Virco N.v.

Tibotec Pharmaceuticals Ltd.

Tibotec Bvba

Virco Bvba

Tibotec-virco Virology Bvba

Kurt Hertogs

Jan Heeres

Abdellah Tahri

Bart Rudolf Romanie Kesteleyn

Paul Adriaan Jan Janssen

Dominique Louis Nestor Ghislain Surleraux

Brendan Larder

Rudi Pauwels

Eva Bettens

Lucien Maria Henricus Koymans

Jerôme Emile Georges Guillemont

Paulus Joannes Lewi

Frederik Frans Desiré Daeyaert

Hendrik Maarten Vinkers

Pascale Alfons Rosa Dehertogh

Michael Eissenstat

Marc René De Jonge

Piet Tom Bert Paul Wigerinck

Marie-Pierre De B&eacute;thune

Elisabeth Thérese Jeanne Pasquier

Jerome Emile Guillemont

Elisabeth Therese Pasquier

Marie-Pierre T M M G De Bethune

Wim Van De Vreken

Lieve Emma Jan Michiels

Dong Xie

Sandra De Meyer

Stuart Bloor

Natalie Maria Francisca Kindermans

Maxime Francis Jean-Marie Ghislain Canard

Dechao Wang

Frank Xavier Jozef Herwig, Legal Representative

Rudy Jean Marc Mortier

Richard P Harrigan

Rong Jian Lu

Frank Xavier Jozef Herwig Arts

Dirk Edward Désiré Jochmans

Veronique Corine Paul De Vroey

Paul Adriaan Janssen

Paul Adrian Janssen

Rudi Wilfried Pauwels

Jing Wang

The invention provides novel mutations, mutation combinations or mutational profiles of HIV-1 reverse transcriptase and/or protease genes correlated with phenotypic resistance to HIV drugs. More particularly, the present invention relates to the use of genotypic characterization of a target population of HIV and the subsequent correlation of this information to phenotypic interpretation in order to correlate virus mutational profiles with drug resistance. The invention also relates to methods of utilizing the mutational profiles of the invention in databases, drug development, i.e., drug design, and drug modification, therapy and treatment design, clinical management and diagnostic analysis.

Mutational profiles in HIV-1 reverse transcriptase correlated with phenotypic drug resistance

The present invention concerns the compounds of formula (I) their N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, wherein n is 1, 2 or 3; Ris H, CN, halo, aminoC(&#x2550;O), C(&#x2550;O)OH, CalkyloxyC(&#x2550;O), CalkylC(&#x2550;O), mono- or di(Calkyl)aminoC(&#x2550;O), arylaminoC(&#x2550;O), N-(aryl)-N&#x2014;(Calkyl)aminoC(&#x2550;O), methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(Calkyl)methanimidamidyl, Hetor Het; Ris H, Calkyl, Calkenyl, Ccycloalkyl, wherein said Calkyl, Calkenyl and Ccycloalkyl may be optionally substituted; Ris nitro, cyano, amino, halo, hydroxy, Calkyloxy, hydroxyC(&#x2550;O), aminoC(&#x2550;O), CalkyloxyC(&#x2550;O), mono- or di(Calkyl)aminoC(&#x2550;O), CalkylC(&#x2550;O), methanimidamidyl, mono- or di(Calkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het; for use as a medicine. The invention further relates to a novel subgroup of the compounds of formula (I), and to compositions comprising compounds of formula (I).

Substituted indolepyridinium as anti-infective compounds

This invention concerns HIV replication inhibitors of formula (I), the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

HIV replication inhibiting pyrimidines and triazines

Mutational profiles in HIV-1 protease and reverse transcriptase correlated with phenotypic drug resistance

This invention concerns HIV replication inhibitors of formula (I), The N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them. 

The present invention concerns a compound having the formula (I) a N-oxide form, a stereochemical isomer, racemic mixture, salt, prodrug, ester or metabolite thereof. It further relates to processes for their preparation as well as pharmaceutical compositions, their use as medicines, and diagnostic kits comprising them. The present invention also concerns combinations of the present entry inhibitors with anti-retroviral agents. It further relates to their use in assays as reference compounds or as reagents. The compounds of the present invention are useful for preventing or treating infection by HIV and for treating AIDS.

Small molecule entry inhibitors

The present invention concerns methods and systems for improving the accuracy of predicting resistance of a disease to a therapy. In one embodiment of the invention, mean and standard deviation (SD) values of fold change in normalized sensitivity, relative to a laboratory wild type standard pathogen or malignant cell are calculated to demonstrate that the patient samples display inherently different degrees of variation in susceptibility to each therapy. In another embodiment, the 2&#xd7;SD value for each therapy is used as the cut-off between sensitive (within normal susceptible range) and resistant (above normal susceptible range).

Establishment of biological cut-off values for predicting resistance to therapy

The present invention concerns methods for measuring drug resistance by correlating genotypic information with phenotypic profiles. In one embodiment, a method for interpreting genotypic information is described wherein a genetic code is generated from a patient sample, a list of mutations known or suspect to play a role in the development of resistance to one or more drugs is obtained from the generated genetic code, a genotype database is interrogated for previous samples with similar mutations relating to said one or more drugs, a phenotype for said sample is located in a phenotype database, the mean change in inhibition is determined based on all the examples located in said phenotype database, a distribution of sensitivities of one or more drugs suitable for treating a specific indication is determined.

Methods for measuring therapy resistance

The present invention is drawn to A method of managing HIV chemotherapy of patients who are HIV positive, which comprises transfecting a cell line susceptible to infection by HIV with a sequence from the pol gene of HIV, which sequence encodes a desired target enzyme, obtained by isolating viral RNA from a sample of a biological material from a patient and reverse transcribing the desired region of said pol gene, and a HIV-DNA construct from which said sequence has been deleted, culturing said transfected cells so as to create a stock of chimeric viruses providing an indication of the resistance profile of the circulating virus, assessing the phenotypic sensitivity of said chimeric viruses to an inhibitor of said enzyme encoded by the pol gene of HIV and assigning a value thereto, constructing a data set comprising said value for chimeric virus sensitivity and the corresponding value for a chimeric wild-type strain of HIV, repeating the sensitivity assessment for at least two further inhibitors and thereby constructing at least three such data sets in total, representing said data sets in two dimensional or three dimensional graphical form such that the difference between the chimeric and wild-type sensitivities in the case of each data set provides a visual measure of the resistance of the chimeric stock to treatment by the inhibitor in question, and selecting the optimum inhibitor(s) on the basis of the graphical representation of the resistance so measured.

Method of managing the chemotherapy of patients who are HIV positive based on the phenotypic drug sensitivity of human HIV strains

The present invention is drawn to A method of managing HIV chemotherapy of patients who are HIV positive, which comprises transfecting a cell line susceptible to infection by HIV with a sequence from the pol gene of HIV, which sequence encodes a desired target enzyme, obtained by isolating viral RNA from a sample of a biological material from a patient and reverse transcribing the desired region of the pol gene, and a HIV-DNA construct from which the sequence has been deleted, culturing the transfected cells so as to create a stock of chimeric viruses providing an indication of the resistance profile of the circulating virus, assessing the phenotypic sensitivity of the chimeric viruses to an inhibitor of the enzyme encoded by the pol gene of HIV and assigning a value thereto, constructing a data set comprising the value for chimeric virus sensitivity and the corresponding value for a chimeric wild-type strain of HIV, repeating the sensitivity assessment for at least two further inhibitors and thereby constructing at least three such data sets in total, representing the data sets in two dimensional or three dimensional graphical form such that the difference between the chimeric and wild-type sensitivities in the case of each data set provides a visual measure of the resistance of the chimeric stock to treatment by the inhibitor in question, and selecting the optimum inhibitor(s) on the basis of the graphical representation of the resistance so measured.

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Antwerp, Belgium

Kurt Hertogs