A376S in the Connection Subdomain of HIV-1 Reverse Transcriptase Confers Increased Risk of Virological Failure to Nevirapine Therapy

Paredes, Roger; Puertas, María C.; Kisic, Mónica; Cozzi‐Lepri, Alessandro; Pou, Christian; Bellido, Rocío; Betancor, Gilberto; Bogner, Johannes R.; Gargalianos, Panagiotis; Bánhegyi, Dénes; Clotet, Bonaventura; Lundgren, Jens D.; Menéndez‐Arias, Luis; Martínez-Picado, Javier

doi:10.1093/infdis/jir385

Cited by 20 publications

(19 citation statements)

References 40 publications

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“…34 The N348I mutation occurred in 11% of viruses in Southern Brazil and it is associated with major resistance to nevirapine, etravirine, and rilpivirine, and as an accessory mutation for thymidine analogs. 40,41,51,52 Of note, A376S has been associated with failure to NNRTI, particularly nevirapine-containing regimens, 53,54 suggesting a functional link between this mutation and K103N.…”

Section: Novel Hiv-1 Rt C-terminal Mutationsmentioning

confidence: 99%

Identification of Novel Resistance-Related Polymorphisms in HIV-1 Subtype C RT Connection and RNase H Domains from Patients Under Virological Failure in Brazil

Barral

Sousa

Santos

et al. 2017

AIDS Research and Human Retroviruses

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Mutations in the connection and RNase H C-terminal reverse transcriptase (RT) domains of HIV-1 have been shown to impact drug resistance to RT inhibitors. However, their impact in the context of non-B subtypes has been poorly assessed. This study aimed to characterize resistance-related mutations in the C-terminal portions of RT in treatment-failing patients from southern Brazil, a region with endemic HIV-1 subtype C (HIV-1C). Viral RNA was isolated and reverse transcribed from 280 infected subjects, and genomic regions were analyzed by polymerase chain reaction, DNA sequencing, and phylogenetic analysis. Two novel mutations, M357R and E529D, were evidenced in Brazilian HIV-1C strains from treatment-failing patients. In global viral isolates of subjects on treatment, M357R was selected in HIV-1C and CRF01_AE and E529D was selected in HIV-1 subtype B (HIV-1B). While most C-terminal RT mutations described for HIV-1B also occur in HIV-1C, this work pinpointed novel mutations that display subtype-specific predominance or occurrence.

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Section: Novel Hiv-1 Rt C-terminal Mutationsmentioning

confidence: 99%

Identification of Novel Resistance-Related Polymorphisms in HIV-1 Subtype C RT Connection and RNase H Domains from Patients Under Virological Failure in Brazil

Barral

Sousa

Santos

et al. 2017

AIDS Research and Human Retroviruses

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“…In vitro selection experiments and drug susceptibility assays have revealed that the major mutations associated with DPV resistance or cross-resistance are V90I, L100I, K103N, V106I, E138K, Y181C, and Y188L (7,8). Mutations outside the polymerase domain of reverse transcriptase in the connection and/or RNase H domains of reverse transcriptase, including G335D, N348I, T369I, A371V, and A376S, have been shown to cause cross-resistance to NNRTIs (9)(10)(11)(12)(13). Such mutations are missed by most standard population-based genotyping tests and require full-length sequencing of reverse transcriptase.…”

mentioning

confidence: 99%

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa

Penrose

Wallis

Brumme

et al. 2017

Antimicrob Agents Chemother

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A vaginal ring containing dapivirine (DPV) has shown moderate protective efficacy against HIV-1 acquisition, but the activity of DPV against efavirenz (EFV)-and nevirapine (NVP)-resistant viruses that could be transmitted is not well defined. We investigated DPV cross-resistance of subtype C HIV-1 from individuals on failing NVP-or EFV-containing antiretroviral therapy (ART) in South Africa. Plasma samples were obtained from individuals with Ͼ10,000 copies of HIV RNA/ml and with HIV-1 containing at least one non-nucleoside reverse transcriptase (NNRTI) mutation. Susceptibility to NVP, EFV, and DPV in TZM-bl cells was determined for recombinant HIV-1 LAI containing bulk-amplified, plasma-derived, full-length reverse transcriptase sequences. Fold change (FC) values were calculated compared with a composite 50% inhibitory concentration (IC 50 ) from 12 recombinant subtype C HIV-1 LAI plasmaderived viruses from treatment-naive individuals in South Africa. A total of 25/100 (25%) samples showed Ͼ500-FCs to DPV compared to treatment-naive samples with IC 50 s exceeding the maximum DPV concentration tested (132 ng/ml). A total of 66/ 100 (66%) samples displayed 3-to 306-FCs, with a median IC 50 of 17.6 ng/ml. Only 9/100 (9%) samples were susceptible to DPV (FC Ͻ 3). Mutations L100I and K103N were significantly more frequent in samples with Ͼ500-fold resistance to DPV compared to samples with a Յ500-fold resistance. A total of 91% of samples with NNRTI-resistant HIV-1 from individuals on failing first-line ART in South Africa exhibited Ն3-fold cross-resistance to DPV. This level of resistance exceeds expected plasma concentrations, but very high genital tract DPV concentrations from DPV ring use could block viral replication. It is critically important to assess the frequency of transmitted and selected DPV resistance in individuals using the DPV ring.KEYWORDS dapivirine, NNRTI, HIV-1, antiretroviral therapy, cross-resistance, drug resistance, human immunodeficiency virus, non-nucleoside reverse transcriptase inhibitor S ustained-release formulations of antiretrovirals could substantially decrease the incidence of HIV-1 infection in sub-Saharan Africa by improving product adherence compared to daily preexposure prophylaxis (PrEP) (1). Dapivirine (DPV) is a potent di-aryl-pyrimidine (DAPY) derivative in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals. The development of DPV for antiretroviral therapy was halted due to suboptimal oral pharmacokinetics (2). Instead, it was formulated as a 25-mg slow-release vaginal ring for HIV-1 prevention because of its favorable safety profile and physical and chemical attributes. Recent phase III DPV ring studies in over 4,500 HIV-1-negative female participants in ASPIRE (MTN-020) (3) and the Ring Study

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“…Paredes et al reported that preexisting A376S was associated with an increased risk of virologic failure to NVP (relative hazard (RH) = 10.4; 95 % confidence interval (CI), 2.0-54.7), but did not affect EFV outcome the same way (RH = 0.5; 95 % CI, 0.1-2.2) (p = 0.013) (Paredes et al 2011). A376S confers selective low-level NVP resistance in vitro (Paredes et al 2011).…”

Section: A376smentioning

confidence: 99%

“…A376S confers selective low-level NVP resistance in vitro (Paredes et al 2011). Interestingly, Gupta et al reported that virologic responses to an ETV-containing regimen were slightly diminished when A376S was present (Gupta et al 2011).…”

Section: A376smentioning

confidence: 99%

HIV-1 Resistance to Reverse Transcriptase Inhibitors

Schauer

Sluis‐Cremer

2014

Handbook of Antimicrobial Resistance

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Purpose of Review: This review discusses the mutations and mechanisms associated with HIV-1 resistance to nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs).Recent Findings: First-line antiretroviral therapy (ART) for the treatment of HIV-1 infection typically includes two NRTIs in combination with an NNRTI or a protease inhibitor. NRTIs and NNRTIs are also routinely used in second-line and salvage ART therapies. HIV-1 resistance to all of the FDA-approved NRTIs and NNRTIs has been documented. An understanding of the mutations associated with RT inhibitor (RTI) resistance, the antagonistic or complementary interactions between RTI-resistance mutations, and the mechanisms of HIV-1 resistance to RTIs is of critical importance for the development and formulation of effective ART therapies. Of concern, there has been a significant increase in circulating and transmitted NNRTI drug resistance in resource-limited settings due to the extensive use of NNRTIs in prevention and treatment strategies for HIV-1 infection. Despite this increase in NNRTI drug resistance, the diarylpyrimidine NNRTIs, dapivirine, etravirine, and rilpivirine, will be increasingly used in resource-limited settings. As such, there is a continued need to monitor and understand NNRTI resistance, particularly in sub-Saharan Africa where non-subtype B HIV-1 predominates.Summary: This review describes HIV-1 resistance to NRTIs and NNRTIs.

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A376S in the Connection Subdomain of HIV-1 Reverse Transcriptase Confers Increased Risk of Virological Failure to Nevirapine Therapy

Abstract: The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.

Cited by 20 publications

References 40 publications

Identification of Novel Resistance-Related Polymorphisms in HIV-1 Subtype C RT Connection and RNase H Domains from Patients Under Virological Failure in Brazil

Identification of Novel Resistance-Related Polymorphisms in HIV-1 Subtype C RT Connection and RNase H Domains from Patients Under Virological Failure in Brazil

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa

HIV-1 Resistance to Reverse Transcriptase Inhibitors

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