The number of participants who experienced SNA events in the SMART and ESPRIT studies exceeded those who experienced AIDS events by almost 50% (435 versus 286 events). As compared to participants who did not develop such an event, the risk of death following SNA events was twice as high compared to AIDS events. This difference in mortality risk for the different types of events was apparent early on and was maintained throughout the follow-up period.
This is consistent with other studies that have shown that, in the era of combination antiretroviral therapy, SNA events dominate morbidity at high CD4+ counts2,16,17
and may even occur more frequently than AIDS events in individuals with advanced HIV.18
Additionally, the majority of deaths in HIV-infected persons are now due to non-AIDS causes.19–21
In this study, the median CD4+ cell counts prior to AIDS and SNA events were 356 cells/mL (IQR: 227–540) and 518 cells/mL (IQR: 360–727), respectively.
As noted in other studies9
, we found that not all AIDS events were associated with the same risk of death. The HR for death following serious AIDS events, events which were associated with a higher risk of death before the availability of HAART,4
was 10.8 compared to 3.1 for all other AIDS events. Recent studies have reported that the risk of death following non-Hodgkin’s lymphoma is particularly high.9,22
In our study, 64% of the serious AIDS events were lymphomas (of any type) which resulted in a HR for death of 9.5.
SNA events were shown to be not only more frequent, but also related to significantly higher mortality than AIDS events. Most of the SNA events in SMART and ESPRIT were CVD and cancer, with substantially fewer renal and hepatic events. Preventing SNA events in some patients may be clinically possible.23
Prevention of CVD is important as it remains the most common SNA event and contributes significantly to all cause mortality. Decreasing modifiable CVD risk factors could thus have an impact on mortality in HIV-infected individuals. Additionally, it has been shown that HIV-infected patients are as likely to achieve conventional risk factor treatment goals, such as normalizing blood pressure or lipid levels, as HIV-uninfected patients.24
The risk of death after experiencing a CVD event did not increase substantially after the first six months following the event. This is similar to reports in the general population in which the risk of death following CVD events was greatest in the early time period after hospitalization with such an event.25,26
Along with CVD, malignancies were the other most common type of SNA events in this analysis and contributed substantially to all-cause mortality. It has been shown that for some non-AIDS defining malignancies there might be a benefit in routine screening.27
Despite this, HIV-infected patients are not always undergoing the same routine cancer screening tests as the general population.28
In addition, there are major risk factors, such as HCV and HBV infection, tobacco smoking or heavy alcohol consumption, which may contribute to specific non-AIDS malignances and can be addressed in clinical practice.29
In our study, lung cancer and prostate cancer were the most common cancers and for these cancers mortality risk varied considerably, consistent with data from the general population.25,26,30–32
In our study, older age, diabetes and co-infection with hepatitis B or C were independent predictors for death following a non-AIDS event. This finding, along with prior information that patients with diabetes are at an increased risk of death following MI33
events in the general population, emphasizes the importance of identifying and properly managing patients with diabetes and other risk factors in order to prevent the occurrence of non-fatal events as well as to increase survival following these events. In contradiction to the findings with AIDS events, latest CD4+ was not an independent predictor for death following a non-AIDS event in our study. This may be due to the fact that these events occurred at higher CD4+ cell counts and that most of the follow-up time was spent at relatively high CD4+ counts.
Excluding participants with a history of non-fatal events at enrollment into SMART and ESPRIT did not change our results. Both studies enrolled relatively healthy participants with high CD4+ levels and patients were not permitted to enroll in ESPRIT if there was any evidence of active clinical disease within the year prior to randomization. AIDS and SNA events experienced prior to enrollment most likely occurred long enough before enrollment into SMART and ESPRIT to allow participants to recover from the non-fatal event attenuating the impact of any disease that occurred prior to enrollment.
The prevalence of risk factors, such as smoking, obesity, and elevated cholesterol levels, for the development of SNA events is high in our cohort and this has been noted in other HIV studies.35
A recent report found that mortality among patients who start ART, survive the first 6 months, and achieve an HIV-RNA level ≤ 500 copies/mL and CD4+ count ≥ 350 cells/mm3
is modestly higher than in the general population.36
The higher mortality may be due to these other risk factors. This highlights the importance of smoking cessation and the management of other modifiable risk factors.
There are some limitations to this study. We studied HIV-infected participants with higher CD4+ counts who met eligibility criteria for the randomized trials. While both trials had broad inclusion criteria, participants who developed events may have been healthier than a random sample of HIV-infected participants. Another limitation was that smoking status was not collected in ESPRIT and hepatitis status and use of lipid lowering and blood-pressure lowering drugs was not available for all ESPRIT participants.
In summary, we have shown by pooling results form 2 large studies in nearly 10,000 HIV-infected patients with carefully documented and adjudicated AIDS and SNA events, that the risk of death is greater following SNA than AIDS events. This finding is important given the much greater frequency of SNA than AIDS events. Further, the risk of death varies by type of AIDS and SNA event. These results have implications for defining major outcomes in clinical studies and for setting priorities for the development and evaluation of interventions to reduce morbidity and mortality among patients infected with HIV.