A randomized trial comparing regimens of four reverse transcriptase inhibitors given together or cyclically in HIV-1 infection--the Quattro Trial. Quattro Steering Committee.
OBJECTIVE
To assess if cyclical therapy with four reverse transcriptase inhibitors is less toxic and as active, based on virological and immunological markers, as the same four drugs given together over a 64-week period.


METHODS
An open randomized trial comparing concurrent therapy (T4) with zidovudine, lamivudine, loviride and zalcitabine with the same four drugs given cyclically each for 8 weeks (C4) and with concurrent zidovudine and lamivudine (T2), all given for a total of 64 weeks. The primary endpoint was the change in plasma HIV RNA level from baseline at weeks 32 and 64. Phenotypic 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 between 31 July 1995 and 11 July 1996, of whom 22 had AIDS; the mean (SD) HIV RNA at baseline was 4.9 (0.7) log10 copies/ml and the median (interquartile range) CD4+ cell count was 170 (100-260) x 10(6)/l. A total of 28 T4, 19 C4 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 participants (P = 0.7). Serious adverse events that were likely to be drug related were observed in three T4, one C4 and four T2 participants. The reduction from baseline in HIV-1 RNA (log10 copies/ml) was greatest in the T4 arm; at 32 weeks the mean reduction (SD) was 1.45 (0.72), 0.42 (0.45) and 1.05 (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 pattern of CD4+ change mirrored the changes in HIV RNA. Very few mutations associated with resistance to loviride or zalcitabine were seen. The mutation at codon 215 associated with zidovudine resistance was detected (> 5% of population 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 of viral resistance including phenotypic assays are ongoing and results will be reported separately.
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001835:Body Weight; D018791:CD4 Lymphocyte Count; D018450:Disease Progression; D004334:Drug Administration Schedule; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D019562:Viral Load
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors