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Evolving Mutation Patterns Traced During Elvitegravir Failure
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
Changing resistance mutation patterns--marked by mutation swaps--proved frequent during failure of salvage regimens containing the integrase inhibitor elvitegravir [1]. Earlier research documented similar "genotypic switching" during raltegravir failure [2]. With both drugs, evolving mutation patterns resulted in more highly resistant virus.
Damian McColl and Gilead colleagues used standard genotyping to track mutations in 38 people taking a failing regimen containing 125 mg of elvitegravir plus 100 mg of ritonavir. They phenotyped viral samples to determine levels of resistance to elvitegravir, and they measured replication capacity of elvitegravir-susceptible and resistant virus. The Gilead team made these measurements at initial virologic failure, then again at confirmed failure.
Before the elvitegravir salvage regimen began, virus from all study participants was fully susceptible to elvitegravir. Viral samples usually carried 1 or 2 integrase mutations upon virologic failure. E92Q proved the most common initial mutation, occurring in 20 of 38 samples (53%). Other initial resistance patterns included N155H in 32%, Q148R/K in 24%, T66I/A/K in 11%, and E138K in 8%. The IAS-USA lists Q148H/K/R and N155H as primary raltegravir mutations [3].
Q148R or E138K conferred 178-fold resistance to elvitegravir, while Q148R conferred 90-fold resistance. E92Q alone conferred 36-fold resistance to elvitegravir. With L88V, E92Q conferred 58-fold resistance. N155H alone conferred 83-fold resistance to elvitegravir. The E92Q-alone analysis involved eight samples, while the others involved one or two samples.
Different mutation patterns emerged as the failing regimen continued in 30 of 38 people (79%). In 16 of those 30 (42% of 38), the viral genotype shifted from one pattern to another. In 14 of the 30 (37% of 38), additional mutations appeared as initial mutations persisted. Initial resistance patterns remained unchanged in 8 of 38 people (21%).
The most common genotypic switch pattern involved replacement of an initial E92Q mutation with a pattern including Q148R/H in 8 of 16 mutation switchers. This switch led to higher resistance levels and, in some cases, improved replication capacity. Among 11 switchers analyzed, resistance relative to nonresistant virus rose from a median of 57-fold with the initial mutation pattern to 201-fold with the new mutation pattern.
Other genotypic switch patterns were E92Q/G to N155H, T66A to N155H, Q148R to N155H, and from one Q184 substitution to another.
The proportion of people with one detectable mutation fell from 58% in early virologic failure to 21% at confirmed virologic failure and to 16% at study discontinuation. In the same three periods, the proportion of people with three mutations rose from 11% to 34% to 38%, and the proportion with four mutations rose from 3% to 5% to 6%.
References
1. Waters J, Margot N, Hluhanich R, et al. Evolution of resistance to the HIV integrase inhibitor (INI) elvitegravir can involve genotypic switching among primary INI resistance patterns. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 116.
2. Miller MD, Danovich RM, Ke Y, et al. Longitudinal analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from P005, a phase II study in treatment-experienced patients. XVII International HIV Drug Resistance Workshop. June 10-14, 2008. Sitges, Spain. Abstract 6.
3. Johnson VA, Brun-Vezinet F, Clotet B et al. Update of the drug resistance mutations in HIV-1: spring 2008. Top HIV Med. 2008;16:62-68.
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