Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters

Abstract

Background: To estimate the clinical benefit of highly active antiretroviral therapy (HAART) initiation vs deferral in a given month in patients with CD4 cell counts less than 800/μL.

Methods: In this observational cohort study of human immunodeficiency virus type 1 seroconverters from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), we constructed monthly sequential nested subcohorts between January 1996 and May 2009, including all eligible HAART-naive, AIDS-free individuals with a CD4 cell count less than 800/μL. The primary outcome was time to AIDS or death in those who initiated HAART in the baseline month compared with those who did not, pooled across subcohorts and stratified by CD4 cell count. Using inverse probability-of-treatment weighted survival curves and Cox proportional hazards regression models, we estimated the absolute and relative effects of treatment with robust 95% confidence intervals (CIs).

Results: Of 9455 patients with 52,268 person-years of follow-up, 812 (8.6%) developed AIDS and 544 (5.8%) died. In CD4 cell count strata of 200 to 349, 350 to 499, and 500 to 799/μL, HAART initiation was associated with adjusted hazard ratios (95% CIs) for AIDS/death of 0.59 (0.43-0.81), 0.75 (0.49-1.14), and 1.10 (0.67-1.79), respectively. In the analysis of all-cause mortality, HAART initiation was associated with adjusted hazard ratios (95% CIs) of 0.71 (0.44-1.15), 0.51 (0.33-0.80), and 1.02 (0.49-2.12), respectively. Numbers needed to treat (95% CIs) to prevent 1 AIDS event or death within 3 years were 21 (14-38) and 34 (20-115) in CD4 cell count strata of 200 to 349 and 350 to 499/μL, respectively.

Conclusion: Compared with deferring in a given month, HAART initiation at CD4 cell counts less than 500/μL (but not 500-799/μL) was associated with slower disease progression.

Figure 1

Construction of sequential nested subcohorts. 1. Identify all eligible patients, assess covariates, and determine exposure group during January 1996 to create the first subcohort. 2. Measure days from February 1, 1996 to the date of first AIDS diagnosis, death or censoring for each patient. 3. Repeat Steps 1 and 2 for each month between Feb 1996 and May 2009 resulting in 161 subcohorts.

Figure 2

Weighted semi-parametric survival curves for time to combined endpoint of first AIDS diagnosis or death from all causes (black lines) or death alone (blue lines) comparing patients who initiated (single weight lines) or deferred (doubly weight lines) HAART stratified by CD4 cell count. I_u = unique individuals in the HAART initiation group who remained in the risk set at time t; D_u = unique individuals in the HAART deferral group who remained in the risk set at time t; Nu = unique individuals in the CD4 stratum overall who remained in the risk set at time t.

Figure 2

Weighted semi-parametric survival curves for time to combined endpoint of first AIDS diagnosis or death from all causes (black lines) or death alone (blue lines) comparing patients who initiated (single weight lines) or deferred (doubly weight lines) HAART stratified by CD4 cell count. I_u = unique individuals in the HAART initiation group who remained in the risk set at time t; D_u = unique individuals in the HAART deferral group who remained in the risk set at time t; Nu = unique individuals in the CD4 stratum overall who remained in the risk set at time t.

Figure 2

Weighted semi-parametric survival curves for time to combined endpoint of first AIDS diagnosis or death from all causes (black lines) or death alone (blue lines) comparing patients who initiated (single weight lines) or deferred (doubly weight lines) HAART stratified by CD4 cell count. I_u = unique individuals in the HAART initiation group who remained in the risk set at time t; D_u = unique individuals in the HAART deferral group who remained in the risk set at time t; Nu = unique individuals in the CD4 stratum overall who remained in the risk set at time t.

Figure 2

Weighted semi-parametric survival curves for time to combined endpoint of first AIDS diagnosis or death from all causes (black lines) or death alone (blue lines) comparing patients who initiated (single weight lines) or deferred (doubly weight lines) HAART stratified by CD4 cell count. I_u = unique individuals in the HAART initiation group who remained in the risk set at time t; D_u = unique individuals in the HAART deferral group who remained in the risk set at time t; Nu = unique individuals in the CD4 stratum overall who remained in the risk set at time t.

Figure 2

Weighted semi-parametric survival curves for time to combined endpoint of first AIDS diagnosis or death from all causes (black lines) or death alone (blue lines) comparing patients who initiated (single weight lines) or deferred (doubly weight lines) HAART stratified by CD4 cell count. I_u = unique individuals in the HAART initiation group who remained in the risk set at time t; D_u = unique individuals in the HAART deferral group who remained in the risk set at time t; Nu = unique individuals in the CD4 stratum overall who remained in the risk set at time t.

Figure 3

Parts A–E. Assessing model sensitivity and results of subgroup analyses. Hazard ratios (on the natural log scale) and 95% confidence intervals for crude (cHR) and adjusted (aHR) analyses of time to first AIDS diagnosis or death from all causes. Sensitivity analyses include censoring outcomes of patients who initiated mono/dual therapy or failed to start HAART within six months after first CD4<200 (S1); censoring at mono/dual therapy for failure to initiate HAART within six months of first CD4 <350 (S2); requiring baseline viral load measure (S3), requiring CD4 cell count within last 45 days of baseline (S4), and beginning follow-up in January 1998 (S5). Subgroup analyses presented for those without (IDU−) and with (IDU+) known injection drug use history.