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 Peoplewith AIDS in the United States

Edgar P. Simard and Eric A. EngelsDivision 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 forcancer. Highly active antiretroviral therapy (HAART), which has been widely available since 1996, has resulted indramatic 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. Weevaluated mortality rates and the fraction of deaths due to cancer. Poisson regression assessed rates according tocalendar year of AIDS onset.

Results. Overall mortality decreased from 302 deaths per 1000 person-years in 1980–1989, to 140 deaths per1000 person-years in 1990–1995, and to 29 deaths per 1000 person-years in 1996–2006. ADC-related mortalitydecreased 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 decreasesin 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 1000person-years from the period 1980–1989 to the period 1996–2006 (P! .05), but the fraction of NADC-deathsincreased 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 dueto AIDS, cancers account for a growing fraction of deaths. Improved cancer prevention and treatment, particularlyfor 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 8September 2010.

Reprints or correspondence: Dr Eric A. Engels, Div of Cancer Epidemiology andGenetics, National Cancer Institute, 6120 Executive Blvd, EPS 7076, Rockville, MD20892 (engelse@mail.nih.gov).

Clinical Infectious Diseases 2010; 51(8):957–962This article is in the public domain, and no copyright is claimed.1058-4838/2010/5108-0013DOI: 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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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 �4 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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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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(297

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)14

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)!.0

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sing

caus

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deat

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,903

(100

)22

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(100

)23

11(1

00)

280

(275

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)11

9(1

17–1

20)

27(2

5–28

)!.0

1

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cer

caus

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deat

h23

8(1

.84)

666

(2.9

3)13

0(5

.63)

5.16

(4.5

3–5.

86)

3.48

(3.2

2–3.

78)

1.49

(1.2

5–1.

77)

!.0

1

AID

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ngca

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136

(1.0

5)31

7(1

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2.95

(2.4

7–3.

49)

1.66

(1.4

8–1.

85)

0.65

(0.5

0–0.

85)

!.0

1

KS

41(0

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63(0

.28)

7(0

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0.89

(0.6

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(0.0

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(0.7

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(0.4

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(0.0

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42)

.35

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102

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1.83

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(0.6

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(0.3

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(53.

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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 followinglocations 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 alsothank Tim McNeel (Information Management Systems, Rockville, MD)for database management.

Financial support. The Intramural Research Program of the NationalCancer Institute, National Institutes of Health.

Potential conflicts of interest. All authors: no conflicts.

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