Managing Antiretroviral Therapy in Treatment-Experienced Patients: First Regimen Failure

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Managing Antiretroviral Therapy in
Treatment-Experienced Patients First Regimen
Failure

• MATEC
• Catherine Creticos, M.D.
• Medical Director

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Objectives

• Explain possible causes of drug failure
• Describe tests used to assess viral resistance
• Explain how to use resistance test results to
  select an effective new regimen
• Discuss strategies for managing patients with
  limited treatment options

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Case Study 1

• A.D. is a 51 yo male HIV since 1989. He started
  Combivir in 1993, and his viral load remained
  undetectable until June 2006, with CD4 in the
  400-600 range. Since June 2006, his viral load on
  2 occasions has been 24,500 and 37,800
  respectively. His most recent CD4 count was 378
  cells.

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First Antiretroviral Treatment Failure

• Assessment
• What are possible causes of increased viral load?
• Is intervention necessary at this point?
• Why / Why not?
• What intervention(s)?

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Reasons for First Antiretroviral Therapy Regimen
Failure

• Viral load ?, but patient not failing regimen
• recent infection (eg, HSV outbreak, bacterial
  infection, acute hepatitis)
• recent vaccination
• Poor adherence regimen may still be salvagable
• Poor absorption (unboosted PIs)
• Drug-drug interactions (eg, PPIs and atazanavir)
• Incompletely suppressive regimen (eg, dual
  nucleoside)

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First Antiretroviral Failure Interventions

• Review adherence last month, last few days
• Probe for recent events, problems (eg, recent
  infection or other issues such as running out of
  medication or not taking medication on a trip)
• Repeat viral load (can be done at same time as
  resistance assay)
• Resistance assay purpose is to identify
  specific drug resistance that has led to failure
  and to assist in the selection of the next regimen

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Rationale for HIV Resistance Testing

• Drug resistance at start of ART is predictor of
  virologic response
• Several prospective studies support use of
  resistance testing to improve response to ART
• Preliminary economic studies suggest resistance
  testing cost-effective after first HAART failure
• Prevalence of resistance in acute/recent HIV
  infection 10-26 in recent studies

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Current Recommendations forUse of Resistance
Testing (DHHS)

• Recommended for selection of active drugs when
  changing therapy if viral suppression is
  suboptimal w/initial regimen
• Recommended for pregnant women initiating therapy
  or with incomplete virologic suppression
• May be useful in cases of acute infection or
  infection within the last 1-2 years
• Not yet recommended at initiation of therapy in
  all treatment-naïve individuals until more
  information available on prevalence however in
  areas of high prevalence, resistance testing may
  be useful
• Both phenotyping and genotyping may be useful in
  patients with complex prior treatment history

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Evolution of Drug Resistance

• Causes of high genetic variability of HIV
• DNA copy of RNA genome for replication
• Lack of proofreading by RT during replication
• Every possible point mutation occurs
  1,000-10,000 times a day double mutants common
• Genetic recombination between different viruses
  in the same cell
• Acquisition of resistance during tx depends on
• Size and heterogeneity of viral population
• Extent of replication during drug therapy
• Ease of acquisition of particular mutation
• Effect of mutation on drug susceptibility and
  viral fitness

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How Drug Resistance Arises
How drug resistance arises. Richman, DD.
Scientific American , July 1998
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Resistance Testing Definitions

• Mutation (molecular definition) change in
  nucleic acid sequence compared with consensus or
  wild-type virus
• point mutation AAA GAC AGTgtAAA AAC AGC
• insertion AAA AAC AGTgt AAA AAC AGT AGT
• deletion AAA AAC AGTgt AAAAGT
• Drug resistant mutation change in amino acid
  sequence (vs. reference strain) that affects
  susceptibility to a drug
• Major, primary can solely affect susceptibility
• Minor, secondary, accessory contributes to
  reduced susceptibility
• Polymorphism a naturally occurring change in
  amino acid sequence not shown to directly impact
  drug susceptibility

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Mutational Nomenclature

• Wild-type amino acid ?G48V? Mutant amino acid
• ?
• Codon Position
• Mixtures are indicated by a slash
• K103K/N indicates mixture of wild-type and mutant
• T215D/Y/F indicates mixture of 3 mutants

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Resistance Assays Phenotype and Genotype

• Phenotype
• Direct assay measures ability of the virus to
  grow in various concentrations of antiretroviral
  drugs.
• Genotype
• Indirect assay detects drug resistance mutations
  that are present in the relevant viral genes.
• Both assays focus on the reverse transcriptase
  (RT) and protease (PR) genes of the virus

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Phenotyping Advantages

• Provides resistance information on each drug
  regardless of the presence of multiple mutations
• Interpretation may be more intuitive than for
  genotype assay
• Very useful in patients with complex drug history
  and complicated mutation profile
• Very useful for deciphering cross-resistance
• May be more useful than genotyping for new drugs
  until appropriate mutations are established by
  clinical data

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Phenotyping Disadvantages

• If drug resistant population is minor, the
  phenotypic effect may not be detected
• Viral load needs to ? 1000 copies/ml
• Very expensive and time-consuming
• Consensus on drug-resistance cut-off values are
  not yet fully determined - drugs to which a
  patient is actually still sensitive may be
  unnecessarily eliminated
• initial cut-offs were based on assay variability
  on repeated testing of known sample
• later cut-offs were based on natural variability
  of wild-type viruses from patients
• current cut-offs are being developed based on
  outcome data from clinical trials

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Antivirogramphenotype
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PhenoSense HIV Report
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Sequence-based Genotyping Assays

• HIV circulating in patients plasma is isolated
  RT and PR genes are copied, amplified
  sequenced.
• The test sequence is compared to a reference HIV
  strain and all changes (mutations) are noted.
• Software compares changes found to a list of the
  mutations known to be associated with resistance.
• A report documents any mutations and (optimally)
  the ARV drugs to which the virus is sensitive or
  resistant based on the presence or absence of
  particular mutations.

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Available Genotypes
Company Product Name Turnaround Time RNA Sensitivity Mixture Sensitivity
Monogram Biosciences GeneSeq HIV 14 Days 500 copies 10
LabCorp GenoSureGenoSure Plus 10-28 Days 1000 copies Not available
Quest Genotype (ABI kit) Vircotype 7-14 Days 600 copies 25
ARUP ViroSeq (ABI kit) Variable 500 copies 10
Specialty Labs GenotypR Plus 7 Days 1000 copies Not available
Virco Genchec Virtual Phenotype 14 Days 1000 copies 10-20
Bayer TRU-Gene (kit) 3-14 Days 1000 copies Not available
ABI ViroSeq (kit) Variable 500 copies 20
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Genotyping Advantages

• Identification of all nucleotides, amino acid
  differences, deletions insertions
• Genotyping has the ability to detect resistant
  virus that constitutes only a small proportion (
  20) of the viral population.
• This can provide predictive early warning of
  resistance before full resistance develops
• Faster and less expensive than phenotype assay

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Genotyping Disadvantages

• Reports may be difficult to interpret unless
  clinician is very experienced
• Labs use different software to predict resistance
  - a consensus on which mutations are important is
  needed
• There is a lot of variation in the quality of the
  product from different labs, especially in the
  ability to detect minority species in the
  population
• Significance of many mutations still poorly
  understood
• Lack of understanding of the significance of
  combinations of mutations
• Viral load needs to ? 1000 copies/ml

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Phenotype/Genotype Discordance

• Interpretation Discordance
• interpretation is incorrect (especially new
  drugs)
• data base is incomplete or lacking
• Test Result Discordance
• PT sensitive but GT resistant
• mixtures
• transitional mutations
• antagonistic mutational interactions

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Genotype-Phenotype Discordance

• Observed differences between phenotype and
  genotype are not uncommon
• Reasons for genotype-phenotype discordance
• use of inaccurate genotype interpretation
  algorithms (not accounting for novel or unknown
  mutations, or for unrecognized effects of
  mutations)
• Presence of mixtures of wild-type and resistant
  strains
• Variability in phenotypic susceptibility with
  specific mutations

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PT/GT Concordance
Drug name
Resistance Mutations
Replication Capacity
Drug susceptibility
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Virtual Phenotype

• Determines genotype of test strain
• Computer algorithm matches genotype to strains
  that have been previously phenotyped
• Presents expected phenotype based on the average
  phenotype of matching isolates

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Virtual Phenotype Pros and Cons

• Pros
• Inexpensive, quick way to generate phenotypic
  information
• Clinical studies show good correlation between
  virtual and real PT and equal efficacy in
  predicting viral suppression

• Cons
• number of matches may be low
• union of limitations of GT and PT techniques
• clinical studies do not demonstrate benefit of
  virtual PT added to GT and expert advice

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NRTIs
Major Mutations
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NRTIsSpecial Considerations

• Require triphosphorylation, complicates in vitro
  assessment PT testing ? discordance b/w in
  vitro and in vivo potency
• NEMs (TAMs) selected primarily in patients
  treated with AZT or D4T 10 of patients on DDI
  monotherapy rarely during ABC monotherapy
• Some NRTI mutations hypersensitize HIV to NNRTIs
• K65R confers intermediate resistance to DDI, ABC,
  TDF, 3TC. Recent study of ABC/3TC/TDF led to high
  failure rate
• Q151M is a 2-base pair change that causes
  intermediate resistance to AZT, DDI, D4T, and ABC
• TDF efficacy reduced by 3 or more TAMs,
  especially in presence of M41L or L210W

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Mutational Interactions M184V

• M184V- causes high-level 3TC resistance and
  low-level resistance to ddI, ddC, ABC
• M184V reverses T215Y-mediated AZT resistance
• Resensitization clinically significant slows AZT
  resistance in patients on AZT/3TC
• M184V appears to reverse effect of NEMs on
  resistance to d4T, TDF

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NNRTIs
Major Mutations
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NNRTI MutationsSpecial Consideration

• Y181C/I causes high-level resistance to NVP and
  DLV, but low-level resistance to EFV. However,
  isolates only transiently respond to EFV
• Y181C and L100I hypersensitize HIV to AZT
• G190A/S are resistant to NVP and EFV but
  hypersensitive to DLV

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PIs
Major Mutations
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PIsSpecial Considerations

• Cross-resistance problematic in one study of
  over 6,000 isolates, 59-80 of isolates with a
  10-fold decrease in susceptibility to one PI also
  had a 10-fold decrease to at least one other
• For LPV/r, at least 4 of 11 mutations may be
  needed for significant resistance
• NFV and ATV when used as first PI may select for
  mutations with little cross-resistance
• NFV D30N
• ATV I50L

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Stanford HIV Database

• http//hivdb.stanford.edu
• Can insert mutations and receive an assessment of
  resistance and a discussion of significance of
  the mutations

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Case Study 1A.D.

• Genotype showsM184V, D67N, K70K/R, and K219K/Q
• Reference lab predicted resistance to AZT, ABC,
  3TC, FTC, d4T
• No resistance to DDI, TDF, all NNRTIs PIs

• Stanford database interpretation
• Nucleoside RTI
• 3TC High-level resistance
• ABC Low-level resistance
• AZT Intermediate resistance
• D4T Low-level resistance
• DDI Potential low-level resistance
• FTC High-level resistance
• TDF Susceptible
• Non-Nucleoside RTI
• DLV Susceptible
• EFV Susceptible
• NVP Susceptible

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Stanford Database Comments on Significance of
Mutations

• D67N contributes some degree of resistance the
  NRTIs except 3TC and FTC. It usually occurs with
  mutations at positions 70 or 215. D67E/G occur in
  heavily treated patients and probably have a
  similar effect as D67N.
• K70R causes low-level AZT and probably D4T
  resistance but appears to have little effect on
  the other NRTIs. K70E reduces TDF susceptibility.
  K70G/N are rare variants of unknown significance.
  

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Stanford Database Comments on Significance of
Mutations

• M184V/I cause high-level resistance to 3TC and
  FTC, and low-level in vitro resistance to DDI and
  ABC. However, it has not been shown to limit the
  effectiveness of DDI and it has only been shown
  to limit the effectiveness of ABC when it occurs
  in combination with multiple TAMs. M184V
  partially reverses T215Y-mediated resistance to
  AZT, TDF, and D4T.
• K219Q/E increase AZT and probably D4T resistance
  when present with K70R or T215Y/F but may not
  have any effect on the remaining NRTIs. K219N/R
  occur commonly in heavily NRTI-treated patients.
• M184V partially reverses AZT, D4T, and TDF
  resistance caused by other TAMs.

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Case Study 1Treatment Selection and Response

• Started Atripla (TDF/3TC/EFV) and Ziagen
• What are other reasonable treatment choices?
• 6 weeks after initiating therapy, patients viral
  load is undetectable
• Continued close f/u is warranted

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Case Study 2

• K.L. is a 36 yo male with diabetes and HIV. He
  has been treated with Combivir and Sustiva as
  well as glipizide. He presents with decreased
  vision bilaterally, RgtgtL eye. An ophtholmologic
  exam reveals acute retinal necrosis and w/u shows
  an RPR 1512. He is treated for syphilitic
  retinitis with significant improvement in his
  vision. His viral load 38,900 and CD4 285. He
  admits to poor adherence over past 2 months. A GT
  is performed and shows K103N M184V mutations.

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Clinical Decisions and Questions

• What antiretroviral combinations would be
  appropriate to consider?
• What type of follow-up should be done if therapy
  is changed?
• What additional concerns need to be addressed?

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Case Study 2Treatment Selection and Response

• His regimen is changed to ATV/RTV/TDF/3TC/ZDV.
• After 3 months, the viral load is undetectable
  and CD4 is 354

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Case Study 3

• K.C. is a 41 y.o. female with a history of former
  IVDU and HCV/HIV co-infection. She was treated
  initially with Viracept and Combivir. She has a
  long history of non-compliance and her viral load
  was never undetectable. She was changed to
  Combivir and Kaletra, but her viral load remained
  high at 53,000. A GT is done and shows no
  resistance mutations. A discussion with the
  patient reveals very poor adherence due to GI
  side effects and difficulty remembering her pills.

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Clinical Decisions and Questions

• What is the meaning of the resistance assay and
  is it believable?
• Is it appropriate to start a new antiretroviral
  regimen in this patient?
• If so, what antiretroviral drugs would be
  appropriate?
• What other concerns should be addressed?
• What follow-up should be done?

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Case Study 3Treatment Selection and Response

• She is changed to ATV/RTV/TDF/ETV and these are
  given daily with her methadone.
• Patients viral load after 3 months (and
  subsequently for the next year) is undetectable