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Journal of Antimicrobial Chemotherapy logoLink to Journal of Antimicrobial Chemotherapy
. 2016 Mar 29;71(7):1948–1953. doi: 10.1093/jac/dkw071

Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors

Bluma G Brenner 1, Réjean Thomas 2, José Luis Blanco 3, Ruxandra-Ilinca Ibanescu 1, Maureen Oliveira 1, Thibault Mesplède 1, Olga Golubkov 1, Michel Roger 4, Federico Garcia 5,6, Esteban Martinez 3, Mark A Wainberg 1,*
PMCID: PMC4896408  PMID: 27029845

Abstract

Objectives

Dolutegravir shows a high barrier to resistance with no previously reported cases of acquired integrase mutations during first-line therapy. In this study, rapid development of the G118R mutation arose following a switch from first-line elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine to dolutegravir monotherapy. The G118R mutation also arose in a treatment-experienced patient switched to dolutegravir monotherapy. The genetic basis for G118R selection and potential phenotypic outcome was ascertained.

Patient and methods

Genotypic analysis was performed on patients with virological failure (<1000 copies/mL) on dolutegravir-containing regimens. The Los Alamos database was queried for glycine codon 118 polymorphisms. Cell culture selections and phenotypic drug susceptibility assays assessed resistance via the G118R pathway.

Results

We report on two patients who developed viral failure while on dolutegravir monotherapy. Both patients had been on a current or previous regimen containing integrase inhibitors. Virological failure (<1000 copies/mL) emerged early within 2 months following the dolutegravir switch. The appearance of G118R in these two cases and subtype C and CRF02_AG in vitro selections were related to a rare GGA natural polymorphism at codon 118 (1.5% prevalence), facilitating a GGA to AGA transition. Cell culture selections were used to assess the in vitro progression of the G118R pathway leading to cross-resistance to all integrase inhibitors.

Conclusions

Although resistance to dolutegravir is typically rare, genetic polymorphisms and monotherapy can facilitate the acquisition of G118R.

Introduction

Combination ART has revolutionized HIV-1/AIDS management, suppressing viral replication in infected individuals and averting HIV transmission at a population level. A limiting factor of the long-term efficacy of the earliest drug classes, including NRTIs, NNRTIs and/or PIs, was the development of mutations by an error-prone HIV RT enzyme conferring resistance to individual drugs and/or drug classes.1 Genotypic drug resistance testing and genotypic/phenotypic drug resistance algorithms can monitor the acquisition of mutations and help to optimize the selection and modification of drug regimens.

Integrase strand transfer inhibitors (INSTIs), including raltegravir, elvitegravir and dolutegravir, approved in 2007, 2012 and 2013, respectively, are the newest class of drugs effective in ART-experienced patients harbouring viruses resistant to other classes.2 Moreover, INSTI-based regimens are also favoured for ART-naive HIV-infected persons, based on improved tolerability, better drug–drug interaction profiles (raltegravir, dolutegravir), dosing (once or twice daily) and a high genetic barrier to resistance.2,3 Indeed, the single tablet co-formulations of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine or dolutegravir/abacavir/lamivudine are now recommended treatment options for ART-naive populations (http://aidsinfo.nih.gov/guidelines).

The long-term efficacy of INSTI inhibitors will require an understanding of pathways implicated in the evolution of drug resistance. Elvitegravir and raltegravir may develop resistance via the N155H and G140A/G148RHQ pathways that confer cross-resistance to raltegravir and elvitegravir or via the Y143R/H/C (raltegravir-specific) or T66I, E92QG, Q146P and S147G (elvitegravir-specific) pathways.2 In contrast, dolutegravir shows a higher genetic barrier to resistance, retaining activity against viral variants harbouring 155, 143, 66 and 92 resistance mutational motifs.2 To date, no drug-resistant strains have been reported in ART-naive persons receiving dolutegravir through 144 weeks of follow-up.46 However, R263K and N155H mutations have been reported in several treatment-experienced, INSTI-naive patients receiving dolutegravir-containing regimens (SAILING study) and both R263K and G118R have been selected by dolutegravir in tissue culture, although not at the same time.7

In the absence of clinical resistance, in vitro cell culture selections have been used to identify potential pathways implicated in viral escape from dolutegravir. Studies in our laboratory have identified R263K, S153F/Y or H51Y mutations in subtype B clinical isolates.2,812 The G118R substitution was also observed with one subtype C and one CRF02_AG isolate.2,812

The use of dolutegravir monotherapy and dolutegravir/lamivudine dual therapy is being debated for streamlined therapy for initial treatment, for heavily treatment-experienced patients with resistant virus, and for those who cannot tolerate adverse side effects.1316 Our study documents two cases of virological failure upon switch to dolutegravir monotherapy. There was a rapid acquisition of a G118R substitution in a Montreal patient who switched to dolutegravir monotherapy after suppression on first-line elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine. In addition, G118R resistance was observed in a treatment-experienced Barcelona patient switched to dolutegravir monotherapy. We postulate that the development of G118R in the virus of both patients and in non-B cell culture selections may be related to a rare natural polymorphism at integrase codon 118 (GGA, 1.5% global prevalence), facilitating a GGA to AGA transition. Cell culture selections on viral isolates harbouring the GGA natural polymorphism were also performed to show that the G118R resistance substitution can lead to viral escape from integrase inhibitors, including dolutegravir.

Patients and methods

Patients and viral sequencing

A Montreal research study at Clinique Médicale l'Actuel, designed to investigate emergent resistance in persons failing first-line INSTI-based regimens (viral loads 50–1000 log copies/mL), identified one person who had rapid (<5 months) viral escape when switched from elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine to dolutegravir monotherapy (300–800 copies/mL).

A Barcelona research study examined the benefit of a switch to dolutegravir monotherapy in virologically suppressed patients with limited therapeutic options due to antiretroviral-related toxicity, comorbidities, risk for significant drug interactions or drug resistance (n = 33).16 After 8 weeks of virologically successful dolutegravir monotherapy, one patient developed persistent low-level viraemia over the remainder of the 24 week period (<200 copies/mL).

Viral RNA or proviral DNA was amplified from plasma, PBMCs and/or cell culture fluids as previously described.9 The integrase gene was genotyped by standard laboratory protocols, using previously described home-brew primers for amplification and sequencing.9,17,18 Ultradeep sequencing analysis was performed using a commercial prototype on the Roche 454-Gs Junior platform. The GenBank accession number for the Quebec patient clinical isolate harbouring the G118R mutation is KT906364.

Ethics

Ethics approval and informed patient consent forms were obtained in accordance with the Declaration of Helsinki, national and institutional standards. The patients provided written informed consent and the protocols were approved by ethics committees at the Clinique Médicale l'Actuel (Veritas independent review board), Jewish General Hospital (protocol 13-076) and the University of Barcelona.

Selection of resistance to integrase inhibitors and phenotypic drug susceptibility

Dolutegravir was provided by ViiV Healthcare Ltd (Research Triangle Park, NC, USA). Elvitegravir was obtained from Gilead Sciences Inc. (Foster City, CA, USA). Raltegravir and the investigational second generation INSTI, MK-2048, were kindly provided by Merck Inc. (West Point, PA, USA).

A subtype C clinical isolate (4742) harbouring the GGA natural polymorphism at codon 118 was amplified through co-culture in phytohaemagglutinin-stimulated cord blood mononuclear cells, as previously described.9 Drug selections were performed in the presence of increasing concentrations of dolutegravir and MK-2048. Drug selections with raltegravir, elvitegravir and dolutegravir was also performed on a pNL-4.3 virus in which G118R was introduced by site-directed mutagenesis, as previously described.8 Aliquots of culture fluid at each passage were stored at −70°C. Genotypic analysis and phenotypic drug susceptibility assays to INSTIs was performed on amplified viruses at designated weeks following in vitro selection.8

Results

Montreal case of viral escape following first-line switch to dolutegravir monotherapy

A 42-year-old Quebec man having sex with men was diagnosed with HIV-1 infection in 1999. He remained asymptomatic and ART-naive until 2013 with viral loads <6000 copies/mL and CD4 cell counts >500 cells/mL. Initiation of ART was considered in August 2014, when he presented with a CD4 cell count <350 cells/mL and a viral load of 4000 copies/mL. Genotypic analysis revealed a subtype B infection and CXCR4 tropism. He tested HLA-*5701 positive, contraindicative for abacavir.

In September 2014, he initiated a once-daily Stribild regimen of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine and was virally suppressed for 5 months. In February 2015, the patient's viral load was undetectable (<40 copies/mL) and his CD4 cell count had increased to >500 cells/mm3. The patient, aware of the existence of so-called ‘light’ therapy prescribed elsewhere, requested a switch to dolutegravir monotherapy to minimize side effects. After discussion with the physician about potential problems involving monotherapy, the patient was switched from Stribild to dolutegravir monotherapy (Tivicay) at that time.

The patient had detectable viral escape (>50 copies/mL) in August 2015. Drug resistance testing on his plasma viral RNA on two occasions in August (300–800 copies/mL) revealed the acquisition of the G118R in viral integrase harbouring the following natural polymorphisms: D10E, E11D, S24D, D25E, N27H, V31I, L45Q, I60IM, V72IL, T112L, T124N, T125A, V126L, R127K, V201I, K215N, I220V, N232D, L234I and D286N (GenBank accession number KT906364). Analysis of the patient's proviral cDNA revealed an absence of G118R in archived virus. Sequencing of RT and protease revealed an absence of any acquired resistance mutations or polymorphisms. The integrase, RT and protease genes were all of subtype B origin.

In August 2015, the patient's ART regimen was changed to darunavir/cobicistat/tenofovir/emtricitabine and his viral load returned to undetectable by September 2015. The patient has remained virally suppressed to date, indicative of treatment adherence.

Barcelona case of virological failure following a switch to dolutegravir monotherapy

In a single-arm Barcelona study, 33 virally suppressed patients with no known resistance to INSTIs were switched to dolutegravir monotherapy (50 mg once daily) due to ART-related adverse effects/toxicity, significant drug–drug interactions or archived resistance compromising ART efficacy. One patient showed virological failure, 8 weeks after successfully switching to dolutegravir monotherapy.16 This 52-year-old patient with prior multidrug abuse had been infected with HIV for 12 years. He failed 10 previous regimens, including a raltegravir-containing regimen. Abstinent of harmful drug abuse for the last 2 years, he maintained viral suppression on darunavir/ritonavir monotherapy. He was also receiving psychotropic (palinperidone, trazodone and lorazepam), antihypertensive (losartan) and lipid-lowering (pitavastatin) therapy. He was switched to dolutegravir monotherapy and maintained viral suppression for 8 weeks. After detecting virological failure at week 8 (80 copies/mL), this patient was recommended to increase his dolutegravir dose to 50 mg twice daily, but he continued 50 mg once daily. The patient's viral load remained persistently detectable over the following 8 months (50–200 copies/mL). The subject reported low adherence, including to the increased dosing of twice-daily dolutegravir. Genotypic resistance testing of plasma viral RNA revealed no acquired integrase resistance mutations at weeks 8 and 24, However, ultradeep sequencing of proviral DNA revealed the presence of G118R in 7% of integrated-DNA in PBMCs at week 24. The patient continued to have low-level viraemia but was otherwise clinically healthy. At week 36, plasma viral RNA revealed the acquisition of G118R. At week 72, the patient was switched to darunavir/cobicistat.

G118R viral escape facilitated by a rare natural polymorphism

Further analysis of the nucleotide sequence of both patients' virus revealed a rare signature GGA motif at amino acid position 118 at baseline (present in 1.5% of Quebec provincial sequences) that may have impacted on the genetic barrier to dolutegravir resistance (Table 1). The generation of a G118R mutation would require a single point mutation from either GGA or GGG (i.e. GGA → AGA or GGG → AGA). In contrast, viral escape to G118R for the majority of clinical viral isolates harbouring GGC (79%) or GGT (18%) glycine motifs would require two point mutations (GGG → AGA or GGU → AGA) or single unfavourable transversions (GGG → CGG or GGU → CGT), respectively.

Table 1.

Analysis of codon usage at amino acid position 118 implicated in development of the G118R mutation conferring resistance to integrase inhibitors

Cohort Viral subtype (n) Glycine codon usage at amino acid position 118
GGA GGG GGC GGT Non-G
Quebec B 1.04 0 79.4 18.2 0
Los Alamos all (12478) 1.49 0.99 68.0 29.0 0.03
B (5128) 1.35 0.20 91.8 6.0 0.06
C (2494) 1.64 0.28 75.6 23.4 0
A1 (437) 0.92 0.23 90.6 6.6 0
CRF01_AE (1840) 1.41 2.34 2.2 93.9 0
CRF02_AG (270) 0.74 0 94.8 3.7 0
F (107) 0 0 93.5 6.5 0
G (97) 0 0 93.8 6.2 0
D (153) 0.65 0 92.2 4.6 0
CRF06 (121) 0 0.82 0.82 96.3 0
clade 0 (33) 9.1 90.9 0 0 0

Los Alamos database was mined on 17/08/2015 for the prevalence of different glycine codons at position 118, including GGG, GGA, GGC and GGU(T). Viral escape to G118R would require mutations leading to arginine codons, including AGG, AGA, CGG, CGA, CGC or CGU(T).

Our previously published studies have documented the preferential in vitro selection of G118R in clinical isolates from two persons harbouring subtype C and CRF02_AG infections.11,19 The generation of G118R was observed to occur under selection pressure with both dolutegravir and the investigational drug, MK-2048. It was noteworthy that re-examination of the nucleotide sequences of both of these non-B subtype viruses revealed the rare GGA signature motif at amino acid position 118 at baseline.

The Los Alamos HIV database was queried to assess glycine codon usage at position 118 among different viral subtypes (http://www.hiv.lanl.gov/components/sequence/HIV/search/search.html). As summarized in Table 1, the overall frequency of GGA at position 118 among HIV-1 subtypes was 1.5%, compared with 1.0%, 68% and 29% for GGG, GGC and GGT, respectively. Interestingly, only HIV groups O and N showed high, i.e. 9% and 100% frequencies, respectively, of the GGA signature motif.

Cell culture selections of G118R-containing viruses leading to cross-resistance to integrase inhibitors

The low viral load in the Montreal patient precluded viral amplification and phenotypic analysis. Previous tissue culture studies documented selection of G118R in one subtype C (4742) and one subtype CRF02_AG viral isolate under selective pressure with the second-generation INSTI investigational drug, MK-2048 and with raltegravir.9 Based on enzymatic analysis, it was assumed that subtype-specific fitness costs would preclude the development of G118R in subtype B viruses.11,19

Cell culture selections and drug susceptibility assays were performed to assess emergent resistance along the G118R resistance pathway. As illustrated in Figure 1, the selections of the subtype C clinical isolate 4742 with both MK-2048 and dolutegravir led to the acquisition of G118R at weeks 19 and 29, respectively, that was not initially associated with reduced drug susceptibility. The acquisition of G118R in MK-2048 was followed by the sequential accumulation of secondary mutations including E138K (week 29), T66A (week 35) and L74M/V151I (weeks 40 and 55). It is noteworthy that the sequential acquisition of G118R with dolutegravir (week 29) was also followed by E138K (week 50) and T66A (week 66).

Figure 1.

Figure 1.

G118R pathway conferring cross-resistance to integrase strand transfer inhibitors. (a) The 4742 subtype C clinical isolate harbouring a GGA at codon 118 in integrase was serially passaged in the presence of increasing doses of MK-2048 or DTG. First appearance and sequential accumulation of resistance mutations are numbered. Similar mutations arose with both drugs, albeit in an attenuated fashion for dolutegravir. (b) G118R mutation was introduced by site-directed mutagenesis into subtype B pNL4.3 virus, Serial passage with increasing concentrations of DTG, RAL and EVG led to the emergence of T66I, E138K and/or E157Q secondary mutations. DTG, dolutegravir; EVG, elvitegravir; RAL, raltegravir.

Site-directed mutagenesis of pNL-43 plasmid viruses was used to generate the G118R mutation within a subtype B integrase backbone.8 Cell culture selections of the G118R viruses in cord blood mononuclear cells resulted in selection of T66I and E138K with dolutegravir (week 25) and raltegravir (week 30) while T66I and E157Q arose with elvitegravir (week 30).

Viral stocks were amplified from the MK-2048 selection to assess the phenotypic drug susceptibility of viruses harbouring G118R in the presence of secondary mutations. As summarized in Table 2, the presence of G118R did not significantly impact on susceptibility to integrase inhibitors, showing IC50 values similar to that observed for WT viruses. The presence of G118R leading to the cumulative acquisition of E138K and T66A led to 2–4- and 5–7-fold cross-resistance to dolutegravir, elvitegravir and raltegravir, respectively. This pathway led to high-level >100-fold resistance to MK-2048.

Table 2.

G118R resistance pathway conferring cross-resistance to integrase inhibitors

Resistance mutation Phenotypic drug susceptibility (fold resistance)
DTG EVG RAL MK-2048
G118R 1 0.9 0.8 0.4
G118R, E138K 1.7 4.1 4.4 139
G118R, E138K, T66A 6.5 6.6 4.6 175
G118R, E138K, T66A, L74M, V151I 8.0 10.0 11.3 300

DTG, dolutegravir; EVG, elvitegravir; RAL, raltegravir.

Viral stocks were amplified from the MK-2048 selection and genotyped. Cell culture phenotypic drug susceptibility monitored fold resistance to DTG, RAL, EVG and MK-2048, relative to a WT virus.

These findings show that the genesis of the G118R pathway may lead to dolutegravir escape and further acquisition of secondary mutations conferring cross-resistance to elvitegravir and raltegravir. In contrast, cell culture selections have shown that the acquisition of R263K and S153Y with dolutegravir leads to marginal resistance (<3-fold) and no further acquisition of resistance mutations.

Taken together, our findings show that although resistance to dolutegravir is typically rare, genetic polymorphisms and monotherapy can facilitate the acquisition of G118R. Baseline genotyping may identify the presence of this GGA polymorphism, forewarning of the possibility of G118R appearance.

Discussion

The evolution of drug resistance is multifactorial, dependent on the fitness of the mutant variant, the level of resistance that a specific mutation confers, and the frequency of that mutation within a given viral population. Dolutegravir-based regimens remain a treatment option of choice, based on high potency with no previously reported cases of emergent resistance in first-line therapy.14,20 Mutations, such as R263K and S153Y, observed in several ART-experienced patients who were switched to dolutegravir-based regimens, confer only low-level resistance at high fitness cost. The rare emergence of the latter two mutations has not led to further accumulation of resistance and/or compensatory mutations.

In this study, we show that GGA mutational bias allowed the favoured selection of G118R. Genetic barrier, defined as the number and nature of nucleotide changes, plays a central role in the generation of drug resistance.21 Transversions and/or multiple nucleotide changes per amino acid substitution represent a higher genetic barrier than transitions and single nucleotide changes. Our tissue culture studies with the investigational INSTI MK-2048 and dolutegravir show G118R selections in subtype B, C and AG isolates were all followed by the sequential acquisition of E138K and T66A/I conferring high-level resistance to MK-2048 (>100-fold) and cross-resistance to dolutegravir, elvitegravir and raltegravir (3–7-fold).

Our findings show that G118R is not a substitution for dolutegravir resistance that is restricted to non-B subtypes.11,12,19,22,23 Rather, G118R selection was predicated on the presence of a GGA natural polymorphism, rarely observed in both B and non-B subtypes.

To our knowledge, this report presents the first documented cases of dolutegravir escape, related in part to a GGA mutational bias, facilitating the selection of G118R on dolutegravir monotherapy regimens. The only previous reported case of G118R in a clinical setting was in a patient harbouring a CRF02_AG virus who failed a raltegravir-based regimen.22 This isolate was observed to confer 8.2-, 3.1- and 10-fold resistance to raltegravir, elvitegravir and dolutegravir, respectively.23 These findings are consistent with our results.

To date, analysis of dolutegravir resistance has been largely restricted to in vitro analysis. Dolutegravir escape mutations, including R263K and S153Y, confer marginal resistance (1–3-fold), accompanied by costs in replication fitness costs and no accumulation of resistance and/or compensatory mutations over time.24,25 Our in vitro studies showed the emergence of G118R in two viral strains with dolutegravir or the investigational INSTI, MK-2048. The Montreal patient in our study was changed to a darunavir-based regimen based on the in vitro observation of potential accumulation of T66I/A and E138K mutations conferring cross-resistance across the INSTI class.

The use of dolutegravir monotherapy is being debated for streamlined therapy, to reduce side effects and for heavily treatment-experienced patients with resistant virus and for those who cannot tolerate adverse side effects.26 The present case captured viral escape through a G118R substitution that may not have occurred in a dolutegravir regimen with three or more active drugs. Indeed, the patient had achieved viral suppression for 5 months on an elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine regimen and an absence of G118R in his archived proviral cDNA. The rapid acquisition of G118R (<6 months) in this patient is consistent with newly emergent resistance to dolutegravir. Similarly, the Barcelona case showed the acquisition of G118R in proviral integrated DNA (7% of the quasispecies) at 24 weeks following a switch to dolutegravir monotherapy. It is possible, however, that the G118R substitution in both these patients may have pre-existed as minority archived species, possibly due to prior use of raltegravir or elvitegravir in the Barcelona and Quebec subjects, respectively, and that this substitution was subsequently amplified by dolutegravir monotherapy.

Although resistance to dolutegravir is typically rare, genetic polymorphisms and monotherapy may have facilitated the acquisition of G118R. Baseline genotyping might have detected the GGA motif at codon 118, averting the potential evolution of G118R resistance.

Funding

This work was supported by grants from the Canadian Institutes for Health Research (CIHR) and Fonds de Recherche du Québec-Santé (FRQS)-Réseau SIDA, and a Large-Scale Applied Research Project in Genomics and Personalized Health HIV142 contract from Genome Canada to M. W. The funders played no decision-making role in the design, execution, and analysis or reporting of the research.

Transparency declarations

M. A. W. has received funds from Gilead Sciences and ViiV Healthcare for speaking and attending symposiums. B. G. B. has received fees for speaking from Gilead Sciences. R. T. has received fees from Gilead for speaking and participating in Advisory boards. E. M. has received research funding, consultancy fees, or lecture sponsorships from, or served on advisory boards for: Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Theratechnologies, Tibotec, and ViiV Healthcare. The remaining authors have no conflicts of interest to declare.

Acknowledgements

The authors acknowledge the assistance of Isabelle Hardy for performing genotyping of clinical samples.

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