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Regimens Lacking CCR5 Antagonists Have Minimal Impact on Coreceptor Use
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
Failing antiretroviral salvage regimens lacking a CCR5 antagonist had little if any impact on viral coreceptor use among people taking placebo with an optimized background regimen in the MOTIVATE trials of maraviroc [1]. The results confirm some earlier trial and cohort findings.
Cohort studies established long ago that about half of all people with HIV undergo a shift in viral coreceptor preference from CCR5 in the early stages of infection to CXCR4 or both primary coreceptors (R5/X4) in later stages of infection. Failure of a regimen containing a CCR5 antagonist can result in emergence of X4- or R5/X4-using virus. But earlier studies of coreceptor use in people not taking a CCR5 antagonist yielded conflicting results and relied on older technologies [2,3].
One study of coreceptor evolution that used the Trofile phenotypic assay found that only 8 of 128 people (6%) who began a salvage regimen without a CCR5 blocker saw their coreceptor preference shift from R5 to X4 [4]. To update these findings, Carlo Perno (University of Rome Tor Vergata) and colleagues at other centers used the original Trofile assay to track coreceptor use in 111 people randomized to placebo plus an optimized background regimen that failed by week 48 in MOTIVATE 1 and MOTIVATE 2 [5].
The investigators did not analyze 98 placebo-arm patients without virologic failure or without matching pretreatment and week-48 Trofile results. The 111 patients analyzed had a starting median CD4 count of 150, had taken antiretrovirals for a median of 122.4 months (range 13.6 to 230.9), and had tried a median of 12 antiretrovirals (range 3 to 18). Genotypic and phenotypic sensitivity scores for background regimens in this group averaged 1.0, meaning these people probably had few active drugs to put in their MOTIVATE regimen.
Among 101 people with R5 virus when the trials began, Trofile determined that 89 (88%) retained R5 virus at virologic failure in MOTIVATE. Coreceptor use shifted to R5/X4 in only 6 of these 101 people (6%) and to X4 in none. Results were nonreportable, nonphenotypable, or below the limit of assay quantitation in another 6 (6%).
Among 7 placebo-group patients with R5/X4 virus before MOTIVATE began, Trofile read the failure virus as R5/X4 in 5 (71%) at failure, as strictly X4 in 1 (14%) and as R5/X4 in 1 (14%). Among 3 people with nonreportable coreceptor use at study entry, Trofile saw R5 virus at failure in 2 and nonreportable virus in 1.
Two analyzed variables correlated with a change from R5 to R5/X4 coreceptor use: (1) Duration of antiretroviral treatment before MOTIVATE was a median 158.7 months in the R5-to-R5/X4 group versus 120 months in the always-R5 group and 124.3 months in the R5/X4-to-R5 group. (2) Viral load at failure had dropped 0.54 log from study entry in the R5-to-R5/X4 group versus 0.14 log in the always-R5 group and 0.27 log in the R5/X4 -to-R5 group. But the import of these differences is hard to figure because of the small number of coreceptor switchers.
Perno concluded that the low rate of coreceptor switching in people taking a regimen excluding a CCR5 antagonist for advanced infection reflects similar low rates in the TORO studies of enfuvirtide [4] and in a recent phenotypic analysis of people with controlled viremia who interrupted a successful regimen [6].
References
1. Perno CF, Nelson M, Waters L, et al. The effect of antiretroviral therapy without CCR5 antagonists on HIV-1 tropism in the MOTIVATE studies of maraviroc in treatment-experienced patients with R5 HIV-1. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 73.
2. Delobel P, Sandres-Saune K, Cazabat M, et al. R5 to X4 switch of the predominant HIV-1 population in cellular reservoirs during effective highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2005;38:382-392.
3. Soulie C, Marcelin AG, Ghosn J, et al. HIV-1 X4/R5 co-receptor in viral reservoir during suppressive HAART. AIDS. 2007;21:2243-2245.
4. Melby T, Despirito M, Demasi R, Heilek-Snyder G, Greenberg ML, Graham N. HIV-1 coreceptor use in triple-class treatment-experienced patients: baseline prevalence, correlates, and relationship to enfuvirtide response. J Infect Dis. 2006;194:238-246.
5. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008;359:1429-1241.
6. Waters L, Scourfield A, Marcano M, Gazzard B, Nelson M. The evolution of co-receptor tropism in patients interrupting suppressive HAART. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 439a.
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