The importance of the established risk factors for these five non-AIDS-defining malignancies (e.g., tobacco, HPV, sunlight; ) cannot be denied. Furthermore, it seems unlikely that HIV-infected persons who lack these exposures are at substantial risk for the cancers. Nonetheless, it would be inappropriate to conclude that HIV is unimportant in the etiology of these non-AIDS-defining malignancies. This situation is similar to that for AIDS-defining conditions, where the presence of additional agents is required for their development. Rather, the relevant question is: in the presence of certain known carcinogens, does HIV infection amplify the effects of these carcinogens to promote development of cancer? The most obvious mechanism by which HIV could facilitate the development of these malignancies is by disturbing the host immune system. Consideration of the epidemiologic evidence and other recent data presented above suggests that several immunologic mechanisms could be involved in the etiology of these malignancies ().
Potential HIV-related immunologic mechanisms involved in development of selected non-AIDS-defining malignancies
The simplest immunologic mechanism to consider is HIV-induced depletion of CD4 cells, leading to deficient cell-mediated immunity. This mechanism is highly relevant for KS and NHL (5
). The epidemiologic hallmarks of this mechanism are strongly increased risk of cancer compared to the general population and clearcut associations with markers of immunosuppression, such as CD4 count, time relative to AIDS onset, and the protective effects of HAART. Another hallmark is an elevated risk for the cancer among transplant recipients, who receive chronic immunosuppressive therapy to prevent graft rejection. It has been hypothesized that an intact immune system can control or eliminate early cancer precursor cells, protecting against a wide range of cancers (i.e., the immune surveillance hypothesis (73
)). Nonetheless, evidence in HIV-infected persons and transplant recipients is strongest that immunodeficiency predisposes to the subset of malignancies caused by oncogenic viruses, likely because of loss of immune control of viral replication and transformation. Regarding the non-AIDS-defining cancers highlighted in this review, this mechanism may be most relevant for some non-melanoma skin cancers, particularly the rare subtypes such as Merkel cell carcinoma and sebaceous carcinoma, where oncogenic viruses could have a direct transforming role. Although limited data on these skin cancers preclude a definitive assessment, the substantially increased risk compared to the general population, in the absence of another obvious explanation, suggests that HIV-related immunosuppression is relevant.
It is useful to speculate on additional immunologic mechanisms related to HIV infection that could potentially play a role in the development of other non-AIDS-defining malignancies (). For anal cancer, there are several salient observations: first, low CD4 counts are associated strongly with detection of anal HPV infection and pre-cancerous lesions, but less strongly with risk of anal cancer itself; second, anal cancer risk increases with progressive time relative to an initial AIDS diagnosis; and third, anal cancer incidence has increased during the HAART era and is elevated among individual HAART users. A model that could account for these observations is that HIV-related immunosuppression is relevant at the earliest stages of anal carcinogenesis (such as HPV persistence and development of low-grade squamous intraepithelial neoplasia) but not involved in the later progression to invasive cancer (39
). Under such a model, HAART would not result in a benefit if administered after the early steps in this process. Indeed, due to the survival benefits associated with HAART use, persons receiving HAART would live long enough to develop anal cancer. In other words, HAART use increases time spent living with early-stage neoplastic lesions, allowing their progression to invasive cancer. Likewise, the increase in anal cancer risk associated with AIDS onset may not reflect the effects of progressive immunosuppression but rather prolonged time spent living with immunosuppression and duration of HPV-related disease.
Given the rarity of liver cancer, a challenge has been to gather sufficient data to assess the effects of HIV infection and related immunosuppression. One possibility is that deficiency of cell-mediated immunity plays a role in the development of liver cancer by reducing immune control of chronic HCV and HBV infections. However, the situation may be more complicated than for anal cancer. Specifically, for liver cancer, immunosuppression not only predisposes to AIDS-related mortality but also liver-related mortality (56
). In the pre-HAART era, one or both of these competing causes of mortality may have obscured an association between immunosuppression and liver cancer risk.
The elevated risk of lung cancer in HIV-infected smokers probably has a different explanation, since risk is not strongly related to markers of HIV-related immunosuppression such as CD4 count and prior AIDS onset. Also, risk is elevated for all lung cancer subtypes, pointing away from involvement of a single oncogenic virus (and thus, pointing away from immunosuppression). One possibility is that HIV infection promotes the development of lung cancer by causing chronic pulmonary inflammation and repeated lung infections, which could induce DNA damage in a synergistic manner with tobacco (75
). In the general population, chronic lung infections due to Chlamydia pneumoniae
and tuberculosis are linked with an increased risk of developing lung cancer (75
). At all stages of infection, HIV is associated with chronic or repeated lung infections, due to micro-organisms that frequently cause pneumonia in the general population (e.g. S. pneumoniae
) as well as opportunistic micro-organisms (e.g., Mycobacterium avium intracellulare, Pneumocystis jirovecii
). HIV infection also leads to expansion of the pool of pulmonary macrophages and elevated levels in the lung of pro-inflammatory cytokines, such as interleukin 1 beta, tumor necrosis factor, and interferon gamma (76
). If HIV amplifies the effects of tobacco by inducing chronic lung inflammation or causing repeated pulmonary insults due to infections, processes that occur at all levels of HIV-related immunosuppression, a strong association of lung cancer risk with CD4 count or advanced HIV disease might not be expected.
For Hodgkin lymphoma, an additional possibility is that some cases arise as part of an immune reconstitution syndrome (32
). This hypothesis is consistent with the nonlinear relationship between CD4 count and Hodgkin lymphoma risk, and with rising Hodgkin lymphoma incidence during the HAART era. Specifically, the increase in CD4 count associated with HAART use among extremely immunodeficient individuals may shift them to a level of immunosuppression (i.e., a CD4 count 200-250 cells/mm3
, ) that puts them at greatest risk for Hodgkin lymphoma. In that setting, Hodgkin lymphoma may develop because the malignant Hodgkin Reed-Sternberg cell may already be present, and partial restoration of immunity allows recruitment of surrounding immune cells and manifestation of the tumor (32
). In other cases, Hodgkin lymphoma may develop in a more direct manner with progressive or prolonged immunosuppression. The situation may be analogous to what is observed for KS, another malignancy in which a substantial component of the lesional cells are not actually malignant. While KS most often arises with progressive loss of cell-mediated immunity, cases with onset or worsening related to HAART-induced immune reconstitution are described (77
In the HAART era, several mechanisms in are likely to become increasingly important in the development of cancer. The role of these various mechanisms in the etiology of non-AIDS-defining cancers should be evaluated in large, well-designed epidemiologic studies. Ideally, the studies should include detailed data on validated cancer cases, and extensive longitudinal measurements of CD4 count, HIV viral load, and use of antiretroviral medications. Given the rarity of most cancer outcomes, use of pooled data from consortia may be required, and given the complexity of the analyses, replication will likely be necessary.
Finally, it will be important to evaluate the possibility that HIV medications could themselves increase risk for some cancers. A possibility is that some medications may have direct genotoxic effects that initiate or promote development of cancer. For example, zidovudine, a nucleoside reverse transcriptase inhibitor, is incorporated into host DNA and can induce point mutations and chromosomal breaks (80
), but whether these changes translate into an increased cancer risk is unknown. Because patients frequently switch antiretroviral medications, and because effects on cancer risk may require years of exposure and follow-up to manifest, it will be extremely challenging to identify whether specific antiretroviral medications cause specific types of cancer.