Excerpt

Understanding the evolution of drug resistance and how to use available diagnostic assays and interpret their results optimally are important aspects of the management of HIV-1-infected patients. This book is aimed at physicians, scientists and other healthcare professionals who wish to gain information about the clinically relevant aspects of antiretroviral resistance.

This book gives the reader insights into the more mechanistic aspects of resistance and the analyses that lie behind the interpretation of resistance. Most importantly, the book aims to provide an up-to-date guide to those aspects of resistance that have the greatest impact on clinical care. The authors of the chapters have internationally recognised expertise in the field of resistance and were chosen because of both their active involvement in research and their strong clinical background. The reader will find their contributions clear, concise and informative, whereas the discussion around the case studies presented in the last chapter will bring the topic into a direct clinical context.

Contents

• Contributors
• Introduction
• 1. Resistance to nucleoside reverse transcriptase inhibitors
  Anne-Geneviève Marcelin.
  • Introduction
  • Mechanisms of NRTI resistance
  • NRTI-associated resistance mutations
  • Conclusion
  • Recommendations for clinical practice
  • References
• 2. Resistance to non-nucleoside reverse transcriptase inhibitors
  Nicola Mackie.
  • Introduction
  • Patterns of resistance mutations
  • Mutations and pathways conferring resistance to NNRTIs
  • Transmission of resistance and persistence of mutations
  • Stopping NNRTI therapy
  • Continuing NNRTI therapy in the presence of resistance
  • NNRTI hypersusceptibility
  • Investigational NNRTIs
  • Recommendations for clinical practice
  • References
• 3. Resistance to protease inhibitors
  Noortje van Maarseveen and Charles Boucher.
  • HIV-1 protease
  • HIV-1 protease inhibitors
  • Resistance mutations
  • Changes in replicative capacity
  • High genetic barrier to protease inhibitors and boosted protease inhibitors
  • Conclusion
  • Recommendations for clinical practice
  • References
• 4. Resistance to entry inhibitors
  Eva Poveda and Vincent Soriano.
  • Introduction
  • Resistance to CD4–gp120 binding inhibitors
  • Resistance to CCR5 and CXCR4 antagonists
  • Resistance to fusion inhibitors
  • Conclusions
  • References
• 5. Resistance assays
  Martin Schutten.
  • Introduction
  • Phenotyping assays
  • Genotyping assays
  • Virtual phenotyping assays
  • Conclusions
  • Recommendations for clinical practice
  • References
• 6. Interpretation algorithms
  Tobias Sing and Martin Däumer.
  • Introduction: selection of antiretroviral therapy
  • The factors of interest: drug activity, viral phenotype and virological response
  • Predicting in vivo antiviral activity of individual drugs
  • Predicting in vitro resistance and replication capacity from the viral genotype
  • Predicting in vivo virological response to combination therapy
  • Summary
  • The future
  • Recommendations for clinical practice
  • Acknowledgments
  • References
• 7. Clinical cut-offs in the interpretation of phenotypic resistance
  Carlo-Federico Perno and Ada Bertoli.
  • Introduction
  • Definition of cut-off for the interpretation of resistance assays
  • Genotypic assays
  • Recommendations for clinical practice
  • References
• 8. Pharmacokinetic implications of resistance
  Marta Boffito.
  • Introduction
  • Pharmacokinetics of antiretroviral agents
  • Therapeutic drug monitoring
  • The inhibitory quotient
  • Conclusion
  • Recommendations for clinical practice
  • Acknowledgement
  • References
• 9. Benefits of resistance testing
  Diane Descamps and Françoise Brun-Vézinet.
  • Introduction
  • Prospective resistance trials: evidence for resistance testing
  • Therapeutic trials: evidence for resistance testing
  • Benefit of resistance testing in drug-naive patients
  • Conclusion
  • Recommendations for clinical practice
  • References
• 10. Transmitted resistance
  Clare Booth.
  • Definition of primary resistance
  • Transmission of drug-resistant mutants
  • Persistence of transmitted drug-resistant mutants
  • Detection of minority transmitted drug-resistant mutants
  • Compartmentalisation of drug-resistant virus and potential for transmission
  • Current guidelines on resistance testing in drug-naive patients
  • The potential impact of superinfection on resistance patterns of drug-naive patients
  • Epidemiology of primary resistance
  • Impact of primary resistance on treatment responses
  • Conclusions
  • Recommendations for clinical practice
  • References
• 11. The significance of minority drug-resistant quasispecies
  Karin Metzner.
  • Introduction
  • The heterogeneity of HIV-1
  • Persistent infection: latency and residual replication
  • Detection and quantification of minority quasispecies of drug-resistant HIV-1
  • Persistence of drug-resistant viral variants
  • Impact of minority quasispecies of drug-resistant HIV-1 on the outcome of antiretroviral therapy
  • Conclusion and future perspectives
  • Recommendations for clinical practice
  • Acknowledgements
  • References
• 12. The impact of resistance on viral fitness and its clinical implications
  Andrea De Luca.
  • Introduction
  • Definition of HIV-1 fitness
  • Methods to determine HIV-1 fitness
  • Genotypic drug resistance and viral fitness
  • Nucleoside reverse transcriptase inhibitor-resistant mutations
  • Non-nucleoside reverse transcriptase inhibitor-resistant mutations
  • Protease inhibitor-resistant mutations
  • Glycoprotein gp41 resistance mutations
  • Viral fitness and therapeutic response: potential clinical applications
  • Conclusions
  • Recommendations for clinical practice
  • References
• 13. The significance of subtype-related genetic variability: controversies and unanswered questions
  Ricardo Camacho.
  • Introduction
  • Current knowledge
  • Subtype-specific mutations
  • Influence of subtypes on the pathways of antiretroviral drug resistance
  • Reliability of phenotypic and genotypic assay results for evaluating resistance in non-B subtypes
  • Entry inhibitors
  • Conclusions
  • Recommendations for clinical practice
  • References
• 14. Database analyses of predictors of resistance
  Caroline Sabin.
  • Introduction
  • Study designs for identifying predictors of resistance
  • Analytical issues
  • Eliminating other causes of bias: interpreting trends over time
  • Recommendations for clinical practice
  • References
• 15. Understanding the statistical analysis of resistance data
  Alessandro Cozzi-Lepri.
  • Introduction: nature of the data
  • Data managing: the choice of reference HIV-1 strain
  • Common assumptions: the importance of basic knowledge of HIV-1 virology
  • Programming interpretation rules and choice of a suitable virological endpoint
  • Possibility of spurious associations
  • Recommendations for clinical practice
  • References
• 16. Case studies
  • Case study 1: Development of resistance on first-line therapy
  • Case study 2: Evolution of resistance during therapy with ritonavir-boosted protease inhibitors
  • Case study 3: Reluctance to take antiretroviral therapy
  • Case study 4: A child with uncertain treatment history and extensive drug resistance
  • Case study 5: Unrecognised transmitted resistance
  • Case study 6: A case of persistent low-level viraemia
  • Case study 7: A young black African woman presenting for HIV testing

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All statements and opinions contained herein are those of the editor and original authors and are independent of the publisher.

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