Abstract
T97A is an HIV-1 integrase polymorphism associated with integrase strand transfer inhibitor (INSTI) resistance. Using pooled data from 16 clinical studies, we investigated the prevalence of T97A (pre-existing and emergent) and its impact on INSTI susceptibility and treatment response in INSTI-naive patients who enrolled on elvitegravir (EVG)- or raltegravir (RAL)-based regimens. Prior to INSTI-based therapy, primary INSTI resistance-associated mutations (RAMs) were absent and T97A pre-existed infrequently (1.4%; 47 of 3367 integrase sequences); most often among non-B (5.3%) than B (0.9%) HIV-1 subtypes. During INSTI-based therapy, few patients experienced virologic failure with emergent INSTI RAMs (3%; 122 of 3881 patients), among whom T97A emerged infrequently in the presence (n = 6) or absence (n = 8) of primary INSTI RAMs. A comparison between pre-existing and emergent T97A patient populations (i.e., in the absence of primary INSTI RAMs) showed no significant differences in EVG or RAL susceptibility in vitro. Furthermore, among all T97A-containing viruses tested, only 38–44% exhibited reduced susceptibility to EVG and/or RAL (all of low magnitude; <11-fold), while all maintained susceptibility to dolutegravir. Of the patients with pre-existing T97A, 17 had available clinical follow-up: 16 achieved virologic suppression and 1 maintained T97A and INSTI sensitivity without further resistance development. Overall, T97A is an infrequent integrase polymorphism that is enriched among non-B HIV-1 subtypes and can confer low-level reduced susceptibility to EVG and/or RAL. However, detection of T97A does not affect response to INSTI-based therapy with EVG or RAL. These results suggest a very low risk of initiating INSTI-based therapy in patients with pre-existing T97A.
Highlights
Combination antiretroviral therapy has revolutionized HIV/AIDS management, reducing viral burden and HIV-related morbidity and mortality rates [1]
The remaining patients (799 of 3881; 21%) were highly TE, but integrase strand transfer inhibitor (INSTI) treatment-naive, with pre-existing antiretroviral resistance and enrolled on ritonavir-boosted EVG or RAL, each administered with a background regimen containing a fully active ritonavir-boosted protease inhibitors (PIs) and an active or inactive second agent
As part of study-specific prospective screening requirements or retrospective ad hoc baseline analyses, INSTInaive patients were analyzed for pre-existing resistance in integrase, including patients that did not enroll on INSTI-based treatment arms
Summary
Ethics statementWritten informed consent was obtained from all patients prior to any study-related procedures. Clinical investigation in each of the following previously published clinical studies was conducted according to the principles expressed in the Declaration of Helsinki and the guidelines of the International Conference on Harmonisation Good Clinical Practice. As indicated below, these studies were conducted at multiple study centers/sites in multiple countries and were approved by a central institutional review board (Chesapeake IRB, Columbia, MD) and site-specific institutional review boards/ethics committees. Eligible patients were required to be INSTI-naive with screening plasma HIV-1 RNA of at least 500 copies/mL (COBAS Amplicor HIV-1 Monitor Test, v1.5; Roche Diagnostics, Basel, Switzerland). INSTI-naive and INSTI-treated patients received, in their optimized regimen, at least one NRTI, one boosted PI, and/or one NNRTI plus, for some of them, maraviroc (MVC) or enfuvirtide (ENF)
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