DHSPP

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HIV/AIDS 2008 Update David H. Spach,
MDClinical Director, NWAETCProfessor of
MedicineDivision of Infectious
DiseasesUniversity of Washington, Seattle
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HIV/AIDS 2008 Update

• HIV Epidemiology
• HIV Rapid Testing
• 2008 DHHS ARV Therapy Guidelines
• Antiretroviral Therapy New Information in 2008
• New Scientific Discoveries

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Epidemiology
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Question

• In August 2008, the CDC reported their use of new
  epidemiologic methods that has led to significant
  revisions in the estimates of HIV incidence in
  the United States.

From CDC Prevention. JAMA 2008300520-9.
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In this recent report, which one of the following
statements is TRUE regarding HIV infections in
the United States in 2006?

• The number of estimated new infections in 2006
  has been revised to a lower number (now 32,000
  instead of 40,000)
• The rate (per 100,000 persons) of new infections
  in blacks was 7x whites
• Heterosexual sex has replaced male-to-male sex as
  the leading transmission category for new
  infections
• The number of new infections in women was greater
  than men

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• Based on extrapolations from these data, the
  estimated number of new infections for the United
  States in 2006 was 56,300. CDC
  Prevention. JAMA 2008300(5)520-9.

• ... the level of new HIV infections in the
  United States is higher than had previously been
  known, in fact approximately 40 higher than
  early estimates Kevin Fenton, MD,
  PhDCenters for Disease Control Prevention.

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Estimated Rates of New US HIV Infections, 2006
Per 100,000 population
From CDC Prevention. JAMA 2008300520-9.
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New US HIV Infections () by Race/Ethnicity, 2006
From CDC Prevention. JAMA 2008300 (5)520-9.
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New US HIV Infections, by Gender, 2006
From CDC Prevention. JAMA 2008300 (5)520-9.
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New US HIV Infections () by Transmission
Category, 2006
From CDC Prevention. JAMA 2008300 (5)520-9.
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• What impact do you think the new CDC
  epidemiologic data will have on the AETCs?

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HIV Rapid Testing
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Rapid HIV Tests

• In the June 18, 2008 issue of the MMWR, the NY
  City Department of Health and the CDC reported a
  problem with the OraQuick ADVANCE Rapid HIV-1/2
  Antibody Test.

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What was the reported problem with the OraQuick
rapid HIV test?

• Contamination of test kits with mold
• Kits were shipped too close to the expiration
  date
• Failure of external Kit Controls to validate the
  assay
• Increased numbers of False-Positive results with
  oral fluid samples

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Persons NOT Infected with HIV
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Rapid HIV Testing
OraQuick Rapid ORAL HIV Test
Confirmatory HIV Test (EIA/WB)
WB
Oral
EIA
Preliminary Positive
Reactive
Positive
Oral Fluid
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Possible Revised Approach Rapid HIV Testing
OraQuick Rapid HIV Tests
Confirmatory HIV Test (EIA WB)
Oral
Preliminary Positive
Reactive
Positive
Reactive
Oral Fluid
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EXAMPLE Specificity of HIV Antibody Test
Persons NOT Infected with HIV (N 15)
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EXAMPLE Specificity of HIV Antibody Test
Antibody Test Result Persons NOT Infected with
HIV
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EXAMPLE Specificity of HIV Antibody Test
Test Results N 15
True Negatives
False Positive


N 2
N 13
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EXAMPLE Specificity of HIV Antibody Test
True Negatives True Negatives False
Positives
Specificity

13 13 2
13 15
Specificity


.87
Specificity
.87 87
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HIV Antibody Testing in Low Prevalence Setting
990 HIV-Negative
N 1,000 persons 1 Infected with HIV(1
Prevalence)
10 HIV-Infected
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HIV Antibody Testing in Low Prevalence Setting
HIV Test Specificity 99.0
990 HIV-Negative
N 1,000 persons 1 Infected with HIV(1
Prevalence)
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HIV Antibody Testing in Low Prevalence Setting
980 True Negative
HIV Test Specificity 99.0
990 HIV-Negative
N 1,000 persons 1 Infected with HIV(1
Prevalence)
10 False Positives
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HIV Antibody Testing in Low Prevalence Setting
980 True Negative
HIV Test Specificity 99.0
990 HIV-Negative
N 1,000 persons 1 Infected with HIV(1
Prevalence)
10 False Positives
10 HIV-Infected
HIV Test Sensitivity 99.0
10 HIV-Infected
0 False Positives
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HIV Antibody Testing in Low Prevalence Setting
HIV Test Specificity 99.0
990 HIV-Negative
N 1,000 persons 1 Infected with HIV(1
Prevalence)
10 False Positives
10 HIV-Infected
HIV Test Sensitivity 99.0
10 HIV-Infected
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Antiretroviral Therapy 2008 DHHS Guidelines
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DHHS ARV GuidelinesInitiating Antiretroviral
Therapy

• As a group, make a list of at least 5
  recommendations regarding initiating
  antiretroviral therapy that are new/different in
  current 2008 guidelines when compared with
  guidelines that existed one year ago at this time
  (at that time October 2006 most recent updated
  version).1. 2. 3. 4. 5.

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DHHS ARV GuidelinesInitiating Antiretroviral
Therapy

• NEW RECOMMENDATIONS1. New CD4 threshold (350
  cells/mm3 in 2008 instead of 200)2. New
  indications for starting ARV (chronic HBV, HIVAN)
  in 20083. Less impact of HIV RNA level in 2008
  4. Zidovudine-lamivudine removed from preferred
  list in 20085. Abacavir-lamivudine added to
  preferred list in 20086. Do HLA-B5701 testing
  if considering using abacavir

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Initiating Antiretroviral TherapyJanuary 2008
DHHS Guidelines
500
Consider Antiretroviral Therapy
350
Initiate Antiretroviral Therapy
Year 1
Source DHHS Guidelines. www.aidsinfo.nih.gov
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Initiating Antiretroviral TherapyJanuary 2008
DHHS Guidelines
Other Reasons to Initiate ARV Rx -
AIDS-defining Illness- Chronic HBV-
HIV-associated nephropathy - Pregnancy
500
Consider Antiretroviral Therapy
350
Initiate Antiretroviral Therapy
Year 1
Source DHHS Guidelines. www.aidsinfo.nih.gov
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We know the DHHS recommendations, but what you
think is the correct CD4 count to initiate ARV Rx
(assume client adherent willing)?

• CD4 count lt 200 cells/mm3
• CD4 count 200-350 cells/mm3
• CD4 count 350-500 cells/mm3
• All patients regardless of CD4 count

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DHHS Panel January 2008 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 (Truvada)
Abacavir/Lamivudine (Epzicom) for patients who
test negative for HLA-B5701
PIAtazanavir Ritonavir Fosamprenavir
Ritonavir BIDLopinavir/ritonavir (Kaletra) BID
Picture
Source DHHS Guidelines. www.aidsinfo.nih.gov
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Recent Concerns Regarding Abacavir

• DAD Study1- Recent use (within prior 6 months)
  of abacavir or didanosine associated with
  increased risk for myocardial infarction
  relative risk 1.94 with abacavir
• SMART Study2- N 5472 Use of abacavir
  associated with increased risk for myocardial
  infarction- Relative risk 4.3 with abacavir
• Glaxo Data3- N gt 14, 600. Retrospective
  analysis of 54 company-sponsored clinical trials
  showed no increased risk of MI with abacavir use
• ACTG 52024- N 5472 Higher failure rate in
  abacavir-containing regimens with HIV RNA gt
  100,000 copies/ml

1. Lancet 20083711417-26 2. Lundgren J, et al.
IAC. 2008 Abstract THAB0305.3. CutrelI A, et
al. 2008 Abstract WEAB006.4. Sax P, et al. IAC.
2008 Abstract THAB0303.
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• At this point, the Panel concludes that the
  preliminary information available for these
  studies does not warrant a change in its current
  recommendations regarding the use of
  antiretroviral drugs in adults and adolescents.
  

DHHS Panel
Source DHHS Guidelines. www.aidsinfo.nih.gov
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Antiretroviral TherapyNew Information in 2008
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Host Cellular ReceptorsCD4, CCR5, CXCR4
Extracellular Space
CCR5
CXCR4
CD4 Receptor
Host Cell Membrane
Intracellular Space
Co-Receptors
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HIV (R5) Viral Entry Co-Receptor Binding
R5 HIV
CD4 Receptor
Extracellular Space
CXCR4
CCR5
Host Cell Membrane
Intracellular Space
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Entry Inhibitor Maraviroc (Selzentry)
R5 HIV
CD4 Receptor
Maraviroc
Extracellular Space
CXCR4
CCR5
Host Cell Membrane
Intracellular Space
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HIV Co-Receptor Tropism AssayMonogram
Biosciences Trofile Assay
HIV-1 Tropism Assay
R5-Tropic
X4-Tropic
R5X4 (Dual)-Tropic
Mixed Tropic
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Question

• A new HIV Tropism (Trofile) assay is now
  available.

From Monogram Biosciences
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What is the major difference in the new ENHANCED
Trofile assay when compared with the older
Trofile assay?

• The new assay has a lower limit of detection of
  minor species (lt1 compared with previous lower
  limit of 10)
• Results can be obtained in 7 days with the new
  assay
• The new assay is accurate with very low HIV RNA
  levels (accurate down to 100 copies/ml)
• The new assay detects CCR5 mutants resistant to
  Maraviroc

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HIV Co-Receptor Tropism AssayMonogram
Biosciences ENHANCED Trofile Assay

• Viral Load Required - Above 1,000 copies/ml
• Detection of Minor Species - Reliably detected
  at 0.3

HIV-1 Tropism Assay
R5-Tropic
X4-Tropic
R5X4 (Dual)-Tropic
Mixed Tropic
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Tenofovir 3TC (Efavirenz or
Raltegravir)Antiretroviral Naïve Protocol 004
.
Protocol 004N 198
Eligibility - HIV-infected - Treatment Naive
- HIV RNA gt 5,000 copies/ml - CD4 count gt 100
cells/mm3 - Randomized, double-blind
Tenofovir Lamivudine Efavirenz (n 38)
1x
4x
Tenofovir Lamivudine Raltegravir (n 160)
Up to week 48, raltegravir dosed bid at 200,
400, 600, or 800 mgAfter week 48, all
raltegravir dosed at 400 mg bid
From Markowitz M, et al. 17th IAC2008Abstract
TUAB0102.
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Tenofovir 3TC (Efavirenz or Raltegravir)Week
96 Data
CD4 counts higher in LPV-RTV arms
From Markowitz M, et al. 17th IAC.2008Abstract
TUAB0102.
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Raltegravir Resistance
HIV Integrase
Resistance to Raltegravir
C Terminal Domain

• Resistance Pathways- Q148R/H/K Subsequent
  Mutations- N155H Subsequent Mutations
• Y143CHR identified as possible pathway
• Q148R/H/K plus G140S depend on R/H/K
• N155H plus E92Q increases resistance

N Terminal Domain
Catalytic CoreDomain
Genotype Mutations
CCD
50
212
1
50
212
1
288
288
Q
N
Y
CTD
NTD
CCD
CTD
NTD
148
143
155
H
HKR
CHR
Integrase Amino acids
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Baseline NNRTI Resistance Response to
Etravirine DUET 1 2 Studies
Study Design
Virologic Response Week 24

• Background - Pooled data from DUET 1 2
• Patients (N 599) - ARV experienced -
  Failed NNRTI regimen - 3 or more PI mutations
  - HIV RNA gt 1,000 copies/ml
• Etravirine Associated Mutations (n 13) -
  V90I - A98G - L100I - K101E/P - V106I, -
  V179D/F - Y181C/I/V - G190S/A

From Cahn P, et al. 2007 ICAAC. Abstract H-717.
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Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
STUDY C204
INVESTIGATIONAL
Study Design Phase II
Results (ITT) 96 Weeks

• Background - N 368 - ARV-naïve - HIV RNA gt
  5,000 copies/ml - Randomized, double-blind
• Regimens (all include 2 NRTIs) - Efavirenz
  600 mg qd - Rilpivirine 25 mg qd -
  Rilpivirine 75 mg qd - Rilpivirine 150 mg qd

CD4 counts higher in LPV-RTV arms
P 0.04
P 0.003
25 mg
Zidovudine Lamivudine (75)Tenofovir
Emtricitabine (25)
From Pozniak A, et al. 17th IAC. 2008 Abstract
144-LB.
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• Does anyone have questions or want to bring up
  any other important recent information recent
  antiretroviral therapy?

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New Scientific Discoveries
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A Cure for HIV?

• In July 2008, our patients starting coming in
  asking about the news reports regarding the newly
  discovered cure for HIV. The report that came
  out in July 2008 was related to HIV gp120
  (envelope).

HIV
Envelope
gp120
gp41
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What new therapeutic strategy was discovered?

• A CD4 coating molecule that is an inhibitor of
  gp120-CD4 binding
• Use of Abzymes to destroy a critical region of
  gp120
• A new enzyme that cause gp120 to separate from
  gp41
• A new particle that destroys the human
  co-receptor CCR5 and thus prevents gp120-CCR5
  binding

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HIV Basic Structure
Envelope
gp41
gp120
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HIV Envelope
HIV
gp41
gp120
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HIV gp120
From Zolla-Pazner S. Nat Rev Immunol
20044199-212.
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HIV gp120
AA 421-433
G
L
L
L
T
R
D
G
G
N
N
N
G
N
L
L
L
T
R
D
HIV superantigen regionConserved
Region Important in CD4 Binding
G
G
N
N
N
N
From Zolla-Pazner S. Nat Rev Immunol
20044199-212.
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HIV Cell Binding and Entry
HIV
gp120
CD4 Receptor
Extracellular Space
CCR5
Host Cell Membrane
Intracellular Space
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Abzyme (Catalytic Antibody)
Y
Abzymes- Antibodies with enzymatic activity-
Can break down thousands of virus particles per
molecule of abzyme
From Planque S, et al. Auoimmun Rev.
20087473-9.
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HIV gp120
Abzyme
G
L
L
Y
L
T
R
D
G
G
N
N
N
N
Y
G
L
L
L
T
R
D
G
G
N
N
N
N
From Planque S, et al. Auoimmun Rev.
20087473-9.
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HIV gp120 Abzyme Interaction
HIV
gp120
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HIV gp120 Abzyme Interaction
HIV
gp120
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HIV gp120 Abzyme Interaction
HIV
gp120
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Abzyme (Catalytic Antibody)
HIV-Negative Patients with Lupus (SLE)
Abzyme
Y
Y
Y
Y
From Planque S, et al. Auoimmun Rev.
20087473-9.
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HIV Life Cycle Host Cell Defenses

HIV
Nucleus
CCR5
CD4
HIV RNA
HIV DNA
mRNA
HIV
Gag
Host Cell
Gag-Pol
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HIV Life Cycle Cellular Restriction


HUMAN
HUMAN
Tetherin
APOBEC 3G
APOBEC 3G
Tetherin
HIV
Nucleus
CCR5
CD4
HIV RNA
HIV DNA
mRNA
HIV
Gag
Host Cell
Gag-Pol
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Viral Defenses HIV Accessory Proteins
HIV Accessory Proteins
Vif
Vpu
Viral Inhibitor Factor (Vif)
Viral Protein U (Vpu)
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Cellular Restriction and Viral Defenses
Human Cellular Restriction
HIV Viral Defense
APOBEC 3G
Vif
Tetherin
Vpu
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Host Defense ABOBEC 3G


Reverse Transcription
Host Protein
APOBEC 3G
Nucleus
CCR5
CD4
HIV RNA
HIV DNA
HIV
Reverse Transcriptase
Host Cell
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HIV Reverse Transcription
Human Cell
Human Nucleotides
HIV RNA
HIV Reverse Transcriptase
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APOBEC 3G Production of Defective HIV DNA
Human Cell
Human Nucleotides
G to A Hypermutation
HumanAPOBEC 3G
Defective HIV DNA
HIV RNA
HIV Reverse Transcriptase
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HIV Defense (Vif) of APOBEC 3G
Human Cell
HumanAPOBEC 3G
HIV Accessory Protein
Vif
Defective HIV DNA
HIV RNA
HIV Reverse Transcriptase
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HIV Defense (Vif) of APOBEC 3G
Human Cell
Vif
Human APOBEC 3G
NORMAL HIV DNA
HIV RNA
HIV Reverse Transcriptase
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HIV Life Cycle Budding

HIV
Nucleus
CCR5
CD4
HIV RNA
HIV DNA
mRNA
HIV
Gag
Host Cell
Gag-Pol
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Host Defense Tetherin


HUMAN
Tetherin
HIV
Tetherin
Nucleus
CCR5
CD4
HIV RNA
HIV DNA
mRNA
HIV
Gag
Host Cell
Gag-Pol
From Neil SJ, et al. Nature200845 425-31.
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HIV Defense (Vpu) Defense of Tetherin

HIV Accessory Protein
Vpu
HIV
Tetherin
Nucleus
CCR5
CD4
HIV RNA
HIV DNA
mRNA
HIV
Gag
Host Cell
Gag-Pol
From Neil SJ, et al. Nature200845 425-31.
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HIV Defense (Vpu) Defense of Tetherin

HIV
HIV Accessory Protein
Vpu
Tetherin
Nucleus
CCR5
CD4
HIV RNA
HIV DNA
mRNA
HIV
Gag
Host Cell
Gag-Pol
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Translation of Basic Science Discoveries to
Potential Future Therapies
Y

• Abzyme- Isolate/develop compounds that
  inactivate key gp120 segment
• Human APOBEC-3G and Vif- Develop Vif
  inhibitors- Develop APOBEC-3G-like compounds
  that cause hypermutations in HIV DNA formation
• Human Tetherin and Vpu- Develop Vpu inhibitors-
  Develop tetherin-like compounds

G
L
L
L
T
R
D
G
G
N
N
N
N
Human
HIV
Vif
APOBEC 3G
Human
HIV
Vpu
Tetherin
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TRUE or FALSE. In the US, in 2006, there were
more NEW HIV infections involving MEN than WOMEN?

• TRUE
• FALSE

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With regard to HIV testing, if SPECIFICITY is how
accurately you identify people who dont have HIV
infection, what do you think SENSITIVITY is?

• The number of false-negatives
• How accurately you identify people who truly have
  HIV infection
• The inverse prevalence of the disease

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How did the drugs Raltegravir (Integrase
Inhibitor) and Rilpivarine (NNRTI) fare in terms
of virologic responses when compared head-to-head
with Efavirenz (combined with 2 nucleosides)?

• They were clearer superior to efavirenz
• About the same as efavirenz
• They were clearer inferior to efavirenz

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According to the 2008 DHHS Guidelines, which of
the following are indications to initiate ARV
therapy?

• CD4 count lt 350 cells/mm3
• Chronic active hepatitis B virus infection
• HIV-associated nephropathy
• All of the above

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MATCH EM UP

• Enzyme that destroys part of gp120
• Human protein that causes defective RT
• Human protein that prevents HIV release

Tetherin
Y
G
L
L
L
T
R
D
G
G
N
N
N
N
APOBEC 3G
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What does HIV use to neutralize these human
cellular restriction proteins ?

• HIV Protease
• HIV reverse transcriptase
• HIV accessory proteins

Vif
Vpu
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HIV/AIDS 2008 Update Summary

• HIV Epidemiology
• HIV Rapid Testing
• 2008 DHHS ARV Therapy Guidelines
• Antiretroviral Therapy New Information in 2008
• New Scientific Discoveries

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Questions?
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