Sensitivity of Phenotypic Susceptibility Analyses for Nonthymidine Nucleoside Analogues Conferred by K65R or M184V in Mixtures with Wild-Type HIV-1

Underwood, Mark; Ross, Lisa; Irlbeck, David M.; Gerondelis, Peter; Rouse, Elizabeth; Clair, M H St; Trinh, Lan; Parkin, Neil; Lanier, E. Randall

doi:10.1086/595296

Cited by 8 publications

(10 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings underscore the limitation of stand-alone phenotypic susceptibility results and emphasize the importance of complementary and/or more sensitive genotyping techniques when evaluating for resistance [13]. In addition, these data further suggest that the impact of drug resistance mutations on therapy is multi-factorial and should take into account the proportion of the variant present, the mutational load, and the specific mutation present [10].…”

Section: Discussionmentioning

confidence: 68%

Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

et al. 2012

View full text Add to dashboard Cite

BackgroundIt is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects.ObjectiveTo determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen.Methods/ResultsPatients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r.ConclusionAmong persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping.

show abstract

Section: Discussionmentioning

confidence: 68%

Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

et al. 2012

View full text Add to dashboard Cite

show abstract

“…M184V was detected as the main mutation in most patients failing this regimen. It has been suggested that failure may have been attributable to viruses with K65R in addition EFV NVP ETV DRV NFV SQV LPV ATV APV IDV TPV RAL EVG ENF M41L K65R M41L T215Y WT WT WT WT WT WT WT WT T215Y WT M184V K65R M184V WT K65R M184V K65R M184V K103N WT Y181C G190S K103N Y181C Y181I G190S K101P Y181C Y181I I50V I54L I84V D30N L90M WT WT WT WT WT WT WT WT WT L90M G48V V32I I47A I47V V82A V82T V82F I50L I84V N88S I50V I84V M46I I84V M46L V82T V82F I84V V82T L33F G36D N42T Q40H V38A N43D Y143C Y143H G140S N155H Q148H Y143R Q148K Q148R WT N155H Q148H Q148K Q148R V82F K65R NRTI NNRTI PI InSTI FI to M184V (51,52). In many failing patients, however, this double mutant was not detected.…”

Section: Analysis Of Resistance Mutations Using Primary Cells Vs Tramentioning

confidence: 99%

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Sampah¹,

Shen

Jilek³

et al. 2011

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

129

View full text Add to dashboard Cite

HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC 50 caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC 50 , however, and inhibition at clinical concentrations can only be predicted from IC 50 if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC 50 . For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC 50 is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC 50 , and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC 50 , does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.HIV/AIDS | pharmacology | virology | highly active antiretroviral therapy | evolution

show abstract

“…The mechanism underlying the increased emergence of K65R and the unanticipated interaction between TDF + ABC and TDF + ddI, remain unclear [28–33]. Poor virological suppression could not be directly associated with either circulating drug levels or intracellular NRTI triphosphate levels [28].…”

Section: Barrier To K65r Selection Is Dependent On Nrti and Nnrti Regimensmentioning

confidence: 99%

“…Poor virological suppression could not be directly associated with either circulating drug levels or intracellular NRTI triphosphate levels [28]. Virological failure was initially associated with the rapid emergence of M184V and K65R on separate viral genomes [28–33]. …”

Section: Barrier To K65r Selection Is Dependent On Nrti and Nnrti Regimensmentioning

confidence: 99%

See 1 more Smart Citation

The K65R Mutation in HIV-1 Reverse Transcriptase: Genetic Barriers, Resistance Profile and Clinical Implications

Brenner¹,

Coutsinos²

2009

HIV Ther.

View full text Add to dashboard Cite

Resistance to antiviral therapy is the limiting factor in the successful management of HIV. In general, the K65R mutation is rarely selected (1.7-4%) with tenofovir disoproxil fumarate (TDF), abacavir (ABC), didanosine (ddI), and stavudine (d4T), as compared with the high incidence (>40%) of thymidine analog mutations associated with zidovudine and d4T. The high barrier to the development of K65R may reflect a combination of factors, including the high potency of K65R-selecting drugs, including recommended TDF/emtricitabine and ABC/lamivudine (ABC/3TC) combinations; the partial (low-intermediate level) profile of cross-resistance conferred by K65R to TDF, ABC and 3TC; the favorable viral fitness constraint imposed by K65R and the 3TC/emtricitabine-associated M184V mutations; the bidirectional antagonism between the K65R and thymidine analog mutation pathways; and unique RNA structural considerations in the region surrounding codon 65. Nevertheless, surprisingly high levels of treatment failures and K65R resistance may be associated with triple nucleoside analog regimens. The use of TDF + ABC, TDF + ddI and ABC + d4T in combination with 3TC or emtricitabine should be avoided. This selection of K65R may be reduced by the inclusion of zidovudine in two-four nucleoside reverse-transcriptase regimens. Clinical studies have demonstrated an increased frequency of K65R in association with suboptimal d4T and ddI regimens, as well as nevirapine and its resistance mutations Y181C and G190A. The potential for the development of the K65R mutation in subtype C is particularly problematic wherein a signature KKK nucleotide motif, at codons 64, 65 and 66 in reverse transcriptase, appear to lead to template pausing, facilitating the selection of K65R. Optimizing regimens may attenuate the emergence of K65R, leading to better long-term treatment management in different geographic settings. TDF-based regimens are the leading candidates for first-and second-line therapy, microbicides and chemoprophylaxis strategies.

show abstract

Sensitivity of Phenotypic Susceptibility Analyses for Nonthymidine Nucleoside Analogues Conferred by K65R or M184V in Mixtures with Wild-Type HIV-1

Cited by 8 publications

References 7 publications

Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

The K65R Mutation in HIV-1 Reverse Transcriptase: Genetic Barriers, Resistance Profile and Clinical Implications

Contact Info

Product

Resources

About