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Welcome to I-TECH HIV/AIDS Clinical Seminar Series
15 October, 2009
New Insights into HIV Pathogenesis and Antiretroviral Therapy Update
David H. Spach, MD & Chris Behrens, MD
DHS/PP
2009: New Insights into HIV Pathogenesis and Antiretroviral Therapy Update
David H. Spach, MD
Professor of MedicineDivision of Infectious Diseases
University of Washington, Seattle
Natural History of Untreated HIV
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
Acute CD4Depletion
1
Natural History of Untreated HIV
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
Immune ActivationAcute CD4Depletion
1 2
Natural History of Untreated HIV
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
Immune SuppressionAcute CD4Depletion
2 31
Immune Activation
Natural History of Untreated HIV
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
Immune Activation
Natural History Phases
From: Mehandru S. PRN Notebook. December 2007.
CD4
CD8
HIV
Epithelium
Profound Loss of Intestinal CD4 Cells
Normal Intestine
Acute HIV Infection
Destruction of CD4 Cells in Gut
Natural History Phases
From: Mehandru S. PRN Notebook. December 2007.
CD4
CD8
HIV
Epithelium
Profound Loss of Intestinal CD4 Cells
Normal Intestine
Acute HIV Infection
Destruction of CD4 Cells in Gut
Natural History Phases
From: Mehandru S. PRN Notebook. December 2007.
CD4
CD8
HIV
Epithelium
Profound Loss of Intestinal CD4 Cells
Normal Intestine
Acute HIV Infection
Destruction of CD4 Cells in Gut
Natural History Phases
From: Mehandru S. PRN Notebook. December 2007.
CD4
CD8
HIV
Epithelium
Profound Loss of Intestinal CD4 Cells
Normal Intestine
Acute HIV Infection
Destruction of CD4 Cells in Gut
Reasons for Massive Gut Mucosal CD4 Depletion
• Large Population of Preferred Target Cells for Acute Infection- Gut: 50-70% express CCR5- Blood: 10-20% express CCR5
• Dense Clustering of Cells in GI Mucosa- Close proximity leads to cell-to-cell HIV transmission
• Binding to Integrin Receptor (alpha-4, beta7)- This integrin receptor preferentially expressed on gut CD4 cells
DHS/PP
MODIFIED From: Mehandru S. PRN Notebook. December 2007.
CD4 Depleted Gut
CD8
CD4
CD4 Depleted Gut: Consequences
Enteropathy- Diarrhea- Malabsorption- Increased Gut Permeability
MODIFIED From: Mehandru S. PRN Notebook. December 2007.
CD4 Depleted Gut
CD8
CD4
CD4 Depleted Gut: Bacterial Translocation
Bacterial Translocation
Gut Involvement in Chronic Inflammatory State
DHS/PP
Massive Gut CD4 Cell Depletion
Massive Gut CD4 Cell Depletion Increased Gut
PermeabilityIncreased Gut Permeability
Bacterial Translocation
Bacterial Translocation
Chronic Inflammation
Chronic Inflammation
Increased Bacterial LPS
Increased Bacterial LPS
Structural Damage Enteropathy
Natural History Phases: Interventions
• Phase 1: Acute CD4 Depletion- Gut depletion severe within 4 weeks- Vaccine that would lessen effect on “GALT”
• Phase 2: Inflammation and Immune activation- Antiretroviral Therapy: ? Optimal Timing- Gut Repair/Restoration- Specific Anti-Inflammatory/Immunosuppressant
• Phase 3: Immune Suppression- OI Treatment and Prophylaxis- Antiretroviral Therapy
DHS/PP
From: Molina JM, et al. Lancet 2008;72:646-55.
TDF-FTC + (Atazavir-RTV or Lopinavir-RTV)CASTLE Study
Patients (N = 883) - ARV naïve, HIV RNA > 5,000 copies/ml - Randomized trial
Regimens (backbone TDF-FTC qd) - Atazanavir 300 mg qd + RTV 100 mg qd - LPV-RTV* (400-100 mg bid)
Study Design HIV RNA < 50 copies/ml*: Week 48
DHS/PP
* Capsules during first 48 weeks
* TLOVR = Time to Loss of Virologic Response
<100k
From: Eron J et al. Lancet 2006;368:476-82.
ABC + 3TC + (Fosamprenavir-RTV or Lopinavir-RTV)KLEAN-ESS100732
Patients (N = 887) - ARV naïve, HIV RNA > 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)
Study Design Results*: 48 Weeks (TLOVR)
DHS/PP
* No differences in response in patients with HIV RNA > 100K
* TLOVR = Time to Loss of Virologic Response
From: Walmsley S, et al. JAIDS 2009;50(5):367-74.
Saquinavir-RTV vs. Lopinavir-RTV in ARV-NaiveGEMINI Study
Patients (N = 337) - Open-label, randomized trial - ARV naïve, HIV RNA > 10,000 copies/ml - CD4 count < 350 cells/mm3
Regimens (backbone TDF + FTC qd) - Saquinavir + RTIV (1000/100 mg bid) - Lopinavir-RTV (400-100 mg bid)
Study Design Results*: 48 Weeks (ITT)
DHS/PP
* ITT = Intention to Treat
From: Ortiz R, et al. AIDS 2008;22:189-97.
Darunavir + RTV vs Lopinavir-RTV in ARV-NaiveARTEMIS Trial: 48 Week Data
Patients (N = 689) - ARV-naive - HIV RNA > 5,000 copies/ml - Randomized trial (non-blinded)
Regimens (All Received TDF-FTC*) - ^Darunavir-RTV: 800/100 mg qd -+LPV-RTV: 400/100 mg bid or 800/200 mg qd
Study Design Results*: 48 Weeks (ITT-TLOVR)
DHS/PP
^ Darunavir: 400 mg tablets
* TDF = tenofovir 300 mg; FTC = emtricitabine 200 mg+ Lopinavir-RTV: 77% bid; 15% qd; 7% both qd & bid
*TLOVR-Time to Loss of Virologic Response;Non-completer = Failure
P < 0.06 P < 0.05
<100k
Ritonavir-Boosted PIs
• CASTLE- Atazanavir + Ritonavir = Lopinavir-ritonavir
• KLEAN- Fosamprenavir + Ritonavir = Lopinavir-ritonavir
• GEMINI- Saquinavir + Ritonavir = Lopinavir-ritonavir
• ARTEMIS- Darunavir + Ritonavir > Lopinavir-ritonavir
DHS/PP
HIV Life Cycle: Integration
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV Proviral DNA
IntegrationIntegration
HIV DNA
Integrase
Spach
LEDGF/p75
Host DNA
PREINTEGRATION COMPLEX-HOST DNA BINDING
From: HIV Integration. HIV Web Study (www.HIVwebstudy.org)
Spach
STRAND TRANSFER
Reaction Catalyzed by HIV Integrase
From: HIV Integration. HIV Web Study (www.HIVwebstudy.org)
Spach
Host DNA
Host DNA
HIV DNA
STRAND TRANSFER
From: HIV Integration. HIV Web Study (www.HIVwebstudy.org)
Spach
STRAND TRANSFER
Host DNA
Host DNA
HIV DNA
From: HIV Integration. HIV Web Study (www.HIVwebstudy.org)
Spach
Host DNA
HIV DNA
Integrase Inhibitor Strand Transfer Inhibitors
Integrase InhibitorsStrand Transfer Inhibitors
3’ Hydroxyl Group
3’ Hydroxyl Group
From: HIV Integration. HIV Web Study (www.HIVwebstudy.org)
Raltegravir (Isentress)
• Class- Integrase Inhibitor
• Dose- 400 mg PO bid (400 mg tabs)
• Adverse Effects- Diarrhea, increased CPK (with statin)- No adverse effects on lipids
DHS/PP
.
DHS/PP
Tenofovir-Emtricitabine + Efavirenz^ (n = 282)
Eligibility - HIV-infected - Treatment Naïve - HIV RNA > 5,000 copies/ml - CD4 count > 100 cells/mm3 - No baseline resistance to TDF or FTC - Randomized, double-blind
Tenofovir-Emtricitabine + Raltegravir* (n = 281)
Tenofovir-Emtricitabine + (Efavirenz or Raltegravir)Antiretroviral Naïve: STARTMRK
STARTMRK ProtocolN = 563
^Efavirenz: 600 mg*Raltegravir: 400 mg bid
1x
1x
From: Lennox J, et al. Lancet. 2009;July 31 [E=pub ahead of print].
DHS/PPFrom: Lennox J, et al. Lancet. 2009;July 31 [E=pub ahead of print].
Tenofovir-Emtricitabine + (Efavirenz or Raltegravir)Antiretroviral Naïve: STARTMRK 48 Week Data
Rifampin and Raltegravir
• Rifampin 600 mg/d with Raltegravir 400 mg bid
- Raltegravir AUC decreased 40%
- Raltegravir MIC decreased 61%
• Recommendation with use of rifampin and raltegravir
- Increase raltegravir to 800 mg bid
DHS/HIV/PP
When Should Patients with HIV be Treated with HAART?
• Benefits– reduced morbidity & mortality
– immune system recovery
• Drawbacks– Toxicities
– potential for developing resistance
– expense
When Should Patients with HIV be Treated with HAART?
• Benefits– reduced morbidity & mortality
– immune system recovery
– Reduced infectivity
– Reduce immune activation?
• Drawbacks– Toxicities
– potential for developing resistance
– expense
Initiation of Antiretroviral Therapy: Key Considerations
• Symptoms & Opportunistic Infections
• Anticipated Adherence - patient ‘readiness’
• CD4 count
CD4-guided initiation of Antiretroviral Therapy for the asymptomatic patient
Year 1
DHS/PP
350
500
200
Acute HIV
CD4-guided initiation of Antiretroviral Therapy for the asymptomatic patient
Year 1
DHS/PP
350
500
200
“Clinical Latency”
“Asymptomatic”
Acute HIV
Initiating ART for asymptomatic patients2006 WHO Guidelines
Year 1
DHS/PP
consider treatment; start before CD4 drops below 200
350
500
200
Treat
Do not Treat
Source: WHO ART Guidelines, 2006
Initiating Antiretroviral Therapy2008 United States DHHS Guidelines
Year 1 DHS/PP
Treat
Consider Treatment350
500
Source: DHHS Guidelines. www.aidsinfo.nih.gov
Do not Treat
200
Mounting Evidence that Earlier Initiation of Therapy results in better clinical outcomes
Study Type Setting Main Findings
CIPRA 0011 RCT Haiti Deferring ART until CD4<200 associated with higher mortality than starting when CD4 between 200 and 350
SMART substudy2
RCT Europe, Australia
Deferring ART until CD4<250 associated with higher mortality than starting when CD4 between 350 and 250
ART-CC3 Obs Europe, North America
Significant increase in risk of AIDS and death when therapy was delayed until patients CD4+ counts fell below 350 cells/mm3 compared to earlier treatment.
NA-ACCORD4
Obs North America
Lower mortality in those who initiated in 350-500 range than those who deferred; Lower mortality in those who initiated at CD4 > 500 than in those who deferred
1. Interim analysis, June 20092. JID 2008;197:1133–1144
3. 16th CROI, Montreal, 2009 Abstract 72LB4. N Engl J Med 2009;360.
NA-ACCORD
17,517 asymptomatic, ARV-naive patients with HIV infection in North America who received medical care 1996 through 2005
stratified according to their CD4+ count at baseline: 351 to 500 cells per cubic millimeter or more than 500 cells per cubic millimeter
compared survival between patients who started antiretroviral therapy within the given CD4+ stratum with those who waited until after the CD4+ count fell below the stratum.
N Engl J Med 2009;360.
NA-ACCORD: Results
N=8362 patients
2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy.
Among patients in the deferred-therapy group there was an increase in the risk of death of 69%
N=9155 patients
2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy.
Among patients in the deferred-therapy group, there was an increase in the risk of death of 94%
N Engl J Med 2009;360.
Analysis #1: 500>CD4>350Analysis #2: CD4> 500
SMART Study
Drug Conservation (DC)
Defer use of ART until CD4+ < 250; episodic ART based on CD4+ cell count to
increase counts to > 350
Viral Suppression (VS)
Continuous use of ART to maintain viral load as low as possible
CD4+ cell count >350 cells/mm3 N= 5,472
n = 2,752 n = 2,720
Primary Endpoint: Opportunistic Disease or Death
Drug Conservation (DC) Strategy Associated with Increased Risk of Serious AIDS and Non-AIDS Events
No. of Patients with EventsEndpoint
Serious AIDS 59 1.3 0.4
Favors VS ►►Favors DC
Hazard Ratio (DC/VS) (95% CI)
Rate**DC VS
3.6
1.9
Serious non-AIDS* 186 3.2 2.01.6
•Cardiovascular, renal, hepatic, non-AIDS malignancy, others** Per 100 person-years
Serious AIDS or 239 4.4 2.4non-AIDS
Curr Opin HIV AIDS 2008;3:112-117
0.1 1 10
• Unchecked HIV replication• T cell apoptosis immunosuppression
Unifying FrameworkHIV-Associated Immune Activation
Adapted from Wafa El-Sadr, IAS 2009
Unifying FrameworkHIV-Associated Immune Activation
• Unchecked HIV replication T cell apoptosis immunosuppression
• Unchecked HIV replication Inflammation & coagulopathy
non-AIDS morbidity & mortality– Coronary Artery Dz - Liver disease– Osteoporosis - Neurocognitive decline– Renal disease - Malignancies
Ross, NEJM 1999
Adapted from Wafa El-Sadr, IAS 2009
C Reactive Protein Levels Increase over Time prior to AIDS Diagnosis
C re
activ
e pr
otei
n, g
eom
etric
mea
n ug
/L
Months from AIDS DiagnosisLau et al, Arch Intern Med 2006
AIDS
Effect of ART Interruption on Biomarkers Change from Baseline to Month 1 Change from Baseline to Month 1
SMART StudySMART Study
Marker DC Group VS Group
NMedian M1-bl
(IQR) NMedian M1-bl
(IQR)P-
value1
IL-6 247 0.60(-0.17-1.87)
249 0.12(-0.88-0.97)
<.0001
D-dimer 248 0.05(-0.07-0.18)
248 0.00(-0.13-0.08)
<.0001
1 Wilcoxon 2-sided test comparing DC and VS from baseline to month 1
Natural Course of HIV Infection
Year 1
DHS/PP
350
500
200
“Clinical Latency”
Chronic Inflammation => ongoing morbidity & mortality
Natural Course of HIV Infection
Year 1
DHS/PP
350
500
200
“Clinical Latency”
Chronic Inflammation => ongoing morbidity & mortality
Initiating Antiretroviral Therapy for the Asymptomatic Patient: future guidelines?
Year 1
DHS/PP
Initiate Antiretroviral Therapy
500
350
200
HIV transmission rate, per coital act, by plasma viral load of source partner - Rakai
HIV transmission rate (per coital act)
The Lancet Volume 357, Issue 9263 , 14 April 2001, Pages 1149-1153
Mathematical Model: Universal ART in SA
Lancet, Volume 373, Issue 9657, Pages 48 - 57, 3 January 2009
START Study HIV-infected, ART-naïve CD4+ count > 500 cells/mm3
Early ART GroupInitiate ART immediately
Deferred ART GroupDefer ART until CD4+ count < 350 cells/mm3 or AIDS
Primary OutcomeSerious AIDS, Serious non-AIDS Events or Death
Measurement of biomarkers
Effect of Rosuvastatin on CVD in General Population with High CRP & Low LDL-
Jupiter Study
Ridker et al, N Engl J Med 2008
Cum
ulati
ve In
cide
nce
Years
Atorvastatin
Placebo Atorvastatin
Placebo
Week 0 20 48
Arm A
Arm B
28
A5275A5275 – – Pilot Study of Effects of Pilot Study of Effects of Atorvastatin on Biomarkers in HIVAtorvastatin on Biomarkers in HIV
WASHOUT
Biomarkers of Inflammation, Coagulopathy, Angiogenesis, Biomarkers of Inflammation, Coagulopathy, Angiogenesis, and T-lymphocyte Activationand T-lymphocyte Activation
• HIV infected
• On boosted-PI regimen with HIV RNA <50 copies/ml
• LDL < 130 mg/dl • D-dimer >0.34
Initiating Antiretroviral Therapy2007 CAREC/CHART Guidelines
Year 1
DHS/PP
Offer treatment; start before CD4 < 200
Treatment generally not recommended*
350
500
Source: CAREC/CHART ART Guidelines, 2007
200
Treat
Do not Treat