis of the initial AIDS-defining condition.

Results
Among the 1504 patients infected with HIV who were seen at CDC between 1985 and the end of 2001, 834 developed one or more AIDS-defining conditions (table 1). The most frequent initial AIDS-defining disease episodes were due to Pneumocystis carinii pneumonia (35.7% of total diagnoses), M. tuberculosis (22.7%), herpes simplex (chronic mucocutaneous) (7.4%) and candidiasis (esophageal or tracheobronchial) (6.9%) (table 1). 1742 AIDS-defining disease episodes were recorded (table 2). Infectious diseases accounted for the 10 most frequent AIDS-defining conditions. The most frequent AIDS-defining disease episodes were Pneumocystis carinii pneumonia (25.1%), M. tuberculosis (16.2%), cytomegalovirus retinitis (9.5%), herpes simplex (chronic mucocutaneous) (8.2%), disseminated M. avium (8.2%) and candidiasis (esophageal or tracheobronchial) (7.8%) (table 2).

504 patients had died up to the end of 2001, of whom 318 died from an AIDS-defining condition (table 3). The most frequent principal causes of death were disseminated M. avium (17.5% of cases), M. tuberculosis (9.7%) and Cryptococcosus neoformans (6.7%) (table 3).

Discussion
The major causes of morbidity and mortality among HIV patients in Singapore are infectious diseases. This is in contrast to Western cohorts where non-infectious causes such as malignancy, cardiovascular and liver disease now dominate (4). The pattern of morbidity and mortality among HIV patients in Singapore also differs from that recorded in Thailand. A cohort study of AIDS patients in Bangkok, between 1987 and 1993, found that the most common initial AIDS-defining diagnoses were extrapulmonary tuberculosis (22.8%), Pneumocystis carinii pneumonia (7.0%) and cryptococcal meningitis (10.9%) [33] (5). Between 1993 and 1996, extrapulmonary cryptococcosis became the most common initial AIDS-defining diagnosis (6). Pneumocystis carinii pneumonia caused a much higher proportion of AIDS-defining diseases in Singapore than in Bangkok and cryptococcal meningitis occurred more frequently in Bangkok. The most common diagnoses at the time of death in Bangkok between 1987 and 1993 were cryptococcal meningitis (26.3%), extrapulmonary tuberculosis (19.7%) and Pneumocystis carinii pneumonia (13.2%) (5). M. avium caused a much higher proportion of deaths among HIV patients in Singapore than in Bangkok and cryptococcal meningitis caused more deaths in Bangkok.

Disseminated M. avium infection was the leading cause of death in patients with HIV in Singapore. It was a more frequent cause of death than has been found in Western cohorts, South America, Africa and Thailand (5). Among patients with HIV in Singapore, M. avium accounted for a higher proportion of deaths (17.5%) than initial AIDS-defining conditions (3.6%) and total AIDS diagnoses (8.2%) (tables 2, 3 and 4). In contrast M. tuberculosis and Pneumocystis carinii pneumonia accounted for a much smaller proportion of deaths (9.7% and 5.4% respectively) than AIDS-defining diagnoses (22.7% and 35.7%) and total AIDS diagnoses (16.2% and 25.1%) (tables 2, 3 and 4). It is notable that the commonest causes of death among HIV patients in Singapore (i.e. M. avium) and Thailand (i.e. Cryptococcus neoformans) require expensive long-term
treatments. This emphasizes the need for subsidized treatment for opportunistic infections to be made available to patients in Asia. Free or at least subsidized highly active anti-retroviral therapy (HAART) offers the best long-term hope for patients with HIV infection. However M. avium infection is still the commonest cause of death in patients with HIV in Singapore despite the availability of HAART. It is essential that patients can access affordable treatment for opportunistic infections to ensure that those who present with advanced disease survive long enough to benefit from HAART.

References
1. Bellamy R, Sangeetha S & Paton NI. Causes of death among patients with HIV in Singapore, from 1985 to 2001: results from the Singapore HIV Observational Cohort Study (SHOCS). HIV Medicine 2004;5:289-295.
2. Bellamy R, Sangeetha S & Paton NI. AIDS-defining illnesses among patients with HIV in Singapore, 1985 to 2001: results from the Singapore HIV Observational Cohort Study (SHOCS). BioMed Central Infectious Diseases 2004:4:47.
3. Centers for Disease Control and Prevention. 1993 Classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbid Mortal Wkly Rep 1992;41(RR-17):1-19.
4. Mocroft A, Brettle R, Kirk O, et al. Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study. AIDS 2002;16:1663-1671.
5. Kitayaporn D, Tansuphaswadikul S, Lohsomboon P, et al. Survival of AIDS patients in the emerging epidemic in Bangkok, Thailand. J AIDS Hum Retrovirol 1996;11:77-82.
6. Tansuphasawadikul S, Amornkul PN, Tanchanpong C, et al. Clinical presentation of hospitalized adult patients with HIV infection and AIDS in Bangkok, Thailand. J AIDS 1999,21:326-332.

 

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