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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

HIV Resistance TestingClinical Implications

Cyril K. Goshima, M.D.

Director, AIDS Education Project

June, 2009

i am a
I am a?
  • Physician
  • Nurse
  • Pharmacist
  • Dentist
  • Student
  • Patient
  • Other
when to use resistance testing
When to Use Resistance Testing
  • 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
Resistance Testing
  • 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
Requirements for Resistance Testing
  • 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
Genotypic Resistance Testing
  • 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
Genotypic Resistance Testing
  • 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
Phenotypic Resistance Testing
  • 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
Phenotypic Resistance Testing
  • 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
Other Tests
  • 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
Other Tests
  • 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
How We Identify a Mutation
  • 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
How We Identify a Mutation
  • 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
How We Identify a Mixture

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
Definitions for Phenotypic Resistance Testing
  • 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
Definitions for Phenotypic Resistance Testing
  • 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
nrti mutations
NRTI Mutations
  • 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
Common Mutations: NRTIs
  • 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
NRTI Signature Mutations

*TAMS=Thymidine analog mutations.

common mutations nnrtis
Common Mutations: NNRTIs
  • 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
NNRTI Multi-Drug Resistance

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
NNRTI Novel Mutations
  • Those exhibiting a > 10 fold change:
    • K103R and V179D (in combination)
    • K101P
nnrti etravirine
NNRTI: Etravirine
  • 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
pi resistance
PI Resistance
  • 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 hypersusceptibility
PI Hypersusceptibility
  • Mutation I50V, selected by LPVr and APV, increased susceptibility to ATV, TPV.
integrase and entry inhibitor resistance
Integrase and Entry Inhibitor Resistance
  • 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
Case Discussion
  • 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
Case Discussion
  • 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
Case Discussion
  • 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
Discordance
  • 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
Clinical Implications
  • 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
Clinical Implications
  • 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
Clinical Implications
  • 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
Clinical Implications
  • 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
Clinical Implications
  • 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
Clinical Implications
  • Replication Capacity
    • Lower RC with certain NRTI (3TC) and PI (NFV).
    • No change in RC with NNRTI
acknowledgements
Acknowledgements
  • 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

Thank You

Questions?

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