scholarly journals Emergence of Resistance in HIV-1 Integrase With Dolutegravir Treatment in a Pediatric Population From the IMPAACT P1093 Study

2021 ◽  
Author(s):  
Cindy Vavro ◽  
Theodore Ruel ◽  
Andrew Wiznia ◽  
Nicole Montañez ◽  
Keith Nangle ◽  
...  
Keyword(s):  
Virologic Failure ◽  
Pediatric Population ◽  
Resistance Mechanisms ◽  
Replication Capacity ◽  
Strand Transfer ◽  
Open Label ◽  
Structural Examination ◽  
Open Label Phase ◽  
Transfer Inhibitor ◽  
Hiv 1

P1093 is a multicenter, open-label, phase I/II study of pharmacokinetics, safety, and tolerability of dolutegravir plus an optimized background regimen in pediatric participants aged 4 weeks to <18 years with HIV-1. Most participants were highly treatment experienced. We report the mechanisms of emergent integrase strand transfer inhibitor (INSTI) resistance among adolescents and children receiving dolutegravir. Plasma was collected at screening and near protocol-defined virologic failure (PDVF) for population- and, for some samples, clonal-level integrase genotyping, phenotyping, and replication capacity. HIV-1 RNA was assessed in all available plasma samples. Phylogenetic analysis of clonal integrase sequences and homology modeling of HIV-1 intasome complexes containing resistance-associated substitutions were performed. Treatment-emergent INSTI resistance was detected in 8 participants who met PDVF criteria. Rare INSTI resistance-associated substitutions G118R or R263K developed in 6 participants. On-study secondary integrase substitutions E157Q or L74I were observed in 2 participants. G118R reduced dolutegravir susceptibility and integrase replication capacity greater than R263K and demonstrated greater reduction in susceptibility and integrase replication capacity when present with specific secondary integrase substitutions, including L74M, T66I, and E138E/K. Continuing evolution after R263K acquisition led to reduced dolutegravir susceptibility and integrase replication capacity. Structural examination revealed potential mechanisms for G118R- and R263K-mediated INSTI resistance. G118R or R263K INSTI resistance substitutions, which are distinct to second-generation INSTIs, were detected in adolescents and children with prior virologic failure who received dolutegravir. This study provides additional molecular and structural characterization of integrase to aid in the understanding of INSTI resistance mechanisms in antiretroviral-experienced populations (ClinicalTrials.gov identifier: NCT01302847).

scholarly journals Impact of Primary Elvitegravir Resistance-Associated Mutations in HIV-1 Integrase on Drug Susceptibility and Viral Replication Fitness

2013 ◽  
Vol 57 (6) ◽  
pp. 2654-2663 ◽  
Author(s):  
Michael E. Abram ◽  
Rebecca M. Hluhanich ◽  
Derrick D. Goodman ◽  
Kristen N. Andreatta ◽  
Nicolas A. Margot ◽  
...  
Keyword(s):  
Viral Replication ◽  
Drug Susceptibility ◽  
Viral Fitness ◽  
Cross Resistance ◽  
Replication Capacity ◽  
Strand Transfer ◽  
Recombinant Viruses ◽  
Transfer Inhibitor ◽  
Replication Fitness ◽  
Hiv 1

ABSTRACTElvitegravir (EVG) is an effective HIV-1 integrase (IN) strand transfer inhibitor (INSTI) in advanced clinical development. Primary INSTI resistance-associated mutations (RAMs) at six IN positions have been identified in HIV-1-infected patients failing EVG-containing regimens in clinical studies: T66I/A/K, E92Q/G, T97A, S147G, Q148R/H/K, and N155H. In this study, the effect of these primary IN mutations, alone and in combination, on susceptibility to the INSTIs EVG, raltegravir (RAL), and dolutegravir (DTG); IN enzyme activities; and viral replication fitness was characterized. Recombinant viruses containing the six most common mutations exhibited a range of reduced EVG susceptibility: 92-fold for Q148R, 30-fold for N155H, 26-fold for E92Q, 10-fold for T66I, 4-fold for S147G, and 2-fold for T97A. Less commonly observed primary IN mutations also showed a range of reduced EVG susceptibilities: 40- to 94-fold for T66K and Q148K and 5- to 10-fold for T66A, E92G, and Q148H. Some primary IN mutations exhibited broad cross-resistance between EVG and RAL (T66K, E92Q, Q148R/H/K, and N155H), while others retained susceptibility to RAL (T66I/A, E92G, T97A, and S147G). Dual combinations of primary IN mutations further reduced INSTI susceptibility, replication capacity, and viral fitness relative to either mutation alone. Susceptibility to DTG was retained by single primary IN mutations but reduced by dual mutation combinations with Q148R. Primary EVG RAMs also diminished IN enzymatic activities, concordant with their structural proximity to the active site. Greater reductions in viral fitness of dual mutation combinations may explain why some primary INSTI RAMs do not readily coexist on the same HIV-1 genome but rather establish independent pathways of resistance to EVG.

scholarly journals Virologic failure after 48 weeks of raltegravir-based regimen in low HIV-1 incidence setting

2020 ◽  
Vol 28 ◽  
pp. 204020662092790
Author(s):  
Wassim Chehadeh ◽  
Osama Albaksami ◽  
Shaikhah Al-Shammari
Keyword(s):  
Salvage Therapy ◽  
Virologic Failure ◽  
Strand Transfer ◽  
Adherence To Treatment ◽  
First Line ◽  
Transfer Inhibitor ◽  
High Level ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1 ◽  
Level Resistance

Background With the advent of next generation integrase strand transfer inhibitors, the rates of virologic failure in treated subjects are expected to decrease. In this study, we analyzed the mutation patterns leading to virologic failure before and after starting integrase strand transfer inhibitor-based regimen as first-line or salvage therapy. Methods Between 2016 and 2019, blood samples were received from 258 patients with HIV-1 infection. Plasma HIV-1 RNA concentrations, and pol gene sequences were determined at baseline, and 16–48 weeks of treatment with integrase strand transfer inhibitor-based regimen. Only patients who did not achieve viral suppression at 48 weeks of integrase strand transfer inhibitor-based treatment were eligible for the current study. Results Virologic failure was observed in seven patients on raltegravir-based regimen. All patients with virologic failure but one were infected with CRF01_AE virus subtype. Raltegravir based-regimen was offered as first-line therapy for four patients, and as salvage therapy for three patients. M184V mutation associated with high level resistance to lamivudine and emtricitabine was detected in six out of seven patients. Primary mutations (Y143C, N155H, T66I, G118R, E138K) conferring high level resistance to raltegravir were detected in only three patients. Pre-existing polymorphic integrase mutation (T97A) was detected in two patients. Furthermore, two patients reported low adherence to treatment. Conclusions Emergence of primary mutations in the integrase gene can account for virologic failure in less than half of patients on raltegravir-based regimen. Low adherence to treatment, pre-existing accessory mutations, and resistance to reverse transcriptase inhibitors may have some role in virologic outcome.

scholarly journals HIV-1 Subtype C Drug Resistance Mutations in Heavily Treated Patients Failing Integrase Strand Transfer Inhibitor-Based Regimens in Botswana

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 594
Author(s):  
Kaelo K. Seatla ◽  
Dorcas Maruapula ◽  
Wonderful T. Choga ◽  
Tshenolo Ntsipe ◽  
Nametso Mathiba ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virologic Failure ◽  
Resistance Testing ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Subtype C ◽  
Genotypic Resistance Testing ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1

There are limited real-world mutational and virological outcomes data of treatment-experienced persons diagnosed with HIV-1 subtype C (HIV-1 C) who are failing Integrase Strand Transfer Inhibitor-based regimens. Requisition forms sent for HIV-1 genotypic resistance testing (GRT) between May 2015 and September 2019 were reviewed and participants experiencing virologic failure while on dolutegravir (DTG) or raltegravir (RAL) cART at sampling recruited. Sanger sequencing of the HIV-1 Pol gene was performed from residual plasma samples and drug resistance mutational (DRM) analysis performed using the Stanford University HIV drug resistance database. 40 HIV-1C integrase sequences were generated from 34 individuals, 24 of whom were on DTG cART, three on RAL cART and seven on an unknown (DTG or RAL)-anchored cART at time of GRT. 11/34 (32%) individuals had DRMs to DTG and other integrase inhibitors. 7/11 (64%) patients had exposure to a RAL-based cART at the time of sampling. Out of the 11 individuals with DRMs, one (9%) had 2-class, 6 (55%) had 3-class, and 4 (36%) had 4-class multidrug-resistant HIV-1C. 7/11 individuals (64%) are currently virologically suppressed. Of the four individuals not virologically suppressed, three had extensive DRMs involving 4-classes of ARV drugs and one individual has demised. Resistance to DTG occurs more often in patients exposed to RAL cART. Individuals with 4-class DRMs plus integrase T97 and E157Q mutations appear to have worse outcomes. There is a need for frequent VL monitoring and GRT amongst treatment-experienced HIV-1C diagnosed individuals.

scholarly journals Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor

2010 ◽  
Vol 84 (18) ◽  
pp. 9210-9216 ◽  
Author(s):  
Tamara Bar-Magen ◽  
Richard D. Sloan ◽  
Daniel A. Donahue ◽  
Björn D. Kuhl ◽  
Alexandra Zabeida ◽  
...  
Keyword(s):  
Viral Replication ◽  
First Generation ◽  
Second Generation ◽  
Integrase Inhibitor ◽  
Replication Capacity ◽  
Strand Transfer ◽  
Viral Replication Capacity ◽  
Transfer Inhibitor ◽  
Potential Basis

ABSTRACT MK-2048 represents a prototype second-generation integrase strand transfer inhibitor (INSTI) developed with the goal of retaining activity against viruses containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). Here, we report the identification of mutations (G118R and E138K) which confer resistance to MK-2048 and not to RAL or EVG. These mutations were selected in vitro and confirmed by site-specific mutagenesis. G118R, which appeared first in cell culture, conferred low levels of resistance to MK-2048. G118R also reduced viral replication capacity to approximately 1% that of the isogenic wild-type (wt) virus. The subsequent selection of E138K partially restored replication capacity to ≈13% of wt levels and increased resistance to MK-2048 to ≈8-fold. Viruses containing G118R and E138K remained largely susceptible to both RAL and EVG, suggesting a unique interaction between this second-generation INSTI and the enzyme may be defined by these residues as a potential basis for the increased intrinsic affinity and longer “off” rate of MK-2048. In silico structural analysis suggests that the introduction of a positively charged arginine at position 118, near the catalytic amino acid 116, might decrease Mg2+ binding, compromising enzyme function and thus leading to the significant reduction in both integration and viral replication capacity observed with these mutations.

Transmission of integrase strand-transfer inhibitor multidrug-resistant HIV-1: case report and response to raltegravir-containing antiretroviral therapy

2011 ◽  
Vol 16 (2) ◽  
pp. 253-256 ◽  
Author(s):  
Benjamin Young ◽  
Signe Fransen ◽  
Kenneth S Greenberg ◽  
Amy Thomas ◽  
Sharon Martens ◽  
...  
Keyword(s):  
Case Report ◽  
Antiretroviral Therapy ◽  
Multidrug Resistant ◽  
Strand Transfer ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1
Sign in / Sign up

Export Citation Format

Share Document