Population-based V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies

McGovern, Rachel A.; Thielen, Alexander; Mo, Theresa; Dong, Winnie; Woods, Conan K.; Chapman, Douglass; Lewis, Marilyn; James, Ian; Heera, Jayvant; Valdez, Hernán; Harrigan, P. Richard

doi:10.1097/qad.0b013e32833e6cfb

Cited by 105 publications

(109 citation statements)

References 17 publications

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“…GTT provides a rapid, inexpensive and widely available approach for tropism testing. Clinical outcome studies have recently indicated that GTT is reliable for predicting virological responses to maraviroc in both treatment-experienced and treatment-naïve patients [17,18]. In these studies, GTT was applied to plasma samples of patients with a viral load of 41000 copies/mL.…”

Section: Discussionmentioning

confidence: 99%

“…The higher the FPR cut-off, the greater the likelihood of detecting CXCR4-using virus, but also of falsely identifying a sequence as X4. Clinical evidence provides support for the validity of using an FPR cut-off of approximately 5-10% [17,18].In a comparison of the results for 165 simultaneous plasma RNA/proviral DNA samples, the concordance in predicted tropism between the two sample types was high, ranging from 95.2% at an FPR of 10% to 96.4% at an FPR of 5%. In addition, the concordance in absolute FPR values for the two sample types was very good (r 5 0.8510).…”

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confidence: 99%

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Concordance between HIV-1 genotypic coreceptor tropism predictions based on plasma RNA and proviral DNA

et al. 2011

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ObjectiveThe aim of the study was to evaluate the use of proviral DNA as a source of viral genetic material for genotypic coreceptor tropism testing (GTT). MethodsGTT consisted of bulk V3 sequencing followed by geno2pheno interpretation with the interpretative cut-off [false positive rate (FPR)] set at 5 and 10%. GTT was performed for 165 patients with a viral load of 4500 HIV-1 RNA copies/mL on simultaneously collected plasma RNA and proviral DNA, and for 126 patients with a viral load of o500 copies/mL on current proviral DNA and pretreatment plasma RNA. Phenotypic tropism testing (PTT) results were available for 142 samples. ResultsIn the simultaneous RNA/DNA comparison, concordance in prediction was 95.2% (at FPR 10%) and 96.4% (at FPR 5%). Six RNA-R5/DNA-X4 and two RNA-X4/DNA-R5 discordances were observed at an FPR of 10%, and six RNA-R5/DNA-X4 discordances were observed at an FPR of 5%. In the longitudinal RNA/DNA comparison, concordance was 88.1% (at FPR 10%) and 90.5% (at FPR 5%). Eight RNA-X4/DNA-R5 and seven RNA-R5/DNA-X4 discordances were seen at an FPR of 10%, and 10 RNA-R5/DNA-X4 and two RNA-X4/DNA-R5 discordances at an FPR of 5%. The overall concordance of RNA GTT with PTT was 82% (at FPR 10%) and 83% (at FPR 5%). The overall concordance of DNA GTT with PTT was 85% (at both 10 and 5% FPRs). ConclusionsGTT produced highly concordant tropism predictions for proviral DNA and plasma RNA. GTT on proviral DNA offers a promising approach for tropism prediction in clinical practice, particularly for the assessment of treated patients with low or suppressed viraemia.Keywords: chemokine (C-C motif) receptor 5 (CCR5) inhibitors, genotypic tropism testing, HIV-1 coreceptor, HIV-1 proviral DNA Accepted 25 January 2011Introduction Chemokine (C-C motif) receptor 5 (CCR5) antagonists, members of the class of HIV-1 entry inhibitors, selectively inhibit the replication of CCR5-using (R5) viral strains. Before introducing a CCR5 antagonist as a component of antiretroviral therapy (ART), coreceptor usage, or viral tropism, must be determined to exclude the possibility of the presence of chemokine (C-X-C motif) receptor 4 (CXCR4)-using (X4) strains, as these are associated with poor virological response to the drug [1]. The output of the earliest HIV-1 phenotypic tropism testing (PTT) assay was the formation of syncytia in cultured MT2 cells after virus inoculation. This assay is less well suited for use in routine clinical practice because of inherent difficulties with Correspondence: Prof. Chris Verhofstede, AIDS Reference Laboratory, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Tel: 1 32 9 332 51 61; fax: 1 32 9 332 38 41; e-mail: Chris.verhofstede@ugent.be DOI: 10.1111/j.1468-1293.2011.00922.x HIV Medicine (2011 GTT is based on analysis of the V3-loop sequence of the HIV-1 envelope (env) gene using bioinformatic prediction models to deduce coreceptor usage. GTT has the advantage of being less technically demanding, more rapid and less expensive than PTT, thereby meeting today's need for a fast and...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Concordance between HIV-1 genotypic coreceptor tropism predictions based on plasma RNA and proviral DNA

et al. 2011

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“…[22][23][24][25] In addition, in previous studies genotypic tropism tests were retrospectively validated, while here we show that selection of prospective maraviroc regimens using genotypic or phenotypic assays is associated with similar virological and immunological responses. In contrast with expectations, non-R5 tropism was not negatively associated with virological response.…”

Section: Rossetti Et Almentioning

confidence: 94%

Virological and Immunological Response to Antiretroviral Regimens Containing Maraviroc in HIV Type 1-Infected Patients in Clinical Practice: Role of Different Tropism Testing Results and of Concomitant Treatments

Rossetti¹,

Bianco

Bellazzi

et al. 2014

AIDS Research and Human Retroviruses

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We assessed the immunovirological response to antiretroviral regimens containing maraviroc in HIV-infected viremic patients with viral tropism predicted by different assays. We selected antiretroviral treatmentexperienced HIV-1-infected patients initiating regimens containing maraviroc after different phenotypic or genotypic viral tropism assays, with at least one HIV-1 RNA determination during follow-up. Survival analysis was employed to assess the virological response as time to HIV-1 RNA < 50 copies/ml and immunological response as time to a CD4 cell count increase of ‡ 100/ll from baseline. Predictors of these outcomes were analyzed by multivariate Cox regression models. In 191 treatments with maraviroc, virological response was achieved in 65.4% and the response was modestly influenced by the baseline viral load and concomitant drug activity but not influenced by the type of tropism assay employed. Immunological response was achieved in 58.1%; independent predictors were baseline HIV-1 RNA (per log 10 higher: HR 1.29, 95% CI 1.05-1.60) and concomitant therapy with enfuvirtide (HR 2.05, 0.96-4.39) but not tropism assay results. Of 17 patients with baseline R5-tropic virus and available tropism results while viremic during follow-up on maraviroc, seven (41%) showed a tropism switch to non-R5 virus. A significant proportion of experienced patients treated with regimens containing maraviroc achieved virological response. The tropism test type used was not associated with immunovirological response and concomitant treatment with enfuvirtide increased the chance of immunological response. More than half of virological failures with maraviroc were not accompanied by tropism switch.

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“…These tests detect substitutions at the V3 region of gp120 HIV-1 gene in order to predict the CXCR4 use by viruses present in the patient's quaispecie. Although phenotypic and genotypic tests do not fully agree with each other, genotypic tests are probably equally able to predict virologic treatment failure in maraviroc containing antiretroviral schemes [47] and have been advocate as preferential in some guidelines. [49] 3.…”

Section: E Hiv-1 Tropismmentioning

confidence: 99%

“…[47] Therefore, a tropism test before treatment with these drugs is required; gold standard tropism tests being the phenotypic based tests. One phenotypic tropism test constructs pseudoviruses containing the gp160 of patient's viruses and a backbone of HIV-1 laboratory virus plus the luciferase gene.…”

Section: E Hiv-1 Tropismmentioning

confidence: 99%

Nucleic Acid Testing for HIV-1 Diagnosis and Monitoring

Diaz¹

2012

HIV Testing

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Population-based V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies

Cited by 105 publications

References 17 publications

Concordance between HIV-1 genotypic coreceptor tropism predictions based on plasma RNA and proviral DNA

Concordance between HIV-1 genotypic coreceptor tropism predictions based on plasma RNA and proviral DNA

Virological and Immunological Response to Antiretroviral Regimens Containing Maraviroc in HIV Type 1-Infected Patients in Clinical Practice: Role of Different Tropism Testing Results and of Concomitant Treatments

Nucleic Acid Testing for HIV-1 Diagnosis and Monitoring

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