Selected Findings from the Bangkok AIDS Conference

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CROI 2005 Focus on Antiretroviral Therapy and
New Antiretroviral Agents
Roy M. Gulick, MD, MPH
The International AIDS SocietyUSA
RM Gulick, MD. Presented at IASUSA New York
Course, March 17, 2005.
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GS 934 Study 48 Weeks

• Study population HIV-infected, treatment-naïve
  patients, VL gt10K (N517)
• Study treatment (ZDV/3TC vs TDF/FTC) EFV

Gazzard, ICAAC 2004, abstract H-1137c Gilead
Press Release 2/05
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INITIO NNRTI vs. PI 3 vs. 4

• Study Population Rx-naïve (N915)
• Baseline 21 AIDS VL 85K CD4 200
• Study rx
• ddI/d4T/EFV ? ZDV/3TC/ABC/NFV
• ddI/d4T/NFV ? ZDV/3TC/ABC/EFV
• ddI/d4T/EFV/NFV ? selected rx
• Results (3 years)
• VL lt50 74 EFV, 62 NFV, 62 4-drug
• ?VL (logs) -4.4 EFV, -3.9 NFV, -3.7 4-drug
• No differences in CD4 increases, serious AE AE
  leading to d/dc clinical progression
• Conclusion 3-drug EFV regimen superior

Cooper CROI 2005 abst. 165LB
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DART Develop. of ART in Africa

• Study population ART-naïve, symptomatic, CD4
  lt200 from Uganda and Zimbabwe (N3300) (27 with
  TB)
• Study rx ZDV 3TC TDF (n2466)
• Results (Uganda pts on virologic substudy,
  n200)
• Baseline 68 women VL 334K CD4 100
• 24 weeks (ITT MF) 68 lt400 cps/ml 51 lt50
  cps/ml change in VL 3.5 logs CD4 88
• 6 patients died
• Conclusion ZDV/3TC/TDF demonstrates
  antiretroviral activity

Mutuluuza CROI 2005 abst. 22
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A5116 Simplification Strategies

• Study Population Pts taking PI- or NNRTI-based
  regimens with VL lt200 cps/ml X gt18 months (N236)
• Study design Randomized, open-label
• Study rx 2 NRTI EFV vs. LPV/r/EFV
• Results
• Baseline CD4 475
• Higher rate of rx d/c with LPV/r (plt0.001)
• More toxicity with LPV/r (17) vs. EFV (5)
  (P0.002)
• Trend toward more VF with LPV/r (p0.088)
• Conclusion EFV-based regimen superior

Fischl, CROI 2005, abst 162
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The New York Case

• Gay man in his late 40s, previously HIV- (9/00
  and 5/03)
• 10/04 used crystal meth multiple episodes of
  unprotected sex
• Presented 12/04 with pharyngitis and fatigue
  found HIV
• 1/05 HIV confirmed, VL 99K (repeated 232K),
  CD4 65 (repeated 28)
• Progression to AIDS in 4-20 months
• Resistance testing Subtype B NRTI-, NNRTI-,
  PI-resistant but susceptible to T-20 RC 136
• Viral tropism Dual tropic (CCR5 and CXCR4)
  syncytia-inducing

Markowitz CROI 2005 abst 973b
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New Antiretroviral Agents

• NRTIs
• NNRTIs
• PIs
• HIV entry inhibitors
• Chemokine receptors CCR5 inhibitors
• Maturation inhibitors
• Integrase inhibitors

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NNRTIs
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Capravirine (CPV)

• Study 1002
• Study pop Failed prior NNRTI (on rx gt4 weeks,
  VL gt1000) PI naïve (N198)
• Rx 2 NRTI NFV CPV 700 or 1400 bid (or PBO)
• Results (wk 48)
• VL lt50 CPV 700 (40) 1400 (47) PBO (39)
• VL lt400 CPV 700 (43) 1400 (58) PBO (46)
• CD4 and adverse events no difference
• Next study 3-class R LPV/R CPV or PBO

Pesano CROI 2005 abst 555
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TMC 278

• DAPY compound
• Small molecule potential for co-formulation
• Potent in vitro EC50 0.5 nM
• Active against NNRTI-R virus (N3500 clinical
  isolates)
• High genetic barrier in vitro
• PK single and 10d dosing well absorbed
• t ½ 38 hours qd dosing

de Bethune CROI 2005 abst 556
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TMC 278

• Phase IIa Study randomized, double-blind,
  PBO-controlled
• Study pop rx naïve VL gt5K CD4 75-500 no PT
  resistance (N47)
• Rx 25, 50, 100, 150 mg qd (oral solution) or
  PBO monotherapy X 7d
• Results (7d) median -1.2 log HIV RNA without
  dose relationship gr 1 rash (1), gr 3 nausea
  (1) no NNRTI mutations

Goebel CROI 2005 abst 160
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TPV

• Resistance (Schapiro 104)
• RESIST population highly ART-experienced
• median 12 prior ART agents prior 4 PI
• 12 prior T-20
• BL 50 had gt16 PI mutations 2/3 had 2 or more
  PRAMS phenotypic R to LPV/RTV 87X
• ?Best predictor of response?
• PI mutations
• primary PI mutations
• PRAMS (33, 82, 84, 90)
• TPV mutational score (16 loci/21 mutations) NOT
  V82A or L90M
• Conclusion Ditch the UPAMS/PRAMS

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TMC 114

• Potent PI with activity against PI-R HIV
• Studies C213 and C202
• Study pop 3-class exp on PI gt1 primary PI
  mutation VL gt1K any CD4
• Rx TMC 114/RTV at one of 4 doses (400/100 or
  800/100 qd or 400/100 or 600/100 bid) vs. CPI/r
• Planned interim analysis

Haubrich CROI 2005 164LB
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TMC 114

• Results BL VL 4.6 CD4 150 sign PI-R

Haubrich CROI 2005 164LB
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HIV Entry Mechanism
2. Co-receptor interaction
Chemokine Receptor Inhibitors
HIV
gp41
3a. Anchorage
HIV
1. CD4 Attachment
CXCR4 CCR5
CD4
gp41
Cell
CD4 attachment inhibitors
Fusion Inhibitors
3c. Fusion Complete
HIV
3b. coil-coil interaction
HIV
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Maraviroc (MVC, UK 427,857)

• CYP 3A4 substrate (not an inhibitor)
• PK single dose studies in HIV (Muirhead abst
  663)
• EFV decreases MVC by 40-50
• NVP increases Cmax 1.5X, no effect on AUC
• LPV/R increases Cmax 1.8X
• CCR5 cross-R (Westby 96) identified compounds
  that bind CCR5 but are not X-resistant
  (imidazopiperidines) to MVC

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GSK 873140

• CYP3A4 substrate
• PK (Adkison 664) Co-administration with LPV/r
  in HIV negative subjects 6-8X? in 873140
  levels no change in LPV 30 ? in RTV levels
• CCR5 receptor binding (Sparks 77)
• in vitro ½ life gt100 hours
• in vivo ½ life 127 hours
• gt50 receptor occupancy persists for 5d after
  last dose (with undetectable plasma drug levels)
• Suggests mechanism for post-antiviral effect

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TAK-652

• Small molecule CCR5 inhibitor
• TAK-779 poor bioavailability
• TAK-220 compromised potency
• IC50 1 nM active against subtypes A-G, clinical
  isolates and recombinants
• PK HIV negative (N24) at 25, 50, 100 mg single
  oral doses
• Good oral absorption
• 24 hour concentration 9.1 nM (Baba 541)
• In vitro synergy with RTI, PI, T-20 (Tremblay
  542)

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HIV Integrase Mechanism
RM Gulick, MD. Presented at IASUSA New York
Course, March 17, 2005.
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L-870,810

• Investigational integrase inhibitor
• Potent in vitro IC50 3-6 nM
• Active against drug-resistant virus
• Related compound active in animal model
• Protocol 004
• Study pop HIV, naïve or off ART X gt 3 mos
  (N30)
• Rx L-870,810 400 mg or 200 mg bid or PBO X 10d
  monotherapy
• Results HIV RNA decrease (d10)
• L-870,810 -1.7-1.8 log vs. 0.1 log PBO
• no difference in adverse events no resistance
• Development abandoned due to animal tox
• Follow-on compound in clinical development

Little CROI 2005, abst 161
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Maturation (gag processing) inhibitors
not treated
treated with PA-457
Li, et al. PNAS 200310013555
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PA-457

• Betulinic acid derivative
• First in class inhibits gag processing --
  prevents conversion of capsid precursor proteins
  to capsid proteins (p24), resulting in release of
  non-infectious virus
• Demonstrated in vitro activity against wild-type
  and resistant viruses long half-life
• Orally bioavailable with antiretroviral activity
  in SCID-hu Thy/Liv mouse model
• PK in HIV negatives (Martin abst 551)
  dose-dependent linear increase in conc X 10d
  well tolerated long ½ life qd dosing

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PA-457

• Randomized, double-blind, PBO-controlled
• Study pop no ART X gt4 wks CD4 gt200 VL 5-250K
  (N24)
• Rx PA-457 single oral doses 75, 150, 250 mg
  vs. PBO
• Results at 2 higher doses mean VL -0.2 logs
  gt0.5 log decrease from baseline
• PBO 0/6 75 0/6 150 3/6 250 2/6 (up to 0.7
  log)
• Genl well tolerated no resistance
• Multidose study enrolling

Martin CROI 2005 abst 159