According to an analysis of data from a very large North American cohort collaboration, starting antiretroviral therapy at a CD4 cell count between 351-500 cells/mm3 results in a better likelihood of survival. The results were presented to the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington DC on Sunday by lead investigator Mari M Kitihata, on behalf of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).
The best time to start HIV treatment is not known. The current recommendation in Europe is that antiretroviral therapy should be started when a patient’s CD4 cell count falls below 350 cells/mm3. A substantial body of evidence now supports this recommendation, but there is less information about the potential risks and benefits of starting treatment at a CD4 count above 350 cells/mm3.
An analysis of European and North American cohorts presented earlier this year showed a higher risk of death among HIV-positive people with CD4 counts above 350 cells/mm3 compared to the HIV-negative population, but this difference was non-significant among men who have sex with men.
To examine the effects of starting treatment at higher CD4 cell counts, a team of US and Canadian investigators pooled patient data from 22 US and Canadian HIV cohorts. This study was designed to "mimic, using observational data, what would be observed in a clinical trial enrolling asymptomatic [HIV-positive] individuals with a CD4 cell count of 351-500 cells/mm3”.
The pooled cohort contained data from the medical records of 8374 individuals receiving HIV care between 1996 (the year when effective HIV treatment first became widely available) and 2006 (for a total of 24,994 person-years of follow-up). None of the cohort participants had had AIDS-related illnesses, all were antiretroviral- naïve, and all had a CD4 cell count between 351 and 500 cells/mm3.
The investigators compared the risk of death (from any cause) for patients who started treatment when their CD4 cell count was between 351 and 500 cells/mm3 to the risk seen in individuals who did not begin treatment until their CD4 cell count was lower than 351 cells/mm3.
A total of 2473 patients (30% of the cohort) started antiretroviral therapy when their CD4 cell count was between 351 and 500 cells/mm3; the remaining 5901 patients deferred treatment until their CD4 cell count was 350 cells/mm3 or lower.
Raw comparisons of mortality rates in the two groups appeared to indicate only a slight advantage for earlier treatment. However, this was based on the total time spent in follow-up, and did not take into account whether individuals in the deferred-treatment group received no antiretroviral therapy during the follow-up period. This introduces a so-called "lead-time" bias which had to be corrected for. An adjusted analysis was performed which excluded data from patients who did not begin treatment within 1.5 years.
The adjusted figures showed that patients who deferred therapy until their CD4 cell count was 350 or lower had a 71% increased risk of death compared to those individuals who started treatment at higher CD4 cell counts (a relative hazard [RH] of 1.7, with a 95% confidence interval [CI] of 1.4 – 2.1). This difference was statistically significant (p
Nearly identical results were seen when the analysis was restricted to the 77% of participants for whom baseline viral load data were available. Viral load was, itself, not an independent predictor of mortality. The relative risk remained the same in people who were hepatitis C positive, and in injecting drug users.
This interpretation is based on what the investigators themselves describe as observational data that "mimics … what would be seen in a clinical trial", and note that "a randomized clinical trial will be necessary to confirm this finding and support changes to established treatment guidelines." It should also be noted that survival was the only outcome assessed in this study, which did not measure toxicities or any other long-term outcomes.
“Results from this large North American cohort collaboration support initiation of [antiretroviral therapy] at a CD4 of 351-500 cells/mm3, an earlier stage of HIV disease than is currently recommended”, comment the investigators. A further analysis, of the outcomes of starting treatment at CD4 cell counts above 500 cells/mm3, is also ongoing.
A transcript of a press conference at which the results were discussed can be read here.
Kitahata M.M. et al. Initiating rather than deferring HAART at a CD4+ count between 351-500 cells/mm3 is associated with improved survival. 48th Intersciene Conference on Antimicrobial Agents and Chemotherapy, abstract H-896b, Washington, 2008.