HIV-1 Resistance - Implications For Clinicians

HIV-1 Resistance - Implications For Clinicians

Joseph J. Eron Jr., MD

Professor of Medicine

University of North Carolina

Overview of Presentation

• HIV-1 resistance to ARV; a consequence of viral replication and HIV biology

• Suppression of HIV replication limits resistance

• Clinical indications for resistance testing– Genotype vs. phenotype

• Clinical Importance of transmitted resistance

• Multiple causes of virologic failure of ART

• Resistance testing is one key to successful therapy in the treatment experienced patient

• Novel agents – novel resistance

Resistance Is a Matter of DegreeHigh-level resistance Little or no virologic response

Low-level / intermediate resistance

Suboptimal virologic response

Susceptible No reduced drug susceptibility

Suppression of Replication Limits Resistance

Incidence of Resistance Decreasing with use of HAART

Types of Resistance Tests

• Genotype– HIV gene sequencing of the patient’s virus to detect

mutations known to confer drug resistance

• Phenotype– Measures ability of a recombinant virus derived from the

patient sample to grow in different concentrations of antiretroviral drugs

Hirsch et al. Clin Infect Dis. 2003;37:113-28.

Interpretation of Genotypic Assays

• Is an indirect measure of resistance– Requires knowledge of which mutation are associated with a

change in susceptibility

• Expert advice– May not be available– Experts’ views may be inconsistent

• Rules-based algorithms– Provided by most labs, third-party sites– Need regular updating

• Virtual Phenotype (VircoType)– Phenotypic information using genotype– Database of matched genotypes and phenotypes

Provider Knowledge of Specific Resistance Mutations

0

10

20

30

40

50

60

3TC:1

84V

Any N

NRTI

Any A

BC

> 2

ABC

1 TA

M

> 2

TAM

s

NFV:30

or 9

0

Pan N

RTI

Mutations

% P

rovi

ders

Rec

ogni

z ing

Spe

cific

Mut

atio

ns

Salama et al. Clin Infect Dis. 2003;36:101-4.

N = 100

Phenotypic SusceptibilityRelationship Between Drug Concentration and Viral Inhibition

Inhi

bitio

n of

Viru

s R

eplic

atio

n (%

)

50

0

100

Fold resistance

Wild-type IC50 Resistant IC50

Wild-typeResistant

Drug Concentration

Interpretation of Phenotypic Assays• Results reported as IC50 or fold-change (FC)

compared with IC50 of wild-type virus

• Individual results provided for each drug

• Thresholds to define reduced susceptibility– Biologic cutoff: based on biologic variations in treatment-

naive patients (usually 2 SD > median)

– Clinical cutoff:• As good as clinical data used to estimate cut points• Resistance is a continuum – precise breakpoints unlikely• Two relevant breaks?

– Decreased response and

– Minimal response

Clinical Indications for Resistance Testing

Current Guidelines for Resistance Testing

1. DHHS. Guidelines. Oct 10, 2006.2. Hirsch et al. Clin Infect Dis. 2003;37:113-28. 3. Vandamme et al. Antivir Ther. 2004;9:829-48.

DHHS[1] IAS-USA[2] EuroGuidelines [3]

Primary Infection Recommend Recommend Recommend

PEP (Source Pt) — — Recommend

Chronic Recommend RecommendRecommend/

Consider

Treatment Failure Recommend Recommend Recommend

Pregnancy — Recommend * Recommend *

Pediatric — — Recommend **

* Only if mother is viremic** Only if mother was viremic and on treatment at time of birth

Transmitted ARV Resistance

Clinically Important in the Developed World

Surveillance Essential in the Developing World

How Common is Drug Resistance at Diagnosis?• US Variant, Atypical and Resistant HIV Surveillance System (VARHS)

– Estimate prevalence of transmitted resistant mutations– Determine distribution of HIV subtypes

• March 2003 to October 2006; 11 states, 409 sites, n=3130

10%

5%

Any NRTI NNRTI PI MDR

M41L 45.1% of NRTIK103N 70.1% of NNRTIL90M 40.0% of PI95% Subtype B

Wheeler et al. 14th CROI. Los Angeles, 2007. Abs 648

6.9%

3.6%

2.4% 1.9%

FTC-301A: Impact of Baseline Resistance on Treatment Outcome

0

20

40

60

80

100

Any NNRTI NRTI K103N Any NNRTI NRTI K103N

Without baseline mutationWith baseline mutation

Borroto-Esoda et al. 11th CROI, 2004. Abs 672.

Mutation type:

Naive pts, baseline VL > 5000 copies/mL

FTC + ddI + EFV(n=270)

d4T + ddI + EFV(n=276)

Inci

denc

e (%

) of

V

irolo

gic

Fai

lure

How Important Are Minority Variants?

Standard Genotype181C

103N

190A

108I

Antiretroviral Response Following sdNVP

Lockman et al. NEJM 2007;356:135-47.

Resistance and Virologic Failure

Multiple Causes of Virologic Failure

Replication in the Presence of Antiretrovirals Results in Resistance

Insufficient drug level

Resistant virus

Social/personal issuesRegimen issuesToxicities

Poor potency

Wrong dose

Host genetics

Poor absorption

Rapid clearance

Poor activation

Drug interactions

Poor adherence

Viral replication in the presence of drug

Resistant virus

Treatment-Experienced Patients: ARV Treatment Failure

ART resistance testing. National resource center. Available at: http://www.aidsetc.org/aidsetc?page=et-01-00. Accessed November 29, 2006.

Pre-existing resistance

Partiallyeffectiveregimen

Highly effectiveregimen

Adherence

Res

ista

nce

Impact of Suboptimal Adherence

Bangsberg et al. AIDS 2003;17:1925-32.

Resistance Testing in Treatment Experienced Patients• Detectable plasma HIV RNA on therapy

• First Question ‘Is it time to switch therapy?’– Obtain resistance testing

• The greater the resistance the more useful phenotype or virtual phenotype

– Assess clinical situation• Adherence• Previous treatment history – ARV tolerability and toxicity

• Balance clinical urgency with availability of active agents including new drugs and expanded access

• New agents – especially those in a new class are likely to have the most activity

With New Agents in Existing Classes (PI and NNRTI) Resistance Patterns

Are More ComplexDarunavir (DRV)

Tipranavir (TPV)

Etravirine (ETV)

New Agents in Existing Classes

• Mutations to older agents are likely to be present– Majority variants

– Minority variants

• Some degree of cross resistance can be anticipated– Cross resistance increases with the number and type of

mutations

• The activity of a new agent from a new class is likely to be more predictable even with state of the art resistance testing

TORO Studies - Enfuvirtide

9

32

44 4652

08

19 20 19

0

20

40

60

80

100

0 1 2 3 4Baseline 'Active' Drugs in OB

% N

on-S

TI

Pat

ient

s w

ith V

L <

400

copi

es/m

L at

Wee

k 48

ENF + OB (n=541) OB (n=286)

Miralles et al. AIDS 2005;19:2178-9.Lalezari et al. NEJM 2003;348:2185-85.Lazzarin et al. NEJM 2003;348:2186-95.

DC+Switch=Failure *p<0.05

*

**

* *

ENF+OB: 98 179 152 83 27 OB: 49 88 84 46 16


9

32

44 4652

08

19 20 19

0

20

40

60

80

100


% N

on-S

TI

Pat

ient

s w

ith V

L <

400

copi

es/m

L at

Wee

k 48

ENF + OB (n=541) OB (n=286)



*

**

* *

ENF+OB: 98 179 152 83 27 OB: 49 88 84 46 16


9

32

44 4652

08

19 20 19

0

20

40

60

80

100


% N

on-S

TI

Pat

ient

s w

ith V

L <

400

copi

es/m

L at

Wee

k 48

ENF + OB (n=541) OB (n=286)



*

**

* *

ENF+OB: 98 179 152 83 27 OB: 49 88 84 46 16

Resistance Defines an Active Antiretroviral Agent

CCR5 Inhibitors

Integrase Inhibitor

CCR5 Inhibitors

• HIV-1 entry into CD4 cells is dependent on a second receptor: CCR5 (R5 viruses) or CXCR4 (X4 viruses)

• Early in HIV disease course most individuals have only R5 virus detectable

• In more advanced disease and highly treatment experienced patients dual tropic virus or mixtures of R5 and X4 viruses are more common

• CCR5 Inhibitors bind to host receptor (CCR5) blocking entry– Maraviroc and vicriviroc

– Both have shown substantial activity in patients

Association Between Emergence of SI Virus and CD4+ Cell Count

• NSI virus predominates early in disease

• Dual/mixed virus detected in approximately 50% of patients over time

• CD4+ cell count decline accelerates following detection of SI in patients in whom NSI-only virus was previously detected

• Will emergence of X4 variants on R5 inhibitor therapy lead to CD4 cell decline?

-36

Mea

n (S

E)

CD

4+ C

ell C

ount

(c

ells

/mm

3 )

Koot et al. Ann Intern Med. 1993;118:681-688.

NSI

NSI → SI

800

600

400

200

-12-24 0 12 24 36

Time (Months)

0-48

SI

HIV-1 Resistance to CCR5 Antagonists• Two mechanisms

– Selection for (emergence of) viral variants that use CXCR4 (dual tropic viruses or mixed populations)• Occurs about 2/3 of the time• As yet NOT associated with rapid fall in CD4 cell count

– Alterations (mutations) in HIV gp 120• No Change in viral tropism• Allows virus to use CCR5 with inhibitor bound• Plateau in antiviral effect as opposed to change in IC50

– The drug is unable to fully inhibit virus regardless of concentrations achieved

Integrase Inhibitors

• Integrase mechanism has 3 steps– Association with dsHIV DNA – pre-integration complex

– 3’ processing by integrase enzyme

– Strand transfer of HIV DNA into host chromosome

• Potent inhibitors of stand transfer now in development– Raltegravir – Phase III studies recently presented

– Elvitegravir – Phase II studies

Integrase Inhibitor Resistance

• Primary mutations surround the catalytic site

• Raltegravir– Resistance emerged in 3/4 patients with virologic failure

who had genotype results

– Two major pathways with apparent primary mutations but one or more additional mutations• Likely compensatory for fitness

– Cross resistance between integrase inhibitors is not yet known

Summary

• Antiretroviral resistance is a consequence of HIV replication and defines an active antiretroviral

• Resistance Impacts all stages of antiretroviral treatment typically with increasing complexity with increasing antiretroviral treatment experience

• In treatment experienced patients resistance information guides regimen selection but also influences the timing of therapy switch

• New agents with new mechanisms present challenges for the identification, quantification and clinical impact of resistance

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HIV-1 Resistance - Implications For Clinicians