Resistance analyses of integrase strand transfer inhibitors within phase 3 clinical trials of treatment-naive patients

Abstract

The integrase (IN) strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), comprise the newest drug class approved for the treatment of HIV-1 infection, which joins the existing classes of reverse transcriptase, protease and binding/entry inhibitors. The efficacy of first-line regimens has attained remarkably high levels, reaching undetectable viral loads in 90% of patients by Week 48; however, there remain patients who require a change in regimen due to adverse events, virologic failure with emergent resistance or other issues of patient management. Large, randomized clinical trials conducted in antiretroviral treatment-naive individuals are required for drug approval in this population in the US, EU and other countries, with the primary endpoint for virologic success at Week 48. However, there are differences in the definition of virologic failure and the evaluation of drug resistance among the trials. This review focuses on the methodology and tabulation of resistance to INSTIs in phase 3 clinical trials of first-line regimens and discusses case studies of resistance.

Figure 1

Resistance analyses and HIV-1 RNA profiles of eight clinical case studies by study visit. Plasma HIV-1 RNA in copies/mL are indicated on the y-axis, with values at 50 copies/mL and 400 copies/mL indicated by the dotted horizontal lines. The time in weeks of the scheduled and unscheduled study visits are indicated on the x-axis. The viral load at each visit is plotted (black circles and black lines). Emergent resistance to the NRTI or INSTI class is indicated at specific visits with an arrow and text. The RAL Protocols use red triangles (), the EVG Protocols blue circles () and the DTG Protocols orange diamonds (). Filled symbols represent the point at which resistance testing would be conducted. Open symbols represent the visit where a patient would be discontinued from study drugs. No R indicates no nucleos(t)ide reverse transcriptase inhibitor (NRTI) or INSTI resistance emerged.