Genotypic and Phenotypic Characterization of HIV-1 Isolates Obtained From Patients on Rilpivirine Therapy Experiencing Virologic Failure in the Phase 3 ECHO and THRIVE Studies

Rimsky, L; Vingerhoets, Johan; Eygen, Veerle Van; Eron, Joseph J.; Clotet, Bonaventura; Hoogstoel, Annemie; Boven, Katia; Picchio, Gastón

doi:10.1097/qai.0b013e31823df4da

Cited by 149 publications

(196 citation statements)

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“…ETR and RPV were designed with intrinsic flexibility that allows efficient binding to a high-plasticity NNRTI-BP (84,85), and they are active against viruses that contain mutations associated with resistance to NVP and EFV (86,87). Structural studies have revealed similar binding modes within the NNRTI-BP for ETR and RPV (84,88,89), indicating cross-resistance.…”

Section: Discussionmentioning

confidence: 99%

“…In the ECHO and THRIVE clinical trials that led to the approval of RPV for use in treatmentnaive patients, E138K was the most frequent NNRTI mutation at treatment failure (36,87), indicating that E138K is a signature mutation for this drug. In contrast, E138K is much rarer in patients who have failed therapy with ETR, even though this mutation confers resistance to ETR in tissue culture.…”

Section: Discussionmentioning

confidence: 99%

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The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Colby-Germinario

Oliveira

et al. 2014

J Virol

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Clinical resistance to rilpivirine (RPV), a novel nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI), is associated an E-to-K mutation at position 138 (E138K) in RT together with an M184I/V mutation that confers resistance against emtricitabine (FTC), a nucleoside RT inhibitor (NRTI) that is given together with RPV in therapy. These two mutations can compensate for each other in regard to fitness deficits conferred by each mutation alone, raising the question of why E138K did not arise spontaneously in the clinic following lamivudine (3TC) use, which also selects for the M184I/V mutations. In this context, we have investigated the role of a N348I connection domain mutation that is prevalent in treatment-experienced patients. N348I confers resistance to both the NRTI zidovudine (ZDV) and the NNRTI nevirapine (NVP) and was also found to be associated with M184V and to compensate for deficits associated with the latter mutation. Now, we show that both N348I alone and N348I/ M184V can prevent or delay the emergence of E138K under pressure with RPV or a related NNRTI, termed etravirine (ETR). N348I also enhanced levels of resistance conferred by E138K against RPV and ETR by 2.2-and 2.3-fold, respectively. The presence of the N348I or M184V/N348I mutation decreased the replication capacity of E138K virus, and biochemical assays confirmed that N348I, in a background of E138K, impaired RT catalytic efficiency and RNase H activity. These findings help to explain the low viral replication capacity of viruses containing the E138K/N348I mutations and how N348I delayed or prevented the emergence of E138K in patients with M184V-containing viruses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Colby-Germinario

Oliveira

et al. 2014

J Virol

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“…Mutations conferring resistance have been described for each of the currently approved NNRTI (10). The RT-K103N and -Y181C substitutions are the most frequently observed resistance mutations in HIV-1 from patients treated with efavirenz (EFV) and nevirapine (NVP), respectively (11)(12)(13), whereas the RT-E138K is the principal mutation associated with resistance to rilpivirine (RPV) (14)(15)(16).…”

mentioning

confidence: 99%

Altered Viral Fitness and Drug Susceptibility in HIV-1 Carrying Mutations That Confer Resistance to Nonnucleoside Reverse Transcriptase and Integrase Strand Transfer Inhibitors

Kuritzkes

2014

J Virol

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Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) and integrase (IN) strand transfer inhibitors (INSTI)are key components of antiretroviral regimens. To explore potential interactions between NNRTI and INSTI resistance mutations, we investigated the combined effects of these mutations on drug susceptibility and fitness of human immunodeficiency virus type 1 (HIV-1). In the absence of drug, single-mutant viruses were less fit than the wild type; viruses carrying multiple mutations were less fit than single-mutant viruses. These findings were explained in part by the observation that mutant viruses carrying NNRTI plus INSTI resistance mutations had reduced amounts of virion-associated RT and/or IN protein. In the presence of efavirenz (EFV), a virus carrying RT-K103N together with IN-G140S and IN-Q148H (here termed IN-G140S/Q148H) mutations was fitter than a virus with a RT-K103N mutation alone. Similarly, in the presence of EFV, the RT-E138K plus IN-G140S/Q148H mutant virus was fitter than one with the RT-E138K mutation alone. No effect of INSTI resistance mutations on the fitness of RT-Y181C mutant viruses was observed. Conversely, RT-E138K and -Y181C mutations improved the fitness of the IN-G140S/Q148H mutant virus in the presence of raltegravir (RAL); the RT-K103N mutation had no effect. The NNRTI resistance mutations had no effect on RAL susceptibility. Likewise, the IN-G140S/Q148H mutations had no effect on EFV or RPV susceptibility. However, both the RT-K103N plus IN-G140S/Q148H and the RT-E138K plus IN-G140S/Q148H mutant viruses had significantly greater fold increases in 50% inhibitory concentration (IC 50 ) of EFV than viruses carrying a single NNRTI mutation. Likewise, the RT-E138K plus IN-G140S/Q148H mutant virus had significantly greater fold increases in RAL IC 50 than that of the IN-G140S/ Q148H mutant virus. These results suggest that interactions between RT and IN mutations are important for NNRTI and INSTI resistance and viral fitness. IMPORTANCENonnucleoside reverse transcriptase inhibitors and integrase inhibitors are used to treat infection with HIV-1. Mutations that confer resistance to these drugs reduce the ability of HIV-1 to reproduce (that is, they decrease viral fitness). It is known that reverse transcriptase and integrase interact and that some mutations can disrupt their interaction, which is necessary for proper functioning of these two enzymes. To determine whether resistance mutations in these enzymes interact, we investigated their effects on drug sensitivity and viral fitness. Although individual drug resistance mutations usually reduced viral fitness, certain combinations of mutations increased fitness. When present in certain combinations, some integrase inhibitor resistance mutations increased resistance to nonnucleoside reverse transcriptase inhibitors and vice versa. Because these drugs are sometimes used together in the treatment of HIV-1 infection, these interactions could make viruses more resistant to both drugs, further limiting their clinical benefit.

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“…Although Rilpivirine (1, RPV, TMC278) was approved by the FDA in 2011 as a non-nucleoside HIV-1 reverse transcriptase inhibitor to treat Human Immunodeficiency Virus (HIV) [1] for its potent activity against many clinically relevant wild-type (WT) and mutant HIV-1 strains, the corresponding dosing complexity, drug-drug interactions and long-term toxicity of this drug have severely compromised its efficacy [2].…”

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confidence: 99%

Discovery of Biphenyl-Substituted Diarylpyrimidines as New Non-Nucleoside HIV-1 Reverse Transcripttase Inhibitors

Jin

Meng

Chen

et al. 2017

Proceedings of the 1st Molecules Medicinal Chemistry Symposium, Barcelona, Spain

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Genotypic and Phenotypic Characterization of HIV-1 Isolates Obtained From Patients on Rilpivirine Therapy Experiencing Virologic Failure in the Phase 3 ECHO and THRIVE Studies

Cited by 149 publications

References 13 publications

The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Altered Viral Fitness and Drug Susceptibility in HIV-1 Carrying Mutations That Confer Resistance to Nonnucleoside Reverse Transcriptase and Integrase Strand Transfer Inhibitors

Discovery of Biphenyl-Substituted Diarylpyrimidines as New Non-Nucleoside HIV-1 Reverse Transcripttase Inhibitors

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