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Pretreatment Mutations Do Not Affect Etravirine
or Efavirenz Response in SENSE
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Pretreatment mutations, including low-level mutations detected by allele-specific PCR or Ultradeep Sequencing, did not affect 48-week virologic response to regimens based on etravirine or efavirenz in the SENSE trial, which enrolled antiretroviral-naive people [1]. Mutations conferring resistance to nonnucleosides or nucleosides did not emerge in 4 people whose etravirine regimen failed, but new mutations did appear in 3 of 7 people whose efavirenz regimen failed.
The double-blind, placebo-controlled SENSE trial found similar 48-week virologic response rates with two nucleosides plus either etravirine or efavirenz and fewer neuropsychiatric side effects in the etravirine arm [2,3]. The new analysis examined response rates in light of pretreatment resistance mutations in this previously untreated study population.
SENSE enrolled 157 antiretroviral-naive adults in Europe and Israel and randomized them to begin etravirine or efavirenz plus two investigator-selected nucleosides: tenofovir/emtricitabine, abacavir/lamivudine, or zidovudine/lamivudine. Most study participants were men (85% randomized to etravirine and 77% randomized to efavirenz), and most were white (about 85%). Median age stood at 38 years, median pretreatment CD4 count at 331 in the etravirine group and 302 in the efavirenz group, and median viral load at 80,000 copies in both groups. About one third of study participants were infected with HIV-1 subtypes other than B.
SENSE researchers analyzed pretreatment viral samples for resistance mutations with standard population sequencing and with allele-specific PCR and/or Ultradeep Sequencing, which can detect mutations representing 1% or less of the viral population. The investigators defined virologic failure as a viral load above 500 copies at week 12 (slow response), a load above 50 copies at week 48, a rebound from below to above 50 copies during the trial, or stopping treatment with a load above 50 copies.
At treatment week 48 a time-to-loss-of-virologic-response analysis determined that 76% in the etravirine group and 74% in the efavirenz group had a viral load below 50 copies. An analysis that excluded nonvirologic failures figured that 92% taking etravirine and 89% taking efavirenz had a sub-50-copy load at week 48. Response rates did not differ between etravirine and efavirenz when the investigators looked only at people who began treatment with a viral load above or below 100,000 copies.
Standard sequencing detected pretreatment nonnucleoside mutations in 12 people (15.2%) randomized to etravirine and 4 (5.1%) randomized to efavirenz. The standard assay saw 6 pretreatment nucleoside mutations in the etravirine arm (5%) and none in the efavirenz arm. Detection of these mutations by standard sequencing did not correlate with viral suppression in either treatment arm.
The supersensitive assays detected the nucleoside mutation M184V in 2 additional people, 1 in each study arm. These assays spotted the nonnucleoside mutation K103N in 1 person randomized to etravirine and none randomized to efavirenz. (K103N alone does not confer resistance to etravirine but does confer resistance to efavirenz.) Everyone with pretreatment mutations detected by these highly sensitive assays had a viral load below 50 copies at week 48.
Four people in the etravirine group and 7 in the efavirenz group met virologic failure criteria. No new mutations emerged in anyone whose etravirine regimen failed, a result possibly indicating that poor adherence caused these failures. Among the 7 people in whom efavirenz failed, new nucleoside or nonnucleoside mutations emerged in 3 people: V106I plus M184I in the first, K103N in the second, and L74I/V, M184V, K103N, and P225H in the third.
References
1. Geretti A, Conibear T, Johnson JJ, et al. Detection of baseline resistance and HIV RNA suppression to week 48 in the SENSE trial: etravirine versus efavirenz in treatment naïve participants. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H1-373.
2. Rockstroh J, Streinu-Cercel A, Pokrovsky V, et al. The SENSE trial: final 48-week analysis of etravirine versus efavirenz in treatment-naive patients. 6th IAS Conference on HIV Pathogenesis
Treatment and Prevention. July 17-20, 2011. Rome. Abstract TULBPE025. http://www.natap.org/2011/IAS/IAS_60.htm.
3. Gazzard B, Duvivier C, Zagler C, et al. Phase 2 double-blind, randomised trial of etravirine versus efavirenz in treatment-naive patients: 48 week results. AIDS. 2011. Epub ahead of print. http://www.natap.org/2011/HIV/090511_01.htm.
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