Spectrum of cancer risk late after AIDS in the United States

Introduction

Persons infected with human immunodeficiency virus (HIV) have an increased risk of cancer.^1,2 Advanced HIV infection is characterized by profound immunosuppression (i.e., acquired immunodeficiency syndrome [AIDS]), a risk factor for a number of malignancies. Three cancers are AIDS-defining: Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), and cervical cancer.³ These cancers are caused by oncogenic viruses, specifically, Kaposi sarcoma-associated herpesvirus for KS, Epstein Barr virus for the major AIDS-defining NHL subtypes (diffuse large B cell NHL and central nervous system [CNS] NHL), and human papillomavirus (HPV) for cervical cancer.^4-6 HIV-infected people also have an elevated risk for other virus-related cancers (e.g., anal cancer related to HPV, liver cancer related to hepatitis B and C viruses).^5-7 In addition, HIV-infected people have a higher prevalence of lifestyle-associated risk factors for cancer including smoking and alcohol abuse.^8,9

Use of highly active antiretroviral therapy (HAART) among persons with HIV/AIDS can lead to partial immune restoration and prolonged survival.^10,11 Despite declines in cancer incidence attributable to the widespread introduction of HAART in 1996, cancer risk among HIV-infected people remains elevated during the HAART era.^2,12-14 Of note, prior studies of cancer risk in HIV-infected people have largely been limited to the first 1-5 years after an AIDS diagnosis.^1,2,14-16 As persons with AIDS continue to live longer, the number of people surviving for many years after an AIDS diagnosis will increase. This growing population comprises individuals who have lived for a prolonged period with immune suppression. The effects of these chronic immune disturbances, HAART, and long-term infection with oncogenic viruses are unknown. Estimates of cancer risk are needed to inform both public health programs and clinicians treating this population.

To assess the long-term cancer risk among persons with AIDS, we analyzed data from the HIV/AIDS Cancer Match Study, a large, representative cohort of persons with AIDS in the U.S. Previous analyses included persons diagnosed with AIDS during 1978-1996 with cancer information up to 5-years after AIDS,¹⁵ and persons diagnosed with AIDS between 1980-2004 with cancer information up to 2-years after AIDS.² In the current study, we evaluated the period 3-10 years after AIDS onset, to assess cancer risk relative to the general population, and to determine the impact of HAART on cancer incidence over time.

Methods

Results

Demographic characteristics of the 263,254 persons with AIDS included in the study are presented in Table 1. Most were male (80.1%), and the median age at AIDS onset was 36 years. Similar proportions of subjects were non-Hispanic white (39.7%) and non-Hispanic black (40.1%), and 20.2% were Hispanic. Almost half (44.8%) reported MSM and 24.8% had IDU as their mode of HIV exposure (Table 1). CD4 counts at AIDS onset were higher for subjects who contributed follow-up to the 6-10 year period than for those who contributed follow-up only to the 3-5 year period (median 144 vs. 132 cells/μL), consistent with better immune status at AIDS onset conveying longer survival. Additionally, few persons diagnosed with AIDS in 1980-1989 survived long enough to provide follow-up in the 6-10 year period. Also, some people diagnosed with AIDS in 1996-2004 did not have enough time to be followed into the 6-10 year period. As a result, most observation time in the 6-10 year period was provided by people diagnosed with AIDS in 1990-1995 (Table 1).

Risks for the three AIDS-defining cancers were significantly elevated in years 3-5 and 6-10 after AIDS onset (Table 2). KS risk was extremely high in both time periods (SIRs 5321 and 1347 respectively), and NHL risk was also elevated in both periods (SIRs 32 and 15, respectively). Likewise, risks were substantially higher than in the general population for the AIDS-defining NHL subtypes, namely diffuse large B-cell NHL, Burkitt NHL, and especially CNS NHL (Table 2). Cervical cancer risk was increased after AIDS during years 3-5 (SIR 5.6) and years 6-10 (SIR 3.6).

Among non-AIDS-defining cancers (Table 2), risks were elevated in both the 3-5 and 6-10 year periods for cancers of the oral cavity/pharynx, tongue, anus, liver, larynx, lung/bronchus, penis, and for Hodgkin lymphoma. Compared to the general population, risks for anal cancer were especially high (SIRs 27 in the 3-5 year period, 40 in the 6-10 year period). Among Hodgkin lymphoma subtypes, risk was most elevated for the mixed cellularity subtype (SIRs 15 in years 3-5, 17 in years 6-10). Other malignancies for which risk was increased in only one of the two periods after AIDS onset included cancers of the lip and vagina/vulva, multiple myeloma, lymphocytic leukemia, and myeloid/monocytic leukemia (Table 2). In both time periods, risk was lower than in the general population for cancers of the breast and prostate, and during years 3-5 after AIDS for kidney cancer. Overall, for all non-AIDS cancers combined, risk was significantly elevated after AIDS in both years 3-5 (SIR 1.7) and years 6-10 (SIR 1.6).

Table 3 compares cancer incidence in the 3-10 years after AIDS for the pre-HAART era (1990-1995) and HAART era (1996-2006). KS incidence declined by 80% (RR 0.2, 95%CI 0.2-0.2) between the pre-HAART and HAART eras. A joinpoint model fitted to the incidence data revealed that this change corresponded to a steep decline during 1994-1997 (44.3% per year, Figure 1A). Similarly, NHL incidence was 70% lower in the HAART era (RR 0.3, 95%CI 0.2-0.3) than in the pre-HAART era, and the joinpoint model indicated that this corresponded to a 36.9% annual reduction during 1995-1998 (Figure 1B). Declines were similar in magnitude for diffuse large B-cell NHL and CNS NHL (Table 3, Figures 1C and 1D). In contrast, the change in Burkitt NHL incidence was weaker (RR 0.6, 95%CI 0.4-1.0), and cervical cancer incidence did not change significantly (RR 0.8, 95%CI 0. 5-1.2). During the HAART era, persons with AIDS continued to have significantly higher risk for all AIDS-defining cancers than people in the general population (SIRs, Table 3).

Among non-AIDS-defining malignancies, anal cancer exhibited a three-fold increase in incidence between the pre-HAART and HAART eras (RR 2.9, 95%CI 2.1-4.0, Table 3). During the HAART era, anal cancer risk remained significantly elevated relative to the general population (SIR 32). The joinpoint model for anal cancer demonstrated a 10.7% annual increase in incidence over the entire 1990-2006 period, despite a suggested decline in the most recent years (Figure 2A). In a separate analysis among men, anal cancer incidence increased 11.3% (95%CI 5.9%-16.8%) per year during the HAART era (1996-2006). Incidence of local anal cancer increased significantly (14.1%, 95%CI 7.3%-21.3%) among men during the same years. Regional and distant anal cancer increased annually among men during the same period (5.7%, 95%CI -1.0% to 12.9%), although this increase was not significant. There were no anal cancer cases among women prior to 1996. During 1996-2006, anal cancer increased 4.3% (95%CI -10.5% to 21.5%) per year among women.

Hodgkin lymphoma incidence increased significantly between the pre-HAART and HAART eras (RR 2.0, 95%CI 1.3-2.9, Table 3). The Hodgkin lymphoma joinpoint model showed a 14.1% annual increase during 1990-2000, with no significant change subsequently (Figure 2B). The increase in Hodgkin lymphoma incidence was most apparent for the mixed cellularity subtype. During the HAART era, risk of Hodgkin lymphoma remained significantly elevated relative to the general population (SIR 11).

Incidence of lung cancer, the most common non-AIDS-defining cancer, was marginally lower in the HAART era than in the pre-HAART era (RR 0.8, 95%CI 0.6-0.9; Table 3). However, this decline over time was not manifest in the joinpoint model (Figure 2C). There were increases in the HAART era for other less common non-AIDS-defining cancers including cancers of the tongue (RR 2.9) and prostate (RR 1.6).

Overall, the incidence of all non-AIDS cancers increased 20% between the pre-HAART and HAART eras (RR 1.2, 95%CI 1.0-1.3; P=.006). This increase corresponded to a 4.3% annual increase during 1990-2006, although there was a suggestion that incidence declined in the most recent few years (Figure 2D). During the HAART era, people with AIDS had a 60% higher risk for non-AIDS cancers than the general population (SIR 1.6, 95%CI 1.6-1.7).

Comment

This study represents one of the longest and most complete follow-up of persons with AIDS with respect to cancer risk. Our population-based data demonstrated that people with AIDS in the U.S. continue to be at elevated risk for a spectrum of AIDS-defining and non-AIDS-defining cancers years after AIDS diagnosis. While the incidence of KS and NHL has declined substantially in the HAART era, the incidence of non-AIDS-defining cancers overall has risen. Two malignancies in particular, anal cancer and Hodgkin lymphoma, have increased in incidence in recent calendar years.

Among HIV-infected individuals, HAART use has been associated with major decreases in KS and NHL risk, and these decreases have translated into declines in incidence measurable at the population level.^2,14,24,25 We demonstrated that while persons with AIDS remain at considerable risk for KS, incidence of this malignancy first started to decline in 1995, possibly due to use of early combination antiretroviral therapy (e.g., dual nucleoside therapy), and continued to decline during the first years when HAART was available. Likewise, steep declines in the incidence of diffuse large B-cell NHL and CNS NHL may be partly explained by introduction of HAART in 1996. HIV-induced immunosuppression, indicated by low CD4 count, is directly related to risk of KS and these NHL subtypes, and declining incidence in people with longstanding AIDS is plausibly linked to the effectiveness of HAART in improving immune function.²⁶ In contrast, we noted a less dramatic decline in the incidence of Burkitt NHL, a subtype whose incidence is not closely associated with CD4 count.²⁶ Despite overall declines in NHL incidence, NHL was the most common malignancy during the HAART era.

Notable excess risks were observed for cancers of anus, penis, cervix, vagina and vulva, and certain sites in the head and neck (oral cavity, pharynx, tongue), all of which can be attributed to persistent infection with oncogenic HPV subtypes.^5,27 Anal cancer risk was strongly elevated up to 10 years after AIDS onset and, consistent with other reports,^12,28,29 we found that anal cancer incidence increased in the HAART era. This rise was likely not due only to increased anal cancer screening, which has been recommended for HIV-infected MSM,³⁰ because the increasing trend was observed for both men and women, and for regionally advanced disease (which would be detected without screening) as well as for localized disease. Instead, the continued rise of anal cancer incidence in recent years, even in the presence of widespread HAART use, suggests that the key steps susceptible to immune control might have occurred years earlier, and that prolonged survival among people with AIDS has now allowed for the manifestation of invasive cancer. While some investigators have advocated anal cancer screening among HIV-infected people,^30,31 it remains controversial.³²

A similar explanation related to the long latency of the carcinogenic effects of HPV may explain why cervical cancer incidence in women has not declined in the HAART era. HIV-infected women should be screened annually for cervical cancer.³³ A prophylactic HPV vaccine is now available to prevent cervical infection, however its impact will not be realized for several decades, and its efficacy in preventing infection in HIV-positive women or in preventing anal infection is unknown.³⁴

Hodgkin lymphoma risk was also substantially elevated among people with AIDS, and we noted a doubling in Hodgkin lymphoma incidence in this population in the HAART era. Our joinpoint model demonstrated that this increase was largely due to a significant rise throughout 1990-2000. Mixed cellularity Hodgkin lymphoma was the most common subtype and in the context of AIDS, is often associated Epstein Barr virus infection.^1,35 Interestingly, Biggar et al. reported that AIDS-related immunosuppression appears to have a non-linear effect on Hodgkin lymphoma risk. Specifically, Hodgkin lymphoma risk increases as the CD4 count declines, reaching a peak when the CD4 count is approximately 225 to 249 cells/μL, and then falls again at very low CD4 counts.³⁵ A subsequent study did not confirm this non-linear relationship.³⁶ Nonetheless, among people with advanced AIDS, it is possible that use of increasingly effective HIV therapies during the HAART era has resulted in a shift in immune function associated with higher Hodgkin lymphoma risk.

Importantly, we observed a 20% overall increase in the incidence of non-AIDS-defining cancers in this population. Because cancer risk was calculated as a rate (i.e., number of events per unit of follow-up time), this rise in incidence cannot be explained simply by a decline in AIDS-related mortality and a consequent increase in time at risk for cancer. The median attained age increased from 33 to 44 years over the 24-year calendar period of the study, reflecting aging of the U.S. AIDS population with improved survival. Nonetheless, our multivariable analyses comparing cancer risk in different calendar periods adjusted for attained age. Thus, the rate ratios that we report correspond to changes in cancer risk that cannot be explained by aging within the cohort. Instead, we believe that the recent overall increase in incidence of non-AIDS-defining cancers is largely driven by the rises in anal cancer and Hodgkin lymphoma incidence noted above. Indeed, when those malignancies were excluded, the change in incidence of all non-AIDS-defining cancers between the pre-HAART and HAART eras was no longer apparent (RR 1.0, 95%CI 0.9-1.1).

Other specific non-AIDS-defining cancers deserve brief comment. Lung cancer was the most frequent non-AIDS-defining malignancy, accounting for 41% of all non-AIDS cancers. While lung cancer incidence declined slightly with widespread HAART use, persons with AIDS remain at higher risk for lung cancer than the general population. Among HIV-infected individuals, the high risk of lung cancer is partly explained by tobacco use, but HIV may amplify the carcinogenic effects of smoking.³⁷ Liver cancer risk was elevated among people with longstanding AIDS, reflecting the carcinogenic effects of hepatitis C and B viruses, and alcohol use.⁷ Finally, people with longstanding AIDS had a lower risk of prostate and breast cancers than the general population, as has been noted in other studies,^16,38 and we found that prostate cancer incidence increased between 1990-1995 and 1996-2006. These patterns could reflect hormonal effects of HIV infection or other factors that may have changed over time, or could partly reflect low rates of screening compared with the general population.³⁸

Strengths of our study include its large size and population-based nature, representing all major U.S. regions and demographic groups affected by the AIDS epidemic, as well as the long period of evaluation of cancer risk (up to 10 years after AIDS onset). While we could not verify that people with AIDS remained in the cancer registry surveillance catchment areas, we adjusted for plausible rates of out-migration. A limitation of our study is that we lacked individual-level data on important cancer risk factors such as smoking and HAART use. Nonetheless, our results accurately reflect the aggregate impact of these factors and changes in their prevalence over time at the population level.

In summary, individuals with AIDS remain at substantially increased risk for cancer for up to 10 years after AIDS onset. Declines in KS and NHL incidence in recent years can be attributed to introduction and wide availability of HAART, but the continuing occurrence of these cancers in people with AIDS points to the need for improvements in access to HAART, more effective regimens targeting drug-resistant HIV strains, and perhaps interventions to boost immune restoration even with HAART use.^39-41 Of concern, we also observed an increasing incidence of anal cancer and Hodgkin lymphoma. As persons with AIDS continue to live longer after an AIDS diagnosis and as they age, it is possible that cancer risk will increase further.