You are on page 1of 13

A note on Australian AIDS survival

B.D. Ripley and P.J. Solomon

1. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG,
UK
2. Department of Statistics, University of Adelaide, South Australia, Australia 5005
3. Address for correspondence: Dr P.J. Solomon, Department of Statistics, University of
Adelaide, Australia 5005

Abstract
Understanding factors important for AIDS survival is crucial for planning and
modelling. In this article, we present the results of a registry-based study of the
survival of Australian residents diagnosed by July 1991 and reported by January 1992.
We fit semi-parametric Cox models incorporating temporal trends associated with
changes in the Australian Governments treatment policy for HIV/AIDS, and other
available covariates. We also describe a special study of age effects, and demonstrate
the power of sophisticated statistical analyses to provide insight into complex data that
may be missed by a more naive analysis. We find a significant reduction in the hazard of
death associated with the widespread introduction of zidovudine into clinical practice
in mid-1987 for people with advanced HIV disease. The Australian Governments
treatment policy was broadened in August 1990 to make zidovudine available to people
, but there was no further change in
whose CD4 cell/mm counts persist below
the hazard associated with the policy change. People infected via heterosexual contact
have significantly improved survival over homosexual/bisexual males, whereas people
with haemophilia have significantly poorer survival. Queensland has a significantly
increased hazard over that for New South Wales, the largest Australian state. The
very young have a greatly increased hazard of death, which increases steadily from
about aged two years at diagnosis to 75 years, followed by a sharp increase. We
find no real evidence that the survival of people infected via contaminated blood or
blood-products decreases with age. A parametric analysis suggests that an exponential
survival distribution is reasonable and that the baseline hazard is constant. This may
provide insight into underlying trends in the disease process.

Key words:
Australian AIDS survival nonstationarity, treatment effects, age effects; Cox model;
Weibull survival model.

1 INTRODUCTION
It is important that we understand factors affecting the survival of people with AIDS. Its
importance stems from the evolving definition of AIDS which has implications for defining
and estimating the incubation distribution. It is also important for health-care planning,
predicting deaths and prevalence of AIDS, and for providing accurate information to people
with HIV disease.
As our knowledge of some features of the epidemic, such as HIV prevalence, increases,
our knowledge about the incubation distribution is increasingly uncertain (1). Incubation
for AIDS is believed to depend, at least in part, on treatments, age and possibly diseases
at diagnosis. Understanding factors associated with AIDS survival can therefore provide
crucial information about the pattern of disease from initial infection to death.
The purpose of this note is two-fold. Firstly, we describe the results of our recent
study of Australian AIDS survival up to 1992. Using a time-dependent Cox model, we
investigate covariates related to survival and incorporate temporal trends associated with
changes in the Australian Governments treatment policy. We also present a special study
of age effects. Secondly, we demonstrate the power of sophisticated statistical analyses in
providing insight into factors important for survival that may be missed by a more naive
approach.

2 METHODS
2.1

The data

There were 2,843 Australian AIDS cases diagnosed prior to 30 June 1991 and reported to
the National Centre in HIV Epidemiology and Clinical Research in Sydney, by 31 January
1992. The first case was diagnosed in December 1982 and by the studys endpoint, 1,787
of the 2,843 individuals had died.
The HIV epidemic started in New South Wales and spread to Victoria, followed by
Queensland and then the smaller States and Territories. NSW and Victoria are the first and
second largest Australian states. There is considerable regional variability in the epidemic
in Australia, but otherwise the pattern of spread amongst the population is typical of socalled Western countries, where the majority of AIDS cases have been seen amongst men
who have sex with men, and more recently amongst injecting drug users. However, there
have been relatively few cases in this risk group in Australia compared with other countries.
Yearly AIDS incidence for the three largest Australian States and the remainder are shown
in Figure 1.
In all 29 patients were diagnosed with AIDS after death and therefore have zero
survival times. Most of these cases occurred early in the epidemic when AIDS was still
being recognised and are disproportionally distributed amongst the transmission categories:
22 of the cases were homosexual/bisexual males, 6 were infected by blood transfusions or
blood products, and one case was an infant with an infected mother.

2.2

Data quality

AIDS is a notifiable disease in all States and Territories of Australia, and the data are
therefore believed to be relatively complete compared with other countries. However, we
adjusted the endpoint of the study by six months since there are some delays in death
notifications, and to a lesser extent, delays in reporting of AIDS cases.
The delay between diagnosis of AIDS and reporting is variable, which can be seen
in figures published regularly by the NCHIVECR. But reporting delay data are available
2

400
300
0

100

200

NSW
VIC
QLD
Other

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

Figure 1: Annualized yearly AIDS incidence by state in Australia.


only for the recent past, and are not collected or entered into the database in a systematic
way. Direct modelling of the reporting delay distribution is therefore unlikely to be fruitful.
Under-reporting of AIDS is believed to be of the order of % (2).
The quality of the death data is less certain and there is no recent published information
on this, although some death certificate checking is undertaken. The implications of delays
in death reporting, as well as of under-reporting, for estimating survival probabilities have
been discussed recently in the Australian context (3). The national database does not identify
non-AIDS deaths, so that all deaths are assumed to be AIDS deaths for the purposes of
the present analysis.
Survival time is calculated as the number of days between a diagnosis of AIDS and
death or 30 June 1991, whichever is the sooner. The covariates available to us are sex, age at
diagnosis, reported transmission category, State or Territory of diagnosis, and information
on the availability of zidovudine in Australia.

2.3

The model and analysis

We begin with a time-dependent Cox model (4,5) which includes all the available covariates.
We refer to this as the full model.
Detailed descriptions of the covariates now follow.
state or Territory of diagnosis:
The Australian Capital Territory is a small enclave within NSW and is combined with
NSW for the purposes of our analysis. The States and Territories are then

NSW New South Wales and Australian Capital Territory


VIC
Victoria
QLD Queensland
WA
Western Australia
SA
South Australia
TAS
Tasmania
NT
Northern Territory.
Each State or Territory is compared to NSW.
trans
The transmission categories are:
hs
male homosexual or bisexual contact
hsid
as hs and also intravenous drug user
id
female or heterosexual male intravenous drug user
het
heterosexual contact
haem
haemophilia or coagulation disorder
blood
receipt of blood, blood components or tissue
mother mother with or at risk of HIV infection
other
other or unknown.
Here the baseline for comparison is the male homosexual or bisexual contact group.
Temporal effects
The Australian AIDS survival experience shows significant nonstationarity. A dramatic
improvement in survival coincided with, although may not be entirely attributable to,
the widespread introduction of zidovudine into clinical practice in mid-1987 (6), and the
increased use of prophlyactic treatments for opportunistic infections. Early clinical trials
(7) established that ZDV considerably enhances the survival of people with AIDS. Later
evidence (8) suggested that taking ZDV during the symptom-free period might delay the
onset of an AIDS-defining illness. On the basis of these findings, the Australian government
amended its treatment policy in August 1990 to make ZDV available to people whose CD4
cell counts per mm persist below
. The results of the recent Concorde trial (9) have
again thrown open the question of the effects of anti-retroviral treatment on the symptomfree period, and we pursue this point further in the Discussion.
We have modelled directly the observed nonstationarity in AIDS survival by allowing a
proportional change in the hazard from 1 July 1987 to 30 June 1990 (zdv1 t ) and another
from 1 July 1990 (zdv2 t ). These time-dependent covariates represent temporal changes
in survival on a population basis. Detailed data on individual ZDV use are not available to
us.
The full Cox model includes the covariates described above as well as sex (male
female
) and age in years at diagnosis. The hazard is then
;

exp

(1)
where
is the baseline hazard,
is the covariate vector and
and
are vector
parameters.
Using a stepwise regression procedure based on the partial likelihoods, we obtained as
parsimonious a Cox model as possible. We call this the reduced model. In addition, we
compared the results of the Cox model with a parametric Weibull survival model.
4

Special study of age effects


Age is known to be important for survival, with the very young and very old having relatively
poor prognoses. We examined linearity in the hazard of death with age by examining the
martingale residual plot in the first instance. We then split the data into six age groups as
shown below and re-fitted the reduced model. The knots were chosen from prior experience,
giving numbers in each group of
015
39

1630
1022

3140
1583

4150
987

5160
269

61+
85

In each case the baseline for comparison is the 3140 year-old group, and we compared the
results from both the Cox and the parametric Weibull models. We then went on to consider
parametric nonlinear functions of age using a spline function.
The blood-transfusion and blood-product data are quite different and should be considered separately. We investigated the question of whether the survival of patients infected
via blood or blood products decreases with age by splitting the 139 patients concerned into
for age groups: 020, 2140, 4160 and 61+ and then fitting the Cox model including the
time-dependent covariates zdv1(t) and zdv2(t).
Computing
The analyses were done using S-PLUS functions
written by Terry Therneau
(Mayo Foundation). Note that zero survival times are avoided by shifting the deaths by 0.9
days to occur after other events (i.e. deaths or censorings) on the same day.
We used stratified Cox models to examine the separate effects graphically. The S-PLUS
algorithms for the analyses described in this paper are contained in (10) where they are used
for a disguised and simplified version of this data set, and the exact code used is available
from the first author.

3 RESULTS
Fitting the full Cox model
gives the regression estimates shown in Table 1. Sex is not a
significant factor, with a relative risk for males of 1.01 (95% confidence limits (0.72, 1.41)).
Age at diagnosis of AIDS is highly significant, although the increased relative risk of 1.014
for each additional year is relatively slight (we explore the age effects in more detail later).
Queensland, which is the third largest state following NSW and Victoria, has significantly poorer survival than NSW (95% c.i. for relative risk (1.00,1.41)). The survival trends
in the other states are suggestive although not statistically significant. Figure 2 shows the
relative survival pattern adjusted for the presence of the other covariates. The median
survival time for Queensland is 1.15 years, compared with that for NSW of 1.31 years.
The heterosexual transmission group has significantly improved survival over that of
homosexual and bisexual males (the relative risk is reduced by more than half to 0.452,
-value 0.004) whereas people with haemophilia have a significantly increased hazard
of death, corresponding to an increased relative risk of 1.465 ( -value 0.04). Trends in
survival by transmission category are shown in Figure 3. Injecting drug users also do better
than homosexual and bisexual men, although not significantly, and children infected via
a mother with HIV/AIDS, or people infected via blood or blood products (who are not
haemophiliacs) do worse, although again not significantly.
The hazard of death is reduced by half with the introduction of the first time-dependent
covariate in mid-1987 and this effect is highly significant. However, there is no further
5

TABLE 1. Australian AIDS survival: results of fitting the full Cox model (1).

0.0046
0.0136
-0.2968
0.1715
-0.1059
0.1596
0.0057
-0.0720
-0.1175
-0.3472
-0.7932
0.3816
0.1675
0.4182
0.0964
-0.6951
-0.7305

Standard error
0.1716
0.0025
0.5801
0.0871
0.1414
0.3388
0.0608
0.1162
0.1521
0.2405
0.2888
0.1868
0.1362
0.5898
0.1639
0.0660
0.0748

exp
1.005
1.014
0.743
1.186
0.900
1.173
1.006
0.931
0.889
0.707
0.452
1.465
1.182
1.519
1.101
0.499
0.482

-value
0.98
0.04
0.61
0.054
0.45
0.64
0.93
0.54
0.44
0.15
0.006
0.041
0.22
0.48
0.56
0.00
0.00

0.6

0.8

1.0

Covariate
sex
age
state.NT
state.QLD
state.SA
state.TAS
state.VIC
state.WA
trans.hsid
trans.id
trans.het
trans.haem
trans.blood
trans.mother
trans.other
zdv1
zdv2

0.0

0.2

0.4

NSW
QLD
VIC

20

40
months since diagnosis

60

Figure 2: Survival curves for AIDS in Australia by state, adjusted for other covariates.
change in the hazard with the introduction of the second time-dependent covariate in mid1990.

1.0
0.8

1.0
0.8

0.2

0.4

0.6

hs
haem
blood
other

0.0

0.0

0.2

0.4

0.6

hs
hsid
id
het

20

40

60

months since diagnosis

20

40

60

months since diagnosis

Figure 3: Survival curves for AIDS in Australia by transmission category, adjusted for other
covariates.
Reduced model
Since any effect of sex will be confounded with that of transmission category, we dropped
sex from the model. Removing sex and zdv2, the difference in zdv at 1 July 1990, makes
virtually no difference to the partial likelihood ratio statistic: 179.53 on 17 degrees of
freedom changes to 179.13 on 15 df. A stepwise elimination procedure indicated that state
could also be removed (likelihood ratio test 173.59 on 9 df), which leaves the reduced
model:
;
exp
(2)
Table 2 sets out the results of fitting the reduced Cox model.
TABLE 2. Australian AIDS survival: results of reduced model (2).
Covariate
age
trans.hsid
trans.id
trans.het
trans.haem
trans.blood
trans.mother
trans.other
zdv1

0.0136
-0.1172
-0.3673
-0.7840
0.3838
0.1769
0.4055
0.0931
-0.7016

Standard error
0.0025
0.1520
0.2261
0.2686
0.1851
0.1219
0.5839
0.1608
0.0635

exp
1.014
0.889
0.693
0.457
1.483
1.193
1.500
1.098
0.496

-value
0.03
0.44
0.11
0.004
0.033
0.15
0.49
0.56
0.00

Age at diagnosis and the proportional change in the hazard corresponding to zdv1
7

remain highly significant. The effects of the other covariates are not much changed from
the full model.
Parametric analysis
The survival curves suggest the Weibull survival distribution is appropriate. The Weibull
distribution is both a proportional hazards and an accelerated life model (see, for instance,
11) and we included the observed temporal effect by assuming a doubling of survival from
July 1987. The resulting parameter estimates show excellent agreement with the Cox model
for both the full and reduced models, and are not given here. The Weibull index parameter
is estimated to be 0.97 ( -value = 0.11 for a test of being an exponential distribution)
which suggests a monotone decreasing hazard for survival in the presence of the covariates
fitted. Removing the 29 zero survival times, the exponential survival distribution gives an
excellent fit (Weibull index parameter 1.02, -value = 0.30), suggesting that in practice, it
is reasonable to assume a constant baseline hazard. The implications of this are outlined in
the Discussion.
Analysis of age effects
We now consider the possible nonlinearity of the log-hazard with age. As a first step, we
replaced a linear term in age by a step function with the knots as given in the Methods, and
re-fitted the reduced Cox model. The results are set out in Table 3. The difference in partial
likelihoods over the reduced model was 8.24 on 4 df.
TABLE 3. Australian AIDS survival: study of nonlinear age effects.
Covariate
trans.hsid
trans.id
trans.het
trans.haem
trans.blood
trans.mother
trans.other
age.0-15
age.16-30
age.41-50
age.51-60
age.61+
zdv1

-0.133
-0.390
-0.794
0.220
0.003
-0.229
0.019
0.210
-0.094
0.061
0.376
0.746
-0.702

Standard error
0.152
0.227
0.269
0.198
0.136
0.645
0.164
0.288
0.062
0.061
0.095
0.157
0.064

exp
0.875
0.677
0.452
1.246
1.003
0.796
1.019
1.234
0.910
1.063
1.457
2.109
0.496

-value
0.38
0.085
0.003
0.27
0.98
0.72
0.91
0.47
0.13
0.32
0.000075
0.000002
0

Compared to the 3140 age-group, people aged over 50 years at diagnosis of AIDS have
significantly poorer survival. Other trends are suggestive, such as younger people aged up
to 15 also have poorer survival, but the effect is not statistically significant.
People infected via heterosexual contact still do significantly better than homosexual/bisexual men, however haemophiliacs no longer have a significantly increased hazard.
We also fitted a smooth nonlinear function of age using splines. This shows significantly
better fits with the smoothed age effects with the difference in partial likelihoods over the
reduced model of 27.87 on 7 df. Figure 4 shows a greatly increased hazard at age zero,
a decreased hazard in teenage years then a steady increase to age 75, followed by a sharp

-2

-1

predicted change in hazard


0
1
2

increase. Confidence intervals are shown, and the reference is to a 21 year old. For this
model, haemophiliacs again have a significantly increased hazard.

20

40
age

60

80

Figure 4: Relative hazard curves with 95% confidence intervals (dashed) for age, relative
to a 21 year old. The rug shows the distribution of ages.

Age-dependence for blood-contaminated cases


Finally, we investigate whether the survival of the 139 people infected with HIV via blood
or blood products in Australia decreases with age. Table 4 sets out the marginal survival
experience in different age-groups.
TABLE 5. Age-dependence for blood-contaminated cases of AIDS in Australia (days)
up to 20
20+ to 40
40+ to 60
60+ to 80

n
30
37
47
25

events
21
26
27
23

mean
618
384
335
326

s.e.(mean)
115
60
49
84

median
366
268
210
222

95% c.i.
(257, )
(196, 507)
(79, 512)
(110, 479)

The evidence of Figure 5 is suggestive, and for comparison, the survival curve of a
healthy US 65-year-old male is shown. However, a formal analysis comparing the partial
likelihoods for comparable Cox models shows no real evidence of an age effect (see Table
5). (The log partial likelihood ratios were 12.0 on 4 df and 10.8 on 2 df for these models
against 8.6 on 1 df for a model with no age effect.) This is probably due to the relatively
small numbers of patients involved.

1.0
0.8
0.0

0.2

0.4

0.6

0-20
21-40
41-60
60+
normal 65

10

20

30

40

50

months since diagnosis

Figure 5: Survival curves for AIDS in Australia for people infected via blood contamination,
adjusted for other covariates. The curves shown are grouped by age, with a healthy 65-year
old US male for comparison.
TABLE 5. Study of age-dependence for blood-contaminated cases, comparing two Cox
models.
Covariate
zdv1
20+ to 40
40+ to 60
60+
zdv1
age

-0.573
0.312
0.334
0.557
-0.536
0.0073

Standard error
0.214
0.298
0.278
0.306
0.211
0.0049

-value
0.0075
0.29
0.23
0.07
0.011
0.132

reference is to the 0 to 20 age group.

DISCUSSION

The results of our population-based study have established that there are significant temporal
trends in survival in Australian AIDS patients. These trends may, at least in part, be
attributable to the effects of available treatments for people with HIV/AIDS and remain
important in the presence of other factors important for survival. Although such registrybased studies cannot directly assess treatment effects, an advantage is that the data are
broadly representative of the population being treated in medical practice. Of the 41 people
infected via heterosexual contact, 21 are females and 20 are males. The hazard is reduced
by more than half of that for homosexual/bisexual males and the effect is the same for both
males and females.
The reasons for Queenslands relatively poor survival remain obscure and require further
10

investigation. We considered the possibility that it might be due to a high proportion of


blood-contaminated cases: 8.3% of cases diagnosed in Queensland are due to contaminated
blood or blood products, whereas in NSW (which is the largest state, and where most blood
is donated) the figure is 5.8%. Our methodology adjusts for this proportion, but as figure 3
shows, the proportional hazards hypothesis fails for these transmission categories in so far
as the early hazard rate is much larger. However, removing the blood-contaminated cases
from the study only reduced slightly the difference in Queensland.
It is interesting to note that there was no significant effect of the second time-dependent
covariate i.e. that the nonstationarity was captured by the change modelled in mid-1987,
when the hazard was reduced by half, but that there was no further significant change in
the hazard associated with an effect modelled in mid-1990. Both of these time-dependent
covariates reflect changes in the Australian Governments treatment policy: in June 1987,
zidovudine was made widely available to people with advanced HIV disease and then in
August 1990, zidovudine became available in Australia to people with CD4 cell counts less
than 500 per mm .
Our findings contribute to the still incomplete knowledge of the pattern of survival from
initial infection with HIV to death. The European Concorde study (9) suggests that taking
zidovudine early does not prolong life, nor significantly prolong the incubation period for
AIDS. However, questions about the precise effects of anti-retroviral and other treatments
on the incubation period for AIDS remain.
Our analysis suggests that, on a population basis, starting zidovudine in the asymptomatic period has no survival benefit over starting zidovudine later, when the patients
is suffering advanced HIV disease. These results appear to be in broad agreement with
Concorde, although it may be too soon to detect an effect on a population basis. Data on
individual treatment patterns are, unfortunately, not available, nor are data on diseases or
CD4 cell counts at diagnosis of AIDS available to us. Previous studies have shown that men
presenting with Kaposis sarcoma have improved survival over those who present with opportunistic infections such as PCP (see 12, among others). Moreover, the AIDS incubation
distribution may vary by disease at diagnosis, and possibly by detailed infection distribution, so that study of subsequent survival by these criteria is of interest. Nevertheless, we
believe that the findings of our study are of interest in their own right.
The results of the parametric analysis suggest that an exponential survival distribution
is a reasonable model i.e., the baseline hazard of death is constant. This raises the question
of what part of the disease process, if any, is constant. For instance, changes in the
disease process coinciding with the external temporal effects we have modelled cannot
be separately estimated on the basis of the available data. One interpretation is that there
have not been significant trends in the disease process, nor in the effects of treatment on
the incubation period for AIDS, but there are other possible interpretations. In particular,
for people taking zidovudine early, i.e. pre-AIDS, poorer survival following a diagnosis of
an AIDS-defining illness could be disguised by cases being detected at an earlier stage of
disease. Since the definition of AIDS in Australia has not changed in recent years, it seems
more likely that the survival pattern has remained relatively constant as the model suggests.
Our study of age at diagnosis showed, in the first instance, that it is a highly significant
effect, but that overall, the hazard increases only slightly with age. Age has a small effect on
state and transmission category (trans), except for cases infected via mother which have
relatively poor survivalalthough the effect was not statistically significant (see Tables
1 and 2). The step-function and spline analyses confirmed that it is the very young and
very old who are at significantly higher risk of death than people who are infected in
middle-age.
We also found some evidence that the hazard of blood-contaminated cases of AIDS

11

increases with age, but the effect is not statistically significant within this rather small group
of 139 patients.

Acknowledgements
This work was supported in part by the Australian Research Council. We are grateful to the
National Centre in HIV Epidemiology and Clinical Research for making the data available
to us.

Bibliography
1. Bacchetti P, Segal M, Jewell N. Backcalculation of HIV infection rates (with discussion).
Statistical Science 1993; 8:82-119.
2. AIDS Bureau, NSW Health Department. Report on planning for HIV/AIDS care and
treatment services in New South Wales. State Health Publication (AIDS) 1990; 9068.
3. Solomon PJ, Wilson SR. Predicting AIDS deaths and prevalence in Australia. Med J Aust
1992; 157:121125.
4. Cox, DR. Regression models and life tables (with discussion). J R Statist Soc B 1972;
34:187220.
5. Cox, DR. Partial likelihood. Biometrika 1975; 62:269276.
6. Solomon PJ, Wilson SR, Swanson CE, Cooper DA. Effect of zidovudine on survival of
patients with AIDS in Australia. Med J Aust 1990; 153:254257.
7. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in
the treatment of participants with AIDS and AIDS-related complex: a double-blind,
placebo-controlled trial. N Eng J Med 1987; 317:18591.
8. Volberding PA, Lagakos SW, Koch MA et al. Zidovudine in asymptomatic human
immunodeficiency virus infection: a controlled trial in persons with fewer than 500
CD4-positive cells per cubic millimeter. N Eng J Med 1990; 322:941949.
9. Seligmann M, Warrell DA, Aboulker J-P, et al. Concorde: MRC/ANRS randomised
double-blind controlled trial of immediate and deferred zidovudine in symptom-free
HIV infection. The Lancet 1994; 343:871881.
10. Venables WN, Ripley BD Modern applied statistics with S-Plus. Springer, New York
1994.
11. Cox DR, Oakes D. Analysis of survival data. Chapman and Hall, London 1984.
12. Rothenberg R, Woelfe M, Stoneburner R, Milberg J, Parker R, Truman B. Survival with
the acquired immunodeficiency syndrome. N Eng J Med 1987; 317:12971302.

12