Outline

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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