welcome to i-tech hiv/aids clinical seminar series 15 october, 2009 new insights into hiv...

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

DHS/PP

New Insights into the Pathogenesis and Natural History of HIV

Natural History of Untreated HIV

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Immune Activation


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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

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.

Normal Gut

CD4

CD8

Normal Gut


CD4 Depleted Gut

CD8

CD4

CD4 Depleted Gut: Consequences

Enteropathy- Diarrhea- Malabsorption- Increased Gut Permeability


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



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

Which ritonavir boosted protease

inhibitor regimen is best?

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

Update on Raltegravir

HIV Life Cycle: Integration

HIV RNA

HIV

Nucleus

Host Cell

CD4

CCR5

HIV Proviral DNA

IntegrationIntegration

HIV DNA

Integrase

HIV Integrase

DHS/PPFrom: HIV Integration. HIV Web Study (www.HIVwebstudy.org)

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


Spach

Host DNA

Host DNA

HIV DNA

STRAND TRANSFER


Spach

STRAND TRANSFER

Host DNA

Host DNA

HIV DNA


Spach

Host DNA

HIV DNA

Integrase Inhibitor Strand Transfer Inhibitors

Integrase InhibitorsStrand Transfer Inhibitors

3’ Hydroxyl Group

3’ Hydroxyl Group


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

DHS/PP

Questions

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

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200

Acute HIV

CD4-guided initiation of Antiretroviral Therapy for the asymptomatic patient

Year 1

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“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

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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

Initiating Antiretroviral Therapy for the asymptomatic patient

Year 1

DHS/PP

350

500

200

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


Natural Course of HIV Infection

Year 1

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500

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Chronic Inflammation => ongoing morbidity & mortality

Initiating Antiretroviral Therapy for the Asymptomatic Patient: future guidelines?

Year 1

DHS/PP

Initiate Antiretroviral Therapy

500

350

200

JAMA, June 10, 2009—Vol 301, No. 22

Bull World Health Organ 2009;87:488

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

http://www.sciencedirect.com/science?_ob=JournalURL&_cdi=4886&_auth=y&_acct=C000029718&_version=1&_urlVersion=0&_userid=582538&md5=09960a891140e366885abfa121ce0b96

http://www.sciencedirect.com/science?_ob=IssueURL&_tockey=%23TOC%234886%232001%23996420736%23245087%23FLA%23display%23Volume_357,_Issue_9263,_Pages_1141-1216_(14_April_2001)%23tagged%23Volume%23first=357%23Issue%23first=9263%23Pages%23first=1141%23last=1216%23date%23(14_April_2001)%23&_auth=y&view=c&_acct=C000029718&_version=1&_urlVersion=0&_userid=582538&md5=c345e676b1c41354b2cf0c8f54b01ea9

AIDS 2009, 23:1397–1404

Risk of HIV Transmission by VL & ART Use

Mathematical Model: Universal ART in SA

Lancet, Volume 373, Issue 9657, Pages 48 - 57, 3 January 2009

Extra slides

Dramatic Increase in Access to ART;Low & Middle Income Countries

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

HIV: Natural History

Year 1

DHS/PP

Acute HIV

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

Thank you!Next session: 22 October, 2009

Listserv: [email protected]: [email protected]

Welcome to I-TECH HIV/AIDS Clinical Seminar Series

Next session: 22 October, 2009

Roy Colven, MD

HIV Dermatology: Virtual Dermatology

welcome to i-tech hiv/aids clinical seminar series 15 october, 2009 new insights into hiv...

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