Multicentre study to evaluate the relation study to evaluate the - - PowerPoint PPT Presentation

Multicentre Multicentre study to evaluate the relation study to evaluate the relation between the efficacy of treatment with the between the efficacy of treatment with the CCR5 inhibitor CCR5 inhibitor Maraviroc Maraviroc and HIV and HIV-

• 1 co

1 co-

• receptor tropism as determined by V3 loop

receptor tropism as determined by V3 loop sequencing sequencing Dr.

• Dr. Vandekerckhove

Vandekerckhove Linos Linos Dpt

• Dpt. of

. of Infectious Infectious diseases diseases University University Hospital Hospital Ghent Ghent Belgium Belgium

Maraviroc Maraviroc: integration of a : integration of a new antiretroviral drug class new antiretroviral drug class into clinical practice into clinical practice

Vandekerckhove L., Verhofstede C. and Vogelaers D., JAC 2008

Maraviroc Maraviroc: integration of a new : integration of a new 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.

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?

Coreceptor Coreceptor tropism tropism

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 initiating Maraviroc Maraviroc

• To evaluate the influence of minority species of

To evaluate the influence of minority species of X4 virus on X4 virus on maraviroc maraviroc treatment outcome treatment outcome

• To compare phenotypic and genotypic tropism

To compare phenotypic and genotypic tropism determination determination

• To compare genotypic tropism determination

To compare genotypic tropism determination

• n plasma RNA and on cellular DNA
• n 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

Collect and store plasma and buffy buffy coat of coat of patients initiating patients initiating maraviroc maraviroc: screening, : screening, inclusion, 4 weeks, 12 weeks, 24 weeks, inclusion, 4 weeks, 12 weeks, 24 weeks,… …

• Determine

Determine maraviroc maraviroc failures. failures.

• Analyse

Analyse sample at failure (plasma/cells) for sample at failure (plasma/cells) for the presence of X4 strains by genotyping the presence of X4 strains by genotyping (population (population – – clonal clonal) and ) and phenotyping phenotyping ( (Virco Virco) )

X4 strains in plasma (RNA) and cells (DNA)

0218 9111 9515 9601 9615 9228 9514 9526 9429 9532

Patient

10 20 30 40 50 60 70 80 90 100

X4 frequency (%)

<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.002 NS NS NS NS

Plasma Cells

9646

Distribution of PSSM scores – all patients combined

5 10 15 20 25 30

• 14
• 12
• 10
• 8
• 6
• 4
• 2

2

% of all clones Plasma (n = 386)

• Cells (n = 283)

PSSM Score

R5 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 maraviroc (plasma and cells/ (plasma and cells/buffy buffy coat /whole coat /whole blood) blood)

• Genotypic tropism determination by population

Genotypic tropism determination by population sequencing and sequencing and clonal clonal sequencing on plasma sequencing on plasma 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 with regard to maraviroc maraviroc failure/success failure/success

Thank you for your attention Thank you for your attention

Multicentre Multicentre study to evaluate the relation study to evaluate the relation between the efficacy of treatment with between the efficacy of treatment with the CCR5 inhibitor the CCR5 inhibitor Maraviroc Maraviroc and HIV and HIV-

• 1

1 co co-

• receptor tropism as determined by

receptor tropism as determined by V3 loop sequencing V3 loop sequencing

Linos.vandekerckhove@ugent.be Chris.verhofstede@ugent.be Stijn.blot@ugent.be