Mutational pathways of resistance to inhibitors of integrase (INIs) in patients treated with first generation INIs and their impact in Dolutegravir sensitivity.

Abstract

Background: First generation integrase inhibitors, Raltegravir (RAL) y Elvitegravir (EVG) have proven good efficacy and tolerability in HIV-1 patients. However, clinical studies showed that 60% of highly experienced patients in virological failure develop mutations of resistance to INIs (MARS). The most frequently used INI in Argentina is RAL and it has three major mutational pathways: Y143CHR, Q148HKR and N155H. Both INIs have widely cross resistance, preventing their sequential use while the 2nd generation INI Dolutegravir (DTG), only has cross resistance in Q148HKR together with other secondary mutations. Patients under RAL/EVG accumulate secondary mutations and switch pathways. These events can reduce sensitivity to DTG and therefore, early detection of MARS is critical. Objetives: Determine the prevalence and profile of resistance to INIs in experienced patients in virological failure to regimens including RAL or EVG. Establish the impact to DTG sensitivity for its sequential use. Methods & Materials: We analyzed the genotypic profile of the integrase gene of HIV-1 in 67 highly experienced patients: 33 subtype B, 32 subtype BF and 2 subtype C. All patients were in virological failure to treatments including RAL (66) or EVG (1). RNA was extracted from plasma samples, amplified by RT-PCR of the entire gene (corresponding to 288 amino acids), sequenced and interpreted using the Stanford Database. Results: 46 of the 67 patients showed primary mutations (69%), together with secondary ones, except for 1 case. Six patients showed one or more secondary mutations: T66A (1), L74I (1), T97A (3), G163KR (4). The remaining 15 did not demonstrate MARS. The mutational pathways observed were N155H (24), Y143R (12), Q148HKR (9), E92Q (2). All secondary mutations observed were T66A, L74IM. E92A, T97A, G118D, T121Y, A128 T, E138AD, G140AS, V151I, S153F, E157Q, G163RK. Conclusion: The high prevalence of resistance observed demonstrates that RAL has a low genetic barrier. The frequency of the pathways coincides with the literature and N155H is the most frequently selected. Since Q148H and Y143CR increase resistance and give replicative advantage, tend to replace N155H during treatment. Therefore, early detection is clinically relevant. Most of the patients (80%) that failed to RAL/EVG remain sensitive to DTG.