Background:  To assess the effect of different antiretroviral regimens on immunologic recovery in HIV⁺ subjects, large randomized trials are desirable.

Methods:  We randomized 980 antiretroviral-naïve HIV⁺ subjects to start stavudine (d4T)/didanosine (ddI) or zidovudine (AZT)/lamivudine (3TC) with nelfinavir (NFV), efavirenz (EFV) or both NFV and EFV (ACTG 384). In all subjects, CD4 cell counts and plasma viral loads were measured; 623 had additional testing for naïve and memory CD4 phenotype.

Results:  Subjects had a median increase in CD4 cells of 252 at week 96. The mean increase in CD4 count was 11 cells/mm³ per week for the first 8 weeks, followed by a slower steady rise with no evidence of a plateau. In intent-to-treat analysis, initial treatment assignment did not affect the change in CD4 cell counts through week 96.  Subjects assigned to AZT/3TC backbones had a similar increase in CD4 cells as subjects assigned to d4T/ddI start regimens. Subjects initiating regimens with NFV had similar CD4 cell increases as subjects starting regimens with either EFV or NFV/EFV. In univariate regressions, the following were associated with greater CD4 increase:  viral load £ 50 copies/mL (virologic response), greater viral load decline, larger percentage of the way to suppression, higher baseline viral load, and lower baseline CD4 cell count. In a multiple regression model that included baseline CD4 and viral load, virologic response status and initial treatment, only virologic response was associated with a larger increase in CD4 cells. At week 24, of 608 subjects who had a virologic response, 255 (42%) did not have a CD4 increase of > 100 (immunologic response). Of subjects who had a virologic response but not an immunologic response at week 24, 50% of those who maintained a virologic response developed an immunologic response at week 48. In subjects who had memory and naïve phenotyping, there was a greater increase in the memory than in the naïve CD4 cells (median increase 127 and 98, respectively, at week 96, p = 0.002). However, the fold increase in naïve CD4 cells was greater than that for memory CD4 cells (median 2.3- and 1.9-fold, respectively, p = 0.002).

Conclusions:  In this large prospective, randomized trial, there was no significant evidence for a difference in CD4 cell increase based on assignment to different initial treatment regimens. Virologic response was the most important factor associated with CD4 cell rise. About 50% of subjects who had a virologic but not an immunologic response at week 24 subsequently developed an immunologic response at week 48 if they maintained viral suppression. Following therapy, there was a greater fold increase in naïve than in memory CD4 cells.

Keywords: Antiretroviral therapy; Immunologic response; HIV