Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug

Abstract

All VL changes were well below the clinically relevant variation of 0.5 log copies/mL at the end of the interruption. Thus, this study indicates that, for viruses harbouring one of the two main resistance pathways described for raltegravir, no relevant antiviral activity seems to persist in vivo. Even if further observations would be useful to reinforce this conclusion, the cost/benefit and risk/benefit of maintaining raltegravir as part of a salvage regimen in the presence of raltegravir mutations seem debatable, especially in the absence of relevant antiretroviral activity in this context.

Evolution of Integrase Resistance During Failure of Integrase Inhibitor-Based Antiretroviral Therapy

“…This increase in viremia appeared to occur as genotypic/phenotypic evidence for raltegravir resistance waned, suggesting a possible “fitness benefit.” Notably, this is consistent with observations from the SIV-infected macaque model, where removal of an integrase inhibitor in animals harboring the N155H mutation was associated with initial stable viremia, followed by increases in viremia as the mutation waned 11. Our data, however, are inconsistent with a recent report of 5 subjects with raltegravir failure whose plasma HIV RNA levels remained stable after discontinuation of raltegravir 12. Clearly, more data are necessary to define to what degree integrase inhibitors have residual activity in the context of resistance.…”

HIV-1 Integrase Inhibitor Resistance and Its Clinical Implications

“…Third, the substitution of RAL for lopinavir/ritonavir (LPV/r) in the SWITCHMRK trial in patients with stably suppressed HIV-1 infection was associated with an increased risk of virological rebound [36]. Fourth, although RAL resistance mutations have been associated with decreased replication capacity [25–26], no clinical benefit has been observed from continuing RAL in patients with high-level RAL resistance [37], presumably because most primary RAL resistance mutations occur in combination with accessory compensatory mutations [24–26]. …”

Newly approved integrase inhibitors for clinical treatment of AIDS

“…Resistance profile of RAL to patients infected with HIV-2 has been studied [43]. No residual anti-virus activity of RAL was persisted in patients when strains harbouring one of the two major resistance mutations emerged [44]. Previous studies showed that the mutations of integrase gene were mainly involving position 148 or 155 in cases with virological failure in RAL treatment.…”