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HIV/AIDS 2007 Update David H. Spach,
MDClinical DirectorNorthwest AIDS Education and
Training CenterProfessor of MedicineDivision of
Infectious DiseasesUniversity of Washington,
Seattle
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HIV/AIDS 2007 Update

• DHHS Antiretroviral Recommendations
• Data Regarding Preferred Antiretroviral Regimens
• New and Future Medications
• Strategies for Patients with Multi-Drug Resistant
  HIV

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Antiretroviral TherapyCurrent DHHS
Recommendations
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HIV Antiretroviral Therapy
Nucleoside RTI
Entry Inhibitors
Integrase Inhibitors
Nucleus
HIV RNA
HIV DNA
HIV
Host Cell
Non-Nucleoside RTI
Protease Inhibitors
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Starting Antiretroviral Therapy
Acute HIV Infection
350
350
200
200
Year 1
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DHHS Panel October 2006 ARV Therapy Guidelines
Initial Therapy Preferred Regimens
Construct Regimen by choosing one component from
Column A and one component from Column B
Column B
Column A
NNRTIEfavirenz
2-NRTITenofovir/Emtricitabine Zidovudine/Lamivud
ine
PIAtazanavir Ritonavir Fosamprenavir
Ritonavir BIDLopinavir/ritonavir BID
Picture
Source www.aidsinfo.nih.gov
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DHHS Panel October 2006 ARV Therapy Guidelines
Initial Therapy Preferred Regimens
Construct Regimen by choosing one component from
Column A and one component from Column B
Column B
Column A
NNRTIEfavirenz
2-NRTITenofovir/Emtricitabine Zidovudine/Lamivud
ine
PIAtazanavir Ritonavir Fosamprenavir
Ritonavir BIDLopinavir/ritonavir BID
Picture
Source www.aidsinfo.nih.gov
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DHHS Panel October 2006 ARV Therapy Guidelines
Initial Therapy Alternative Regimens
Construct Regimen by choosing one component from
Column A and one component from Column B
Column B
Column A
NNRTINevirapine
2-NRTIAbacavir/Lamivudine Didanosine
Lamivudine
PIAtazanavir (unboosted)Fosamprenavir
(unboosted) Fosamprenavir ritonavir
qdLopinavir/ritonavir qd
Picture
Source www.aidsinfo.nih.gov
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DHHS GuidelinesWhy no Update Since October 2006?
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Antiretroviral TherapyData with Preferred
Regimens
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Tenofovir Emtricitabine Efavirenz (Atripla)

• Classification (2) nRTI (1) nNRTI
• Dose 1 pill qd- Tenofovir 300 mg-
  Emtricitabine 200 mg- Efavirenz 600 mg
• Meal Restrictions without food
• Strong data from Study 934
• Adverse Effects CNS (efavirenz)

Atripla
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Tenofovir Emtricitabine Efavirenz versus
Zidovudine Lamivudine Efavirenz
Study Design GS 934
Results 48 Weeks (ITT)

• Patients (N 517 randomized) - ARV naïve,
  HIV RNA gt 10,000 copies/ml - Randomized trial
• Regimens (N 487) - Tenofovir Emtricitabine
  Efavirenz - Zidovudine Lamivudine
  Efavirenz

TDF TenofovirFTC EmtricitabineZDV
Zidovudine3TC LamivudineEFV Efavirenz
P 0.002
P 0.02
From Gallant JE et al. N Engl J Med.
2006354251-60.
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ABC 3TC (Fos-Amp-RTV or LPV-RTV)KLEAN-ESS1007
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Study Design
Results 48 Weeks (TLOVR)

• Patients (N 887) - ARV naïve, HIV RNA gt
  1,000 copies/ml - Randomized trial
• Regimens (backbone ABC 3TC qd) - FosAmp 700
  mg bid RTV 100 mg bid - LPV-RTV (400-100 mg
  bid)

TLOVR Time to Loss of Virologic Response
No differences in response in patients with HIV
RNA gt 100K
From Eron J et al. Lancet 2006368476-82.
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TDF FTC (Fos-Amp-RTV or ATZ-RTV)ALERT Study
Study Design
Results 48 Weeks (ITT)

• Patients (N 106) - ARV naïve - HIV RNA gt
  1,000 copies/ml - Randomized trial
• Regimens - All patients Tenofovir
  Emtricitabine qd - FosAmp 1400 mg qd RTV 100
  mg qd - ATZ 300 mg qd RTV 100 mg qd

AbbreviationsTDF TenofovirFTC
EmtricitabineFosAmp FosamprenavirRTV
RitonavirATZ Atazanavir
P 0.30
P 0.34
From Smith K, et al. IAS, 2007 WEPEB023.
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Darunavir RTV vs. Lopinavir-RTV in SalvageTITAN
Study Design
Results 48 Weeks (ITT-TLOVR)

• Patients (N 595) - Highly treatment
  experienced - HIV RNA gt 1,000 copies/ml -
  Randomized trial (non-blinded) - Lopinavir and
  darunavir naïve
• Regimens (All Received OBT) - Darunavir-RTV
  600/100 mg bid - LPV-RTV 400/100 mg bid

P lt 0.001
P lt 0.005
Baseline DataOverall 31 were
PI-naïveBaseline Resistance- 2 with phenotypic
resistance to Darunavir- 10 with phenotypic
resistance to Lopinavir-RTV
TLOVR-Time to Loss of Virologic
ResponseNon-completer Failure
From Madruga JV, et al. Lancet 200737049-58.
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HIV Entry
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HIV
Envelope Spikes
gp120
gp41
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HIV Envelope
HIV
gp41
gp120
CD4 Binding Groove
V3 Region
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HIV Envelope
HIV
gp41
gp120
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HIV gp41
HIV
Cytoplasmic tail
Membrane-Spanning Domain
Fusion Peptide
N-heptad Repeat Region(Heptad Repeat 1)
Membrane-Proximal External Region
C-heptad Repeat Region(Heptad Repeat 2)
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Host Cellular ReceptorsCD4 Receptor
Extracellular Space
Host Cell Membrane
CD4 Receptor
Intracellular Space
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Host Cellular ReceptorCysteine-Cysteine
Chemokine Receptor 5 (CCR5)
Extracellular Space
C
C
Host Cell Membrane
CCR5
Intracellular Space
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Host Cellular ReceptorChemokine C-X-C Motif
Receptor (CXCR4)
Extracellular Space
C
C
Host Cell Membrane
CXCR4
Intracellular Space
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Host Cellular ReceptorsCD4, CCR5, CXCR4
Extracellular Space
CCR5
CXCR4
CD4 Receptor
Host Cell Membrane
Intracellular Space
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HIV Cell Binding and Entry
HIV
CD4 Receptor
CD4 Receptor
Extracellular Space
CCR5
Host Cell Membrane
Intracellular Space
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HIV Cell Binding and Entry
HIV
CD4 Receptor
Extracellular Space
CCR5
Host Cell Membrane
Intracellular Space
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HIV Cell Binding and Entry
HIV
CD4 Receptor
Extracellular Space
CCR5
Host Cell Membrane
Intracellular Space
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HIV Cell Binding and Entry
HIV
C-heptad Repeat Region(Heptad Repeat 2)
N-heptad Repeat Region(Heptad Repeat 1)
Extracellular Space
Fusion Peptide
Host Cell Membrane
Intracellular Space
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HIV Cell Binding and Entry
HIV
HIV Membrane
Host Cell Membrane
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CCR5-?32
CCR-?32
CCR5
Extracellular Space
C
C
C
C
Host Cell Membrane
Intracellular Space
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HIV Cell Binding and Receptor Tropism
HIV
CD4 Receptor
CD4 Receptor
Extracellular Space
CXCR4
CCR5
Host Cell Membrane
Intracellular Space
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HIV Cell Binding and Receptor Tropism
HIV
V3 Region
CD4 Receptor
CD4 Receptor
Extracellular Space
CXCR4
CCR5
Host Cell Membrane
Intracellular Space
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Entry InhibitorsCCR5 Inhibitors
CCR5 Inhibitor
Extracellular Space
CCR5
CD4 Receptor
Host Cell Membrane
Intracellular Space
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HIV Co-Receptor Tropism AssayMonogram
Biosciences Trofile Assay

• Assay Measures HIV Tropism - R5 Tropic - X4
  Tropic - Dual Tropic/Mixed Tropic
• Utilizes Entire Envelope Gene - Generates
  pseudoviruses
• Viral Load Required - Above 1,000 copies/ml
• Detection of Minor Species - Reliably detected
  at 5-10

HIV-1 Strains
R5-Tropic
X4-Tropic
R5X4 (Dual)-Tropic
Mixed Tropic
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From Whitcomb JM, et al. Antimicrob Agents Chemo
200751566-75.
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HIV Infection Natural History
HIV Tropism
R5
X4
R5X4 (Dual)
AIDS
Mixed
Year 1
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Prevalence of CXCR4 Tropism among HIV-Infected
Patients with Detectable Viremia
Patients with Dual/Mixed/X4
Study Design

• Patients (N 1152) - ARV-naïve patients n
  976 - ARV-experienced patients n 182
• Measurement - PhenoSense HIV entry assay

P lt .001
P lt .001
P .001
P .005
From Hunt PW, et al. J Infect Dis.
2006194926-30.
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Entry InhibitorsFusion Inhibitors
HIV
C-heptad Repeat Region(Heptad Repeat 2)
C-heptad Repeat Region(Heptad Repeat 2)
N-heptad Repeat Region(Heptad Repeat 1)
Enfuvirtide
Fusion Peptide
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Entry InhibitorsFusion Inhibitors
HIV
C-heptad Repeat Region(Heptad Repeat 2)
N-heptad Repeat Region(Heptad Repeat 1)
Extracellular Space
Fusion Peptide
Host Cell Membrane
Intracellular Space
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Entry InhibitorsFusion Inhibitors
HIV
Extracellular Space
Host Cell Membrane
Intracellular Space
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Integration of HIV Into Host DNA
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Integrase Inhibitors
Integrase Inhibitors
Nucleus
HIV RNA
HIV DNA
HIV
Host Cell
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HIV Integrase
Integrase binding to HIV DNA
1
HIV
Integrase
1
RNA
DNA
Nucleus
Host Cell
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HIV Integrase
3 Processing of HIV DNA
2
HIV
Integrase
2
3
DNA
Nucleus
Host Cell
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HIV Integrase
Nuclear Translocation
HIV
Integrase
DNA
Nucleus
Host Cell
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HIV Integrase
Strand Transfer
3
HIV
Integrase
3
Nucleus
Host Cell
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HIV Integrase
Gap Repair
4
HIV
4
Nucleus
Host Cell
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HIV Integrase Inhibitor
Integrase Inhibitor Strand Transfer
HIV
Nucleus
Host Cell
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Data with New Antiretroviral Agents
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Maraviroc (Selzentry)

• Mechanism CCR5 Inhibitor
• Activity Requires R5-tropic HIV Screening with
  HIV Tropism Assay
• Data MOTIVATE-1 and 2 (Maroviroc plus Optimized
  Therapy in Viremic Antiretroviral
  Treatment-Experienced Patients)
• Dose 150-300 mg bid (dose adjustments required
  with many other medications)
• Adverse Effects well-tolerated long term
  adverse effects unknown
• FDA-approved August 6, 2007

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Maraviroc in ARV-Experienced PatientsMOTIVATE-1
2 Study
Motivate 1 N 601 (Canada, US) Motivate 2 N
475 (Europe, Australia, US)
OBT Placebo
Eligibility - HIV-infected R5-tropic -
Treatment Experienced - HIV RNA gt 5,000
copies/ml - Randomized, double-blind -
Resistance to (and/or) gt 6 months of 3 classes
of ARV drugs
1x
OBT Maraviroc qd (150 or 300)
2x
2x
OBT Maraviroc bid (150 or 300)
Maraviroc 300 mg dose reduced to 150 mg in
patients receiving RTV (except with Tipranavir)
From Lalezari J, et al. 14th CROI 2007. Abstract
104b-LB. Nelson M, et al. 14th CROI
2007. Abstract 104a-LB.
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Maraviroc in ARV-Experienced PatientsMOTIVATE-1
2 Studies
Motivate 2 Results 24 Weeks
Motivate 1 Results 24 Weeks
From Lalezari J, et al. 14th CROI 2007. Abstract
104b-LB. Nelson M, et al. 14th CROI
2007. Abstract 104a-LB.
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HIV Tropism at Time of Virologic
FailureMOTIVATE-1 2 Studies
R5 at Baseline at Failure R5 at
Baseline Dual, Mixed or X4 at Failure
Non-R5 at Baseline or No Tropisms Data at Failure
OBT Placebo
OBT Maraviroc qd
OBT Maraviroc bid
From Lalezari J, et al. 14th CROI 2007. Abstract
104b-LB. Nelson M, et al. 14th CROI
2007. Abstract 104a-LB.
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Raltegravir (Isentress)
INVESTIGATIONAL

• Class- Integrase Inhibitor
• Dose- 400 mg PO bid (400 mg tabs)
• Adverse Effects- Diarrhea most common- No
  adverse effects on lipids
• Data- Excellent results in ARV-naïve and in
  salvage therapy- BENCHMARK 1 2 Studies
• Approval- FDA advisory board to review September
  2007

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Raltegravir versus Efavirenz in ARV-Naive
Protocol 004, Part 2
INVESTIGATIONAL
Study Design
Results 48 Weeks

• Background - N 198 - ARV-naïve - HIV RNA gt
  5,000 copies/ml - CD4 count gt 100 cells/mm3 -
  Randomized, double-blind
• Regimens (all include TDF 3TC) - Efavirenz
  600 mg qd - Raltegravir 100 mg bid -
  Raltegravir 200 mg bid - Raltegravir 400 mg
  bid - Raltegravir 600 mg bid

CD4 counts higher in LPV-RTV arms
P 0.04
P 0.003
Tenofovir Lamivudine
From Markowitz M, et al. JAIDS 2007.
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Percent of Patients with HIV RNA lt 50 copies/mL
(NC F)
INVESTIGATIONAL
Raltegravir vs Efavirenz in ARV-Naïve
PatientsBackbone of Tenofovir Lamivudine
100
80
60
Pts With VL lt 50 c/mL ()

40

20
P lt .001 for MK-0518 at each dose vs EFV
0
0
2
4
8
12
16
24
Week
Raltegravir 100 mg
39
39
39
39
39
39
Raltegravir 200 mg
40
40
40
40
40
40
Raltegravir 400 mg
41
41
41
41
41
41
Raltegravir 600 mg
40
40
40
40
40
40
Efavirenz
38
38
38
38
38
37
Markowitz M, et al. XVI International AIDS
Conference 2006. Abstract THLB0214.
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INVESTIGATIONAL
Raltegravir in ARV-Experienced PatientsBENCHMRK-1
2 Studies
BENCHMRK 1 N 350 (Europe, Asia, Peru)
BENCHMRK 2 N 349 (North South America)
Eligibility - HIV-infected - Treatment
Experienced - HIV RNA gt 1,000 copies/ml -
Randomized, double-blind - Resistance to 3
classes of ARV drugs
OBT Placebo
1x
2x
OBT Raltegravir 400 mg bid
From Cooper DA, et al. 14th CROI 2007. Abstract
105a-LB. Steigbigel R, et al.
14th CROI 2007. Abstract 105b-LB.
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Raltegravir in ARV-Experienced PatientsBENCHMRK-1
2 Study
INVESTIGATIONAL
BENCHMRK 2 16 Week Result
BENCHMRK 1 16 Week Result
CD4 counts higher in LPV-RTV arms
P 0.04
P 0.003
P 0.04
P 0.003
P lt 0.001
P lt 0.001
P lt 0.001
P lt 0.001
From Cooper DA, et al. 14th CROI 2007. Abstract
105a-LB. Steigbigel R, et al. 14th
CROI 2007. Abstract 105b-LB.
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Raltegravir in ARV-Experienced PatientsBENCHMRK-1
2 Combined Data
INVESTIGATIONAL
Week 16 HIV RNA lt 400 copies/ml
From Cooper DA, et al. 14th CROI 2007. Abstract
105a-LB. Steigbigel R, et al. 14th
CROI 2007. Abstract 105b-LB.
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Etravirine, formerly TMC-125
INVESTIGATIONAL

• Class- 2nd Generation NNRTI
• Resistance Properties- Active against
  NNRTI-resistant HIV- High genetic barrier to
  resistance
• Dose- 200 mg PO bid (100 mg tabs)
• Adverse Effects- Rash most common
• Data- Good response in heavily pretreated
  patients (Duet I and II)
• Approval- Submitted to FDA in July 2007

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Etravirine (TMC-125) Study C223Response Related
to Number of NNRTI Mutations
INVESTIGATIONAL
Study Design
24 Week Data

• Background - Phase II trial
• Patients (N 199) - ARV experienced -
  Failed NNRTI regimen - 3 or more PI mutations
  - HIV RNA gt 1,000 copies/ml
• Regimens - Etravirine 400 mg bid OBR -
  Etravirine 800 mg bid OBR - Placebo (OBR
  alone)

Comparable to 200 mg bid in new formulation used
in Phase III trials
No single mutation associated with gt 10-fold mean
change
From TMC-Writing Group. AIDS 200721(6)F1-10.
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INVESTIGATIONAL
Etravirine in ARV-Experienced PatientsDUET 1 2
Studies
DUET 1 N 612 (Multinational) DUET 2 N
591 (Multinational)
OBT Placebo
Eligibility - Treatment Experienced- HIV RNA gt
5,000 copies/ml- Randomized, double-blind, Phase
3 - Resistance to approved NNRTIs- At least 3
PI mutations
1x
OBT Etravirine 200 mg bid
1x
OBT - Darunavir Ritonavir (600/100 mg bid)
- Investigator Chosen NRTIs - Optional
Enfuvirtide
From DUET-1. Madruga JV, et al. Lancet
200737029-38. DUET-2. Lazzarin A, et
al. Lancet 200737039-48.
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Etravirine in ARV-Experienced PatientsDUET 1 2
Studies
INVESTIGATIONAL
DUET 1 Results 24 Weeks
DUET 2 Results 24 Weeks
P 0.001
P lt 0.005
P 0.001
P 0.003
From Madruga JV, et al. Lancet 200737029-38.
From Lazzarin A, et al. Lancet 200737039-48.
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• Strategies for Treating Multi-Resistant HIV

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QUESTION

• A 46-year-old HIV-infected man returns for
  further evaluation to discuss salvage therapy.
  He has a CD4 count of 118 cells/m3 and an HIV RNA
  of 57,000 copies/ml. He is highly experienced
  with antiretroviral therapy and has extensive
  multi-drug resistant HIV. Specifically, he has
  high level resistance to all NRTIs and NNRTIs.
  In addition, he has resistance to all protease
  inhibitors except darunavir and tipranavir.
• He is currently taking tenofovir emtricitabine
  (Truvada) Lopinavir-ritonavir (Kaletra). He
  does not want to take enfuvirtide (Fuzeon).
• What would you recommend for this patient?

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Options for Antiretroviral Medications
INVESTIGATIONAL

• NRTIs- Lamivudine or Emtricitabine Tenofovir?
  Abacavir?
• Protease Inhibitor- Darunavir Ritonavir
• Integrase Inhibitor- Raltegravir
• NNRTI- Etravirine
• Entry Inhibitors- Maraviroc?- Enfuvirtide

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Strategies for Deep Salvage in 2007

• Goal- Undetectable HIV
• Key Medications to Build Regimen Around-
  Darunavir Ritonavir - Raltegravir (if
  available via expanded access)- Etravirine (if
  available via expanded access)
• Possible Other Medications- Maraviroc (if
  patient has pure R5 HIV)- Enfuvirtide (if
  patient willing to do)- NRTIs (partial response
  only)
• OBTAIN EXPERT CONSULTATION

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