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  50th ICAAC
Boston, MA
September 12-15, 2010
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Long-Term Outcomes Good After Coreceptor Switch in Maraviroc Failure
  50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
A study of 15 people whose HIV changed coreceptor use from CCR5 to CXCR4 during maraviroc failure in the MERIT trial showed good CD4 and virologic outcomes when they stopped the CCR5 antagonist and switched to a new regimen [1]. More sensitive screening for coreceptor use before MERIT would have excluded several of these patients from the trial.
When a regimen containing a CCR5-antagonist fails, a person's viral population may change from exclusive use of the CCR5 coreceptor to at least partial use of CXCR4, as happened in the MERIT trial comparing maraviroc with efavirenz (plus zidovudine/lamivudine) in previously untreated people [2]. To assess the long-term consequences of the switch from exclusive CCR5 use to CXCR4 use, MERIT investigators analyzed 15 trial participants whose maraviroc regimen failed with CXCR4-using HIV. These 15 represented 4% of the 360 people assigned to maraviroc in MERIT. The researchers defined failure as discontinuation of maraviroc for lack of efficacy.
The original Trofile assay determined that everyone who enrolled in MERIT had CCR5-using virus. In the new analysis the investigators used the enhanced Trofile assay (ESTA), 454 Life Sciences deep sequencing (with a 2% X4 cutoff), and genotypic analysis with the geno2pheno system to reassess samples of the 15 patients whose maraviroc regimen failed.
In the 15 substudy participants, median pretreatment CD4 count stood at 220 (range 12 to 475) and median viral load at 117,000 copies (range 2360 to 993,000), so these people had relatively advanced HIV infection when they entered MERIT. Pretreatment median CD4 count was somewhat higher (241) and median viral load was lower (92,000 copies) in the full maraviroc study group. Median time to emergence of CXCR4-using virus in these 15 patients was 85 days (range 14 to 504), while median time to a switch from the failing maraviroc regimen stretched to 183 days (range 74 to 548).
Follow-up in the 15 people whose maraviroc regimen failed averaged 192 weeks (range 12 to 240). Their median CD4 gain was 218 cells. Two serious adverse events during this period--secondary syphilis and tuberculosis--were considered unrelated to antiretroviral therapy. The investigators had data on subsequent therapy for 9 people, 5 of whom took a nonnucleoside-based regimen, 3 of whom took a protease inhibitor regimen, and 1 of whom took three nucleosides. All but one person--1 of the people taking a nonnucleoside--had an undetectable viral load at the end of follow-up.
If ESTA had been used to screen for CCR5-using virus before entry into MERIT, this enhanced phenotypic assay would have excluded 7 of the 15 people whose maraviroc regimen failed; these 7 had dual/mixed R5/X4 virus with ESTA screening. The genotypic 454 deep sequencing assay would have excluded 4 people from the trial. Genotyping by geno2pheno would have excluded 5 people from MERIT.
Among 8 people with coreceptor use results after they stopped maraviroc, the coreceptor shift persisted in 2 people with a persistently detectable viral load.
"With extended follow-up," the MERIT team concluded, "no adverse clinical consequences were observed following failure-associated emergence of CXCR4-using virus with maraviroc."
1. Portsmouth S, Lewis M, Craig C, Chapman D, Swenson L, Heera J. Long-term outcome of individuals experiencing an HIV-1 co-receptor tropism switch in the MERIT study. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-923.
2. Sierra-Madero J, Di Perri G, Wood R, et al. Efficacy and safety of maraviroc versus efavirenz, both with zidovudine/lamivudine: 96-week results from the MERIT study. HIV Clin Trials. 2010;11:125-132.