Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy

Background: Current antiretroviral treatment can induce significant and sus tained virological and immunological responses in HIV-1-infected persons ov er at least the short- to mid-term. Objectives: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. Methods: Patients enrolled in the INCAS study in The Netherlands were treat ed for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (Z DV) (n = 9), didanosine (ddl) + ZDV (n 10), or NVP + ddl + ZDV (n = 10). Me mory and naive CD4+ and CD8+ T cells were measured using CD45RA and CD27 mo noclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb st imulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cu t-off < 20 copies/ml). Results: Compared to both double combination regimens the triple combinatio n regimen resulted in the most sustained increase in CD4+ T cells (change i n CD4+ + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduc tion of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + d dl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at leas t 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naive and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failur e, and showed improved T-cell function and normalization of the naive: memo ry CD8+ T-cell ratio. However, individual virological success or failure di d not predict the degree of immunological response. T-cell patterns were in dependent of baseline CD4+ T-cell count, T-cell Function, HIV-1 RNA load or age. Low numbers of naive CD4+ T cells at baseline resulted in modest long -term naive T-cell recovery. Conclusions: Patients with prolonged undetectable plasma HIV-1 RNA levels d uring antiretroviral therapy do not invariably show immune restoration. Nai ve T-cell recovery in the setting of complete viral suppression is a gradua l process, similar to that reported for immune recovery in adults after che motherapy and bone marrow transplantation. (C) 1999 Lippincott WiiIiams & W ilkins.