Mortality in the Highly Active Antiretroviral Therapy Era
Mortality in the Highly Active Antiretroviral Therapy Era
Background: AIDS-related death and disease rates have declined in the highly active antiretroviral therapy (HAART) era and remain low; however, current causes of death in HAART-treated patients remain ill defined.
Objective: To describe mortality trends and causes of death among HIV-infected patients in the HAART era.
Design: Prospective, multicenter, observational cohort study of participants in the HIV Outpatient Study who were treated from January 1996 through December 2004.
Measurements: Rates of death, opportunistic disease, and other non-AIDS-defining illnesses (NADIs) determined to be primary or secondary causes of death.
Results: Among 6945 HIV-infected patients followed for a median of 39.2 months, death rates fell from 7.0 deaths/100 person-years of observation in 1996 to 1.3 deaths/100 person-years in 2004 (P = 0.008 for trend). Deaths that included AIDS-related causes decreased from 3.79/100 person-years in 1996 to 0.32/100 person-years in 2004 (P = 0.008). Proportional increases in deaths involving liver disease, bacteremia/sepsis, gastrointestinal disease, non-AIDS malignancies, and renal disease also occurred (P = <0.001, 0.017, 0.006, <0.001, and 0.037, respectively.) Hepatic disease was the only reported cause of death for which absolute rates increased over time, albeit not significantly, from 0.09/100 person-years in 1996 to 0.16/100 person-years in 2004 (P = 0.10). The percentage of deaths due exclusively to NADI rose from 13.1% in 1996 to 42.5% in 2004 (P < 0.001 for trend), the most frequent of which were cardiovascular, hepatic, and pulmonary disease, and non-AIDS malignancies in 2004. Mean CD4 cell counts closest to death (n = 486 deaths) increased from 59 cells/μL in 1996 to 287 cells/μL in 2004 (P < 0.001 for trend). Patients dying of NADI causes were more HAART experienced and initiated HAART at higher CD4 cell counts than those who died with AIDS (34.5% vs 16.8%, respectively, received HAART for 4 of more years, P < 0.0001; 22.4% vs 7.8%, respectively, initiated HAART with CD4 cell counts of more than 350 cells/μL, P < 0.001).
Conclusions: Although overall death rates remained low through 2004, the proportion of deaths attributable to non-AIDS diseases increased and prominently included hepatic, cardiovascular, and pulmonary diseases, as well as non-AIDS malignancies. Longer time spent receiving HAART and higher CD4 cell counts at HAART initiation were associated with death from non-AIDS causes. CD4 cell count at time of death increased over time.
Marked and sustained reductions in AIDS-related death and opportunistic disease have been observed as a consequence of the extensive use of highly active antiretroviral therapy (HAART) since 1996 in the United States and Europe. These benefits have been observed across diverse patient populations and have resulted in prolonged disease-free survival, durable HIV virologic suppression, immunologic (CD4 cell) repletion, and reductions in hospitalization rates. During this time, new morbidities have been observed among HAART-treated persons that have been variably ascribed to specific antiretroviral therapy (ART) received and to factors other than treatment such as stage of underlying HIV disease, baseline host (patient age, race, and sex), and other factors. Although AIDS-related death and opportunistic disease rates have remained low, increased attention has been paid to the treatment and consequences of important comorbidities such as lipoatrophy, lipoaccumulation, insulin resistance with consequent hyperglycemia, hyperlipidemia, cardiovascular disease, osteopenia, and, less commonly, symptomatic hyperlactatemia. Another consequence of improved long-term management of HIV infection has been recognition of the increased importance of providing effective treatment of chronic coinfections such as hepatitis B and C.
Detailed descriptions of the spectrum of illnesses encountered among HAART-treated persons whose HIV infection is under control and of the conditions that are likely to result in death in such persons are lacking, although there are some reports profiling causes of death among person-with-AIDS diagnoses early in the HAART era, among non-US populations that were less extensively HAART-treated, and among women only. We sought to evaluate the most recent trends in mortality and morbidity among mostly HAART-treated persons in the HIV Outpatient Study (HOPS), a large geographically and ethnically diverse cohort of HIV-infected persons in the United States. We present data profiling rates and causes of death and disease (both opportunistic and nonopportunistic) over time among HOPS participants treated since 1996.
Abstract and Introduction
Abstract
Background: AIDS-related death and disease rates have declined in the highly active antiretroviral therapy (HAART) era and remain low; however, current causes of death in HAART-treated patients remain ill defined.
Objective: To describe mortality trends and causes of death among HIV-infected patients in the HAART era.
Design: Prospective, multicenter, observational cohort study of participants in the HIV Outpatient Study who were treated from January 1996 through December 2004.
Measurements: Rates of death, opportunistic disease, and other non-AIDS-defining illnesses (NADIs) determined to be primary or secondary causes of death.
Results: Among 6945 HIV-infected patients followed for a median of 39.2 months, death rates fell from 7.0 deaths/100 person-years of observation in 1996 to 1.3 deaths/100 person-years in 2004 (P = 0.008 for trend). Deaths that included AIDS-related causes decreased from 3.79/100 person-years in 1996 to 0.32/100 person-years in 2004 (P = 0.008). Proportional increases in deaths involving liver disease, bacteremia/sepsis, gastrointestinal disease, non-AIDS malignancies, and renal disease also occurred (P = <0.001, 0.017, 0.006, <0.001, and 0.037, respectively.) Hepatic disease was the only reported cause of death for which absolute rates increased over time, albeit not significantly, from 0.09/100 person-years in 1996 to 0.16/100 person-years in 2004 (P = 0.10). The percentage of deaths due exclusively to NADI rose from 13.1% in 1996 to 42.5% in 2004 (P < 0.001 for trend), the most frequent of which were cardiovascular, hepatic, and pulmonary disease, and non-AIDS malignancies in 2004. Mean CD4 cell counts closest to death (n = 486 deaths) increased from 59 cells/μL in 1996 to 287 cells/μL in 2004 (P < 0.001 for trend). Patients dying of NADI causes were more HAART experienced and initiated HAART at higher CD4 cell counts than those who died with AIDS (34.5% vs 16.8%, respectively, received HAART for 4 of more years, P < 0.0001; 22.4% vs 7.8%, respectively, initiated HAART with CD4 cell counts of more than 350 cells/μL, P < 0.001).
Conclusions: Although overall death rates remained low through 2004, the proportion of deaths attributable to non-AIDS diseases increased and prominently included hepatic, cardiovascular, and pulmonary diseases, as well as non-AIDS malignancies. Longer time spent receiving HAART and higher CD4 cell counts at HAART initiation were associated with death from non-AIDS causes. CD4 cell count at time of death increased over time.
Introduction
Marked and sustained reductions in AIDS-related death and opportunistic disease have been observed as a consequence of the extensive use of highly active antiretroviral therapy (HAART) since 1996 in the United States and Europe. These benefits have been observed across diverse patient populations and have resulted in prolonged disease-free survival, durable HIV virologic suppression, immunologic (CD4 cell) repletion, and reductions in hospitalization rates. During this time, new morbidities have been observed among HAART-treated persons that have been variably ascribed to specific antiretroviral therapy (ART) received and to factors other than treatment such as stage of underlying HIV disease, baseline host (patient age, race, and sex), and other factors. Although AIDS-related death and opportunistic disease rates have remained low, increased attention has been paid to the treatment and consequences of important comorbidities such as lipoatrophy, lipoaccumulation, insulin resistance with consequent hyperglycemia, hyperlipidemia, cardiovascular disease, osteopenia, and, less commonly, symptomatic hyperlactatemia. Another consequence of improved long-term management of HIV infection has been recognition of the increased importance of providing effective treatment of chronic coinfections such as hepatitis B and C.
Detailed descriptions of the spectrum of illnesses encountered among HAART-treated persons whose HIV infection is under control and of the conditions that are likely to result in death in such persons are lacking, although there are some reports profiling causes of death among person-with-AIDS diagnoses early in the HAART era, among non-US populations that were less extensively HAART-treated, and among women only. We sought to evaluate the most recent trends in mortality and morbidity among mostly HAART-treated persons in the HIV Outpatient Study (HOPS), a large geographically and ethnically diverse cohort of HIV-infected persons in the United States. We present data profiling rates and causes of death and disease (both opportunistic and nonopportunistic) over time among HOPS participants treated since 1996.
