New Antiretroviral Agents

1
New Antiretroviral Agents and How to Use Them
Roy M. Gulick, MD, MPH Professor of
MedicineWeill Cornell Medical College
The International AIDS SocietyUSA
RM Gulick, MD, MPH. Presented at IASUSA Los
Angeles Course, March 31, 2008.
2
Antiretroviral Drug Approval1987 - 2008
RAL MVC
ENF ATV FTC FPV
ETR
DRV
TPV
TDF
EFV ABC
LPV/r
APV
RTV IDV NVP
NFV DLV
3TC SQV
d4T
ddC
AZT
ddI
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Antiretroviral Drugs Challenges and Needs

• Challenges
• Adherence
• Toxicity
• Activity
• Resistance
• Formulation

• Needs
• Improve convenience
• Improve tolerability
• Reduce toxicity
• Improve activity
• wild type virus
• resistant virus
• Penetrate reservoirs
• Exploit new targets

4
Life Cycle of HIV
DS dna COMPLEX
5
Newer ART Agents Stage of Development
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Etravirine (ETR)

• NNRTI
• Diaminopyrimidine (DAPY) compound
  flexible chemical structure
• In vitro EC50 1.4-4.8 nM (wild-type HIV-1) 3.5
  uM (HIV-2)
• In vitro activity against NNRTI-resistant virus
• Metabolism inducer substrate of CYP 3A4 and
  others
• Drug interactions do NOT use with other NNRTI,
  unboosted PI, ATV/r, FPV/r, TPV/r, RIF, antisz
  meds use with caution LPV/r OK with DRV/r,
  SQV/r, methadone Package
  Insert 2008
• FDA approved 1/08

Andries AAC 2004484680 Vingerhoets J
Virol 20057912773 Kakuda Glasgow
2006 PL5.2
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Newer HIV Protease Inhibitors
CH3
OH
H3C
O
O
NH
SO2
N
F3C
tipranavir (TPV)
(DRV)
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HIV Entry Inhibitors
Virus-Cell Fusion
CD4 Binding
Coreceptor Binding
gp41
gp120
V3 loop
CD4
Cell Membrane
CCR5/CXCR4 (R5/X4)
Adapted from Moore JP, PNAS 200310010598-10602.
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Maraviroc (MVC)

• Selective, reversible binder to CCR5 receptor
• IC90 2 nM in vitro cross-clade potency
• Active vs. current class-resist HIV but not
  against X4 virus
• Dorr, AAC 2005494721
• CYP 3A4 substrate (not inhibitor) Pgp substrate
• Dosing
• 300 mg bid with NRTIs, ENF, NVP, TPV/r
• 150 mg bid with CYP3A4 inhibitors (PI/r except
  TPV/r keto/itra clari)
• 600 mg bid with CYP 3A4 inducers (EFV, RIF
  seizure meds)
• Resistance Emergence of pre-existing X4 or
  change in HIV to recognize CCR5-inhibitor
  complex (?)lack of CCR5 antagonist
  cross-resistance Westby J Virol
  2006804909 J Virol 2007812359 CROI 2005
  96
• FDA-approved for treatment-experienced patients
  8/07

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Vicriviroc (VCV)

• Small molecule investigational CCR5 inhibitor
• In vitro EC50 lt3nM, EC90 lt19nM
• In vitro additivity/synergy with existing classes
  of ART
• Orally bioavailable (gt89)
• T1/2 27 hours allows once-daily dosing
• CYP 3A4 substrate not a PGP substrate
• PK concentrations enhanced with RTV 2-5X
• concentrations ? with EFV or NVP 70-80
• Proposed dose 30 mg qd with RTV
• Resistance Emergence of pre-existing X4 or
  change in HIV to recognize CCR5-inhibitor complex
  
• Phase III in rx-experienced

Strizki AAC 2005494911 Schurmann AIDS
2007101293
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ACTG 5211 Phase II in Rx-Experienced
Study pop 3-class exp., R5 virus VL gt5K on RTV
regimen (N118)
placebo
VCV 5 mg
VCV 15 mg
VCV 10 mg
OBR
Gulick, JID 2007196304
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Raltegravir (RAL)

• Strand transfer HIV integrase inhibitor
• In vitro IC95 33nM
• Active against MDR HIV synergistic with ART
• Resistance Substitutions in integrase (N155H or
  Q148H/R)
• PK metabolized by glucuronidation (UGT1A1) no
  CYP P450 metabolism
• Dosing 400 mg bid dosing, regardless of food
• No significant drug interactions
• FDA-approved for treatment-experienced patients
  10/07

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Elvitegravir (EVG)

• Dihydroquinoline carboxylate
• Strand transfer HIV integrase inhibitor
• In vitro IC50 0.2 nM (16 nM protein-adjusted)
• Active against MDR HIV Shimura K J Virol
  200882764
• Resistance Substitutions in integrase (e.g.
  T66I)
• PK
• metabolized by CYP 3A4?moderate inducer (EFV)
  and glucuronidation
• 30 orally bioavailable 99 protein bound
• boosted with RTV 100 mg qd ? AUC 20X, T1/2 9
  hours
• Stage of development Phase II Phase III planned

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How To Use the Newer Drugs (1)

• Treatment-Experienced Patients failing current rx
• Goal 2 (or preferably 3) fully active drugs
• NNRTI ETR check current and old GT for NNRTI
  mutations (lt3 for optimal activity), consider PT
• PI TPV, DRV use phenotype to guide choice and
  activity
• CCR5 inhibitor MVC use tropism testing (if R5
  only, full activity)
• Integrase inhibitor RAL (full activity)

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How To Use the Newer Drugs (2)

• Treatment-Experienced Patients suppressed on rx
• Goal continue virologic suppression, substitute
  drugs for convenience or toxicity
• NNRTI ETR activity depends on NNRTI mutations
  (lt3 or PT suscept. for optimal activity)
• PI DRV could substitute for older PIs
• CCR5 inhibitor MVC cannot use without tropism
  testing
• Integrase inhibitor RAL fully active

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How To Use the Newer Drugs (3)

• Treatment-Naïve Patients
• Goal maximize virologic suppression,
  convenience, toxicity ensure safety
• Role of newer drugs not as clear
• NNRTI RIL phase III planned
• PI DRV ARTEMIS study
• CCR5 inhibitor MVC not non-inferior to EFV
  (tropism assay issue?)
• Integrase inhibitor RAL more rapid virologic
  suppression than EFV similar 48 week responses
  phase III in progress

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ACTG 5241 OPTIONS Study

• Study population Treatment-experienced with VL
  gt1000 cps/ml no prior integrase inhibitor rx
• Study evaluation Hx, GT and PT, tropism testing
• Study rx
• Choice among TPV/r, DRV/r, ENF, MVC, RAL, and
  ETR (/- NRTIs)

18
Acknowledgments

• Cornell HIV Clinical Trials Unit (CCTU)
  212-746-4177
• Weill Medical College of Cornell University
• AIDS Clinical Trials Group (ACTG)
• Division of AIDS, NIAID, NIH
• The patient volunteers!

RM Gulick, MD, MPH. Presented at IASUSA Los
Angeles Course, March 31, 2008.