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What is the optimal CD4 count at which to start antiretroviral therapy?

Current practice guidelines Current guidelines for the use of antiretroviral agents in adults and adolescents infected with human immunodeficiency virus (HIV-1) released by the Department of Health and Human Services in November 2008 recommend that antiretroviral therapy be initiated in patients with a CD4 T-cell count of <350 cells/mm³.¹ The guidelines also recommend that antiretroviral therapy be started in patients with a history of an acquired immunodeficiency syndrome (AIDS)-defining illness, and for the following patients regardless of CD4 T-cell count:

The guidelines also comment that antiretroviral therapy may be considered for some asymptomatic patients with CD4 T-cell counts >350 cells/mm³; however, current data are inadequate to recommend initiation in all patients.¹ The guidelines state that potential benefits must be weighed against potential risks of therapy (Table 1), and that clinical scenarios, the presence of comorbidities, age, patient readiness, potential impact on quality of life, and adherence must all be assessed. Early initiation of antiretroviral therapy may be appropriate for patients who have a rapid decline in CD4 T-cells, defined as a decrease of >120 cells/mm³ per year.

Table 1. Benefits and risks of initiating antiretroviral treatment early.¹

HIV= human immunodeficiency virus

New data supports earlier initiation Researchers with the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) presented data at the 48^th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) which showed that treatment naive patients with HIV-1 infection who initiated antiretroviral therapy earlier had a lower risk of death.² The NA-ACCORD is part of the International Databases to Evaluate AIDS (IEDEA) and is designed to be widely representative of HIV care in the United States and Canada.³ The goals of NA-ACCORD are to establish a collaboration of North American HIV/AIDS cohorts and a data center for compilation of data to address HIV/AIDS research questions that cannot be accomplished through smaller cohorts; to address scientific aims that focus on the failure of highly-active antiretroviral therapy (HAART), with a special focus on multi-drug resistant virus and its consequences and management; to address additional scientific aims related to events that cannot be as well-studied in smaller cohorts (for example, those that require large sample sizes, such as rare events from new HIV therapies, or those that require long-term follow-up, such as malignancy), and emerging issues in HIV clinical care such as the impact of aging on HIV treatment response; to develop and apply novel statistical and epidemiological methodology that is applicable to these scientific research initiatives; and to collaborate with other regional cohorts in IEDEA to compare results and address questions of inter-regional importance.

The researchers of the current analysis conducted an observational study of 8374 patients with CD4 T-cell counts of 351 to 500 cells/mm³ to determine if starting antiretroviral therapy earlier than currently recommended guidelines improved survival.² A total of 2473 patients with CD4 T-cell counts between 351 to 500 cells/mm³ (median 420 cells/mm³) initiated antiretroviral therapy, while 5901 patients deferred therapy until the CD4 count was below 350 cells/mm³ (median 275 cells/mm³).

The investigators noted that patients who deferred therapy had a significantly higher risk of death compared with those who initiated therapy early (relative hazard for death 1.7, p<0.001). ² The risk of death fell by approximately 10% as the CD4 count at treatment initiation rose by 100 cells/mm³. The elevated risk of death in patients who deferred therapy was not related to HIV viral load, history of injectable drug abuse, or hepatitis C coinfection. The investigators concluded that these data support the use of antiretroviral treatment for asymptomatic patients at a CD4 count of 500 cells/mm³ or less because of benefits on survival.

Clinical Implications
The current study suggests that initiating antiretroviral therapy earlier reduces the risk of death. The reported reduction was substantial and many asymptomatic patients may be inquiring about starting therapy early. Patients should be told that current practice guidelines support starting HIV treatment when the CD4 T-cell count falls below 350 cells/mm³. Patients should be counseled on the potential benefits and risks of early initiation and the decision to start therapy earlier should continue to be made on an individual basis (see table 1).

It is important for clinicians to know that the current data were observational and not obtained from a randomized controlled trial. The design of the current trial is not strong enough to change clinical practice; however, it does shed some light onto the potential benefits of initiating antiretroviral therapy earlier, such as the potential to reduce mortality. Data from controlled trials are needed before early initiation of antiretroviral therapy can be routinely recommended.

References