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Low-Level Etravirine Mutations With K103N After NNRTI Failure
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
Ultradeep pyrosequencing uncovered low-frequency etravirine-related mutations in 7 of 20 people in whom standard genotyping spotted only K103N after efavirenz or nevirapine failure [1]. Stanford University investigators suggest their findings mean "etravirine is not likely to be highly active in this population."
Because etravirine retains activity against HIV bearing only the K103N nonnucleoside resistance mutation, Vici Varghese and Stanford colleagues used ultradeep sequencing to analyze virus in two sets of patients with K103N detectable on standard sequencing: 13 previously untreated people with K103N--and no other resistance mutation--and a viral load above 4.5 log (about 30,000 copies), and 20 people in whom efavirenz or nevirapine failed with K103N--and no other nonnucleoside mutation--and a viral load above 4.5 log. All patients had standard genotyping at Stanford Hospital between 1998 and 2007.
Among the 13 antiretroviral-naive people with K103N, 6 had 1 or more additional reverse transcriptase mutations detectable by ultradeep sequencing, including only 1 with the etravirine-related natural polymorphism V90I representing 1.4% of the viral population. The IAS-USA lists V90I as an etravirine mutation [2]. Varghese and coworkers concluded that etravirine is likely to be effective in antiretroviral-naive people in whom standard genotyping spots only K103N.
Among the 20 people in whom efavirenz or nevirapine failed, 14 had virus with one or more reverse transcriptase mutations detectable by ultradeep sequencing including 7 (29%) with the nonpolymorphic nonnucleoside mutations:
· Y181C (7% of the viral population)
· Y181C plus G190A (3.5% and 3.2% of the viral population)
· L100I (13.9% of the viral population)
· L100I plus G190A (31.6% and 5.4% of the viral population)
· K101E plus G190A (3.8% and 4.9% of the viral population)
· K101E plus G190S (4.0% and 4.8% of the viral population)
· G190S (3.1% of the viral population)
Ultradeep sequencing found the polymorphic V90I in samples from 3 of these patients at population percentages of 1.9%, 8.2%, and 10.2%. IAS-USA ranks all of these substitutions except K101E as etravirine mutations [2].
Varghese and coworkers concluded that virus in people with transmitted K103N generally does not harbor other low-frequency nonnucleoside mutations that make HIV resistant to etravirine. In patients whose efavirenz or nevirapine regimen fails with K103N, detection of additional low-frequency nonnucleoside mutations "is consistent with the low genetic barrier to resistance associated with the first-generation NNRTIs."
References
1. Varghese V, Shahriar R, Rhee SH, et al. Minority drug resistance mutations associated with the NNRTI mutation K103N in ARV-naive and NNRTI-treated HIV-1-infected patients. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 122.
2. 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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