Objective: To estimate incidence and predictors of serious or life-threatening events that are not AIDS defining, AIDS events, and death among patients treated with highly active antiretroviral therapy (HAART) in the setting of 5 large multicenter randomized treatment trials conducted in the United States.
Methods: Data were analyzed from 2947 patients enrolled from December 1996 through December 2001. All patients were to receive antiretrovirals throughout follow-up. Data collection was uniform for all main outcome measures: serious or life-threatening (grade 4) events, AIDS, and death.
Results: During follow-up, 675 patients experienced a grade 4 event (11.4 per 100 person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272 died (4.6 per 100 person-years). The most common grade 4 events were liver related (148 patients, 2.6 per 100 person-years). Cardiovascular events were associated with the greatest risk of death (hazard ratio = 8.64; 95% CI: 5.1 to 14.5). The first grade 4 event and the first AIDS event were associated with similar risks of death, 5.68 and 6.95, respectively.
Conclusions: Grade 4 events are as important as AIDS events in the era of HAART. To adequately evaluate the impact of HAART on morbidity, comorbidities and other key factors must be carefully assessed.
The introduction of highly active antiretroviral therapy (HAART) and an improved understanding of HIV-1 viral dynamics led to a dramatic decline in US AIDS-related morbidity and mortality beginning in 1996. 1-4 This dramatic decline, together with the hope that HIV could be eradicated, 5 led clinicians and HIV treatment guideline committees to adopt an aggressive strategy in treating HIV, 6 focusing primarily on the benefits of HAART: hit early, hit hard.7 However, as current antiretroviral therapy is unable to eradicate HIV, 8 and is associated with increased toxicities, HIV treatment guideline committees have recently adopted a less aggressive set of guidelines for treating HIV. 9,10
All 4 classes of antiretrovirals (ARVs) and all 19 Food and Drug Administration-approved ARVs have been directly or indirectly associated with life-threatening events and death. 9,11-13 However, the cause of many serious or life-threatening events is multifactorial and clear attribution to the use of HAART, specific ARV drugs, HIV infection, or other factors is frequently not possible. Potential risk factors for the development of life-threatening clinical events among HIV-infected individuals on HAART include HIV virus-host interactions, 14-17 stage of HIV disease, 18-20 ARV drugs, 9,11-13 genetic predisposition, 21-25 age, 26 comorbid conditions, 27-35 coinfections (e.g., hepatitis B or hepatitis C), 36-44 concomitant medications, 43,45-49 nutritional status, 50-55 recreational drugs and alcohol, 56-58 other social behaviors and practices, 53,59-62 and physician experience. 63,64
The short-term toxicities and benefits of HAART have been well described in the setting of clinical trials; however, data quantifying morbidity in the era of HAART are limited. We therefore estimated the incidence and determinants of serious or life-threatening events that are not AIDS defining, AIDS events, and death among patients treated with HAART in the setting of 5 large multicenter randomized treatment trials conducted in the United States.