Viral Drug Resistance

Long term use of anti-viral therapy has selected for therapeutic resistance in circulating viral pools. Few patients can now be considered to be infected with wild type viral strains. In addition, the introduction of a new therapy is highly likely to result in new resistance strains.

Testing for resistance to therapy is a major strength at Lab21, especially in the area of HIV and Viral Hepatitis. Resistance testing for anti-viral therapeutics is of key interest as FDA and other bodies place increasing emphasis on the collection of information on drug resistance during anti-viral drug development. Development of resistance to therapies already marketed is of further commercial importance.

Please click below for more  information on our viral resistance services.   

• Existing drug resistance
• Predicting resistance to new therapeutics
• Sequencing services
• Phenotyping services

Existing drug resistance                                                                                                     Back to Top

Characterisation of existing drug resistance is highly useful for:

• Selection, stratification and monitoring of clinical trials volunteers
• Predicting likely efficacy of new molecules in the clinic and in defining potential market size and segmentation
• Characterisation of the genotypic and phenotypic patterns and frequency of resistance that exist globally to investigational compounds

Lab21 has in-depth experience in profiling the performance of new anti-viral drugs against:

• A wide range of viruses including HIV, HCV and HBV
• Over 8000 drug resistant laboratory adapted strains
• Wild type strains of different clades
• Clinical samples from disparate geographical locations and subtypes
• Primary clinical viral isolates propagated in PBMC culture
• Sequencing and phenotyping
• HIV, HCV, HBV and other viruses

Types of drugs tested include RTI, NNRTI, Protease inhibitors and Fusion inhibitors. Other drug types may be tested as requested. We are also able to characterise Multi-Drug Resistance upon request.

Predicting resistance to new therapeutics                                                                        Back to Top

Our substantial experience in the in vitro selection of drug resistant (escape) viral mutants means that we can create predictions of anti-viral resistance patterns that are likely to be observed when investigational compounds reach the clinic.

Resistance prediction:

• Viral cultures are passaged in increasingly high concentrations of drug
• Resistant clones appear
• Clones are isolated and characterised phenotypically as well as genotypically to identify genomic sequence variation
• If required we can engineer recombinant virus containing candidate resistance mutations and compare phenotypes to establish the importance of individual mutations in modifying anti-viral efficacy of the investigational compound
• Model of clinical appearance of resistance to therapy

In order to satisfy regulatory requirements, we further undertake cross-resistance studies testing newly selected resistant clones for cross-resistance to existing therapy and other compounds in development to ensure that new chemical entities do not induce resistance that limits therapeutic options.

Additionally, we offer resistance selection services for HCV (replicon system) and other viruses as required. We are also able to study drug combinations upon request.

Sequencing services                                                                                                          Back to Top

Lab21 offers extensive services to examine the genetic basis of viral drug resistance by sequencing. We also have highly sensitive, optimised proprietary protocols for commercially relevant HCV and HIV genes and hold IP covering the nucleotide sequence analysis of the HCV NS3 gene by any technique. Lab21 is therefore the clear choice for studies in this topical area.

Mixed viral populations can be resolved by population and clonal approaches, and analysis of variation can be customised according to requirements including: alignment, phylogenetic trees and analysis of likely drug resistance characteristics.

Examples of sequencing targets include:

• HCV NS3/4A
• HCV NS5B
• HIV Protease
• HIV Reverse Transcriptase
• HIV Integrase
• HIV Fusion Inhibitors
• Other genes and organisms as requested

Phenotyping services                                                                                                         Back to Top

Our team has expertise in phenotypic assays to examine patterns of anti-viral drug resistance in vitro. Our services include:

• Confirmation and characteriation of susceptibility of virus from clinical trials patients
• Chronological comparisons to examine the emergence of resistance to therapy
• Cross-checking of viral resistance to existing therapies to confirm that treatment with an investigational compound does not give rise to undesirable loss of therapeutic options by inducing resistance to other drugs

Examples of phenotyping targets include:

• HCV NS3*
• HCV NS5B*
• HIV Reverse Transcriptase
• HIV Protease
• HIV Fusion inhibitors
• HIV tropism assay (CXCR4/CCR5)
• Similar services are available for other viruses on request

* In development