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Background:  The FORTE trial demonstrated a decreased risk of virological failure with an induction strategy of a 4-drug (3-class) followed by a 3-drug regimen compared with a standard 3-drug (2-class) regimen. The mechanism for this treatment benefit remains uncertain.

Methods:  Induction maintenance:  2 nucleoside reverse transcriptase inhibitor (NRTI) + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) + 1 protease inhibitor (PI) for 24 to 32 weeks to reach a viral load of < 50 copies/mL then 2 NRTI + 1 NNRTI was compared with standard therapy:  2 NRTI + 1 NNRTI in treatment-naοve patients. Genotypic resistance tests were performed at baseline and at time of failure if viral load > 400 copies/mL. Viral subtypes were determined from sequence analysis. Proviral DNA (pDNA) was measured at baseline and week 24. Viral RNA decay slope was estimated from multiple samples taken in the first 2 weeks on treatment in a sub-group of participants.

Results:  We randomized 122 patients into the trial (induction maintenance 62, standard therapy 60) and followed up for a median of 81 weeks (IQR 64 to 145):  37 patients experienced virological failure at or after 32 weeks (induction maintenance 11, standard therapy 26). Genotypic resistance results were available at baseline in 104 patients (induction maintenance 52, standard therapy 52) and at virological failure in 17 (induction maintenance 5, standard therapy 12) of 22 with viral load of > 400 copies/mL. Major resistance mutations were detected in 8 patients at baseline (induction maintenance 8%, standard therapy 8%) and in 13 (76%) at failure (induction maintenance 2 [40%], standard therapy 11 [92%]). All 13 had NNRTI resistance. No resistance to PI was detected in the induction maintenance group at failure. The proportion with non-subtype B was similar in the 2 arms (induction maintenance 24%, standard therapy 22%) and less common in the failures (10% vs 28%, p = 0.06). There was no significant difference in mean fall in log₁₀ pDNA:  induction maintenance (n = 25) –0.67 (0.44), standard therapy (n = 22) –0.71(0.35). Neither baseline pDNA nor change from baseline to 24 weeks predicted failure. Baseline characteristics of patients with or without pDNA results were similar. The mean (95% CI) rate of log₁₀ viral RNA decline/day during the first 2 weeks was similar in both groups: induction maintenance (n = 21) –0.14 (–0.16 to –0.12); standard therapy (n = 16) –0.16 (–0.19 to –0.13), difference 0.02 (–0.003  to 0.05), p = 0.08.

Conclusions: The use of a PI in a 3-class induction regimen did not result in the emergence of PI resistance at failure and overall the incidence of resistance was lower with an induction-maintenance strategy. The improved virological efficacy of the induction-maintenance strategy was not explained by differences between the groups in viral sub-type, baseline resistance, change in pro-viral DNA at 6 months or initial rate of viral RNA decay. Further studies of an induction-maintenance strategy are warranted.

Keywords: Antiretroviral Therapy; Resistance; Induction Maintenance