Data on 39,272 patients with a median follow-up of 3.6 years (interquartile range [IQR], 1.6–6.1) were available. shows patient characteristics at baseline with corresponding years of follow-up and numbers of deaths. Median age was 37 years (IQR, 31–44) and median calendar month of initiation of ART was December 2000 (October 1998–April 2003). The initial antiretroviral regimen contained ≥4 drugs (excluding low-dose ritonavir) in 2264 (6%) and 3 drugs in 37,008 (94%) patients. A protease inhibitor was used in 24,267 (62%) and a nonnucleoside reverse-transcriptase inhibitor in 12,688 (32%) initial regimens.
Characteristics of 39,272 Patients Included in Analyses at the Start of Anti-retroviral Therapy (ART), with Follow-up Time and Number of Deaths
During 154,667 years of follow-up, 1876 (4.8%) patients died. Of these deaths, 1597 (85%) were assigned a cause according to the CoDe categories. shows the number of deaths in each of these categories. The crude all-cause death rate was 12.1 deaths per 1000 person-years (95% confidence interval [CI], 11.6–12.7 deaths per 1000 person-years). Those who died had lower median CD4 counts at baseline (110 cells/mm3; IQR, 33–247 cells/mm3) than those who survived (217 cells/mm3; IQR, 94–343 cells/mm3). In those who died, the median time to death from baseline was 1.8 years (IQR, 0.6–3.8). Compared with patients with an assigned cause of death, the 279 patients with unknown cause of death were more likely to be male, to be an injection drug user, and to have less advanced HIV-1 disease at baseline. At the last clinic visit before death, they were more likely to be receiving treatment and had higher median CD4 counts (215 vs 110 cells/mm3).
Frequencies of Specific Causes of Death According to the Cause of Death (CoDe) Classification in the 1876 Patients Who Died.
shows frequencies of the 8 grouped causes of death. Seven hundred ninety-two (49.6%) of the deaths for which a cause was assigned were due to AIDS, of which 366 (46.2%) could be further classified as infection and 236 (29.8%) as malignancy. The most frequent non-AIDS causes of death were non-AIDS malignancy (11.8%), non-AIDS infection (8.2%), cardiovascular disease (7.9%, of which 40% were myocardial infarction/ischemic heart disease and 18% stroke), violence (7.8%, approximately one-third each of suicide, substance abuse, and homicide/accident/unspecified), and liver disease (7.1%, of which 55.8% were hepatitis related). The most frequent sites for non-AIDS malignancies were respiratory tract or intrathoracic organs (36.7%); digestive organs and peritoneum (28.7%); lip, oral cavity, and pharynx (6.0%); and skin (4.7%). During the first year of ART, 63% of deaths were attributable to AIDS; this subsequently decreased to 43%. shows crude incidence rates per 1000 years of different causes of death; note that these are underestimates because 15% of deaths could not be classified. shows frequencies of cause-specific death by year of death. The proportion of AIDS-related deaths decreased from 58.5% in 1996–1999 to 43.7% in 2003–2006. The proportion of deaths due to AIDS-defining cancers decreased from 20.5% to 12.5%, and the proportion of deaths due to non–AIDS-defining cancers increased from 7.3% to 15.4% over the same time periods.
Frequencies of Specific Causes of Death in the 1597 Patients Who Died, with Crude Incidence Rates per 1000 Person-Years of Follow-up
Frequencies of Specific Causes of Death in the 1597 Patients Who Died by Year of Death
shows adjusted HRs for the association of prognostic factors at baseline with specific causes of death. Lower CD4 counts were associated with higher rates of deaths due to AIDS, non-AIDS malignancy, renal failure, and other causes, as well as with death due to AIDS infection (HR per 100 cell decrease, 1.69; 95% CI, 1.52–1.88) but not AIDS malignancies (HR, 1.05; 95% CI, 0.95–1.17). Higher baseline CD4 counts were associated with higher rates of death due to violent causes. Rates of all specific causes of death except renal failure were higher in injection drug users, with particularly strong associations for liver-related death, respiratory, death, violent death, and death due to infection. AIDS before baseline was associated with higher subsequent rates of death due to both AIDS and non-AIDS infections. Patients with higher baseline viral load had higher rates of death due to AIDS, non-AIDS infection, cardiovascular disease, and respiratory disease.
Figure 1 Adjusted hazard ratios (HRs) and 95% confidence intervals of risk factors at start of antiretroviral therapy for specific causes of death from Cox models with CD4 cell count (per 100 cell decrease), transmission risk group (injection drug user [IDU] vs (more ...)
gives further information on associations of prognostic factors with specific causes of death. Older age was strongly associated with increased rates of non-AIDS malignancy (HR per 10 years, 2.32; 95% CI, 2.04–2.63) and cardiovascular disease (HR per 10 years, 2.05; 95% CI, 1.76–2.39). The cause of death least strongly associated with age was AIDS (HR per 10 years, 1.19; 95% CI, 1.11–1.28). There was a marked increase in rates of renal death in patients aged >60 years. Compared with male patients, female patients had lower rates of all-cause mortality (HR, 0.84; 95% CI, 0.74–0.94) and, in particular, lower rates of death due to AIDS malignancies (HR, 0.58; 95% CI, 0.40–0.84) and non-AIDS malignancies (HR, 0.50; 95% CI, 0.31–0.79).
Mutually Adjusted Hazard Ratios for Specific Causes of Death (Frequency, >20%) for Risk Factors at Start of Antiretroviral Therapy (ART), from Multivariable Cox Models Stratified by Cohort and Calendar Year of Starting ART.
displays cause-specific mortality rates according to time since starting ART. Rates of death due to AIDS, non-AIDS infection, and renal failure decreased markedly with increasing time receiving ART. shows cause-specific mortality incidence rate ratios according to duration of ART and calendar year of starting ART, adjusted for prognostic factors. Rates of AIDS-related mortality decreased with both time on ART (P < .001, by test for trend) and with year of starting ART (P < .001). Rates of death due to non-AIDS infection and renal failure also decreased with time receiving ART.
Bar graph showing crude cause-specific mortality rate according to length of time since start of combination antiretroviral therapy (cART). CVD, cardiovascular disease.
Adjusted Cause-Specific Incidence Rate Ratios by Time Receiving Antiretroviral Therapy (ART) and Calendar Year of Starting ART, from Poisson Models
(upper panel) shows cumulative incidence for AIDS-related, non-AIDS-related, and unknown deaths. The majority of deaths during the first year of receiving ART were AIDS related, but because rates of AIDS-related death decrease with time receiving ART, the cumulative incidence of non–AIDS-related deaths exceeded that of AIDS-related deaths after ~4 years of ART. (lower panel) shows that the total cumulative mortality at 8 years was ~9%, with <4% of deaths classified as AIDS related.
Cumulative incidence of AIDS-related, non–AIDS-related, and unknown deaths (upper panel) and total cumulative mortality partitioned by cause of death (lower panel).