july 24th, 2008 hiv lifecycle and mechanisms of antiretroviral therapy david spach, md
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July 24th, 2008 HIV Lifecycle and Mechanisms of Antiretroviral Therapy David Spach, MD. - PowerPoint PPT PresentationTRANSCRIPT
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Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series
July 24th, 2008
HIV Lifecycle and Mechanisms of Antiretroviral Therapy
David Spach, MD
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DHS/PP
HIV/AIDS 2008 Treatment Update
An In-Depth Look at the Viral Life Cycle to Understand Old and New Antiretroviral Medications
David H. Spach, MD
Professor of MedicineDivision of Infectious Diseases
University of Washington, Seattle
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HIV/AIDS 2008 Treatment Update
• Overview of HIV Structure and Life Cycle
• 2008 DHHS Antiretroviral Therapy Guidelines
• Mechanisms of Action of Antiretroviral Medications
DHS/PP
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DHS/PP
HIV Structure and Life Cycle
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HIV: Basic Structure
DHS/PP
HIV RNA
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HIV: Basic Structure
DHS/PP
gp120 gp41
Envelope
Capsid (p24) HIV RNA
Matrix (p17)
Nucleocapsid (p7)
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HIV: Functional Enzymes
• What are the three key HIV enzymes involved in HIV replication?
DHS/PP
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HIV Enzymes
DHS/PP
Reverse Transcriptase Integrase Protease
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Host (Human) Cell: Key HIV Receptors
DHS/PP
Host Cell
CD4 Receptor
CCR5 Co-Receptor
CXCR4 Co-Receptor
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Question
• What genetic alteration in human co-receptors is associated with relative resistance to HIV infection?
DHS/PP
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CCR5-∆32
DHS/PP
CCR-∆32
Intracellular Space
Extracellular Space
Host Cell Membrane
CC
CCR5
CC
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HIV: Life Cycle
HIV
Nucleus
Host Cell
CD4
CCR5
Host DNA
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HIV: Life Cycle
HIV
Nucleus
Host Cell
CD4
CCR5
EntryEntry
1
3
2
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
EntryEntry UncoatingUncoating
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
EntryEntry UncoatingUncoating Reverse Transcription
Reverse Transcription
HIV DNA
Reverse Transcriptase
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV Proviral DNA
EntryEntry UncoatingUncoating Reverse Transcription
Reverse Transcription IntegrationIntegration
HIV DNA
Integrase
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
mRNA
gRNA
EntryEntry UncoatingUncoating Reverse Transcription
Reverse Transcription IntegrationIntegration TranscriptionTranscription
HIV DNA
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
mRNA
Gag
Gag-Pol
Myr
EntryEntry UncoatingUncoating Reverse Transcription
Reverse Transcription IntegrationIntegration TranscriptionTranscription TranslationTranslation
gp160
HIV DNA Protease
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
Myr
EntryEntry UncoatingUncoating Reverse Transcription
Reverse Transcription IntegrationIntegration TranscriptionTranscription TranslationTranslation Assembly &
BuddingAssembly &
Budding
HIV DNA
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
Nucleoside RTINucleoside RTIIntegrase InhibitorsIntegrase Inhibitors
Protease InhibitorsProtease Inhibitors
Entry InhibitorsEntry Inhibitors
HIV DNA
Non-Nucleoside RTINon-Nucleoside RTI
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DHS/PP
2008 DHHS Antiretroviral Therapy Guidelines
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Case History
• A 32-year-old HIV-infected woman returns to clinic to discuss starting antiretroviral therapy. Her CD4 count is 330 cells/m3 and her HIV RNA is 79,000 copies/ml.
• According to the 2008 DHHS Antiretroviral Therapy Guidelines: - When should you start antiretroviral therapy on this patient?
DHS/PP
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HIV: Natural History
0
200
400
600
800
1000
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Years
CD
4 C
ell C
ou
nt
Year 1
DHS/PP
Acute HIV
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Initiating Antiretroviral Therapy
0
200
400
600
800
1000
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Years
CD
4 C
ell C
ou
nt
Year 1
DHS/PP
350
500
200
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Initiating Antiretroviral TherapyJanuary 2008 DHHS Guidelines
0
200
400
600
800
1000
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Years
CD
4 C
ell C
ou
nt
Year 1
DHS/PP
Initiate Antiretroviral Therapy
Consider Antiretroviral Therapy350
500
Source: DHHS Guidelines. www.aidsinfo.nih.gov
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Question
• Why do you think we are more enthusiastic about starting antiretroviral therapy earlier now than 2-3 years ago?
DHS/PP
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Rationale for Earlier Antiretroviral Therapy
• More effective regimens
• More convenient regimens
• Less toxic regimens
• Expanding data suggesting benefit of earlier therapy
DHS/PP
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Case History
• A 32-year-old HIV-infected woman returns to clinic to discuss starting antiretroviral therapy. Her CD4 count is 330 cells/m3 and her HIV RNA is 79,000 copies/ml.
• According to the 2008 DHHS Antiretroviral Therapy Guidelines:
- What regimen would you use?
DHS/PP
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DHHS Panel: January 2008 ARV Therapy Guidelines Initial Therapy: Preferred Regimens
Picture
NNRTIEfavirenz
Column B
2-NRTITenofovir/Emtricitabine (Truvada) Abacavir/Lamivudine (Epzicom): for patients who test negative for HLA-B5701
Column A
DHS/PP
PIAtazanavir + Ritonavir Fosamprenavir + Ritonavir BIDLopinavir/ritonavir (Kaletra) BID
Construct Regimen by choosing one component from Column A and one component from Column B
Source: DHHS Guidelines. www.aidsinfo.nih.gov
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DHHS Panel: January 2008 ARV Therapy Guidelines Initial Therapy: Alternative Regimens
Picture
NNRTINevirapine
Source: www.aidsinfo.nih.gov
Column B
2-NRTIZidovudine/Lamivudine (Combivir) Didanosine + (Emtricitabine or Lamivudine)
Column A
DHS/PP
PIAtazanavir (unboosted)Fosamprenavir (unboosted)Fosamprenavir + ritonavir qdLopinavir/ritonavir (Kaletra) qd Saquinavir + ritonavir
Construct Regimen by choosing one component from Column A and one component from Column B
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Case History
• A 32-year-old HIV-infected woman returns to clinic to discuss starting antiretroviral therapy. Her CD4 count is 330 cells/m3 and her HIV RNA is 79,000 copies/ml.
• According to the 2008 DHHS Antiretroviral Therapy Guidelines:
- How should you ideally monitor after treatment is started?
DHS/PP
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DHS/PP
Antiretroviral Therapy: HIV RNA MonitoringOptimal Response: HIV RNA < 50 copies/ml
10
100
1000
10000
100000
HIV
RN
A (
log
10)
Antiretroviral Therapy Started
50
Time (Months)
1 2 3 4 5 6 7 8 9
√ CD4
√ CD4 √ CD4
Goal: HIV RNA < 50 copies/mlGoal: HIV RNA < 50 copies/ml
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DHS/PP
Entry Inhibitors
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HIV: Life Cycle
HIV RNA HIV DNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
Myr
Entry Inhibitors
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HIV: Basic Structure
DHS/PP
gp120
gp41
Envelope
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HIV: Envelope
DHS/PP
gp41
HIV
gp120
CD4 Binding Groove
V3 Region
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HIV: gp41
DHS/PP
HIV
gp41
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Host Cellular ReceptorsCD4, CCR5, & CXCR4
DHS/PP
Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
CCR5 CXCR4
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HIV Cell Binding and Entry
DHS/PP
HIV
CCR5
CD4 Receptor
CD4 Receptor
Host Cell Membrane
Extracellular Space
Intracellular Space
gp120
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
HIV
CCR5
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
HIV
CCR5
V3 Region
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
HIV
CCR5
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
Extracellular Space
HIV
CCR5
CD4 Receptor
Intracellular Space
gp41
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
Extracellular Space
HIV
Intracellular Space
gp41
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
Extracellular Space
HIV
Intracellular Space
Heptad Repeat 1 [HR1]
Heptad Repeat 2 [HR2]
HR1
HR2gp41
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
Extracellular Space
HIV
Intracellular Space
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
HIV
HIV Membrane
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HIV Cell Binding and Entry
DHS/PP
Host Cell Membrane
HIV
HIV Membrane
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R5-Tropic Virus: Binds to CCR5
DHS/PP
R5-Tropic HIV
CCR5
CD4 Receptor
CD4 Receptor
Host Cell Membrane
Extracellular Space
Intracellular Space
CXCR4
V3 Region
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X4-Tropic Virus: Binds to CXCR4
DHS/PP
X4-Tropic HIV
CCR5
CD4 Receptor
CD4 Receptor
Host Cell Membrane
Extracellular Space
Intracellular Space
CXCR4
V3 Region
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Dual-Tropic Virus: Binds to CCR5 or CXCR4
DHS/PP
Dual Tropic HIV
CCR5
CD4 Receptor
CD4 Receptor
Host Cell Membrane
Extracellular Space
Intracellular Space
CXCR4
V3 Region
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Question
• What human co-receptor does the drug Maraviroc block?
DHS/PP
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Entry InhibitorsCCR5 Inhibitor: Maraviroc (Selzentry)
DHS/PP
Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
R5 HIV
CCR5
Maraviroc
NOTE: Blocks Human Protein
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DHS/PP
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%
R5-Tropic
X4-Tropic
R5X4 (Dual)-Tropic
Mixed Tropic
HIV-1 Tropism Assay
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DHS/PP
$1960
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Entry InhibitorsFusion Inhibitor: Enfuvirtide (Fuzeon)
DHS/PP
HIV
Heptad Repeat 1
Heptad Repeat 2
Fusion Peptide
Heptad Repeat 2
Enfuvirtide36 amino acid peptide
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DHS/PP
Host Cell Membrane
Extracellular Space
HIV
Intracellular Space
Heptad Repeat 1
Heptad Repeat 2
Fusion Peptide
Entry InhibitorsFusion Inhibitors (Fuzeon)
Enfuvirtide
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DHS/PP
Host Cell Membrane
Extracellular Space
HIV
Intracellular Space
Entry InhibitorsFusion Inhibitors (Fuzeon)
Enfuvirtide
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DHS/PP
Reverse Transcriptase Inhibitors
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
Myr
Nucleoside RTI
HIV DNA
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HIV RNAHIV Reverse Transcriptase
Human Nucleotides
Human Cell
HIV Reverse Transcription
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HIV Reverse Transcription
HIV RNAHIV Reverse Transcriptase
Human Nucleotides
Human Cell
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Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
NRTI
HIV RNAHIV Reverse Transcriptase
Human Nucleotides
Human Cell
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Fixed-Drug NRTI Combinations
• Preferred- Tenofovir-Emtricitabine (Truvada)- Abacavir-Lamivudine (Epzicom)
• Alternative- Zidovudine-Lamivudine (Combivir)
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Case History
• A 38-year-old HIV-infected woman has a CD4 count of 257 cells/mm3 and a serum creatinine of 1.6. The provider would like to use abacavir + lamivudine.
• What test can you use to screen for abacavir hypersensitivity?
• Are there differences in the incidence of abacavir hypersensitivity in different races?
DHS/PP
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From: Gallant JE et al. N Engl J Med. 2006;354:251-60.
TDF + FTC + Efavirenz vs. ZDV + 3TC + Efavirenz Truvada versus Combivir
Patients (N = 517 randomized) - ARV naïve, HIV RNA > 10,000 copies/ml - Randomized trial Regimens (N = 487) - Tenofovir + Emtricitabine + Efavirenz - Zidovudine + Lamivudine + Efavirenz
Study Design Results: 48 Weeks (ITT)
84
7380
70
0
20
40
60
80
100
Pat
ient
s (%
)< 400 < 50
HIV RNA (copies/ml)
TDF + FTC + EFV ZDV + 3TC + EFV
DHS/PP
TDF= TenofovirFTC = EmtricitabineZDV = Zidovudine3TC = LamivudineEFV = Efavirenz
P = 0.002 P = 0.02
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HIV: Life Cycle
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
Myr
HIV DNA
Non-Nucleoside RTI
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DHS/PP
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTI
Reverse Transcriptase
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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)
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Etravirine (Intelence)
• Second Generation NNRTI
• Dose: 200 mg bid
• High genetic barrier of resistance
• Adverse Effects: Mainly Rash (mild)
• Risk of Rash: No Correlation with Prior NNRTI Rash
DHS/PP
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Case History
• A 26-year-old HIV-infected man returns to clinic after failing a regimen of tenofovir + lamivudine + efavirenz. His CD4 count is 148 cells/m3 and his HIV RNA is 41,000 copies/ml.
• His genotype shows a M184V mutation (lamivudine resistance) and a K103N mutations (efavirenz resistance).
• Is it likely that he will respond to etravirine?
DHS/PP
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Baseline NNRTI Resistance & Response to Etravirine DUET 1 & 2 Studies
DHS/PP
75
60 58
41
25
0
20
40
60
80
100
Pat
ient
s w
ith H
IV R
NA
< 5
0 co
pies
/ml
0 1 2 3 > 4
Baseline Etravirine Associated Mutations
Virologic Response: Week 24
From: Cahn P, et al. 2007 ICAAC. Abstract H-717.
Background - Pooled data from DUET 1 & 2
Patients (N = 599) - ARV experienced & failed NNRTI regimen - 3 or more PI mutations - HIV RNA > 1,000 copies/ml
Etravirine Associated Mutations (n = 13) - V90I - A98G - L100I - K101E/P - V106I, - V179D/F - Y181C/I/V - G190S/A
Study Design
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DHS/PP
Integrase Inhibitors
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HIV: Life Cycle
HIV RNA HIV DNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
Myr
Integrase Inhibitors
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Spach
Raltegravir Strand Transfer Inhibitor
Enzyme Active SiteDDE Catalytic Triad
Raltegravir (Isentress)Strand Transfer
Inhibitor
Catalytic Core Domain
Integrase Inhibitor
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DHS/PP
OBT + Placebo
Eligibility - HIV-infected - Treatment Experienced (Median 10 years)
- HIV RNA > 1,000 copies/ml - Randomized, double-blind - Resistance to 3 classes of ARV drugs
OBT + Raltegravir 400 mg bid
From: Cooper DA, et al. 15th CROI 2008. Abstract 788. Steigbigel R, et al. 14th CROI 2008. Abstract 789.
Raltegravir in ARV-Experienced PatientsBENCHMRK-1 & 2 Studies
BENCHMRK 1: N = 350 (Europe, Asia, Peru)
BENCHMRK 2: N = 349 (North & South America)
1x
2x
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From: Cooper DA, et al. 15th CROI 2008. Abstract 788. Steigbigel R, et al. 14th CROI 2008. Abstract 789.
Raltegravir in ARV-Experienced PatientsBENCHMRK-1 & 2 Study: 48 Week Data
DHS/PP
* CD4 counts higher in LPV-RTV arms
39
76
33
63
0
20
40
60
80
100
Pa
tie
nts
(%
)
HIV RNA < 400 copies/ml HIV RNA < 50 copies/ml
OBT + Placebo
OBT + Raltegravir
P < 0.001 P < 0.001
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DHS/PP
Protease Inhibitors
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HIV: Life Cycle
HIV RNA HIV DNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
Myr
Protease Inhibitors
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HIV: Life Cycle
Nucleus
Host Cell
Host DNA HIV Precursor Polyprotein
HIV Protease
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HIV: Life Cycle
Nucleus
Host Cell
Host DNA HIV Precursor Polyprotein
Proteins
HIV Protease
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HIV Protease Inhibitor
DHS/PP
Protease Inhibitor
Protease Inhibitor
HIV Protease Inhibitor
Active Site
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Recent Studies with Ritonavir-Boosted PIs
• KLEAN Trial- Fosamprenavir + Ritonavir = Lopinavir + Ritonavir (Kaletra)
• CASTLE Trial- Atazanavir + Ritonavir = Lopinavir + Ritonavir (Kaletra)
• GEMINI Trial- Saquinavir + Ritonavir = Lopinavir + Ritonavir (Kaletra)
• TITAN and ARTEMIS Trials- Darunavir + Ritonavir > Lopinavir + Ritonavir (Kaletra)
DHS/PP
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DHS/PP
Questions
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Welcome to UW I-TECH HIV/AIDS Clinical Seminar Series
Next session: July 31st, 2008
Marcia Weaver, Debbie Winters, MaryAnn Vitello
Task Shifting