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HIV/AIDS 2008 Update
David H. Spach, MD
Clinical Director, NWAETCProfessor of Medicine
Division of Infectious DiseasesUniversity of Washington, Seattle
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 2008;300:520-9.DHS/PP
In this recent report, which one of the following statements is TRUE regarding HIV infections in the United States in 2006?
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1. The number of estimated new infections in 2006 has been revised to a lower number (now 32,000 instead of 40,000)
2. The rate (per 100,000 persons) of new infections in blacks was 7x whites
3. Heterosexual sex has replaced male-to-male sex as the leading transmission category for new infections
4. 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 2008;300(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.
Estimated Rates* of New US HIV Infections, 2006
12
84
29
1015
0
20
40
60
80
100
Rate (per 100,000 persons)
White
Black
Hispanic
Asian/PI
AI/AN
From: CDC & Prevention. JAMA 2008;300:520-9.
*Per 100,000 population
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New US HIV Infections (%) by Race/Ethnicity, 2006
From: CDC & Prevention. JAMA 2008;300 (5):520-9.
White35%
AI/ANl1%
Asian/PI2% Hispanic
17%
Black45%
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New US HIV Infections, by Gender, 2006
56,300
41,400
15,000
0
10,000
20,000
30,000
40,000
50,000
60,000
New HIV Infections
Total Male Female
From: CDC & Prevention. JAMA 2008;300 (5):520-9. DHS/PP
New US HIV Infections (%) by Transmission Category, 2006
From: CDC & Prevention. JAMA 2008;300 (5):520-9.
High-Risk Heterosexual
Contact31%
Injection Drug Use (IDU)
12%
Male-to-Male & IDU
4%
Male-to-Male Sexual Contact
53%
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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?
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1. Contamination of test kits with mold
2. Kits were shipped too close to the expiration date
3. Failure of external Kit Controls to validate the assay
4. 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
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OraQuick Rapid ORAL HIV Test Confirmatory HIV Test (EIA/WB)
PreliminaryPositive
Positive
EIA
WB
Reactive
Oral Fluid
Oral
Possible Revised Approach: Rapid HIV Testing
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OraQuick Rapid HIV Tests Confirmatory HIV Test (EIA & WB)
PreliminaryPositive
Reactive PositiveReactive
Oral
Oral Fluid
EXAMPLE: Specificity of HIV Antibody Test
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Persons NOT Infected with HIV (N = 15)
EXAMPLE: Specificity of HIV Antibody Test
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Antibody Test Result: Persons NOT Infected with HIV
EXAMPLE: Specificity of HIV Antibody Test
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Test Results = N =15
“False Positive”True Negatives
N = 13
N = 2
+ +
EXAMPLE: Specificity of HIV Antibody Test
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Specificity =True Negatives
True Negatives + False Positives
Specificity =13
13 + 2
Specificity = .87 = 87%
13
15=
+
= .87
HIV Antibody Testing in Low Prevalence Setting
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N =1,000 persons1% Infected with HIV
(1% Prevalence)
990 HIV-Negative
10 HIV-Infected
HIV Antibody Testing in Low Prevalence Setting
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N =1,000 persons1% Infected with HIV
(1% Prevalence)
990 HIV-Negative
HIV Test Specificity 99.0%
HIV Antibody Testing in Low Prevalence Setting
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N =1,000 persons1% Infected with HIV
(1% Prevalence)
990 HIV-Negative
HIV Test Specificity 99.0%
980 True Negative
10 False Positives
HIV Antibody Testing in Low Prevalence Setting
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N =1,000 persons1% Infected with HIV
(1% Prevalence)
990 HIV-Negative
10 HIV-Infected
HIV Test Specificity 99.0%
980 True Negative
10 False Positives
10 HIV-Infected
0 False Positives
HIV Test Sensitivity 99.0%
HIV Antibody Testing in Low Prevalence Setting
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N =1,000 persons1% Infected with HIV
(1% Prevalence)
990 HIV-Negative
10 HIV-Infected
HIV Test Specificity 99.0%
10 False Positives
10 HIV-InfectedHIV Test Sensitivity 99.0%
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 RECOMMENDATIONS
1. New CD4 threshold (350 cells/mm3 in 2008 instead of 200)
2. New indications for starting ARV (chronic HBV, HIVAN) in 2008
3. Less impact of HIV RNA level in 2008
4. Zidovudine-lamivudine removed from preferred list in 2008
5. Abacavir-lamivudine added to preferred list in 2008
6. Do HLA-B5701 testing if considering using abacavir
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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
CD4 Cell Count
Year 1
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*Initiate Antiretroviral Therapy
Consider Antiretroviral Therapy350
500
Source: DHHS Guidelines. www.aidsinfo.nih.gov
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
CD4 Cell Count
Year 1
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*Initiate Antiretroviral Therapy
Consider Antiretroviral Therapy350
500
Source: DHHS Guidelines. www.aidsinfo.nih.gov
*Other Reasons to Initiate ARV Rx - AIDS-defining Illness- Chronic HBV- HIV-associated nephropathy - Pregnancy
We know the DHHS recommendations, but what you think is the correct CD4 count to initiate ARV Rx (assume client adherent & willing)?
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1. CD4 count < 200 cells/mm3
2. CD4 count 200-350 cells/mm3
3. CD4 count 350-500 cells/mm3
4. All patients regardless of CD4 count
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
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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
Recent Concerns Regarding Abacavir
• D:A:D 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 = > 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 > 100,000 copies/ml
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1. Lancet 2008;371:1417-26 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.”
Source: DHHS Guidelines. www.aidsinfo.nih.gov
DHHS Panel
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Antiretroviral TherapyNew Information in 2008
Host Cellular ReceptorsCD4, CCR5, & CXCR4
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Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
CCR5 CXCR4
Co-Receptors
HIV (R5) Viral Entry: Co-Receptor Binding
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Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
R5 HIV
CXCR4 CCR5
Entry Inhibitor: Maraviroc (Selzentry)
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Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
R5 HIV
Maraviroc
CXCR4 CCR5
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HIV Co-Receptor Tropism AssayMonogram Biosciences Trofile Assay
R5-Tropic
X4-Tropic
R5X4 (Dual)-Tropic
Mixed Tropic
HIV-1 Tropism Assay
Question
• A new HIV Tropism (Trofile) assay is now available.
From: Monogram Biosciences DHS/PP
What is the major difference in the new ENHANCED Trofile assay when compared with the older Trofile assay?
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1. The new assay has a lower limit of detection of minor species (<1% compared with previous lower limit of 10%)
2. Results can be obtained in 7 days with the new assay
3. The new assay is accurate with very low HIV RNA levels (accurate down to 100 copies/ml)
4. 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%
R5-Tropic
X4-Tropic
R5X4 (Dual)-Tropic
Mixed Tropic
HIV-1 Tropism Assay
.
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Tenofovir + Lamivudine + Efavirenz (n = 38)
Eligibility - HIV-infected - Treatment Naive - HIV RNA > 5,000 copies/ml - CD4 count > 100 cells/mm3 - Randomized, double-blind
Tenofovir + Lamivudine + Raltegravir* (n = 160)
From: Markowitz M, et al. 17th IAC2008;Abstract TUAB0102.
Tenofovir + 3TC + (Efavirenz or Raltegravir)Antiretroviral Naïve: Protocol 004
Protocol 004N = 198
*Up to week 48, raltegravir dosed bid at 200, 400, 600, or 800 mgAfter week 48, all raltegravir dosed at 400 mg bid
1x
4x
Tenofovir + 3TC + (Efavirenz or Raltegravir)Week 96 Data
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* CD4 counts higher in LPV-RTV arms
84 84 84 83
0
20
40
60
80
100
Patients (%)
HIV RNA < 400 copies/ml HIV RNA < 50 copies/ml
TDF + 3TC + Efavirenz TDF + 3TC + Raltegravir
From: Markowitz M, et al. 17th IAC.2008;Abstract TUAB0102.
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1 288
HKR
Q N
H
Genotype: Mutations
• 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
148 155
Raltegravir: Resistance
HIV Integrase Resistance to Raltegravir
CTDNTD50 212
Integrase Amino acids
CCD1 288
CHR
Y
143NTD CTD
CCD50 212
Catalytic CoreDomain
N Terminal Domain
C Terminal Domain
Baseline NNRTI Resistance & Response to Etravirine DUET 1 & 2 Studies
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75
60 58
41
25
0
20
40
60
80
100
Patients with HIV RNA < 50 copies/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
From: Pozniak A, et al. 17th IAC. 2008; Abstract 144-LB.
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive STUDY C204
Study Design: Phase II Results (ITT): 96 Weeks
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P = 0.04 P = 0.003
* CD4 counts higher in LPV-RTV arms
7176
72 71
0
20
40
60
80
100
Patients (%)
HIV RNA < 50 copies/ml
Efavirenz: 600 mg Rilpivirine: 25 mg
Rilpivirine: 75 mg Rilpivirine: 150 mg
INVESTIGATIONAL
Background - N = 368 - ARV-naïve - HIV RNA > 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
*Zidovudine + Lamivudine (75%)*Tenofovir + Emtricitabine (25%)
25 mg
• Does anyone have questions or want to bring up any other important recent information recent antiretroviral therapy?
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New Scientific Discoveries
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).
gp120
gp41
EnvelopeHIV
What new therapeutic strategy was discovered?
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1. A CD4 coating molecule that is an inhibitor of gp120-CD4 binding
2. Use of Abzymes to destroy a critical region of gp120
3. A new enzyme that cause gp120 to separate from gp41
4. A new particle that destroys the human co-receptor CCR5 and thus prevents gp120-CCR5 binding
HIV: Basic Structure
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gp120
gp41 Envelope
HIV: Envelope
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HIV
gp120
gp41
HIV: gp120
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From: Zolla-Pazner S. Nat Rev Immunol 2004;4:199-212.
HIV: gp120
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From: Zolla-Pazner S. Nat Rev Immunol 2004;4:199-212.
L GLLTR D G G N N N
N HIV superantigen regionConserved RegionImportant in CD4 Binding
LG
LL
T
R
DG G N N
NN
AA 421-433
HIV Cell Binding and Entry
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Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
HIV
CCR5
gp120
Abzyme (Catalytic Antibody)
DHS/PPFrom: Planque S, et al. Auoimmun Rev. 2008;7:473-9.
YYAbzymes- Antibodies with enzymatic activity- Can break down thousands of virus particles per molecule of abzyme
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HIV: gp120
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L GLLTR D G G N N N
N
Abzyme
LG
LL
T
R
D
GG N N
N
NYY
YY
From: Planque S, et al. Auoimmun Rev. 2008;7:473-9.
HIV gp120: Abzyme Interaction
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HIV
gp120
YY
HIV gp120: Abzyme Interaction
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HIV
gp120
YYYY
HIV gp120: Abzyme Interaction
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HIV
gp120
YYYY
Abzyme (Catalytic Antibody)
DHS/PPFrom: Planque S, et al. Auoimmun Rev. 2008;7:473-9.
YYYYYY
YYQuickTime™ and a
decompressorare needed to see this picture.
HIV-Negative Patients with Lupus (SLE) Abzyme
HIV Life Cycle: Host Cell Defenses
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
HIV DNA
HIV Life Cycle: Cellular Restriction
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
HIV DNA
HUMAN
APOBEC 3G
HUMAN
APOBEC 3GTetherin
Tetherin
Viral Defenses: HIV Accessory Proteins
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HIV Accessory Proteins
Viral Inhibitor Factor (Vif) Viral Protein U (Vpu)
Vif Vpu
Cellular Restriction and Viral Defenses
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APOBEC 3G
Human: Cellular Restriction HIV: Viral Defense
Vif
Tetherin Vpu
Host Defense: ABOBEC 3G
HIV
Nucleus
Host Cell
CD4
CCR5
HIV RNA
Reverse Transcription
Reverse Transcription
HIV DNA
Reverse Transcriptase
Host ProteinAPOBEC 3G
HIV RNAHIV Reverse Transcriptase
Human Nucleotides
Human Cell
HIV: Reverse Transcription
HIV RNAHIV Reverse Transcriptase
Human Nucleotides
Human Cell
APOBEC 3G & Production of Defective HIV DNA
G to A Hypermutation
HumanAPOBEC 3G
Defective HIV DNA
HIV RNAHIV Reverse Transcriptase
Human Cell
HIV Defense (Vif) of APOBEC 3G
HumanAPOBEC 3G
Defective HIV DNA
Vif HIV Accessory Protein
HIV RNAHIV Reverse Transcriptase
Human Cell
HIV Defense (Vif) of APOBEC 3G
NORMAL HIV DNA
Vif
Human APOBEC 3G
HIV Life Cycle: Budding
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
HIV DNA
Host Defense: Tetherin
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
HIV DNA
Tetherin
HUMAN
Tetherin
From: Neil SJ, et al. Nature2008;45: 425-31.
HIV Defense (Vpu) Defense of Tetherin
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
HIV DNA
Tetherin
Vpu
HIV Accessory Protein
From: Neil SJ, et al. Nature2008;45: 425-31.
HIV Defense (Vpu) Defense of Tetherin
HIV RNA
HIV
Nucleus
Host Cell
CD4
CCR5
HIV
mRNA
Gag
Gag-Pol
HIV DNA
Vpu
Tetherin
HIV Accessory Protein
Translation of Basic Science Discoveries to Potential Future Therapies
• 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
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YYAPOBEC 3G
Vpu
L GL
LTR D G G N N N
N
Vif
Tetherin
HIV
HIV
Human
Human
TRUE or FALSE. In the US, in 2006, there were more NEW HIV infections involving MEN than WOMEN?
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1. TRUE
2. FALSE
With regard to HIV testing, if SPECIFICITY is how accurately you identify people who don’t have HIV infection, what do you think SENSITIVITY is?
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1. The number of false-negatives
2. How accurately you identify people who truly have HIV infection
3. The inverse prevalence of the disease
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)?
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1. They were clearer superior to efavirenz
2. About the same as efavirenz
3. They were clearer inferior to efavirenz
According to the 2008 DHHS Guidelines, which of the following are indications to initiate ARV therapy?
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1. CD4 count < 350 cells/mm3
2. Chronic active hepatitis B virus infection
3. HIV-associated nephropathy
4. All of the above
MATCH EM UP
Enzyme that destroys part of gp120
Human protein that causes defective RT
Human protein that prevents HIV release
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YY
APOBEC 3G
L GL
LTR D G G N N N
N
Tetherin
What does HIV use to neutralize these human cellular restriction proteins ?
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0% 0%0%0%
1. HIV Protease
2. HIV reverse transcriptase
3. HIV accessory proteins
VpuVif
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?