Emergence of Resistance to Integrase Strand Transfer Inhibitors during Dolutegravir Containing Triple-Therapy in a Treatment-Experienced Patient with Pre-Existing M184V/I Mutation.
Result: This resistance test newly revealed the E138K, Q148R, and R263K INSTI mutations at frequencies of 100% by means of next-generation sequencing (NGS), causing high-level resistance to RAL, EVG, DTG, and BIC.
High predictive efficacy of integrase strand transfer inhibitors in perinatally HIV-1-infected African children in therapeutic failure of first- and second-line antiretroviral drug regimens recommended by the WHO.
PMID: 30891603
2019
The Journal of antimicrobial chemotherapy
Abstract: Two (2/18; 11.1%) viruses from children treated with a first-line regimen had INSTI DRMs at codon 138 (E138K and E138T), which is known to harbour major resistance mutations, and also had the accessory mutations L74I, G140K, G140R and G163R.
Discussion: Furthermore, previous studies evaluating the variability of the IN gene revealed that amino acid variations at codon 138 (E138A/D/K/T) could arise from G-to-A hypermutation resulting from APOBEC-mediated RNA editing, and also from natural polymorphism during viral replication.
Discussion: In this study, one child exhibited the DRM E138K, conferring potent
Prevalence and persistence of transmitted drug resistance mutations in the German HIV-1 Seroconverter Study Cohort.
Introduction: However, the landscape of antiretrovirals is changing continuously and new mutations such as E138A/G/K/Q/R (that confers resistance to the NNRTI rilpivirine (RPV), approved in 2011) are therefore not covered by this list.
Result: Mutations E138A/G/K/R were found in 99 of 186 viruses (52.9%) showing RPV resistance, which account for 40% of all NNRTI-resistant viruses.
Result: The most common TDRMs found in baseline samples were the T215 revertants, followed by E138A/G/K/Q/R, K103NS, V179DE and M41L (S1 Table).
Discussion: Competition experiments have shown that E138A
Development of the R263K Mutation to Dolutegravir in an HIV-1 Subtype D Virus Harboring 3 Class-Drug Resistance.
PMID: 30648124
2019
Open forum infectious diseases
Introduction: A number of additional mutations observed in patients can increase DTG resistance, including L74M and E138K.
High Levels of HIV-1 Drug Resistance in Children Who Acquired HIV Infection Through Mother to Child Transmission in the Era of Option B+, Haiti, 2013 to 2014.
PMID: 30640198
2019
The Pediatric infectious disease journal
Result: Twenty-nine (9.5%) of the children had additional NNRTI mutations (A98G, E138A/G/K/Q, H221Y, and M230L) that confer resistance to second generation NNRTI drugs etravirine and rilpivirine.
Identification of Dihydrofuro[3,4- d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties.
PMID: 30624934
2019
Journal of medicinal chemistry
Conclusion: Especially, 13c2 and 13c4 proved to be the exceptionally potent inhibitors, exhibiting EC50 values of 0.9-7.0 nM against single NNRTI-resistant strains L100I, K103N, Y181C, Y188L, and E138K in MT-4 cells and bringing approximately 1.3- to 3.6 fold improvement in potency compared with ETV (EC50 = 3.3-20.4 nM).
Result: As noted above, 13c2 can inhibit single (L100I, K103N, Y181C, Y188L, E138K) and double (F227+V106A) mutated HIV-RT variants (see Figure S3 for the location of these mutations).
Result: In the case of
Predicted antiviral activity of tenofovir versus abacavir in combination with a cytosine analogue and the integrase inhibitor dolutegravir in HIV-1-infected South African patients initiating or failing first-line ART.
PMID: 30380053
2019
The Journal of antimicrobial chemotherapy
Result: While no major mutation was described for dolutegravir resistance, we found some accessory integrase mutations in 98/524 (18.7%), such as L74I/M (n = 81/98, 82.7%), T97A (n = 8/98, 8.2%) and E157Q (n = 5/98, 5.1%), and more sporadically E138D/K (n = 2), V151I (n = 1) and G163R (n = 1).
Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles.
PMID: 30721060
2019
Journal of medicinal chemistry
Abstract: Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility.
Abstract: The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 muM, EC50(E138K) = 0.0075 muM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 >= 173 muM).
Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted Human Immunodeficiency Virus Type 1 Drug Resistance in a Large US Clinic Population.
Method: Several additional DRMs not on the SDRM list were analyzed including (1) the primarily tenofovir disoproxil fumarate (TDF)-selected DRMs A62V, K65N, and K70G/N/Q/S/T and (2) the primarily rilpivirine (RPV)-selected DRMs E138A/G/K/Q, of which E138A is polymorphic, occurring in 1%-4% of viruses from ART-naive individuals.
Result: The mutations E138A/G/K/Q, which are associated with reduced RPV susceptibility but are not on the SDRM list, occurred in 99 individuals, including 90 without an SDRM.
Virological outcomes of boosted protease inhibitor-based first-line ART in subjects harbouring thymidine analogue-associated mutations as the sole form of transmitted drug resistance.
PMID: 30544247
2019
The Journal of antimicrobial chemotherapy
Method: TDR mutations were defined according to the WHO 2009 surveillance list, with the addition of any unlisted change at position T215 and the non-polymorphic RT mutation E138K.
HIV mutation literature information.
PMID: 
2020
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