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Epidemiology
AIDS-defining Cancers
In 1982, the United States Center for Disease Control and Prevention expanded the case definition of AIDS to include HIV-infected individuals diagnosed with Kaposi sarcoma and primary central nervous system lymphoma (PCNSL). Cervical cancer and intermediate-grade and high-grade forms of non-Hodgkin lymphoma (NHL) were added to the list of ADCs shortly thereafter. The risk of cancer in PLWHA can be defined by the standard incidence ratio (SIR). For malignancies associated with HIV infection, the SIR compares the rate of cancers in the HIV/AIDS population to the number expected in the general population at any given time. In the HAART era, the SIR has decreased for all ADCs, with the exception of invasive cervical carcinoma. However, the risk for each of the ADCs remains above that of the general population (Table 1).
Prior to the emergence of HIV, Kaposi sarcoma was a rare disorder. Between 1987 and 1993, Kaposi sarcoma incidence increased 66-fold from 0.5 to 33 patients per 100 000 patient-years in PLWHA. During this period, NHL incidence increased by a more modest three-fold. Based on the complex epidemiology and histologic interpretation of lymphomas, nine subtypes were defined by the WHO as associated with HIV infection (Table 2). Among these nine, all are considered ADCs except low-grade lymphomas, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT), and Hodgkin lymphoma. The most common AIDS-defining NHLs are of B-cell origin, present with advanced stage disease, and follow an aggressive clinical course. These AIDS-defining NHLs include PCNSL, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), plasmablastic lymphoma, and primary effusion lymphoma (PEL). In the pre-HAART era, DLBCL and PCNSL were the most common NHLs in PLWHA, presenting with an incidence of 453 and 233 cases per 100 000 patient-years, respectively. Between 2001 and 2007, the most common AIDS-defining NHL remained DLBCL, although its incidence had decreased to 120 cases per 100 000 patient-years. During this same period, and with an incidence of 32 cases per 100 000 patient-years, Burkitt's lymphoma supplanted PCNSL as the second most common AIDS-defining NHL.
Together, Kaposi sarcoma and NHL accounted for 99% of all ADCs in the pre-HAART era. From 1991–1995 to 2001–2005 when ART was introduced, the number of Kaposi sarcoma cases declined by 84% and the number of NHL cases declined by 54%. During this same interval, the incidence of all ADCs decreased by 70%. In the HAART era, however, ADCs continue to be a major problem. Between 2001 and 2005, more than 2000 cases per year were diagnosed in the United States, and these malignancies currently account for 15–19% of all deaths in PLWHA. One of the most important risk factors for NHL and Kaposi sarcoma is immune suppression as reflected by the CD4 T-cell count. In retrospective analyses, the SIR for NHL increased from 35.8 to 145 and for Kaposi sarcoma from 76 to 571 when the CD4 T-cell count decreased from 500 to less than 100 cells/μl. In contrast, the incidence of Burkitt's lymphoma increased from 9.6 to 30.7 per 100 000 person-years as the CD4 T-cell count increased from less than 50 to greater than 250 cells/μl. This paradoxical observation is further discussed in the Etiology section below.
Non-AIDS-defining Cancers
In the United States, NADC incidence increased greater than three-fold, from 3193 to 10 059 cases when comparing the intervals 1991–1995 and 2001–2005. In resource-rich countries in the pre-HAART era, NADCs accounted for approximately 8–38% of all HIV malignancies. In the HAART era, this number has increased to 50–58%. Depending on the malignancy, the SIR for most NADCs ranges from 2 to 35 (Table 1). The most important risk factors for NADCs are advancing age and the length of time one has been infected with HIV. Additional important factors that impact NADC incidence are exposure to cigarette smoke and oncogenic viruses. Less clear risk factors include a low CD4 T-cell count and the use of anti-HIV therapy. In a multivariate analysis, two risk factors for NADCs emerge: a CD4 cell count less than 200 cells/μl and the use of HAART. However, the link between low CD4 T-cell count and NADCs is conflicting and is disease-dependent and time-dependent. The SIR for anal cancer increases from 22 to 68 when the CD4 T-cell count remains less than 200 cells/μl for more than 5 years compared to 2 years. In contrast, the SIR for Hodgkin lymphoma increases from 5 to 14 as the CD4 T-cell count rises from 50 to 200 cells/μl. When PLWHA are compared to recipients of solid organ transplants, both populations have similar risks for Kaposi sarcoma and NHL as well as certain NADCs including Hodgkin lymphoma, anal, liver, and lung cancer. In the case of lung cancer, even when correcting for cigarette smoking, the incidence remains greater in PLWHA than in the general population, although no correlation between low CD4 T-cell count and lung cancer risk has been identified.
The role of HAART as a possible contributor to malignancy has not been validated by all studies. NADCs are prevalent among long-term surviving HIV-infected patients not requiring therapy or in developing countries without access to therapy. Therefore, HAART may be a risk factor due to its ability to increase longevity rather than its direct carcinogenic or anticarcinogenic potential. Of interest, statins (like HAART) have, through alternative modes of action, anti-inflammatory properties that reduce immune activation. In a recent retrospective analysis, they were associated with a 57% decrease in NADCs. Additional studies are needed to better understand the role of chronic inflammation as a mediator of cancer risk.
The effects of both NADCs and ADCs are profound and 26–30% of PLWHA will die from these malignancies. In the United States, more than 4000 new cases of cancer are diagnosed in PLWHA each year. The median age of PLWHA in the United States now exceeds 50 years. Developing robust strategies to screen this group for preventable cancers will become increasingly important. Unfortunately, standard guidelines for cancer screening in this group do not exist. More research and algorithms are needed to improve cancer detection rates while also examining behaviors that can influence risk factors for cancer such as unsafe sex, heavy alcohol consumption, and cigarette smoking.
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