What Causes Poor CD4-Cell Recovery in the Setting of Suppressive Antiretroviral Therapy?

The best way to raise CD4-cell counts in HIV-infected patients is to control viral replication with potent antiretroviral therapy (ART). However, many patients are unable to achieve a robust increase in CD4 cells despite suppressive therapy, and this lack of immunologic response may place them at increased risk for malignancy, liver disease, cardiovascular disease, and death.

To further explore the causes of poor CD4-cell recovery, researchers conducted a cross-sectional study among 230 patients who were receiving standard ART regimens and had maintained viral loads <50 copies/mL for at least 2 years: 135 had CD4 counts >400 cells/mm³ (the concordant group), and 95 had CD4 counts <350 cells/mm³ (the discordant group).

Compared with the concordant group, the discordant group had the following:

• A lower median nadir CD4 count (71 vs. 234 cells/mm³)

• Greater activation of CD8 cells, as measured by percent expression of CD38, CD95, HLA-DR, and HLA-DR/CD95

• A similar percent expression of CD38 on CD4 cells, but a higher percent expression of CD95, HLA-DR, and CD95/HLA-DR

• Lower naive CD4-cell production

• Increased cell death (mainly by intrinsic apoptosis) in ex-vivo peripheral blood mononuclear cell cultures

• Higher levels of soluble CD14 (sCD14), suggesting increased bacterial translocation, although sCD14 exhibited only a modest correlation with T-cell activation

On multivariate analysis, lower nadir CD4-cell count, greater CD4-cell activation, and increased CD4-cell death were each independently associated with discordant immune response. No association was seen between the specific antiretrovirals used (abacavir/3TC vs. tenofovir/FTC, and protease inhibitors vs. nonnucleoside reverse transcriptase inhibitors) and immune recovery.