| |
Incidence of Types of Cancer among HIV-Infected Persons Compared with the General Population in the United States, 1992-2003
|
| |
| |
Annals of Internal Medicine
20 May 2008 | Volume 148 Issue 10 | Pages 728-736
At the CROI HIV Conference in early 2008, several studies were presented showing detectable viral load and low CD4 count can contribute to the development of cancers.
"In addition to encouraging tobacco cessation, HIV care providers should be aware of these elevated risks and screen for preventable diseases, such as cervical and colorectal cancer (73-75). Screening programs for early detection and treatment of precancerous anal lesions should be evaluated and will probably become more important as the HIV-infected population ages and lives longer."
To describe cancer diagnoses in persons at all stages of HIV infection, we analyzed data from 2 large prospective cohort studies in the United States: the Adult and Adolescent Spectrum of HIV Disease (ASD) Project and the HIV Outpatient Study (HOPS). We compared incidence rates of cancer among these persons with incidence rates in the general population, derived from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (44, 45) for 1992 to 2003. In addition, we determined incidence trends for selected types of cancer among persons at all stages of HIV infection and in the general population for 3 periods defined on the basis of HAART availability: 1992 to 1995 (pre-HAART), 1996 to 1999 (early HAART), and 2000 to 2003 (recent HAART). Finally, we examined the risk factors that could lead to increased rates of selected cancer types among HIV-infected persons.
The incidence of many types of non-AIDS-defining cancer was higher among HIV-infected persons than among the general population from 1992 to 2003.
.....This study found that the incidence of several types of non-AIDS-defining cancer (Hodgkin lymphoma; melanoma; leukemia; and cancer of the liver, lung, anus, vagina, oropharynx, colon or rectum, and kidney) were significantly higher among a large, diverse, HIV-infected population than in the general population reported in the SEER database.
......Patients infected with HIV-and their clinicians-should be alert for signs of non-AIDS-related cancer.
Risk Factors for Cancer
Acquisition of HIV through male-male sex was associated with increased risk for Kaposi sarcoma (relative risk, 2.88; P < 0.001) and non-Hodgkin lymphoma (1.53; P < 0.001). Antiretroviral therapy was independently associated with decreased risk for Kaposi sarcoma (relative risk, 0.61; P < 0.001), non-Hodgkin lymphoma (0.68; P < 0.001), cervical cancer (0.48; P = 0.019), breast cancer (0.35; P = 0.013), colorectal cancer (0.50; P = 0.027), and lung cancer (0.52; P < 0.003). A low nadir CD4 count was associated with increased risk for Kaposi sarcoma (relative risk, 8.34; P < 0.001), non-Hodgkin lymphoma (6.03; P < 0.001), cervical cancer (3.70; P = 0.010), anal cancer (5.82; P = 0.017), colorectal cancer (6.27; P = 0.013), and lung cancer (2.42; P = 0.017). Co-infection with hepatitis B or C was associated with increased risk for liver cancer (relative risk, 3.63; P < 0.001).
AUTHORS:Pragna Patel, MD, MPH; Debra L. Hanson, MS; Patrick S. Sullivan, DVM, PhD; Richard M. Novak, MD; Anne C. Moorman, BSN, MPH; Tony C. Tong, MS; Scott D. Holmberg, MD, MPH; John T. Brooks, MD, for the Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators*
ABSTRACT
Background: Persons who are HIV-infected may be at higher risk for certain types of cancer than the general population.
Objective: To compare cancer incidence among HIV-infected persons with incidence in the general population from 1992 to 2003.
Design: Prospective observational cohort studies.
Setting: United States.
Patients: 54 780 HIV-infected persons in the Adult and Adolescent Spectrum of HIV Disease Project (47 832 patients) and the HIV Outpatient Study (6948 patients), who contributed 157 819 person-years of follow-up from 1992 to 2003, and 334 802 121 records from the Surveillance, Epidemiology, and End Results program of 13 geographically defined, population-based, central cancer registries.
Measurements: Standardized rate ratios (SRRs) to compare cancer incidence in the HIV-infected population with standardized cancer incidence in the general population.
Results:
The incidence of the following types of non-AIDS-defining cancer was significantly higher in the HIV-infected population than in the general population: anal (SRR, 42.9 [95% CI, 34.1 to 53.3]), vaginal (21.0 [CI, 11.2 to 35.9]), Hodgkin lymphoma (14.7 [CI, 11.6 to 18.2]), liver (7.7 [CI, 5.7 to 10.1]), lung (3.3 [CI, 2.8 to 3.9]), melanoma (2.6 [CI, 1.9 to 3.6]), oropharyngeal (2.6 [CI, 1.9 to 3.4]), leukemia (2.5 [CI, 1.6 to 3.8]), colorectal (2.3 [CI, 1.8 to 2.9]), and renal (1.8 [CI, 1.1 to 2.7]). The incidence of prostate cancer was significantly lower among HIV-infected persons than the general population (SRR, 0.6 [CI, 0.4 to 0.8]). Only the relative incidence of anal cancer increased over time.
Limitations: Lower ascertainment of cancer in the HIV cohorts may result in a potential bias to underestimate rate disparities. Tobacco use as a risk factor and the effect of changes in cancer screening practices could not be evaluated.
Conclusion: The incidence of many types of non-AIDS-defining cancer was higher among HIV-infected persons than among the general population from 1992 to 2003.
Discussion
In the largest analyses of cancer incidence trends among HIV-infected persons in the United States, we observed significantly higher rates of several types of cancer from 1992 to 2003 among HIV-infected persons than in the general population. Non-AIDS-defining types of cancer with higher incidence rates were anal, colorectal, liver, lung, oropharyngeal, renal, and vaginal cancer; Hodgkin lymphoma; leukemia; and melanoma. These findings are consistent with previous reports of cancer incidence among persons with HIV or AIDS (Table 4). We extend these previous findings by examining cancer incidence trends over time among persons with all stages of HIV infection, showing that incidence rates increased significantly for melanoma; Hodgkin lymphoma; and colorectal, anal, and prostate cancer-despite the advent of HAART. Immune dysfunction (52); concomitant infection with oncogenic viruses (53-55); and lifestyle factors, such as smoking, may account for the higher cancer incidence among HIV-infected persons.
Immunosuppression may accelerate the progression of melanoma and other types of cancer in individuals who are already predisposed to them, as described in studies of transplant recipients (56-62). In our study, a low nadir CD4 cell count was associated with significantly increased risk for colorectal cancer, whereas use of antiretroviral therapy significantly decreased risk, suggesting that pathogenesis of colorectal cancer may be immune-mediated; this finding is consistent with previous reports (63). However, incidence rates for melanoma and colorectal cancer increased significantly across the 3 periods, suggesting a role of other contributing factors (such as behavioral or lifestyle factors).
Although survival in Hodgkin lymphoma has improved, rates of Hodgkin lymphoma have increased in the HAART era (64). The strong association of Hodgkin lymphoma with Epstein-Barr virus infection in HIV-infected individuals and the influence of immunosuppression may explain this finding (35); Righetti and colleagues (65) suggested that immune reconstitution while receiving HAART increases B-cell stimulation and the number of Epstein-Barr virus-infected cells, which may in turn increase risk for Epstein-Barr virus-associated cancer.
Anal cancer is the only type that increased in both incidence among HIV-infected persons and relative incidence compared with the general population over time. Although this finding is concerning, it is not surprising. The predominance of men who have sex with men among the HIV-infected population and the resultant higher prevalence of anal human papillomavirus (HPV) infection are associated with anal intraepithelial neoplasia (66, 67). The interaction between HIV and HPV allows for persistence of HPV infection in HIV-infected persons, who are more commonly infected with the oncogenic HPV subtypes 16 and 18, leading to development of dysplasia (14, 68, 69). Because HAART does not alter the incidence or progression of anal intraepithelial neoplasia (20, 70), persons who are successfully treated with HAART but are co-infected with HIV and HPV are expected to remain at greater risk for anal cancer over time and incidence rates are expected to increase as HIV-infected persons live longer.
We found a lower rate of prostate cancer among HIV-infected persons than in the general population, in contrast to smaller published reports (19, 40). However, our results were consistent with those from an AIDS-cancer registry match (32) in which the investigators attributed the lower observed risk in the general population to less prostate cancer screening. In our analyses, rates of prostate cancer among HIV-infected persons increased over time but remained consistently lower than in the general population. We know of no reason why HIV-related immunosuppression would decrease prostate cancer risk (71). Differential screening among men with and without HIV may explain these results, although many men with HIV are under closer medical supervision. In addition, persons with HIV are known to have lower androgen levels, which may in turn decrease their risk for prostate cancer. Because androgens have long been known to contribute to the risk for prostate cancer (19), patients receiving replacement therapy with exogenous testosterone or anabolic steroids may need to be monitored carefully.
Our study has limitations. First, the case ascertainment standard for SEER is 98% (44), whereas case ascertainment in the ASD Project and HOPS is undoubtedly lower (75% to 85%, as determined by an ASD Project-local cancer registry match in select project areas). In addition, the completeness of cancer ascertainment has not been formally evaluated in the ASD Project or HOPS. Because the HIV incidence rate is in the numerator, the potential bias would be to underestimate the standardized rate ratio-suggesting that standardized rate ratios showing increased incidence are minimum estimates of the rate disparity. Standardized rate ratios may be further underestimated by double-counting of cases in areas where SEER registries overlap with the ASD Project or HOPS sites, because SEER does not collect data on HIV status. Second, although the ASD Project and HOPS have large cohorts, they are not representative of all persons with HIV infection in the United States, and SEER is not representative of the general U.S. population; our findings may therefore have limited generalizability. The SEER program covers 14% of the U.S. population, has a higher proportion of foreign-born persons, and tends to be more urban than the general population (44). In a comparison of SEER data with data from the National Program of Cancer Registries, the incidence rates of head or neck cancer, anal cancer, and Hodgkin disease were similar; however, the rate of lung cancer was slightly underestimated and the rates of melanoma and liver cancer were slightly overestimated (72). The ASD Project and HOPS also represent different geographical areas from SEER. Third, we had inadequate information on smoking behavior; because the prevalence of smoking varies among specific groups in the United States (for example, by sex, race, or HIV risk), some characteristics associated with cancer in our analyses may have been surrogates for smoking status. Finally, we could not account for changes in screening practices over time.
In conclusion, our findings indicate that HIV-infected persons are at higher risk than the general population for many non-AIDS-defining types of cancer. In addition to encouraging tobacco cessation, HIV care providers should be aware of these elevated risks and screen for preventable diseases, such as cervical and colorectal cancer (73-75). Screening programs for early detection and treatment of precancerous anal lesions should be evaluated and will probably become more important as the HIV-infected population ages and lives longer. Furthermore, primary prevention strategies to reduce HPV infection and HPV-associated diseases, such as vaccination and circumcision, warrant further evaluation.
Results
From 1992 to 2003, 54 780 HIV-infected persons (47 832 persons from the ASD Project and 6948 from HOPS) contributed 157 819 person-years of observation. The median follow-up time was 2.0 years in the ASD Project and 2.6 years in HOPS. Of the 3550 incidents of cancer identified in the combined ASD Project and HOPS data for this analysis, 2842 (80%) were categorized as AIDS-defining and 708 (20%) as non-AIDS-defining. Of the 27 types of cancer observed, 5 non-AIDS-defining types of cancer occurred seldom or never: penile (4 cases), uterine (2 cases), ovarian (2 cases), gallbladder (0 cases), and biliary (0 cases).
The populations differed in age, race, and sex distributions; HIV-infected persons were more likely to be male (76%) and nonwhite (61%). The age distribution of the combined ASD Project and HOPS population was clustered among young adults (range, 25 to 50 years), whereas the age distribution of the SEER population was more evenly distributed.
Cancer Incidence in the HIV-Infected Population Compared with the General Population
The incidence of several non-AIDS-defining types of cancer was significantly higher in the HIV-infected population than in the general population: anal (standardized rate ratio [SRR], 42.9 [95% CI, 34.1 to 53.3]), vaginal (21.0 [CI, 11.2 to 35.9]), Hodgkin lymphoma (14.7 [CI, 11.6 to 18.2]), liver (7.7 [CI, 5.7 to 10.1]), lung (3.3 [CI, 2.8 to 3.9]), melanoma (2.6 [CI, 1.9 to 3.6]), oropharyngeal (2.6 [CI, 1.9 to 3.4]), leukemia (2.5 [CI, 1.6 to 3.8]), colorectal (2.3 [CI, 1.8 to 2.9]), and renal (1.8 [CI, 1.1 to 2.7]). Incidence was significantly lower for prostate cancer (standardized rate ratio, 0.6 [CI, 0.4 to 0.8]) (Appendix Table 2 and Appendix Figures 1 and 2). We found no significant difference between the 2 populations in the rates of other types of cancer we examined.
Incidence Rates among HIV-Infected Persons
The analysis of trends over time in cancer rates for the HIV-infected population indicated that incidence rates decreased significantly for Kaposi sarcoma and non-Hodgkin lymphoma and increased significantly across the 3 periods for anal, prostate, and colorectal cancer; melanoma; and Hodgkin lymphoma (Table 2; Appendix Tables 3 and 4 and Appendix Figure 3). We observed no change in the rates of cervical cancer and several non-AIDS-defining types of cancer (liver, lung, oropharyngeal, and breast cancer).
|
|
| |
| |
|
|
|
