Multicentre study to evaluate the relation study to evaluate the relation Multicentre between the efficacy of treatment with the between the efficacy of treatment with the CCR5 inhibitor Maraviroc Maraviroc and HIV and HIV- -1 co 1 co- - CCR5 inhibitor receptor tropism as determined by V3 loop receptor tropism as determined by V3 loop sequencing sequencing Dr. Vandekerckhove Vandekerckhove Linos Linos Dr. Dpt. of . of Infectious Infectious diseases diseases Dpt University Hospital Hospital Ghent Ghent University Belgium Belgium
Maraviroc: integration of a : integration of a Maraviroc new antiretroviral drug class new antiretroviral drug class into clinical practice into clinical practice Vandekerckhove L., Verhofstede C. and Vogelaers D., JAC 2008
Maraviroc: integration of a new : integration of a new Maraviroc antiretroviral drug class into antiretroviral drug class into clinical practice clinical practice The clinical availability of the co-receptor antagonist maraviroc precedes the scientific understanding that is needed to clearly position this class of drugs in the total spectrum of treatment options and this gap must be filled as soon as possible.
Coreceptor tropism tropism Coreceptor Different assays for determination (Standard?) Recombinant phenotypic assays Construction of recombinant virus � infection of CXCR4+/CCR5+ cells Genotypic assays V3 loop sequencing � bioinformatic tools MT2 assay Infection of MT2 (CXCR4+) cells Different source of material to perform the analysis on (Plasma RNA – Cellular DNA) Sensitivity of the assays? Importance of minority species?
Aims of the study Aims of the study To set up an (international) cohort of patients - To set up an (international) cohort of patients - initiating Maraviroc Maraviroc initiating To evaluate the influence of minority species of - To evaluate the influence of minority species of - X4 virus on maraviroc maraviroc treatment outcome treatment outcome X4 virus on To compare phenotypic and genotypic tropism - To compare phenotypic and genotypic tropism - determination determination To compare genotypic tropism determination - To compare genotypic tropism determination - on plasma RNA and on cellular DNA on plasma RNA and on cellular DNA
Infectious Diseases Research Unit University Hospital Ghent (Vandekerckhove L. and Vogelaers D.) AIDS reference Laboratory University Ghent (Verhofstede C.) Virco (Mechelen) (Stuyver L.) 2007: Roll out of the study in most Belgian centres
2008: roll out in UK/ Germany/ Spain 2008: roll out in UK/ Germany/ Spain Germany Dr. Jan van Lunzen Dr. Hans-Jürgen Stellbrink Dr. Eva Wolf Dr. Jürgen Rockstroh Dr. Rolf Kaiser
? Clonal sequencing ? Population sequencing of proviral DNA ? Phenotyping
Influence of minority X4 Influence of minority X4 populations on response to populations on response to maraviroc . maraviroc . Collect and store plasma and buffy buffy coat of coat of Collect and store plasma and - - patients initiating maraviroc maraviroc: screening, : screening, patients initiating inclusion, 4 weeks, 12 weeks, 24 weeks,… … inclusion, 4 weeks, 12 weeks, 24 weeks, - Determine maraviroc maraviroc failures. failures. - Determine Analyse sample at failure (plasma/cells) for sample at failure (plasma/cells) for Analyse - - the presence of X4 strains by genotyping the presence of X4 strains by genotyping (population – – clonal clonal) and ) and phenotyping phenotyping ( (Virco Virco) ) (population
X4 strains in plasma (RNA) and cells (DNA) Cells Plasma 100 <0.0001 90 <0.0001 80 NS <0.0001 <0.0001 X4 frequency (%) <0.002 NS 70 <0.0001 60 50 40 30 NS 20 NS 10 0218 9111 9515 9601 9615 9228 9514 9526 9429 9532 9646 Patient
Distribution of PSSM scores – all patients combined Plasma (n = 386) Cells (n = 283) - 30 25 % of all clones 20 15 10 5 -14 -12 -10 -8 -6 -4 -2 0 2 R5 PSSM Score X4 The PSSM Score was on average 3.2 (95% CI [2.6;3.7], p<.0001) units lower in the plasma samples. The odds of R4 virus was 6.6 times (95% CI [4.5;9.8],p<.0001) higher in infected PBMC (based on a logistic regression model).
Comparison of phenotypic and genotypic Comparison of phenotypic and genotypic methods for tropism determination methods for tropism determination - Samples collected at screening/initiation of Samples collected at screening/initiation of - maraviroc (plasma and cells/ (plasma and cells/buffy buffy coat /whole coat /whole maraviroc blood) blood) - Genotypic tropism determination by population Genotypic tropism determination by population - sequencing and clonal clonal sequencing on plasma sequencing on plasma sequencing and RNA and cellular DNA RNA and cellular DNA - Compare the results of these determinations with Compare the results of these determinations with - the phenotypic tropism determination the phenotypic tropism determination - Evaluate the results of population and Evaluate the results of population and clonal clonal - genotypic tropism determination on cellular DNA genotypic tropism determination on cellular DNA with regard to maraviroc maraviroc failure/success failure/success with regard to
Multicentre study to evaluate the relation study to evaluate the relation Multicentre between the efficacy of treatment with between the efficacy of treatment with the CCR5 inhibitor Maraviroc Maraviroc and HIV and HIV- -1 1 the CCR5 inhibitor co- -receptor tropism as determined by receptor tropism as determined by co V3 loop sequencing V3 loop sequencing Linos.vandekerckhove@ugent.be Chris.verhofstede@ugent.be Stijn.blot@ugent.be Thank you for your attention Thank you for your attention
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