Drugs in traditional drug classes (nucleoside reverse transcriptase inhibitor/nonnucleoside reverse transcriptase inhibitor/protease inhibitors) with activity against drug-resistant virus (tipranavir, darunavir, etravirine)

2009 ◽  
Vol 4 (6) ◽  
pp. 507-512 ◽  
Author(s):  
Jose R Arribas
Keyword(s):  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Drug Resistant ◽  
Resistant Virus ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Drug Classes ◽  
Traditional Drug ◽  
Reverse Transcriptase Inhibitor ◽  
Drug Resistant Virus

scholarly journals Characterization of a Mutant HIV-1 Reverse Transcriptase Resistant to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150)

1994 ◽  
Vol 5 (4) ◽  
pp. 278-281
Author(s):  
H. Samanta ◽  
R. Rose ◽  
A. K. Patick ◽  
C. M. Bechtold ◽  
J. Trimble ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Serial Passage ◽  
Transcriptase Inhibitor ◽  
Viral Resistance ◽  
Resistant Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

A virus strain resistant to R82150, a non-nucleoside reverse transcriptase (NNRT) inhibitor (tetrahydro-imidazo [4,5, 1- jk] [1,4] benzodiazepine-2(1 H)-thione), was isolated following serial passage of HIV-1 RF in CEM-SS cells. The virus is cross-resistant to another non-nucleoside reverse transcriptase inhibitor, TGG-II-23A [1,4-dimethyl-1-[5,5-dimethyl-2-oxazoionyl]-naphthalen-2-one), but remains susceptible to AZT, DDI, D4T and phosphonoformate (PFA). DNA sequencing of reverse transcriptase genes from resistant virus indicated that R82150 selects for amino acid alterations Y181C and V108I. In vitro mutagenized reverse transcriptase and recombinant HIV-1 (pNL4-3) carrying either of the mutations have been generated. Genotypic and phenotypic analyses identified V108I as an unreported R82150-associated mutation. Both reverse transcriptase and viral resistance assays indicated that the resistance conferred by the V108I mutation is 7-fold less than that conferred by Y181C.

scholarly journals Association of Virologic Failure and Nonnucleoside Reverse Transcriptase Inhibitor Resistance Found in Antiretroviral-Naive Children Infected With Human Immunodeficiency Virus and Given Efavirenz-Based Treatment

2019 ◽  
Vol 9 (2) ◽  
pp. 261-264
Author(s):  
Nikki Higa ◽  
Amy Pelz ◽  
Donald Birch ◽  
Ingrid A Beck ◽  
Tatiana Sils ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Virologic Failure ◽  
Transcriptase Inhibitor ◽  
Nnrti Resistance ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Inhibitor Resistance ◽  
Reverse Transcriptase Inhibitor

Abstract Among 66 antiretroviral-naive children aged <3 years with human immunodeficiency virus (HIV) or coinfected with HIV and tuberculosis and initiating efavirenz-based antiretroviral therapy (ART), non–nucleoside reverse transcriptase inhibitor (NNRTI) resistance was detected before ART in 5 (7.6%). Virologic failure occurred in 2 of these children; they were last tested at 16 and 24 weeks of ART. Pre-ART NNRTI resistance was not associated with virologic failure.

scholarly journals In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

2006 ◽  
Vol 80 (9) ◽  
pp. 4440-4446 ◽  
Author(s):  
Mohammad M. Hossain ◽  
Michael A. Parniak
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Resistant Virus ◽  
Microbicidal Activity ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT The nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781 is under development as a microbicide to prevent sexual transmission of the human immunodeficiency virus type 1 (HIV-1). However, NNRTI-resistant HIV-1 is increasingly prevalent in the infected population, and one of the concerns for NNRTI-based microbicides is that they will be ineffective against drug-resistant virus and may in fact selectively transmit NNRTI-resistant virus. We evaluated the microbicidal activity of UC781 against UC781-resistant (UCR), efavirenz-resistant (EFVR), and nevirapine-resistant (NVPR) strains in a variety of microbicide-relevant tests, including inactivation of cell-free virus, inhibition of cell-to-cell HIV-1 transmission, and the ability of UC781 pretreatment to protect cells from subsequent infection in the absence of exogenous drug. UC781 was 10- to 100-fold less effective against NNRTI-resistant HIV-1 compared to wild-type (wt) virus in each of these tests, with UC781 microbicidal activity against the various virus strains being wt ≥ NVPR > UCR ≥ EFVR. Breakthrough experiments using UC781-pretreated cells and mixtures of wt and NNRTI-resistant HIV-1 showed that UC781-pretreatment selected for NNRTI-resistant HIV-1. However, the efficacy of UC781 was dose dependent, and 25 μM UC781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wt virus. The amount of UC781 in topical microbicide formulations under current development is approximately 100-fold greater than this concentration, so transmission of NNRTI-resistant virus may not be an issue at these microbicide formulation levels of UC781. Nonetheless, the reduced microbicidal activity of UC781 against NNRTI-resistant HIV-1 suggests that additional antiviral agents should be included in NNRTI-based microbicide formulations.

scholarly journals A Diarylsulphone Non-Nucleoside Reverse Transcriptase Inhibitor with a Unique Sensitivity Profile to Drug-Resistant Virus Isolates

1996 ◽  
Vol 7 (5) ◽  
pp. 243-252 ◽  
Author(s):  
R.W. Buckheit ◽  
V. Fliakas-Boltz ◽  
J.D. Russell ◽  
M. Snow ◽  
L.A. Pallansch ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Resistant Virus ◽  
Rt Inhibitors ◽  
Reverse Transcriptase Inhibitor ◽  
Virus Isolates ◽  
Hiv 1 ◽  
Sensitivity Profile

Structure-activity relationship evaluations with a series of diarylsulphone non-nucleoside reverse transcriptase (RT) inhibitors indicated that the steric properties of the molecule and compound lipophilicity primarily contributed to the overall level of activity of the compounds against human immunodeficiency virus type 1 (HIV-1). The most active compounds in the diarylsulphone series had an orthonitro group and yielded anti-HIV activity at sub-micromolar concentrations. Compounds of the diarylsulphone class exhibited antiviral properties similar to other members of the pharmacologic class of HIV-1 specific non-nucleoside reverse transcriptase inhibitors, including activity in a wide variety of established and primary human cells, activity against a wide variety of laboratory and clinical virus isolates, and activity when challenged at high multiplicity of infection. Synergistic inhibition of HIV-1 was observed when the diarylsulphone NSC 667952 was used with the nucleoside analogues AZT, ddl, 3TC and d4T, the protease inhibitor KNI 272 and the sulphonated dye resobene; additive effects were observed when NSC 667952 was used with the nucleoside analogue ddC and other non-nucleoside RT inhibitors. The diarylsulphones exhibited a unique sensitivity profile when evaluated against both virus isolates and purified reverse transcriptase containing non-nucleoside reverse transcriptase inhibitor resistance-engendering mutations. Unlike other members of the class of non-nucleoside compounds, NSC 667952 remained active against virus isolates with the L100I amino acid change in the RT. The compound was, however, highly sensitive to Y181C., K103N and K101E amino acid changes in the RT. The diarylsulphone selected for resistant virus populations which possessed the Y181C amino acid change in the reverse transcriptase and which exhibited enhanced sensitivity to the non-nucleoside inhibitors calanolide A and costatolide.

scholarly journals Prevalence of minority Human Immunodeficiency virus multi-drug resistant mutations among patients failing a Nucleoside Reverse Transcriptase Inhibitor based regimen in Uganda

2021 ◽  
Author(s):  
Immaculate Lillian Nankya ◽  
Eva Nabulime ◽  
Fred Kyeyune ◽  
Cissy Mutuluza Kityo ◽  
Miguel Mateu Quinones
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Susceptible Genotype ◽  
Subtype C ◽  
Subtype A ◽  
Reverse Transcriptase Inhibitor

Abstract Objective To determine the prevalence of multi-drug resistant variants among patients failing on a nucleoside reverse transcriptase inhibitor (NRTI) based regimen with a detectable viral load ≥ 1000 copies/ml among patients harboring HIV subtype A, C and D. Methods Samples were obtained from patients who were failing on an NRTI based regimen. Sanger based sequencing was performed as part of the standard of care. Mutation analysis was performed using the Stanford HIV drug Resistance database. A subset of these patient samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off Results Analysis of the Non-nucleoside reverse transcriptase inhibitor (NNRTI) coding region revealed that the K101 and the Y181 mutations were more predominant among subtype C than subtype A and D. Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. Furthermore, the Q151M mutation complex which involves mutations in multiple domains was significantly more prominent among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique. Conclusion Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex being significantly more predominant among patients harboring subtype C viruses. Even in patients with a susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that by the time they are detectable, cross resistance to other drugs has occurred in some cases.

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