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Because no prospective clinical trial has directly addressed the issue of immediate versus deferred antiretroviral therapy (ART) for asymptomatic HIV-infected patients, clinical guideline panels have relied mainly on cohort study data to inform their recommendations. This month, findings were published from two major collaborative cohort studies, both of which were presented at scientific meetings in the past year (JW AIDS Clin Care Nov 10 2008 and Mar 9 2009).
In the NA-ACCORD study, investigators conducted two parallel analyses using data pooled from 22 cohorts in North America. Patients were eligible for the first analysis if, at any point during the study period (1996–2005), they had a CD4 count of 351 to 500 cells/mm3 and no history of AIDS-defining illness or ART use. Of the 8362 patients who met these criteria, 2084 started ART immediately (within 6 months after entering the CD4-cell range of interest), and 6278 deferred. Deferral of therapy was associated with a 69% increased risk for death during follow-up. The second analysis was identical to the first, except that patients had CD4 counts >500 cells/mm3. Again, only about 25% of patients (2220 of 9155) started ART immediately, and deferral of therapy was associated with a significant increase in mortality risk (94%). In both analyses, patients who started ART earlier generally had more-favorable baseline characteristics (e.g., lower rates of injection-drug use [IDU] and hepatitis C virus coinfection), and they achieved higher rates of virologic suppression with treatment, suggesting a better rate of medication adherence. However, even after adjustment for some of these factors, the survival advantage of earlier therapy remained.
The merits of early therapy were also assessed by the When to Start Consortium, which evaluated pooled data from 15 cohorts in Europe and North America. Patients were eligible for analysis if they started ART in 1998 or later with a CD4 count <550 cells/mm3, no history of AIDS-defining illness, and a presumed acquisition mode other than IDU. In order to estimate the lead time before starting therapy and the clinical events that took place during this time, the investigators applied cohort data from the pre-ART era (1989–1995) to the current era. More than 24,000 patients were included in the analysis. Deferral of ART until the CD4 count fell to between 251 and 350 cells/mm3 (compared with 351–450 cells/mm3) was associated with a 28% increased risk for AIDS or death; no significant increase was seen for death alone.
Kitahata MM et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009 Apr 1; [e-pub ahead of print]. (http://dx.doi.org/doi:10.1056/NEJMoa0807252)
Sax PE and Baden LR. When to start antiretroviral therapy — Ready when you are? N Engl J Med 2009 Apr 1; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMe0902713)
When To Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: A collaborative analysis of 18 HIV cohort studies. Lancet 2009 Apr 9; [e-pub ahead of print]. (http://dx.doi.org/doi:10.1016/S0140-6736(09)60612-7)
Wood R and Lawn SD. Should the CD4 threshold for starting ART be raised? Lancet 2009 Apr 9; [e-pub ahead of print]. (http://dx.doi.org/doi:10.1016/S0140-6736(09)60654-1)
Comment
These two studies represent a fascinating example of how advanced statistical techniques can be applied to observational data to try and answer a clinical question — in this case, when to start ART in asymptomatic patients. Although the observational nature of these studies prevents either research group from claiming to “prove” that therapy should be started at higher CD4-cell counts — a point that both editorials hasten to mention — the data do add to a substantial body of evidence showing that untreated HIV infection has negative consequences, even at higher CD4-cell counts. (Neither study can claim that those who start ART earlier are the same as those who defer — they may have been more “health seeking” and hence did better for reasons unrelated to ART.) The NA-ACCORD data are particularly striking and are even stronger than those presented at the 2009 Retrovirus Conference. Although the two research groups reach different conclusions about the precise threshold for when to start therapy, they are consistent in the most important message — that treatment should be started before the CD4 count falls below 350 cells/mm3, and perhaps earlier.