Background:  Previous work suggests differential HAART-associated CD4⁺ T cell reconstitution in Africans than in other populations, but the mechanism remains unclear.

Methods:  The parent study population consists of 301 treatment-naïve patients followed for 48 weeks in a randomized clinical trial of 3 different doses of atazanavir vs nelfinavir plus didanosine and stavudine (BMS-424-007). We herein report on detailed immunologic analyses in a subset of 79 study subjects. Data are presented as medians. Nonparametric statistics were used throughout; a p value £0.05 was considered significant.

Results:  South Africans had reduced CD4⁺ T cell reconstitution at 48 weeks than North Americans (109 vs 162 cells/mm³, p <0.001), despite a higher proportion of complete virologic responses. South African subjects in the immunology substudy exhibited a similar pattern, and had lower CD4⁺ T-cell counts at every time point during the study period, even after controlling for baseline CD4 (estimated difference/week 30 cells/mm³, 95% CI, 6 to 54, p = 0.01). These differences were largely driven by differences in naïve T-cell increase, which was significantly greater among North Americans from week 24 on (53 vs 32 cells/mm³, p = 0.05); memory CD4⁺ T cell increases were similar in the 2 groups. Overall CD4⁺ and CD8⁺ T cell activation declined consistently during the study period. Among South Africans, the proportion of activated CD8⁺ T cells was greater at baseline (40 vs 24%, p = 0.05), and remained higher through week 48 (14 vs 5%, p = 0.03); this trend persisted in analyses restricted to subjects with complete virologic response. CD4 activation showed a similar pattern. CD4 and CD8 activation levels showed a strong inverse correlation with CD4⁺ T cell count both at baseline (r = –0.66 and r = –0.49, respectively, p<0.01) and at subsequent time points.

Conclusions:  Despite better virologic response, South African subjects exhibited smaller total and naïve CD4 cell count increases in response to an initial HAART regimen, compared with North Americans. These differences were accompanied by strikingly higher levels of CD4 and CD8 activation among South Africans, which persisted through 48 weeks of follow-up and correlated inversely with CD4⁺ T cell count at most time points. Heightened immune activation, perhaps reflecting increased cellular turnover or persistence in tissue, may underlie the disparity in HAART-associated immune reconstitution seen in certain patient groups.