Immunodeficiency is known to be associated with a higher hazard of AIDS-defining malignancy and our results are in accordance with this body of knowledge. Moreover, our study shows that HIV replication, as both current and cumulative exposure to uncontrolled plasma HIV RNA viral load were associated with a higher hazard AIDS-defining malignancy, has a major impact on the risk of occurrence of AIDS-defining malignancies, particularly NHL. This suggests that the control of plasma HIV RNA is a key factor to prevent NHL occurrence, at all stages of immune deficiency. HIV replication, through activation of the immune system, could be independently involved in the occurrence of NHL in patients with high CD4+ cell counts [28
]. The fact that exposure to cART was only associated with a lower risk of AIDS-defining malignancy needs to be further explored. However, it is difficult to disentangle the proper effect of cART, immune deficiency and viral replication and one may speculate that the absence of significant association between cART exposure and non-AIDS-defining malignancy is linked to the absence of association with HIV replication. Thus, the potential benefit of cART for controlling non-AIDS-defining malignancy might be due to immune reconstitution rather than control of viral replication per se. In other hand, both longer and current exposure to uncontrolled plasma HIV RNA and immunosuppression were associated with a higher risk of AIDS-defining malignancy, underlining that the best possible control of HIV infection is warranted to prevent AIDS-defining malignancies and especially NHL occurrence.
Several cohort studies have shown a higher risk of non-AIDS-defining malignancy in HIV-infected patients when compared with the general population but none of them considered the duration of exposure to immunodeficiency [9
]. Another large study failed to show any relationship between immunodeficiency at AIDS diagnosis and the risk of malignancy [30
]. Our results are consistent with a higher incidence of non-AIDS-defining malignancies observed in solid organ transplant recipients, chronically exposed to immunosuppressive therapy, indirectly suggesting that immunodeficiency is independently associated with a higher risk of non-AIDS-defining malignancies in HIV-infected patients [31
]. Furthermore, our results regarding the latest CD4+ cell count showed that current immunodeficiency may be involved in the risk of malignancy. This suggests that, following a prescription of cART, the risk of malignancy may decrease when the CD4+ cell count rises above 500 cells/mm3
. Our results regarding cumulative exposure to CD4+ <500 cells/mm3
conveys important additional results, since they suggest that patients with longstanding immunodeficiency experience a higher rate of malignancy compared to patients without immunodeficiency. This could help to target a high risk population to implement prevention and screening policies.
Based on Akaike criterion, our analysis does not indicate a particular advantage of cumulative exposure to low CD4+ cells in comparison to the latest CD4+ cell count for both AIDS-defining and non-AIDS-defining malignancies. However, the consistent finding of a raised risk of AIDS and non-AIDS-defining malignancies associated with cumulative time spent below CD4+ < 200/mm3 or 500/mm3 provides a stronger argument that HIV infected patients may benefit from early initiation of antiretroviral treatment to decrease the risk of AIDS and non-AIDS-defining malignancies.
Burgi et al found that the use of cART was protective for malignancies, [33
] and the D:A:D cohort collaboration found that the incidence of fatal non-AIDS malignancies was related to exposure to cART [34
]. Our main objective was not to estimate the independent effect of cART exposure on the risk of malignancy, and further studies including more patients should specifically address this issue. However, our results show that early control of HIV replication and maintenance of high levels of CD4+ cell count are associated with lower risk of malignancies.
The incidence rate of non-AIDS-defining malignancies was higher in men than in women, as it is commonly observed in the general population in France [35
Due to incomplete data regarding the risk factors for non-AIDS-defining malignancies (tobacco consumption, HBV or HCV infections), we could not take these risk factors into account in the analyses of the entire cohort. However, these confounding factors were controlled for in analyses estimating the risk of non-AIDS-defining malignancy in a large subgroup of patients free of missing values concerning these data. The association between immunosuppression and the occurrence of specific non-AIDS-defining malignancies could not be explored in this study. We acknowledge that larger number of cases is needed to reach larger statistical power to adequately address this issue for each type of non-AIDS-defining malignancy.
Finally, our study showed that exposure to uncontrolled plasma HIV-RNA was associated with a higher risk of AIDS-defining malignancy, regardless of CD4+ cell count and the use of cART. Furthermore, immunodeficiency was associated with a higher risk of malignancy, whether AIDS-defining or not. Considering the global ageing of the HIV-infected population in developed countries, malignancy, which is already one of the main causes of mortality, is likely to become the first clinical and public health challenge in the long-term management of HIV-infected patients.
According to our observations, the objective of cART should aim at reaching and maintaining not only an undetectable plasma HIV RNA, but also a CD4+ cell count higher than 500 cells/mm3 to prevent the occurrence of malignancy, AIDS-defining or not. In HIV infected population, this should be integrated to malignancy prevention policies.