HIV-1 Integrase Sequence Variability in Antiretroviral Naïve Patients and in Triple-Class Experienced Patients Subsequently Treated with Raltegravir

Varghese, Vici; Liu, Tommy F.; Rhee, Soo-Yon; Libiran, Paolo; Trevino, Christina; Fessel, W. Jeffrey; Shafer, Robert W.

doi:10.1089/aid.2010.0123

Cited by 31 publications

(30 citation statements)

References 15 publications

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“…The L74M substitution is a recognized INI resistance-associated substitution that does not decrease INI susceptibility alone but that can significantly reduce RAL and EVG susceptibility when present with major INI mutations (11). In this analysis, L74M was detected in our panel of sequences at a frequency of 2.9%; other studies have confirmed this low frequency of L74M in antiretroviral therapy-naive patients (3,21).…”

Section: Discussionsupporting

confidence: 57%

Prevalent Polymorphisms in Wild-Type HIV-1 Integrase Are Unlikely To Engender Drug Resistance to Dolutegravir (S/GSK1349572)

Vavro

Hasan

Madsen

et al. 2013

Antimicrob Agents Chemother

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dThe majority of HIV-1 integrase amino acid sites are highly conserved, suggesting that most are necessary to carry out the critical structural and functional roles of integrase. We analyzed the 34 most variable sites in integrase (>10% variability) and showed that prevalent polymorphic amino acids at these positions did not affect susceptibility to the integrase inhibitor dolutegravir (S/GSK1349572), as demonstrated both in vitro (in site-directed mutagenesis studies) and in vivo (in a phase IIa study of dolutegravir monotherapy in HIV-infected individuals). Ongoing clinical trials will provide additional data on the virologic activity of dolutegravir across subject viruses with and without prevalent polymorphic substitutions. More specifically, the major amino acid substitutions located within the catalytic domain known to contribute to high-level INI resistance were not generally found to occur as natural polymorphisms; however, two unique samples containing N155H and Q148H were identified in samples originating from Australia. Rhee et al. (7) evaluated the prevalence of natural HIV-1 IN polymorphisms from clinical group M (multiple clades) strains from Ͼ1,500 INI treatmentnaive subjects. In their analyses, the defined INI resistance mutations were overall nonpolymorphic (defined as a cutoff of 0.5% frequency), with the exception of E157Q, which was present at a 1.1% frequency and was considered to be a primary mutation for elvitegravir (4). In the Rhee study, secondary resistance mutations (e.g., L74M, T97A, V151I, G163R, and S230N) possessed polymorphism rates between 0.5% and 2.0%. In another study, Ceccherini-Silberstein et al. (3) There have been multiple analyses looking at the response in the clinic based on natural variation. In the case of RAL, two different analyses have been presented (8, 9). Marcelin et al. (9) concluded that "HIV-1 subtype and baseline integrase polymorphisms do not influence the virologic response to RAL," whereas Armenia et al. (8) concluded that "among all integrase polymorphisms, only T122I and S119P were associated with poorer virologic response to raltegravir either at 24 or 48 weeks during treatment." Overall, these studies indicate that the effect of polymorphisms on response and resistance in the INI class is not as clear as has been observed for bevirimat (2) and suggest that additional investigation may be needed. Dolutegravir (DTG; S/GSK1349572) is being developed for INI-naive patients as a once-daily, unboosted, HIV INI. To date,

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Section: Discussionsupporting

confidence: 57%

Prevalent Polymorphisms in Wild-Type HIV-1 Integrase Are Unlikely To Engender Drug Resistance to Dolutegravir (S/GSK1349572)

Vavro

Hasan

Madsen

et al. 2013

Antimicrob Agents Chemother

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“…Of the noted variants, four (L68V, T97A, V151I, E157Q) have previously been described as polymorphic, occurring in >1% of integrase sequences [25]. These integrase mutations were more prevalent in the subtype B viruses with E157Q occurring at higher frequencies than previously reported [46-50]. In the previous reports this polymorphism was shown to impair the integrase 3′end processing and strand transfer [17] but was associated with only minimal reduction of the susceptibility to RAL and elvitegravir (<6 fold) [25,26,51,52].…”

Section: Discussionmentioning

confidence: 95%

HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland

et al. 2012

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BackgroundHIV integrase inhibitor use is limited by low genetic barrier to resistance and possible cross-resistance among representatives of this class of antiretrovirals. The aim of this study was to analyse integrase sequence variability among antiretroviral treatment naive and experienced patients with no prior integrase inhibitor (InI) exposure and investigate development of the InI drug resistance mutations following the virologic failure of the raltegravir containing regimen.MethodsSequencing of HIV-1 integrase region from plasma samples of 80 integrase treatment naive patients and serial samples from 12 patients with observed virologic failure on raltegravir containing treatment whenever plasma vireamia exceeded >50 copies/ml was performed. Drug resistance mutations were called with Stanford DB database and grouped into major and minor variants. For subtyping bootstrapped phylogenetic analysis was used; Bayesian Monte Carlo Marcov Chain (MCMC) model was implemented to infer on the phylogenetic relationships between the serial sequences from patients failing on raltegravir.ResultsMajority of the integrase region sequences were classified as subtype B; the remaining ones being subtype D, C, G, as well as CRF01_AE , CRF02_AG and CRF13_cpx recombinants. No major integrase drug resistance mutations have been observed in InI-treatment naive patients. In 30 (38.5%) cases polymorphic variation with predominance of the E157Q mutation was observed. This mutation was more common among subtype B (26 cases, 54.2%) than non-B sequences (5 cases, 16.7%), p=0.00099, OR: 5.91 (95% CI:1.77-22.63)]. Other variants included L68V, L74IL, T97A, E138D, V151I, R263K. Among 12 (26.1%) raltegravir treated patients treatment failure was observed; major InI drug resistance mutations (G140S, Q148H and N155H, V151I, E92EQ, V151I, G163R) were noted in four of these cases (8.3% of the total InI-treated patients). Time to the development of drug resistance ranged from 2.6 to 16.3 months with mean increase of HIV viral load of 4.34 (95% CI:1.86-6.84) log HIV-RNA copies/ml at the time of emergence of the major mutations. Baseline polymorphisms, including E157Q were not associated with the virologic failure on raltegravir.ConclusionsIn InI treatment naive patients polymorphic integrase sequence variation was common, with no major resistance mutants. In the treatment failing patients selection of drug resistance occurred rapidly and followed the typical drug resistance pathways. Preexisting integrase polymorphisms were not associated with the treatment failure.

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“…Several accessory mutations that contribute to INI resistance only in the presence of primary INI resistance mutations have been, however, reported among B and non-B strains, 2,6,7 and included some of those we reported here. A recent study analyzing 4470 sequences of INI-untreated patients and including 52% of non-B isolates reported frequencies between 0.5% and 2.5% for L74M (2.5%), T97A (2.2%), E157Q (2.0%), G163K (0.4%), and R263K (0.1%) 8 and except for E157Q, the frequencies of these mutations were shown to increase significantly among RAL failing patients 4 illustrating their contribution when primary mutations are selected. These mutations were also reported as occurring at higher proportion among non-B compared to B isolates.…”

mentioning

confidence: 99%

“…2,3,6 E157Q, found in 5% of INI-naive patients in the present study, is considered as an accessory mutation in many studies. 4,8 In addition, using the QuickAlign tool from the HIV Sequence Database shows that the E157 is replaced (usually by Q) in 2.56% of sequences in the alignment of 1804 sequences used by that tool (http://www.hiv.lanl.gov/content/sequence/QUICK_ALIGN/QuickAlign.html).…”

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confidence: 99%

Drug Resistance Mutations of HIV Type 1 Non-B Viruses to Integrase Inhibitors in Treatment-Naive Patients from Sub-Saharan Countries and Discordant Interpretations

Monleau

Aghokeng

Chaix

et al. 2012

AIDS Research and Human Retroviruses

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The routine use of integrase inhibitors in sub-Saharan Africa where HIV-1 non-B viruses predominate is limited, but evaluating their effectiveness on HIV-1 subtypes and CRFs that circulate in this region is essential. We here analyzed 97 integrase sequences from HIV-1 non-B-infected individuals from African countries. Using currently available interpretation algorithms (ANRS, HIVdb, and Rega), we identified the presence of mutations at nine resistance-associated positions including L74M (3.1%), T97A (9.3%), K156N (2.1%), E157Q (5.2%), G163K (1.0%), T206S (48.5%), S230N (1.0%), D232N (1.0%), and R236K (1.0%). All but one (E157Q) were considered as accessory resistant mutation by the algorithms. E157Q identified in 5% of patients tested (5/97) was selected by the ANRS algorithm as a primary mutation, which alone can confer resistance to raltegravir. These results illustrated the need of further in vitro and clinical studies involving non-B viruses to better understand the real significance of observed mutations and harmonize interpretations.

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HIV-1 Integrase Sequence Variability in Antiretroviral Naïve Patients and in Triple-Class Experienced Patients Subsequently Treated with Raltegravir

Cited by 31 publications

References 15 publications

Prevalent Polymorphisms in Wild-Type HIV-1 Integrase Are Unlikely To Engender Drug Resistance to Dolutegravir (S/GSK1349572)

Prevalent Polymorphisms in Wild-Type HIV-1 Integrase Are Unlikely To Engender Drug Resistance to Dolutegravir (S/GSK1349572)

HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland

Drug Resistance Mutations of HIV Type 1 Non-B Viruses to Integrase Inhibitors in Treatment-Naive Patients from Sub-Saharan Countries and Discordant Interpretations

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