New Issues in Antiretroviral Drug Resistance

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New Issues in Antiretroviral Drug Resistance
Daniel R. Kuritzkes, MD Professor of
MedicineHarvard Medical School
International AIDS SocietyUSA
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Novel agents

• Etravirine
• Integrase inhibitors
• CCR5 antagonists

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Etravirine Resistance summary

• 17 etravirine resistance mutations
• Genotype interpretation depends on weighted score
• Y181C alone gives intermediate resistance
• Phenotypic cut-offs now defined
• Lower cutoff 2.9 or 3.0
• Upper cutoff 13 (?)

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Integrase inhibitor resistance (1)

• Integrase strand-transfer inhibitors (INSTI)
  select for specific resistance mutations in HIV-1
  IN
• Three pathways identified for raltegravir
• N155H
• Q148K/R/H
• Y143C/R
• Extensive cross-resistance between raltegravir
  and elvitegravir

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Integrase inhibitor resistance (2)

• Virologic failure of integrase inhibitors
  frequently associated with drug resistance
• INSTI-resistant viruses have reduced replication
• Cross-resistance among existing drugs in class
• Clinical impact of reduced replication of
  INSTI-resistant viruses uncertain

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Inhibition curves for competitive versus
non-competitive inhibitors of HIV-1
Competitive inhibitor Non-competitive
inhibitor
inhibition
inhibition
Log drug concentration
Log drug concentration
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Change in coreceptor usage in subjects receiving
CCR5 antagonists

• The dominant pathway to virologic failure
• 57 of subjects in MOTIVATE-1 and -2
• 35 of subjects in ACTG 5211
• 31 of subjects in MERIT
• Origin of CXCR4-using viruses
• Emergence from pre-existing minority population

Fätkenheuer G, et al. N Engl J Med.
20083591442-1455. Gulick R, et al. J Infect
Dis. 2007196304-312. Heera J, et al. 15th CROI.
Boston, 2008. Abstract 40LB.
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V3 Loop of gp120

• One of 5 variable loops in gp120
• Averages 35 amino acids in length
• 105 nucleotides
• Major determinant of co-receptor usage
• Major effect on rate of gp41 conformational
  changes
• Can accelerate the rate-limiting step of entry
• Immunodominant region of gp120 for humoral
  immunity
• Protected/obscured by glycan shield

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Resistance to CCR5 antagonists

• Resistance to CCR5 antagonists emerges slowly
• Mutations in V3 and other regions of envelope
• No canonical mutations or positions identified to
  date
• Each virus likely to follow unique path to
  resistance
• Plateau effect in phenotypic assays
• Limited data on cross-resistance

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Ultra-deep sequencing of HIV-1 V3 in patients
receiving a CCR5 antagonist

• The V3 loop of HIV-1 Env displays extraordinary
  sequence diversity
• Rapid fluxes in the viral population allow rare
  forms to become dominant over short time spans
• After expansion, diversification occurs as
  variants seek to fill available sequence space
• These results also provide data in support of the
  quasispecies hypothesis

Tsibris et al 17th Intl HIV Drug Resist Workshop,
Sitges, Spain, June, 2008