Understanding Diagnostics and Lab Tests
in the Management of HIV Disease
1
Objectives
• Increase awareness of the importance of regular lab testing in the management
of HIV disease
• Discuss how diagnostics/lab tests, approved and in development, may be used
in the management of HIV disease
• Provide an overview of diagnostic tests commonly used by health care
providers in the management of HIV disease
2
HIV Treatment Today and Tomorrow
Today
Tomorrow
• There has been a great deal of
research to better understand and
treat HIV
• More drugs and diagnostic tools
that work in new and different ways
are coming online
• Advances in medications and lab
tests have revolutionized the
detection, monitoring, and
management of HIV
• Increasingly, HIV treatment can
offer the hope of better health
• With about 30 HIV drugs available,
including combination medications,
people with HIV are living longer
and healthier lives
FDA. Drugs used in the treatment of HIV infection. Available at: http://www.fda.gov/oashi/aids/virals.html.
3
The HIV Life Cycle
CD4+ T-Cell
Viral RNA
Cell DNA
gp 120
New HIV Particle
Nucleus
Viral DNA
Viral Proteins
CD4 Receptor
Co-receptor
(CCR5 or CXCR4)
Step 1
Viral Entry
Step 2
Reverse
Transcription
Step 3
Integration
Step 4
Transcription and
Translation
Step 5
Assembly and
Budding
HIV reproduces inside the CD4+ T-cell
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
..
4
The HIV Life Cycle
CD4+ T-Cell
Viral RNA
Cell DNA
gp 120
New HIV Particle
Nucleus
Viral DNA
Viral Proteins
CD4 Receptor
Co-receptor
(CCR5 or CXCR4)
Step 1
Viral Entry
Step 2
Reverse
Transcription
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
Step 3
Integration
Step 4
Transcription and
Translation
Step 5
Assembly and
Budding
5
The HIV Life Cycle
CD4+ T-Cell
Viral RNA
Cell DNA
gp 120
New HIV Particle
Nucleus
Viral DNA
Viral Proteins
CD4 Receptor
Co-receptor
(CCR5 or CXCR4)
Step 1
Viral Entry
Step 2
Reverse
Transcription
.
Hoffmann CJ, Gallant JE. Infect Dis.
2007;33:1-33.
..
Step 3
Integration
Step 4
Transcription and
Translation
Step 5
Assembly and
Budding
6
The HIV Life Cycle
CD4+ T-Cell
Viral RNA
Cell DNA
gp 120
New HIV Particle
Nucleus
Viral DNA
Viral Proteins
CD4 Receptor
Co-receptor
(CCR5 or CXCR4)
Step 1
Viral Entry
Step 2
Reverse
Transcription
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
Step 3
Integration
Step 4
Transcription and
Translation
Step 5
Assembly and
Budding
7
The HIV Life Cycle
CD4+ T-Cell
Viral RNA
Cell DNA
gp 120
New HIV Particle
Nucleus
Viral DNA
Viral Proteins
CD4 Receptor
Co-receptor
(CCR5 or CXCR4)
Step 1
Viral Entry
Step 2
Reverse
Transcription
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
Step 3
Integration
Step 4
Transcription and
Translation
Step 5
Assembly and
Budding
8
The HIV Life Cycle
CD4+ T-Cell
Viral RNA
Cell DNA
gp 120
New HIV Particles
Nucleus
Viral DNA
Viral Proteins
CD4 Receptor
Co-receptor
(CCR5 or CXCR4)
Step 1
Viral Entry
Step 2
Reverse
Transcription
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
..
Step 3
Integration
Step 4
Transcription and
Translation
Step 5
Assembly and
Budding
9
Advances in Treatment and Lab Tests
ART Era
Pre-ART Era
Early
1980s
Mid
1980s
Late
1980s
Early
1990s
HAART 1
Mid
1990s
Late
1990s
HAART 2
Today
Early
2000s
2008
10
Advances in Treatment and Lab Tests
ART Era
Pre-ART Era
HAART 1
HAART 2
Today
Protease
inhibitors,
1st DHHS
treatment
guidelines
New formulations
and combinations
to reduce number
of pills,
1st fusion
inhibitor
CCR5
antagonists,
integrase
inhibitors
Monotherapy and dual therapy
Effective
prophylaxis
for lifethreatening OIs
Early
1980s
Mid
1980s
Late
1980s
AZT used to
prevent
mother-to-child
transmission
Early
1990s
Mid
1990s
Late
1990s
Early
2000s
2008
ART = antiretroviral therapy; AZT = zidovudine; OIs = opportunistic infections; HAART = highly active antiretroviral therapy;
DHHS = Department of Health and Human Services.
FDA. HIV/AIDS historical time line. Available at: http://www.fda.gov/oashi/aids/miles.html.
11
Advances in Treatment and Lab Tests
ART Era
Pre-ART Era
HAART 1
HAART 2
Today
Protease
inhibitors,
1st DHHS
treatment
guidelines
New formulations
and combinations
to reduce number
of pills,
1st fusion
inhibitor
CCR5
antagonists,
integrase
inhibitors
Monotherapy and dual therapy
Effective
prophylaxis
for lifethreatening OIs
Early
1980s
Mid
1980s
Late
1980s
AZT used to
prevent
mother-to-child
transmission
Early
1990s
Mid
1990s
Early
2000s
VL testing
HIV isolated,
1st HIV antibody test
OraSure test
Treatment decisions primarily
based on CD4+ T-cell count
Late
1990s
OraQuick rapid test
2008
Tropism test,
entry inhibitor test,
integrase inhibitor
test
Sensitive VL tests (<400, <50)
Genotype and phenotype resistance tests
VL = viral load.
FDA. HIV/AIDS historical time line. Available at: http://www.fda.gov/oashi/aids/miles.html.
12
Summary
• Understanding the HIV life cycle has helped researchers develop
new and improved drugs to fight HIV
• Drugs used to treat HIV prevent the virus from reproducing by
stopping it at different points in its life cycle
• HIV treatment and care options, including new drugs and lab
tests, are evolving
• Today, new classes of drugs are available that work in different
ways
13
Why Are Lab Tests Important?
• Current lab tests look at 3 key areas:
1
2
3
The Immune System and
Response to Treatment
The Virus
Overall Health
• Lab tests help health care providers:
– Determine when to start treatment
– Evaluate response to treatment
– Determine when to switch treatments
– Determine which drugs to use
– Determine if drugs are causing side
effects or toxicities
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC:
Office of AIDS Research Advisory Council, US Dept of Health and Human Services; December 1, 2007.
14
Starting Point
• Determine HIV status
1
2
3
• Baseline tests
The Immune System and
Response to Treatment
The Virus
Overall Health
15
Starting Point
• Determine HIV status
1
2
3
The Immune System and
Response to Treatment
The Virus
Overall Health
• Baseline tests
– CD4+T-cell count
– VL
– Drug resistance testing if VL>1000
–
–
–
–
Chem screen
Complete blood count
Liver function tests
Pap test
– STD tests
– Hepatitis tests
– Opportunistic infection tests:
toxoplasmosis, tuberculosis
Chem = chemical; STD = sexually transmitted disease.
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC:
Office of AIDS Research Advisory Council, US Dept of Health and Human Services; December 1, 2007.
16
Understanding Lab Work
• Test values are usually given as a range or reference
Low
Normal Range
High
• Lab tests show whether results are in the normal range
• Normal range will depend on individual factors including age, race/ethnicity,
gender
• An out-of-range test result may not signal a major problem
• Trends over time are more important
• Discuss lab test results with a health care provider
17
Key Questions
•
3 important questions to ask the health care provider about lab
tests:
1.
Why is this test important?
2.
How often should I have it done?
3.
What do the results mean and how do they affect my health and HIV
treatment?
18
1
Tests That Tell About
The Immune System and
Response to Treatment
19
CD4+ T-Cell Count and Viral Load
• CD4+ T-cell count and VL are related to 2 main goals of HIV treatment
Goals of Treatment
High CD4+ T-Cell
Count
Low VL
VL <50 copies/mL for
Treatment Naïve and
Treatment Experienced
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
20
CD4+ T-Cell Count
Test
CD4+ T-Cell Count
Measures how many
CD4+ T-cells are
circulating in the
bloodstream
Goal of Treatment
High CD4+ T-Cell
Count
Results
>500
cells/mm3
350-500
cells/mm3
What It Means
Immune system is relatively health
Best time to initiate therapy in
asymptomatic patients is not well defined;
<349
cells/mm3
Increased risk of some illnesses; HIV
treatment recommended
<200
cells/mm3
AIDS diagnosis – increased risk of
opportunistic infections; preventive therapy
for opportunistic infections may be needed
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
21
CD4+ T-Cell Count Is a Key Factor in
Determining When to Start Treatment
• CD4+ T-cell count is key in deciding when to start treatment
• A branch of the government called the Department of Health and Human
Services, or DHHS, publishes guidelines for the treatment of HIV
Lab Results
Recommendation
CD4+ T-cell count >350 cells/mm3
Risks and benefits of treatment should be taken into
consideration
CD4+ T-cell count <350 cells/mm3
Start treatment
Treat all:
CD4+ T-cell count of any value
•
Pregnant women
•
People with HIV-associated kidney disease
•
People coinfected with hepatitis B (HBV) who require
HBV treatment
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
22
Viral Load
Test
Goal of Treatment
VL
Measures the
amount of HIV
circulating in the
bloodstream
What It Means
•
May be a consideration in the decision to
initiate therapy
•
Critical for evaluating the response to
therapy
•
Undetectable (goal)
VL<50 for Treatment
Naïve and Treatment
Experienced
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
23
Viral Load
Clinical Laboratory Report
Patient Name
DOE, JOHN
Specimen Number
123273
Date Received
12/20/06
Patient I.D./SSN
12345/234-56-7890
Date Drawn
12/20/06
Date of Report
12/22/06
Sex
M
Time Drawn
11:00 AM
Account Number
12345
Ordering Physician
SMITH
123094789
Client Name / Address
MEDICAL CENTER
YOUR DOCTOR, MD
123 MAIN STREET
ANYTOWN US 10023
Client I.D. Number
78987456
Test Name
HIV-1 RNA, PCR, 2ND GEN
HIV-RNA, PCR
LOG COPIES/ML
Results
885.0 H
2.95 H
Reference Range
<50
<1.7
Age
33
Units
Copies/mL
Log copies/mL
24
Exercise: Sam Gets His Test Results
Sam’s Story
Discussion
•
Sam is a 30-year-old man recently
diagnosed with HIV disease
•
How would you explain CD4+ T-cell
count and VL to Sam?
•
He just received his CD4+ T-cell count
and VL test results
•
•
Sam is confused and asks his case
manager for help in understanding the
lab results
What would you tell Sam is the most
important information he needs to know
about each test?
•
What questions should Sam ask his
health care provider about
each test?
25
2
Tests for Learning More About
The Virus
26
Resistance Testing
• Drug resistance means that HIV continues to multiply even when a person is
taking HIV drugs
• When this happens, VL usually goes up and CD4+ T-cell count usually goes
down – this may indicate that the medications are less effective
• Resistance tests are used to:
– Check which drugs in a treatment regimen no longer work (or no longer work as
well)
– Help determine which other drugs the virus will respond to
• The DHHS guidelines recommend resistance testing:
– Before starting treatment
– If starting treatment does not lead to undetectable VL
– If undetectable VL becomes detectable while on medication
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected. Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
27
Genotype and Phenotype Tests
Genotype Test
• Tests for virus mutations associated
with resistance to a particular drug
• Recommended as 1st resistance
test for people who are new to
treatment
• Requires more interpretation than
phenotype test
• Costs less and is more widely
available than phenotype test
Phenotype Test
• Measures how well the virus can
reproduce in the presence of
different drugs
• Provides more information than
genotype test about which drugs
will work against your virus
• Easier to interpret than genotype
test
• More expensive than genotype test
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
28
Exercise: Sam Gets a Resistance Test
Sam’s Story
• After having an undetectable VL for
a number of years, Sam’s VL is
now detectable
• Sam knows about drug resistance
and calls a treatment hotline to ask
about resistance tests
Discussion
• How would you explain genotype
and phenotype testing to Sam?
• What would you tell Sam is the
most important information he
needs to know about each test?
• What questions should Sam ask his
health care provider about each
test?
29
New Tests
• Many lab tests that are commonly used today (such as VL) were first used in
research settings such as clinical trials
• As these tests were shown to provide valuable information to help manage HIV,
they became part of routine care
• Just as new drugs are continually being developed to improve care, new lab
tests are continually being investigated
• Such tests may help to further individualize treatment and improve health
outcomes
• Some of the new tests include:
– Tropism test
– Entry inhibitor test
– Integrase inhibitor test
30
Viral Entry Is a 3-Stage Process
• Tropism test focuses on the second stage of viral entry, called co-receptor
binding
2. Co-receptor Binding
1. Attachment
CD4 binding
inhibitors
3. Fusion
Fusion inhibitors
CCR5
antagonists
gp41
gp120
Cell Membrane
CCR5/CXCR4
Adapted from: Moore JP, Doms RW. Proc Natl Acad Sci USA. 2003;100:10598-10602. Copyright 2003 National Academy of Sciences, USA.
Poveda E, Briz V, Quiñones-Mateu M, Soriano V. AIDS. 2006;20:1359-1367.
31
Tropism Test
• The tropism test determines which co-receptor HIV uses to enter CD4+ T-cells
– CCR5 (CCR5-tropic virus)
– CXCR4 (CXCR4-tropic virus)
– CCR5 and CXCR4 (dual- or mixed-tropic virus)
• The tropism test identifies which people may benefit from co-receptor
antagonists
– These drugs inhibit HIV from using a co-receptor to enter a CD4+ T-cell – this
prevents HIV from infecting the cell
– A tropism test can inform a health care provider about whether or not a patient may
benefit from a co-receptor antagonist
Poveda E, Briz V, Quiñones-Mateu M, Soriano V. AIDS. 2006;20:1359-1367.
32
Tropism Test Results
•
You and your doctor may consider if a CCR5
antagonist is right for you
•
According to the DHHS treatment guidelines,
a tropism test should be performed whenever
the use of a CCR5 antagonist is being
considered
•
Blood is drawn for a tropism test and results
are provided within 2 weeks after the lab
receives the sample
•
Results will indicate if the virus is:
– CCR5-tropic (R5)
– Dual/Mixed-tropic (DM)
– CXCR4-tropic (X4)
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
Monogram Biosciences. FAQs-patient questions. Available at: http://www.trofileassay.com/FAQ_Patient_Questions.
33
Exercise: Sam Gets a Tropism Test
Sam’s Story
•
•
•
Sam is on his 3rd regimen and has
learned that his virus is multidrug
resistant
His health care provider has
recommended a tropism test
Sam is attending a treatment education
workshop and asks the facilitator about
tropism testing
Discussion
•
How would you explain the tropism test
to Sam?
•
Under what circumstances might Sam
require a tropism test?
•
What would you tell Sam is the most
important information he needs to know
about the tropism test?
•
What questions should Sam ask his
health care provider about the tropism
test?
34
Entry Inhibitor Assay
• The entry inhibitor test assesses resistance to Fuzeon® (enfuvirtide)
• Entry inhibitor tests may be used:
– Before changing a regimen that includes Fuzeon
– Before adding Fuzeon if a health care provider suspects resistance
Fuzeon is a registered trademark of Roche Laboratories Inc. and Trimeris, Inc.
Monogram Biosciences. PhenoSense Entry advanced technology for assessing HIV. Available at:
http://www.monogramhiv.com/assays/hcp/phenoEntryAssay.aspx.
Monogram Biosciences. PhenoSense Entry technology. Available at: http://www.monogramhiv.com/assays/hcp/phenoEntryAssay.aspx.
35
Integrase Inhibitor Assay
• The integrase inhibitor test assesses resistance to integrase
inhibitors
• This test can help health care providers determine:
– Whether HIV is resistant to integrase inhibitors and NRTIs
– How active HIV is in the presence of integrase inhibitors
NRTIs = nucleoside reverse transcriptase inhibitors.
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
Biosciences. PhenoSense™ and GeneSeq™ for integrase inhibitors assays. Available at: http://www.monogrambio.com/416.aspx.
Monogram
36
Summary
• Looking at a person’s lab results—including CD4+ T-cell count, VL, and
resistance—can help in making the best decisions for that individual
• Just as new drugs are continually being developed to improve care, new lab
tests are continually being investigated
• Such tests may help to further individualize treatment and improve health
outcomes
• Tropism testing is now available which allow health care providers to determine
the co-receptor tropism of a patient’s virus
• The DHHS guidelines recommend tropism testing prior to the initiation of a
CCR5 antagonist
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
37
3
Tests for Tracking
Overall Health
38
Tracking Overall Health
• Tracking a patient’s overall health will help a health care provider:
– Monitor toxicities or other problems caused by HIV and the drugs used to treat it
– Track other health conditions that may arise because of aging or other factors
• Most tests are done at baseline (when first diagnosed with HIV or starting care)
and then usually every 3 to 6 months, depending on individual risk factors and
health care provider recommendations
39
Chemical Screen
What Is It?
Blood test to measure a number of
important chemicals produced by the body
to help it function properly
Why Is It Important?
• Monitors:
– Liver, kidney, heart, and pancreas function
– Drug toxicities and side effects
• Helps determine whether another
infection is present
• May influence treatment decisions
Tests performed at baseline and usually every 3 to 6 months thereafter,
depending on individual factors as determined by the health care provider.
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
HIVInSite. Understanding laboratory tests. Available at: http://hivinsite.ucsf.edu/InSite?page=pb-diag-02-00.
40
Complete Blood Count
What Is It?
Why Is It Important?
• Blood test that examines the
components of blood, including red and
white blood cells and platelets
• Some drugs can cause low red or white
blood cell counts, which can lead to
anemia or other blood disorders
Tests performed at baseline and usually every 3 to 6 months thereafter,
depending on individual factors as determined by the health care provider.
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
41
Tests for Other Related Health Conditions
•Test
What Is the Purpose?
Why Is it Important?
Hepatitis A, B, C
• Screen for hepatitis infections
• If left untreated, hepatitis B
and C can lead to severe
scarring of the liver, liver
failure, and liver cancer
Tuberculosis
(TB) and
Toxoplasmosis
• Screen for opportunistic
infections, TB, and
toxoplasmosis
• These infections can become
very serious if undiagnosed
and untreated
Sexually
Transmitted
Diseases
(STDs)
• Screen for syphilis,
chlamydia, gonorrhea, and
other STDs
• These infections can become
serious if untreated, and may
be transmitted to sexual
partners
Hoffmann CJ, Gallant JE. Infect Dis. 2007;33:1-33.
DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington, DC: Office of AIDS Research Advisory
Council, US Dept of Health and Human Services; December 1, 2007.
CDC. Viral Hepatitis B. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/b/fact.htm.
42
Special Lab Tests/
Exams for Women and Men
Women
Men
What are
other special
tests for
women?
What are
other special
tests for
men?
43
Special Lab Tests/
Exams for Women and Men
Women
Men
• Pap test (cervical and • Anal screening
anal)
• Prostate cancer
• Pelvic exam
screening
• Colposcopy
• Hormone levels
• Breast exam
• Mammogram
• Hormone levels
44
Tips For Lab Tests
• Before taking a test, be sure to follow the health care provider’s instructions:
– Are there any food restrictions?
– Are there any drugs that a person should avoid taking?
• To help ensure the accuracy of the test results, it’s important to:
– Tell the person collecting the sample if these instructions have not been followed,
and how
– Inform the health care provider of any personal, medical, and family history and
about any medications you are taking
• Other tips?
45
Conclusion
• Advances in medications and lab tests have revolutionized the
detection, monitoring, and management of HIV
• Lab tests are essential for getting the most out of HIV treatments
• With new drugs and diagnostic tests that work in different ways,
we look forward to improved approaches to managing HIV
46
Learn More
• Find more information about HIV lab tests on these Web sites:
– ACRIA.org (AIDS Community Research Initiative of America)
– AIDSmeds.com
– AIDSInfoNet.org
– HIVandHepatitis.com
– ProjectInform.org (Project Inform)
– TheBody.com
– TPAN.com (Test Positive Aware Network)
Pfizer accepts no responsibility for the content of these Web sites.
47
Thank You!
MV281830 © 2008 Pfizer Inc. All rights reserved. Printed in USA/January 2008
48