A randomized trial comparing regimens of four reverse transcriptase inhibitors given together or cyclically in HIV-1 infection - The Quattro Trial

Objectives: To assess if cyclical therapy with four reverse transcriptase i nhibitors is less toxic and as active, based on virological and immunologic al markers, as the same four drugs given together over a 64-week period. Methods: An open randomized trial comparing concurrent therapy (T4) with zi dovudine, lamivudine, loviride and zalcitabine with the same four drugs giv en cyclically each for 8 weeks (C4) and with concurrent zidovudine and lami vudine (T2), all given for a total of 64 weeks. The primary endpoint was th e change in plasma HIV RNA level from baseline at weeks 32 and 64. Phenotyp ic and genotypic resistance, CD4+ cell counts, and clinical and laboratory assessments of safety were also compared. Patients were followed for up to a further 32 weeks beyond 64 weeks. Eligible patients had CD4+ cell counts between 50 and 350 x 10(6)/l and no prior antiretroviral therapy. Results: One hundred individuals (34 T4, 34 C4, 32 T2) were recruited betwe en 31 July 1995 and 11 July 1996, of whom 22 had AIDS; the mean (SD) HIV RN A at baseline was 4.9 (0.7) log(10) copies/ml and the median (interquartile range) CD4+ cell count was 170 (100-260) x 10(6)/l. A total of 28 T4, 19 C 4 and 26 T2 participants were still on the allocated regimen at week 64. A new AIDS event or death was reported in three T4, seven C4 and five T2 part icipants (P = 0.7). Serious adverse events that were likely to be drug rela ted were observed in three T4, one C4 and four T2 participants. The reducti on from baseline in HIV-1 RNA (log(10) copies/ml) was greatest in the T4 ar m; at 32 weeks the mean reduction (SD) was 1.45 (0.72), 0.42 (0.45) and 1.0 5 (0.70) in T4, C4 and T2 respectively (global P = 0.0001) and at week 64 1 .24 (0.86), 0.73 (0.91) and 0.78 (0.55) respectively (P = 0.02). The patter n of CD4+ change mirrored the changes in HIV RNA. Very few mutations associ ated with resistance to loviride or zalcitabine were seen. The mutation at codon 215 associated with zidovudine resistance was detected (>5% of popula tion mutant) in 11 out of 24 T4 participants compared with three out of 21 C4 and 11 out of 20 T2 participants at week 64 (P = 0.02). Further assays o f viral resistance including phenotypic assays are ongoing and results will be reported separately. (C) 1999 Lippincott Williams & Wilkins.