Our population-based investigation focused on early mortality of AIDS cases, and it showed that, over time, a slight amelioration in the proportion of PWA who died within six months from AIDS (from 81.2 % in PWA diagnosed in 1999–2000 to 82.9 % in 2009). Improvements were also documented in five-year survival, from 60.7 % in 1999–2002 to 65.4 % in 2005–2006. Our findings, together with the reduced risk of early mortality for PWA diagnosed in more recent years that emerged from the multivariate analysis, seemed to suggest a progress in the management of AIDS that has led to a slight, but clinically significant, improvement also in short term survival. This latter encouraging observation is consistent with findings reported elsewhere [14], and it probably reflects general improvements in the management of comorbidities and non-HIV specific interventions, in addition to enhancement of antiretroviral therapies [15].
Overall, the findings indicated that, 18.9 % of Italian PWA, diagnosed between 1999 and 2009, died within six months from AIDS diagnosis. This quantification of early mortality risk is particularly high when compared with findings from clinical trials [16]. It should be noted, however, that this is a population-based descriptive investigation, including 40.9 % of PWA with less than 50 CD4 cell count at AIDS diagnosis in contrast, for instance, with a median of 280 CD4 cell count at enrolment in the cited trial [16]. In addition, and in agreement with similar observations recorded in France [6] and in Brazil [17], the results of this analysis strongly indicated that the largest part of one year post-AIDS mortality occurs within six months after diagnosis.
Approximately one fifth of Italian AIDS cases diagnosed between 1999 and 2009 were aged 50 years or older, and older age was confirmed to be a strong negative prognostic factor also for early mortality. In this study, the negative effect of older age on early mortality was clear overall, after adjusting by CD4 cell count, HIV transmission group, or other factors, or when stratifying by time elapsed from first HIV-positive test to AIDS. This finding is in agreement with the results of a recently published article showing that, in France, PWA aged 60 years or more were at a nearly 3-fold higher risk of late HIV presentation, and this event was strongly associated to an elevated risk of death in the first six months after AIDS diagnosis [18].
Overall, women with AIDS, who constitute about 22 % of Italian PWA included in this analysis, showed a risk of early mortality similar to men. This result seems in line with lack of gender difference reported in the proportion of HIV late presenters in Italy [19], or life expectancy of HIV-infected people on cART [14, 20]. It must be stressed that a strong HIV prevention effort has been addressed to women in recent years in Italy. National guidelines focusing on HIV testing in pregnancy have been issued to avoid mother-to-child transmission and, indirectly, to identify unaware HIV-infected women [21].
Some of the characteristics herein investigated have been previously recognized as risk factors for mortality of PWA [7], namely injecting drug use, older age, a low number of CD4 cells at AIDS diagnosis, and severe AIDS-defining diseases. Nevertheless, some findings deserve to be highlighted.
In our study, the use of cART before AIDS was associated to a slight increased risk of early mortality (OR = 1.12). In Italy, cART is administered free of charge to every HIV-infected individual fitting standardized clinical and laboratory criteria [22]. In line with the literature, our results suggest that cART-treated individuals benefit from a longer AIDS-free lifetime and that they develop a full-blown AIDS when the immune suppression is already at an advanced stage. Therefore, the risk of early mortality in the pre-AIDS treated group was related to the final depletion of the immune system and/or the presence of other life threatening conditions. Moreover, this finding may also be due to channelling bias (i.e., treated people are those with the worse prognosis) and/or to the presence of unmeasured confounding factors.
The type of AIDS-defining disease turned out to be a strong negative prognostic factor for early mortality. Among these, non-Hodgkin lymphomas and multifocal leukoencephalopathy were associated to more than 3-fold higher ORs, similarly to what reported in other population-based and clinical studies conducted in several high-income countries [20, 23].
Finally, IDU showed the highest early mortality risk compared to PWA who acquired the infection through sexual contact; however, among IDU we observed the lowest proportion of individuals with a low CD4 cell count, suggesting that the elevated risk of early mortality was, in this group. mainly attributable to a longer duration of HV infection and/or to comorbidities, such as liver diseases or cancer, rather than to immune suppression.
The main strengths of this population-based, retrospective-cohort study are the national coverage for both AIDS notifications data and death certificates; the quality of data, in terms of completeness and representativeness; the large size of the study population; and the long observation period. It is relevant to mention that the linkage between the two independent databases allowed the detection of all PWA who died for any reason, and not only for AIDS-related conditions, without the inconvenience of losses to follow-up that can occur in cohort studies based on a unique data source. However, we are aware that prospective cohort studies, in comparison with retrospective ones could provide a larger set of information and a more precise assessment of follow-up time for the survival analysis.
Conversely, a major study limitation is the exclusion of non-Italian PWA from the analysis whose contribution to the AIDS epidemic in Italy is relevant. However, the linkage methodology used in this study –despite taking into account frequent spelling errors in names– could be less sensitive when matching foreign names and surnames due to a higher inaccuracy, in addition to a higher tendency of foreign citizens to migrate. Information on date of HIV-seroconversion is not collected by RNAIDS, as well as duration of adherence to treatment with cART; therefore, the duration of HIV infection of PWA and major parameters of treatment with cART could not be used for the aims of this investigation. Moreover, data on post-AIDS use of cART are not available at the RNAIDS, and this represents another important limitation that could have concealed the impact of cART on short term mortality.