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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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0% 0%0%0%

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?