Immune restoration in HIV-positive, antiretroviral-naive patients after 1 year of zidovudine/lamivudine plus nelfinavir or nevirapine.

OBJECTIVES: To evaluate the immunological response in HIV-1-infected, antiretroviral-naive patients receiving highly active antiretroviral therapy regimen of two nucleosides plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. DESIGN AND METHODS: Of 142 patients included in a randomized, open, multicentre trial comparing zidovudine/lamivudine plus nelfinavir (NFV) or nevirapine (NVP), 36 patients (16 NFV, 20 NVP) were enrolled in an immunological substudy. Mean baseline CD4 T-cell counts was 360/mm3 (range: 11-679) and mean baseline plasma viral load >50000 copies/ml (range: 2240-1468210). Viral load (VL), T-cell subsets and T-cell functions were analysed at baseline and after 1 year of treatment. RESULTS: After 12 months of follow-up, plasma viral load was reduced similarly in both groups, with 78% (NFV) and 83% (NVP) of patients achieving a VL <200 copies/ml. A significant increase in CD4 T cells was observed in both groups (mean: +182 cells, P=0.001). Both regimens were similarly effective in reducing activated T cells (CD38 and DR). A significant increase of both CD4 and CD8 CD28 T cells occurred in both arms of treatment. Patients of both regimens showed a significant decrease of activated memory (CD45RA-CD45RO+) CD8 T cells and a clear increase of naive (CD45RA+CD45RO-) CD8 T cells. Peripheral blood mononuclear cell proliferative responses to polyclonal stimuli (CD3 and CD3 +CD28) as well as to ubiquitous cytomegalovirus antigen increased significantly in both groups after 12 months of follow-up. Nevertheless, neither at baseline nor after 1 year of treatment, these patients showed any significant T-cell responsiveness to HIV-1 recombinant proteins gp160 or p24. CONCLUSIONS: Our data indicate that immune restoration achieved after 1 year of therapy with either NFV or NVP was similar. This reinforces the role of NVP-containing regimens as a valid option for initiating antiretroviral therapy. Nevertheless, additional therapeutic approaches should be envisaged to restore HIV-1-specific T-cell responses.

Immunologic reconstitution after 1 year of highly active antiretroviral therapy, with or without protease inhibitors.

OBJECTIVES: To assess the effectiveness of two triple antiretroviral combinations (2 nucleoside reverse transcriptase inhibitors [NRTIs] + 1 protease inhibitors [PI] vs. 2 NRTIs + 1 nonnucleoside reverse transcriptase inhibitor [NNRTI]) to correct T-cell subsets abnormalities and to restore immune functions in asymptomatic antiretroviral-naive HIV-1-infected patients with a baseline CD4 T-cell counts >500/mm3 and plasma viral load >5000 copies/mL. DESIGN AND METHODS: Twenty randomized patients from 2 cohort studies receiving either stavudine (d4T) + lamivudine (3TC) + indinavir (n = 9), or d4T + didanosine (ddI) + nevirapine (NVP) (n = 11) were studied. Viral load, T-cell subsets and T-cell functions were analyzed at baseline and after 1 year of treatment. RESULTS: After 1 year of follow-up, the PI regimen was significantly more effective in reducing plasma and lymphoid tissue VL to undetectable levels. A significant increase in CD4+ T cells was observed in patients treated with PI (p =.0007) compared with those treated with NVP. Percentages of CD8+ T-cells and of activated CD8+ T-cells (CD38+ and DR+ as well as memory CD45RO+) decreased in all patients. An increase of the CD28+ subset of CD8+ T-cells also occurred in both groups of treatment. Naive T cells were maintained in the CD4+ subset and augmented in the CD8+ subset in all patients. In both PI and NVP groups, memory CD4+ T-cells increased significantly (p =.03). Peripheral blood mononuclear cell responsiveness to polyclonal stimuli and to tetanus toxoid and cytomegalovirus (CMV) antigen was similar in both groups of treatment. HIV-infected patients treated for 1 year with both triple combinations lacked significant T-cell responsiveness to HIV-1 proteins. CONCLUSIONS: These data suggest that immune reconstitution achieved after 1 year of therapy with PI-containing or PI-sparing regimens is similar, despite the higher effectiveness of PI-containing regimens in reducing viral load. Additional therapeutic approaches should be designed to restore HIV-1-specific responses.