New Antiretroviral Agents

1

Newer Approved Antiretroviral Drugs What Do We
Know Now?
Roy M. Gulick, MD, MPH Professor of
MedicineChief, Division of Infectious
DiseasesWeill Cornell Medical College
International AIDS SocietyUSA
From RM Gulick, MD, MPH, at San Francisco, CA
April 20, 2009, IASUSA.
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Antiretroviral Drug Approval1987 - 2009
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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Etravirine (ETR)

• NNRTI
• Diaminopyrimidine (DAPY) compound
  flexible chemical structure
• In vitro EC50 1.4-4.8 nM (wild-type HIV-1)
• In vitro activity against NNRTI-resistant virus
• Dose 2 X 100 mg twice daily
• 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,
  antiseizure meds use with caution with 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
4
DUET 12 OBT /- ETR at 48 weeks
Study pop 3-class exp. with NNRTI gt3 primary
PI mutations (N1203) OBT DRV/R 600/100 BID
with optimized NRTIs ENF
ETR (n 599)
100
ITT-TLOVR
Placebo (n 604)
90
80
61
70
60
Patients With HIV-1 RNA lt 50 c/mL ( 95 CI)
50
40
30
40
20
10
P lt .0001
0
0
20
48
40
32
24
2
4
8
12
16
Time (Weeks)
Haubrich CROI 2008, 790 Johnson 791
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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 ? cross-resistance
  Westby J Virol
  2006804909 J Virol 2007812359 CROI 2005
  96
• FDA-approved for treatment-experienced patients
  8/07

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Motivate III 48-week Results
Study population 3-class experienced, VLgt5K, R5
virus (N1049)
96 weeks Hardy, Glasgow 2008, abstract O425
Gulick NEJM 20083591429
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HIV Integrase Mechanism
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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,
  Y143C/H/R or Q148H/K/R)
• PK metabolized by glucuronidation (UGT1A1) no
  CYP P450 metabolism
• Dosing 400 mg bid dosing, regardless of food
• No significant drug interactions
• Except for RIF ? dose to 800 mg bid (1/09)
• FDA-approved for treatment-experienced patients
  10/07

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BENCHMRK 1 2 RAL 48 weeks
Study population 3-class experienced VLgt1K
(N699)
achieving HIV RNA lt50 c/mL (95
CI)(non-completerfailure)
BENCHMRK-2
BENCHMRK-1
96-week data Steigbigel CROI 2009 571b
Steigbigel NEJM 2008359339-54
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RAL Virologic Failure and Resistance

• 105/462 (23) had VF on the Phase III RAL studies
• 94 were genotyped
• 64 (68) had mutations in integrase known to be
  associated with resistance to RAL
• Y143, Q148, N155
• 48 (75) had gt2 mutations
• Factors associated with resistance
• PSS/GSS 68 of patients with VF had GSS of 0
• Baseline viral load gt 100,000 copies/ml

Cooper NEJM 2008359355
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Newer ART Agents Stage of Development (partial
list)
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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 (use weighted score), 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 underlying
  NNRTI mutations switch may be risky
• PI DRV could substitute for older PIs
• CCR5 inhibitor MVC cannot use without tropism
  testing
• Integrase inhibitor RAL active, but need to
  protect by using other active drugs

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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 supports first-line use
• CCR5 inhibitor MVC not non-inferior to EFV
  (tropism assay issue)
• Integrase inhibitor RAL more rapid virologic
  suppression than EFV similar 96 week responses