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Malignancy-Related Deaths among HIV-Infected Patients: increasing problems with cancers & non-AIDS events - EDITORIAL COMMENTARY
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Clinical Infectious Diseases March 1 2009;48:640-641
Antonella d'Arminio Monforte
Department of Medicine, Surgery, and Dentistry, Clinic of Infectious and Tropical Disease, University of Milan, San Paolo Hospital, Milan, Italy
"......the D:A:D study demonstrated that severe immunodepression is a strong independent risk factor of death attributable not only to AIDS_defining but also to non-AIDS_defining malignancies. The D:A:D study further demonstrated that long term cART is associated with an increased risk of death attributable to non-AIDS_defining malignancies but not of death attributable to AIDS_defining malignancies......The role of a long_term compromised immune system that, despite being adequate in terms of CD4 counts and function in preventing opportunistic events, may be not completely adequate in preventing the growth of malignant cells, should be further investigated......In conclusion, prospective data on the incidence of malignancies among HIV_infected patients, with stringent follow_up and end point criteria are needed, to better elucidate possible complex interactions between immunodeficiency, HIV, and cART in HIV_infected subjects, who also have traditional risk factors....."
Bonnet et al. [1] have recently published a study on malignancy_related deaths among human immunodeficiency virus (HIV)-infected subjects, comparing data from 2 surveys on deaths conducted in France in 2000 and 2005 (Mortalite 2000 and Mortalite 2005). Globally, in their analysis, malignancies represented the second most common cause of death in 2005, after AIDS_related diseases, and accounted for more than one_third of deaths in the same period. Comparing the 2 surveys, the authors demonstrated an increase in the proportion of malignancy_related deaths and a decrease in the proportion of AIDS_related deaths.
In detail, they outline the increasing prevalence of deaths attributable to non-AIDS_related, non-liver_related, and liver_related cancers between 2000 and 2005, whereas deaths attributable to AIDS_related cancers remained constant. Lung cancer represented the first most common cause of death among non-AIDS_related, non-liver_related cancers in both 2000 and 2005, whereas the relative role of hepatitis B virus (HBV) infection in deaths attributable to liver_related cancers decreased concomitant with an increase in the role of hepatitis C virus (HCV) infection. It was not possible to examine the roles of immunodepression and combination antiretroviral therapy (cART) in this study; the only observation that Bonnet et al. [1] underline is that, despite the increasing percentage of patients receiving cART, the proportion of non_Hodgkin lymphoma did not substantially decrease between 2000 and 2005.
The data from the 2 Mortalite surveys must be compared with those from the Data Collection on Adverse Events of Anti_HIV Drugs (D:A:D) study recently published elsewhere [2]. There are several important differences between the 2 studies. First, the Mortalite study is a nationwide survey of deaths among the HIV_infected population, whereas the D:A:D study is a prospective, observational study with very stringent criteria for inclusion, follow_up, and monitoring of end points. Second, deaths were recorded differently in the 2 studies; the Mortalite study used the International Classification of Diseases, 10th revision, and the D:A:D study used the Code system, a detailed information system that has been validated in HIV_infected individuals [3]. Finally, the geographical areas observed in the 2 studies are different, the Mortalite surveys were limited to France, whereas the D:A:D study extended to different European and non_European countries. Moreover, the primary objective of the Mortalite surveys was to detect any differences in the distribution of the underlying causes of death attributable to malignancies observed in 2 different calendar years, whereas the primary objective of the D:A:D analysis regarding malignancies was to investigate the relationship between immunodeficiency and death attributable to AIDS_defining and non-AIDS_defining malignancies.
Indeed, the D:A:D study demonstrated that severe immunodepression is a strong independent risk factor of death attributable not only to AIDS_defining but also to non-AIDS_defining malignancies. The D:A:D study further demonstrated that long term cART is associated with an increased risk of death attributable to non-AIDS_defining malignancies but not of death attributable to AIDS_defining malignancies.
Among the different non-AIDS_defining cancers, lung cancer was most common tumor in both the Mortalite and D:A:D studies, which emphasizes the need for preventive campaigns in the HIV_infected population. With regard to liver cancers, the 2 studies had partially different results. The Mortalite surveys demonstrated a decreased frequency of HBV_related liver cancer in 2005, compared with 2000, and an opposite trend for HCV. However, HBV_positive serostatus was an independent predictor of death attributable to liver cancer in the D:A:D study, but HCV serostatus did not demonstrated any predictive value. Bonnet et al. [1] speculate that this might be related to the extended use of antiretroviral drugs that also act against HBV (i.e., lamivudine and tenofovir), which may have reduced the proportion of HBV_related deaths. On the other hand, the findings of the D:A:D analysis might be interpreted according to the different natural history of chronic hepatitis due to HBV versus HCV, because HCV_related chronic hepatitis has demonstrated a more rapid progression to death attributable to decompensated liver cirrhosis rather than to hepatocellular carcinoma, as reported elsewhere by the D:A:D group [4].
Globally, the main limitations of both studies are that only events with fatal outcomes are taken into account and that a real picture of the incidence of cancers in the late HAART era is not available. The increased survival of HIV_infected patients because of effective cART has resulted in long_term survival and an increased probability of death attributable to non-HIV_related events. In the case of cancers, their occurrence might be caused by traditional risk factors present in the general population, such as smoking for lung cancer, HBV and HCV infection for liver cancer, or human papillomavirus infection for anal and cervical cancers. The role of a long_term compromised immune system that, despite being adequate in terms of CD4 counts and function in preventing opportunistic events, may be not completely adequate in preventing the growth of malignant cells, should be further investigated.
In conclusion, prospective data on the incidence of malignancies among HIV_infected patients, with stringent follow_up and end point criteria are needed, to better elucidate possible complex interactions between immunodeficiency, HIV, and cART in HIV_infected subjects, who also have traditional risk factors.
References
1Bonnet F, Burty C, Lewden C, et al. Changes in cancer mortality among HIV_infected patients: the Mortalite 2005 survey. Clin Infect Dis 2009;48:633-9 (in this issue).
2Monforte A, Abrams D, Pradier C, et al.; The Data Collection on Adverse Events of Anti_HIV Drugs (D:A:D) Study Group. HIV_induced immunodeficiency and mortality from AIDS_defining and non-AIDS_defining malignancies. AIDS 2008;22;2143-53.
3Olsen CH, Friis_Moller, d'Arminio Monforte A, et al.; the CoDe Working Group. Pilot of the CoDe (Coding of Death) project-a standardized approach to code causes of death in HIV infected individuals [poster PE18.4/9]. In: Program and abstracts of the 10th European AIDS Conference (Dublin). 2005.
4Weber R, Sabin CA, Friis_Moller N, et al. Liver_related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006;166:1632-41.
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