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  • Title: Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients.
    Author: Swenson LC, Mo T, Dong WW, Zhong X, Woods CK, Jensen MA, Thielen A, Chapman D, Lewis M, James I, Heera J, Valdez H, Harrigan PR.
    Journal: J Infect Dis; 2011 Jan 15; 203(2):237-45. PubMed ID: 21288824.
    Abstract:
    BACKGROUND: The Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies compared maraviroc versus placebo in treatment-experienced patients with CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1), screened using the original Trofile assay. A subset with non-R5 HIV infection entered the A4001029 trial. We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials. METHODS: V3 amplicons were prepared from 1827 screening plasma samples and sequenced on a Roche/454 GS-FLX to a depth of >3000 sequences/sample. Samples were considered non-R5 if ≥2% of their viral population scored greater than or equal to -4.75 or ≤3.5 using the PSSM(x4/R5) or geno2pheno algorithms, respectively. RESULTS: Deep sequencing identified more than twice as many maraviroc recipients as having non-R5 HIV, compared with the original Trofile. With use of genotyping, we determined that 49% of maraviroc recipients with R5 HIV at screening had a week 48 viral load <50 copies/mL versus 26% of recipients with non-R5. Corresponding percentages were 46% and 23% with screening by Trofile. In cases in which screening assays differed, median week 8 log₁₀ copies/mL viral load decrease favored 454. Other parameters predicted by genotyping included likelihood of changing to non-R5 tropism. CONCLUSIONS: This large study establishes deep V3 sequencing as a promising tool for identifying treatment-experienced individuals who could benefit from CCR5-antagonist-containing regimens.
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