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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 - PowerPoint PPT Presentation
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Rationale and Uses For a Public HIV Drug Rationale and Uses For a Public HIV Drug Resistance DatabaseResistance Database
Bob Shafer, MDBob Shafer, MDProfessor of Medicine and by Courtesy PathologyProfessor of Medicine and by Courtesy Pathology
(Infectious Diseases)(Infectious Diseases)
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OutlineOutline
• HIV drug therapy essentials
• HIVDB
• Examples of public health applications
• Surveillance of transmitted drug resistance
• Genetic mechanisms of acquired drug resistance
HIV-1 Genome
HIV Replication and Targets of Therapy
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AAntintirretroetrovviral Inhibitors (ARVs)iral Inhibitors (ARVs)
AZT
1990 1995 2000 2005
ddId4TddC3TC
SQVRTVIDVNVP
TDFABCNFVAPVDLVEFV
LPV ATVT20
TPV DRV RALMVC
FTC ETR
Nucleoside RT Inhibitor
Nonnucleoside RT inhibitor
Protease Inhibitor
Fusion Inhibitor
CCR5 Inhibitor
Integrase Inhibitor
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HIV Genetic VariationHIV Genetic Variation
• Generation of variation
• High mutation rate
• Recombination
• Proviral DNA “archive”
• Selective evolutionary pressures
• Immunological
• Antiretroviral drugs (ARVs)
Tebit DM, Arts EJ. Tracking a century of global expansion and evolution of HIV. Lancet Infect Dis 2011
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HIV-1 RT: Active Site, Template, Primer, and dNTP
Incoming nucleotide
Active site
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NNRTI Resistance Mutations
EtravirineNNRTI resistance mutations
Active site
HIV-1 Protease Drug Resistance Mutations
Active site & substrate cleft
Lopinavir Major resistance mutations
Minor resistance mutations
Models Relating HIV Drug Resistance to Treatment Response
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10 Million Patients on Antiretroviral Therapy
2013 Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS)
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OutlineOutline
• HIV drug therapy essentials
• HIVDB
• Examples of public health applications
• Surveillance for transmitted drug resistance
• Genetic mechanisms of acquired drug resistance
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Database RationaleDatabase Rationale
• Drug resistance knowledge important for
Interpreting genotypic resistance tests
Designing surveillance studies and public health decisions
Assisting drug development.
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How we know what we know about HIV How we know what we know about HIV drug resistance mutationsdrug resistance mutations
• Genotype-treatment correlations – 1998
• Genotype-phenotype correlations – 2002
• Genotype-outcome correlations – 2005
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Database RationaleDatabase Rationale
• Large amounts of drug resistance data are important for generating drug-resistance knowledge.
• Uniform representation of 3 main data correlations facilitates meta-analyses.
Genotype-RxGenotype-PhenotypeGenotype-Outcome
Clinical managementEpidemiologic studies
Drug development
http://hivdb.stanford.edu
Genotypic HIV Resistance Testing
CCTCAGATCACTCTTTGGCAACGACCCATAGTCACAATAAAGATAGCGGGACAACTAAAGGAAGCTCTATTAGATACAGGAGCAGATGATACAGTATTAGAAGAAATGAATTTGCCAGGAAAATGGAAACCAAAAATAATAGTGGGAATTGGAGGGTTTACCAAAGTAAGACAGTATGATCATGTACAAATAGAAATCTGTGGACATAAAGTTATAGGTGCAGTATTAATAGGACCTACACCTGCCAATATAATTGGAAGAAATCTGTTGACTCAGCTTGGCTGTACTTTAAATTTT
PQITLWQRPIVTIKIAGQLKEALLDTGADDTVLEEMNLPGKWKPKIIVGIGGFTKVRQYDHVQIEICGHKVIGAVLIGPTPANIIGRNLLTQLGCTLNF
Differences from Consensus B:
L10I, G17R, K20I, E35D, N37S, M46I, I62V, L63P, A71I, G73S, I84V, L90M, I93L
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
HIVdb: Genotypic Resistance Interpretation
http://hivdb.stanford.edu
HIVdb: Genotypic Resistance Interpretation
HIVdb: Genotypic Resistance Interpretation
HIVdb: Genotypic Resistance Interpretation
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Surveillance for Transmitted Drug Resistance
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OutlineOutline
• HIV drug therapy essentials
• HIVDB
• Examples of public health applications
• Surveillance for transmitted drug resistance
• Genetic mechanisms of acquired drug resistance
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Rationale for Surveillance for Drug Resistance Rationale for Surveillance for Drug Resistance in ARV-Naive Populationsin ARV-Naive Populations
• Assess extent of transmitted drug resistance (TDR).
• Monitor the expected efficacy of first-line therapies.
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Challenges to ARV-Resistance SurveillanceChallenges 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).
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Challenges to ARV-Resistance SurveillanceChallenges 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.
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Surveillance Drug Resistance Mutations (SDRMs)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
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HIV-1 Resistance in ARV-Naïve Populations:HIV-1 Resistance in ARV-Naïve Populations:Analysis of Published RT and PR SequencesAnalysis 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.
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Calibrated Population Resistance Analysis ToolCalibrated Population Resistance Analysis Tool
Gifford, RJ et al. The calibrated population resistance tool: standardizedgenotypic estimation of transmitted HIV-1 drug resistance. AIDS 2008
• Standardized approach to handling missing data and poor sequence quality.
• Applies SDRM list to a set of sequences
• Backward-compatibility
HIV-1 Resistance in ARV-Naïve Populations:HIV-1 Resistance in ARV-Naïve Populations:Prevalence by RegionPrevalence by Region
Region No. Studies
No.Persons
% ResistanceMedian
% ResistanceIQR
North America 24 11,038 11.4 8.8 – 14.0
Europe 44 11,419 9.3 6.0 – 15.1
Latin America 39 5,802 7.6 4.0 – 10.1
High-income Asia 11 3,190 5.5 3.5 – 9.0
Former Soviet Union 11 1,124 3.4 0.0 – 6.4
South/Southeast Asia 49 4,181 3.3 2.0 – 5.3
Sub-Saharan Africa 86 9,904 2.8 1.1 – 5.7
264 46,660
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HIV-1 Resistance in ARV-Naïve Populations: HIV-1 Resistance in ARV-Naïve Populations: Sub-Saharan AfricaSub-Saharan Africa
http://hivdb.stanford.edu/surveillance/map/
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HIV-1 Resistance in ARV-Naïve Populations: HIV-1 Resistance in ARV-Naïve Populations: South / Southeast AsiaSouth / Southeast Asia
http://hivdb.stanford.edu/surveillance/map/
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HIV-1 Resistance in ARV-Naïve Populations: HIV-1 Resistance in ARV-Naïve Populations: Most Common SDRMs by Region and ARV ClassMost Common SDRMs by Region and ARV Class
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• 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.
HIV-1 Resistance in ARV-Naïve Populations: HIV-1 Resistance in ARV-Naïve Populations: ConclusionsConclusions
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OutlineOutline
• HIV drug therapy essentials
• HIVDB
• Examples of public health applications
• Surveillance for transmitted drug resistance
• Genetic mechanisms of acquired drug resistance
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RationaleRationale
• 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.
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Genetic Mechanisms of Resistance in Patients Genetic Mechanisms of Resistance in Patients with Virological Failurewith Virological Failure
• Choosing second-line therapy.
• Developing point-of-care (POC) diagnostic tests.
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WHO-Recommended First-Line ARV Regimens WHO-Recommended First-Line ARV Regimens
WHO-Recommended Regimens, 2016 to 2013
NRTI NRTI NNRTI / PI
d4T (being phased out) 3TC (or FTC) EFV
AZT NVP
TDF LPV (PI, 2nd line)
ABC (children)
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Number of Patients by Regimen and SubtypeNumber of Patients by Regimen and Subtype
A B C AE AG D G Misc Total
d4T/3TC/NVP 50 55 121 430 123 27 122 40 1121
AZT/3TC/NVP 45 99 394 45 50 42 46 21 469
d4T/3TC/EFV 13 92 188 16 9 2 3 11 540
AZT/3TC/EFV 25 244 274 45 20 17 26 11 576
133 490 977 536 202 88 197 83 2706
Data summary from mid 2012
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Sources of Patient Data and SequencesSources of Patient Data and Sequences
Number Studies Number Patients %
10 largest 1,409 51%
20 largest 1,981 72%
50 largest 2,640 98%
Data summary from mid 2012
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Question From WHO: Which NRTI should be Question From WHO: Which NRTI should be substituted in patients stopping d4T?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.
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Impact of NNRTI, Subtype, and Years on NRTI-Impact of NNRTI, Subtype, and Years on NRTI-Resistance Mutations in 1,840 Patients Receiving d4T Resistance Mutations in 1,840 Patients Receiving d4T
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Impact of Subtype on AZT and TDF Cross-Resistance in Impact of Subtype on AZT and TDF Cross-Resistance in 1,840 Patients Receiving d4T 1,840 Patients Receiving d4T
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Rationale for Point-Of-Care (POC) Resistance Testing Rationale for Point-Of-Care (POC) Resistance Testing in Low/Middle-Income Countries?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.
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Sensitivity for Detecting Resistance after 1st-Line Sensitivity for Detecting Resistance after 1st-Line Failure: 4 NNRTI and 6 NRTI-Resistance MutationsFailure: 4 NNRTI and 6 NRTI-Resistance Mutations
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Sensitivity for Detecting Resistance in Untreated Sensitivity for Detecting Resistance in Untreated Patients: 4 NNRTI and 6 NRTI-Resistance MutationsPatients: 4 NNRTI and 6 NRTI-Resistance Mutations
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ConclusionsConclusions
• 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.
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Acknowledgements
FundingNIAID – Division of AIDSBill and Melinda Gates Foundation
Database / Data analysisSoo-Yon Rhee, M.S.Tommy Liu, B.S.Michele Tang, M.D.Vici Varghese, Ph.D.
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HIV-1 Evolution and Drug Resistance: An Example
Fessel WJ, et al. The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment. Antivir Res 2011