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Mortality and survival trends in patients with AIDS in North East England from 1984–1992
Journal of Infection (1995) 30, 23-27
Mortality and Survival Trends in Patients with AIDS in North East England from 1984-1992 L. Dorrell, M. H. Snow and E. L. C. Ong Infectious Diseases Unit, Newcastle General Hospital, Newcastle Upon Tyne NE4 6BE, U.K. Accepted for publication 2 7 M a y 1 9 9 4
Objective: to study trends in mortality and survival in patients with AIDS attending an ID unit. Method: retrospective analysis of patients developing an AIDS-defining illness between April 1984, and November 1992. Survival was analysed by calculation of survival p~vduct-limit. Results: 71 patients were analysed (including four women), 23 of whom are still alive. Pneumocystis carinii pneumonia (PCP) was the most frequent AIDS-index diagnosis: n = 36 (51%); 24 of these patients have died. HIV encephalopathy was the most frequent diagnosis at death; n = 16 (22.5%), followed by mycobacteriaI infection; n = 1i (15.5%), and PCP and CMV infection, each occurring in 10 (14%). One-, 2- and 3-year survival probabilities for patients with AIDS before 1987 were 0.46, 0.15 and 0 compared with probabilities of 0.63, 0.5 and 0.3 in those diagnosed after I987; log rank - P < 0.01. One- and 2-year survival probabilities in patients who received at least 3 months' zidovudine (AZT) therapy were 0.76 and 0.53 in those who are still alive compared with 0.55 and 0.33 in the deceased, while values for deceased AZTnaive patients were 0.29 and O. 1; - P < 0.01. Thirteen (27%) deaths occured within 2 months of an AIDS-index disease. In 10 patients this was their first presentation to the department. PCP accounted for 8 (61%) of these deaths. Conclusions: survival in patients with AIDS has increased since 1987, when AZT was introduced. Early AIDS-related deaths are frequent in patients who have had no prior medical care. This has implications for education and provision of care in individuals with asymptomatic HIV infection.
Introduction
Methods
An increase in survival in individuals with AIDS has been observed in a number of centres over the past 5 years, 13 though this phenomenon has only occurred in developed nations. 4 Explanations postulated for the changing mortality of AIDS include the prevention of opportunistic infections, earlier diagnosis of, and more effective treatment of HIV-related disease and the introduction of zidovudine.5' 6 An example of this is Pneumocystis carinii pneumonia (PCP): mortality associated with first-episode PCP was approximately 20% a decade ago; 7 the diagnosis and treatment of this infection at an earlier stage in its natural history and the use of specific prophylaxis have reduced PCP-associated mortality significantly.8.9 The availability of techniques for measuring so-called surrogate markers of disease progression, for example, CD4 lymphocyte count, has made possible the identification of individuals at high risk of disease progression, to w h o m specific therapies can be offered. ~° We report survival trends after AIDS diagnosis in patients referred to our unit from 1984 to 1992.
Patients
Address correspondence to: Dr E. L. C. Orig. 0163~J~453/95/010023 +05 $08.00/0
Data were obtained from the medical records of patients referred to the Infectious Disease Unit, Newcastle General Hospital. Inclusion criteria were the occurrence of an AIDS-index disease (198 7 definition), evidence of regular attendance at the out-patient department and in the case of deceased patients, death in hospital. The study period was from April 1984, when the first case of AIDS in this hospital was documented, to the end of November 1992. The following information was recorded: age; sex; mode of acquisition of HIV infection; date of first AIDS-indicator disease; date and cause of death; CD4 lymphocyte count at the time of the AIDS-index disease and before death (last available count); the use of zidovudine and PCP prophylaxis.
Interventions
Zidovudine was introduced in 1987 at doses of 1 2 0 0 - 1 5 0 0 mg daily; the standard dose was reduced to 600 mg daily in 1990 when the higher safety profile of lower doses was recognised. PCP prophylaxis was offered © 1995 The British Societyfor the Study of Infection
24
Mortality and Survival Trends in Patients with AIDS
Table 1. Demographic characteristics of the study population Age (mean): living deceased Sex (no. of females) HIV risk (n): homosexual/bisexual heterosexual haemophiliac intravenous drug user other CD4 count ( x 106/1): AIDS median death - median CD4 count <200 at AIDS diagnosis (n) CD4 count < 100 at AIDS diagnosis (n) Zidovudine therapy (n): >3/12 <3/12 or nil PCP prophylaxis (n) -
37.3 35 38.4 4 52 10 5 6 4 70 20 53 39
(range: 0-510) (range: 0-410) (87%) (64%)
45 (63%) 26 (37%) 49 (69%)
Table 2. AIDS diagnoses by year 1984-86
1987-89
1990-92
total
AIDS-index disease and deaths by year AIDS 16 22 42 80 diagnoses (n) patients with new 13 19 39 71 AIDS diagnosis (48 (n) deceased) deaths 11 6 33 50 Frequency of major ADS-index diseases by year and diagnosis PCP 6 14 i6 36 OC 7 0 8 15 KS 1 3 6 10 Frequency of mNor causes of death by year HIV enceph. 2 2 12 16 MAC 0 4 7 11 PCP 3 3 4 10 CMV 0 2 8 10 PCP P. carinii pneumonia; OC- Oesophageal candidiasis; KS - Kaposi's sarcoma; MAC-M. avium complex; CMV - cytomegalovirus -
Key: n=number of patients; HIV risk--6 patients had ~ 1 risk; CD4 count--available in 61 patients with AIDS, 39 patients at death.
Morbidity to patients w i t h CD4 < 2 0 0 x 106/1 ( p r i m a r y prophylaxis) a n d to patients w i t h a history of PCP ( s e c o n d a r y prophylaxis) from 19 8 5. The p r o p h y l a c t i c a g e n t s m o s t comm o n l y used w e r e d a p s o n e 100 m g plus p y r i m e t h a m i n e 12.5 m g weekly a n d p e n t a m i d i n e 3 0 0 m g fortnightly by nebuliser u n t i l 19 9 2, w h e n co-trimoxazole 9 60 m g threetimes w e e k l y was used in patients w i t h no k n o w n allergy to co-trimoxazole.
PCP was the m o s t frequent AIDS-index disease, o c c u r r i n g in 3 6 (51%) patients, followed by o e s o p h a g e a l candidiasis in 15 (22%) a n d Kaposi's s a r c o m a in t e n (14.1%). AIDS diagnoses by y e a r are s h o w n in Table 2. Other diagnoses were: cryptosporidiosis, n = 3; n o n - H o d g k i n ' s l y m p h o m a , n = 3 ; c y t o m e g a l o v i r u s (CMV) retinitis, n = 2 ; w a s t i n g syndrome, n = 2; progressive multifocal leuk o e n c e p h a l o p a t h y , n = 1; Mycobacterium avium complex infection, n = 1; Herpes simplex infection, n = 1 a n d cerebral toxoplasmosis, n = 1. More t h a n one diagnosis was m a d e in six patients.
Statistical analysis Post-AIDS survival was a n a l y s e d by e v a l u a t i o n of survival product-limit. Survival curves were c o m p a r e d b y calc u l a t i o n of the l o g - r a n k statistic.
Results
Patients A t the e n d of N o v e m b e r 1992, 80 patients h a d h a d at least one AIDS-defining disease. Twenty-six were still alive a l t h o u g h t h r e e of these were excluded from analysis (two were lost to follow-up a n d one w a s a t e m p o r a r y resident). Of the 54 deceased patients, four h a d died in o t h e r hospitals or at h o m e a n d t h e details of the d e a t h s w e r e n o t k n o w n . Two patients died of causes u n r e l a t e d to HIV infection. These six patients were also excluded from analysis. The d e m o g r a p h i c characteristics of the s t u d y p o p u l a t i o n a r e s h o w n in Table 1.
Mortality Cause of d e a t h was defined as n o t e d in the p a t i e n t s ' records, or w h e r e available, a c c o r d i n g to a u t o p s y findings. In some patients, m o r e t h a n one diagnosis w a s given. The m o s t frequently recorded diagnosis at d e a t h was HIV e n c e p h a l o p a t h y , o c c u r r i n g in 16 (33 %) patients, followed by M y c o b a c t e r i a l infections, n = 11 (2 3 %); PCP, n = l O (21%) a n d CMV infection, n = l O (21%). Other causes of d e a t h were Kaposi's s a r c o m a , n = 7; l y m p h o m a , n = 6; cryptosporidiosis, n = 5; toxoplasmosis, n = 4 ; progressive multifocal leukoencephalopathy, n = 1; a n d oes o p h a g e a l candidiasis, n = 1. Nine d e a t h s were u n r e l a t e d to HIV infection. Deaths by y e a r are s h o w n in Table 2.
Survival Survival estimates were c a l c u l a t e d for patients developing AIDS before a n d after 19 8 7 (Fig. 1). Survival probabilities
L. Dorrell et al.
25
1.0
0.8
I
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,
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0.4
0.2 . . . . . . . . . . . . . . !
I
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24 Time ( m o n t h s )
Figure 1, Probability of survival in patients with AIDS before and after 1987. (. . . .
!
I
I
36
48
) 1984-1986; ( - - )
1987-1992.
1.0
0.8
"! 0-6
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i
0.4
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0.2 i .........
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12
24
36
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48
Time (months) Figure 2. Probability of survival in zidovudine-treated and untreated patients with AIDS. ( - - ) deceased patients who received zidovudine; (. . . . . ) deceased untreated patients.
at 1, 2 and 3 years were 0.46, 0.15 and 0 for patients diagnosed from 1984 to the end of 1986, and 0.63, 0.5 and 0.3 for patients diagnosed from 1987 to 1992; log rank: P < 0.01. Median survival increased from less t h a n 6 months to 24 months after 1987. The effect of zidovudine on post-AIDS survival is shown in Fig. 2. Deceased patients who received less t h a n 3 months' or no zidovudine (n = 21) were compared with both deceased ( n = 2 7 ) and living patients ( n = 18) who received more than 3 months' therapy. There were five living patients who had received less t h a n 3 months' zidovudine for reasons of non-compliance ( n = 2 ) , intolerance (n = 1), current gancyclovir therapy (n = 1) and
living patients receiving zidovudine; (. . . . . . .
)
late entry into the study (n = 1). These patients were not included in view of the small size of this group. Survival probabilities at 1, 2 and 3 years were: 0.76, 0.53 and O. 17 for living patients receiving zidovndine; O. 55, O. 33 and 0.11 for deceased patients who received more than 3 months' zidovudine; and 0.29, 0.1 and 0 for deceased zidovudine-untreated patients. Log-rank: P <0.01.
Timing of zidovudine therapy Survival was further analysed by stratification according to whether zidovudine was started at least 3 months
26
Mortality and Survival Trends in Patients with AIDS 1.0 0.8
:---[. 'I -
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Time ( m o n t h s ) Figure 3. Probability of survival in patients with AIDS according to timing of zidovudine therapy. ( ) patients receiving zidovudine after or less than 3 months before AIDSdiagnosis; (. . . . ) patients receiving zidovudine at least 3 months before AIDSdiagnosis.
before the AIDS-index disease or whether it was introduced from 3 months before or after the diagnosis of AIDS. Survival curves are shown in Fig. 3. Post-AIDS survival was significantly longer in patients who started zidovudine after their AIDS-index disease; log rank: P <0.001.
Early deaths Twelve patients (25%) died within 2 months of the onset of their AiDS-index disease. Nine of these were new referrals to the Unit, six of w h o m were unaware of their HIV status. Mean age of these patients was 37 years. Only one of the deaths was unrelated to their HIV infection (a retroperitoneal h a e m o r r h a g e in a haemophifiac). PCP was diagnosed in seven (58%) of these patients and was the sole cause of death in four. Eight of these patients had received no prior zidovudine or PCP prophylaxis.
Discussion In this study we have examined the pattern of AIDS morbidity and mortality in the population attending our unit over the past 9 years. Although the cohort is too small to allow comment on changes in prevalence of separate AiDS-related diseases, our findings are similar to those of studies referred to earlier. PCP is the most frequently observed AIDS-index disease in this population. This reflects the ubiquitous nature of this pathogen. Serological evidence of exposure to P. carinii has been found in up to 98% of healthy children
in the first 2 years of life 11 and the development of PCP in immunocompromised individuals is thought to be due to reactivation of latent infection. The majority of cases of PCP were in patients newly referred to the unit who had not previously received prophylaxis. In the same population we have found that the number of PCP episodes due to failed prophylaxis is fairly low (unpublished data). Furthermore, of the patients in w h o m prophylaxis failed, none died and none required artificial ventilation during the course of their pneumonic episode. The outcome of PCP has been shown to be related to the degree of pneumonitis at presentation and PCP prophylaxis m a y modify the extent of the disease if and when it does occur, s Our findings of increased post-AIDS survival after 1987 can be partly attributed to zidovudine usage. Zidovudine has been found to reduce morbidity and mortality in patients with AIDS 12 but its ability to delay the onset of disease in asymptomatic individuals is debatable: large multi-centre trials have produced conflicting results, partly due to a difference in the duration of followup.13.14 Our data indicate that probability of survival up to 3 years after AIDS diagnosis was significantly higher in patients who received at least 3 months' zidovudine therapy. Interestingly, the post-AIDS survival benefit was greater in patients who started zidovudine less than 3 months before, or after their AiDS-index disease compared with those who started therapy at least 3 months prior. This finding m a y be interpreted in two ways: either, that zidovudine has a more beneficial effect on survival in patients with advanced disease t h a n in asymptomatic individuals; alternatively, zidovudine m a y postpone symptomatic disease in the latter but not alter survival
L. Dorrell et al, once an AIDS-index disease has occurred, resulting in a compression of AIDS morbidity. This could only be confirmed if the date of the seroconversion of our patients were known but such data were not available. We have found differences in disease patterns at the onset of AIDS and at death. PCP, oesophageal candidiasis and Kaposi's sarcoma accounted for approximately 75% of AIDS-index diseases, whereas at death, other pathologies predominated, namely, HIV encephalopathy and infection with M. avium complex and cytomegalovirus. This is not surprising in view of the lack of effective, nontoxic therapies for such infections. The prevalence of these diseases at death is also a reflection of the progression of CD4 lymphocytopaenia in the course of HIV infection since they seldom occur in individuals with CD4 lymphocyte counts of >100 x 10~/1. ~° Moreover, the more frequent diagnosis of HIV encephalopathy at death may reflect the insidious nature of this disease, the clinical features being more obvious with advancing immunological decline than earlier in the patients' history. Post-mortem studies have revealed a higher prevalence of HIV-related neuropathology than that suggested by epidemiological studies of living patients with AIDS. 15' 16 Psychometric analysis may detect cognitive deficits in a higher proportion of individuals with neurological morbidity, ~7 therefore, we may be underestimating the prevalence of HIV encephalopathy in our patients. The large proportion of early deaths i.e. within 2 months of the onset of the AIDS-index disease is disturbing. Most of the patients in this group were new referrals to the unit and had received no prior medical intervention. Moreover, in two-thirds, their HIV status was unknown until their terminal hospital admission. The high frequency of PCP in this group reflects the considerable mortality of PCP in patients in whom therapy is delayed, either because of failure to seek medical attention or because of failure to make the correct diagnosis. Our data emphasise the importance of maintaining a high index of suspicion in patients with atypical pneumonia who present to primary health care providers since with the diagnostic methods and therapies currently available, PCP-deaths are largely preventable. In conclusion, we have observed an increase in survival of patients with AIDS over the past 5 years which can be attributed to a combination of greater experience in
27
the management of HIV disease, the use of zidovudine and PCP prophylaxis and regular out-patient review. The significant number of deaths in individuals who present late in the course of their disease has implications for the provision of information and care to both asymptomatic HIV-seropositive individuals and to the general population.
References 1 Pedersen C, Gerstoft J, Tauris P e t al. Trends in survival of Danish AIDS patients from 1981 to 1989. AIDS 1990; 4: 1111-1116. 2 Bindels P, Poos R, ]ong J e t al. Trends in mortality among AIDS patients in Amsterdam 1982-1988. AIDS 1991; 5: 853-858. 3 Peters BS, Beck E, Coleman D et al. Changing disease patterns in patients with AIDS in a referral centre in the United Kingdom: the changing face of AIDS. BM] 1991; 302: 203-207. 4 Chequer P, Hearst N, Sid Hughes E et al. Determinants of survival in adult Brazilian AIDS patients. AIDS 1992; 6: 483~t87. 5 Lemp G, Payne S, Neal D et al. Survival trends for patients with AIDS. JAMA 1990; 263: 402-406. 6 Moore R, Hidalgo J, Sugland Bet al. Zidovudine and the natural history of the acquired immunodeficiency syndrome. N Engl J Med 1991; 324: 1412-1416. 7 Montgomery AB. Pneumocystis carinii pneumonia prophylaxis: past, present and future. AIDS 1992; 6:227 228. 8 BeckE, FrenchP, HelbertMetal. ImprovedoutcomeofPneumocystis carinii pneumonia in AIDS patients: a multifactorial treatment effect. Int J STD O AIDS 1992: 3: I82-187. 9 Leoung G, Feigal D, Montgomery ABet al. Aerosolised pentamidine for prophylaxis against P. carinii pneumonia. N Engl ] Med 1990; 323: 769-775. 10 Crowe S, Carlin J, Stewart K et al. Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in H1Vqnfected persons. J AIDS 199I; 4: 770-776. 11 Meuwissen ], Tauber I, Leewenberg P e t al. J Infect Dis 1977; 136: 43-49. 12 Fischl M, Richman D, Grieco M e t al. The efficacy of AZT in the treatment of patients with AIDS and AIDS-related complex: a double-blind placebo-controlled trial. N Engl ] Med 1987; 317: 185-191. 13 Volberding R Lagakos S, Koch Met al. Zidovudine in asymptomatic HIV infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimetre. N Engl ] Med 1990; 322: 941 949. 14 Aboulker J-P, Swart M et al. Preliminary analysis of the Concorde trial. Lancet 1993; 341: 889-890. 15 Tyndel F. Clinical neurology of HIV infection. Can ] Diag 1990: 7: 1"29-151. 16 Janssen R, Nwanyanwu O, Selik R et al. Epidemiology of human immunodeficiency virus encephalopathy in the United States. Neurology 1992; 42:1472 1476. 17 Grant I, Atkinson ], Henelink J e t o.1. Evidence for early CNS involvement in the acquired immunodeficiencysyndrome and other human tmmunodeficiency virus infections. Ann Intern Med 1987; 107: 828-836.
Mortality and Survival Trends in Patients with AIDS in North East England from 1984-1992 L. Dorrell, M. H. Snow and E. L. C. Ong Infectious Diseases Unit, Newcastle General Hospital, Newcastle Upon Tyne NE4 6BE, U.K. Accepted for publication 2 7 M a y 1 9 9 4
Objective: to study trends in mortality and survival in patients with AIDS attending an ID unit. Method: retrospective analysis of patients developing an AIDS-defining illness between April 1984, and November 1992. Survival was analysed by calculation of survival p~vduct-limit. Results: 71 patients were analysed (including four women), 23 of whom are still alive. Pneumocystis carinii pneumonia (PCP) was the most frequent AIDS-index diagnosis: n = 36 (51%); 24 of these patients have died. HIV encephalopathy was the most frequent diagnosis at death; n = 16 (22.5%), followed by mycobacteriaI infection; n = 1i (15.5%), and PCP and CMV infection, each occurring in 10 (14%). One-, 2- and 3-year survival probabilities for patients with AIDS before 1987 were 0.46, 0.15 and 0 compared with probabilities of 0.63, 0.5 and 0.3 in those diagnosed after I987; log rank - P < 0.01. One- and 2-year survival probabilities in patients who received at least 3 months' zidovudine (AZT) therapy were 0.76 and 0.53 in those who are still alive compared with 0.55 and 0.33 in the deceased, while values for deceased AZTnaive patients were 0.29 and O. 1; - P < 0.01. Thirteen (27%) deaths occured within 2 months of an AIDS-index disease. In 10 patients this was their first presentation to the department. PCP accounted for 8 (61%) of these deaths. Conclusions: survival in patients with AIDS has increased since 1987, when AZT was introduced. Early AIDS-related deaths are frequent in patients who have had no prior medical care. This has implications for education and provision of care in individuals with asymptomatic HIV infection.
Introduction
Methods
An increase in survival in individuals with AIDS has been observed in a number of centres over the past 5 years, 13 though this phenomenon has only occurred in developed nations. 4 Explanations postulated for the changing mortality of AIDS include the prevention of opportunistic infections, earlier diagnosis of, and more effective treatment of HIV-related disease and the introduction of zidovudine.5' 6 An example of this is Pneumocystis carinii pneumonia (PCP): mortality associated with first-episode PCP was approximately 20% a decade ago; 7 the diagnosis and treatment of this infection at an earlier stage in its natural history and the use of specific prophylaxis have reduced PCP-associated mortality significantly.8.9 The availability of techniques for measuring so-called surrogate markers of disease progression, for example, CD4 lymphocyte count, has made possible the identification of individuals at high risk of disease progression, to w h o m specific therapies can be offered. ~° We report survival trends after AIDS diagnosis in patients referred to our unit from 1984 to 1992.
Patients
Address correspondence to: Dr E. L. C. Orig. 0163~J~453/95/010023 +05 $08.00/0
Data were obtained from the medical records of patients referred to the Infectious Disease Unit, Newcastle General Hospital. Inclusion criteria were the occurrence of an AIDS-index disease (198 7 definition), evidence of regular attendance at the out-patient department and in the case of deceased patients, death in hospital. The study period was from April 1984, when the first case of AIDS in this hospital was documented, to the end of November 1992. The following information was recorded: age; sex; mode of acquisition of HIV infection; date of first AIDS-indicator disease; date and cause of death; CD4 lymphocyte count at the time of the AIDS-index disease and before death (last available count); the use of zidovudine and PCP prophylaxis.
Interventions
Zidovudine was introduced in 1987 at doses of 1 2 0 0 - 1 5 0 0 mg daily; the standard dose was reduced to 600 mg daily in 1990 when the higher safety profile of lower doses was recognised. PCP prophylaxis was offered © 1995 The British Societyfor the Study of Infection
24
Mortality and Survival Trends in Patients with AIDS
Table 1. Demographic characteristics of the study population Age (mean): living deceased Sex (no. of females) HIV risk (n): homosexual/bisexual heterosexual haemophiliac intravenous drug user other CD4 count ( x 106/1): AIDS median death - median CD4 count <200 at AIDS diagnosis (n) CD4 count < 100 at AIDS diagnosis (n) Zidovudine therapy (n): >3/12 <3/12 or nil PCP prophylaxis (n) -
37.3 35 38.4 4 52 10 5 6 4 70 20 53 39
(range: 0-510) (range: 0-410) (87%) (64%)
45 (63%) 26 (37%) 49 (69%)
Table 2. AIDS diagnoses by year 1984-86
1987-89
1990-92
total
AIDS-index disease and deaths by year AIDS 16 22 42 80 diagnoses (n) patients with new 13 19 39 71 AIDS diagnosis (48 (n) deceased) deaths 11 6 33 50 Frequency of major ADS-index diseases by year and diagnosis PCP 6 14 i6 36 OC 7 0 8 15 KS 1 3 6 10 Frequency of mNor causes of death by year HIV enceph. 2 2 12 16 MAC 0 4 7 11 PCP 3 3 4 10 CMV 0 2 8 10 PCP P. carinii pneumonia; OC- Oesophageal candidiasis; KS - Kaposi's sarcoma; MAC-M. avium complex; CMV - cytomegalovirus -
Key: n=number of patients; HIV risk--6 patients had ~ 1 risk; CD4 count--available in 61 patients with AIDS, 39 patients at death.
Morbidity to patients w i t h CD4 < 2 0 0 x 106/1 ( p r i m a r y prophylaxis) a n d to patients w i t h a history of PCP ( s e c o n d a r y prophylaxis) from 19 8 5. The p r o p h y l a c t i c a g e n t s m o s t comm o n l y used w e r e d a p s o n e 100 m g plus p y r i m e t h a m i n e 12.5 m g weekly a n d p e n t a m i d i n e 3 0 0 m g fortnightly by nebuliser u n t i l 19 9 2, w h e n co-trimoxazole 9 60 m g threetimes w e e k l y was used in patients w i t h no k n o w n allergy to co-trimoxazole.
PCP was the m o s t frequent AIDS-index disease, o c c u r r i n g in 3 6 (51%) patients, followed by o e s o p h a g e a l candidiasis in 15 (22%) a n d Kaposi's s a r c o m a in t e n (14.1%). AIDS diagnoses by y e a r are s h o w n in Table 2. Other diagnoses were: cryptosporidiosis, n = 3; n o n - H o d g k i n ' s l y m p h o m a , n = 3 ; c y t o m e g a l o v i r u s (CMV) retinitis, n = 2 ; w a s t i n g syndrome, n = 2; progressive multifocal leuk o e n c e p h a l o p a t h y , n = 1; Mycobacterium avium complex infection, n = 1; Herpes simplex infection, n = 1 a n d cerebral toxoplasmosis, n = 1. More t h a n one diagnosis was m a d e in six patients.
Statistical analysis Post-AIDS survival was a n a l y s e d by e v a l u a t i o n of survival product-limit. Survival curves were c o m p a r e d b y calc u l a t i o n of the l o g - r a n k statistic.
Results
Patients A t the e n d of N o v e m b e r 1992, 80 patients h a d h a d at least one AIDS-defining disease. Twenty-six were still alive a l t h o u g h t h r e e of these were excluded from analysis (two were lost to follow-up a n d one w a s a t e m p o r a r y resident). Of the 54 deceased patients, four h a d died in o t h e r hospitals or at h o m e a n d t h e details of the d e a t h s w e r e n o t k n o w n . Two patients died of causes u n r e l a t e d to HIV infection. These six patients were also excluded from analysis. The d e m o g r a p h i c characteristics of the s t u d y p o p u l a t i o n a r e s h o w n in Table 1.
Mortality Cause of d e a t h was defined as n o t e d in the p a t i e n t s ' records, or w h e r e available, a c c o r d i n g to a u t o p s y findings. In some patients, m o r e t h a n one diagnosis w a s given. The m o s t frequently recorded diagnosis at d e a t h was HIV e n c e p h a l o p a t h y , o c c u r r i n g in 16 (33 %) patients, followed by M y c o b a c t e r i a l infections, n = 11 (2 3 %); PCP, n = l O (21%) a n d CMV infection, n = l O (21%). Other causes of d e a t h were Kaposi's s a r c o m a , n = 7; l y m p h o m a , n = 6; cryptosporidiosis, n = 5; toxoplasmosis, n = 4 ; progressive multifocal leukoencephalopathy, n = 1; a n d oes o p h a g e a l candidiasis, n = 1. Nine d e a t h s were u n r e l a t e d to HIV infection. Deaths by y e a r are s h o w n in Table 2.
Survival Survival estimates were c a l c u l a t e d for patients developing AIDS before a n d after 19 8 7 (Fig. 1). Survival probabilities
L. Dorrell et al.
25
1.0
0.8
I
0.~
I ,,
,
]
0.4
0.2 . . . . . . . . . . . . . . !
I
0
I
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24 Time ( m o n t h s )
Figure 1, Probability of survival in patients with AIDS before and after 1987. (. . . .
!
I
I
36
48
) 1984-1986; ( - - )
1987-1992.
1.0
0.8
"! 0-6
! i
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0.4
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24
36
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48
Time (months) Figure 2. Probability of survival in zidovudine-treated and untreated patients with AIDS. ( - - ) deceased patients who received zidovudine; (. . . . . ) deceased untreated patients.
at 1, 2 and 3 years were 0.46, 0.15 and 0 for patients diagnosed from 1984 to the end of 1986, and 0.63, 0.5 and 0.3 for patients diagnosed from 1987 to 1992; log rank: P < 0.01. Median survival increased from less t h a n 6 months to 24 months after 1987. The effect of zidovudine on post-AIDS survival is shown in Fig. 2. Deceased patients who received less t h a n 3 months' or no zidovudine (n = 21) were compared with both deceased ( n = 2 7 ) and living patients ( n = 18) who received more than 3 months' therapy. There were five living patients who had received less t h a n 3 months' zidovudine for reasons of non-compliance ( n = 2 ) , intolerance (n = 1), current gancyclovir therapy (n = 1) and
living patients receiving zidovudine; (. . . . . . .
)
late entry into the study (n = 1). These patients were not included in view of the small size of this group. Survival probabilities at 1, 2 and 3 years were: 0.76, 0.53 and O. 17 for living patients receiving zidovndine; O. 55, O. 33 and 0.11 for deceased patients who received more than 3 months' zidovudine; and 0.29, 0.1 and 0 for deceased zidovudine-untreated patients. Log-rank: P <0.01.
Timing of zidovudine therapy Survival was further analysed by stratification according to whether zidovudine was started at least 3 months
26
Mortality and Survival Trends in Patients with AIDS 1.0 0.8
:---[. 'I -
I
i I L. . . . . .
I
I
0.6 o
0-4
0.2 . . . . . . . . . . . . . . . . . . .
, 0
I 12
,
I 24
,
I
[ 36
, 48
Time ( m o n t h s ) Figure 3. Probability of survival in patients with AIDS according to timing of zidovudine therapy. ( ) patients receiving zidovudine after or less than 3 months before AIDSdiagnosis; (. . . . ) patients receiving zidovudine at least 3 months before AIDSdiagnosis.
before the AIDS-index disease or whether it was introduced from 3 months before or after the diagnosis of AIDS. Survival curves are shown in Fig. 3. Post-AIDS survival was significantly longer in patients who started zidovudine after their AIDS-index disease; log rank: P <0.001.
Early deaths Twelve patients (25%) died within 2 months of the onset of their AiDS-index disease. Nine of these were new referrals to the Unit, six of w h o m were unaware of their HIV status. Mean age of these patients was 37 years. Only one of the deaths was unrelated to their HIV infection (a retroperitoneal h a e m o r r h a g e in a haemophifiac). PCP was diagnosed in seven (58%) of these patients and was the sole cause of death in four. Eight of these patients had received no prior zidovudine or PCP prophylaxis.
Discussion In this study we have examined the pattern of AIDS morbidity and mortality in the population attending our unit over the past 9 years. Although the cohort is too small to allow comment on changes in prevalence of separate AiDS-related diseases, our findings are similar to those of studies referred to earlier. PCP is the most frequently observed AIDS-index disease in this population. This reflects the ubiquitous nature of this pathogen. Serological evidence of exposure to P. carinii has been found in up to 98% of healthy children
in the first 2 years of life 11 and the development of PCP in immunocompromised individuals is thought to be due to reactivation of latent infection. The majority of cases of PCP were in patients newly referred to the unit who had not previously received prophylaxis. In the same population we have found that the number of PCP episodes due to failed prophylaxis is fairly low (unpublished data). Furthermore, of the patients in w h o m prophylaxis failed, none died and none required artificial ventilation during the course of their pneumonic episode. The outcome of PCP has been shown to be related to the degree of pneumonitis at presentation and PCP prophylaxis m a y modify the extent of the disease if and when it does occur, s Our findings of increased post-AIDS survival after 1987 can be partly attributed to zidovudine usage. Zidovudine has been found to reduce morbidity and mortality in patients with AIDS 12 but its ability to delay the onset of disease in asymptomatic individuals is debatable: large multi-centre trials have produced conflicting results, partly due to a difference in the duration of followup.13.14 Our data indicate that probability of survival up to 3 years after AIDS diagnosis was significantly higher in patients who received at least 3 months' zidovudine therapy. Interestingly, the post-AIDS survival benefit was greater in patients who started zidovudine less than 3 months before, or after their AiDS-index disease compared with those who started therapy at least 3 months prior. This finding m a y be interpreted in two ways: either, that zidovudine has a more beneficial effect on survival in patients with advanced disease t h a n in asymptomatic individuals; alternatively, zidovudine m a y postpone symptomatic disease in the latter but not alter survival
L. Dorrell et al, once an AIDS-index disease has occurred, resulting in a compression of AIDS morbidity. This could only be confirmed if the date of the seroconversion of our patients were known but such data were not available. We have found differences in disease patterns at the onset of AIDS and at death. PCP, oesophageal candidiasis and Kaposi's sarcoma accounted for approximately 75% of AIDS-index diseases, whereas at death, other pathologies predominated, namely, HIV encephalopathy and infection with M. avium complex and cytomegalovirus. This is not surprising in view of the lack of effective, nontoxic therapies for such infections. The prevalence of these diseases at death is also a reflection of the progression of CD4 lymphocytopaenia in the course of HIV infection since they seldom occur in individuals with CD4 lymphocyte counts of >100 x 10~/1. ~° Moreover, the more frequent diagnosis of HIV encephalopathy at death may reflect the insidious nature of this disease, the clinical features being more obvious with advancing immunological decline than earlier in the patients' history. Post-mortem studies have revealed a higher prevalence of HIV-related neuropathology than that suggested by epidemiological studies of living patients with AIDS. 15' 16 Psychometric analysis may detect cognitive deficits in a higher proportion of individuals with neurological morbidity, ~7 therefore, we may be underestimating the prevalence of HIV encephalopathy in our patients. The large proportion of early deaths i.e. within 2 months of the onset of the AIDS-index disease is disturbing. Most of the patients in this group were new referrals to the unit and had received no prior medical intervention. Moreover, in two-thirds, their HIV status was unknown until their terminal hospital admission. The high frequency of PCP in this group reflects the considerable mortality of PCP in patients in whom therapy is delayed, either because of failure to seek medical attention or because of failure to make the correct diagnosis. Our data emphasise the importance of maintaining a high index of suspicion in patients with atypical pneumonia who present to primary health care providers since with the diagnostic methods and therapies currently available, PCP-deaths are largely preventable. In conclusion, we have observed an increase in survival of patients with AIDS over the past 5 years which can be attributed to a combination of greater experience in
27
the management of HIV disease, the use of zidovudine and PCP prophylaxis and regular out-patient review. The significant number of deaths in individuals who present late in the course of their disease has implications for the provision of information and care to both asymptomatic HIV-seropositive individuals and to the general population.
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