Resistance profile and cross-resistance of HIV-1 among patients failing a non-nucleoside reverse transcriptase inhibitor-containing regimen

2001 ◽  
Vol 65 (3) ◽  
pp. 445-448 ◽  
Author(s):  
C. Delaugerre ◽  
R. Rohban ◽  
A. Simon ◽  
M. Mouroux ◽  
C. Tricot ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Cross Resistance ◽  
Resistance Profile ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

scholarly journals In VitroCross-Resistance Profile of Nucleoside Reverse Transcriptase Inhibitor (NRTI) BMS-986001 against Known NRTI Resistance Mutations

2013 ◽  
Vol 57 (11) ◽  
pp. 5500-5508 ◽  
Author(s):  
Zhufang Li ◽  
Brian Terry ◽  
William Olds ◽  
Tricia Protack ◽  
Carol Deminie ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Fold Change ◽  
Site Directed Mutagenesis ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
Wild Type ◽  
Resistance Profile ◽  
Reverse Transcriptase Inhibitor

ABSTRACTBMS-986001 is a novel HIV nucleoside reverse transcriptase inhibitor (NRTI). To date, little is known about its resistance profile. In order to examine the cross-resistance profile of BMS-986001 to NRTI mutations, a replicating virus system was used to examine specific amino acid mutations known to confer resistance to various NRTIs. In addition, reverse transcriptases from 19 clinical isolates with various NRTI mutations were examined in the Monogram PhenoSense HIV assay. In the site-directed mutagenesis studies, a virus containing a K65R substitution exhibited a 0.4-fold change in 50% effective concentration (EC50) versus the wild type, while the majority of viruses with the Q151M constellation (without M184V) exhibited changes in EC50versus wild type of 0.23- to 0.48-fold. Susceptibility to BMS-986001 was also maintained in an L74V-containing virus (0.7-fold change), while an M184V-only-containing virus induced a 2- to 3-fold decrease in susceptibility. Increasing numbers of thymidine analog mutation pattern 1 (TAM-1) pathway mutations correlated with decreases in susceptibility to BMS-986001, while viruses with TAM-2 pathway mutations exhibited a 5- to 8-fold decrease in susceptibility, regardless of the number of TAMs. A 22-fold decrease in susceptibility to BMS-986001 was observed in a site-directed mutant containing the T69 insertion complex. Common non-NRTI (NNRTI) mutations had little impact on susceptibility to BMS-986001. The results from the site-directed mutants correlated well with the more complicated genotypes found in NRTI-resistant clinical isolates. Data from clinical studies are needed to determine the clinically relevant resistance cutoff values for BMS-986001.

scholarly journals Frequent cross-resistance to rilpivirine among subtype C HIV-1 from first-line antiretroviral therapy failures in South Africa

2018 ◽  
Vol 26 ◽  
pp. 204020661876298 ◽  
Author(s):  
Kerri J Penrose ◽  
Chanson J Brumme ◽  
Maritsa Scoulos-Hanson ◽  
Kristen Hamanishi ◽  
Kelley Gordon ◽  
...  
Keyword(s):  
South Africa ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Cross Resistance ◽  
Subtype C ◽  
First Line ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

Background Rilpivirine (TMC278LA) is a promising drug for pre-exposure prophylaxis of HIV-1 because of its sub-nanomolar potency and long-acting formulation; however, increasing transmission of non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 with potential cross-resistance to rilpivirine could reduce its preventive efficacy. This study investigated rilpivirine cross-resistance among recombinant subtype C HIV-1 derived from 100 individuals failing on first-line non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy in South Africa whose samples were sent for routine HIV-1 drug resistance testing to Lancet Laboratories (Johannesburg, South Africa). Methods Plasma samples were selected from individuals with HIV-1 RNA > 10,000 copies/ml and ≥1 non-nucleoside reverse transcriptase inhibitor-resistance mutation in reverse transcriptase. Recombinant HIV-1LAI-containing bulk-cloned full-length reverse transcriptase sequences from plasma were assayed for susceptibility to nevirapine (NVP), efavirenz (EFV) and rilpivirine in TZM-bl cells. Fold-change (FC) decreases in drug susceptibility were calculated against a mean IC50 from 12 subtype C HIV-1 samples from treatment-naïve individuals in South Africa. Cross-resistance was evaluated based on biological cutoffs established for rilpivirine (2.5-FC) and the effect of mutation combinations on rilpivirine phenotype. Results Of the 100 samples from individuals on failing antiretroviral therapy, 69 had 2.5- to 75-fold decreased susceptibility to rilpivirine and 11 had >75-fold resistance. Rilpivirine resistance was strongly associated with K103N especially in combination with other rilpivirine-associated mutations. Conclusion The frequently observed cross-resistance of HIV-1 suggests that the preventive efficacy of TMC278LA pre-exposure prophylaxis could be compromised by transmission of HIV-1 from individuals with failure of first-line non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy.

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.

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