HIV-1 Resistance - Implications For Clinicians

Joseph J. Eron Jr., MD

Professor of Medicine

University of North Carolina

Disclosures

Types of Resistance Tests

Genotype and Phenotype

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

Question: What is the significance of the RT mutation K103N?

Confers resistance to 3TC/FTC

Confers resistance to tenofovir

Confers resistance to efavirenz

All of the above

None of the above

Provider Knowledge of Specific Resistance Mutations

0

10

20

30

40

50

60

3TC:184VAny NNRTIAny ABC > 2 ABC

1 TAM> 2 TAMs

NFV:30 or 90Pan NRTI

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-

naïve 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

Question:Resistance testing should be obtained in which treatment naïve patients?

Only in HIV infected patients with acute infection

Individuals thought to have been infected within the last 2 years

All treatment naïve patients

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, 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 mutation

With baseline mutation

Borroto-Esoda et al. AIDS Res Hum Retroviruses 2007;23:988-95.

Mutation type:

Naïve 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.

Cum

ulat

ive

Rat

e of

Fai

lure

(%

)

Women Starting ART <6 Months Post Partum

Months Since the Start of ART

Women Starting ART ≥6 Months Post Partum

60

50

40

30

20

10

0Placebo

Single dose of NVP

Placebo

Single dose of NVP

0 6 12 18 24 30 36

Months Since the Start of ART

60

50

40

30

20

10

00 6 12 18 24 30 36

Resistance and Virologic Failure

Multiple Causes of Virologic Failure

Replication in the Presence of Antiretrovirals Results in Resistance

Resistant virus

Social/personal issues

Regimen issues

ToxicitiesPoor potency

Wrong dose

Host genetics

Poor absorption

Rapid clearance

Poor activation

Drug interactions

Insufficient drug level

Viral replication in the presence of drug

Resistant virus

Poor adherence

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

Management of Virologic Failure in Treatment Experienced Patients• Definition: detectable plasma HIV RNA on therapy

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

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

Are More ComplexDarunavir

10 codons; 11 substitutions

Tipranavir

16 codons; 21 substitutions

Etravirine

8 codons; 13 substitutions

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

New Agents in New Classes

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 CCR5 blocking entry– Activity only in patients with R5 virus

– Maraviroc and vicriviroc

Association Between Emergence of SI Virus and CD4+ Cell Count

• 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

Prevalence of Coreceptor Tropism

1. Demarest et al. ICAAC 2004. Abstract H-1136. 2. Brumme et al. J Infect Dis. 2005;192:466-474. 3. Moyle et al. J Infect Dis. 2005;191:866-872. 4. Melby et al. J Infect Dis. 2006;194:238-246. 5. Wilkin et al. Clin Infect Dis. 2007;44:591-595. 6. Nelson et al. CROI 2007. Abstract 104aLB. 7. Lalezari et al. CROI 2007. Abstract 104bLB.

Study Authors Population Sample (n) R5 Only Dual/Mixed X4 Only

Demarest et al[1] Naive 325 88% 12% 0%

HOMER[2] Naive 979 82% 18% 0.1%

Moyle et al[3] Naive 402 81% 19% NA

Demarest et al[1] Experienced 117 67% 28% 5.0%

Moyle et al[3] Experienced 125 78% 22% NA

Melby et al[4] Experienced 724 50% 48% 2.0%

Wilkin et al[5] Experienced 391 49% 47% 4.0%

Nelson, Lalezari et al[6,7]

Experienced 1076 56% 44%

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 currently in development appears likely

Question: In those patients who have experienced virologic failure on multiple regimens including NNRTI, NRTI and PI, which agent is most likely to be fully active?

Darunavir

Etravirine

Tipranavir

Integrase Inhibitors

CCR5 inhibitors

4 and 5