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2006 Asilomar HIVAIDS Medical Update David H. Spach, MD Clinical Director, NWAETC Professor of Medic

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Title: 2006 Asilomar HIVAIDS Medical Update David H. Spach, MD Clinical Director, NWAETC Professor of Medic


1
2006 Asilomar HIV/AIDS Medical Update
David H. Spach, MDClinical Director,
NWAETCProfessor of MedicineDivision of
Infectious DiseasesUniversity of Washington,
Seattle
DHS/PP
2
Asilomar 2006 HIV/AIDS Medical Update Outline
  • Update on DHHS Antiretroviral Therapy Guidelines
  • New Data with Established Antiretroviral
    Medications
  • New Medications
  • O-Receptor Inhibitors

DHS/PP
3
Antiretroviral TherapyDHHS May 2006 Guidelines
DHS/PP
4
HIV Antiretroviral Therapy
Nucleoside RTI
Nucleotide RTI
Entry Inhibitors
RT
HIV RNA
HIV DNA
HIV
Nucleus
Protease Inhibitors
Host Cell
Non-Nucleoside RTI
5
Initiating Antiretroviral Therapy
  • A 37-year-old HIV-infected woman presents for
    follow-up to consider starting antiretroviral
    therapy. Laboratory studies show a CD4 count of
    395 cells/mm3 and a HIV RNA level of 88,000
    copies/ml repeat testing one month later shows
    basically the same values.
  • Assuming she is motivated and able to take
    antiretroviral therapy, what would the May 2006
    DHHS Antiretroviral Therapy guidelines
    recommend?1. Start antiretroviral therapy.2.
    Offer therapy after discussing the pros and
    cons.3. Defer antiretroviral therapy and
    continue to follow.

DHS/PP
6
  • DHHS Panel May 2006 Antiretroviral
    GuidelinesInitial Therapy, Chronically Infected

DHS/PP
Source http//wwwaidsinfo.nih.gov
7
Initiating Antiretroviral Therapy
Acute HIV Infection
350
350
200
200
Year 1
DHS/PP
8
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
DHS/PP
9
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
DHS/PP
10
DHHS Panel 2006 Antiretroviral Guidelines
Initial Therapy Preferred Regimens
PI-Based Regimens
NNRTI-Based Regimens
EfavirenzLamivudine or Emtricitabine
Zidovudine or Tenofovir
Lopinavir-RitonavirLamivudine or Emtricitabine
Zidovudine
Picture
Source www.aidsinfo.nih.gov
DHS/PP
11
Resistance Testing in Antiretroviral Naive
  • A 35-year-old HIV-infected man presents new to
    your clinic. He first tested positive for HIV 3
    years ago. His most recent lab studies showed a
    CD4 count of 288 cells/mm3 and a HIV RNA of
    59,000 copies/ml. He is antiretroviral therapy
    naïve and he has never had a resistance test. The
    decision is made to start antiretroviral therapy.
  • Based on October 2006 DHHS Antiretroviral Therapy
    Guidelines, what would you recommend regarding
    resistance testing. 1. No reason to do since
    was infected more than 3 years ago.2. Obtain
    genotype resistance assay.3. Obtain phenotype
    resistance assay.4. Obtain both genotype and
    phenotype resistance assay.

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12
October 2006 DHHS ARV Therapy GuidelinesNew
Recommendation for Resistance Testing
  • The Panel recommends performance of genotypic
    resistance testing prior to initiation of
    antiretroviral therapy in patients with acute or
    chronic HIV infection.(BIII)
  • Genotypic resistance testing may be considered in
    patients entering into care but not yet requiring
    therapy.(CIII)

DHS/PP
13
Antiretroviral TherapyNew Data with
Established Medications
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14
To D/C 3TC or Not To D/C 3TC
  • A patient with advanced HIV disease has a
    genotype showing highly-resistant HIV, including
    a M184V. The patient will be starting on a new
    regimen that will include Enfuvirtide (Fuzeon)
    and Darunavir (Prezista).
  • The patient is taking lamivudine (Epivir). As
    part of the new regimen, do you think there is
    any benefit in continuing lamivudine? 1. Yes2.
    No 3. Not sure

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15
HIV RNA Response to ZDV, 3TC, ZDV 3TC
0.5
0.0
ZDV only
-0.5
3TC (150 mg BID)/ZDV
3TC 300 mg BID only
-1.0
3TC (300 mg BID)/ZDV
-1.5
ZDV 200 mg q8h
-2.0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Treatment time (weeks)
From Eron JJ, et al. N Engl J Med
19953331662-9.
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HIV RNA Response to ZDV, 3TC, ZDV 3TC
0.5
0.0
-0.5
3TC 300 mg BID only
-1.0
-1.5
3TC Resistance (M184V)
-2.0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Treatment time (weeks)
From Eron JJ, et al. N Engl J Med
19953331662-9.
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17
Lamivudine Monotherapy versus Treatment
Interruption in Patients with M184V Mutation
Patients on failing therapy requesting treatment
interruptionCD4 gt 500HIV RNA gt 1,000M184V
Mutationn 58
All ARV Meds Discontinuedn 29
Lamivudine 300 mg qdn 29
Resume Therapy- CD4 lt 350 - CDC B or
C Event
DHS/PP
From Castagna A, et al. AIDS. 200620795-803.
18
Lamivudine Monotherapy versus Treatment
Interruption in Patients with M184V Mutation
Lamivudine Continued
All ARVs Stopped
Parameter at Week 48
  • Change in CD4 Cell Count -141 -215
  • Change in CD4 Cell -3 -8
  • Change in HIV RNA 0.57 log 1.11 log
  • gt Grade 3 Adverse Events 7 31
  • Immunologic/Clinical Failure 41 69

P 0.001P 0.002 P lt 0.001
Patients who continued on Lamivudine had less fit
virus (decreased replicative capacity)
DHS/PP
From Castagna A, et al. AIDS. 200620795-803.
19
Lamivudine
No Lamivudine
Change in CD4 Cell Count
Immunologic/Clinical Failure
No Lamivudine
Change in CD4 Percent
Lamivudine
Change in HIV RNA
DHS/PP
From Castagna A, et al. AIDS. 200620795-803.
20
Continuing Lamivudine (or Emtricitabine) with
M184V Potential Benefits
  • Partial Virologic Response (0.4-0.5 log)
  • Immunologic Benefit
  • Delays/Prevents formation of TAMs
  • Increases activity of zidovudine in presence of
    TAMs
  • Slightly increases activity of tenofovir

DHS/PP
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Abacavir Use in NRTI-Experienced Patients
  • A patient with advanced HIV disease has
    previously received zidovudine (Retrovir),
    Lamivudine (Epivir), and Nevirapine (Viramune)
    and on this regimen developed virologic
    breakthrough. You order a genotype to help in
    are constructing a new PI-based second-line
    regimen. As part of the new regimen, you are
    considering using abacavir (Ziagen).
  • With which of the following would you expect
    essentially no virologic response to abacavir?
    1. M184V2. M184V 2-3 Thymidine Analogue
    Mutations (TAMs)3. M184V gt 4 Thymidine
    Analogue Mutations (TAMs)4. Both 2 and 3

TAMs M41L, D67N, K70R, L210W, T215Y/F, K219Q/E
DHS/PP
22
Abacavir Response with Prior NRTI Use
  • M184V Alone- Does not appear to impact response
    to AbacavirHarrigan PR, et al. JID
    2000181912-20. Lanier ER, et al. Antivir
    Ther 2004937-45.
  • M184V 2-3 Thymidine Analogue Mutations
    (TAMs)- Impairs virologic response to Abacavir
    Lanier ER, et al. Antivir Ther 2004937-45.
  • M184V gt 4 Thymidine Analogue Mutations
    (TAMs)- No virologic response to Abacavir
    Lanier ER, et al. Antivir Ther 2004937-45.

TAMs M41L, D67N, K70R, L210W, T215Y/F, K219Q/E
DHS/PP
23
Lopinavir-Ritonavir versus Fosamprenavir
Ritonavir
  • A 28-year-old antiretroviral therapy naïve
    HIV-infected man presents for follow-up to start
    antiretroviral therapy. His most recent labs
    showed a CD4 count of 224 cells/mm3 and a HIV RNA
    level of 164,000 copies/ml. He is ready to start
    antiretroviral therapy. He has battled depression
    and insomnia and the decision is made not to use
    efavirenz (Sustiva).
  • Which of the following statements best
    categorizes data from the recently published
    KLEAN study, which compared lopinavir-ritonavir
    (Kaletra) to Fosamprenavir (Lexiva) plus
    Ritonavir (Norvir) both were used with a
    backbone of abacavir lamivudine (Epzicom)?1.
    These regimens performed equally, regardless of
    baseline values.2. Lopinavir-ritonavir was
    superior at all baseline HIV RNA levels.3.
    Lopinavir-ritonavir was superior, but only at
    baseline HIV RNA levels gt 100,000.

DHS/PP
24
ABC 3TC (Fos-Amp-RTV or LPV-RTV)KLEAN-ESS1007
32
Study Design
Results 48 Weeks (ITT)
  • 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)

No differences in response in patients with HIV
RNA gt 100K
From Eron J et al. Lancet 2006368476-82.
DHS/PP
25
2NRTIs LPV-RTV versus 2NRTIs EFVACTG 5142
Study
Study Design
Results 96 Weeks (ITT)
  • Patients (N 887) - ARV naïve - HIV RNA gt
    2,000 copies/ml - Any CD4 count - Randomized
    trial
  • Regimens - 2 NRTIs LPV-RTV - 2 NRTIs EFV
    - LPV-RTV EFV

From Riddler SA, et al. XVI International AIDS
Conference. 2006 Abstract THLB024.
Significantly higher CD4 counts in LPV-RTV Arms
DHS/PP
26
3-Drug Versus 4-Drug Regimen
  • A antiretroviral-naïve patient with a CD4 cell
    count of 125 cells/mm3 and a HIV RNA of 187,000
    copies/ml is getting ready to start
    antiretroviral therapy.
  • Based on new data from ACTG 5095 what would you
    recommend regarding a 4-drug regimen (3 NRTIs
    EFV) versus a 3-drug regimen (2 NRTIs EFV).
    1. Expect a similar response with 3-drug and
    4-drug regimens2. The 4-drug regimen clearly
    better 3. The 3-drug regimen clearly better

DHS/PP
27
Initial Treatment for HIVThree versus Four Drug
Regimen ACTG 5095
Study Design
HIV RNA lt 50 Copies/ml (ITT)
  • Patients (N 765 received treatment) - ARV
    naïve, HIV RNA gt 400 copies/ml - Randomized
    trial, double-blinded
  • Regimens - Zidovudine Lamivudine Efavirenz
    - Zidovudine Lamivudine Efavirenz
    Abacavir
  • Baseline Characteristics - Mean CD4 240
    cells/mm3 - Mean HIV RNA 72,444 copies/ml -
    HIV RNA gt 100,000 41

4-Drug Regimen 3-Drug Regimen
From Gulick RM, et al. JAMA. 2006296769-81.
DHS/PP
28
Antiretroviral TherapyNewer Medications
DHS/PP
29
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
DHS/PP
30
TDF FTC EFV versus ZDV 3TC EFVStudy GS934
Study Design
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
  • No patient developed K65R
  • Development of M184V - 3 in Combivir arm -
    1 in Truvada arm

P 0.002
P 0.02
From Gallant JE et al. N Engl J Med.
2006354251-60.
DHS/PP
31
Tipranavir (Aptivus)
  • Which of the following is TRUE regarding the use
    of Tipranavir (Aptivus)?1. It can be used with
    or without Ritonavir in treatment-naïve patients
    2. Tipranavir Ritonavir is superior to
    Lopinavir-Ritonavir in treatment-naïve
    patients3. Side effects include hepatotoxicty
    and intracranial hemorrhage4. PRAMs accurately
    predict Tipranavir response

Protease Resistance Associated Mutations (30,
82, 84, 90)
DHS/PP
32
Tipranavir (Aptivus)
  • Classification- Protease Inhibitor
  • Dose 2 pills bid with Ritonavir- Tipranavir
    500 mg bid- Ritonavir 200 mg bid
  • Meal Restrictions- Must take with food
  • Indication- For highly PI-resistant
  • Adverse Effects- Hepatotoxicity intracranial
    hemorrhage

Tipranavir Ritonavir
DHS/PP
33
Tipranavir (Aptivus) in Antiretroviral Naïve
PatientsBI 1182.33
  • Background- N 558 ARV naïve patients
  • Regimens (NRTIs as Backbone)- Tipranavir 500 mg
    bid Ritonavir 200 mg bid- Tipranavir 500 mg
    bid Ritonavir 100 mg bid- Lopinavir/Ritonavir
    400/100 mg bid
  • Results- Ritonavir 200 mg bid arm stopped
    because of increased hepatotoxicity- Ritonavir
    100 mg bid arm stopped because of poor efficacy
    compared with Lopinavir/Ritonavir

DHS/PP
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Tipranavir (Aptivus) Adverse Effects
  • Hepatotoxicity- Black box warning- Fatalities
    have been reported- Extra vigilance in patients
    with hepatitis B or C
  • Intracranial Hemorrhage- Dear Healthcare
    Provider letter issued on June 30, 2006-
    Intracranial hemorrhage in 14 of 6840 on
    RTV-boosted tipranavir - 8 of 14 with
    intracranial hemorrhage have died
  • Sulfonamide Component- Caution in patients with
    known sulfa allergy

DHS/PP
35
Darunavir (Prezista), formerly TMC-114
  • Classification- Protease Inhibitor
  • Dose 2 pills bid with Ritonavir- Darunavir 600
    mg bid- Ritonavir 100 mg bid
  • Meal Restrictions- Take with food
  • Indication- For PI-resistant
  • Adverse Effects- GI, rash (sulfonamide component)

Darunavir Ritonavir
am
pm
DHS/PP
36
Darunavir/Ritonavir 600/100 mg bid Analysis
Analysis from Power Studies 1, 2, and 3
Study Design
24 Week Data
  • Background - Darunavir is novel PI - Active
    against PI-resistant isolates - POWER 1, 2, 3
    Studies
  • Patients - Prior Failure of PI regimen - 1
    or more PI mutation - HIV RNA gt 1,000
    copies/ml
  • Regimens (all OBR) - Darunavir 600 mg/RTV
    100 mg bid - Comparator PI

Duranavir Ritonavir 45 with HIV RNA lt 50
DHS/PP
From De Meyer S, et al. 13th CROI. 2006
Abstract 157.
37
Predictors of Darunavir (Prezista) Response
Analysis from Power Studies 1, 2, and 3
  • Baseline total PI Mutations-gt 10 protease
    mutations associated with decreased response
  • Baseline mutations associated with reduced
    response- V32I, L33F, I47V, I54L, L89V
  • Virologic failure associated with emergence of
    these 5 mutations
  • Tipranavir increased only by median 0.82 in
    rebounders at failure

From De Meyer S, et al. 13th CROI. 2006
Abstract 157.
DHS/PP
38
Antiretroviral TherapyCo-Receptor Inhibitors
DHS/PP
39
HIV Cell Binding and Entry
DHS/HIV/PP
From Levy J. N Engl J Med 19963351528-30.
40
HIV Cell Binding and Entry
1
2
3
CD4
CCR5
CXCR4
CCR5
Fusion Domain
Fusion Domain
From Levy J. N Engl J Med 19963351528-30.
DHS/HIV/PP
41
HIV Cell Binding and Entry
CD4 Cell
R5 HIV
CCR5
CD4
CXCR4
DHS/PP
42
HIV Cell Binding and Entry
CD4 Cell
X4 HIV
CCR5
CD4
CXCR4
Effect of X4 HIV- More rapid progression-
Syncitium induction
DHS/PP
43
HIV Infection Natural History
R5 HIV
R5 HIV
X4 HIV
R5 HIV
AIDS
Year 1
DHS/PP
44
HIV Infection Natural History
R5 HIV
X4 HIV
AIDS
Year 1
DHS/ARV Rx/PP
DHS/PP
45
Inhibitors of HIV Cell Binding and Entry
HIV
CD4 Cell
Maraviroc
Fusion Domain
CCR5
CD4
CXCR4
Fusion Domain
DHS/PP
46
HIV Cell Binding and Entry
CD4 Cell
R5 HIV
CCR5
CD4
CXCR4
DHS/PP
47
HIV Cell BindingPotential Shift from R5 HIV to
X4 HIV
CD4 Cell
R5 HIV
CCR5
CD4
X4 HIV
CXCR4
DHS/PP
48
HIV Cell BindingPotential Shift from R5 HIV to
X4 HIV
CD4 Cell
R5 HIV
CCR5
X4 HIV
CD4
CXCR4
DHS/PP
49
Maraviroc (UK-427,857) CCR5 Receptor Antagonist
INVESTIGATIONAL
  • Novel entry inhibitor (CCR5 Inhibitor)
  • Provides approximately 1.5 log decrease as
    monotherapy
  • BID dosing likely
  • Levels of maraviroc increased with most Pis (no
    change with TPV)
  • Levels of maraviroc decreased with efavirenz
  • Optimal dose unknown

DHS/PP
50
HIV Co-Receptor AssayMonogram Biosciences
Trofile Assay
INVESTIGATIONAL
  • Assay Measures HIV Tropism - R5 Tropic - X4
    Tropic - Dual Tropic
  • Analyzes Entire Envelope Gene

R5 Tropic HIV
X4 Tropic HIV
Dual Tropic HIV
Mixed Tropic HIV
DHS/PP
51
Antiretroviral TherapyIntegrase Inhibitors
DHS/PP
52
lt 50 copies/mL at Week 24 (NC F)
MK-0518 vs Efavirenz
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
MK-0518 100 mg
39
39
39
39
39
39
MK-0518 200 mg
40
40
40
40
40
40
MK-0518 400 mg
41
41
41
41
41
41
MK-0518 600 mg
40
40
40
40
40
40
EFV
38
38
38
38
38
37
Markowitz M, et al. IAC 2006. Abstract THLB0214.
53
  • www.HIVwebstudy.org
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