Rilpivirine resistance mutations in HIV patients failing non-nucleoside reverse transcriptase inhibitor-based therapies

Anta, Lourdes; Llibre, Josep M; Poveda, Eva; Blanco, José Luis Santiago; Alvarez, Marta; Pérez-Elías, María Jesús; Aguilera, Antonio; Caballero, Estrella; Soriano, Vincent; Mendoza, Carmen de

doi:10.1097/qad.0b013e3283584500

Cited by 58 publications

(46 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…E138K and M184I/V have a mutual compensatory effect in regard to RT processivity and viral replication capacity (9,11,43,44). However, unlike N348I, E138K is relatively rare in treatment-experienced patients (40,(45)(46)(47), despite the fact that it can mutually compensate for M184I/V (43,44).…”

mentioning

confidence: 86%

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

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 86%

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

View full text Add to dashboard Cite

show abstract

“…Moreover, 32% of 48 Senegalese children with virologic failure had the Y181C mutation (36). Further large-scale analysis in Spain showed that the rates of prevalence of Y181C, Y181I, and Y181V were 21.8%, 0.5%, and 0.2%, respectively, in 1,064 HIV-1-infected patients failing EFV, NVP, or ETR therapy (37). The Y181C mutation, which requires a single nucleotide change, is frequently observed in NNRTI-treated patients compared to Y181I or Y181V, each of which requires a double-nucleotide change.…”

Section: Discussionmentioning

confidence: 99%

Different Effects of Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Cytotoxic T Lymphocyte Recognition between HIV-1 Subtype B and Subtype A/E Infections

Kuse

Rahman

Murakoshi

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…Mutations associated with resistance to NVP and EFV include L100I, K101E/P, K103N/S, V106A/M, Y181C/I/V, Y188C/L/H, G190A/E/S, and M230L (Stanford University HIV Drug Resistance Database: http://hivdb.stanford.edu/). Although ETV and RIL have been reported to have higher in vitro genetic barriers to resistance than EFV or NVP (Andries et al 2004;Azijn et al 2010), 17 mutations in HIV-1 RT have been associated with decreased virologic response to ETV (V90I, A98G, L100I, K101E/H/P, V106I, E138A, V179D/F/T, Y181C/I/ V, G190A/S, and M230L) ) and 15 mutations with decreased virologic response to RIL (K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, and M230I/L) (Anta et al 2013). The locations of the mutations associated with NVP, EFV, RIL, and ETV resistance are shown in Fig.…”

Section: Hiv-1 Resistance To Nnrtismentioning

confidence: 98%

HIV-1 Resistance to Reverse Transcriptase Inhibitors

Schauer

Sluis‐Cremer

2014

Handbook of Antimicrobial Resistance

View full text Add to dashboard Cite

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.

show abstract

Rilpivirine resistance mutations in HIV patients failing non-nucleoside reverse transcriptase inhibitor-based therapies

Abstract: RPV resistance is overall recognized in nearly 20% of patients failing other NNRTIs. It is more common following ETR (27.6%) or NVP (25%) failures than EFV (14.5%). E138 mutants are rarely seen in this context.

Cited by 58 publications

References 10 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

Different Effects of Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Cytotoxic T Lymphocyte Recognition between HIV-1 Subtype B and Subtype A/E Infections

HIV-1 Resistance to Reverse Transcriptase Inhibitors

Contact Info

Product

Resources

About