Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

When To Start Consortium, Jonathan A C Sterne, Margaret May, Dominique Costagliola, Frank de Wolf, Andrew N Phillips, Ross Harris, Michele Jönsson Funk, Ronald B Geskus, John Gill, François Dabis, Jose M Miró, Amy C Justice, Bruno Ledergerber, Gerd Fätkenheuer, Robert S Hogg, Antonella D'Arminio Monforte, Michael Saag, Colette Smith, Schlomo Staszewski, Matthias Egger, Stephen R Cole, Hans Reinhard Brodt, Jordi Casabona, Geneviève Chêne, Dominque Costagliola, François Dabis, Antonella D'Arminio Monforte, Julia del Amo, Frank de Wolf, Matthias Egger, Gerd Fätkenheuer, John Gill, Jodie Guest, Robert Hogg, Amy Justice, Mari Kitahata, Fiona Lampe, Bruno Ledergerber, Amanda Mocroft, Peter Reiss, Michael Saag, When To Start Consortium, Jonathan A C Sterne, Margaret May, Dominique Costagliola, Frank de Wolf, Andrew N Phillips, Ross Harris, Michele Jönsson Funk, Ronald B Geskus, John Gill, François Dabis, Jose M Miró, Amy C Justice, Bruno Ledergerber, Gerd Fätkenheuer, Robert S Hogg, Antonella D'Arminio Monforte, Michael Saag, Colette Smith, Schlomo Staszewski, Matthias Egger, Stephen R Cole, Hans Reinhard Brodt, Jordi Casabona, Geneviève Chêne, Dominque Costagliola, François Dabis, Antonella D'Arminio Monforte, Julia del Amo, Frank de Wolf, Matthias Egger, Gerd Fätkenheuer, John Gill, Jodie Guest, Robert Hogg, Amy Justice, Mari Kitahata, Fiona Lampe, Bruno Ledergerber, Amanda Mocroft, Peter Reiss, Michael Saag

Abstract

Background: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies.

Methods: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL.

Findings: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL).

Interpretation: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.

Figures

Figure 1
Figure 1
Comparison of analyses from (A) initiation of treatment and (B) time of first CD4 cell count measurement in the upper range
Figure 2
Figure 2
Cumulative probability of (A) AIDS or death or (B) death alone after initiation of combination antiretroviral therapy, according to range of CD4 cell count at the time of treatment initiation
Figure 3
Figure 3
Adjusted hazard ratios for (A) AIDS or death and (B) death alone for initiation of combination antiretroviral therapy at a lower CD4 cell count threshold (ie, deferred initiation) versus initiation in a range up to 100 cells per μL higher The horizontal axis shows the threshold values (upper limits of the CD4 cell count ranges in the deferred initiation groups [from 351–450 cells per μL, in steps of 25 cells per μL, to 0–100 cells per μL]). See table 2 and table 3 for lists of hazard ratios and 95% CIs.
Figure 4
Figure 4
Hazard ratios for the cumulative effect of deferred initiation of combination antiretroviral therapy for (A) AIDS or death and (B) death alone, compared with starting treatment at CD4 cell count range 351–450 cells per μL The horizontal axis shows the upper limits of the lower CD4 cell count range (251–350 cells per μL, 151–250 cells per μL, and 51–150 cells per μL).

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