A randomized study comparing triple versus double antiretroviral therapy or no treatment in HIV-1-infected patients in very early stage disease: the Spanish Earth-1 study

Background: Most current guidelines state that antiretroviral therapy shoul d be considered for HIV-infected patients with plasma HIV RNA > 5000-10000 copies/ml and CD4 cells, 500 x 10(6) cells/l. However, there is increasing concern about whether this is the optimal point to begin treatment or wheth er it is better to delay the initiation to more advanced stages. Objective: To study the immunological and virological benefits of starting antiretrov iral therapy at these early stages. Methods: A total of 161 HIV-infected asymptomatic patients with CD4 cell co unt > 500 x 10(6) cells/l and viral load > 10000 copies/ml were randomly as signed to one of five treatment groups: no treatment, twice daily zidovudin e and thrice daily zalcitabine (ZDV-ddC), twice daily zidovudine and didano sine (ZDV-ddI), twice daily stavudine and didanosine (D4T-ddI), or a twice daily three-drug regimen with stavudine and lamivudine and ritonavir. The e ndpoints were progression to < 350 x 10(6) cells/l CD4 cells, to < 500 x 10 (6) cells/l with either two Centers for Disease Control class B symptoms or an increase of viral load > 0.5 log(10) copies/ml above baseline, or to AI DS or death. In various substudies, the lymphoid tissue and cerebrospinal f luid viral load, development of genotypic resistance, proliferative respons es to mitogens and cytomegalovirus, and HIV-1 specific antigens and other i mmunophenotypic markers were also analysed. Results: Progression rates to study endpoints within 1 year were greater in the control group (31%) than in all groups receiving antiretroviral therap y pooled together (5%; estimated hazard ratio 7.41; 95% confidence interval 5.72-74.55; P < 0.001). The peak mean viral load decrease was greater in t he three-drug group when compared with any of the three groups with a two-d rug regimen (2.32, 1.65, 1.72 and 1.84, respectively; P less than or equal to 0.001). At 1 year, viral load remained below 20 copies/ml in 30 out of 3 3 patients in the three-drug group (91%) and in only eight out of 94 patien ts (9%) in two-drug groups (P = 0.001). The peak mean increase in CD4 cells was also greater in the three-drug group than in the double treatment arms (259 versus 85, 144 and 145 x 10(6) cells/l, respectively; P = 0.001). By comparison, 36% of patients in the three-drug group regimen had to change t he therapy as a result of adverse events. Substudies were performed in GO p atients recruited at two sites. Tonsillar tissue HIV RNA was measured in se ven patients (two in the two-drug groups and five in the three-drug group) in whom plasma HIV RNA was < 20 copies/ml at 1 year. It was 15 151 and 133 333 copies/mg tissue in the two patients from the two-drug group, < 40 copi es/mg tissue in four patients in the three-drug group, and 485 copies/mg in one patient in the three-drug group. At 1 year there was a mean increase o f 4.21 +/- 2.94% in CD8+CD38+ cells in the control group and a decrease of 9.48 +/- 3.36% in the two-drug groups (P = 0.01), and 19.87 +/- 3.64 in the three-drug group (P = 0.001 and P = 0.05, for comparisons with control gro up and two-drug groups, respectively). Although proliferative responses to cytomegalovirus antigens were significantly greater in those receiving anti retroviral therapy, response to HIV-1 p24 antigen was not detected in any p atient in either treatment group. Conclusions: This study supports the recommendation to start antiretroviral therapy with a three-drug combination during very early stages of HIV-1 di sease, at least if viral load is above a cut-off point (10000 copies/ml in our study). The risk of progression was sevenfold higher in non-treated pat ients at 8 months of Follow-up. Some immune system parameters improved towa rd normal values after 1 year of antiretroviral therapy, but the proliferat ive response of CD4 T lymphocytes against the p24 HIV-1 antigen was not rec overed. Therapeutic approaches with more potent, better-tolerated and more convenient regimens will increasingly favour early intervention with antire troviral therapy. (C) 1999 Lippincott Williams & Williams.