Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal

Abstract

Background: The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy.

Methods: We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together to form a "rare ADEs" category.

Results: During a median follow-up period of 43 months (interquartile range, 19-70 months), 2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-Hodgkin's lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84-22.35) and progressive multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70-14.92). Three groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped confidence intervals: severe (non-Hodgkin's lymphoma and progressive multifocal leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55-9.48]), moderate (cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76-3.13]), and mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08-2.00]).

Conclusions: In the combination antiretroviral therapy era, mortality rates subsequent to an ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in clinical end point trials, prognostic studies, and patient management.

Figure 1

Median patient CD4⁺ cell count at diagnosis (interquartile range [IQR]) for each type of AIDS-defining event (ADE). COC, cryptococcosis; CMV, cytomegalovirus infection; DEM; AIDS dementia complex; ESO, esophageal candidiasis; HSD, herpes simplex disease; KSA, Kaposi’s sarcoma; MAC, disseminated mycobacterial disease; NHL, non-Hodgkin’s lymphoma (including primary brain lymphoma); OTH, all ADEs that occurred in <50 patients; PCP, Pneumocystis jiroveci (carinii) pneumonia; PML, progressive multifocal leukoencephalopathy; SPO; cryptosporidiosis; TBC; pulmonary tuberculosis; TEX, extrapulmonary tuberculosis; TOX, cerebral toxoplasmosis; WAS, HIV wasting syndrome.

Figure 2

AIDS-defining events (ADEs) stratified by patient viral load at diagnosis of each type of ADE. COC, cryptococcosis; CMV, cytomegalovirus infection; DEM; AIDS dementia complex; ESO, esophageal candidiasis; HSD, herpes simplex disease; KSA, Kaposi’s sarcoma; MAC, disseminated mycobacterial disease; NHL, non-Hodgkin’s lymphoma (including primary brain lymphoma); OTH, all ADEs that occurred in <50 patients; PCP, Pneumocystis jiroveci (carinii) pneumonia; PML, progressive multifocal leukoencephalopathy; SPO; cryptosporidiosis; TBC; pulmonary tuberculosis; TEX, extrapulmonary tuberculosis; TOX, cerebral toxoplasmosis; WAS, HIV wasting syndrome.

Figure 3

Adjusted mortality hazard associated with each type of AIDS-defining event (ADE) after initiation of combination antiretroviral therapy (cART). The model was stratified by cohort and adjusted for age, sex, exposure group, number of drugs in the initial cART regimen, type of cART regimen, date of cART initiation, and patient CD4⁺ cell count and viral load at cART initiation. COC, cryptococcosis; CMV, cytomegalovirus infection; DEM; AIDS dementia complex; ESO, esophageal candidiasis; HSD, herpes simplex disease; KSA, Kaposi’s sarcoma; MAC, disseminated mycobacterial disease; NHL, non-Hodgkin’s lymphoma (including primary brain lymphoma); OTH, all ADEs that occurred in <50 patients; PCP, Pneumocystis jiroveci (carinii) pneumonia; PML, progressive multifocal leukoencephalopathy; SPO; cryptosporidiosis; TBC; pulmonary tuberculosis; TEX, extrapulmonary tuberculosis; TOX, cerebral toxoplasmosis; WAS, HIV wasting syndrome.