Cancer in the HIV/AIDS Population in Iowa, 1991–2015

Abstract

PURPOSE:

As survival rates for individuals with HIV/AIDS diagnoses increase, cancer is becoming a more prevalent disease in this population. Data regarding the concurrent diagnoses of HIV/AIDS and cancer has not previously been examined and analyzed in the state of Iowa.

METHODS:

The Iowa Cancer Registry and Iowa Department of Public Health’s HIV/AIDS surveillance databases were linked, and matches were identified. Characteristics of Iowans with HIV/AIDS later diagnosed with cancer between 1991 and 2015 were compared to Iowans without HIV/AIDS using proportional incidence ratios (PIRs).

RESULTS:

490 patients met inclusion criteria; 91% had AIDS and 9% had HIV only. Compared to individuals without HIV/AIDS, significantly higher PIRs for cancer were found in younger persons, males, African Americans, metropolitan (metro) residents, and Iowans with Medicaid or uninsured. Specifically, PIRs associated with the following cancers were higher in the population with HIV/AIDS: Kaposi sarcoma, non-Hodgkin lymphomas (NHL), and squamous cell neoplasms of the anus. When stratified by AIDS-defining cancers and non-AIDS-defining cancers the main differences were individuals with AIDS-defining cancers had elevated PIRs among those diagnosed between 1991–1998 and had Kaposi sarcoma or Burkitt lymphoma, while those with non-AIDS-defining cancers were diagnosed between 2007–2015 and were diagnosed with anal, male or female genital, lymphoma other than NHL, liver, lung, or other squamous cell neoplasm cancers. When comparing non-metropolitan (non-metro) vs metro Iowans with HIV/AIDS, PIRs for non-metro patients were elevated in those diagnosed with cancer between 50–59 years old, Whites, and individuals diagnosed with squamous cell neoplasms.

CONCLUSION:

Our results indicate Iowans with HIV/AIDS have higher proportions of certain types of cancers compared to the general population and provide baseline information for future initiatives aimed at preventing or detecting cancer among those living with HIV/AIDS.

The human immunodeficiency virus (HIV) affects the immune system by infecting and destroying CD4+ cells, also known as T-helper cells.¹ CD4+ cells play a key role in the immune system by helping make antibodies to defend against infections.² Healthy individuals typically have 800–1200 CD4+ cells/mm³ of blood. The HIV diagnoses transform into an acquired immune deficiency syndrome (AIDS) diagnosis when a person’s CD4+ cell count diminishes to 200 CD4+ cells/mm³ of blood.¹ The incubation period, or time between the HIV diagnosis and AIDS diagnosis varies significantly, but averages about ten years in healthy young adults.³

Minorities, especially African Americans and Hispanics, are at a greater risk of developing HIV. In 2017, African Americans made up 3% of Iowa’s population, but accounted for 30% of new HIV diagnoses, 66% of them being males.⁴ Youth and young adults, ages 15–24, represented 25% of the HIV diagnoses in 2017. The median age of diagnosis in 2017 was 32.0 years, lower than the previous five-year median of 36.5 years.⁴ People in a lower socioeconomic class are also more likely to contract HIV largely as a result of limited education.⁵

People with HIV/AIDS are at greater risk for certain types of cancer. These cancers include aggressive non-Hodgkin lymphoma (NHL), Kaposi sarcoma, and invasive cervical cancer, which are referred to as AIDS-defining cancers, because they signal when a person’s HIV has developed into AIDS.⁶ Potential reasons for this increased risk include immunosuppression due to the reduction of CD4+ cell count, lifestyle factors and risky behaviors, and increased risk to viruses such as human papillomavirus (HPV) and Hepatitis B and C (HBV, HCV).⁷ Non-AIDS-defining cancers include Hodgkin lymphoma, and cancers involving the anus, liver, oral cavity and pharynx, lung, testis, penis, and colorectum.⁸ Since the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a reduction in the risk of some of these cancers as the target of HAART is to increase the CD4+ cell count.⁹ Due to the increasing survival of people with HIV/AIDS largely from HAART, non-AIDS-defining cancers in patients with HIV/AIDS are becoming a more prominent issue.

A study by Robbins et al. examined the number of cancers among people infected with HIV and the excess numbers of these cancers. The HIV/AIDS Cancer Match (HACM) Study was used to calculate these estimates. This dataset is a linkage of population-based state HIV registries and a limited number of cancer registries that do not include Iowa. Robbins et al. estimated that 859,522 people were living with diagnosed HIV in the US in 2010. The number of cancers that occurred in 2010 within this population was estimated at 7,760 cancers with 3,920 of these in excess when compared to similar cancers in the general population not diagnosed with HIV/AIDS.¹⁰ A statistically significant excess of NHL and other lymphomas, Kaposi sarcoma, cervical, lung, anal, liver, and oral cavity/pharyngeal cancers were found.

Linkage between the Iowa population-based HIV and cancer surveillance databases had not previously been attempted. The purpose of this study was to examine the number of cancers among people with an HIV/AIDS infection and identify excesses of cancer types as compared to the remaining Iowa population. To identify excesses of certain cancers compared to the rest of the Iowa population, proportional incidence ratios (PIRs) were used. This analysis is also a limitation of the study, because the relative frequency of other cancer sites can affect the proportional incidence for the site of interest. Thus, PIRs can only suggest that a risk exists. Calculating standard incidence ratios is a stronger analysis, but due to lack of access to data on person-years at risk we were unable to perform this analysis.

Methods

Data Sources & Study Population

Data for patients with HIV/AIDS were obtained from the Iowa Department of Public Health (IDPH). These data are reported as 99% complete⁴, which is determined using a program developed by the Centers for Disease Control (CDC) that takes into account Iowa’s HIV prevalence and expected number of annual cases along with other variables. These data were linked to the Iowa Cancer Registry (ICR) and placed in their SEER Data Management System (SEER*DMS), since HIV/AIDS status is a SEER-reportable variable. This database contains information on patient sociodemographics, tumor characteristics, specific cancer markers, stage at diagnosis, first course of treatment, and patient survival. Eligible patients included residents of Iowa who received their first cancer diagnosis at the same time (within 3 months) or after their HIV/AIDS diagnosis, and were diagnosed with an in situ or malignant cancer between 1991 and 2015. The Iowa comparison group included the remaining in situ or malignant cancer patients diagnosed between 1991 and 2015 in Iowa.

Linkage

To link IDPH HIV/AIDS data to ICR data, a data sharing agreement was required. With approval of this agreement, IDPH HIV/AIDS data are now annually linked to ICR data. The linkage process begins with ICR querying the SEER*DMS database for eligible patients and creates a delimited text file containing unique identifiers for each patient and matching variable that IDPH can use to link to their own database. The file is sent to IDPH through a secure data transfer site that is encrypted and uses a unique password for each exchange. IDPH then performs the linkage using deterministic matching methods to link HIV and cancer datasets to minimize time for manual reviews.

A SAS program used in a similar study by the CDC was modified to perform the data linkage.¹¹ Seven variables were assessed for completeness in each dataset and included in the matching process (i.e., social security number (full and partial), first, middle and last name, date of birth, gender and race). The SAS program matched data on 14 keys and provided a linkage summary and score for each matched case. A perfect score was obtained by cases that also matched on race and middle name. Cases that matched to more than one case in the other dataset and cases that have discordance gender or race were manually adjudicated. Once completed, IDPH sent the output file to the ICR via the same secure transfer site.

Study Variables

Patient demographic variables included age of cancer diagnosis, age of HIV diagnosis, age of AIDS diagnosis, HIV/AIDS status, race, sex, area of residence, marital status, insurance status, poverty status, and year of diagnosis for cancer, HIV, and AIDS. Tumor characteristics included location, histology, behavior, and SEER Historic Stage A. Treatment variables included surgery, radiation, and chemotherapy. Cancers were categorized as AIDS-defining cancers if they were invasive cervical cancer, NHL, primary central nervous system lymphoma, or Kaposi sarcoma. Non-AIDS-defining cancers were all other cancers and, if in the population with HIV/AIDS, were diagnosed with the cancer at least three months after an HIV/AIDS diagnosis (23 patients did not meet these criteria). Area of residence was created using the United States Department of Agriculture (USDA) 2013 Rural-Urban Continuum Codes (Metro: 1–3; Non-metro: 4–9).

Statistical Analysis

Frequency distributions were calculated for patient, tumor, and treatment characteristics. PIRs were calculated on a log scale between the HIV/AIDS cancer study population and the remaining cancer cases in Iowa using an in-house SAS program that uses an equation proposed by Breslow and Day:¹²

$$PIR= \frac{d/t}{d^{*}/t^{*}}$$

$$SE\left(\mathit{\text{logPIR}}\right)=\frac{{\left(d\left(t-d/t\right)\right)}^{1/2}}{d}$$

Where, for this study, d is the number of cancer diagnoses in the HIV/AIDS study population within a variable category, t is the total number of cancer diagnoses in the HIV/AIDS study population within a variable, d* is the number of cancer diagnoses remaining in the Iowa population within a variable category, and t* is the total number of cancer diagnoses remaining in the Iowa population within a variable. PIRs compare the proportional distribution of a characteristic in one population to the proportional distribution of the same characteristic in the remaining population. If PIRs are elevated for some categories, then other categories have to be depressed. Analyses were conducted in SAS version 9.4 (SAS Institute, Cary, NC).

Results

Between 1991 and 2015 there were 490 patients diagnosed with cancer three months before an HIV/AIDS diagnosis or thereafter. Overall, 91% of these patients were diagnosed with AIDS, while 9% were only diagnosed with HIV. Table 1 displays the characteristics of patients with HIV/AIDS and cancer. Among Iowans with HIV/AIDS, the majority of patients were diagnosed with cancer and HIV/AIDS between 30 and 49 years of age. In addition, this population mostly consisted of Whites (85%), males (88%), and single persons (66%). Insurance coverage was not collected prior to 2007, but when available, the majority of patients had private insurance (24%), followed by Medicaid (14%). The greatest number of patients lived in a county with between 10% and 19% of the population living below 200% of the poverty level (27%).

Table 1.

Characteristics of patients with HIV/AIDS and cancer in Iowa, 1991–2015 (N=490)

		HIV/AIDS	Population
		N	%
Cancer diagnosis year	1991–1998	160	32.7%
	1999–2006	116	23.7%
	2007–2015	214	43.7%
HIV diagnosis year	1983–1989	108	22.0%
	1991–1998	219	44.7%
	1999–2006	94	19.2%
	2007–2015	69	14.1%
AIDS diagnosis year	1983–1989	25	5.1%
(42 missing, n=448)	1991–1998	239	48.8%
	1999–2006	108	22.0%
	2007–2015	76	15.5%
Cancer diagnosis age	00–29	39	8.0%
(years)	30–39	118	24.1%
	40–49	163	33.3%
	50–59	113	23.1%
	60–69	45	9.2%
	70+	12	2.5%
HIV diagnosis age	00–29	114	23.3%
(years)	30–39	179	36.5%
	40–49	119	24.3%
	50–59	56	11.4%
	60–69	16	3.3%
	70+	6	1.2%
AIDS diagnosis age	00–29	67	13.7%
(years)	30–39	165	33.7%
(42 missing, n=448)	40–49	126	25.7%
	50–59	65	13.3%
	60–69	17	3.5%
	70+	8	1.6%
HIV/AIDS diagnosis	AIDS	448	91.4%
	HIV	42	8.6%
Cancer diagnosis time	Cancer diagnosed after	402	82.0%
	Cancer diagnosed at same time	88	18.0%
Race	White	418	85.3%
	Black	55	11.2%
	Other	17	3.5%
Sex	Female	57	11.6%
	Male	433	88.4%
Area	Metro	340	69.4%
(6 missing, n=484)	Non-metro	144	29.4%
Marital status	Married	70	14.3%
	Divorce	66	13.5%
	Single	323	65.9%
	Widowed	11	2.2%
	Unknown	20	4.1%
Insurance	Insured	117	23.9%
(276 missing, n=214)	Medicaid	67	13.7%
	Uninsured	18	3.7%
	Unknown	12	2.5%
Poverty status	0% – <5% poverty	53	10.8%
	5% – <10% poverty	100	20.4%
	10% – <20% poverty	132	26.9%
	20% – 100% poverty	84	17.1%
	Unknown	121	24.7%
Site/Histology	Anus and Anal Canal / Squamous Cell Neoplasms	45	9.2%
	Anus and Anal Canal / Other	5	1.0%
	Female Genital Organs / Squamous Cell Neoplasms	13	2.7%
	Kaposi Sarcoma	90	18.4%
	Liver and Intrahepatic Bile Duct / Adenocarcinomas	13	2.7%
	Lung and Bronchus / Adenocarcinomas	19	3.9%
	Lung and Bronchus / Squamous Cell Neoplasms	8	1.6%
	Lung and Bronchus / Other	11	2.2%
	Lymph Nodes / NHL, Burkitt lymphoma	16	3.3%
	Lymph Nodes / NHL, DLBCL	76	15.5%
	Lymph Nodes / NHL, T-cell	10	2.0%
	Lymph Nodes / NHL, Other	41	8.4%
	Lymph Nodes / Other	24	4.9%
	Male Genital Organs / Adenocarcinomas	9	1.8%
	Male Genital Organs / Squamous Cell Neoplasms	8	1.6%
	Male Genital Organs / Other	7	1.4%
	Oral Cavity and Pharynx / Squamous Cell Neoplasms	6	1.2%
	Skin / Nevi and Melanomas	5	1.0%
	Other / Adenocarcinomas	25	5.1%
	Other / Ductal and Lobular Neoplasms	7	1.4%
	Other / Leukemias	9	1.8%
	Other / Squamous Cell Neoplasms	11	2.2%
	Other / Other	32	6.5%
Behavior code	In situ	44	9.0%
	Malignant	446	91.0%
Stage	In situ/Local	108	22.0%
	Regional	45	9.2%
	Distant	57	11.6%
	Unstaged	280	57.1%
Cancer number	First cancer	437	89.2%
	Second or higher cancer	53	10.8%
Surgery	Yes	152	31.0%
	No	338	69.0%
Radiation	Yes	125	25.5%
	No	365	74.5%
Chemotherapy	Yes	193	39.4%
	No	297	60.6%

Abbreviations: DLBCL: diffuse large B-cell lymphoma

The four most common cancers and histologies among people with HIV/AIDS were Kaposi sarcoma (18%), diffuse large B-cell lymphoma (DLBCL) (16%), squamous cell neoplasms of the anus (9%), and other types of NHL (8%) (Table 1). Although 57% of tumors were unstaged, 22% were in situ or localized and 12% were distant. This population has a high percentage of unstaged tumors because of the high number of lymphomas and Kaposi sarcomas, which are not staged in the SEER Historic Stage A variable and accounted for 91% of the unstaged tumors. Most cases were the first tumor the patient had diagnosed (89%). The majority of the population did not receive surgery (69%), radiation (75%), or chemotherapy (61%).

Proportional incidence ratios (PIRs) were calculated for available patient and cancer characteristics (Table 2). The PIRs compared the proportional distribution of a characteristic in the population with HIV/AIDS to the proportional distribution of the same characteristic in the non-HIV/AIDS population in Iowa. Significantly higher PIRs were found among males in the population with HIV/AIDS along with those diagnosed between 2007–2015, age of diagnosis under 60 years, African American, metro residence, Medicaid or uninsured, and had Kaposi sarcoma, NHL, other lymphomas, squamous cell neoplasm or another histology of the anus, squamous cell neoplasm of male genital organs, or adenocarcinoma of the liver.

Table 2.

Unadjusted proportional incidence ratios (PIR) by patient and tumor characteristics, Iowa, 1991–2015.

		HIV/AIDS Population	Iowa Population	PIR	95% CI
		(N=490)	(N=436,101)
Cancer diagnosis	1991–1998	160	130,168	1.09	(0.96, 1.24)
year	1999–2006	116	137,449	0.75	(0.64, 0.88)
	2007–2015	214	168,484	1.13	(1.02, 1.25)
Cancer diagnosis	00–29	39	10,837	3.20	(2.37, 4.33)
age (years)	30–39	118	13,619	7.71	(6.59, 9.02)
	40–49	163	32,631	4.45	(3.92, 5.04)
	50–59	113	67,923	1.48	(1.26, 1.74)
	60–69	45	105,365	0.38	(0.29, 0.50)
	70+	12	205,726	0.05	(0.03, 0.09)
Race	White	418	424,847	0.88	(0.84, 0.91)
	African American	55	5,936	8.25	(6.43, 10.58)
	Other	17	5,318	2.85	(1.78, 4.54)
Sex	Female	57	218,351	0.23	(0.18, 0.30)
	Male	433	217,750	1.77	(1.71, 1.83)
Area of residence	Metro	340	217,429	1.18	(1.11, 1.25)
(71,979 missing)	Non-metro	144	146,699	0.74	(0.64, 0.85)
Insurance status	Insured	117	152,539	0.63	(0.56, 0.71)
(260,415 missing)	Medicaid	67	6,367	8.65	(7.09, 10.55)
	Uninsured	18	3,301	4.48	(2.88, 6.97)
	Unknown	12	13,693	0.72	(0.42, 1.25)
Site / Histology	Anus and Anal Canal / Squamous Cell Neoplasms	45	896	44.70	(33.84, 59.05)
	Anus and Anal Canal / Other	5	356	12.50	(5.23, 29.90)
	Female Genital Organs / Squamous Cell Neoplasms	13	7,104	1.63	(0.95, 2.79)
	Kaposi Sarcoma	90	324	247.22	(205.13, 297.96)
	Liver and Intrahepatic Bile Duct / Adenocarcinomas	13	3,418	3.39	(1.98, 5.79)
	Lung and Bronchus / Adenocarcinomas	19	19,444	0.87	(0.56, 1.35)
	Lung and Bronchus / Squamous Cell Neoplasms	8	12,710	0.56	(0.28, 1.11)
	Lung and Bronchus / Other	11	25,530	0.38	(0.21, 0.69)
	Lymph Nodes / NHL, Burkitt lymphoma	16	182	78.24	(48.32, 126.69)
	Lymph Nodes / NHL, DLBCL	76	6,549	10.33	(8.40, 12.70)
	Lymph Nodes / NHL, T-cell	10	639	13.93	(7.54, 25.72)
	Lymph Nodes / NHL, Other	41	9,675	3.77	(2.81, 5.06)
	Lymph Nodes / Other	24	2,554	8.36	(5.66, 12.36)
	Male Genital Organs / Adenocarcinomas	9	51,050	0.16	(0.08, 0.30)
	Male Genital Organs / Squamous Cell Neoplasms	8	531	13.41	(6.74, 26.66)
	Male Genital Organs / Other	7	6,867	0.91	(0.44, 1.89)
	Oral Cavity and Pharynx / Squamous Cell Neoplasms	6	6,930	0.77	(0.35, 1.71)
	Skin / Nevi and Melanomas	5	23,480	0.19	(0.08, 0.45)
	Other Sites / Adenocarcinomas	25	96,654	0.23	(0.16, 0.34)
	Other Sites / Ductal and Lobular Neoplasms	7	60,989	0.10	(0.05, 0.21)
	Other Sites / Leukemias	9	13,379	0.60	(0.31, 1.14)
	Other Sites / Squamous Cell Neoplasms	11	9,414	1.04	(0.58, 1.87)
	Other Sites / Other	32	77,426	0.37	(0.26, 0.51)
AIDS-defining vs	Kaposi Sarcoma	90	324	247.22	(205.13, 297.96)
Non-AIDS-defining	NHL, Burkitt lymphoma	16	178	80.00	(49.41, 129.54)
cancers	NHL, DLBCL	76	6,292	10.75	(8.74, 13.22)
(23 missing*)	NHL, T-cell	10	635	14.02	(7.59, 25.88)
	NHL, Other	41	9,572	3.81	(2.84, 5.11)
	Primary central nervous system lymphoma	0	368	0.00	-
	Cervical	0	3,002	0.00	-
	Non-AIDS-defining cancers	257	415,730	0.55	(0.51, 0.60)

^*23 cases are missing due to their cancers being diagnosed within 3 months of an HIV/AIDS diagnosis

Abbreviations: DLBCL: diffuse large B-cell lymphoma

Subset PIR analyses of AIDS-defining cancers and non-AIDS-defining cancers were done. The population with HIV/AIDS did not have any cases of invasive cervical cancer or primary central nervous system lymphoma that met inclusion criteria. In the population with AIDS-defining cancers, significantly higher PIRs were found among those diagnosed between 1991–1998, diagnosed under 50 years, were non-White, male, metro residence, had Medicaid or were uninsured, and had Kaposi sarcoma or Burkitt lymphoma (Table 3). Similar findings were found in the population with non-AIDS-defining cancers, except that significantly higher PIRs were found among those diagnosed between 2007–2015 and were diagnosed with any cancer of the anus, squamous cell neoplasms of male or female genital organs, lymphoma other than NHL, adenocarcinoma of the liver, squamous cell neoplasms of other sites, and adenocarcinoma of the lungs (Table 4).

Table 3.

Unadjusted proportional incidence ratios (PIR) of patients with AIDS-defining cancers by patient and tumor characteristics, Iowa, 1991–2015.

		HIV/AIDS Population	Iowa Population	PIR	95% CI
		(N=233)	(N=20,371)
Cancer diagnosis	1991–1998	128	5,926	1.89	(1.68, 2.12)
year	1999–2006	53	6,456	0.72	(0.57, 0.91)
	2007–2015	52	7,989	0.57	(0.45, 0.72)
Cancer diagnosis	00–29	26	724	3.14	(2.19, 4.51)
age (years)	30–39	80	1,227	5.70	(4.77, 6.81)
	40–49	84	1,962	3.74	(3.15, 4.44)
	50+	43	16,458	0.23	(0.17, 0.30)
Race	White	207	19,874	0.91	(0.87, 0.95)
	African American	17	254	5.85	(3.70, 9.25)
	Other	9	243	3.24	(1.71, 6.14)
Sex	Female	15	11,369	0.12	(0.07, 0.19)
	Male	218	9,002	2.12	(2.05, 2.19)
Area of residence	Metro	171	10,230	1.24	(1.15, 1.33)
(3,373 missing)	Non-metro	59	6,774	0.64	(0.52, 0.80)
Insurance status	Insured	26	7,373	0.57	(0.44, 0.75)
(12,302 missing)	Medicaid	15	351	6.93	(4.52, 10.62)
	Uninsured	11	707	2.52	(1.49, 4.26)
AIDS-defining cancers	Kaposi Sarcoma	90	324	24.29	(20.66, 28.55)
	NHL, Burkitt lymphoma	16	178	7.86	(4.90, 12.61)
	NHL, DLBCL	76	6,292	1.06	(0.88, 1.27)
	NHL, T-cell	10	635	1.38	(0.75, 2.52)
	NHL, Other	41	9,572	0.37	(0.28, 0.49)
	Primary central nervous system lymphoma	0	368	0.00	-
	Cervical	0	3,002	0.00	-

^*Significantly elevated PIRs are bolded

Abbreviations: DLBCL: diffuse large B-cell lymphoma

Table 4.

Unadjusted proportional incidence ratios (PIR) of patients diagnosed with a non-AIDS-defining cancer at least 3 months after an HIV/AIDS diagnosis by patient and tumor characteristics, Iowa, 1991–2015.

		HIV/AIDS Population	Iowa Population	PIR	95% CI
		(N=234)	(N=415,753)
Cancer diagnosis	1991–1998	26	124,248	0.37	(0.26, 0.53)
year	1999–2006	57	130,999	0.77	(0.62, 0.97)
	2007–2015	151	160,506	1.67	(1.52, 1.84)
Cancer diagnosis	00–29	11	10,115	1.93	(1.09, 3.44)
age (years)	30–39	32	12,398	4.59	(3.32, 6.33)
	40–49	75	30,673	4.34	(3.60, 5.24)
	50+	116	362,567	0.57	(0.50, 0.65)
Race	White	192	404,992	0.84	(0.79, 0.89)
	African American	34	5,686	10.62	(7.79, 14.50)
	Other	8	5,075	2.80	(1.42, 5.53)
Sex	Female	37	206,987	0.32	(0.24, 0.43)
	Male	197	208,766	1.68	(1.59, 1.77)
Area of residence	Metro	154	207,214	1.11	(1.01, 1.22)
(68,611 missing)	Non-metro	78	139,932	0.83	(0.70, 1.00)
Insurance status	Insured	83	145,174	0.63	(0.55, 0.73)
(248,439 missing)	Medicaid	49	6,019	9.03	(7.17, 11.37)
	Uninsured	19	16,287	1.29	(0.85, 1.97)
Site / Histology	Anus and Anal Canal / Squamous Cell Neoplasms	41	900	80.94	(61.30, 106.88)
	Anus and Anal Canal / Other	5	356	24.95	(10.48, 59.39)
	Female Genital Organs / Squamous Cell Neoplasms	12	5,102	4.18	(2.41, 7.25)
	Liver and Intrahepatic Bile Duct / Adenocarcinomas	12	3,419	6.24	(3.59, 10.82)
	Lung and Bronchus / Adenocarcinomas	19	19,444	1.74	(1.13, 2.67)
	Lung and Bronchus / Squamous Cell Neoplasms	8	12,710	1.12	(0.57, 2.21)
	Lung and Bronchus / Other	10	25,531	0.70	(0.38, 1.28)
	Lymph Nodes / Other	20	2,558	13.89	(9.14, 21.12)
	Male Genital Organs / Adenocarcinomas	9	51,050	0.31	(0.17, 0.59)
	Male Genital Organs / Squamous Cell Neoplasms	7	532	23.38	(11.27, 48.49)
	Male Genital Organs / Other	6	6,868	1.55	(0.70, 3.42)
	Oral Cavity and Pharynx / Squamous Cell Neoplasms	6	6,930	1.54	(0.70, 3.39)
	Other Sites / Adenocarcinomas	23	96,040	0.43	(0.29, 0.63)
	Other Sites / Ductal and Lobular Neoplasms	7	60,989	0.20	(0.10, 0.42)
	Other Sites / Leukemias	9	13,377	1.20	(0.63, 2.27)
	Other Sites / Squamous Cell Neoplasms	10	9,415	1.89	(1.03, 3.46)
	Other Sites / Other	30	100,532	0.53	(0.38, 0.74)

^*Significantly elevated PIRs are bolded

Table 5 displays the PIRs for patients diagnosed with HIV/AIDS and who resided in a metro vs non-metro area. Compared to the metro population in Iowa, the non-metro population had higher PIRs for 50–59 years at cancer diagnosis, Whites, and squamous cell neoplasm cancers.

Table 5.

Unadjusted proportional incidence ratios (PIR) of non-metro vs metro population with HIV/AIDS by patient and tumor characteristics, Iowa, 1991–2015.

		HIV/AIDS Population
		Non-metro	Metro	PIR	95% CI
		(N=144)	(N=340)
Cancer diagnosis	1991–1998	44	114	0.91	(0.71, 1.17)
year	1999–2006	37	77	1.13	(0.86, 1.50)
	2007–2015	63	149	1.00	(0.83, 1.20)
Cancer diagnosis	00–29	11	28	0.93	(0.53, 1.64)
age (years)	30–39	27	88	0.72	(0.52, 1.02)
	40–49	48	113	1.00	(0.80, 1.26)
	50–59	42	70	1.42	(1.10, 1.83)
	60+	16	41	0.92	(0.58, 1.46)
Race	White	132	280	1.11	(1.06, 1.17)
	Other	12	60	0.47	(0.27, 0.81)
Sex	Female	16	41	0.92	(0.58, 1.46)
	Male	128	299	1.01	(0.95, 1.07)
Site / Histology	Anus and Anal Canal / Squamous Cell Neoplasms	14	29	1.14	(0.69, 1.88)
	Female Genital Organs / Squamous Cell Neoplasms	6	7	2.02	(0.92, 4.43)
	Kaposi Sarcoma	20	69	0.68	(0.46, 1.03)
	Lung and Bronchus / Adenocarcinomas	7	12	1.38	(0.67, 2.84)
	Lung and Bronchus / Other	5	14	0.84	(0.36, 2.00)
	Lymph Nodes / NHL, DLBCL	19	56	0.80	(0.53, 1.22)
	Lymph Nodes / NHL, Other	20	46	1.03	(0.68, 1.54)
	Lymph Nodes / Other	8	15	1.26	(0.64, 2.47)
	Other Sites / Adenocarcinomas	13	34	0.90	(0.54, 1.52)
	Other Sites / Squamous Cell Neoplasms	11	14	1.86	(1.05, 3.27)
	Other Sites / Other	21	44	1.13	(0.76, 1.67)

^*Significantly elevated PIRs are bolded

Abbreviations: DLBCL: diffuse large B-cell lymphoma

Discussion

Overall, many demographic and tumor characteristics were found in significant excess in patients with HIV/AIDS. Males and African Americans were proportionally more likely to develop cancer if they were diagnosed with HIV/AIDS, while females and Whites were proportionally less likely to develop cancer if they were diagnosed with HIV/AIDS. We also found that the HIV/AIDS population were proportionally more likely to be diagnosed with cancer at a younger age compared to the remaining Iowa population. Diagnosis of cancers at younger ages in the population with HIV/AIDS has been observed in other studies for non-AIDS-defining cancers.^13–15 As with these studies, this study did not account for the underlying age differences in the population at risk of cancer. Shiels et al. was able to account for the differences in the population at risk and found the age at cancer diagnosis did not differ between the population with HIV/AIDS and the general population, with the exception of small age differences for lung and anal cancer.¹⁶

Those with AIDS-defining cancers had significantly elevated PIRs in earlier years, which may have been because their cancer diagnosis led to an HIV/AIDS diagnosis. This was opposite of what was found in those with non-AIDS-defining cancers who had significantly elevated PIRs in later years. This may be due to individuals with HIV/AIDS living longer and the introduction of HAART. Engels et al. found a similar trend where the SIRs of AIDS-defining cancers were elevated in earlier years, with decreasing risk in later years.⁶ No change over time was found for non-AIDS-defining cancers.

Kaposi sarcomas had the highest PIRs in patients with HIV/AIDS, followed by NHLs, squamous cell neoplasms of the anus and male genital organs, and adenocarcinoma of the liver. These results were supported in the Swiss HIV Cohort Study that showed AIDS-defining cancers consisting of Kaposi sarcoma and NHL and non-AIDS-defining cancers of the anus, liver, prostate, and testis incidences were elevated in patients with HIV/AIDS.¹⁷ Of these cancers, it has been shown that higher rates of anal cancer occurred in men who have sex with men (MSM). Silverberg et al. found that among persons with HIV, MSM had three times the risk of anal cancer compared with heterosexual men.¹⁸ HPV is a major risk factor for cancers of the oral cavity, genital organs, and anus, while HBV and HCV are major risk factors for liver cancer.¹⁹ Prior studies have shown a higher prevalence of anal HPV infection among MSM, who are more frequently infected with HIV (85%–95%) compared to MSM who do not have an HIV infection (57%–61%).^20,21 Due to a suppressed immune system, patients with HIV/AIDS are at a higher risk for these viruses, which is likely contributing to an excess of these cancers in patients with HIV/AIDS.¹⁰

Our results found patients with HIV/AIDS have proportionally less cancer in other cancer sites, which included the colon, rectum, and breasts, which other studies in the United States have found as well.^6,10 One study did find an excess incidence of colon and rectal cancer, but only with MSM.²²

In contrast to most studies, overall, we found a decreased proportion of lung cancers in patients with HIV/AIDS, but did find an elevated proportion of adenocarcinoma of the lung in patients with non-AIDS-defining cancers. Other studies note that an excess of lung cancer is due to smoking and other social risk factors rather than from immunosuppression.^6,17,23,24 Even though one study found smoking status was not significantly greater in those diagnosed with HIV, they did find cigarette smoking almost perfectly coincided with injection drug users (IDU), whose exposure to contaminated needles is a common form of transmitting HIV.²⁵

The majority of the skin cancers were Kaposi sarcoma (n=70), which is not surprising given Kaposi sarcoma had the greatest PIR and is considered an AIDS-defining-cancer. NHL and other lymphomas followed Kaposi sarcoma with the next highest PIRs. According to other studies that measured CD4+ cell counts, a decrease in CD4+ cell count or decrease in immunosuppression directly corresponded with an increased incidence of Kaposi sarcoma and NHL.^26,27 Patients with a higher CD4+ cell count and who were receiving treatment with HAART, were at a lower risk of Hodgkin lymphoma and NHL.²⁶ Hodgkin lymphoma and NHL are often caused by Epstein-Barr virus (EBV), while Kaposi sarcoma is caused by Human herpesvirus 8 (HHV-8), providing evidence that the excess incidence is a direct result of immunosuppression.^6,7 Notably, because HAART treatment targets the increase of CD4+ cell count, there has been a decrease in AIDS-defining cancers.⁸

Those diagnosed between age 50–59 years old, Whites, and had squamous cell neoplasms cancers were proportionally in excess in non-metro areas. This is opposite of what we found between the entire population with HIV/AIDS and the rest of Iowa, which is likely due to the fact that a large portion of rural Iowa is comprised of older persons who are White.²⁸ In comparison to our data, one study found that patients living with HIV in a rural area were more likely older, female, and of indigenous ancestry.²⁹ Area of residence for HIV/AIDS and cancer patients plays an important role as rural populations have been found to have less access to frequent, quality medical care.^29,30

A limitation of this study was the lack of access to measurements of immunosuppression and social behaviors such as smoking and drinking habits, sexuality, and drug use. Access to measurements of immunosuppression or social behaviors would have allowed us to study the correlation of these factors with certain types of cancer, like CD4+ cell count and the excess of NHL. Further, a problem with the interpretation of PIRs is that the relative frequency of other cancer sites can affect the proportional incidence for the site of interest. Thus, PIRs can only suggest that a risk exists. Calculating standard incidence ratios is a stronger analysis, but due to lack of access to data on person-years at risk we were unable to perform this analysis. Additionally, due to social behaviors and the lack of diversity in Iowa, our population underrepresents women and minorities. Although women are less likely to have HIV, and thus less likely diagnosed with an HIV/AIDS cancer, we were unable to see any notable differences in cancer excess in minorities other than in African Americans. It should also be noted that the IDPH states that 99% of newly diagnosed HIV cases in the state of Iowa have been reported, but the Centers for Disease Control and Prevention reports that, nationally, 12.8% of people with HIV remain undiagnosed.⁴

This study does have important strengths. For the first time, we were able to assess the cancer distribution in Iowa patients with HIV/AIDS compared to the remaining cancer population in Iowa across patient, tumor, and treatment characteristics. Given our population, we were able to look at these variables in relation to rurality. There have also been few studies that examined the differences in treatment of cancer in patients with HIV/AIDS based on the stage of the cancer. Using population-based data, we avoided the selection bias that is naturally inherent in the clinical trial setting. This study would not have been possible without access to the state’s HIV/AIDS, which was provided by IDPH.

Our results provide implications for the future. First, by comparing the PIRs to the general population, the study provides an understanding of who is likely at a higher risk to develop certain types of cancer. Second, the results provide baseline information for future strategies to combat and prevent cancer in the population with HIV/AIDS and the importance of adherence toHAART therapy among people living withHIV, as the relationship between suppressed immunity and cancer outcomes is still largely unknown. In Iowa, this may include having those diagnosed with HIV/AIDS participate more frequently in skin cancer screenings, anal pap tests, and other cancer screening examinations. This study also provides additional evidence of the challenges facing people living with HIV who are aging. The life expectancy of people living with HIV (who are adherent to treatment) is now near normal, but we still lack understanding of the effects of aging on people living with HIV. As the number of older people living with HIV is expected to continue to increase substantially, research into this area will gain importance. Future studies are also needed to confirm the cause of specific cancers in patients with HIV/AIDS; whether it be social behaviors or immunosuppression. In doing so, more specific cancer prevention and control opportunities may be provided.

Finally, our results highlight the utility of data linkages to better understand prevalence and implications of co-existing chronic diseases. While state-based linkages are highly valuable, national datasets like the HACM have an even bigger potential to address a broad spectrum of critical clinical and research questions. Greater participation of states in HIV and cancer linkages throughout the country have the potential to increase the representativeness of the HACM. In addition, this type of linkage could be replicated in the future with extensions to other cancer-related infectious disease statewide surveillance databases, such as hepatitis B & C and HPV vaccination. This could improve the assessment of population-based impacts, high-risk subgroups, and susceptible geographic areas.