Managing Antiretroviral Failure Case Discussion

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Managing Antiretroviral FailureCase Discussion
Michael S. Saag, MD
The International AIDS SocietyUSA
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For purposes of discussion, we will assume that
each of the following drugs are approved and
available to all for useMaravirocRaltegravirE
travirine
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When to Change Therapy

• Intolerance, inconvenience, or toxicity of
  regimen
• Treatment failure
• Plasma HIV-1 RNA target for first and
  multiple-regimen failure is now the same ie,
  lt50 copies/mL. This goal is achievable in a
  substantial proportion of heavily
  treatment-experienced persons given availability
  of enfuvirtide, tipranavir, and darunavir
• At least 2, and preferably 3, fully active agents
  should be brought to bear against patients
  resistant virus.

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Case 1

• 34 yo woman diagnosed with HIV 6 years ago
• Initially presented with PCP
• Initial Lab values
• CD4 82 cells/uL
• VL 106,000 c/mL
• Started on ZDV / 3TC (FDC) plus EFV
• Did well for a while, then the regimen failed
• Experienced multiple other regimens that failed

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Now on ZDV / 3TC / LPV/r

• VL 78,000 c/mL CD4 125 cells/uL
• Resistance Test Ordered
• M41L, D67N, V118I, M184V, L210W, T215Y
• No NNRTI mutations
• L10I, I13L, L33F, E34Q, M46L, I54K, L63P, A71V,
  V77I, V82A

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Would you include an NNRTI in the next regimen?

• Yes
• No
• Not sure

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Case 1
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Which nRTI drugs would you include?

• ZDV / 3TC
• TDF / FTC
• ZDV / TDF
• D4T / 3TC
• ddI / TDF
• ddI / 3TC
• ABC / 3TC
• ZDV / 3TC / ABC
• Another choice

M41L D67N V118I M184V L210W T215Y
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Case 1
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Which ritonavir-boosted PI would you include?

• LPV / r
• SQV / r
• F-AMP / r
• ATZ / r
• IND / r
• TPR / r
• DRV (TMC-114) / r
• I would not use a PI here

L10I I13L L33F E34Q M46L I54K L63P A71V V77I V82A
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Which EAP drug would you include?

• Raltegravir (MK 0518 integrase inhibitor)
• Maraviroc (CCR5 inhibitor)
• Etravirine (TMC125)
• All of the above
• I dont have enough information to decide

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Case 2

• 42 year old man diagnosed with HIV in 1991
  multiple opportunistic infections
• Has taken all existing antiretroviral drugs
  available except DRV and EAP drugs
• Currently on TDF / FTC / TPV / r
• CD4 count 33 / uL (nadir CD4 6)
• CD4 count 3 months ago was 76 cells/uL
• HIV RNA 98,000 c/mL (max VL 167,000)

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Would you change his ARV regimen now?

• Yes
• No
• It depends

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Would you use 3TC or FTC?

• Yes
• No
• It depends

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Which nRTI would you include?

• ZDV
• TDF
• D4T
• ddI
• ABC
• I wouldnt use any other nRTI agents

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Would you use raltegravir?

• Yes
• No
• It depends

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If he has R5 tropic virus, would you use
maraviroc?

• Yes
• No
• It depends

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If he has R5/X4 (D/M) tropic virus, would you use
maraviroc?

• Yes
• No
• It depends

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1029 Pilot Study Evaluating Safety of Maraviroc
as an Add-On to OBT in ARV-Experienced non-R5
Patients

• Selection criteria
• X4 or X4/R5 virus or indeterminate tropism
  phenotype
• Randomized (111), Blinded, Placebo Controlled
• ? 3 months of treatment with 3/4 classes of ARV
  AND/OR resistance to at least one member of 2 of
  4 classes of ARVs
• At least one active drug (PI, NNRTI, or ENF) as
  part of OBT
• HIV RNA gt5000 c/mL
• Age 16 years

OBT 3 to 6 ARVs (note PK boosting doses of RTV
will not be counted as an ARV). 150 mg
maraviroc with PIs provides similar exposure as
300 mg without PIs.
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1029 Virologic and Immunologic Outcomes Vs. OBT
at 24 Weeks - FAS, Dual/Mixed Tropic
a 4 missing values
OBT Optimized Background therapy
No differences in HIV RNA between Placebo OBT
and MVC OBT (QD or BID) were statistically
significant
Pfizer confidential For internal use only
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Change from Baseline in HIV RNA With GS-9137 125
mg Influence of Activity of OBT
Data from GS-9137 125 mg patients after addition
of a PI were excluded
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If he had used enfuvirtide in the past and
experienced treatment failure while on
enfuvirtide, would you recommend enfuvirtide?

• Yes
• No
• Not sure

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Summary of Principles

• Avoid Sequential Monotherapy Wait for new agents
  if possible.
• Hypersusceptability can occur with 3TC / FTC
  mutations
• Mutations can be harbored well after a drug has
  been used
• Phenotypes are often helpful in determining which
  drugs are active when complex genotypes are
  likely
• Goal of Therapy is lt 50 c/ml in any patient
  regardless of stage of disease or prior exposure

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Summary of Principles

• Key to achievement of lt 50 c/ml is the
  availability of at least 2 potent drugs the
  more, the better
• If at least 2 potent drugs are not available, it
  is usually best to hold the current regimen until
  they are available
• No evidence for double-boosted PIs Double
  boosted PIs only count as one active drug
• Likely some residual benefit of continued 3TC or
  FTC
• No consensus / clarity on how to count
  partially active drugs in a new regimen
• Many new drugs in the pipeline Significant hope
  for the future