High frequency of dolutegravir resistance in patients failing a raltegravir-containing salvage regimen.
OBJECTIVE
Dolutegravir is a second-generation integrase strand transfer inhibitor (InSTI) that has been recently approved by the FDA to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those already exposed to the first-generation InSTI. Despite having a different mutational profile, some cross-resistance mutations may influence its susceptibility. The aim of this study was to evaluate the impact of a raltegravir-containing salvage regimen on dolutegravir activity.


METHODS
Blood samples of 92 HIV-infected individuals with virological failure (two or more viral loads >50 copies/mL after 6 months of treatment) using raltegravir with optimized background therapy were sequenced and evaluated according to the Stanford University HIV Drug Resistance Database algorithm.


RESULTS
Among the 92 patients analysed, 32 (35%) showed resistance to dolutegravir, in most cases associated with the combination of Q148H/R/K with G140S/A mutations. At genotyping, patients with resistance to dolutegravir had viral load values closer to the highest previously documented viral load.


CONCLUSIONS
Changes in viraemia during virological failure may indicate the evolution of raltegravir resistance and may predict the emergence of secondary mutations that are associated with a decrease in dolutegravir susceptibility. Early discontinuation of raltegravir from failing regimens might favour subsequent salvage with dolutegravir, but further studies are necessary to evaluate this issue.
Laboratório de Retrovirus, Instituto Adolfo Lutz, São Paulo, Brazil.
Jaqueline de Souza
Jde S
Cavalcanti
Laboratório de Retrovirus, Instituto Adolfo Lutz, São Paulo, Brazil.
João Leandro de Paula
JL
Ferreira
Laboratório de Retrovirus, Instituto Adolfo Lutz, São Paulo, Brazil.
Paula Morena de Souza
PM
Guimarães
Instituto de Infectologia Emílio Ribas, São Paulo, Brazil.
Jose Ernesto
JE
Vidal
Laboratório de Retrovirus, Instituto Adolfo Lutz, São Paulo, Brazil lubrigido@gmail.com.
Luis Fernando de Macedo
LF
Brigido
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones / Q000627:therapeutic use*; D000068898:Raltegravir Potassium; D016879:Salvage Therapy / Q000379:methods; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D055815:Young Adult; D000099226:Dolutegravir
D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir
Brazil; HIV; antiretroviral resistance; integrase inhibitors