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HIV Resistance Testing Clinical Implications. Cyril K. Goshima, M.D. Director, AIDS Education Project June, 2009. I am a?. Physician Nurse Pharmacist Dentist Student Patient Other. Resistance Testing will tell us what meds will work for a patient?. True False.

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Hiv resistance testing clinical implications l.jpg

HIV Resistance TestingClinical Implications

Cyril K. Goshima, M.D.

Director, AIDS Education Project

June, 2009


I am a l.jpg
I am a?

  • Physician

  • Nurse

  • Pharmacist

  • Dentist

  • Student

  • Patient

  • Other





The k103n mutation is an nnrti mutation l.jpg
The K103N mutation is an NNRTI Mutation less than 500.

  • True

  • False


M184v is a common pi mutation l.jpg
M184V is a common PI Mutation less than 500.

  • True

  • False


When to use resistance testing l.jpg
When to Use Resistance Testing less than 500.

  • DHHS Guidelines

    • Recommend testing: acute infection, suboptimal virologic suppression after treatment is initiated, treatment failure, prior to the initiation of therapy.

    • Consider: chronic infection < 2 yrs.

    • Which test is not recommended


Resistance testing l.jpg
Resistance Testing less than 500.

  • Genotypic Resistance Testing

  • Phenotypic Resistance Testing

  • Combined Geno/Pheno

  • “Virtual Phenotype” Testing

  • Trofile (HIV Tropism Assay)

  • PhenoSense Entry (FI Resistance Testing)

  • Integrase Resistance Testing

  • Replication Capacity


Requirements for resistance testing l.jpg
Requirements for Resistance Testing less than 500.

  • Viral Load must be greater than 500 for genotype & phenotype resistance testing, integrase resistance testing

  • Viral load must be greater than 1000 for Trofile and PhenoSense Entry


Genotypic resistance testing l.jpg
Genotypic Resistance Testing less than 500.

  • Detects mutations in the HIV genome associated with resistance to specific drugs.

  • Advantages

    • Adequate turn-around time (1-2 wks)

    • Less expensive

    • Detect mutations that may precede phenotypic resistance

    • Widely available

    • More sensitive in detecting mixtures of resistant and wild type viruses


Genotypic resistance testing12 l.jpg
Genotypic Resistance Testing less than 500.

  • Disadvantages

    • Indirect measure of resistance

    • Relevance of some mutations unclear

    • Unable to detect minority variants (<20 – 25% of viral sample)

    • Complex patterns may be difficult to interpret

    • Genotypic correlates of resistance not well defined for non-B subtypes.


Phenotypic resistance testing l.jpg
Phenotypic Resistance Testing less than 500.

  • Measures the patient’s HIV isolates ability to replicate in the presence of varying concentration of specific drugs.

  • Advantages

    • Direct and quantitative measure of resistance

    • Method can be applied to any agent incl. new where genotypic correlates are unclear

    • Can assess interactions among mutations

    • Accurate with non-B HIV subtypes.


Phenotypic resistance testing14 l.jpg
Phenotypic Resistance Testing less than 500.

  • Disadvantages

    • Susceptibility cut-offs not standard between assays

    • Clinical cut-offs not defined for some drugs

    • Unable to detect minority species

    • Complex technology

    • More expensive

    • Longer turn-around time.


Other tests l.jpg
Other Tests less than 500.

  • Geno/Phenotype Resistance Testing

    • e.g. Phenosense GT from Monogram

    • Both tests are performed

    • The discordance is reported

  • “Virtual” Phenotype

    • Genotyping is performed and the phenotype is determined by looking at all the matched pairs of genotype with phenotype in a data set to give the best estimate


Other tests16 l.jpg
Other Tests less than 500.

  • Fusion Inhibitor Resistance Testing

    • Resistance to Enfuvirtide

  • Replication Capacity

    • How weak is your patient’s virus?

  • Chemokine Receptor Identification

    • CCR5, CXCR4, or mixed virus present

  • Integrase Inhibitor Resistance Testing


How we identify a mutation l.jpg
How We Identify a Mutation less than 500.

  • How do we identify a resistance mutation?

M 184 M

“M” is the “wild type” amino acid

“184” is the codon position


How we identify a mutation18 l.jpg
How We Identify a Mutation less than 500.

  • How do we identify a resistance mutation?

M 184 V

“M” is the “wild type” amino acid

“184” is the codon position

“V” is the mutant amino acid


How we identify a mixture l.jpg
How We Identify a Mixture less than 500.

M 184 M/V

“M” is the “wild type” amino acid

“184” is the codon position

“M/V” is the mixture of wild type & mutant amino acid


Definitions for phenotypic resistance testing l.jpg
Definitions for Phenotypic Resistance Testing less than 500.

  • IC50 = Concentration of drug required to inhibit replication by 50%

  • Fold Change = IC50 pt./IC50 reference

  • Cut Off = Fold change or concentration below which the virus is considered susceptible, above which non-susceptible

  • Biological Cut Off = Fold change based on variations in clinical samples from treatment naïve individuals.


Definitions for phenotypic resistance testing21 l.jpg
Definitions for Phenotypic Resistance Testing less than 500.

  • Clinical Cut Off = Fold change based on virologic response to ARV in Clinical Trials

  • Replication Capacity: The ability of a pt’s virus to replicate in the absence of drug


Nrtis l.jpg
NRTIs less than 500.


Nrti mutations l.jpg
NRTI Mutations less than 500.

  • Single point mutation can result in high level resistance e.g. M184V (3TC, FTC), K65R (TDF)

  • TAMS pattern of mutations e.g. codons 41, 67, 70, 210, 215, 219 (AZT, D4T)

  • 2 other patterns that are selected for by AZT/DDI & DDI/D4T

    • Q151M:resist. all NRTI except TDF

    • T69insertion + 1 or more TAMS @ 41, 210, 215: resist. all NRTI


Common mutations nrtis l.jpg
Common Mutations: NRTIs less than 500.

  • TAMS = thymidine analog mutations (aka ZDV mutations): M41L, D67N, K70R, L210W, T215F/Y, K219E/Q

  • NAMS = nucleoside analog mutations: TAMS plus E44A/D, A62V*, K65R, T69D, T69ins, L74I/V, V75A/I*/M/S/T, V77L*, Y115F, F116Y*, V118I, Q151M, M184I/V

    *Secondary mutations seen with Q151M


Nrti signature mutations l.jpg
NRTI Signature Mutations less than 500.

*TAMS=Thymidine analog mutations.


Nnrtis l.jpg
NNRTIs less than 500.


Common mutations nnrtis l.jpg
Common Mutations: NNRTIs less than 500.

  • Delavirdine (DLV)

    • L100I, K103N, V106M, Y181C, I; Y188L, G190E/Q

    • P236L(rare), Y318F

  • Efavirenz (EFV)

    • L100I, K103N, V106M, Y181C, I; Y188L, G190A, S, E, Q…; P225H

  • Nevirapine (NVP)

    • L100I, K103N, V106A, M; Y181C, I; Y188C, L, H; G190A, E, S, Q…,F227L


Nnrti multi drug resistance l.jpg
NNRTI Multi-Drug Resistance less than 500.

Class Resistance

  • L100I, K101E or P, K103N or S, V106A or M, Y188C, H, or L, M230L

  • Resistance to one NNRTI usually confers cross resistance to all other agents (exceptions: 181 and EFV, 190A/S and DLV)

  • Continued viral replication in the presence of NNRTI results in accumulation of additional resistance mutations

    • May impact clinical utility of future NNRTIs


  • Nnrti novel mutations l.jpg
    NNRTI Novel Mutations less than 500.

    • Those exhibiting a > 10 fold change:

      • K103R and V179D (in combination)

      • K101P


    Nnrti etravirine l.jpg
    NNRTI: Etravirine less than 500.

    • K103N NNRTI mutation is not associated with resistance to Etravirine

    • Multiple Resistance Associated Mutations (RAMS)

    • Scoring of the number of RAMS determines resistance to Etravirine

    • Similar to Protease Inhibitor Scoring


    Slide31 l.jpg
    PIs less than 500.


    Pi resistance l.jpg
    PI Resistance less than 500.

    • Cross resistance is common

    • PI mutations are uncommon in boosted PI regimens

    • Multiclass experienced pts. may have been exposed to unboosted regimens

    • The number of primary PI mutations may predict the response to therapy e.g. TPV score 0-3 good, 4-7 intermediate, >8 poor or Kaletra


    Pi common mutations l.jpg
    PI Common Mutations less than 500.


    Hypersusceptibility l.jpg

    Hypersusceptibility less than 500.





    Pi hypersusceptibility l.jpg
    PI Hypersusceptibility less than 500.

    • Mutation I50V, selected by LPVr and APV, increased susceptibility to ATV, TPV.


    Integrase and entry inhibitor resistance l.jpg
    Integrase and Entry Inhibitor Resistance less than 500.

    • Resistance has been seen against the Entry Inhibitors and Integrase Inhibitors

    • There are resistance tests that can be ordered

    • For CCR5 it may just be a repeat of the Trophile test to determine change to mixed or dual tropic viruses


    Case discussion l.jpg
    Case Discussion less than 500.

    • Patient CB, 42 y/o, homosexual male

    • Current Regimen (05/31/06): CBV/TDF/EFV

    • Past Drugs: CBV/ IDV, CBV/NFV

    • CD4/VL

      • Date: 09/08/05 349/8,810

      • Date: 03/07/06 192/10,300

      • Date: 06/02/06 186/9,400

      • Date: 09/18/06 92/6,610

      • Date: 10/17/06 /12,000


    Case discussion45 l.jpg
    Case Discussion less than 500.

    • NRTI

      • M184V present (3TC/FTC resist, TDF hs)

      • Multiple TAMs

      • No K65R (TDF sens despite 41 & 215 mut)

    • NNRTI

      • No significant mutations

    • PI

      • 4 TPV assoc mut (intermediate response)

      • DRV sens


    Case discussion46 l.jpg
    Case Discussion less than 500.

    • Was the CBV/TDF/EFV regimen a reasonable one?

    • There has been no response to this therapy after 3 mos.

    • What should you do?

    • Any suggestions on a possible new regimen?


    Discordance l.jpg
    Discordance less than 500.

    • Inaccurate genotype interpretation algorithm that does not account for novel or previously unknown mutation effect

    • Mixtures of wild type and resistant strains. Phenotype underestimates resistance

    • Variability in phenotypic susceptibility with specific mutations

    • Believe the genotype. Genotypic change may precede phenotypic resistance.


    Clinical implications l.jpg
    Clinical Implications less than 500.

    • Is there evidence for sequencing of NRTIs?

    • Should the initial regimen be a boosted PI or a NNRTI?

    • Is 3TC = FTC as far as resistance is concerned?


    Clinical implications49 l.jpg
    Clinical Implications less than 500.

    • Try to use at least 2 new potent agents to switch from a failing regimen.

    • The longer a failing regimen is continued, the more mutations accumulate. If there is no new agent, better to cont. the same regimen unless compelled to do otherwise.

    • Resistance is relative. 3TC cont. to have virological effect despite M184V mutation. Boosted PIs may have more of a response than an unboosted PI evidenced by a lower fold change.


    Clinical implications50 l.jpg
    Clinical Implications less than 500.

    • NRTI

      • TAMs can prevent K65R mutation. K65R is associated with multiple NRTI resistance and TDF resistance. ? Add ZDV to failing regimen

      • Continue 3TC or FTC despite a M184V mutation (hypersusc. ZDV, TDF, D4T; RC)

    • NNRTI

      • DC NNRTI as soon as mutations develop. There is no virological or RC advantage.


    Clinical implications51 l.jpg
    Clinical Implications less than 500.

    • PI

      • Never use an unboosted PI.

    • Antiretroviral susceptibility is on a continuum. Using drugs with the most activity (lower fold change) is a reasonable choice.


    Clinical implications52 l.jpg
    Clinical Implications less than 500.

    • In initial therapy, a boosted PI regimen may have an advantage over a NNRTI regimen because of fewer HIV mutations. (J. Bartlett, et al, JAIDS, 4(3): 323-331; Swiss HIV Cohort Study, oral abstract 72, XV International HIV Drug Resistance Workshop) Possible explanations maybe lower genetic barrier and pharmacokinetics with missed doses.


    Clinical implications53 l.jpg
    Clinical Implications less than 500.

    • Replication Capacity

      • Lower RC with certain NRTI (3TC) and PI (NFV).

      • No change in RC with NNRTI





    The k103n mutation is an nnrti mutation57 l.jpg
    The K103N mutation is an NNRTI Mutation less than 500.

    • True

    • False


    M184v is a common pi mutation58 l.jpg
    M184V is a common PI Mutation less than 500.

    • True

    • False


    Acknowledgements l.jpg
    Acknowledgements less than 500.

    • Monogram Bioscience, Sharon Martens, MN, ARNP/FNP

    • Dr. Joel Gallant, MD, MPH from Clinical Care Options HIV LLC, “Use and Interpretation of Resistance Tests in Multi-Class Experienced Patients,” September 2, 2005.


    Thank you l.jpg

    Thank You less than 500.

    Questions?


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