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Patterns of the hazard of death after AIDS through the evolution of
antiretroviral therapy: 1984-2004

AIDS:  Volume 19(17)  18 November 2005  

The purpose of this analysis was to characterize the effect of
introduction and prolonged use of HAART on the changing pattern of
survival after clinical AIDS among participants enrolled in the
Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV
Study (WIHS), two cohort studies among men and women in the United
States that use similar methods and the same data-coordinating center.

The study focused on the important subgroup of individuals with
incident clinical AIDS as these patients are at greater risk for
disease progression in both the natural history setting and while
taking HAART. The individuals in this group may be at higher risk for
the emergence of viral resistance because they are more likely to have
received antiviral therapies prior to HAART initiation, have the
highest rates of viral replication, and have significant comorbidity.

ABSTRACT
Methods: A total of 1504 men and 461 women were followed for all-cause
mortality after an incident AIDS diagnosis. Relative hazards of death
and relative times to death were determined in five therapy eras:
no/monotherapy (July 1984-December 1989), monotherapy/combination
therapy (January 1990-December 1994), HAART introduction (January
1995-June 1998), short-term stable HAART use (July 1998-June 2001),
and moderate-term stable HAART use (July 2001-December 2003).

Results:
A total of 1057 (54%) study participants died. The time at which 25%
of individuals died after an AIDS diagnosis increased significantly
from 0.56 years [95% confidence interval (CI), 0.50-0.64] in the
no/monotherapy era to 0.74 (95% CI, 0.67-0.82), 1.78 (95% CI,
1.29-2.44), 4.22 (95% CI, 2.94-6.05) and 5.08 years (95% CI,
2.39-10.79) in the four subsequent therapy eras, respectively.

Inferences on the beneficial effects of HAART were confirmed after
adjustment by age, sex, type of AIDS diagnosis and CD4 cell count at
diagnosis. The pattern of the hazard of death after AIDS changed from
increasing in the pre-HAART era to being lower and non-increasing in
the eras of HAART.

Conclusions: The sustained beneficial effect of HAART, even in
individuals with clinical AIDS and extensive treatment histories,
attenuates concerns about emergence of resistance but augurs that a
substantial number of HIV-infected individuals may require care for
very long periods.

Discussion
Showing the beneficial effect of HAART in individuals who have
progressed to clinical AIDS is reassuring because many were treated in
a stepwise fashion (Table 2), which is the ideal scenario for
emergence of resistance. Benefits of HAART are expected to be even
better in individuals who start therapy with more potent and tolerable
combinations.

Deaths
1984-1989: person-years 685; deaths (no. (% person-years) 388 (57%);
relative hazard 1; relative time: 1
1990-1994: person-years 912; deaths 445 (49%); relative hazard 0.65;
relative time 1.42 yrs
1995-1998: person-years 796; deaths 109 (14%); relative hazard 0.21;
relative time 3.57 yrs
1998-2001: person-years 1,156; deaths 71 (6%); relative hazard 0.08;
relative time 7.82 yrs
2001-2003: person-years 992; deaths 44 (4%); relative hazard 0.06;
relative time 10.65 yrs

Substantial differences in survival were seen between the last two
HAART eras and the no/monotherapy era, with the time from AIDS to
death (adjusted by age, sex, type of AIDS diagnosis and CD4 cell count
at diagnosis) expanded by factors close to 8 and 11 in the periods
July 1998 to June 2001 and July 2001 to December 2003, respectively.

Although the cumulative mortality rates after AIDS were lower in the
monotherapy/combination therapy era compared with the no/monotherapy
era, large declines in mortality rates were not observed until the
three therapy eras during which HAART was primarily used. Mortality
was lowest in the last therapy era (July 2001 to December 2003) where
we estimate that a cumulative 30% (95% confidence interval, 22-38%) of
individuals die 8 years after their initial AIDS diagnosis.

The hazards of death in the two earliest therapy eras increased
monotonically over time. In contrast, the hazards of death in all
three HAART eras decreased over time, with the greatest decline
occurring in the first 6 months after AIDS. The hazards of death in
the last two HAART eras were very low, with a slight and
non-significant (P = 0.23) decrease between the short-term stable
HAART era and the moderate-term stable HAART era.

The times at which 25% of participants died after AIDS (i.e., the
first quartiles) in each of the therapy eras are depicted with closed
triangles in Fig. 2. Relative to the no/monotherapy era where the
first quartile was close to half of a year, the survival times were
extended in the stable HAART eras with the first quartiles being close
to 4 and 5 years, respectively. Furthermore, if the conditions of the
latest era were to remain, the model predicts that 50% of the persons
who had AIDS will survive more than 16.0 years after their initial
AIDS diagnosis, compared with the observed median of 1.2 years in the
no/monotherapy era.

Author discussion:
Many of the MACS and WIHS participants initiated therapy in a stepwise
fashion, as they first received monotherapy consisting of one
nucleoside reverse transcriptase inhibitor, then combination therapy
(multiple nucleoside reverse transcriptase inhibitors), and finally
HAART, a pattern that is more likely to foster virological resistance.
As expected, poor adherence and the inability to sustain long-term use
has resulted in resistance to HAART, the development of virological
failure, and the lack of immune reconstitution. Toxicity to HAART has
been well described, and liver failure is the most common cause of
non-AIDS death in the WIHS cohort. Nevertheless, our data demonstrated
a nearly 11-fold increase in survival after AIDS diagnosis despite the
difficulties with adherence, the development of resistance, the high
rate of regimen switching, and adverse events. These improvements in
survival were sustained, if not improved, in the last two calendar
periods. In spite of these reassuring results, cohort studies must
continue to monitor individuals using HAART, since long-term use of
the therapies may result in new and deleterious toxicities.

Authors:
Schneider, Michael Fa; Gange, Stephen Ja; Williams, Carolyn Mb;
Anastos, Kathrync; Greenblatt, Ruth Md; Kingsley, Lawrencee; Detels,
Rogerf; Muñoz, Alvaroa

bDivision of AIDS, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Maryland
cDepartments of Medicine and Epidemiology and Population Health,
Montefiore Medical Center, Bronx, New York
dDepartments of Medicine and Epidemiology, University of California,
San Francisco, California
eGraduate School of Public Health, University of Pittsburgh,
Pittsburgh, Pennsylvania
fDepartment of Epidemiology, University of California Los Angeles
School of Public Health, Los Angeles, California, USA.

DISCUSSION
Concern that the success of HAART will wane is based on the common
occurrence of treatment non-adherence and discontinuation, the
frequency by which viral resistance emerges, and the development of
clinically significant toxicities. Adherence to therapy by MACS and
WIHS participants has been shown to be heterogeneous [31,32]. Here we
have shown that adherence to therapy was not 100%, with more than 20%
of person-visits reporting less than 95% adherence.

Many of the MACS and WIHS participants initiated therapy in a stepwise
fashion, as they first received monotherapy consisting of one
nucleoside reverse transcriptase inhibitor, then combination therapy
(multiple nucleoside reverse transcriptase inhibitors), and finally
HAART, a pattern that is more likely to foster virological resistance.
As expected, poor adherence and the inability to sustain long-term use
has resulted in resistance to HAART, the development of virological
failure, and the lack of immune reconstitution [33-35]. Toxicity to
HAART has been well described, and liver failure is the most common
cause of non-AIDS death in the WIHS cohort [24]. Nevertheless, our
data demonstrated a nearly 11-fold increase in survival after AIDS
diagnosis (Table 3) despite the difficulties with adherence (Table 2),
the development of resistance, the high rate of regimen switching, and
adverse events. These improvements in survival were sustained, if not
improved, in the last two calendar periods (Fig. 2a). In spite of
these reassuring results, cohort studies must continue to monitor
individuals using HAART, since long-term use of the therapies may
result in new and deleterious toxicities.

The high effectiveness of HAART shown here was based on considering
all causes of death as the endpoint of interest. HAART has not only
extended survival times after AIDS but also decreased the percentages
of deaths caused by AIDS, with the expected rise of non-AIDS deaths
(i.e., competing risks) resulting from increasing age. In our
multivariate analysis, we included age at AIDS diagnosis, thus
providing age-specific mortality. Our results are conservative; that
is, restricting the analysis only to deaths from AIDS would result in
better survival in the HAART era than those reported in Table 3.

Not only did the Weibull regression models fit the data (i.e.,
Kaplan-Meier curves) well and provide the estimated factor by which
survival times after AIDS were expanded in the periods in which HAART
was used, but they also proved to be useful for showing that HAART has
changed the pattern of the hazard of death after AIDS. In the first
two therapy eras, longer survival after AIDS was associated with a
higher hazard of death. In contrast, the hazard of death decreased
over time during the HAART era, indicating a lower risk of death among
treated individuals surviving longer with AIDS. This is consistent
with increasing immunosuppression in the early eras when there were no
effective therapies, whereas the CD4 cell count of treated individuals
was higher in the later eras owing to the reconstitution made feasible
by HAART (Tables 2 and 3). However, only long-term studies of this and
other similar cohorts will provide data to assess whether the hazard
of death may start increasing after some time (i.e., a bath-tub-shaped
curve).

In order to determine whether the shape of the hazard of death was
different in the two cohorts in the eras of stable HAART, we tested
the possible heterogeneity by gender of the Weibull model for the
period July 1998 to December 2003. We found that there was no
difference in the two cohorts for that period (χ2 = 2.1; degrees of
freedom = 2; P = 0.35). This similarity, in spite of differential use
of HAART (Fig. 1), reflects the influence of other concurrent factors,
including duration of infection, prior exposure to antiretroviral
therapy, and type of AIDS diagnosis (Table 1). These issues underscore
the importance of the adjustments made in the multivariate models
presented in Table 3.

The use of survival analysis methods that incorporated staggered
entries allowed us to capitalize on the extensive follow-up of the
MACS and the WIHS. The use of staggered entry analysis methods avoids
the survival bias present in analyses that inappropriately include
individuals who survive from previous periods as if they were at risk
for death the entire time in the period of interest. Using these
methods, we repeated the analysis allowing MACS participants in the
first two eras to contribute to subsequent periods (i.e., a full
period analysis). From this full period analysis, the RH values of the
last four periods relative to the first (0.85, 0.33, 0.09, 0.08,
respctively) were similar to those shown in Table 3 and yielded the
same inferences.

Our results have important public-health implications. Population
effectiveness analyses are ecological in the sense that they reflect
many factors, including access, practice style, efficacy, adherence,
discontinuation, regimen switching, and the occurrence of viral
resistance to therapy components. They represent the net reduction on
disease burden at the population level. Cohort studies offer an
opportunity to quantify the effect of interventions that more closely
represent the effect in the whole population than those reported in
clinical trials. However, cohort studies may not fully represent the
population at large. Previously, we have used similar methods for the
assessment of effectiveness of therapies on the time from HIV
infection to AIDS and death [13]. In that context, our findings have
been confirmed by several other cohort studies [18,36,37].
Replications of our findings on survival after AIDS in other cohort
studies will add to the generalization of our results.

A strength of our analysis is the inclusion of only incident AIDS
cases, allowing us to anchor the analysis at the date of AIDS
diagnosis. Many of the individuals never received therapy and those
who did received it at different times and for different reasons. An
advantage of the period analysis presented here is that in a given
period there is a vast heterogeneity of therapy usage at the
individual level. Therefore, our analysis allows for the dynamics of
therapy usage by HIV-infected individuals in the population and is not
subject to the biases of patients seeking care at a late stage of
disease progression.

The prognosis of patients who are currently alive and being treated
with HAART, including factors for treatment failure, have been widely
studied [10-12] and complement the findings presented here. Our
findings project that the demand for HIV care in areas where therapies
are available will increase over time.

Study population
The MACS was initiated in 1983 to study the natural history of HIV-1
infection among homosexual and bisexual men in the United States. The
study design and characteristics of the participants, including race
and socio-economic status, have been described previously [22]. A
total of 2788 participants were either HIV positive at enrollment
(79%) or were documented to acquire HIV infection during follow-up
(21%). The WIHS is a multicenter prospective cohort study of the
natural history of HIV-1 infection in women. Methods and baseline
cohort characteristics have been described previously [23]. A total of
2074 participants were either HIV positive at enrollment (99%) or were
documented to have acquired HIV infection during follow-up (1%).
Studies were approved by the Committees of Human Research of
participating institutions.

Outcome variable
The origin for survival times was the diagnosis of an incident
AIDS-defining condition. At each semi-annual visit, participants were
asked to report dates of AIDS diagnoses. When the precise date was not
reported, the date of AIDS diagnosis was defined by the midpoint
between the last AIDS-free date and the first date with AIDS.
Individuals who missed visits in between these two dates, and where
the resulting lag time was more than 1 year, were not included in the
analysis. Participant deaths were ascertained continuously in both
cohorts using a combination of active (e.g., death certificate
abstraction upon notification of a participant death) and passive
(e.g., national death registry searches) surveillance methods.
Detailed evaluations of the causes of death in the WIHS have been
published previously [24]. Here, changes in all-cause mortality after
an incident AIDS diagnosis are reported. AIDS was defined as a
clinical illness consistent with 1993 Centers for Disease Control
clinical surveillance conditions [25] but excluding the
immunological-based criterion of low CD4 cell count. Analyses
incorporated data through December 2003 with participants alive at the
end of follow-up contributing censored observations.

Exposure variables
Distinct calendar periods that serve as proxies for different therapy
eras were the primary exposures and were used to measure the
effectiveness of antiretroviral therapy and HAART at the population
level. HAART, combination therapy, and monotherapy have been described
previously for the MACS and WIHS cohorts [26].

The five calendar periods used were July 1984 through December 1989,
January 1990 through December 1994, January 1995 through June 1998,
July 1998 through June 2001, and July 2001 through December 2003.

The impacts of age, sex, type of AIDS diagnosis, and CD4 cell count at
diagnosis on survival after AIDS were evaluated. Clinical AIDS
diagnoses were classified into seven categories as described by Muñoz
et al. [27].

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