Etravirine: the renaissance of non-nucleoside reverse transcriptase inhibitors

Jayaweera, Dushyantha; Espinoza, Luis; Castro, J. López

doi:10.1517/14656560802489569

Cited by 9 publications

(4 citation statements)

References 27 publications

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“…Generally, second-line treatment is limited to boosted protease inhibitor based regimes for patients failing first-line therapy. ETR offers a higher genetic barrier to the development of viral resistance than the first-generation NNRTIs [35]. Yet, to date little is known about the drug's potential effectiveness in sub-Saharan Africa although on a positive note over 90% of patients previously exposed in southern Africa treatment programs would remain susceptible to ETR [36].…”

Section: Discussionmentioning

confidence: 99%

Low-Abundance Resistant Mutations in HIV-1 Subtype C Antiretroviral Therapy-Naive Individuals as Revealed by Pyrosequencing

González¹,

Tully²,

Gondwe³

et al. 2013

Current HIV Research

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Given the recent scale-up of antiretroviral therapy (ART) in sub-Saharan Africa, we sought to determine how often and at what levels do drug-resistant mutant variants exist in ART-naïve HIV subtype C infected individuals. Samples from 10 ART-naïve Zambian individuals were subjected to ultra-deep pyrosequencing (UDPS) to characterize the frequency of low-abundance drug resistance mutations in the pol gene. Low-abundance clinically relevant variants were detected for nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in eight of the ten subjects. Intermediate to high-level resistance was predicted for the majority of NRTIs. Mutations conferring resistance to most first-line and some second-line therapy drugs were also observed. UDPS detected a number of additional major resistant mutations suggesting that these individuals may have an increased risk of virological failure after initiating ART. Moreover, the effectiveness of first-line and even some second-line ART may be compromised in this setting.

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Section: Discussionmentioning

confidence: 99%

Low-Abundance Resistant Mutations in HIV-1 Subtype C Antiretroviral Therapy-Naive Individuals as Revealed by Pyrosequencing

González¹,

Tully²,

Gondwe³

et al. 2013

Current HIV Research

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“…There is a new NNRTI, etravirine, which, in contrast to nevirapine and efavirenz, requires multiple mutations to reduce drug susceptibility [10,11]. Therefore, it is important to assess the prevalence of etravirine-associated mutations in children who have experienced failure of first-line NNRTI treatment in order to predict the potential role of etravirine as a component of second-line regimens.…”

Section: Introductionmentioning

confidence: 99%

“…Data from an HIV-infected adult Thai cohort showed that the majority of patients who experienced failure of NNRTI regimens had M184V (89%), NNRTI resistance mutations (92%), thymidine analogue mutations (37%), Q151M (8%) and K65R (6%). High plasma HIV RNA at the time of treatment failure was associated with a higher risk of multi-NRTI resistance [9].There is a new NNRTI, etravirine, which, in contrast to nevirapine and efavirenz, requires multiple mutations to reduce drug susceptibility [10,11]. Therefore, it is important to assess the prevalence of etravirine-associated mutations in children who have experienced failure of first-line NNRTI treatment in order to predict the potential role of etravirine as a component of second-line regimens.…”

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confidence: 99%

HIV‐1 drug resistance mutations in children after failure of first‐line nonnucleoside reverse transcriptase inhibitor‐based antiretroviral therapy

et al. 2010

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ObjectivesThe aim of the study was to assess the prevalence, predictors and patterns of genotypic resistance mutations in children after failure of World Health Organization-recommended initial nonnucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimens. MethodsWe carried out a multicentre retrospective study of genotyping tests performed for all HIV-infected children at eight paediatric centres in Thailand who experienced failure of NNRTI therapy at a time when virological monitoring was not routinely available. ResultsOne hundred and twenty children were included in the study. Their median age (interquartile range) was 9.1 (6.8-11.0) years, the median duration of their NNRTI regimens was 23.7 (15.7-32.6) months, their median CD4 percentage was 12% (4-20%), and their median plasma HIV RNA at the time of genotype testing was 4.8 (4.3-5.2) log 10 HIV-1 RNA copies/mL. The nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations found were as follows: 85% of the children had M184V/I, 23% had at least four thymidine analogue mutations, 12% had the Q151M complex, 5% had K65R, and 1% had the 69 insertion. Ninety-eight per cent of the children had at least one NNRTI resistance mutation, and 48% had etravirine mutation-weighted scores 4. CD4 percentage o15% prior to switching regimens [odds ratio (OR) 5.49; 95% confidence interval (CI) 2.02-14.93] and plasma HIV RNA45 log 10 copies/mL (OR 2.46; 95% CI 1.04-5.82) were independent predictors of at least four thymidine analogue mutations, the Q151M complex or the 69 insertion. ConclusionsIn settings without routine viral load monitoring, second-line antiretroviral therapy regimens should be designed assuming that clinical or immunological failure is associated with high rates of multi-NRTI resistance and NNRTI resistance, including resistance to etravirine. IntroductionThe widespread use of antiretroviral therapy (ART) for the treatment of HIV-infected children has dramatically changed the course of HIV infection, leading to reductions in morbidity and mortality [1][2][3]. A triple drug combination including two nucleoside reverse transcriptase inhibitors (NRTIs) plus one nonnucleoside reverse transcriptase inhibitor (NNRTI) or one protease inhibitor (PI) [4] is widely recommended as first-line therapy. For resource-limited settings, the World Health Organization (WHO) recommends an NNRTI-based regimen, which is preferred because it is effective, well tolerated and inexpensive. Plasma HIV RNA monitoring after initiation of ART is usually not available through treatment programmes in resource-limited settings [5]. For example, the Thai national AIDS programme provides antiretroviral drugs for HIVinfected patients and CD4 monitoring every 6 months. Annual plasma HIV viral load monitoring was only recently incorporated into the national programme in 2008. Thus, in the past, the majority of Thai children were diagnosed with treatment failure when they had clinical or immunological failure, that is a long time after virological replication had ...

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“…Moreover, Y181C also confers resistance to the recently introduced NNRTIs etravirine (ETR) and rilpivirine (RPV) (6,8,9). In addition to the issue of resistance, currently approved NNRTIs also cause adverse effects, are difficult to combine with other drugs due to cytochrome P450 interactions, or require twice-daily dosing (10)(11)(12). The development of three pipeline NNRTIs (RDEA-806, fosdevirine, and lersivirine) was recently stopped due to safety issues and/or strategic reasons.…”

mentioning

confidence: 99%

In VitroandIn VivoActivities of AIC292, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor

Wildum

Paulsen

Thede

et al. 2013

Antimicrob Agents Chemother

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bNonnucleoside reverse transcriptase inhibitors (NNRTIs) are important and frequently used elements of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. However, the development of drug resistance, as well as the side effects of existing drugs, defines a medical need for novel NNRTIs with excellent tolerability, improved activity against NNRTI-resistant viruses, and a low barrier to resistance. Within the chemical class of diarylpyrazole-[imidazolidinone]-carboxamides, AIC292 was identified as a promising novel HIV-1 NNRTI and has successfully completed single-dose clinical phase I studies. Here, we report on the antiviral activity of AIC292, evaluated in vitro against wild-type and NNRTI-resistant HIV-1 isolates and in vivo using an engineered mouse xenograft model. AIC292 inhibited wild-type HIV-1 laboratory strains at low nanomolar concentrations, was well tolerated in different cell lines, and showed excellent selectivity in a lead profiling screen. In addition, activity of AIC292 could be demonstrated against a broad panel of wild-type HIV-1 group M and group O clinical isolates. AIC292 also retained activity against viruses harboring NNRTI resistance-associated mutations (RAMs), including the most prevalent variants, K103N, Y181C, and G190A. Interestingly, viruses bearing the L100I RAM were hypersusceptible to AIC292. Two-drug combination assays showed no antagonistic interactions between AIC292 and representative marketed HIV drugs with regard to antiviral activity. Furthermore, AIC292 displayed potent antiviral in vivo efficacy in a mouse xenograft model when applied once daily. Taken together, these data show that AIC292 represents a molecule with the antiviral properties of a novel NNRTI for the treatment of HIV-1 infection.

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Etravirine: the renaissance of non-nucleoside reverse transcriptase inhibitors

Cited by 9 publications

References 27 publications

Low-Abundance Resistant Mutations in HIV-1 Subtype C Antiretroviral Therapy-Naive Individuals as Revealed by Pyrosequencing

Low-Abundance Resistant Mutations in HIV-1 Subtype C Antiretroviral Therapy-Naive Individuals as Revealed by Pyrosequencing

HIV‐1 drug resistance mutations in children after failure of first‐line nonnucleoside reverse transcriptase inhibitor‐based antiretroviral therapy

In VitroandIn VivoActivities of AIC292, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor

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