Of the 1,633 potentially eligible patients, 95 (5.8%) females were excluded from the analysis because they were followed only during pregnancy. Of the 1,538 eligible patients, who contributed 7,037 person-years of follow-up, 226 (14.7%) were known to have died during the study period, yielding a mortality rate of 3.2/100 person-years. Eighty-two deaths (36.3%) were identified only through the linkage algorithm with the Rio de Janeiro Mortality Database; compared to the mortality rate before the linkage algorithm was applied (2.0/100 py), the retrieval of these cases represented a greater than 50% increase (difference = 1.2; 95%CI = 0.9,1.4; p < 0.01). The median follow-up time was 4.61 years (IQR = 5.63 years) and the loss to follow-up rate was 2.4/100 person-years.
Characteristics of all patients are described in . Compared to patients remaining in care, those lost to follow-up were younger, more likely to be female, on HAART and on a PI-based regimen, had higher baseline CD4 cell counts, and a shorter follow-up time (p < 0.05 for all).
General descriptions of variables analyzed
Of the 226 known deaths, 111 (49.1%) were classified as due to AIDS-related, and 98 deaths (43.4%) as due non-AIDS-related causes; 17 (7.5%) were due to unknown causes. Patients who died from non-AIDS related conditions contributed more follow-up time than patients who died from AIDS-related conditions (median time = 3.39 py vs. 1.45 py, respectively, p < 0.01) (). Rates of death from AIDS-related causes (1.58/100 py) and from non-AIDS-related causes (1.39/100 py) were not statistically different (p = 0.37).
Alive patients had higher baseline CD4 cell counts than deceased patients in pairwise comparisons with both patients who died from AIDS- and from non-AIDS-related causes of death (p < 0.01 for both comparisons). The difference in baseline CD4 counts between the latter two groups did not reach statistical significance after multiple comparisons adjustment (148 vs. 95 cells/mm3, respectively, p = 1).
Causes of death are shown in . Opportunistic infections were the leading causes of death (37.6%). Among non-AIDS-related causes, infectious diseases were also the most frequent causes (8.4%), followed by external causes (4.9%) and CVD (4.0%).
Groups of specific causes of death
Overall death rates remained fairly stable during the study period (p = 0.57). In contrast, AIDS-related causes of death declined significantly over time (p < 0.01), and non-AIDS-related causes of death increased over time, although not significantly (p = 0.46) ( and ). Nonetheless, in the most recent period analyzed (2005-2006) the rate of non-AIDS related causes of deaths was higher than that of AIDS-related causes of death (1.59/100 py and 1.24/100 py, respectively). CVD as an underlying cause of death increased over time, although the increase did not reach statiscal significance (p = 0.09) ().
Trends of overall, AIDS-related causes, non-AIDS-related causes and CVD death rates per 100 person-years over time and 95% confidence intervals for all patients
Figure 1 Temporal trends of deaths in the cohort. A – Overall death rates and 95% CIs and linear trend over time (Poisson model); B – AIDS and Non-AIDS-related death rates and 95% CIs and linear trend over time (Poisson model); C – Cumulative (more ...)
The cumulative incidence functions for the hazards subdistributions for AIDS-related, non-AIDS-related, and unknown causes of death in a competing risks framework are shown in . The cumulative incidence of AIDS-related causes of death was higher than non–AIDS-related causes of death at the beginning of the observation period, with a reversal of this pattern during the subsequent seven years. In we present models for the hazard subdistributions of AIDS- and non-AIDS related causes of death, with age at the start of the observation period as a time-dependent variable, adjusted for baseline CD4 cell count, gender, and HIV transmission category. The models indicate that higher baseline CD4 cell counts were strongly associated with protection for both AIDS- and non-AIDS-related causes of death (10% and 13% per 50 cells increase, respectively) and that patients in the intravenous drug use transmission category were at higher risk of dying of a non-AIDS-related cause of death (aHR = 4.96; 95% CI: 2.34,10.52; p < 0.01), but not of an AIDS-related cause of death. Although baseline age was not associated with non-AIDS-related causes of death, there was a 46% increase in risk per 10 years of baseline age for AIDS-related causes of death, with a significant and negative interaction over time (p = 0.02), indicating that risk decreased significantly over time.
Table 4 Models for the hazards of the subdistributions and specific-hazards of deaths due to AIDS- and to non-AIDS-related causes including baseline age (per 10 year increase), CD4 cell counts (per 50 cells increase), gender (reference: female) and risk group (more ...)
HAART and PI use during the observation time were not significantly associated with non-AIDS-related causes of death (HR = 0.7; 95%CI: 0.44,1.09; p = 0.11 and HR = 1.23; 95%CI: 0.82,1.86; p = 0.32, respectively).
Death rates due to causes not related to immunodeficiency increased significantly over time (0.54 vs. 0.84 deaths per 100 py, in 1997-1998 and 2005-2006, respectively; p < 0.01), even though death rates due to causes related to immunodeficiency were consistently and significantly higher throughout the study period (data not shown).
Eight cases that lacked data on the causes of death were classified as AIDS-related based solely on the CD4 cell count 6 months prior to death. A sensitivity analysis recoding these cases as unknown did not change the results (data not shown).