AETC: Resistance Considerations and Multiclass Resistance Management

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AETC Resistance Considerations and Multi-class
Resistance Management

• Jeffrey P. Nadler
• Professor of Medicine
• AETC Faculty
• USF College of Medicine
• Tampa, FL

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Disclosure of Financial Relationships

• This speaker has the following financial
  relationships with commercial entities to
  disclose
• Research support Boehringer Ingelheim,
  Bristol-Myers Squibb, Gilead, Glaxo SmithKline,
  Hoffmann-LaRoche, Incyte, Merck, Pfizer, Tanox,
  Tibotec
• Consultant BI, BMS, Gilead, GSK, Pfizer, Tibotec
• Honoraria in past year Bristol-Myers Squibb,
  Gilead, Glaxo SmithKline, MonogramBio
  (ex-Virologics), Tibotec, Virco, Vertex, (for
  educational programs)

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
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Topics

• Resistance test examples
• What else besides the report
• Interpretation of tests
• Baseline resistance testing should be standard of
  care
• Earlier failure geno is often enough
• On line tools great but non-contributory?
• Why not to stop ART
• Clinical trial referral

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Resistance Test Types

• Genotype
• RT, PI
• Envelope (gp41)
• Integrase?
• virtual phenotype
• Phenotype
• Co-receptor tropism assay

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Genotype Examples
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Genotype Examples
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Genotype Examples
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Phenotype Examples
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Phenotype Examples
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Virtual Phenotype
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Combination Report Genotype/Phenotype
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Report Interpretation

• Useful in context
• What ART is the patient on?
• What ART were they on before, when, why was it
  changed?
• Intrinsic limitations of reports
• measures one drug at a time
• is the interpretive algorithm complete and
  current?
• lab and test sensitivity and technical
  reliability
• Additional considerations
• Drug level inter-individual variability
  (unboosted PIs)
• Drug interactions and PK (ATV and PPIs, TB Rx and
  NNRTIs) PD levels in hepatic disease?
• Race? Sex? (NVP best studied)

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Controversies?

• Naïve patient should the genotype be standard
  of care?
• Transmitted resistance variable, but up to 16 or
  so percent in most communities
• Common preferred regimen have a low genetic
  barrier, if one drug is already compromised, may
  easily develop resistance to another, markedly
  limiting future therapy options, defeats the very
  intent of simple regimens

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Controversies?

• In early failure, is the genotype enough?
• Partially, it depends on the initial regimen and
  why it failed, and for how long
• Typical dual nuc/NNRTI situation, failure in
  the first few months is likely to present a
  simple pattern, so a simple geno should be
  sufficient. Need the test to find out which class
  (hopefully only one) is compromised
• Probably true for first PI regimens, too,
  especially if not boosted
• Role for VP here? Probably, if the provider
  personal knowledge base/comfort level is limited,
  consultation not available. Nominal additional
  cost.

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On Line Tools

• Most useful for looking up impact of rare
  mutations or unusual combinations
• Eg, 101P or 103R/179D NNRTI mutations
• 53 PI mutation
• 44/118 NNRTI impact
• Dont account for your individual patient factors
  noted above
• Require easy, high speed computer access and
  knowledge of how to access/use the available data

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Why Not to Stop ART

• Side effects, inconvenience, cost, etc may
  suggest that a patient failing everything may
  have therapy stopped
• BAD IDEA
• Patients carry a mixture of viral variants, and
  some may retain some susceptibility to some
  drugs, but not be measured since they are
  suppressed by therapy
• Maintenance of some resistance mutations may
  reduce the viral replicative fitness
  (indirectly measured by replication assay), and
  slow the disease process remember, viral load
  (reproduction) drives T cell loss

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RC Replication Capacity

• An indirect measure of fitness, given as part of
  an add-on assay to PhenoGT
• Expressed as a percent, compared to wild-type
• Normal range is highly variable, perhaps 40-140
• May very for different drugs, classes
• NRTIgtPIgtgtgtgtNNRTI in this regard

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Managing MDR Patients

• Get as much information as possible
• Treatment history
• Resistance test(s)
• Geno with VP, pheno, RC, env sequence
• Consult an expert
• Treatment options
• Heres where to add enfuvirtide, but will work
  best (quantitative VL decrease, durability gt 6-12
  months) if theres at least one other active
  agent thus, ENF is better used as the
  penultimate agent! (But do you know when that
  is?)
• Consider playing the fitness card (keep 3TC on
  or add it back, its tolerable and non-toxic)
• Consider clinical trials!
• I know your patients have bonded, but premature
  death is not a good result of the therapeutic
  relationship
• Be wary of untested drug combinations (eg, triple
  PIs, nuc sparing )
• Do not stop therapy altogether (except when death
  is imminent?)

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Clinical Trials

• Patients ARE NOT guinea pigs!
• Patients have a choice, guinea pigs dont
• Guinea pigs are exposed earlier in the drug
  development process when less is known most
  trials are based on some experience (exception
  phase I, sometimes) with reasonable benefit to
  risk expectation and disclosure (the IRB process)
• DO NOT promise a positive result it may not
  work, there may be side effects or toxicities not
  yet known (eg, apliviroc, higher dose adefovir)
• A good trial provides expertise, tools to help
  optimize the background therapy, and a plan for
  managing failure

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Current Drug Trials

• New classes in development
• NcRTI
• CCR5 inhibitors, CXCR4 inhibitors
• Integrase inhibitors
• Assembly/budding inhibitors
• Novel fusion inhibitors
• Evolutionary/revolutionary development in
  existing classes
• Strategy/novel combination trials
• Immune intervention trials (therapeutic vaccines)
• In future, activation/reservoir reduction trials?
  Mostly still in guinea pigs!)

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Illustrative Case
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Disease and Rx Response Hx 1

• HIV Dx 1997
• 1999 CD4 nadir 128/12, VL gt50,000
• Rx initiated with ABC/EFV/SQV 600 BID/RTV 400 BID
• EFV changed to NVP due to unacceptable AEs
• 10/00 Rx changed to Kaletra/ZDV/ABC/NVP and then
  NVP D/Cd 11/00

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Disease and Rx Response Hx 2

• 4/01 Rx ABC/ddI/d4T for simplicity and
  tolerability per patient request
• 10/01 CD4 147/14
• 5/02 CD4 234/19.5, VL 8132
• Lost to follow-up for a year says he continued
  same regimen, again lost after first resistance
  test (4/03) PhenoGT done see next. He may have
  been given amprenavir during this period, but
  cannot access records

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Disease and Rx Response Hx 3

• 6/04 Rx ABC/ddI/IDV 800 BID/rtv 200 BID, based on
  5/04 PhenoGT (next)
• 9/04 CD4 158/18.8, VL 2039 screened for TMC
  125 study
• 10/04 On study, control PI group, based on VP Rx
  ABC/ddI/FPV/rtv 100 BID
• No response, and 1 log increase VL with CD4
  decrease to 120, 17

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Disease and Rx Response Hx 4

• 4/05 VircoType and Antivirogram done (next 2
  slides), rolled over to active TMC 125 800 BID
  with new optimized background of TDF/ddI/IDV
  800/rtv 200 BID
• B/L VL 6123, CD4 171/18.8
• Wk 2-8 nadir VL 141 and 361 copies
• CD4 max wk 8, sustained through end of study,
  approx 190-200/21

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Notes

• No 3TC Rx history, but moderately resistant by VP
  (44/118), just sensitive by actual pheno obtained
  for future Rx planning
• Should the fitness card be played does 44/118
  confer reduced fitness?
• Add T-20?
• What about PIs?
• Does the absent 184 explain the high TDF
  resistance?
• 103S/N is a mixture with a revertant, 5 yrs after
  NNRTI exposure
• No 82 mutations. Implications for new PIs (TPV)?

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