Morte por causas associadas a AIDS

1. HIV/AIDS • CID 2010:51 (15 October) • 957
H I V / A I D SM A J O R A R T I C L E
Cancer as a Cause of Death among People
with AIDS in the United States
Edgar P. Simard and Eric A. Engels
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
(See the article by Puhan et al, on pages 947–956.)
Background. People with human immunodeficiency virus (HIV) infection and AIDS have an elevated risk for
cancer. Highly active antiretroviral therapy (HAART), which has been widely available since 1996, has resulted in
dramatic decreases in AIDS-related deaths.
Methods. We evaluated cancer as a cause of death in a US registry-based cohort of 83,282 people with AIDS
(1980–2006). Causes of death due to AIDS-defining cancers (ADCs) and non-ADCs (NADCs) were assessed. We
evaluated mortality rates and the fraction of deaths due to cancer. Poisson regression assessed rates according to
calendar year of AIDS onset.
Results. Overall mortality decreased from 302 deaths per 1000 person-years in 1980–1989, to 140 deaths per
1000 person-years in 1990–1995, and to 29 deaths per 1000 person-years in 1996–2006. ADC-related mortality
decreased from 2.95 deaths per 1000 person-years in 1980–1989 to 0.65 deaths per 1000 person-years in 1996–
2006 (P!.01), but the fraction of ADC-related deaths increased from 1.05% to 2.47% in association with decreases
in other AIDS-related deaths. Non-Hodgkin lymphoma was the most common cancer-related cause of death (36%
of deaths during 1996–2006). Likewise, NADC-related mortality decreased from 2.21 to 0.84 deaths per 1000
person-years from the period 1980–1989 to the period 1996–2006 (P!.05), but the fraction of NADC-deaths
increased to 3.16% during 1996–2006. Lung cancer was the most common NADC cause of death (21% of cancer-
related deaths in 1996–2006).
Conclusions. Cancer-related mortality decreased in the HAART era, but because of decreasing mortality due
to AIDS, cancers account for a growing fraction of deaths. Improved cancer prevention and treatment, particularly
for non-Hodgkin lymphoma and lung cancer, would reduce mortality among people with AIDS.
Cancer is an important source of morbidity and mor-
tality among human immunodeficiency virus (HIV)–
infected people. Advanced HIV infection is character-
ized by profound immunosuppression (ie, AIDS), itself
a risk factor for malignancy. There are 3 AIDS-defining
cancers (ADCs): Kaposi sarcoma (KS), non-Hodgkin
lymphoma (NHL), and cervical cancer [1]. These can-
cers are caused by loss of immune control of oncogenic
viruses–specifically, KS-associated herpesvirus for KS,
Epstein-Barr virus for NHL, and human papillomavirus
Received 12 March 2010; accepted 21 May 2010; electronically published 8
September 2010.
Reprints or correspondence: Dr Eric A. Engels, Div of Cancer Epidemiology and
Genetics, National Cancer Institute, 6120 Executive Blvd, EPS 7076, Rockville, MD
20892 (engelse@mail.nih.gov).
Clinical Infectious Diseases 2010;51(8):957–962
This article is in the public domain, and no copyright is claimed.
1058-4838/2010/5108-0013
DOI: 10.1086/656416
for cervical cancer [2, 3]. For other malignancies that
are considered non-ADCs (NADCs), elevated risks are
linked to persistent immunosuppression, coinfection
with oncogenic viruses, and a high prevalence of life-
style-related cancer risk factors, such as smoking and
alcohol intake [4, 5].
Highly active antiretroviral therapy (HAART) for
HIV infection has been widely available in the United
States since 1996, and increasing population-level use
of HAART has resulted in dramatic decreases in AIDS-
related mortality [6, 7]. HIV-infected people are also
aging, and with the decrease in AIDS-related deaths,
other chronic conditions such as cancer may become
increasingly important as causes of death. Cancer mor-
tality rates reflect both cancer incidence and survival
after a cancer diagnosis. High cancer-related mortality
among people with AIDS may be due in part to in-
adequate access to care or poor cancer treatment out-
comes [8, 9]. Prolonged duration of HAART, as well
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2. 958 • CID 2010:51 (15 October) • HIV/AIDS
as continued exposures to environmental and lifestyle cancer
risk factors, may change cancer outcomes for persons surviving
AIDS in the HAART era.
Large and systematic evaluations of cancer as a cause of death
among people with AIDS in the United States are lacking. Fur-
thermore, little is known about how the changing spectrum of
cancer risk among people surviving AIDS for many years in-
fluences cancer mortality. One US study noted an increase over
time in deaths due to NHL and lung cancer, but follow-up
stopped in 1999 [10]. Another study from New York City
showed no change in overall mortality rates attributable to
NADCs during the period 1999–2004 [11]. A recent study from
Europe found NADCs to be the most frequent non-AIDS-
related cause of death among HIV-infected people but did not
provide mortality rates for individual cancers separately [12].
Detailed cancer-specific cause of death information is neces-
sary to accurately describe and monitor the contribution of
individual malignancies to the overall mortality experience
of people with AIDS.
Evaluating cancer as a cause of death among people with
AIDS is complicated, because they often have multiple under-
lying medical conditions, and mortality attributable to these
conditions may change over time. It is necessary to consider
both the fraction of deaths due to cancer and cancer mortality
rates, because the fraction of deaths due to cancer may increase
when overall mortality rates decrease. We conducted a popula-
tion-based evaluation of cancer-related mortality among people
with AIDS to describe trends in cancer-related deaths relative to
widespread HAART use.
METHODS
The current analyses used data from the HIV/AIDS Cancer
Match Study, a population-based registry linkage study of peo-
ple with HIV infection or AIDS diagnosed during 1980–2008
in 15 US states and metropolitan regions [4, 5]. Following
linkage, only deidentified data were retained for analyses. In-
stitutional review boards at participating sites approved the
study.
We constructed a cohort of people with AIDS (excluding
people with HIV infection alone) who had been free of cancer
as of the time of AIDS onset. AIDS onset was defined using
the 1993 Centers for Disease Control and Prevention surveil-
lance case definition [1]. Of 574,242 potentially eligible subjects,
we excluded individuals with any cancer reported to the cancer
registry, or an ADC reported to the HIV/AIDS registry, before
or during the 3 months after AIDS onset (18,107 and 33,374
persons, respectively), so that we could eliminate the possibility
that cancer contributed to development of AIDS. Furthermore,
16,073 people with AIDS who were not undergoing follow-up
(according to the cancer registries) after month 4 were also
excluded, because they contributed no person-time to this anal-
ysis. People who received a diagnosis of AIDS before 1980 (n
p11) and children aged !14 years (np6546) were also ex-
cluded from the study. We also excluded sites that did not
routinely obtain underlying causes of death or provide them
for the study (10 sites; np416,849). These exclusions yielded
a cohort of 83,282 adults and adolescents who received a di-
agnosis of AIDS during 1980–2006 from 5 participating sites
(Colorado; Massachusetts; New Jersey; Seattle, Washington; and
San Francisco, California).
Deaths among people with AIDS occurring у4 months after
AIDS onset were then evaluated. HIV/AIDS registries obtain
vital status information via routine linkage to state and national
mortality files. Matching of AIDS records to multiple sources
increases the likelihood of HIV/AIDS registries detecting deaths
among people who may have migrated out of their catchment
area [13, 14]. Underlying cause of death (hereafter referred to
as the cause of death) is the medical condition that initiated
the train of events leading directly to death and was ascertained
by interpreting the multiple causes of death listed on death
certificates [15]. Causes of death were coded using codes from
the International Classification of Diseases, 9th Revision (during
1979–1998) [16], and International Classification of Diseases,
10th Revision (from 1999 onward) [17]. On the basis of in-
formation regarding contributory causes, the final (underlying)
cause of death was determined at each study site. To limit
underascertainment of specific causes of death among people
with AIDS diagnosed most recently, deaths and follow-up times
were censored 2 years prior to the last month and calendar
year of death recorded in each individual registry.
On the basis of International Classification of Diseases codes
for causes of death, we classified deaths with specified causes
as cancer related (ADC or NADC), AIDS related (excluding
ADCs), and other, non–cancer related, non-AIDS related. We
classified subjects according to calendar period of AIDS onset:
1980–1989 (no or limited availability of antiretroviral therapy),
1990–1995 (monotherapy and/or dual therapy), and 1996–2006
(HAART). We calculated mortality rates per 1000 person-years
with exact 95% confidence intervals (CIs). Person-years were
calculated from the start of the fourth month after AIDS onset
to the end of the risk period (which was the first of death, end
of cancer registry coverage, or censoring as defined above). We
used Poisson regression to assess trends in rates across the 3
calendar periods, and P values !.05 were considered to be sta-
tistically significant.
RESULTS
Among 83,282 people with AIDS included in the study, most
were male (81.3%). With regards to race or ethnicity, almost
one-half (49.4%) of all subjects were non-Hispanic white and
33.4% were non-Hispanic black. Most subjects were aged 30–
39 years (47.3%) or 40–49 years (28.6%) at the time of AIDS
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3. HIV/AIDS • CID 2010:51 (15 October) • 959
onset, and most experienced onset of AIDS during 1990–1995
(51.2%) or 1996–2006 (30.6%).
Overall mortality rates decreased markedly over time, from
302 to 140 to 29 deaths per 1000 person-years for persons who
had onset of AIDS during 1980–1989, 1990–1995, and 1996–
2006, respectively (Table 1). Cause of death was specified for
93%, 85%, and 93% of these cases, respectively. Remaining
analyses focus on deaths with a specified cause.
Mortality rates for cancer overall, ADC, and NADC de-
creased significantly across the calendar periods of AIDS onset
(P!.05 for all comparisons) (Table 1). For ADC, mortality rates
decreased 78% (2.95 and 0.65 deaths per 1000 person-years in
1980–1989 and 1996–2006, respectively). Likewise, for NADC,
mortality rates decreased 62% across the same intervals (2.21
and 0.84 deaths per 1000 person-years). Nonetheless, cancer-
associated deaths represented an increasing fraction of deaths
over time, due to steep decreases in deaths due to the remaining
causes (particularly for AIDS-related deaths, which showed a
95% decrease, as well as other non–cancer-related, non–AIDS-
related deaths, which showed a 79% decrease over time) (Ta-
ble 1).
Among ADCs, KS mortality rates exhibited a 11-fold decrease
and NHL exhibited a 4-fold decrease over time. There was little
change in the fraction of deaths with KS as the cause, but with
the sharp decreases in other causes, the fraction of deaths caused
by NHL increased over time. Despite decreases in NHL mor-
tality rates, NHL remained the most common cancer-related
cause of death in the HAART era (36% during 1996–2006).
Cervical cancer was a much rarer cause of death, and mortality
rates did not change significantly.
Among NADCs, lung cancer was the most common cause
of death (22% of all cancer-related deaths during the HAART
era) followed by liver cancer and Hodgkin lymphoma (Table
1). Mortality rates for lung cancer decreased almost 3-fold
across calendar periods, and mortality rates for Hodgkin lym-
phoma and liver cancer also decreased steeply. Mortality rates
for anal cancer did not exhibit a significant trend. Mortality
from the remaining NADCs significantly decreased 56% over
time, but individual cancer types were too uncommon to an-
alyze separately. The proportion of all deaths attributable to
lung cancer, liver cancer, and the remaining group of other
NADCs increased over time, as a result of the dramatic de-
creases in other causes of death.
To evaluate the quality of mortality information in both HIV/
AIDS and cancer registries, we conducted an additional analysis
of the 389 people with NHL listed as the cause by the HIV/
AIDS registry. Of those 389 persons who died of NHL, 278
(72%) had a prior incident NHL recorded in the cancer registry,
and the cancer registry indicated that 141 (36%) of them died
with NHL as the cause of death. As another example, of the
179 people with AIDS who died with lung cancer listed as the
cause of death, 127 (71%) had an incident lung cancer recorded
in the cancer registry, and 103 (58%) had lung cancer listed as
a cause of death in the cancer registry.
DISCUSSION
In this population-based assessment of causes of death among
people with AIDS, we demonstrated dramatic decreases in over-
all mortality, which reflected decreasing mortality attributable
to AIDS, cancer, and other causes. Across calendar periods of
AIDS onset, the decreases in mortality due to ADC (specifically
KS and NHL) and other AIDS-related conditions (opportu-
nistic infections) can likely be attributed to immune restoration
associated with widespread HAART use, and have been dem-
onstrated in other studies in the United States and elsewhere
[7, 11, 18, 19]. Prior studies have not specifically evaluated
mortality due to individual ADCs and NADCs as reported by
death certificates or have not provided rates for these causes
of death.
Despite decreases in ADC mortality, NHL remained the most
common cancer-related cause of death. Although the incidence
of NHL among people with AIDS has decreased and survival
following NHL diagnosis has improved in the HAART era, a
large fraction of people with AIDS-associated NHL still die of
malignancy [5, 9, 20, 21]. For example, in a recent European
analysis of patients with AIDS-related NHL, 34% had died by
1 year after diagnosis and 45% by 5 years after diagnosis [22].
Major adverse prognostic factors included a diagnosis of central
nervous system NHL, advanced immunodeficiency, and prior
receipt of HAART (presumably reflecting incomplete adherence
or development of drug-resistant HIV) [22].
Treatment options for AIDS NHL are complicated by late
presentation [23]. For patients with AIDS-related NHL, a recent
phase 2 trial demonstrated the safe addition of rituximab (a
chimeric monoclonal B-cell antibody) to concurrent infusional
chemotherapy, resulting in complete remission for 73% of pa-
tients evaluated [24]. Another recent study found that NHL
tumor subtype was an independent predictor of outcome, em-
phasizing the heterogeneity of AIDS NHLs and the need for
additional clinical studies that evaluate treatments for individ-
ual histologic subtypes of NHL [25, 26]. Finally, improved
HAART regimens could also have a major impact on NHL
mortality, both by decreasing NHL incidence and increasing
survival among people with AIDS who develop NHL.
We also demonstrated notable decreases in mortality due to
NADCs. Because the incidence of these malignancies has not
fallen over time in a corresponding manner [5, 20], the decrease
in mortality may reflect improvements in cancer prognosis,
perhaps due to earlier detection, better access to cancer care,
or more effective use of cancer therapy in conjunction with
HAART. Among people with AIDS who died in the HAART
era, lung cancer was the most frequent NADC cause of death,
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4. Table1.CausesofDeathamongPeoplewithAIDSintheUnitedStates,1980–2006(np83,282)
Causeofdeath
No.(%)ofdeaths,accordingto
calendaryearofAIDSonset
a
No.ofdeathsper1000person-years(95%CI),
accordingtocalendaryearofAIDSonset
b
Pc
1980–19891990–19951996–20061980–19891990–19951996–2006
DeathsreportedtoHIV/AIDSregistry13,92426,8472491302(297–307)140(139–142)29(27–30)!.01
Nonmissingcauseofdeath12,903(100)22,713(100)2311(100)280(275–285)119(117–120)27(25–28)!.01
Cancercauseofdeath238(1.84)666(2.93)130(5.63)5.16(4.53–5.86)3.48(3.22–3.78)1.49(1.25–1.77)!.01
AIDS-definingcancer
All136(1.05)317(1.40)57(2.47)2.95(2.47–3.49)1.66(1.48–1.85)0.65(0.50–0.85)!.01
KS41(0.32)63(0.28)7(0.30)0.89(0.64–1.21)0.33(0.25–0.42)0.08(0.03–0.17)!.01
NHL92(0.71)250(1.10)47(2.03)2.00(1.61–2.45)1.31(1.15–1.48)0.54(0.40–0.72)!.01
Cervicalcancerd
3(0.23)4(0.13)3(0.50)0.49(0.10–1.44)0.12(0.03–0.30)0.14(0.03–0.42).35
Non–AIDS-definingcancer
All102(0.79)349(1.54)73(3.16)2.21(1.80–2.69)1.83(1.64–2.03)0.84(0.66–1.05)!.05
Lungcancer40(0.31)111(0.49)28(1.21)0.87(0.62–1.18)0.58(0.48–0.70)0.32(0.21–0.46)!.01
Livercancer6(0.05)19(0.08)5(0.22)0.13(0.05–0.28)0.10(0.06–0.16)0.06(0.02–0.13)!.01
Hodgkinlymphoma7(0.05)15(0.07)1(0.04)0.15(0.06–0.31)0.08(0.04–0.13)0.01(0.00–0.06)!.01
Analcancere
2(0.02)14(0.06)0(0)0.04(0.06–0.16)0.07(0.04–0.12)0(0–0.04).51
Othernon-AIDS-definingcancers47(0.33)190(0.84)39(1.69)1.02(0.75–1.36)0.99(0.86–1.15)0.45(0.32–0.61).17
AIDS-related(excludingAIDS-definingcancer)9566(74.14)17,301(76.17)951(41.15)207(203–212)90(89–92)11(10–12)!.01
Othernon-cancer,non-AIDS-related3099(24.02)4746(20.90)1230(53.22)67(65–70)25(24–26)14(13–15)!.01
NOTE.CI,confidenceinterval;HIV,humanimmunodeficiencyvirus;KS,Kaposisarcoma;ICD-9,InternationalClassificationofDiseases,9thRevision;ICD-10,InternationalClassificationofDiseases,
10thRevision;NHL,non-Hodgkinlymphoma.
a
Atotalof15,191peoplehadAIDSonsetduring1980–1989,42,596peoplehadAIDSonsetduring1990–1995,and25,495peoplehadAIDSonsetduring1996–2006.Columnpercentagesuse
deathswithanonmissingunderlyingcauseasdenominator.
b
Therewere46,118person-yearsoffollow-upavailableamongpeoplewithAIDSonsetduring1980–1989,191,247person-yearsavailableamongpeoplewithAIDSonsetduring1990–1995,and
87,260person-yearsavailableamongpeoplewithAIDSonsetduring1996–2006.
c
PvaluewasdeterminedusingPoissonregression.
d
Analysiswasrestrictedtowomen.Percentagereflectsfrequencyofcervicalcancerasacauseofdeathamongdeathswithanonmissingcause.Amongwomen,therewere1316deaths(6082
person-years)during1980–1989,2910deaths(34,168person-years)during1990–1995,and602deaths(20,847person-years)during1996–2006.
e
Theseentriesincludeanalcancerdeaths(7deathswithICD-9code154.3and4deathswithICD-10codeC21.0)andrectalcancerdeaths(4deathswithICD-9code154.1and1deathwithICD-
10codeC20).Rectalcancerscanbemisclassifiedanalcancers,especiallyinpeoplewithAIDS.
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5. HIV/AIDS • CID 2010:51 (15 October) • 961
underscoring the importance of this malignancy. HIV-infected
people have an elevated risk for lung cancer owing to an excess
of smoking [27, 28]. In addition, other factors such as frequent
pulmonary infections or inflammation may also contribute in
synergy with tobacco [29]. Although we observed declining
mortality rates due to lung cancer, survival among HIV-infected
lung cancer patients remains poor [9, 30], emphasizing a need
to encourage smoking cessation in people with AIDS. Data from
lung cancer treatment trials limited to the HIV-infected pop-
ulation are lacking. For those with early stage cancer, surgi-
cal resection is an option, but optimum radiation and chemo-
therapy protocols are unknown.
Liver cancer mortality rates decreased significantly across
calendar periods in our study, but with decreases in other
causes, the fraction of deaths due to liver cancer increased
in the HAART era. The overall burden of liver cancer deaths
may continue to rise in people with AIDS as the combined
effects of alcohol use and coinfection with hepatitis B or C
viruses manifests as liver disease [31].
The decrease in mortality from other causes led to an increase
in the fraction of all deaths due to cancer (both ADC and
NADC). We note the importance of considering both mortality
rates and the fraction of all deaths attributable to a specific
cause, since they yield complementary information. In an ad-
ditional analysis of NHL and lung cancer deaths (which were
the most common cancer-related causes of death in our study),
we found that most had had that cancer reported to the cancer
registry. However, the lack of perfect concordance between in-
formation on the cause of death in the HIV/AIDS and cancer
diagnoses in the cancer registries suggests that some death cer-
tificate diagnoses could have been inaccurate.
A strength of this study is our use of data from population-
based HIV/AIDS registries to capture and classify all deaths
among people with AIDS. Although information on cause of
death was available from only 5 of our study sites, the de-
mographic characteristics of our cohort of people with AIDS
were generally similar to the overall population of persons with
AIDS in the Untied States. Cause of death was specified for
the majority of included subjects, but a limitation is that this
information was missing for some (between 7% and 15%, de-
pending on the calendar period). We note that it takes multiple
years for cause of death information to be verified, and com-
pleteness increases over time. Furthermore, as people’s under-
standing of HIV disease and deaths in this population evolved
over time, the attribution of death to a given cause likely
changed in parallel (eg, HIV disease is now considered less
limiting, so attribution to other causes may have increased over
time). Nonetheless, the overall decreases we note in mortality
rates are consistent with what has been reported by other stud-
ies. It should also be noted that we lacked individual data on
HAART use. However, our results accurately reflect overall the
population-level effects of HAART use on mortality. Our goal
was to evaluate cancer-related causes of death, so we did not
separately evaluate other causes of death. Other studies suggest
that cardiovascular disease and substance abuse contribute sub-
stantially to this category and should be a focus of prevention
programs [7, 11]. Finally, we evaluated only people with AIDS
and did not consider people with less advanced HIV infection.
Although we did not include data on this group, one would
expect lower mortality rates among HIV-infected people with-
out AIDS.
In summary, our findings demonstrate that cancer mortality
among people with AIDS has decreased in the HAART era, but
with concomitant decreases in other causes of death, cancers
now account for a growing fraction of deaths. As HIV-infected
people continue to live longer following an AIDS diagnosis and
as they age, cancer may increase as a cause of mortality. In
particular, improved prevention and treatment of NHL and
lung cancer, the 2 most common cancer-related causes of death,
would be expected to favorably impact survival among HIV-
infected people.
Acknowledgments
We thank the staff at the HIV/AIDS and cancer registries at the following
locations for providing data to the HIV/AIDS Cancer Match Study: Col-
orado; Connecticut; Florida; Illinois; Georgia; Massachusetts; Michigan;
New Jersey; New York, New York; Los Angeles, San Diego, and San Fran-
cisco, California; Seattle, Washington; Texas; and Washington, DC. We also
thank Tim McNeel (Information Management Systems, Rockville, MD)
for database management.
Financial support. The Intramural Research Program of the National
Cancer Institute, National Institutes of Health.
Potential conflicts of interest. All authors: no conflicts.
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