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Resistance at Failure Less Likely With Dolutegravir
Than Raltegravir or Elvitegravir

 
 
  16th European AIDS Conference, October 25-27, 2017. Milan
 
Mark Mascolini
 
HIV resistant to the integrase inhibitor dolutegravir (DTG) emerged at DTG failure much less often than HIV resistant to raltegravir (RAL) or elvitegravir (EVG) when those two integrase inhibitors failed, according to results of a French national survey [1]. Cross-resistance also proved less frequent upon DTG failure. This 513-patient analysis linked every 10-fold higher viral load at failure to 30% higher odds of selecting at least 1 integrase resistance mutation.
 
Integrase inhibitors, the newest class of antiretrovirals, have given clinicians an important and potent option for first-line therapy and rescue regimens. But most data on HIV resistance to integrase inhibitors come from lab work or from trials of these agents, which typically include few failures. Researchers working in ANRS, the French national HIV trials network, aimed to gather more data on resistance patterns upon virologic failure of integrase inhibitors by conducting a nationwide survey of such failures in clinical practice.
 
The analysis included patients in whom a regimen containing RAL, EVG, or DTG failed virologically, with failure defined as consecutive viral loads at or above 50 copies from January 2014 through 2017. Technicians genotyped HIV at virologic failure to identify resistance-related mutations in integrase, reverse transcriptase, and protease. The ANRS team interpreted these genotypes with the latest ANRS genotypic algorithm (http://www.hivfrenchresistance.org), which lists mutations associated with resistance to individual antiretrovirals and mutations associated with possible resistance.
 
The study focused on 513 people, 66% of them men, with a median age of 48.6. Only 53 people (10.3%) were taking an integrase inhibitor in their first antiretroviral regimen. Median time since HIV diagnosis stood at 16.7 years and median time taking the current integrase inhibitor at 0.9 year. Median viral load when the group began an integrase inhibitor was 3.1 log10 copies (about 1250 copies), and median load at failure was 2.9 log10 copies (about 800 copies). Most people (54%) took their integrase inhibitor with two nucleos(t)ides, while 14% took it with one protease inhibitor and one nucleos(t)ide.
 
Among the 513 study participants, 285 were taking RAL, 122 EVG, and 106 DTG. At virologic failure of the integrase inhibitor regimen, 58% of viral samples harbored no integrase mutations, while 42% did (25% one mutation, 10% two mutations, 7% more than two mutations).
 
Resistance patterns varied from one integrase inhibitor to the next. Upon RAL failure, the ANRS algorithm said detectable mutations meant 34% of patients had virus resistant to RAL, 35% had resistance to EVG, 27% had resistance to once-daily DTG, and 2% had virus resistant to twice-daily DTG. Upon EVG failure, those proportions were 20%, 43%, 24%, and 4%. Upon DTG failure, those proportions were 19%, 19%, 15%, and 7%. People in whom a DTG regimen failed had significantly fewer integrase mutations than people in whom RAL failed (P = 0.003) or EVG failed (P = 0.001). These findings confirm the higher barrier to resistance with DTG than with other integrase inhibitors; they also indicate that twice-daily DTG may be an option after failure of any of the three integrase inhibitors.
 
Viral load at integrase inhibitor failure correlated with percent of viral samples harboring detectable integrase mutations. With a failing load below 100 copies, only 5.6% of samples had detectable integrase mutations. With a failing load between 100 and 1000 copies, 35.1% of samples had detectable integrase mutations. And with a failing load above 1000 copies, 59.4% of samples had detectable integrase mutations. The French team calculated that every 10-fold higher viral load at failure raised odds of integrase mutations 30% (odds ratio 1.3 per 10-fold higher).
 
Among 31 people in whom first-line RAL failed, 8 (26%) had integrase mutations at failure. Among 16 people with first-line EVG failure, 6 (37.5%) had integrase mutations at failure. Among 6 people with first-line DTG failure, none had detectable integrase mutations or nucleos(t)ide mutations at failure.
 
The ANRS investigators believe their findings "confirmed the robustness of DTG regarding resistance selection in case of virological failure in routine clinical care."
 
Reference
 
1. Marcelin AG, Grude M, Charpentier C, et al. French national survey of resistance to integrase inhibitors in a context of routine hospital care. 16th European AIDS Conference. October 25-27, 2017. Milan. Abstract PS3/1.