Comparison of immunologic restoration and virologic response in plasma, tonsillar tissue, and cerebrospinal fluid in HIV-1-infected patients treated with double versus triple antiretroviral therapy in very early stages: The Spanish Earth-2 Study

The objective of antiretroviral therapy is to obtain an almost complete and durable suppression of viral replication in all compartments to facilitate recovery of the immune system. We assessed the virologic effect in plasma, tonsillar tissue, and cerebrospinal fluid (CSF) in 94 HIV-1-infected patie nts with CD4 counts >500 x 10 degrees cells per liter and viral load >5000 copies/ml randomly assigned to triple antiretroviral therapy (two nucleosid e reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor) ver sus double therapy (two NRTIs). We also analyzed the immunologic recovery i n this cohort of patients. Lymphoid tissue and cerebrospinal fluid viral le nd, development of genotypic resistance, proliferative responses to HIV-1 s pecific antigens, and other immunophenotypic markers were analyzed. The pro portion of patients who achieved a decrease in HIV RNA levels to <200 copie s/ml was significantly greater in the triple therapy group than in the two drug groups (p = .0002 for each pair-wise difference). At week 52, tonsilla r tissue HIV RNA from 5 patients treated with triple therapy was lower than the limit of detection, whereas the mean +/- standard error in patients wi th double therapy (n = 5) was 5.03 +/- 0.34 copies/mg/tissue. Tn all 10 pat ients, CSF viral load (VL) was <20 HIV-1 RNA copies/ml at week 52. CSF cell counts and protein levels tended to decrease after 52 weeks of antiretrovi ral therapy. After 1 year of therapy, 13 of 21 patients (62%) in the double -therapy groups (zidovudine plus lamivudine [n = 9] and stavudine plus lami vudine [n = 12]) had evidence of M184V mutation. None of the 10 samples of patients receiving triple therapy could be amplified because of low HIV RNA levels. The mean increase in CD4 cells at week 52 was greater in the stavu dine and lamivudine and indinavir group than in the double-treatment arms ( 186 versus 67 and 102, respectively; p = .03). In patients treated with tri ple therapy, the increase in naive T cells (CDS and CD8) was greater than i n patients treated with double therapy. Markers of activation decreased fur ther in patients treated with the regimen that included protease inhibitors . Proliferative responses to HIV-1 p24 antigen were never recovered after d ouble or triple therapy. Our study suggests that even in very early stages of HIV-1 disease only therapy with two NRTIs and one protease inhibitor red uces plasma, lymphoid tissue, and CSF VL to undetectable levels. HIV-1-rela ted immune system abnormalities improved but were still defective after 1 y ear of antiretroviral therapy.