Delaying ART in patients with HIV reduces likelihood of restoring CD4 counts

The goal of ART has been focused primarily on achieving an undetectable HIV viral load (VL) because not doing so has been associated with impaired immune recovery. However, a specific CD4+ T-cell count as a target for optimal immunologic health has not been validated nor has an interval from infection to ART initiation that promotes this goal been established.

Jason F. Okulicz, M.D., of the Uniformed Services University of Health Sciences, Bethesda, Md., and colleagues examined the timing of ART relative to HIV infection on the normalization of CD4+ T-cell counts, risk of AIDS development, and immune function. The authors evaluated participants in the U.S. Military HIV Natural History Study with documented EDS who achieved virologic suppression with ART. Normalization of CD4+ T-cell counts was to 900 cells/μL or higher.

Results show that among 1,119 HIV-infected patients, 38.4 percent achieved CD4+ normalization after initiating ART within 12 months of the EDS vs. 28.3 percent of patients who initiated ART after 12 months. Patients with CD4+ counts of 500 cells/μL or higher when they entered the study or started ART had increased CD4+ normalization rates compared with other patients with HIV. However, even among patients with CD4+ counts of 500 cells/μL or higher at both entry to the study and before ART, the odds of CD4+ normalization were lower in those patients who initiated ART after 12 months from the EDS and study entry.

Researchers also found that starting ART within 12 months of EDS instead of later was associated with a lower risk of AIDS (7.8 percent vs. 15.3 percent), reduced T-cell activation and increased responsiveness to the hepatitis B virus (HBV) vaccine.

"Achieving CD4+ normalization is an imminently feasible therapeutic goal, provided ART is started within 12 months of the EDS at higher CD4+ counts (greater than or equal to 500 cells/μL). The importance of a public health strategy that includes frequent HIV testing in persons at risk and prompt initiation of ART after diagnosis is underscored by two findings: the rate of unwitnessed CD4+ count decline that occurs in the interval between HIV acquisition and diagnosis cannot be predicted, and the duration of the infection cannot be predicted by the CD4+ count. This strategy may offer the best chance for rapidly terminating the progressive immune damage (eg. lymphoid tissue fibrosis) that constrains optimal immune reconstitution with ART," the study concludes.

Commentary: Defining Success with Antiretroviral Therapy

In a related commentary, Timothy W. Schacker, M.D., of the University of Minnesota, Minneapolis, writes: "This important study reminds us that the goal of HIV therapy should be full restoration of immune function and not just suppression of viral replication. Okulicz and colleagues have provided the clearest signal to date that we will not restore immunity with the drugs we have available. Under ideal conditions only approximately one-third of the patients who receive treatment could achieve this goal. Most of the 35 million people infected with HIV live in conditions where only a few will have the opportunity to start therapy within 12 months of seroconversion. We need better formulations of antiretroviral drugs that fully suppress virus replication in tissues. However, we also need adjunctive therapies that eliminate the causes of persistent immune activation and restore lymphoid tissues to their normal anatomy and function."