10/24/2012

Resistance Testing
Where Do I Start?
Ivn Melndez-Rivera, MD
Fellow, 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

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.

10/24/2012

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

Definition of Antiviral Drugs 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.

10/24/2012

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.

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

0%
A.

0%
B.

10/24/2012

When does resistance occur?

Resistance occurs when the virus has an
opportunity to replicate in the presence of subinhibitory 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

Selective Pressures of Therapy

Drugsusceptiblequasispecies
Drugresistantquasispecies

Viralload

Treatmentbegins

Selectionofresistant
quasispecies
Incompletesuppression
Inadequatepotency
Inadequatedruglevels
Inadequateadherence
Preexistingresistance

Time

10/24/2012

What is viral resistance?

A continuum of reduced susceptibility of
HIV to the inhibitory effects of drugs

More Susceptible

MoreResistant

Theterms"drugresistance"and"reduceddrugsusceptibility"havesimilarmeanings,providedthateachtermisviewedas
representingacontinuumbetweensusceptibleandhighlyresistant.
Becauseantiretroviraldrugsdifferintheirpotencies,reductionsinsusceptibilitymustberelatedtotheactivityofthedrugagainst
wildtypeviruses.

Why is it important to measure drug

resistance?
WILD VIRUS VS MUTANT VIRUS

10/24/2012

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

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)

10/24/2012

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

What is the Impact of HIV Mutations?

Tothevirus,mutationscanbe:

Decreasingthevirusability
tosurviveand/orreplicate
(viralfitness)ormaymake
thevirushypersusceptible
tocertainantiretrovirals
(ARVs)

Noeffecton
virusfunction

Changingthestructureofthe
virustoevadeantiretroviral
treatment.Thesemutations
mayormaynotaffectviral
fitness

JohnsonVA,etal.TopicsinHIVMedicine.2009;17:138145.

10/24/2012

Single-base Mutations May Confer

Antiretroviral Resistance
3nucleotidesspecifyanaminoacid
HIVRNAwild
type
Singlebasemutation
Drugresistant

HIVRNA
mutant

123

Wildtype
PositionAA:
AA:X
123

Mutant

AA:Y
AA=aminoacid
HoffmanCetal.HIVMedicine2007.15thed.Paris,France:FlyingPublisher.
2007.

Resistance Profile and Potential for Cross Resistance

RegionofHIVRNAassociatedwithantiretroviraldrugclassspecificresistance

HIVRNA
Mutant
DrugA
DrugB
DrugC
Bcrossresistance

DrugD
A&B&Ccrossresistance

Adaptedfrom:Paredes R,etal.AntiviralRes.2010Jan;85(1):24565.

10/24/2012

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

RESISTANCE MUTATIONS PER HIV

CLASS THERAPY

10/24/2012

Available Antiretroviral Agents

NucleosideReverse
Transcriptase
Inhibitors(RTIs)
Zidovudine(ZDV)
Didanosine (ddI)
Zalcitabine (ddC)
Stavudine(d4T)
Lamivudine(3TC)
Abacavir(ABC)
Emtricitabine(FTC)
TenofovirDF(TDF)

Nonnucleos(t)ideRTIs

ProteaseInhibitors

Nevirapine(NVP)
Delavirdine (DLV)
Efavirenz(EFV)
Etravirine(ETR)
Rilpivirine(RPV)

Saquinavir(SQV)
Ritonavir(RTV)
Indinavir (IDV)
Nelfinavir (NFV)
Amprenavir (APV)
Lopinavir/r(LPV/r)
Atazanavir (ATV)
Fosamprenavir(FosAPV)
Tipranavir(TPV)
Darunavir(DRV)

IntegraseInhibitors
Raltegravir(RAL)
Elvitegravir(ELV)*
Dolutegravir(DTG)*

Boosters
Ritonavir(RTV)

FusionInhibitor
Enfuvirtide (T20)

Cobicistat (cobi)

CCR5Antagonist

* In expanded access

Maraviroc (MVC)

August 28, 2012

Nucleoside Reverse Transcriptase Inhibitors

(NRTIs)

Zidovudine (ZDV)
Didanosine (ddI)
Stavudine (d4T)
Lamivudine (3TC)
Abacavir (ABC)
Tenofovir (TDF)
Emtricitabine (FTC)
StructureofacovalentlytrappedcatalyticcomplexofHIV1RTpublishedbyHuangHet
al,Science1998.http://hivdb.stanford.edu/pages/3DStructures/rt.htmlAccessedSept
3,2012

10

10/24/2012

NRTIs Resistance Mutations

Red:PrimaryMutationstoconferresistance Gray:SecondaryMutations
***:Increasesusceptibility
Adaptedfrom:http://hivdb.stanford.edu/DR/NRTIResiNote.html.AccessedSept3,2012

NRTIs Signature Mutations

Mutation

Medicationwithdecrease susceptibility

M184V
K65R
L74V
Y215F
T69insor
Q151M

Lamivudine(3TC) andEmtricitabine(FTC)
Tenofovir(TDF)
Abacavir(ABC)andDidanosine (ddI)
Zidovudine(ZDV) andStavudine(d4T)
Allexcept,Lamivudine(3TC)andEmtricitabine
(FTC)

11

10/24/2012

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/cgibin/rules_comments_hivdb.cgi?class=NRTI

Non-Nucleoside Reverse Transcriptase

Inhibitors (NNRTIs)

Nevirapine (NVP)
Efavirenz (EFV)
Etravirine (ETR)
Rilpivirine (RPV)

NonnucleosideRTinhibitor(NNRTI)resistancemutations
http://hivdb.stanford.edu/pages/3DStructures/rt.htmlAccessedSept3,2012

12

10/24/2012

NRTIs Resistance Mutations

Red:HighestLevelsofresistanceGray:Intermediatelevelofresistance

Adaptedfrom:http://hivdb.stanford.edu/DR/NRTIResiNote.html.AccessedSept3,2012

NNRTIs Signature Mutations

Mutation

Medicationwithdecrease susceptibility

K103N
Y181I/V
Y188L
K101P

Efavirenz(EFV)andNevirapine(NVP)
Etravirine(ETR)andRilpivirine (RPV)
Rilpivirine (RPV)
ALLNNRTI

13

10/24/2012

Protease Inhibitors (PIs)

Saquinavir (SQV)
Ritonavir (RTV)
Indinavir (IDV)
Nelfinavir (NFV)
Lopinavir/r (LPV/r)
Atazanavir (ATV)
Fosamprenavir (FPV)
Tipranavir (TPV)
Darunavir (DRV)

Majorproteaseinhibitor(PI)resistancemutations
http://hivdb.stanford.edu/pages/3DStructures/rt.html,AccessedSept3,2012

PIs Resistance Mutations

Red:HighestLevelsofresistanceGray:Intermediatelevelofresistance

Adaptedfrom:http://hivdb.stanford.edu/DR/NRTIResiNote.html.AccessedSept3,2012

14

10/24/2012

PIs Signature Mutations

Mutation

Medicationwithdecrease susceptibility

D30N
I50L
I47V
I54V
I84V

Nelfinavir (NFV)
Atazanavir(ATV)
ALLexceptSaquinavir (SQV)
ALLexceptDarunavir(DRV)
ALLexceptDarunavir(DRV)

Integrase Inhibitors (INI)

Raltegravir (RAL)
Elvitegravir(ELV)
Dolutegravir(DTG)*
*Investigational
http://www.scientistlive.com/EuropeanScience
News/Pharmacology/HIV_integrase_inhibitor_effective_when_beginnin
g_treatment/23101/ Accessed06/OCT/12

15

10/24/2012

INI Resistance Mutations

Red:HighestLevelsofresistanceGray:Intermediatelevelofresistance

Adaptedfrom:http://hivdb.stanford.edu/DR/NRTIResiNote.html.AccessedSept3,2012

INI Signature Mutations

Mutation

Medicationwithdecrease susceptibility

Q148H/K/R

Raltegravir(RAL)andElvitegravir(ELV)
*Inexpandedaccess

16

10/24/2012

Fusion Inhibitors (FI)

Enfuvirtide (T-20)

www.fuzeon.com AccessedSept3,2012

Fusion Inhibitor Resistance Mutations

Gray:Intermediatelevelofresistance

Adaptedfrom:http://hivdb.stanford.edu/DR/NRTIResiNote.html.AccessedSept3,2012

17

10/24/2012

CCR5 Antagonist
Maraviroc (MVC)

MooreJ,etal.Proc Natl Acad Sci USA.2003;100:1059810602;YostR,

etal.AmJHealthSyst Pharm.2009;66:715726AccessedSept3,2012

CCR5 Antagonist Resistance is Associated with

Amino Acid Changes in the V3 Loop of gp120*
G/A

Variable pattern of Maraviroc

resistance-associated amino
acid substitutions

Tip

Tip

No signature mutations have

been identified

Currently, there is no assay

available to assess Maraviroc

resistance

Stem

Stem

Base

Base

*Substitutions outside the V3 loop of gp120 may also

contribute to reduced susceptibility to Maraviroc

Change
Insertion

Maraviroc-resistant

Deletion
Adapted from Data on file. ViiV Healthcare, RTP, NC.

18

10/24/2012

CCR5-Resistant Virus Recognizes DrugBound Receptors

MVCresVirus
MVCres

gp120

Mutatedgp120
recognizesCCR5
differently

Bindingsite
NOT disrupted
bymaraviroc
MoriJ,etal.16th IHIVDRW.Barbados,2007.
Abstract10.

Entry

RECOMMENDATIONS FOR DRUG

RESISTANCE TESTING

19

10/24/2012

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)

0%

0%

A.

B.

0%
C.

0%
D.

Trends of Phenotypic 1-, 2-, and 3-Class

Resistance
2ClassResistance
60
50

PIandNRTI
PIandNNRTI
NRTIandNNRTI

3ClassResistance
60
50

40

40

30

30

30

20

20

20

10

10

10

2003
2004
2005
2006
2007
2008
2009
2010

40

2003
2004
2005
2006
2007
2008
2009
2010

ResistantSamples(%)

50

PI
NNRTI
NRTI

2003
2004
2005
2006
2007
2008
2009
2010

1ClassResistance
60

NNRTI=non-nucleoside reverse transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor;

PI=protease inhibitor.

AdaptedfromPaquet Aetal.51stInterscience ConferenceonAntimicrobialAgentsandChemotherapy;

September1720,2011;Chicago,Illinois.AbstractH2800.

20

10/24/2012

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
CoffeyS.GuidelinesfortheUseofAntiretroviralAgentsinAdultsandAdolescents:InitiationofTherapy[PowerPoint].AIDS
EducationandTrainingCenters,NationalResourceCenter;March2012.Availableathttp://aidsetc.org/aidsetc?page=etres
display&resource=etres6.AccessedSept03,2012.

Drug Resistance Testing: Recommendations

RECOMMENDED

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.

CoffeyS.GuidelinesfortheUseofAntiretroviralAgentsinAdultsandAdolescents:InitiationofTherapy[PowerPoint].AIDS Educationand
TrainingCenters,NationalResourceCenter;March2012.Availableathttp://aidsetc.org/aidsetc?page=etresdisplay&resource=etres6.
AccessedSept03,2012.

21

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Drug Resistance Testing: Recommendations(2)

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.

CoffeyS.GuidelinesfortheUseofAntiretroviralAgentsinAdultsandAdolescents:InitiationofTherapy[PowerPoint].AIDS Educationand
TrainingCenters,NationalResourceCenter;March2012.Availableathttp://aidsetc.org/aidsetc?page=etresdisplay&resource=etres6.
AccessedSept03,2012.

Drug Resistance Testing: Recommendations(3)

RECOMMENDED
Pregnancy

COMMENT
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.

CoffeyS.GuidelinesfortheUseofAntiretroviralAgentsinAdultsandAdolescents:InitiationofTherapy[PowerPoint].AIDS Educationand
TrainingCenters,NationalResourceCenter;March2012.Availableathttp://aidsetc.org/aidsetc?page=etresdisplay&resource=etres6.
AccessedSept03,2012.

22

10/24/2012

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

CoffeyS.GuidelinesfortheUseofAntiretroviralAgentsinAdultsandAdolescents:InitiationofTherapy[PowerPoint].AIDS Educationand
TrainingCenters,NationalResourceCenter;March2012.Availableathttp://aidsetc.org/aidsetc?page=etresdisplay&resource=etres6.
AccessedSept03,2012.

AVAILABLE
RESISTANCE
TEST

http://www.tumblr.com/tagged/genotype Accessed06/OCT/12

23

10/24/2012

Genotypic and Phenotypic Resistance Tests

HIVRNA
Translationintolinearstringofaminoacids

Foldingintofunctionalprotein
Genotypicassays
testthis

Phenotypic
assaystestthis

Available Tests
NRTI, NNRTI AND PI
GENOTYPE
Virtual Phenotype
PHENOTYPE

ENTRY INHIBITORS
PHENOTYPE

INTEGRASE INHIBITORS
GENOTYPE
PHENOTYPE

Co-Receptor Tropism Assay

RNA
DNA

24

10/24/2012

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 sampleespecially common after drug
discontinuation
Resistant strains that are in viral reservoirs
also not detected

Reversion to Predominant Wild-Type Virus After

Discontinuing ART

BehrensC,Kindrick A,HarringtonR.AntiretroviralResistanceTestingintheManagementofHIVInfectedPatients[PowerPoint].
NorthwestAIDSEducationandTrainingCenter;July2006.Availableathttp://aidsetc.org/aidsetc?page=etresdisplay&resource=etres9.AccessedSEP3,2012.
IllustrationbyDavidSpach,MD

25

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GENOTYPE

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

26

10/24/2012

Genotype Report

The Virtual Phenotype

Genotype

HIV

Access Data

RT Protease

Virtual Phenotype

Genotype & Phenotype

Data

Wild-type HIV
Resistant HIV

BehrensC,Kindrick A,HarringtonR.AntiretroviralResistanceTestingintheManagementofHIVInfectedPatients[PowerPoint].
NorthwestAIDSEducationandTrainingCenter;July2006.Availableathttp://aidsetc.org/aidsetc?page=etresdisplay&resource=etres9.AccessedSEP3,2012.
IllustrationbyDavidSpach,MD

27

10/24/2012

Advantages and Disadvantages of Virtual Phenotype Testing

Advantages

Disadvantages

Similar advantages to genotype

(turnaround time, cost, sensitivity)

Defines resistance based on

database of in vivo responses in
treated patients

Is an estimated phenotype based

on the patients 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
obvioususes a proprietary virtual
phenotype linear regression

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

PHENOTYPE

28

10/24/2012

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/ResistancetoHIVAIDS/ Accessed06/OCT/12

Advantages and Disadvantages of Phenotype Testing

Advantages:

Disadvantages:

Provides direct and quantitative

measure of resistance

Susceptibility cutoffs not standardized

between assays

Methodology can be applied to any

antiretroviral agent, including new drugs,
for which genotypic correlates of
resistance are unclear

Clinical cutoffs not defined for some

agents

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

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

Indicates which drugs have partial

activity

Can assess interactions among

mutations

Accurate with non-B HIV subtypes

29

10/24/2012

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,etal.ICAAC/IDSA2008.Abstract1214.AccessedSEP3,2012
http://www.clinicaloptions.com/HIV/Conference%20Coverage/Washington%202008/Tracks/Experienced/Capsules/1214.aspx

TROPISMS TEST

30

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Typical HIV Co-Receptor

Usage Patterns
R5Viruses
UseonlytheCCR5coreceptor
Mostprevalentinearlydisease
Predominatethroughoutinfection

X4Viruses
UseonlytheCXCR4coreceptor
Emergeinlaterdisease
AssociatedwithacceleratedCD4+celldecline
anddiseaseprogression

DualTropicViruses
UseeithertheCCR5orthe
CXCR4coreceptor

MixedTropic
VirusPopulation
Tsibris AMN,Kuritzkes DR.Annu Rev Med.2007;58:445459.

DemonstrationofR5virus

Lightgenerated
Virus
CCR5Use
R5Virus

Nolightgenerated
NoCXCR4Use
NotanX4Virus
Virus

Virus

CCR5

CXCR4

31

10/24/2012

Demonstrationofdualvirus
LightisgeneratedonbothCCR5andCXCR4celllines
ThisisaDUALvirus
Virus

CCR5

Virus

CXCR4

32

10/24/2012

Demonstrationofmixedviruspopulation

ThispopulationshowsCCR5ANDCXCR4coreceptoruse
Thisisamixedpopulation

CCR5

CXCR4

33

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Virologic Failure With Resistance

ViralLoad

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

Resistant Virus

TimeonAntiviralTherapy
BasedonClaveletal.3
1. AIDSinfo.GlossaryofHIV/AIDSrelatedterms.7thed.2011.Availableathttp://www.aidsinfo.nih.gov/ContentFiles/GlossaryHIVrelatedTerms.pdf.
AccessedNovember18,2011
2. DHHSGuidelines.http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.AccessedNovember18,2011.
3. ClavelFetal.NEnglJMed.2004;350:10231035.

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CASE PRESENTATION

The follow factors leads to developing drugresistance EXCEPT?

A.
B.
C.
D.

Poor drug absorption

Poor adherence
High drug levels
Pre-existing
resistance
E. Interactions with
other drugs,
supplements or
recreational drugs

0%
A.

0%

0%

B.

C.

0%

0%

D.

E.

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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

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

Wild-Type

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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10/24/2012

Case 1: 42 y/o AA female

What 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.

0%
A.

0%
B.

0%
C.

0%
D.

Case 1: 42 y/o AA female

With this genotype result, is Efavirenz still available?

0%
0%

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.

NRTIs: M184V
NNTRIs: K103N
PIs: I50L

Based on new resistance pattern (NRTIs: M184V

NNTRIs: K103N; PIs: I50L) which statement is true?
A. All NNRTs 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 NRTIs

0%
A.

0%

0%

B.

C.

0%

0%

D.

E.

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Case 2
A 45 year-old man who is highly treatmentexperienced with antiretroviral therapy has virologic
failure on tenofovir/emtricitabine and
lopinavir/ritonavir.
His enhanced Trofile assay reveals a dual/mixedtropic 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.

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
0%
A.

0%

0%

B.

C.

0%

0%

D.

E.

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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.

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

0%
A.

0%

0%

B.

C.

0%

0%

D.

E.

40

10/24/2012

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=etresdisplay&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=etresdisplay&resource=etres-6. Accessed Sept 03, 2012.
http://www.targethiv.org/library/hiv-resistance-intersectionbetween-treatment-and-prevention. Accessed Sept 03, 2012

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