Activity of the integrase inhibitor S/GSK1349572 in subjects with HIV exhibiting raltegravir resistance: week 24 results of the VIKING study (ING112961)

Eron, Joseph J.; Jm, Livrozet; Morlat, Philippe; Lazzarin, Adriano; Katlama, Christine; Hawkins, Trevor; Fujiwara, Tamio; Cuffe, Robert; Vavro, Cindy; Santiago, Julio Montes; Ait‐Khaled, Mounir; Min, Sherene; Yeo, JM

doi:10.1186/1758-2652-13-s4-o51

Cited by 18 publications

(21 citation statements)

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“…RAL blocks the strand-transfer activity of the viral integrase (IN), necessary for the integration of the proviral DNA into the host genome. In addition, other strandtransfer inhibitors are already in clinical studies [1][2][3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The SnoB study: frequency of baseline raltegravir resistance mutations prevalence in different non-B subtypes

Sierra

Lübke

Walter

et al. 2011

Med Microbiol Immunol

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The SnoB study analysed the variability of the integrase (IN) gene of non-B viruses from treatment-naïve patients to determine whether non-B subtypes carry natural resistance mutations to raltegravir (RAL). Plasma viral RNA from 427 patients was gained, and IN sequences were subtyped and screened for subtype-specific highly-variable residues. Seven viruses of different subtypes were phenotypically tested for RAL susceptibility; 359/427 samples could be sequenced. One hundred and seventy samples (47%) were classified as non-B subtypes. No primary RAL resistance-associated mutations (RRAMs) were detected. Certain secondary mutations were found, mostly related to specific non-B subtypes. L74 M was significantly more prevalent in subtype 02_AG, T97A in A and 06_cpx, V151I in 06_cpx, and G163R in 12_BF. Various additional mutations were also detected and could be associated with the subtype too. While K156 N and S230 N were correlated with B subtype, V72I, L74I, T112I, T125A, V201I and T206S were more frequent in certain non-B subtypes. The resistance factors (RF) of 7 viral strains of different subtypes ranged from 1.0 to 1.9. No primary or secondary but subtype-associated additional RRAMs were present. No correlation between RF and additional RRAMs was found. The prevalence of RRAMs was higher in non-B samples. However, the RFs for the analysed non-B subtypes showed lower values to those reported relevant to clinical failure. As the role of baseline secondary and additional mutations on RAL therapy failure is actually not known, baseline IN screening is necessary.

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Section: Introductionmentioning

confidence: 99%

The SnoB study: frequency of baseline raltegravir resistance mutations prevalence in different non-B subtypes

Sierra

Lübke

Walter

et al. 2011

Med Microbiol Immunol

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“…The INSTI-resistant patient VIKING pilot study and phase 3 (VIKING-3) study have shown the clinical utility of DTG in patient populations who have failed to respond to INSTI therapy (10,18,19).…”

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confidence: 99%

Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir Resistance In Vitro

Seki

Suyama-Kagitani

Kawauchi-Miki

et al. 2015

Antimicrob Agents Chemother

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cThe recently approved HIV-1 integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) (S/GSK1349572) has overall advantageous activity when tested in vitro against HIV-1 with raltegravir (RAL) and elvitegravir (EVG) resistance signature mutations. We conducted an in vitro resistance selection study using wild-type HIV-1 and mutants with the E92Q, Y143C, Y143R, Q148H, Q148K, Q148R, and N155H substitutions to assess the DTG in vitro barrier to resistance. No viral replication was observed at concentrations of >32 nM DTG, whereas viral replication was observed at 160 nM RAL or EVG in the mutants. In the Q148H, Q148K, or Q148R mutants, G140S/Q148H, E138K/Q148K, E138K/Q148R, and G140S/Q148R secondary mutations were identified with each INSTI and showed high resistance to RAL or EVG but limited resistance to DTG. E138K and G140S, as secondary substitutions to Q148H, Q148K, or Q148R, were associated with partial recovery in viral infectivity and/or INSTI resistance. In the E92Q, Y143C, Y143R, and N155H mutants, no secondary substitutions were associated with DTG. These in vitro results suggest that DTG has a high barrier to the development of resistance in the presence of RAL or EVG signature mutations other than Q148. One explanation for this high barrier to resistance is that no additional secondary substitution of E92Q, Y143C, Y143R, or N155H simultaneously increased the fold change in 50% effective concentration (EC 50 ) to DTG and infectivity. Although increased DTG resistance via the Q148 pathway and secondary substitutions occurs at low concentrations, a higher starting concentration may reduce or eliminate the development of DTG resistance in this pathway in vitro.

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“…For example, DTG was shown to have wild-type or near wild-type activity in vitro against site-directed mutants with the single primary resistance mutations observed in vivo at Q148 (including Q148H/K/R), at N155, and at Y143 (25,30) and against clinical isolates harboring genotypes with the Y143 and N155 pathway mutations (46) alone or with additional secondary IN mutations. DTG has also demonstrated in vivo activity in subjects with RAL resistance in the VIKING study (16). As described herein, we investigated the dissociation of DTG, RAL, and ELV from wild-type and mutant IN proteins complexed with DNA to obtain a better understanding of INI dissociation kinetics and the relationship between dissociation rates and INI resistance.…”

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Dolutegravir (S/GSK1349572) Exhibits Significantly Slower Dissociation than Raltegravir and Elvitegravir from Wild-Type and Integrase Inhibitor-Resistant HIV-1 Integrase-DNA Complexes

Hightower

Wang

Deanda

et al. 2011

Antimicrob Agents Chemother

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Activity of the integrase inhibitor S/GSK1349572 in subjects with HIV exhibiting raltegravir resistance: week 24 results of the VIKING study (ING112961)

Abstract: 7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Cited by 18 publications

References 0 publications

The SnoB study: frequency of baseline raltegravir resistance mutations prevalence in different non-B subtypes

The SnoB study: frequency of baseline raltegravir resistance mutations prevalence in different non-B subtypes

Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir Resistance In Vitro

Dolutegravir (S/GSK1349572) Exhibits Significantly Slower Dissociation than Raltegravir and Elvitegravir from Wild-Type and Integrase Inhibitor-Resistant HIV-1 Integrase-DNA Complexes

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