In comparison to these crude trends, time trends after adjustment for demographics were significantly weaker for Kaposi sarcoma (1996–2000: adjusted APC −25.6%, 95% CI −29.5%, −21.6%, P < 0.001 for comparison with crude trend; 2000–2010: −5.7%, 95% CI −7.7%, −3.7%, P < 0.001), liver cancer (6.6%, 95% CI 2.7%, 10.7%, P = 0.006), and prostate cancer (2.9%, 95% CI −0.3%, 6.3%, P < 0.001) (Table 2). For lung cancer, the decreasing trend became stronger after adjustment −(adjusted APC −6.8%, 95% CI −8.5%, −5.0%, P < 0.001). For breast and colorectal cancers, adjusted trends differed significantly from crude trends (P < 0.001 for both), but neither differed significantly from zero. For liver, lung, and prostate cancers, these differences in trends are visible graphically by comparison of crude and standardized HIV-infected cancer incidence rates (comparison of solid and dashed lines, Fig. 2e–g). In our supplementary analysis, adjustment only for age accounted for the difference in crude and adjusted APCs for breast, colorectal, liver, lung, and prostate cancers (see Table, Supplemental Digital Content 4, http://links.lww.com/QAD/A457, which lists APCs adjusted for individual demographic factors). This implies that among various demographic shifts over time, aging specifically had the greatest influence on incidence rates of these cancers. For Kaposi sarcoma, on the contrary, adjustment for HIV/AIDS-relative time had the greatest impact.
Incidence in the general population increased over time for anal (APC 3.3%, 95% CI 1.4%, 5.2%) and liver cancers (5.6%, 95% CI 4.6%, 6.6%), and decreased for NHL (2003–2010: −2.2%, 95% CI −3.3%, −1.0%) and cervical (−2.4%, 95% CI −3.4%, −1.3%), breast (−0.8%, 95% CI −1.2%, −0.5%), colorectal (−0.7%, 95% CI −1.1%, −0.3%), and lung (−3.2%, 95% CI −3.5%, −2.8%) cancers (Table 2). The directions of these trends were consistent with those in the HIV population, with the exception of breast and colorectal cancers, which showed no significant trend in the HIV population. General population trends are visually evident for cervical, anal, liver, and lung cancers (solid lines with markers, Figs. 1c and 2a, e, and f).
Decreasing SIRs contributed to trends over time for Kaposi sarcoma (1996–2000; APC −26.3%, 95% CI −30.2%, −22.3%; 2000–2010: −2.7%, 95% CI −4.8%, −0.7%), NHL (1996–2003: −14.5%, 95% CI −16.2%, −12.7%; 2003–2010: −4.0%, 95% CI −6.5%, −1.5%), cervical cancer (−9.4%, 95% CI −12.9%, −5.8%), Hodgkin lymphoma (−3.2%, 95% CI −5.9%, −0.5%), and lung cancer (−4.4%, 95% CI −6.2%, −2.6%) (Table 2). Graphically, the declining magnitude of SIRs is visible as a decreasing gap over time between standardized incidence rates in the HIV-infected and general populations for NHL, cervical cancer, and lung cancer (decreasing gap between dashed lines and solid lines with markers, Fig. 1b, 1c, and 2f).
The incidence of many cancers changed over time in the U.S. HIV population during 1996–2010, and these trends were variably influenced by demographic shifts in the HIV population, changing cancer rates in the general population, and changes in the HIV-associated relative risk of cancer. In Table 3, we summarize these trends and the epidemiologic factors contributing to them. As we elaborate below, our results suggest that changes in demographics and in general population incidence rates were influential for most NADCs. In contrast, declines in ADCs were largely driven by decreasing relative risks.
Each ADC has a viral cause: human herpes virus 8 for Kaposi sarcoma, Epstein–Barr virus (EBV) for a large fraction of NHLs, and human papillomavirus (HPV) for cervical cancer. Dramatic declines in Kaposi sarcoma and NHL have been attributed to improved immune control of oncogenic viruses with HIV treatment [5,6,17]. Since 1996, clinical guidelines have recommended earlier HIV treatment, raising and finally eliminating the minimum CD4+ cell count threshold for treatment initiation [18–20]. Further, during 2000–2008, HAART use increased in the U.S. HIV population . The falling SIRs that we observed for Kaposi sarcoma and NHL likely reflect this expanding uptake and increasing effectiveness of HAART. For cervical cancer, declining relative risk may reflect the effects of HAART on HPV infection [22,23] or perhaps improvements in cervical cancer screening among HIV-infected women.
It has been suggested that aging and other demographic shifts in the HIV population are producing a rise in incidence of NADCs [8,10,11]. Our results indicate this is true for some, though not all, of the cancers we studied. We found that demographic shifts contributed to increases in liver cancer, and they were the only factor contributing to the rise in prostate cancer. These demographic shifts also masked a more rapid decline in lung cancer that would have been observed if the population characteristics had not changed over time. For these NADCs, aging was the main factor influencing trends (see Table, Supplemental Digital Content 4, http://links.lww.com/QAD/A457). Adjustment for HIV/AIDS-relative time produced the largest change for Kaposi sarcoma (see Table, Supplemental Digital Content 4, http://links.lww.com/QAD/A457), due to lower Kaposi sarcoma risk among the increasing number of individuals surviving more than 5 years after an AIDS diagnosis (data not shown).
Time trends in general population incidence rates contributed to HIV-infected trends for several NADCs, specifically, for anal, breast, colorectal, liver, and lung cancers. Increasing liver cancer incidence in the U.S. general population has been attributed to long-term exposure to hepatitis B and C viruses , which have high prevalence in the HIV population . For lung cancer, declines in the general population are due to falling smoking prevalence , which may also be occurring in the HIV population. For breast and colorectal cancers, gradual decreases in the general population were countered by aging in the HIV population (Table 2, Supplemental Digital Content 4, http://links.lww.com/QAD/A457) leading to nonsignificant upward HIV-infected trends. Among ADCs, declines in the general population contributed to favorable NHL and cervical cancer trends, although changes in SIRs were likely more important.
Among NADCs, we observed decreasing trends in SIRs for lung cancer and HL. For lung cancer, this could reflect a faster decline in smoking prevalence in the HIV population than in the general population. Alternatively, the declining SIR may reflect benefits of HAART, since immune suppression and inflammation have been linked to development of lung cancer [12,27]. For HL, previous studies (including some using data from the HACM Study) reported an increase or no change over time in incidence among HIV-infected people [1,2,10,28], but we observed a decline. This difference may be due to the addition of more recent data (through 2010) or the inclusion of large numbers of HIV-infected people who have not developed AIDS. HAART facilitates immune control of EBV, which contributes to the majority of HL cases among HIV-infected people .
Over 80% of anal cancers are caused by prolonged HPV infection , and HIV-infected people have nearly 30-fold increased anal cancer risk . According to our results, increasing anal cancer incidence among people with HIV was attributable to increasing background rates. However, because HIV-infected anal cancers have strongly influenced general population trends among men , the background trend we observed was likely affected by HIV-infected cases. If one were able to remove the HIV-infected cases, the general population trend would be flatter . Thus, we cannot exclude that the trend in the HIV population is actually due to a masked trend in relative risk. Further, we observed heterogeneity among registries for anal cancer. In additional analyses, the HIV-infected anal cancer trend was no longer significant upon removal of the New Jersey registry, which showed a robust upward trend (Figure, Supplemental Digital Content 3, http://links.lww.com/QAD/A457). We do not have an explanation for this heterogeneity, but its presence complicates understanding of the average trends across registries. For these reasons, our results for anal cancer should be interpreted with caution.
Changes in cancer screening programs over time, including screening methods, recommendations, and public awareness, can influence cancer trends in complex ways that vary by cancer site. In our analysis, the observed impact of screening trends largely depends on how changes in screening compare between the HIV and general populations. Specifically, if screening among HIV-infected people increases over time for a cancer where screening reduces incidence (e.g. cervical cancer), then the HIV-infected incidence will show a downward trend. A general population contribution to this trend will be observed if the rate of screening uptake in the HIV population reflects the same uptake in the general population. If uptake is more rapid in the HIV population, then the relative difference will manifest as a decreasing SIR.
Strengths of our study include use of population-based data from seven U.S. states that cover most of the HAART era. We used a unique approach to evaluate complementary influences on cancer trends among HIV-infected people. One limitation is that our methodology may have failed to detect small contributions to these trends. For example, the lack of a significant P-value for a weak trend in the general population does not rule out that a trend in background incidence has affected the HIV population. Although it would be ideal to explicitly decompose the crude trends into three components, our method does not allow us to quantify the relative contributions of the three factors to the crude trend. For instance, one should not expect the APCs for the general population and SIR to sum to either the adjusted or crude APC. As noted above, our data are derived from seven different registries whose period of coverage is not homogeneous, though our analyses adjust for this limitation. Finally, we lack individual-level data describing HIV treatment, diagnosis or treatment of carcinogenic infections such as hepatitis B and C viruses, and cancer screening. Thus, we were unable to address these factors in our analyses.
In conclusion, our results indicate that the causes of recent trends in cancer incidence among HIV-infected people were multifaceted and differed by cancer site. HAART has reduced the incidence of many virus-related cancers by lowering the relative risk, and this result highlights the importance of continued improvement in accessible, early, and effective HIV treatment. However, for anal and liver cancers, the SIRs have not changed and incidence has increased. These adverse trends support efforts to make screening and prevention of these cancers a priority. For other cancers, especially prostate cancer, increasing incidence largely reflects the consequences of aging, and incidence should be expected to rise further as the HIV population continues to age.
Conception of study and study design: H.A.R., M.S.S., R.M.P., E.A.E. Statistical analyses: H.A.R., R.M.P. Interpretation of the results: H.A.R., M.S.S., R.M.P., E.A.E. Drafting of article: H.A.R. Revision and final approval of article: H.A.R., M.S.S., R.M.P., E.A.E.
The authors gratefully acknowledge the support and assistance provided by individuals at the following state HIV/AIDS and cancer registries: Colorado, Connecticut, Florida, Georgia, Michigan, New Jersey, and Texas. We also thank Timothy McNeel at Information Management Services for programming support.
The following cancer registries were supported by the SEER Program of the National Cancer Institute: Connecticut (HHSN261201000024C) and New Jersey (HHSN261201000027C, N01-PC-2010–0027). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: Colorado (U58 DP000848–04), Georgia (5U58DP003875–01), Michigan (5U58DP000812–03), New Jersey (1US58/DP0039311–01), and Texas (5U58DP000824–04). The New Jersey Cancer Registry was also supported by the state of New Jersey.
The views expressed in this article are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, HIV/AIDS or cancer registries, or their contractors.
This research was supported, in part, by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2014 Lippincott Williams & Wilkins, Inc.
cancer; HIV/AIDS; statistical modeling; trends; United States