Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study

Castagna, Antonella; Maggiolo, Franco; Penco, Giovanni; Wright, David P.; Mills, Anthony; Grossberg, Robert; Molina, Jean Michel; Chas, Julie; Durant, J.; Moreno, Santiago; Doroana, Manuela; Ait‐Khaled, Mounir; Huang, Jenny; Min, Sherene; Song, Ivy; Vavro, Cindy; Nichols, Garrett; Yeo, Jane; Aberg, Judith A.; Akil, Bisher; Arribas, José Ramón; Baril, Jean-Guy; Arévalo, José Luis Blanco; Quintana, F. Blanco; Blick, Gary; Martínez, Vicente Boix; Bouchaud, Olivier; Branco, Teresa; Bredeek, U. Fritz; Iglesias, Manuel C.; Clumeck, Nathan; Conway, Brian; DeJesus, Edwin; Delassus, Jean L.; Truchis, Pierre de; Perri, Giovanni Di; Pietro, Massimo Di; Duggan, Joan; Duvivier, Claudine; Elion, Richard; Eron, Joseph; Fish, Douglas N.; Gathe, Joseph; Haubrich, Richard; Henderson, Harold; Hicks, Charles B.; Hocqueloux, Laurent; Hodder, Sally; Hsiao, CB; Katlama, Christine; Kozal, Michael J.; Kumar, Princy; Lalla-Reddy, Sujata N.; Lazzarin, Adriano; Leoncini, F; Llibre, Josep M; Kamal, Mehnaz; Morlat, Philippe; Mounzer, Karam; Murphy, M.; Newman, Cheryl; Nguyen, Thuy; Nseir, Bacel; Philibert, Patrick; Pialoux, Gilles; Poizot‐Martin, Isabelle; Ramgopal, Moti; Richmond, Gary; Ceron, Dominique Salmon; Sax, Paul E.; Scarsella, Anthony; Sension, Michael; Shalit, Peter; Sighinolfi, Laura; Sloan, Louis; Small, Catherine B.; Stein, David; Tashima, K.; Tebas, Pablo; Torti, Carlo; Tribble, Marc; Troisvallets, Didier; Tsoukas, Christos; Fernandez, Paula; Ward, Douglas J.; Wheeler, Darrell P.; Wilkin, Timothy; Yeni, Guy Patrick; Martin-Carpenter, J. Louise; Uhlenbrauck, G.

doi:10.1093/infdis/jiu051

Cited by 286 publications

(277 citation statements)

References 14 publications

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“…7B). This is consistent with reports that the preexistence of Q148 ϩ Ն1 resistance substitutions, but not Q148 mutations alone, were statistically associated with lower success rates in the clinic with DTG than when this drug was used in first-line therapy (56). The G118R variant enzyme displayed low-level resistance against all INSTIs, also in agreement with tissue culture resistance studies using TZM-bl cells (12) and with data on HIV-1 (32,53).…”

Section: Discussionsupporting

confidence: 90%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

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We previously showed that the simian immunodeficiency virus SIVmac239 is susceptible to human immunodeficiency virus (HIV) integrase (IN) strand transfer inhibitors (INSTIs) and that the same IN drug resistance mutations result in similar phenotypes in both viruses. Now we wished to determine whether tissue culture drug selection studies with SIV would yield the same resistance mutations as in HIV. Tissue culture selection experiments were performed using rhesus macaque peripheral blood mononuclear cells (PBMCs) infected with SIVmac239 viruses in the presence of increasing concentrations of dolutegravir (DTG), elvitegravir (EVG), and raltegravir (RAL). We now show that 22 weeks of selection pressure with DTG yielded a mutation at position R263K in SIV, similar to what has been observed in HIV, and that selections with EVG led to emergence of the E92Q substitution, which is a primary INSTI resistance mutation in HIV associated with EVG treatment failure. To study this at a biochemical level, purified recombinant SIVmac239 wild-type (WT) and E92Q, T97A, G118R, Y143R, Q148R, N155H, R263K, E92Q T97A, E92Q Y143R, R263K H51Y, and G140S Q148R recombinant substitution-containing IN enzymes were produced, and each of the characteristics strand transfer, 3=-processing activity, and INSTI inhibitory constants was assessed in cell-free assays. The results show that the G118R and G140S Q148R substitutions decreased K m = and V max =/K m = for strand transfer compared to those of the WT. RAL and EVG showed reduced activity against both viruses and against enzymes containing Q148R, E92Q Y143R, and G140S Q148R. Both viruses and enzymes containing Q148R and G140S Q148R showed moderate levels of resistance against DTG. This study further confirms that the same mutations associated with drug resistance in HIV display similar profiles in SIV. IMPORTANCEOur goal was to definitively establish whether HIV and simian immunodeficiency virus (SIV) share similar resistance pathways under tissue culture drug selection pressure with integrase strand transfer inhibitors and to test the effect of HIV-1 integrase resistance-associated mutations on SIV integrase catalytic activity and resistance to integrase strand transfer inhibitors. Clinically relevant HIV integrase resistance-associated mutations were selected in SIV in our tissue culture experiments. Not only do we report on the characterization of SIV recombinant integrase enzyme catalytic activities, we also provide the first research anywhere on the effect of mutations within recombinant integrase SIV enzymes on drug resistance.T he limitations of current highly active antiretroviral therapy (HAART) include the incidence of drug resistance observed in patients, issues of drug adherence, and numbers of newly acquired infections. The emergence of drug-resistant viruses can lead to increases in viral load and treatment failure, and such viruses can be transmitted to both healthy individuals as well as to untreated HIV-positive individuals, therefore threatening the long-term effica...

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Section: Discussionsupporting

confidence: 90%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

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“…The most recently approved INSTI dolutegravir (DTG) is for once-daily dosing without a pharmacokinetic booster and shows efficacy for treatment-naive subjects and treatment-experienced but INSTI-naive subjects, as well as subjects who failed RAL and EVG treatment (9)(10)(11)(12)(13). DTG was approved by the U.S. FDA in August 2013 for treatment-naive and treatment-experienced INSTI-naive adults, as well as for INSTI-resistant adults.…”

mentioning

confidence: 99%

“…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).…”

mentioning

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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“…There is also a high degree of cross-resistance between RAL and EVG, since the major resistance substitutions for RAL are located at positions G140, Y143, Q148, and N155, while those for EVG are located at positions T66, E92, G140, S147, Q148, and N155 (1,3). Although resistance during initial therapy has not yet been reported for DTG, patients can fail DTG therapy if they were previously treated with RAL or EVG and possess relevant mutations for these drugs (4)(5)(6).…”

mentioning

confidence: 99%

The Combination of the R263K and T66I Resistance Substitutions in HIV-1 Integrase Is Incompatible with High-Level Viral Replication and the Development of High-Level Drug Resistance

Liang

Mésplède

Oliveira

et al. 2015

J Virol

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The R263K substitution in integrase has been selected in tissue culture with dolutegravir (DTG) and has been reported for several treatment-experienced individuals receiving DTG as part of salvage therapy. The R263K substitution seems to be incompatible with the presence of common resistance mutations associated with raltegravir (RAL), a different integrase strand transfer inhibitor (INSTI). T66I is a substitution that is common in individuals who have developed resistance against a different INSTI termed elvitegravir (EVG), but it is not known whether these two mutations might be compatible in the context of resistance against DTG or what impact the combination of these substitutions might have on resistance against INSTIs. E138K is a common secondary substitution observed with various primary resistance substitutions in RAL-and EVG-treated individuals. Viral infectivity, replicative capacity, and resistance against INSTIs were measured in cell-based assays. Strand transfer and 3= processing activities were measured biochemically. The combination of the R263K and T66I substitutions decreased HIV-1 infectivity, replicative capacity, and strand transfer activity. The addition of the E138K substitution partially compensated for these deficits and resulted in high levels of resistance against EVG but not against DTG or RAL. These findings suggest that the presence of the T66I substitution will not compromise the activity of DTG and may also help to prevent the additional generation of the R263K mutation. Our observations support the use of DTG in second-line therapy for individuals who experience treatment failure with EVG due to the T66I substitution. IMPORTANCEThe integrase strand transfer inhibitors (INSTIs) elvitegravir and dolutegravir are newly developed inhibitors against human immunodeficiency virus type 1 (HIV-1). HIV drug-resistant mutations in integrase that can arise in individuals treated with elvitegravir commonly include the T66I substitution, whereas R263K is a signature resistance substitution against dolutegravir. In order to determine how different combinations of integrase resistance mutations can influence the outcome of therapy, we report here the effects of the T66I, E138K, and R263K substitutions, alone and in combination, on viral replicative capacity and resistance to integrase inhibitors. Our results show that the addition of R263K to the T66I substitution diminishes viral replicative capacity and strand transfer activity while not compromising susceptibility to dolutegravir. This supports the use of dolutegravir in second-line therapy for patients failing elvitegravir therapy who harbor the T66I resistance substitution. R ecent strategies to treat HIV-1 infection involve the use of integrase strand transfer inhibitors (INSTIs), which are the most potent antiretroviral drugs (ARVs) to date and include raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) (1). Despite this, the emergence of drug resistance mutations in integrase (IN) represents a concern for the future use ...

show abstract

Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study

Cited by 286 publications

References 14 publications

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

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

The Combination of the R263K and T66I Resistance Substitutions in HIV-1 Integrase Is Incompatible with High-Level Viral Replication and the Development of High-Level Drug Resistance

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