Latest Concepts in Antiretroviral Therapy Failure

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Latest Concepts in Antiretroviral Therapy Failure
Carlos del Rio, MD
C del Rio, MD.Presented at IASUSA/RWCA Clinical
Conference, June 2005.
The International AIDS SocietyUSA
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Goal of ARV therapy

• In first (and second) regimens the goal of
  therapy is complete suppression of viral
  replication (to lt 50 copies/ml) and thus to
  minimize resistance which would preserve future
  options
• In patients with advanced treatment failure and
  multidrug resistance the goal should be to reduce
  the viral load as much as possible and to
  maintain immunological and clinical integrity.
• Deeks SG, NEJM 2001 344 472

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What is treatment failure in initial therapy?

• Clinical failure
• Progression of disease is spite of therapy
• Failure due to toxicity or intolerance
• Poor tolerability or adverse events
• Immunologic failure
• CD4 decline
• Virologic failure
• When the viral load does not reach lt 50 copies/ml
  or rebounds after suppression

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Clinical significance of blips

• No association between blips and virologic
  failure or development of drug resistance
• Havlir DV at al. JAMA 2001 286171
• Most blips are due to normal and statistical
  variation and are not associated with new drug
  resistance mutations
• Nettles RE et al. JAMA 2005 293817.

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Why does failure occur?

• Median time on initial regimen 1.6 years
• Adherence
• Toxicity and poor tolerability
• Inconvenience dosing frequency and food
  interactions
• Decreased adherence, regardless of reason, may
  promote virologic failure

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Why does failure occur?

• Pharmacologic/pharmacogenetic factors
• Drug interactions
• Inadequate drug exposure potential resistance
  and virologic failure
• Excessive drug exposure potential toxicity
• Competition for nucleoside pools (TDF ddI)
• Pharmacogenetic factors
• Prolonged half life or EFV due to CYP2B6 516GgtT
• Mitocondrial haplotypes may influence toxicity
• Inadequate or excessive dose for body weight,
  renal or hepatic function

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Why does failure occur?

• Inadequately potent or antagonistic combinations
  TDF/ABC/3TC
• Unrecognized pre-existing or emerging drug
  resistance
• Low-level mutant populations in plasma or
  archived mutant virus in reservoirs
• Clonal analysis may demonstrate mutations not
  seen by population genotyping/phenotyping

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When to change?

• NNRTI-based regimens
• Because of low genetic barrier of current NNRTI
  changes should be made as soon as virologic
  failure is confirmed even if resistance testing
  is not available.
• PI-based regimens
• PIs with low genetic barrier such as nelfinavir
  should be changed early
• Boosted PI regimens may have a higher genetic
  barrier

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Choosing the next regimen

• The goal of a second regimen when active drugs
  are available is to construct a potent regimen
  that will achieve virologic suppression to lt 50
  copies/ml
• When available, resistance testing should guide
  choice of therapy
• When resistance testing is not available,
  knowledge of common resistance patterns likely to
  result from the first regimen should be taken
  into account.

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Choosing the next regimen

• The successful management of ARV therapy failure
  depends on the ability to construct a regimen
  that contains at least three active drugs.
• The number of active drugs in the regimen
  correlates with subsequent virologic success even
  in heavily pretreated patients.

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What to change to?

• Goals of therapy
• Limited prior treatment maximal virologic
  suppression
• Extensive prior treatment preserve immune
  function and avoid clinical progression
• Review ART history
• Assess adherence, tolerability and drug
  interactions
• Perform resistance testing while on drugs
• Identify susceptible drugs/drug classes
• Consider novel strategies (TDM, investigational
  agents?)

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Initial Salvage StudiesLessons Learned

• Improved response with
• Lower HIV RNA
• Adding new class of drugs (e.g. NNRTI, EI)
• Using 2 PIs
• Using a ritonavir-boosted PI
• Sequencing of PI may be important (SQV, NFV, APV,
  ATV, investigational PIs)
• 3 new drugs (i.e. drugs not yet taken) is not
  sufficient (due to cross resistance)

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Current Use of Double Boosted PI Therapy

• Salvage therapy
• Driven by extensive resistance to NRTIs and
  NNRTIs
• Need to rely on activity of PIs
• NRTI-sparing regimen
• When minimal or no activity is expected from NRTI
• Desire driven by mitochondrial toxicity

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Is treatment interruption a valid option?

• Not for those with advanced immune suppression at
  time of failure
• Possibly for those with high nadir CD4 count and
  reasonable current counts

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Summary Current approach to a failing regimen

• Review goals of therapy
• Review ARV history
• Assess adherence, tolerability and PK
• Perform resistance testing while on drugs
• Identify susceptible drugs/classes
• Consider PK enhancement with RTV
• Consider novel strategies (TDM?)
• Consider newer agents through clinical trials or
  expanded access programs