1 / 51

Outline

Rationale and Uses For a Public HIV Drug Resistance Database Bob Shafer, MD Professor of Medicine and by Courtesy Pathology (Infectious Diseases). Outline. HIV drug therapy essentials HIVDB Examples of public health applications Surveillance of transmitted drug resistance

blaise
Download Presentation

Outline

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Rationale and Uses For a Public HIV Drug Resistance DatabaseBob Shafer, MDProfessor of Medicine and by Courtesy Pathology(Infectious Diseases)

  2. Outline • HIV drug therapy essentials • HIVDB • Examples of public health applications • Surveillance of transmitted drug resistance • Genetic mechanisms of acquired drug resistance

  3. HIV-1 Genome

  4. HIV Replication and Targets of Therapy

  5. 5 Antiretroviral Inhibitors (ARVs) EFV NVP DLV IDV APV T20 ddI 3TC RTV NFV LPV MVC ATV AZT ddC d4T SQV ABC TDF TPV DRV FTC RAL ETR 1990 1995 2000 2005 Protease Inhibitor Fusion Inhibitor Integrase Inhibitor Nucleoside RT Inhibitor Nonnucleoside RT inhibitor CCR5 Inhibitor

  6. 6 HIV Genetic Variation • Generation of variation • High mutation rate • Recombination • Proviral DNA “archive” • Selective evolutionary pressures • Immunological • Antiretroviral drugs (ARVs)

  7. Tebit DM, Arts EJ. Tracking a century of global expansion and evolution of HIV. Lancet Infect Dis 2011

  8. HIV-1 RT: Active Site, Template, Primer, and dNTP Active site Incoming nucleotide

  9. NNRTI Resistance Mutations Active site NNRTI resistance mutations Etravirine

  10. HIV-1 Protease Drug Resistance Mutations Major resistance mutations Lopinavir Active site & substrate cleft Minor resistance mutations

  11. Models Relating HIV Drug Resistance to Treatment Response

  12. 10 Million Patients on Antiretroviral Therapy 2013 Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS)

  13. Outline • HIV drug therapy essentials • HIVDB • Examples of public health applications • Surveillance for transmitted drug resistance • Genetic mechanisms of acquired drug resistance

  14. 14 Database Rationale Drug resistance knowledge important for Interpreting genotypic resistance tests Designing surveillance studies and public health decisions Assisting drug development.

  15. 15 How we know what we know about HIV drug resistance mutations • Genotype-treatment correlations – 1998 • Genotype-phenotype correlations – 2002 • Genotype-outcome correlations – 2005

  16. 16 Database Rationale Large amounts of drug resistance data are important for generating drug-resistance knowledge. Uniform representation of 3 main data correlations facilitates meta-analyses.

  17. Genotype-Rx Genotype-Phenotype Genotype-Outcome Clinical management Epidemiologic studies Drug development http://hivdb.stanford.edu

  18. Genotypic HIV Resistance Testing CCTCAGATCACTCTTTGGCAACGACCCATAGTCACAATAAAGATAGCGGGACAACTAAAGGAAGCTCTATTAGATACAGGAGCAGATGATACAGTATTAGAAGAAATGAATTTGCCAGGAAAATGGAAACCAAAAATAATAGTGGGAATTGGAGGGTTTACCAAAGTAAGACAGTATGATCATGTACAAATAGAAATCTGTGGACATAAAGTTATAGGTGCAGTATTAATAGGACCTACACCTGCCAATATAATTGGAAGAAATCTGTTGACTCAGCTTGGCTGTACTTTAAATTTT PQITLWQRPIVTIKIAGQLKEALLDTGADDTVLEEMNLPGKWKPKIIVGIGGFTKVRQYDHVQIEICGHKVIGAVLIGPTPANIIGRNLLTQLGCTLNF Differences from Consensus B: L10I, G17R, K20I, E35D, N37S, M46I, I62V, L63P, A71I, G73S, I84V, L90M, I93L

  19. HIV-1 Genotypic Resistance Testing: Online Interpretation Meaningful Results (1) Quality control (2) Sequence Interpretation (3) Literature references (4) Clinical education / advice Shafer RW et al. HIV-1 RT and Protease Search Engine for Queries. Nat Med 2000

  20. HIVdb: Genotypic Resistance Interpretation http://hivdb.stanford.edu

  21. HIVdb: Genotypic Resistance Interpretation

  22. HIVdb: Genotypic Resistance Interpretation

  23. HIVdb: Genotypic Resistance Interpretation

  24. Surveillance for Transmitted Drug Resistance

  25. Outline • HIV drug therapy essentials • HIVDB • Examples of public health applications • Surveillance for transmitted drug resistance • Genetic mechanisms of acquired drug resistance

  26. Rationale for Surveillance for Drug Resistance in ARV-Naive Populations • Assess extent of transmitted drug resistance (TDR). • Monitor the expected efficacy of first-line therapies.

  27. Challenges to ARV-Resistance Surveillance • There is no perfect definition of genotypic resistance. • There are many different drug-resistance mutations (DRMs). • Drug resistance mutations occasionally occur in the absence of selective drug pressure. Therefore, not all drug-resistance mutations are evidence for transmitted drug resistance (TDR).

  28. Challenges to ARV-Resistance Surveillance • More than 300 studies of genotypic resistance in ARV-naïve patients have been published. • Findings differ by region, time, study population, and potentially study methods.

  29. Surveillance Drug Resistance Mutations (SDRMs) • Drug-resistance mutations with a high sensitivity and specificity for detecting selective ARV pressure. • Nonpolymorphic. • Applicable to all HIV-1 subtypes. Shafer RW, et al. HIV drug resistance mutations for drug resistance surveillance. AIDS 2007

  30. HIV-1 Resistance in ARV-Naïve Populations:Analysis of Published RT and PR Sequences • Well-characterized representative population of ARV-naïve persons. • Country and year of virus isolation known. • HIV-1 RT ± PR sequence is publicly available.

  31. Calibrated Population Resistance Analysis Tool • Applies SDRM list to a set of sequences • Standardized approach to handling missing data and poor sequence quality. • Backward-compatibility Gifford, RJ et al. The calibrated population resistance tool: standardized genotypic estimation of transmitted HIV-1 drug resistance. AIDS 2008

  32. HIV-1 Resistance in ARV-Naïve Populations:Prevalence by Region

  33. HIV-1 Resistance in ARV-Naïve Populations: Sub-Saharan Africa http://hivdb.stanford.edu/surveillance/map/

  34. HIV-1 Resistance in ARV-Naïve Populations: South / Southeast Asia http://hivdb.stanford.edu/surveillance/map/

  35. HIV-1 Resistance in ARV-Naïve Populations: Most Common SDRMs by Region and ARV Class

  36. HIV-1 Resistance in ARV-Naïve Populations: Conclusions • Significant differences in prevalence of resistance in ARV-naïve patients by region and year. • Transmitted NNRTI resistance is increasing in Sub-Saharan Africa and South/Southeast Asia. • Analysis of data from many studies is required to obtain meaningful estimates of transmitted drug resistance.

  37. Outline • HIV drug therapy essentials • HIVDB • Examples of public health applications • Surveillance for transmitted drug resistance • Genetic mechanisms of acquired drug resistance

  38. Rationale • In resource-limited regions, ~25% of patients receiving first-line ART develop virological failure within 1 year. • Drug-resistance mutations are detected in 50% to 90% of patients with virological failure. • Regimens used in resource-limited countries differ from those used in well-resourced countries. • Patients in resource-limited countries are monitored infrequently and second-line therapy is chosen without genotypic resistance testing.

  39. Genetic Mechanisms of Resistance in Patients with Virological Failure • Choosing second-line therapy. • Developing point-of-care (POC) diagnostic tests.

  40. WHO-Recommended First-Line ARV Regimens

  41. Number of Patients by Regimen and Subtype Data summary from mid 2012

  42. Sources of Patient Data and Sequences Data summary from mid 2012

  43. 43 Question From WHO: Which NRTI should be substituted in patients stopping d4T? Patients with virological failure on d4T can develop resistance by two mutually exclusive mutational pathways: Thymidine analog mutations: cross-resistance to AZT Non-thymidine analog mutations particularly K65R: cross-resistance to TDF and increased susceptibility to AZT In vitro studies have shown that viruses belonging to subtype C are at increased risk for developing K65R.

  44. Impact of NNRTI, Subtype, and Years on NRTI-Resistance Mutations in 1,840 Patients Receiving d4T

  45. Impact of Subtype on AZT and TDF Cross-Resistance in 1,840 Patients Receiving d4T

  46. Rationale for Point-Of-Care (POC) Resistance Testing in Low/Middle-Income Countries? • POC test for detecting virological failure have been developed. • A POC resistance test for a limited number of the most important mutations could be used: • To confirm virological failure • To suggest among second-line therapy options • Be used prior to therapy in regions with elevated TDR or in patients with uncertain treatment history.

  47. Sensitivity for Detecting Resistance after 1st-Line Failure: 4 NNRTI and 6 NRTI-Resistance Mutations

  48. Sensitivity for Detecting Resistance in Untreated Patients: 4 NNRTI and 6 NRTI-Resistance Mutations

  49. 49 Conclusions Drug resistance knowledge is important for interpreting genotypic resistance tests, designing surveillance studies, and drug development. Large amounts of drug resistance data are important for generating drug-resistance knowledge. Drug-resistance data consists mostly of correlations between genotype-treatment, genotype-phenotype, and genotype-virological outcome.

  50. 50 Acknowledgements Database / Data analysis Soo-Yon Rhee, M.S. Tommy Liu, B.S. Michele Tang, M.D. Vici Varghese, Ph.D. Funding NIAID – Division of AIDS Bill and Melinda Gates Foundation

More Related