resistance testing – where do i start? iván meléndez-rivera, md fellow, american academy of...
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Resistance Testing – Where Do I Start?
Iván Meléndez-Rivera, MDFellow, American Academy of Family Physicians
Assistant Professor of Family Medicine
Ponce School of Medicine, Ponce PR, USA
Board Member, American Academy of HIV Medicine
Faculty, Florida/Caribbean AETC
Medical Director, Centro Ararat, Inc Ponce PR, USA
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Disclosures of Financial Relationships
This speaker has significant financial relationships with the following commercial entities to disclose:• Advisory Board or Panel: Gilead, Merck• Consultant: Bristol-Myers Squibb• Grants/Research Support: Abbott, Boehringer,
GlaxoSmithKline, Napo, Pfizer• Speakers Bureau: Abbott, Boehringer, Bristol-Myers Squibb,
GlaxoSmithKline, Merck, Pfizer, Tibotec
This speaker will not discuss any off-label use or investigational product during the program.
This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.
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Objectives
• Introduce major resistance mutations for each class of HIV therapy
• Order currently available resistance tests
• Present illustrative case(s) of diagnosing resistance pattern resulting in treatment plan adjustment
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Definition of Antiviral Drug’s Resistance
• Presence of viral mutations that reduce drug susceptibility compared with the susceptibility of wild-type viruses.
• Can directly or indirectly interfere with a drug's activity.
• Should be distinguished from other causes of drug failure such as: – Non-adherence– Insufficient drug levels– Drug regimens with intrinsically weak antiviral
activity.
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Why does Resistance Develop?
• HIV can develop resistance quickly because:– HIV reverse transcriptase makes errors in matching
bases when converting HIV RNA to DNA– HIV replicates at a rapid rate: 1 to 10 billion viral
particles produced daily– In an untreated infected host, every possible mutation
occurs at least once every 24 hours, some of which may impart drug resistance.
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If you have developed resistance to a drug, does that mean that you are resistant to ALL the drugs in
the same class?
A. True
B. False
A. B.
80%
20%
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When does resistance occur?
• Resistance occurs when the virus has an opportunity to
replicate in the presence of sub-inhibitory concentrations
of drugs.
– Treatment with <3 active drugs– Inappropriate selection of drugs
• Pharmacokinetics or drug-drug interactions lead to inadequate drug exposures
– Non-adherence to the treatment regimen• Interruption of treatment (even for a few days)
– Adding one drug to a failing regimen– Prolonging a failing regimen
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Selective Pressures of Therapy
Selection of resistant quasispecies
Incomplete suppression• Inadequate potency• Inadequate drug levels• Inadequate adherence• Pre-existing resistance
Vira
l loa
d
Time
Drug-susceptible quasispeciesDrug-resistant quasispeciesTreatment begins
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What is viral resistance?
• A continuum of reduced susceptibility of HIV to the inhibitory effects of drugs
More Susceptible More Resistant
The terms "drug resistance" and "reduced drug susceptibility" have similar meanings, provided that each term is viewed as representing a continuum between susceptible and highly resistant. Because antiretroviral drugs differ in their potencies, reductions in susceptibility must be related to the activity of the drug against wild-type viruses.
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WILD VIRUS VS MUTANT VIRUS
Why is it important to measure drug resistance?
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What is wild-type virus?
• HIV virus that has not been exposed to drug therapy
• The predominant sequence of nucleotide bases in a heterogeneous mixture of virions
• It is the most fit form of HIV in the absence of drug
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Identifying Mutations
• How do we identify a resistance mutation?
M 184 M
“184 is the codon position”
M is the “wild-type” amino acid (AA)
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Identifying Mutations
• How do we identify a resistance mutation?
M 184 V
“184 is the codon position”
V is the mutant AA
M is the “wild-type” amino acid
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• To the virus, mutations can be:
What is the Impact of HIV Mutations?
Decreasing the virus’ ability to survive and/or replicate (viral fitness) or may make the virus hypersusceptible to certain antiretrovirals (ARVs)
No effect on virus function
Changing the structure of the virus to evade antiretroviral treatment. These mutations may or may not affect viral fitness
Johnson VA, et al. Topics in HIV Medicine. 2009;17:138-145.
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HIV RNA mutant
Drug resistant
Single-base Mutations May Confer Antiretroviral Resistance
123Position AA:
123 Mutant
AA: Y
YWild-type
AA: X
X
3 nucleotides specify an amino acid
Single-base mutation
HIV RNA wild type
Hoffman C et al. HIV Medicine 2007. 15th ed. Paris, France: Flying Publisher. 2007.
AA=amino acid
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Resistance Profile and Potential for Cross Resistance
HIV RNA Mutant
Drug A
Drug B
Drug C
Drug D
B cross resistance
A & B & C cross resistance
Adapted from: Paredes R, et al. Antiviral Res. 2010 Jan;85(1):245-65.
Region of HIV RNA associated with antiretroviral drug class specific resistance
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How is resistance measured?
By Genotype• Amino acid substitution on chain
By phenotype (IC50)
• IC50
– The minimum concentration of a drug needed to inhibit the growth of the virus by 50% in vitro
• IC50 is analogous to MIC90
– IC90 is not sufficiently reproducible for routine clinical use
• The lower the IC50, the more potent the drug
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RESISTANCE MUTATIONS PER HIV CLASS THERAPY
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Available Antiretroviral Agents
Nucleoside ReverseTranscriptase Inhibitors (RTIs)• Zidovudine (ZDV)• Didanosine (ddI)• Zalcitabine (ddC)• Stavudine (d4T)• Lamivudine (3TC)• Abacavir (ABC)• Emtricitabine (FTC)• Tenofovir DF (TDF)
Nonnucleos(t)ide RTIs• Nevirapine (NVP)• Delavirdine (DLV)• Efavirenz (EFV)• Etravirine (ETR)• Rilpivirine (RPV)
Protease Inhibitors• Saquinavir (SQV)• Ritonavir (RTV)• Indinavir (IDV)• Nelfinavir (NFV)• Amprenavir (APV)• Lopinavir/r (LPV/r)• Atazanavir (ATV)• Fosamprenavir (Fos-APV)• Tipranavir (TPV)• Darunavir (DRV)
Boosters• Ritonavir (RTV)• Cobicistat (cobi)
Fusion Inhibitor• Enfuvirtide (T-20)
CCR5 Antagonist• Maraviroc (MVC)
Integrase Inhibitors• Raltegravir (RAL)• Elvitegravir(ELV)*• Dolutegravir (DTG)*
* In expanded access
August 28, 2012
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Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)
• Zidovudine (ZDV)• Didanosine (ddI)• Stavudine (d4T)• Lamivudine (3TC)• Abacavir (ABC)• Tenofovir (TDF)• Emtricitabine (FTC)
Structure of a covalently trapped catalytic complex of HIV-1 RT published by Huang H et al, Science 1998. http://hivdb.stanford.edu/pages/3DStructures/rt.html Accessed Sept 3, 2012
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NRTI’s Resistance Mutations
Adapted from: http://hivdb.stanford.edu/DR/NRTIResiNote.html. Accessed Sept 3, 2012
Red: Primary Mutations to confer resistance Gray: Secondary Mutations***: Increase susceptibility
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NRTI’s Signature Mutations
Mutation Medication with decrease susceptibility
M184V Lamivudine (3TC) and Emtricitabine (FTC)
K65R Tenofovir (TDF)
L74V Abacavir (ABC) and Didanosine (ddI)
Y215F Zidovudine (ZDV) and Stavudine (d4T)
T69ins or Q151M
All except, Lamivudine (3TC) and Emtricitabine (FTC)
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Not ALL mutations are bad
• M184V/I cause high-level resistance to 3TC and FTC and low-level resistance to ddI and ABC.
• M184V/I are not contraindications to continued treatment with 3TC or FTC because they increase susceptibility to AZT, TDF, and d4T and are associated with clinically significant decreased HIV-1 replication.
http://hivdb.stanford.edu/DR/cgi-bin/rules_comments_hivdb.cgi?class=NRTI
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Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)
• Nevirapine (NVP)• Efavirenz (EFV)• Etravirine (ETR)• Rilpivirine (RPV)
Non-nucleoside RT inhibitor (NNRTI)-resistance mutationshttp://hivdb.stanford.edu/pages/3DStructures/rt.html Accessed Sept 3, 2012
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NRTI’s Resistance Mutations
Adapted from: http://hivdb.stanford.edu/DR/NRTIResiNote.html. Accessed Sept 3, 2012
Red: Highest Levels of resistance Gray: Intermediate level of resistance
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NNRTI’s Signature Mutations
Mutation Medication with decrease susceptibility
K103N Efavirenz (EFV) and Nevirapine (NVP)
Y181I/V Etravirine (ETR) and Rilpivirine (RPV)
Y188L Rilpivirine (RPV)
K101P ALL NNRTI
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Protease Inhibitors (PI’s)
Saquinavir (SQV) Ritonavir (RTV) Indinavir (IDV) Nelfinavir (NFV) Lopinavir/r (LPV/r) Atazanavir (ATV) Fosamprenavir (FPV) Tipranavir (TPV) Darunavir (DRV)
Major protease inhibitor (PI)-resistance mutationshttp://hivdb.stanford.edu/pages/3DStructures/rt.html, Accessed Sept 3, 2012
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PI’s Resistance Mutations
Adapted from: http://hivdb.stanford.edu/DR/NRTIResiNote.html. Accessed Sept 3, 2012
Red: Highest Levels of resistance Gray: Intermediate level of resistance
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PI’s Signature Mutations
Mutation Medication with decrease susceptibility
D30N Nelfinavir (NFV)
I50L Atazanavir (ATV)
I47V ALL except Saquinavir (SQV)
I54V ALL except Darunavir (DRV)
I84V ALL except Darunavir (DRV)
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Integrase Inhibitors (INI)
Raltegravir (RAL)Elvitegravir(ELV)Dolutegravir(DTG)*
* Investigational
http://www.scientistlive.com/European-Science-News/Pharmacology/HIV_integrase_inhibitor_effective_when_beginning_treatment/23101/ Accessed 06/OCT/12
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INI Resistance Mutations
Adapted from: http://hivdb.stanford.edu/DR/NRTIResiNote.html. Accessed Sept 3, 2012
Red: Highest Levels of resistance Gray: Intermediate level of resistance
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INI Signature Mutations
Mutation Medication with decrease susceptibility
Q148H/K/R Raltegravir (RAL) and Elvitegravir(ELV)
* In expanded access
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Fusion Inhibitors (FI)
Enfuvirtide (T-20)
www.fuzeon.com Accessed Sept 3, 2012
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Fusion Inhibitor Resistance Mutations
Adapted from: http://hivdb.stanford.edu/DR/NRTIResiNote.html. Accessed Sept 3, 2012
Gray: Intermediate level of resistance
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CCR5 Antagonist
Maraviroc (MVC)
Moore J, et al. Proc Natl Acad Sci USA. 2003;100:10598-10602; Yost R, et al. Am J Health-Syst Pharm. 2009;66:715-726 Accessed Sept 3, 2012
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CCR5 Antagonist Resistance is Associated withAmino Acid Changes in the V3 Loop of gp120*
• Variable pattern of Maraviroc resistance-associated amino acid substitutions
• No signature mutations have been identified
• Currently, there is no assay available to assess Maraviroc resistance
ChangeMaraviroc-resistant
Base
Tip
StemStem
Tip
Base
Deletion
Insertion
G/A
*Substitutions outside the V3 loop of gp120 may also contribute to reduced susceptibility to Maraviroc
Adapted from Data on file. ViiV Healthcare, RTP, NC.
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CCR5-Resistant Virus Recognizes Drug-Bound Receptors
Mutated gp120recognizes CCR5differently
MVCres Virus
MVCresgp120
Binding siteNOT disruptedby maraviroc
Entry
Mori J, et al. 16th IHIVDRW. Barbados, 2007. Abstract 10.
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RECOMMENDATIONS FOR DRUG RESISTANCE TESTING
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In which one of the following situations would HIV resistance testing NOT usually be recommended?
A. Acute HIV infection, regardless of whether treatment is to be started
B. Chronic HIV infection, at entry into care
C. After discontinuation (>4 weeks) of ARVs
D. Suboptimal suppression of viral load after starting antiretroviral therapy (ART) A. B. C. D.
25%
16%
52%
7%
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Trends of Phenotypic 1-, 2-, and 3-Class Resistance
NNRTI=non-nucleoside reverse transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor; PI=protease inhibitor.
60
50
40
30
20
10
0
2003
2004
2005
2006
2007
2008
2009
2010
60
50
40
30
20
10
0
2003
2004
2005
2006
2007
2008
2009
2010
2-Class Resistance 3-Class Resistance60
50
40
30
20
10
0
2003
2004
2005
2006
2007
2008
2009
2010
1-Class Resistance
Resi
stan
t Sam
ples
(%)
PINNRTINRTI
PI and NRTIPI and NNRTINRTI and NNRTI
Adapted from Paquet A et al. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2011; Chicago, Illinois. Abstract H2-800.
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Testing for Drug Resistance• Before initiation of ART:
– Transmitted resistance in 6-16% of HIV-infected patients– In absence of therapy, resistance mutations may decline over
time and become undetectable by current assays, but may persist and cause treatment failure when ART is started
– Identification of resistance mutations may optimize treatment outcomes
– Resistance testing (genotype) recommended for all at entry to care
– Recommended for all pregnant women
• Patients with virologic failure:– Perform while patient is taking ART, or ≤4 weeks after
discontinuing therapy– Interpret in combination with history of ARV exposure
and ARV adherence
Coffey S. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents: Initiation of Therapy [PowerPoint]. AIDS Education and Training Centers, National Resource Center; March 2012. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-6. Accessed Sept 03, 2012.
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Drug Resistance Testing: RecommendationsRECOMMENDED COMMENT
Acute HIV infection, regardless of whether treatment is to be started
To determine if resistant virus was transmitted; guide treatment decisions.If treatment is deferred, consider repeat testing at time of ART initiation.Genotype preferred.
Chronic HIV infection, at entry into care
Transmitted drug-resistant virus is common in some areas; is more likely to be detected earlier in the course of HIV infection.If treatment is deferred, consider repeat testing at time of ART initiation.Genotype preferred to phenotype.Consider integrase genotypic resistance assay if integrase inhibitor resistance is a concern.
Coffey S. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents: Initiation of Therapy [PowerPoint]. AIDS Education and Training Centers, National Resource Center; March 2012. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-6. Accessed Sept 03, 2012.
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RECOMMENDED COMMENT
Virologic failure during ART
To assist in selecting active drugs for a new regimen. Genotype preferred if patient on 1st or 2nd regimen; add phenotype if known or suspected complex drug resistance pattern.If virologic failure on integrase inhibitor or fusion inhibitor, consider specific genotypic testing for resistance to these to determine whether to continue them.(Coreceptor tropism assay if considering use of CCR5 antagonist; consider if virologic failure on CCR5 antagonist.)
Suboptimal suppression of viral load after starting ART
To assist in selecting active drugs for a new regimen.
Drug Resistance Testing: Recommendations(2)
Coffey S. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents: Initiation of Therapy [PowerPoint]. AIDS Education and Training Centers, National Resource Center; March 2012. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-6. Accessed Sept 03, 2012.
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RECOMMENDED COMMENT
Pregnancy Recommended before initiation of ART or prophylaxis. Recommended for all on ART with detectable HIV RNA levels.Genotype usually preferred; add phenotype if complex drug resistance mutation pattern.
Drug Resistance Testing: Recommendations(3)
Coffey S. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents: Initiation of Therapy [PowerPoint]. AIDS Education and Training Centers, National Resource Center; March 2012. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-6. Accessed Sept 03, 2012.
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Drug Resistance Testing: Recommendations(4)
NOT USUALLY RECOMMENDED
COMMENT
After discontinuation(>4 weeks) of ARVs
Resistance mutations may become minor species in the absence of selective drug pressure
Plasma HIV RNA <500 copies/mL
Resistance assays cannot consistently be performed if HIV RNA is low
Coffey S. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents: Initiation of Therapy [PowerPoint]. AIDS Education and Training Centers, National Resource Center; March 2012. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-6. Accessed Sept 03, 2012.
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AVAILABLE RESISTANCE TEST
http://www.tumblr.com/tagged/genotype Accessed 06/OCT/12
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Genotypic and Phenotypic Resistance Tests
Translation into linear string of amino acids
Folding into functional protein
HIV RNA
Phenotypic assays test this
Genotypic assays test this
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Available Tests
• NRTI, NNRTI AND PI– GENOTYPE– Virtual Phenotype– PHENOTYPE
• ENTRY INHIBITORS– PHENOTYPE
• INTEGRASE INHIBITORS– GENOTYPE– PHENOTYPE
• Co-Receptor Tropism Assay– RNA– DNA
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General Limitations of Resistance Testing
• Lack of uniform quality controls across different laboratories
• High cost compared with other tests routinely done in HIV care
• Cannot be reliably performed with HIV RNA < 500-1000 copies/mL
• May not be able to detect minority populations of resistant virus if they account for < 20% of the sample—especially common after drug discontinuation
• Resistant strains that are in viral reservoirs also not detected
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Reversion to Predominant Wild-Type Virus After Discontinuing ART
Behrens C, Kindrick A, Harrington R. Antiretroviral Resistance Testing in the Management of HIV-Infected Patients [PowerPoint]. Northwest AIDS Education and Training Center; July 2006. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-9. Accessed SEP 3, 2012.Illustration by David Spach, MD
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GENOTYPE
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Advantages and Disadvantages of Genotype Testing
Advantages• Rapid turnaround
(1-2 wks)• Less expensive than
phenotyping• Detection of mutations
may precede phenotypic resistance
• Widely available• More sensitive than
phenotype for detecting mixtures of resistant and wild-type virus
Disadvantages• Indirect measure of
resistance• Relevance of some
mutations unclear• Unable to detect minority
variants (< 20% to 25% of viral sample)
• Complex mutational patterns may be difficult to interpret
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Genotype Report
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The Virtual Phenotype
Genotype
ProteaseRTHIV
Access Data
Genotype & Phenotype Data
Virtual PhenotypeWild-type HIV
Resistant HIV
Behrens C, Kindrick A, Harrington R. Antiretroviral Resistance Testing in the Management of HIV-Infected Patients [PowerPoint]. Northwest AIDS Education and Training Center; July 2006. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-9. Accessed SEP 3, 2012.Illustration by David Spach, MD
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Advantages and Disadvantages of “Virtual” Phenotype Testing
Advantages
• Similar advantages to genotype
(turnaround time, cost, sensitivity)
• Defines resistance based on
database of in vivo responses in
treated patients
• Uses 2 clinical cutoffs (CCO) to
define spectrum of resistance– CCO1: value below which
response expected to be
comparable to wild type– CCO2: value above which most
virologic response would be
lost
• Indicates which drugs have partial
activity
Disadvantages
• Is an estimated phenotype based
on the patient’s genotype, not an
actual measured phenotype
• Reliability will depend on the
accuracy of the genotype
• Available only from 1 vendor
• More expensive than genotype
alone
• Methodology of linking genotype
to phenotypic database not
intuitively obvious—uses a
proprietary “virtual phenotype
linear regression
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PHENOTYPE
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Drug Susceptibility Testing
• Involves culturing a fixed inoculum of HIV-1 in the presence of serial dilutions of an inhibitory drug. – The concentrations of drug required to inhibit
virus replication by 50% (IC50) or 90% (IC90)
• Drug susceptibility results depend on: – inoculum size of virus tested– cells used for virus replication– the means of assessing virus replication.
https://www.23andme.com/health/Resistance-to-HIV-AIDS/ Accessed 06/OCT/12
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Advantages and Disadvantages of Phenotype Testing
Advantages:
• Provides direct and quantitative measure of
resistance
• Methodology can be applied to any
antiretroviral agent, including new drugs,
for which genotypic correlates of resistance
are unclear
• Uses 2 clinical cutoffs (CCO) derived from
clinical cohorts to define spectrum of
resistance– CCO1: value below which reduced
virologic response is likely– CCO2: value above which a virologic
response is unlikely
• Indicates which drugs have partial activity
• Can assess interactions among mutations
• Accurate with non-B HIV subtypes
Disadvantages:
• Susceptibility cutoffs not
standardized between assays
• Clinical cutoffs not defined for
some agents
• May be unable to detect
minority variants for some
mutations (< 20% to 25% of
viral sample)
• Complex technology with
longer turnaround (~ 3 wks)
• More expensive than
genotyping
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Integrase Phenotype• Phenotypic integrase resistance assay is commercially available
– Amplification threshold: HIV-1 RNA > 500 copies/mL – Biological cutoff for raltegravir is fold change (FC) > 1.5– Clinical cutoff not yet determined– Report does not detail genotypic mutations
• High assay accuracy demonstrated by IC50 fold change values reported for site-directed mutants
Fransen S, et al. ICAAC/IDSA 2008. Abstract 1214. Accessed SEP 3, 2012 http://www.clinicaloptions.com/HIV/Conference%20Coverage/Washington%202008/Tracks/Experienced/Capsules/1214.aspx
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TROPISMS TEST
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Typical HIV Co-ReceptorUsage Patterns
R5 VirusesUse only the CCR5 co-receptorMost prevalent in early diseasePredominate throughout infection
X4 VirusesUse only the CXCR4 co-receptorEmerge in later diseaseAssociated with accelerated CD4+ cell decline and disease progression
Dual-Tropic Viruses Use either the CCR5 or theCXCR4 co-receptor
Mixed-TropicVirus Population
Tsibris AMN, Kuritzkes DR. Annu Rev Med. 2007;58:445-459.
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Light generated CCR5 UseR5 Virus
No light generatedNo CXCR4 Use
Not an X4 Virus
Demonstration of R5 virus
CCR5 CXCR4
Virus
Virus
Virus
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Light is generated on both CCR5 and CXCR4 cell lines
This is a DUAL virus
Demonstration of dual virus
CCR5CXCR4
Virus Virus
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This population shows CCR5 AND CXCR4 co-receptor use
This is a mixed population
Demonstration of mixed virus population
CCR5 CXCR4
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Virologic Failure With Resistance
Resistant Virus
Vira
l Loa
d
Time on Antiviral Therapy
Virologic failure is defined as the inability of ARV regimen to achieve virologic suppression or occurrence of virologic rebound1
A confirmed viral load >200 copies/mL can be considered virologic failure2
1. AIDSinfo. Glossary of HIV/AIDS-related terms. 7th ed. 2011. Available at http://www.aidsinfo.nih.gov/ContentFiles/GlossaryHIVrelatedTerms.pdf. Accessed November 18, 2011
2. DHHS Guidelines. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed November 18, 2011.3. Clavel F et al. N Engl J Med. 2004;350:1023-1035.
Based on Clavel et al.3
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CASE PRESENTATION
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The follow factors leads to developing drug-resistance EXCEPT…?
A. Poor drug absorption
B. Poor adherence
C. High drug levels
D. Pre-existing resistance
E. Interactions with other drugs, supplements or recreational drugs
A. B. C. D. E.
0% 2%
11%9%
78%
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Case 1: 42 y/o AA female
• Dx in 2006• Current Medical Hx
– Diabetes– Hyperlipidemia– Hypertension
• Baseline Labs (1/06)– VL: 230,000– CD4: 320 cells/mm3
• Baseline Genotype– Wild-Type
• Pt request a once a day pill ARV and start 5/06 on EFV/TDF/ETC FDC
• Viral Load quickly becomes undetectable and CD4+ counts raises over time
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Case 1: 42 y/o AA female
Date VL CD4
11/06 <400 400
05/07 <50 480
05/08 <50 600
05/09 <50 680
11/09 30,000 600
• Patient experiences virologic failure on Nov 2009 while taking EVF/TDF/FTC
• Pt. reports occasional poor adherence due to occasional sleep disturbances and concerns about lipid problems
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Case 1: 42 y/o AA femaleWhat would be your next step?
A. Enforce patient adherence and continue with same regimen.
B. Perform Genotype test and keep patient on the same regiment until genotype results.
C. Perform a tropism and Phenotype test and remove patient from medicines because there are toxic.
D. Change patient regiment without any resistance test performed.
A. B. C. D.
11%
0%7%
82%
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Case 1: 42 y/o AA femaleWith this genotype result, is Efavirenz still available?
85%
15% A. Yes
B. No
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Case 1: 42 y/o AA female
• January 2010 patient was place on EPZ/ATV• Labs 04/10
– CD4: 700 cells/mm3
– VL: <50 copies
• Pt. continue with non-detectable (ND) viral load until 04/12– CD4 800 cells/mm3
– VL: 15,000 copies
• Resistance testing result.– NRTI’s: M184V– NNTRI’s: K103N– PI’s: I50L
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Based on new resistance pattern (NRTI’s: M184V NNTRI’s: K103N; PI’s: I50L) which statement is true?
A. All NNRT’s are available to use
B. Atazanavir still available for use
C. 3Tc is a full active drug
D. Patient loss susceptibility to rilpivirine
E. Keeping patient on efavirenz will increase the amount of NNRTI mutations and reduce the susceptibility to all other NRTI’s
A. B. C. D. E.
10%
21%
38%
18%
13%
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Case 2
• A 45 year-old man who is highly treatment-experienced with antiretroviral therapy has virologic failure on tenofovir/emtricitabine and lopinavir/ritonavir.
• His enhanced Trofile assay reveals a dual/mixed-tropic virus.
• His current genotype reveals reverse transcriptase mutations M41l, V90I, K103N, M184V, L210W, T215Y and protease inhibitors mutations V32I, I47V, I54A, V82L, I84V, and L90M.
• In addition, a 2006 genotype also reveled the envelope glycoprotein 41 mutation G36D.
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The next BEST antiretroviral regimen for this patient would include which of the following?
A. Enfuvirtide
B. Maraviroc
C. Etravirine
D. Ritonavir-boosted darunavir
E. Ritonavir-boosted tipranavir
A. B. C. D. E.
0%
20%
6%
57%
17%
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Bonus Case
• A 21 years-old man who acquired HIV through vertical transmission presents for routine care.
• Recent genotypic analysis reveals a 69 insertion complex and K103N reverse transcriptase mutations and L10I, K20M, M46I, G48V, I50V, N88S and L90M protease mutations.
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Which regimen would be the BEST for him?
A. Raltegravir, etravirine, and atazanavir/ritonavir
B. Raltegravir, etravirine, and darunavir/ritonavir
C. Raltegravir, etravirine, and fosamprenavir/ritonavir
D. Raltegravir, etravirine, and indinavir/ritonavir
E. Raltegravir, etravirine, and maraviroc
A. B. C. D. E.
0%
28%
50%
3%
19%
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Reference• http://hivdb.stanford.edu/• http://www.hivresistanceweb.com/index.shtml• https://www.iasusa.org/content/hiv-drug-resistance-mutations• Behrens C, Kindrick A, Harrington R. Antiretroviral Resistance
Testing in the Management of HIV-Infected Patients [PowerPoint]. Northwest AIDS Education and Training Center; July 2006. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-9. Accessed Sept 03, 2012.
• Coffey S. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents: Initiation of Therapy [PowerPoint]. AIDS Education and Training Centers, National Resource Center; March 2012. Available at http://aidsetc.org/aidsetc?page=etres-display&resource=etres-6. Accessed Sept 03, 2012.
• http://www.targethiv.org/library/hiv-resistance-intersection-between-treatment-and-prevention. Accessed Sept 03, 2012