Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients – Impact of HIV subtypes and prior raltegravir experience

doi:10.1016/j.antiviral.2011.03.178

Antiviral Research

Volume 90, Issue 3, June 2011, Pages 164-167

https://doi.org/10.1016/j.antiviral.2011.03.178 Get rights and content

Abstract

Dolutegravir (S/GSK1349572) is a second-generation HIV-1 integrase inhibitor (INI) in advanced clinical development. It has shown good antiviral activity in most patients with prior raltegravir failure, although changes at the integrase codon 148, particularly when combined with other mutations, confer reduced susceptibility and may impair dolutegravir activity.

Mutations believed to be associated with dolutegravir resistance at positions 92, 101, 124, 148, 153, and 193 were assessed in patients either INI-naïve or experiencing failure to raltegravir-based regimens. The integrase coding region was sequenced using an in-house nested-PCR protocol. HIV-1 subtyping was carried out using the Stanford algorithm.

A total of 638 plasma samples were analyzed from 535 INI-naïve and 103 raltegravir-experienced patients. Non-B subtypes were recognized in 20.8% patients. Mutations L101I and T124A were significantly more prevalent in patients with non-B subtypes (66.9% vs. 45.7% for L101I; 61.7% vs. 25.9% for T124A; and 39.1% vs. 12.7% for L101I + T124A; p < 0.001 in all cases). E92Q and Q148H/R were only seen in raltegravir-experienced patients and exclusively infected with subtype B (1.9% vs. 0%, p = 0.026, for E92Q and 12.6% vs. 0%, p < 0.001, for Q148H/R). On the contrary, T124A was more frequent in INI-naïve than raltegravir-experienced patients (35.1% vs. 24.3%, p = 0.040). S153Y/F was absent in this dataset.

Polymorphic changes L101I and T124A were more frequent in HIV-1 non-B than B subtypes. T124A was more frequent in INI-naïve patients but E92Q and Q148H/R were only seen in raltegravir-experienced individuals. Thus, both HIV-1 subtype and raltegravir exposure may influence the antiviral activity of dolutegravir.

Introduction

Dolutegravir, formerly S/GSK1349572 (Shionogi/GlaxoSmithKline) is a second-generation HIV integrase inhibitor (INI), which preferentially blocks the strand transfer step during the viral integration process. The drug has demonstrated potent antiviral activity both in vitro (Johns et al., 2010) and in vivo (Rockstroh et al., 2010, Eron et al., 2010a). Dolutegravir displays some important advantages relative to first-generation INIs raltegravir and elvitegravir, as it is administered once daily, does not require boosting, and displays activity against most isolates resistant to raltegravir or elvitegravir (Eron et al., 2010a, Kobayashi et al., 2010, Seki et al., 2010, Sato et al., 2009).

Limited information exists about the resistance profile of dolutegravir. Two in vitro studies have identified changes at the integrase gene following serial virus passages, including E92Q, L101I, T124A, S153Y/F and G193E (Kobayashi et al., 2010, Seki et al., 2010, Sato et al., 2009). In the first study, after 56 days of virus culture in the presence of dolutegravir, mutation T124A either alone or accompanied by S153F, emerged. At days 84 and 112, four different mutants appeared: T124A, S153Y, T124A + S153Y and L101I + T124A + S153F. Interestingly, these mutants displayed only limited phenotypic resistance to dolutegravir with a maximum fold change of 4.1 (Sato et al., 2009). In another in vitro experiment, after 56 days of serial virus passages with dolutegravir, mutants harboring E92Q or G193E were selected, once again with minor impact on phenotypic susceptibility (average fold change 3.2) (Kobayashi et al., 2010). Mutations E92Q and S153Y have been associated with raltegravir and/or elvitegravir resistance, while changes at residue 124 have occasionally been observed in some in vitro experiments using different integrase inhibitors with no significant impact on drug susceptibility (Kobayashi et al., 2008). Mutation L101I had never been described so far.

Recently, Marcelin et al. (2010) examined the rate of dolutegravir-associated resistance mutations in a group of INI-naïve and raltegravir-experienced patients infected with HIV-1 subtype B in France. They found a significantly higher rate of T124A and L101I + T124A in patients with prior raltegravir failure than in INI-naïve subjects. Another study (Underwood et al., 2009) found that mutations at codon 148 along with some secondary changes such as G140S or E138K, which are often selected in patients failing raltegravir, were associated with a reduced phenotypic susceptibility to dolutegravir, with a median of 19-fold loss of susceptibility. The aim of our study was to assess the rate of dolutegravir resistance associated mutations in a large group of INI-naïve and raltegravir-experienced patients infected with different HIV-1 subtypes.

Section snippets

Patients and methods

Consecutive plasma specimens collected from HIV-1-infected individuals on regular follow-up at several Spanish HIV outclinics and one referral hospital in London during year 2008 were analyzed. Bulk sequencing of the HIV-1 integrase coding region was carried out following an in-house nested-PCR protocol described elsewhere (Garrido et al., 2010). All sequences were analyzed using Seqscape v2.5. We considered as resistance mutations potentially associated with dolutegravir those that had been

Results

A total of 638 HIV-1 integrase sequences were analyzed. They belonged to 535 (83.9%) INI-naïve and 103 (16.1%) raltegravir-experienced patients, all of them naïve for dolutegravir. Overall, 505 (79.2%) belonged to subjects infected with clade B variants and 133 (20.8%) to individuals infected with non-B subtypes. The distribution of non-B subtypes was as follows: 15 (11.3%) A, 19 (14.3%) C, 10 (7.5%) D, 20 (15%) F, 18 (13.5%) G, 18 (13.5%) CRF01_AE, and 33 (24.8%) CRF02_AG.

Some mutations

Discussion

The advent of INIs has expanded the therapeutic options for HIV-infected individuals. Raltegravir, the first drug approved in this class, has shown potent antiviral activity as well as a satisfactory safety profile (Lennox et al., 2009, Steigbigel et al., 2008). Accordingly, the drug has been approved for the treatment of both antiretroviral-naive and -experienced patients, and is currently widely used in western countries in multiple clinical scenarios, including switch strategies (Eron et

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Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients – Impact of HIV subtypes and prior raltegravir experience

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Lancet

Antiviral Res.

Lancet

Secondary integrase resistance mutations found in HIV-1 minority quasispecies in integrase therapy-naive patients have little or no effect on susceptibility to integrase inhibitors

Antimicrob. Agents Chemother.

Longitudinal analysis of raltegravir susceptibility and integrase replication capacity of HIV type 1 during virologic failure

Antimicrob. Agents Chemother.

Integrase variability and susceptibility to HIV integrase inhibitors: impact of subtypes, antiretroviral experience and duration of HIV infection

J. Antimicrob. Chemother.