Emergent drug resistance with integrase strand transfer inhibitor-based regimens

Lepik, Katherine J; Harrigan, P. Richard; Yip, Benita; Wang, Lu; Robbins, Marjorie; Zhang, Wendy W.; Toy, Junine; Akagi, Linda; Lima, Viviane D.; Guillemi, Silvia; Montaner, Julio S. G.; Barrios, Rolando

doi:10.1097/qad.0000000000001494

Cited by 90 publications

(71 citation statements)

References 26 publications

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“…Overall, the mutation pattern Q148H/K/R plus at least one of G140A/C/S and E138A/K/T conferring resistance to DTG was detected in 15% of patients, without differences between groups, this rate being similar to those observed in randomized clinical trials and observational cohorts enrolling heavily pretreated patients . R263K was not observed in our setting, which is in line with its rare detection in clinical practice .…”

Section: Discussionsupporting

confidence: 88%

Prevalence and determinants of resistance mutations in HIV‐1‐infected patients exposed to integrase inhibitors in a large Italian cohort

et al. 2018

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Objectives The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)‐experienced HIV‐1‐infected patients and its predictors. Methods We selected HIV‐1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI‐experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by χ2 test and predictors of resistance were analysed by logistic regression. Results We included 462 genotypes from INSTI‐exposed individuals: 356 ‘INSTI‐failing' patients and 106 ‘previously INSTI‐exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17–110 weeks]). Overall, at least low‐level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non‐B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008–2009. Conclusions The results support integrase resistance testing in INSTI‐experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation.

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Section: Discussionsupporting

confidence: 88%

Prevalence and determinants of resistance mutations in HIV‐1‐infected patients exposed to integrase inhibitors in a large Italian cohort

et al. 2018

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“…HIV-1 readily develops resistance to RAL and EVG both in vitro and in vivo as a result of mutations in IN; however, DTG is more difficult for the virus to escape (42,60,61). Recently, IN-R263K has emerged in ARV-experienced, INSTI-naïve patients experiencing virological failure on a DTG regimen and in a patient during DTG monotherapy (62)(63)(64). IN-R263K confers weak DTG resistance but, interestingly, can spread in culture in the context of cell-to-cell transmission (32,65).…”

Section: Discussionmentioning

confidence: 99%

Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle

Duyne

Kuo

Pham

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The p6 domain of HIV-1 Gag contains highly conserved peptide motifs that recruit host machinery to sites of virus assembly, thereby promoting particle release from the infected cell. We previously reported that mutations in the YPXnL motif of p6, which binds the host protein Alix, severely impair HIV-1 replication. Propagation of the p6–Alix binding site mutants in the Jurkat T cell line led to the emergence of viral revertants containing compensatory mutations not in Gag but in Vpu and the envelope (Env) glycoprotein subunits gp120 and gp41. The Env compensatory mutants replicate in Jurkat T cells and primary human peripheral blood mononuclear cells, despite exhibiting severe defects in cell-free particle infectivity and Env-mediated fusogenicity. Remarkably, the Env compensatory mutants can also rescue a replication-delayed integrase (IN) mutant, and exhibit reduced sensitivity to the IN inhibitor Dolutegravir (DTG), demonstrating that they confer a global replication advantage. In addition, confirming the ability of Env mutants to confer escape from DTG, we performed de novo selection for DTG resistance and observed resistance mutations in Env. These results identify amino acid substitutions in Env that confer broad escape from defects in virus replication imposed by either mutations in the HIV-1 genome or by an antiretroviral inhibitor. We attribute this phenotype to the ability of the Env mutants to mediate highly efficient cell-to-cell transmission, resulting in an increase in the multiplicity of infection. These findings have broad implications for our understanding of Env function and the evolution of HIV-1 drug resistance.

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“…In the ACTG A5353 study investigating the use of DTG plus 3TC in treatment-naive participants, one participant developed M184V in RT plus the DTG-selected mutation R263R/K in IN (22). The mutation R263K has additionally been reported in four patients who were ART experienced but INSTI naive and received a DTG-containing regimen (23,24). Other mutations, including Q148H/R, N155H, G118R, S230R, and R263K, have been reported following failure after DTG monotherapy (25)(26)(27).…”

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confidence: 99%

Resistance Analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 Weeks

Acosta

Willkom

Martin

et al. 2019

Antimicrob Agents Chemother

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In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravirabacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTGϩF-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.Of the 1,421 participants with screening genotypes, only 3 had protocol-defined exclusion mutations (1 with M184V, 1 with M184M/V, and 1 with M184V, M41L, L210W, T215F/Y, and K219Q in RT) and were excluded for drug resistance reasons. The studies enrolled and dosed 1,274 participants who showed full sensitivity to FTC and TAF based on the proprietary genotypic algorithm from Monogram Biosciences. No participant had HIV-1 with the tenofovir or FTC-3TC resistance-associated substitutions K65R/E/N or M184V/I, respectively, according to the population genotype at screening. Retrospective deep-sequencing analyses of PR, RT, and integrase (IN) were performed on baseline samples of enrolled participants using the deepType HIV assay (Seq-IT GmbH & Co. KG, Kaiserslautern, Germany), and resistance mutations seen at frequencies of Ն15% were tabulated and combined with population sequencing results (Table 1). The 15% cutoff was chosen to mirror population sequencing thresholds and to ensure that mutations were above the background error of the assay. Primary NRTI resistance (NRTI-R) substitutions were observed in 2.7% (35 of 1,274) of participants, and the most frequent substitutions were M41L and K219E/N/Q/R in RT. These are thymidine analog resistance mutations (TAMs) and remain sensitive to FTC and tenofovir when fewer than three TAMs are present (7). Although not detected by population sequencing at screening, K65R/E was observed by deep sequencing above the 15% threshold in three participants (two with K65E in the B-F-TAF group; frequencies of 15% to 23%). Primary NNRTI resistance (NNRTI-R) substitutions were observed in 14.1% (179 of 1,274) of participants, and the most frequent substitutions were K103N/S and E138A/G/K/Q in RT. Primary protease inhibitor (PI) resistance substitutions were observed in 3.5% (44 of 1,274) of participants, and the most frequent substitutions were M46I/L, Q58E, and L90M in PR. The frequencies of baseline-transmitted resistance to antiretrovirals (ARVs) were consistent with findings of other reports (8-10).No genotyping of HIV integrase (IN) was conducted at screening in studies 1489 and 1490. However, retrospective baseline IN genotypic data...

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Emergent drug resistance with integrase strand transfer inhibitor-based regimens

Cited by 90 publications

References 26 publications

Prevalence and determinants of resistance mutations in HIV‐1‐infected patients exposed to integrase inhibitors in a large Italian cohort

Prevalence and determinants of resistance mutations in HIV‐1‐infected patients exposed to integrase inhibitors in a large Italian cohort

Mutations in the HIV-1 envelope glycoprotein can broadly rescue blocks at multiple steps in the virus replication cycle

Resistance Analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 Weeks

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