<i>In Vitro</i>Characterization of MK-1439, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor

Lai, Ming‐Tain; Feng, Meizhen; Falgueyret, Jean‐Pierre; Tawa, Paul; Witmer, Marc; DiStefano, Daniel J.; Li, Yuan; Burch, Jason D.; Sachs, Nancy A.; Lu, Meiqing; Cauchon, Elizabeth; Campeau, Louis‐Charles; Grobler, Jay A.; Yan, Yong-Bin; Ducharme, Yves; Côté, Bernard; Asante‐Appiah, Ernest; Hazuda, Daria J.; Miller, Michael D.

doi:10.1128/aac.02403-13

Cited by 104 publications

(98 citation statements)

References 45 publications

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“…DOR displayed efficacy against the wild-type (WT) virus, as well as the most common NNRTI-resistant variants such as the K103N and Y181C mutant viruses (11). The mutant profile of DOR is superior to that of EFV and comparable to that of RPV (11). In preclinical toxicity studies, no article-related findings were observed in either antemodem or postmodem analyses.…”

Section: Nrtis Such As Atripla (Efavirenz [Efv]-tenofovir Disproxil mentioning

confidence: 89%

“…To this end, a novel NNRTI, doravirine (DOR), was identified as a potential new antiviral agent. DOR displayed efficacy against the wild-type (WT) virus, as well as the most common NNRTI-resistant variants such as the K103N and Y181C mutant viruses (11). The mutant profile of DOR is superior to that of EFV and comparable to that of RPV (11).…”

Section: Nrtis Such As Atripla (Efavirenz [Efv]-tenofovir Disproxil mentioning

confidence: 91%

“…RPV was shown to have suboptimal efficacy in patients with viral loads of Ͼ100,000 copies/ml or CD4 ϩ cell counts below 200 copies/ml at the baseline (9,10). In addition, the E138K substitution, accounting for the majority of mutants in patients who have experienced RPV-containing regimen failure, was found to be associated with the most prevalent NRTI mutants containing M184V/I substitutions (11)(12)(13).…”

Section: Nrtis Such As Atripla (Efavirenz [Efv]-tenofovir Disproxil mentioning

confidence: 99%

“…For example, a virus with the K103N substitution exhibits a high level of resistance to EFV, NVP, and DLV. A Y181C mutant is highly resistant to NVP and DLV and displays a low level (ϳ4-fold) of resistance to RPV and ETR (11). In the clinical setting, a Y181C mutant has also been associated with virologic failures of regimens containing NVP, RPV, or ETR (10,14).…”

Section: Nrtis Such As Atripla (Efavirenz [Efv]-tenofovir Disproxil mentioning

confidence: 99%

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In Vitro Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development Pathways

Feng

Wang

Grobler

et al. 2015

Antimicrob Agents Chemother

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EC 95 in the presence of 10% fetal bovine serum. In the resistance selection of subtype B virus with DOR, a V106A mutant virus led to two mutation pathways, followed by the emergence separately of either F227L or L234I. In the resistance selection of subtype A and C viruses, similar mutation development pathways were detected, in which a V106A or V106M mutant was also the starting virus in the pathways. Mutations that are commonly associated with RPV and EFV in clinical settings were also identified in subtype B viruses such as the E138K and K103N mutants, respectively, in this in vitro resistance selection study. The susceptibility of subtype B mutant viruses selected by DOR, RPV, and EFV to NNRTIs was evaluated. Results suggest that mutant viruses selected by DOR are susceptible to RPV and EFV and mutants selected by RPV and EFV are susceptible to DOR. When the replication capacity of the V106A mutant was compared with that of the wild-type (WT) virus, the mutant virus was 4-fold less fit than the WT virus.

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Section: Nrtis Such As Atripla (Efavirenz [Efv]-tenofovir Disproxil mentioning

confidence: 89%

Section: Nrtis Such As Atripla (Efavirenz [Efv]-tenofovir Disproxil mentioning

confidence: 91%

Section: Nrtis Such As Atripla (Efavirenz [Efv]-tenofovir Disproxil mentioning

confidence: 99%

Section: Nrtis Such As Atripla (Efavirenz [Efv]-tenofovir Disproxil mentioning

confidence: 99%

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In Vitro Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development Pathways

Feng

Wang

Grobler

et al. 2015

Antimicrob Agents Chemother

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“…For highly protein-bound inhibitors, in vitro antiviral potencies shift significantly when the assays are conducted in the presence of 50% serum compared with 10% serum (14)(15)(16)(17). Although it is highly desirable to assess activity in the presence of 100% serum, the potency at 100% serum is often extrapolated from the potency determined at a lower percentage of serum, assuming a linear relationship between inhibitory potency and serum concentration.…”

Section: Resultsmentioning

confidence: 99%

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Feng

Sachs

et al. 2016

Antimicrob Agents Chemother

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Doravirine (DOR), which is currently in a phase 3 clinical trial, is a novel human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI). DOR exhibits potent antiviral activity against wild-type virus and K103N, Y181C, and K103N/Y181C mutant viruses, with 50% inhibitory concentrations (IC 50 s) of 12, 21, 31, and 33 nM, respectively, when measured in 100% normal human serum (NHS). To assess the potential for DOR to suppress NNRTI-associated and rilpivirine (RPV)-specific mutants at concentrations achieved in the clinic setting, inhibitory quotients (IQs) were calculated by determining the ratio of the clinical trough concentration over the antiviral IC 50 for each virus with DOR and RPV and efavirenz (EFV). DOR displayed IQs of 39, 27, and 25 against the K103N, Y181C, and K103N/Y181C mutants, respectively. In contrast, RPV exhibited IQs of 4.6, 1.4, and 0.8, and EFV showed IQs of 2.5, 60, and 1.9 against these viruses, respectively. DOR also displayed higher IQs than those of RPV and EFV against other prevalent NNRTI-associated mutants, with the exception of Y188L. Both DOR and EFV exhibited higher IQs than RPV when analyzed with RPV-associated mutants. Resistance selections were conducted with K103N, Y181C, G190A, and K103N/Y181C mutants at clinically relevant concentrations of DOR, RPV, and EFV. No viral breakthrough was observed with DOR, whereas breakthrough viruses were readily detected with RPV and EFV against Y181C and K103N viruses, respectively. These data suggest that DOR should impose a higher barrier to the development of resistance than RPV and EFV at the concentrations achieved in the clinic setting.T he introduction of highly active antiretroviral therapy (HAART) in 1996 has significantly reduced the morbidity and mortality associated with HIV-1 infection (1, 2). However, the clinical and immunologic benefits of antiretroviral therapy can be compromised by the emergence of drug-resistant viruses due to suboptimal treatment or adherence.Drug-resistant mutants can be transmitted to an uninfected individual. Transmitted drug-resistant (TDR) mutants limit the choice of first-line combination antiretroviral therapy, decrease the efficacy of subsequent antiretroviral regimens, and increase the risk of treatment failure (3-5). TDR mutants have been documented among treatment-naive patients, with prevalences ranging from 3% to 24%, depending on the cohort and geographic characteristics (6). Importantly, transmitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants are of particular concern, as they have the ability to persist for years after initial infection, suggesting the low impact of NNRTI-resistant mutations on viral fitness (7-9). The persistence of NNRTI-associated mutants after the discontinuation of an NNRTI-containing regimen may contribute to the prevalence of NNRTI-associated TDR mutants.Three mutants, K103N, Y181C, and G190A, account for Ͼ90% of the NNRTI-associated TDR mutants in the United States (10). K103N, Y181C, and K103N/Y181...

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Pharmaceutical Approaches to HIV Treatment and Prevention

Yavuz

Morgan

Showalter

et al. 2018

Advanced Therapeutics

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Human immunodeficiency virus (HIV) infection continues to pose a major infectious disease threat worldwide. It is characterized by the depletion of CD4 + T cells, persistent immune activation, and increased susceptibility to secondary infections. Advances in the development of antiretroviral drugs and combination antiretroviral therapy have resulted in a remarkable reduction in HIV-associated morbidity and mortality. Antiretroviral therapy (ART) leads to effective suppression of HIV replication with partial recovery of host immune system and has successfully transformed HIV infection from a fatal disease to a chronic condition. Additionally, antiretroviral drugs have shown promise for prevention in HIV pre-exposure prophylaxis and treatment as prevention. However, ART is unable to cure HIV. Other limitations include drug-drug interactions, drug resistance, cytotoxic side effects, cost, and adherence. Alternative treatment options are being investigated to overcome these challenges including discovery of new molecules with increased anti-viral activity and development of easily administrable drug formulations. In light of the difficulties associated with current HIV treatment measures, and in the continuing absence of a cure, the prevention of new infections has also arisen as a prominent goal among efforts to curtail the worldwide HIV pandemic. In this review, the authors summarize currently available anti-HIV drugs and their combinations for treatment, new molecules under clinical development and prevention methods, and discuss drug delivery formats as well as associated challenges and alternative approaches for the future.

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In VitroCharacterization of MK-1439, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor

Cited by 104 publications

References 45 publications

In Vitro Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development Pathways

In Vitro Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development Pathways

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Pharmaceutical Approaches to HIV Treatment and Prevention

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