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Epidemiology and Social

Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era

1997–2012

Park, Lesley S.; Tate, Janet P.; Sigel, Keith; Rimland, David; Crothers, Kristina; Gibert, Cynthia; Rodriguez-Barradas, Maria C.; Goetz, Matthew Bidwell; Bedimo, Roger J.; Brown, Sheldon T.; Justice, Amy C.; Dubrow, Robert

Author Information
doi: 10.1097/QAD.0000000000001112

Abstract

Introduction

Cancer is a leading cause of death among persons living with HIV/AIDS [1–4]. Before the advent of combination antiretroviral therapy (ART) in 1996, AIDS-defining cancers [ADC; Kaposi sarcoma, nonHodgkin lymphoma (NHL), and invasive cervical cancer] represented most cancer cases among HIV-infected (HIV+) persons [5]. The introduction of ART was followed by a substantial decrease in ADC incidence rate [5–13]. Simultaneously, the increasing lifespan and consequent aging of the HIV+ population [14] resulted in an increased crude nonAIDS-defining cancer (NADC) incidence rate [5,6,8,12,15] and a shift in cancer burden from ADC to NADC [5]. Although the crude NADC incidence rate increased between the pre-ART and ART eras, once age and other demographic factors were taken into account, the NADC incidence rate declined [5], remained steady [11], or increased [12,13].

Cancer time trend studies restricted to the ART era have for the most part focused on a limited number of cancer types and have varied in range and recency of calendar years studied [11,16–26]. Studies of adjusted incidence rate time trends that classified NADC into broad groupings have produced inconsistent results [20,23–25]. Evidence supports decreasing trends for lung cancer and Hodgkin lymphoma and an increasing trend for liver cancer, but results for anal cancer have been inconsistent; many nonsignificant trends for specific NADC have been observed, perhaps due to insufficient statistical power [11,16–19,21–23,26]. The ADC adjusted incidence rate has continued to decline during the ART era [9,11,17,18,20,23,24].

Despite the continued decline of the ADC incidence rate, the relative risk (HIV+ versus uninfected) remains elevated, even in the more recent ART era [9,11,23]. The relative risk for NADC (grouped) [11,12,20,23] and for specific NADC, including oral cavity and pharynx, anal, lung, and liver cancers and Hodgkin lymphoma, is elevated as well [27–29]. However, few studies have examined time trends in cancer relative risk during the ART era [9,16,18,19,23]. Several of these studies compared HIV+ persons with the general population using standardized incidence ratios (SIR) [18,19], but we are aware of only one study (from Kaiser Permanente in California during 1996–2007) that examined cancer incidence rate ratio (IRR) time trends in HIV+ versus demographically similar uninfected persons across a range of cancer groupings and specific types [23].

Our objective was to conduct a comprehensive assessment of cancer incidence time trends during the ART era (1997–2012) in the Veterans Aging Cohort Study (VACS), a large national HIV cohort that includes a demographically similar uninfected comparison group.

Methods

The VACS is an open cohort assembled from national Veterans Health Administration (VHA) databases (e.g., demographic, vital status, inpatient and outpatient encounters, laboratory results) with no direct researcher–patient contact [30]. VACS enrolls HIV+ veterans when they begin HIV care in the VHA and matches two uninfected veterans by age, sex, race/ethnicity, and clinical site. Veterans Affairs Connecticut Healthcare System and Yale University Institutional Review Boards have approved this study.

We linked VACS to the Veterans Affairs Central Cancer Registry (VACCR), a national registry of cancer cases diagnosed or treated at the VHA [31] and mapped International Classification of Diseases for Oncology Third Edition [32] topography and morphology codes from VACCR records to specific cancer types, consistent with Surveillance, Epidemiology, and End Results recoding algorithms [33]. We then further classified select NADC anatomic sites (oral cavity and pharynx, anal, liver, vagina, vulva, penis) into virus-related NADC (virus-NADC; Appendix Table 1, http://links.lww.com/QAD/A913) and nonvirus-related NADC (nonvirus-NADC). We used the following cancer group classification: all cancer; ADC; all NADC; virus-NADC; nonvirus-NADC; nonlung, nonvirus-NADC; and poorly specified cancers (Appendix Table 1, http://links.lww.com/QAD/A913). For cancer group incidence rate analyses, the endpoint for a given person was the first diagnosis of a cancer type classified in the group. To calculate the proportion of cancer cases by cancer type or group, we included all incident cancer cases, not just the first diagnosis per person. For example, a person diagnosed with both prostate and colorectal cancer contributed two nonvirus-NADC cases.

For each cancer group or type and calendar period (1997–2000, 2001–2004, 2005–2008, or 2009–2012), we used the direct method to calculate age-, sex-, and race/ethnicity-standardized incidence rates [34] stratified by HIV status; a standardized IRR (HIV+ versus uninfected); and 95% confidence intervals (95% CI). Henceforth, ‘incidence rate’ and ‘IRR’ signify standardized calculations, whereas ‘crude incidence rate’ signifies a nonstandardized crude incidence rate. Incidence rates provide information about HIV-status-specific absolute risk (after controlling for demographic factors), whereas IRRs provide information about risk in HIV+ relative to uninfected.

For direct standardization, we used the age (5-year groups), sex, and race/ethnicity (nonHispanic white, nonHispanic black, Hispanic, and other/unknown) person-year distribution of the entire VACS as the standard weights, with age and calendar period classified at each day of observation [35]. We calculated observation time for each person from 180 days after VACS entry date to the earliest of diagnosis date for the specific cancer group or type being analyzed, death date, loss to follow-up date (180 days after last VHA visit), or 30 September 2012. We excluded the first 180 days of observation time to remove prevalent cancer cases.

To calculate the incidence rate P trend across calendar periods, we used the Cochran–Armitage test of trend to calculate the one degree-of-freedom total chi-square statistic and P value [36], taking the standardization into account. For the IRR P trend across calendar periods, we calculated the one degree-of-freedom Mantel–Haenszel chi-square statistic and P value [37,38].

We performed statistical analyses using SAS version 9.4 [39]. We defined statistical significance as P less than 0.05 (two sided).

Results

Between 1997 and 2012, among the 44 787 HIV+ persons who contributed 329 084 person-years of observation time to this analysis, 3519 persons developed 3714 incident primary cancers. Among 96 852 uninfected persons who contributed 820 676 person-years, 5434 persons developed 5760 incident primary cancers. HIV+ and uninfected persons had similar distributions of age, sex, race/ethnicity, alcohol abuse/dependence, and smoking status (Table 1). The mean age at cohort entry was 48 years. Both groups were mostly men and approximately half nonHispanic black. Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections were more prevalent among HIV+ persons (21% HCV chronic, 3% HBV+) than uninfected persons (10% HCV chronic, 0.3% HBV+). Of total observation time, 16% was in 1997–2000, 25% in 2001–2004, and 30% each in 2005–2008 and 2009–2012.

Table 1
Table 1:
Baseline characteristics of persons who contributed observation time.

All cancer

Although the all cancer crude incidence rate increased over the four periods in the HIV+ (P trend = 0.0019, Fig. 1), once age-, sex-, and race/ethnicity-standardized, the incidence rate declined significantly (P trend <0.0001). In the uninfected, the increase in the crude all cancer incidence rate (P trend <0.0001) was more pronounced than in HIV+, but there was no significant trend in the standardized incidence rate (P trend = 0.074). With decreasing HIV+ incidence rates and stable uninfected incidence rates, the IRR declined (P trend <0.0001, Fig. 2), but remained elevated during the most recent calendar period (IRR = 1.6; 95% CI: 1.5–1.7; Table 2).

Fig. 1
Fig. 1:
All cancer crude and standardized incidence rates by HIV status and calendar period and P values for incidence rate period trend.HIV+, HIV-infected; IR, incidence rate.
Fig. 2
Fig. 2:
Cancer group standardized incidence rates (per 100 000 person-years) by HIV status and calendar period, standardized incidence rate ratios with 95% confidence intervals by period, and P values for standardized incidence rate ratio period trend.ADC, AIDS-defining cancer; HIV+, HIV-infected; IR, standardized incidence rate; IRR, standardized incidence rate ratio; NADC, nonAIDS-defining cancer; Nonvirus-NADC, nonvirus-related nonAIDS-defining cancer; Virus-NADC, virus-related nonAIDS-defining cancer. Note that Y-axis scale varies by cancer group.
Table 2
Table 2:
Numbers of cancer cases, standardized incidence rates (per 100 000 person-years) and standardized incidence rate ratios with 95% confidence interval by calendar period, and P values for period trend, for cancer groups and specific cancer types.
Table 2
Table 2:
(Continued) Numbers of cancer cases, standardized incidence rates (per 100 000 person-years) and standardized incidence rate ratios with 95% confidence interval by calendar period, and P values for period trend, for cancer groups and specific cancer types.

AIDS-defining cancers

Among HIV+, the proportion of cancer cases that were ADC decreased from 31% in 1997–2000 to 11% in 2009–2012 (Fig. 3). The ADC incidence rate decreased in the HIV+ across the four periods (P trend <0.0001; Table 2). In the uninfected, the incidence rate increased modestly (P trend = 0.014), driven by the increase in the NHL incidence rate (Table 2). Resultant IRRs decreased significantly across periods (P trend <0.0001; Fig. 2), but remained elevated in the most recent period (IRR = 5.5; 95% CI: 3.7–8.4). In the HIV+, both the NHL and Kaposi sarcoma incidence rate declined by more than one-half between 1997–2000 and 2009–2012 (both P trends <0.0001). In the uninfected, the NHL incidence rate increased across periods (P trend = 0.021), and there were no Kaposi sarcoma cases. The NHL IRR dropped from 12 (95% CI: 5.8–24) in 1997–2000 to 3.6 (95% CI: 2.3–5.5) in 2009–2012 (P trend <0.0001). Due to the small proportion of women (3%), invasive cervical cancer did not meaningfully contribute to the ADC time trends.

Fig. 3
Fig. 3:
Proportion of cancer cases among HIV+ persons by cancer group in each calendar period.ADC, AIDS-defining cancer; HIV+, HIV-infected; Nonvirus-NADC, nonvirus-related nonAIDS-defining cancer; Virus-NADC, virus-related nonAIDS-defining cancer. To calculate cancer group proportions, we included all incident cancer cases, not just the first diagnosis for each person. For example, a person diagnosed with both Kaposi sarcoma and colorectal cancer during the observation period contributed one ADC case and one nonvirus-NADC case, and a person diagnosed with both hepatocellular carcinoma and Hodgkin lymphoma contributed two virus-NADC cases.

Virus-related nonAIDS-defining cancers

Among HIV+, the proportion of cancer cases that were virus-NADC increased from 16% in 1997–2000 to 21% in 2009–2012 (Fig. 3). In the latter period, 44% of virus-NADC were hepatocellular carcinoma (HCC) and 33% were anal squamous cell carcinoma (SCC). The virus-NADC incidence rate was stable for HIV+ (P trend = 0.43, Table 2) but increased significantly for uninfected (P trend = 0.0082), driven by an increasing HCC incidence rate trend. Consequently, the virus-NADC IRR decreased across the four periods with a borderline significant trend (P trend = 0.071; Fig. 2), but remained elevated during the most recent period (IRR = 3.5; 95% CI: 2.7–4.5; Table 2). The HCC incidence rate increased in HIV+ (P trend = 0.043), but moreso in uninfected (P trend <0.0001), resulting in an IRR decrease from 9.8 (95% CI: 2.9–33) in 1997–2000 to 2.1 (95% CI: 1.5–2.8) in 2009–2012 (P trend = 0.0002). The human papillomavirus (HPV)-related oral cavity and pharynx SCC incidence rate did not change significantly for HIV+ (P trend = 0.43), but decreased in the uninfected (P trend = 0.023), resulting in an increasing IRR trend (P trend = 0.048). We observed no trend in the anal SCC incidence rate or IRR. In HIV+ between 1997–2000 and 2001–2004, the Hodgkin lymphoma incidence rate fell from 55 to 28 cases per 100 000 person-years and then stabilized (P trend = 0.047), with no IRR trend (P trend = 0.79). For each mentioned virus-NADC, we found a significantly elevated IRR in the most recent calendar period.

Nonvirus-related nonAIDS-defining cancers

Among HIV+, the proportion of cancer cases that were nonvirus-NADC increased from 51% in 1997–2000 to 68% in 2009–2012 (Fig. 3). Thus, the majority of incident cancer cases were nonvirus-NADC, which includes common cancer types such as colorectal, lung, and prostate. During 2009–2012, 27% of nonvirus-NADC were lung cancers and 35% were prostate cancers. We observed a decreasing trend for the HIV+ incidence rate (P trend <0.0001; Table 2), uninfected incidence rate (P trend = 0.0011), and IRR (P = 0.049; Fig. 2), but the IRR remained slightly elevated during the most recent period (IRR = 1.2; 95% CI: 1.1–1.3). The lung cancer incidence rate decreased significantly in both HIV+ (P trend = 0.0008) and uninfected (P trend = 0.0017), with the IRR significantly elevated between 1.7 and 2.0 over the four periods (P trend = 0.52). Lung cancer was the only nonvirus-NADC type with consistently elevated IRRs across periods. After removing lung cancer from the nonvirus-NADC group, the IRR trend was no longer significant (P trend = 0.12), and the IRR moved toward the null and was only marginally or borderline significant in each calendar period.

Discussion

We utilized the largest HIV cohort in North America to conduct one of the few comprehensive assessments of cancer incidence time trends among HIV+ versus uninfected persons during the ART era. We observed a growing cancer burden among HIV+, evidenced by an increasing crude incidence rate trend. However, after taking age, sex, and race/ethnicity into account, we observed highly significant HIV+ incidence rate declines for all cancer (25% decline between 1997–2000 and 2009–2012), ADC (55% decline), NADC (15% decline), and nonvirus-NADC (20% decline); highly significant IRR declines for all cancer (from 2.0 to 1.6) and ADC (from 19 to 5.5); and marginally or borderline significant IRR declines for NADC (from 1.6 to 1.4), virus-NADC (from 4.9 to 3.5), and nonvirus-NADC (from 1.4 to 1.2). Although these declines were encouraging, it is important to note that the all cancer incidence rate was still 60% higher in HIV+ compared with uninfected in 2009–2012, driven mainly by ADC, virus-NADC, and within the nonvirus-NADC group, lung cancer (IRR = 1.8).

We found that the continuing decline in the HIV+ ADC incidence rate and the ADC IRR during the ART era that also has been observed by others [9,11,17,18,20,23,24] has extended through 2012 both for ADC overall and for Kaposi sarcoma and NHL, the main ADC components in our predominantly male cohort. The significant HIV+ NADC incidence rate decline that we observed during the ART era was not observed by others [11,22], perhaps due to shorter calendar times of observation or fewer cancer diagnoses resulting in less statistical power. However, the NADC IRR decline that we observed, which took into account the decline in the uninfected NADC incidence rate that also occurred during the observation period, was only borderline significant, similar to the Kaiser Permanente California result [23].

We found no evidence for a trend in the HIV+ virus-NADC incidence rate, consistent with findings from the HIV Outpatient Study [24], but inconsistent with a study from northern Italy, which observed an increasing trend (but with no reported P trend) [20] and with the Kaiser study, which observed a significant decreasing trend [23]. However, the borderline significant decreasing trend that we observed in the virus-NADC IRR, which took into account the increasing uninfected virus-NADC incidence rate trend (driven by the increasing HCC incidence rate trend), was consistent with the significant decreasing IRR trend observed in the Kaiser study [23]. In the VACS cohort, HCC accounted for almost 40% of virus-NADC among HIV+ and almost 60% of virus-NADC among uninfected persons. HCC may be less common in other populations, accounting for differences in virus-NADC trends.

The significant decreasing trend we observed in the HIV+ nonvirus-NADC incidence rate was consistent with findings from the HIV Outpatient Study [24], but inconsistent with results from northern Italy, where a borderline significant increasing trend was observed [25] and from Kaiser, where no trend was observed, either in the HIV+ incidence rate or in the IRR [23]. The decreasing nonvirus-NADC IRR trend that we observed, which took the decreasing uninfected nonvirus-NADC incidence rate trend into account, was only marginally significant. Furthermore, removal of lung cancer, the only nonvirus-NADC with an elevated IRR in each of the four periods, resulted in a nonsignificant IRR trend with marginally or borderline significant period-specific IRRs of only 1.1–1.2. This reflected the fact that most of the common epithelial cancer types, including colorectal and prostate, did not exhibit elevated incidence in HIV+ persons, consistent with the literature [27,28]. We observed no trend in the prostate cancer incidence rate in either HIV+ or uninfected persons, with the IRR consistently null across the four periods. These results suggested stable prostate specific antigen screening rates during 1996–2012, with similar screening rates in HIV+ and uninfected persons.

With respect to specific NADC types, the decreasing HIV+ incidence rate trends for lung cancer and Hodgkin lymphoma, and the increasing trend for HCC were consistent with previous reports [17–19]. However, we observed no trend in the lung cancer IRR, which took into account the decreasing uninfected lung cancer incidence rate trend. This result was inconsistent with studies that observed a decreasing lung cancer IRR (or SIR) trend [18,19,23]. Furthermore, we observed a decreasing HCC IRR trend, which was driven by the steeply increasing uninfected HCC incidence rate trend. Other studies have observed no HCC IRR (or SIR) trend [18,19,23]. We observed no trend in the HIV+ anal cancer incidence rate or in the IRR; trends observed in other studies have been inconsistent [16–19,22,23,26].

In general, time trends in cancer incidence are determined by secular trends in the prevalence of cancer risk factors. The decreasing lung cancer and increasing HCC incidence rate trends in both HIV+ and uninfected were consistent with secular trends in the US general population [40], driven by decreasing smoking prevalence [41] and increasing duration of chronic HCV infection [42], respectively.

Among HIV+ persons, the prevalence of traditional cancer risk factors, particularly smoking and oncogenic virus infections, is elevated [43], although prevalence time trends have not been well characterized. Furthermore, impaired immune function and inflammation resulting from HIV infection itself are associated with appreciable cancer risk [27,44]. The strong inverse association between CD4+ cell count and ADC risk is well established, and evidence has accumulated in favor of a weaker, more subtle inverse association between CD4+ cell count and risk for virus-NADC and possibly some nonvirus-NADC [27,44]. Thus, the decreasing ADC trends were probably driven by improvements in HIV care since the introduction of ART, including higher CD4+ cell count at diagnosis [45], earlier postdiagnosis initiation of ART [46], improved ART regimens [47,48], increased ART adherence [49], and increased virological suppression [49,50]. These HIV care trends likely contributed to the decreasing NADC trends as well.

We found that among HIV+ persons, the shift in cancer burden from ADC to NADC (especially nonvirus-NADC) has continued (Fig. 3). By 2009–2012, only 11% of HIV+ cancer cases were ADC, and four of the five most commonly diagnosed cancer types (prostate, lung, HCC, NHL, and anal SCC) were NADC, although prostate cancer did not exhibit elevated incidence among HIV+ persons.

Our results have implications for cancer prevention among HIV+ persons. First, given the continued elevated ADC and NADC IRRs and the association between impaired immune function and increased ADC and, to a lesser extent, NADC risk, it is likely that even further improvements in HIV care would result in further declines in cancer incidence, especially for NHL, now the most common ADC.

Second, lung, liver, anal, and prostate cancers represent targets for prevention due to their high incidence. Prevention research efforts in the setting of HIV infection should include smoking cessation [51,52]; validation and optimization of computed tomography screening for lung cancer [53,54], ultrasonography screening for HCC [55], and anal dysplasia screening for anal cancer [56]; optimization of HBV vaccination for HCC [57,58] and HPV vaccination for HPV-related cancers [59–63]; and optimization of HCV [64,65], HBV [57,66], and alcohol abuse/dependence treatment [67,68] for HCC. Prostate specific antigen screening for prostate cancer is controversial [69].

Our study had limitations. First, due to the paucity of women in VACS, we were unable to assess woman cancer type time trends or to generalize our results to women. Second, VACCR does not capture 10–20% of cancer cases, in part due to utilization of healthcare outside the VHA system [29,31], resulting in underestimation of incidence rates. However, in a validation study, we determined that IRRs are either unbiased or possibly biased downward [29], meaning that the ‘true’ IRRs would be at least as high as the IRRs we observed. The elevated IRRs we observed were generally consistent with the literature [27,28].

Our study also had strengths. First, VACS is the largest HIV cohort in North America and one of the few to include a demographically-similar uninfected comparison group, which is superior to a general population comparison group for identifying HIV-specific effects. Second, although cancer case ascertainment was incomplete, the positive predictive value of VACCR diagnoses is high [29]. Finally, our study extended from the start of the ART era through 2012, the most extensive cancer time trends study performed to date.

In summary, after adjusting for demographic factors, we observed a generalized decline in both absolute and relative cancer incidence among HIV+ persons during the ART era. HIV+ incidence rates declined for all cancer groups except virus-NADC, and IRRs declined for all cancer groups, although IRR trends for NADC, virus-NADC, and nonvirus-NADC were only marginally or borderline significant. In spite of these declines, the all-cancer incidence rate remained 60% higher in HIV+ compared with uninfected in 2009–2012, driven mainly by elevated IRRs for ADC, virus-NADC, and lung cancer. Improved HIV care most likely contributed to the declines, and we could anticipate that further adoption of early and sustained ART combined with ongoing ART regimen enhancements will produce additional declines in cancer incidence. Research and clinical practice efforts to reduce cancer risk factor prevalence and to promote evidence-based screening could also contribute to future cancer incidence declines among HIV+ persons.

Acknowledgements

Author contributions: L.S.P., J.P.T., A.C.J., and R.D. designed the study. L.S.P. and R.D. wrote the initial drafts of the manuscript. L.S.P. performed the analyses with supervision from J.P.T., A.C.J., and R.D. All authors contributed to the overall intellectual content of the manuscript, read and edited subsequent drafts, and approved the final version.

We are grateful to the Veterans Affairs Central Cancer Registry (VACCR) for linking the VACS with the VACCR database and providing us with a dataset containing the linked records. This study would not have been possible without the VACCR's generous assistance.

Sources of funding: This research was supported by the US Veterans Health Administration and by grants from the National Institute on Alcohol Abuse and Alcoholism (U01-AA020790, U24-AA020794, U10-AA013566), National Institute of Mental Health (T32-MH020031, P30-MH062294), National Institute of Allergy and Infectious Diseases (U01-A1069918), National Cancer Institute (F31-CA180775, R01-CA165937, R01-CA173754), and National Institute of Diabetes and Digestive and Kidney Diseases (3T32-DK007217) of the National Institutes of Health.

Disclaimers: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs.

Conflicts of interest

There are no conflicts of interest.

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