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ARV Drug Resistance

HAIVNHarvard Medical School

AIDS Initiative in Vietnam

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Learning Objectives

By the end of this session, participants should be able to:

Explain how HIV develops resistance Describe the factors that increase

the risk of developing HIV resistance Outline the types of resistance tests Explain data about resistance in

Vietnam

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HIV Life Cycle

HIV is a “retrovirus” Replication occurs from RNA to DNA

using “reverse transcriptase” enzyme The DNA created is then integrated

into host cell genome (T lymphocyte) New HIV viruses are then produced

using this DNA complex

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HIV - Life Cycle & ARV Drugs

ProteaseInhibitors(9)

Fusion/EntryInhibitors (2)

IntegrationInhibitors (1)

ReverseTranscriptaseInhibitors(11)

Source:wires.wiley.com-2010

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HIV Drug Resistance: Introduction

HIV reverse transcriptase is very prone to errors resulting in mutations

HIV mutations occur naturally during HIV replication

Mutations in the virus can cause resistance

HIV is “resistant” to a drug if it keeps multiplying while patients are taking the drug

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How Does HIV Develop Resistance? (1)

Administration of ARVs in an insufficiently potent manner exerts reproductive pressure that selects for resistant strains

Only resistant strains continue to reproduce, which then become the majority strain of HIV in that patient

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How Does HIV Develop Resistance? (2)

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How Does HIV Develop Resistance? (3)

Changes of drug concentration in blood during treatment

Drug concentration in blood

Lower limit of effective drug concentration in blood

Regular medication Wild-type HIVResistant HIV

Failed to take medication

Time

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How Does HIV Develop Resistance? (4)

Insufficient drug level

Viral replication in the presence of drug

Resistant virus

Poor adherence

Social/personal issues

Regimen issues

Toxicities

Poor potency

Wrong dose

Host genetics

Poor absorption

Rapid clearance

Poor activation

Drug interactions

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Resistance Testing: Types of Resistance Tests

Genotypic testing: look for specific

mutations that could cause drug resistance

Phenotypic testing: measure ability of a

patient’s virus to grow in different concentrations of ARV

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Genotypic Testing: Limitations (1)

Patient must be taking ARV at time the test is done

Test only detects mutations present in ≥ 20% of circulating virus

Viral load must be ≥ 1,000 copies/ml

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Genotypic Testing: Limitations (2)

Reversion to Wild-Type Virus After Discontinuing ARV

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Genotypic Testing: Genetic Code (1)

The genetic code of the sample virus is compared to the wild type

The genetic code is a long chain of molecules called nucleotides

Each group of 3 nucleotides (called a codon), defines a particular amino acid used to build a new virus

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Genotypic Testing: Genetic Code (2)

Codon

Nucleotide

Amino acid

AAA ATG AGC

Lys Met Ser

Genetic Code

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Genotypic Testing: Mutation (1)

Mutations are described by a combination of letters and numbers, i.e.: M184V = 3TC resistance• M (Methionine): name for the amino

acid in the wild type virus• 184: identifies the position of the codon• V (Valine): name for the “changed”

amino acid in the mutant sample

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Genotypic Testing: Mutation (2)

Codon 184 MutationCodon 184

Nucleotide

Amino acid

AAA ATG AGC AAA GTG AGC

Lys Met Ser Lys Val Ser

Mutation

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Genotypic Testing: Disadvantages

Resistance test are not available everywhere

Expensive Work better when viral load is higher Results can be difficult to understand

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Resistance Concepts (1): Genetic Barrier

Low genetic barrier High genetic barrier

• High level resistance with one mutation:

• NVP, EFV: K103N

• 3TC: M184V

• ≥3 mutations needed to develop high level resistance to most PIs

Genetic barrier is number of mutations required to confer resistance to a drug

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Resistance Concepts (2): Cross-Resistance

A mutant version of HIV is resistant to more than one drug

Cross-resistance within classes is common• Resistance to one NNRTI means resistance

to other NNRTIs (NVP and EFV)• Resistance to one NRTI can indicate

resistance to other NRTI (3TC and FTC) Use the results of resistance testing to

choose second-line drugs

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HIV Drug Resistance in Vietnam

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Treatment Experienced and ARV Resistance (1)

248 patients in 11 PEPFAR-supported clinics: • suspected treatment failure on first line

therapy or • history of suboptimal ARV treatment

June - December 2007• Viral Load: 148/248 (59.7%) detectable• Genotype results available on 136 patients• Mutations found in 121/136 (89%) patients

Giang LT, AIDS Conference 2008

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Treatment Experienced and ARV Resistance (2)

Mutations %

NRTI 95.9

• M184V 77.6

• TAMS (> 1) 71.7

• TAMS (> 3) 49.1

• K65R 9.4

• Q151M 7.8

NNRTI 88.4

PI 8.3

Treatment Experienced and ARV Resistance (3)

ARV Resistance

High level (%)

NRTI

• 3TC 76.3

• AZT 37.3

• d4T 34.2

• ABC 32.5

• DDI 31.4

• TDF 0.8

NNRTI 85.2

PI 0

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When to Do Resistance Testing

Patient currently taking ARV with good adherence for at least 6 months

Evidence for treatment failure Viral load testing done first and result

> 1,000 More than one 2nd-line ARV regimen

available

Indications for ordering test in Vietnam: all criteria should be met

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Case Study

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Key Points

Resistance develops in the setting of an inadequately suppressive ARV therapy

For the patient who is failing therapy: check adherence issues first

Testing for HIV resistance to ARVs is an important component of clinical care

Resistance assays can assist the clinician in selecting a maximally effective 2nd-line ARV regimen

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Thank You

Questions?