Objective: To ascertain whether delaying the initiation of highly active antiretroviral therapy (HAART) compromises functional immune reconstitution in HIV-1 infection in persons who regain ‘normal’ CD4 T-cell counts after suppressive antiretroviral therapies.
Design: Prospective open-label study carried out at two University-affiliated HIV-outpatient clinics in the USA.
Subjects: and methods: Response to immunization was used as a model for in vivo functional immune competence in 29 HIV-1 infected patients with CD4 T-cell counts > 450 × 106cells/l and HIV-RNA < 400 copies/ml for > 12 months after HAART and nine HIV-1 seronegative controls. After immunization with tetanus toxoid, diphtheria-toxoid, and keyhole limpet hemocyanin, immune response scores (IRS) were calculated using postimmunization antibody concentrations, lymphocyte proliferation, and delayed-type hypersensitivity responses to vaccine antigens.
Results: Despite normal numbers of circulating CD4 T-cells, the CD4 T-cell nadir before HAART initiation predicted the immune response to immunization (ρ = 0.5; P < 0.005) while current CD4 T-cell count did not. Likewise, CD4 T-lymphocyte expression of the co-stimulatory molecule CD28 was also an independent predictor of response to immunization (ρ = 0.5; P < 0.005).
Conclusions: Even among persons who controlled HIV replication and normalized CD4 T-cell counts with HAART, pretreatment CD4 T-cell count and numbers of circulating CD4+CD28+ T-cells at immunization, but not current CD4 T-cell count, predict the ability to respond to vaccination. Delaying the initiation of HAART in chronic HIV-1 infection results in impaired functional immune restoration despite normalization of circulating CD4 T-cell numbers.
From the Center for AIDS Research, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, and aMetroHealth Medical Center, Cleveland, Ohio, USA.
Dr. Lange is currently affiliated with the Medical Clinic of the Borstel Research Center, Germany.
Correspondence to M. M. Lederman, Case Western Reserve University, University Hospitals of Cleveland, Department of Medicine, Division of Infectious Diseases, 2061 Cornell Rd. Room 301 C, Cleveland, OH 44106, USA.
Note: Presented in part at the Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, February 2002 and the XIV International Conference on AIDS, Barcelona, July 2002.
Dedication: This manuscript is dedicated to the late Linda Grinberg whose enthusiastic support made this work possible.
Received: 7 November 2002; revised: 13 March 2003; accepted: 8 April 2003.