HIV and the CNS in the Current HIV and the CNS, 2009 ... · February , 12, 2009: Recent Advances in...

RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology

HIV and the CNS in the Current Treatment Era, 2009

Selected Issues


HIV and the CNS, 2009: Outline

Topics• Continued Opportunistic Disease: PML• Advances in Antiretroviral Therapy (ART)• HIV-Related Brain Disease: Then, Now and in

the FutureBackground Theme• Evolving Diseases and Pathogenetic Concepts


Introduction: Pathogenesis of HIV Diseases

HIVReplication

CD4+ cellloss

CNS HIVInfection

ImmuneActivation

Gut HIVInfection

microbialtranslocation

Spectrum of Diseases


HIV and the CNS, 2009

Topics• Continued Opportunistic Disease: PML

� Epidemiology� Pathogenesis� Clinical Presentation and Diagnosis� Current Treatment� PML IRIS� Prospects for New Treatments

• Advances in Antiretroviral Therapy (ART)• HIV-Related Brain Disease: Then, Now and in

the FutureBackground Theme• Evolving Concepts of HIV Disease Pathogenesis


1994

1995

1996

1997

1998

1999

2000

2001

0.1

1

10

100

CNS DiseaseNon-CNS Disease

Year

Inci

denc

e/10

0 pa

tient

yrs

Impact of ART on CNS Diseases


PML in Current Era

• Decreased incidence• But less decrease than

other CNS OIs • Can develop in patients

with relatively high CD4 counts

• No specific propylaxis• Associated with

immune reconstitution inflammatory syndrome (IRIS)

1994

1995

1996

1997

1998

1999

2000

2001

0.01

0.1

1

10

ADC

PCNSLFocal

ToxoCrypt

PML

Year

Inci

denc

e/10

0 pa

tient

yrs


PML: Pathogenesis

• Etiology: JC Virus� Ubiquitous, ‘innocent’ persistent infection� Opportunistic demyelinating CNS infection

• Pathology� Lytic oligodendroglial infection� Swollen, intranuclear inclusions� Centrifugal loss of myelin

� Bizarre astrocytes� Sparing of neurons� Exception: cerebellar granule cells

� Absence of inflammation (classical PML)• Multiple Steps in Disease Pathogenesis


“bizarre” astrocte

“Demyelinating” PML

Infected oligodendrocyte (ISH)

“Early” PML

PML: Lytic Oligo Infection


PML: Demyelinating Infection

• Demyelination

• JCV-infected oligodendrocytes

• Bizarre astrocytes

• Lipid-laden macrophages


JCV & PML:Steps in

Pathogenesis

Acute JCVInfection

JCVExposurePrimary JCV

Infection

Anti-JCVimmunityAnti-JCVimmunity

Chronic JCVInfectionChronic JCV

Carrier State

Acute JCVInfection


Infection

BBBBreach: CNS

SeedingDevelopment/Progression

ofPML

HIVInfection

Anti-JCVimmunity


Carrier State

CNS JCVReplicaton

Acute JCVInfection


Infection

BBBBreach: CNS


ofPML

HIVInfection

Anti-JCVimmunity


Carrier State

cART

CNS JCVSuppression

TreatedPML

CNS JCVReplicaton

Acute JCVInfection


Infection

CNS PMLInflammatory

BBBBreach: CNS


ofPML

HIVInfection

Anti-JCVimmunity


Carrier State

cART

CNS JCVSuppression

TreatedPML

CNS JCVReplicaton

Acute JCVInfection


Infection

JCVActivators

CNS PMLInflammatory

BBBBreach: CNS


ofPML

HIVInfection

Anti-JCVimmunity


Carrier State

cART

CNS JCVSuppression

TreatedPML

CNS JCVReplicaton

Acute JCVInfection


Infection


Diagnosis of PML

• Clinical diagnosis� Progressive focal neurological deficit(s)� Characteristic MRI� Background context

• Laboratory (confirmed) diagnosis� JCV DNA in CSF� Histological/virological


‘Classical’ PML: MRI


Sensitivity

10

20

30

40

100% 77%

82% 92%74%

72%

83%74%

Num

ber o

f cas

es

Moret1993

Gibson1993

Weber1994

McGuire1995

Fong1995

Cinque1996

Perrons1996

De Luca1996

SpecificityM S1 S1 S2 S2 C- C1 C2 C3 C4

50

100

150

200

100%

100%

100%

96%

99%

100%99%

Moret1993

Gibson1993

Weber1994

McGuire1995

Fong1995

Cinque1996

Perrons1996

De Luca1996

Num

ber o

f cas

es

CSF PCR detection of JCV DNA

1990:Qualitative PCR

92%

DNA amplification


PML: Treatment

• ART• Management of PML-IRIS• ‘Specific’ Treatments• Future Prospects


ART and Immune Effects in PML

• Established PML: ART treatment� Initiate� Change� Augment?• Therapeutic Effect:

� Immune restoration� Stabilization/remission in 50%

• Therapeutic Complications� IRIS


August 2005 October 2005 August 2006

JCV-DNA 10,792 c/mLCD4 495 (11%); VL 262,000 c/mL

JCV-DNA 335 c/mLCD4 619 (33%)VL 4198 c/mL

JCV-DNA ndCD4 1252 (45%)VL <50 c/mL

ART

JCV-DNA <100 c/mLCD4 804 (44%)VL <50 c/mL

March 2006

JCV-DNA Level in CSF in a Case with Favorable Outco mePML onset


Concept of Immune Reconstitution Inflammatory Syndrome (IRIS)

• Two types, in context of antiretroviral therapy (ART):

1. Paradoxical worsening of OI following ART2. Unmasking of OI after initiating ART• Usually within 3 months of starting ART• Associated with reduced plasma HIV and

rising blood CD4+ cells• Related to local inflammatory response

to OI pathogen, alive or dead


PML & IRIS

• Paradoxical worsening : deterioration of established PML with ART• Unmasking : appearance of PML after

starting ART• Diagnosis

� MRI: enhancement, edema, mass effect� Usually reduced CSF JCV

• Treatment � Corticosteroids


c.

Courtesy of Pilar Miralles

Paradoxical Worsening of PML after ART


5-Oct-07 31-Jan-0825-Oct-07 15-Nov-07

JCV DNA n.d.CD4 31 (3.8%); VL <50 c/mL

JCV-DNA <100 c/mLCD4 37 VL <50 c/mL

JCV-DNA 455 c/mLCD4 79VL <50 c/mL

JCV-DNA 2320 c/mLCD4 9VL 2930 c/mL

June ‘07

JCV-DNA Level in CSF in a Case of IRIS-PML

ARTHD IV

steroids


Pathogenesis of HIV Diseases

HIVReplication

CD4+ cellloss

CNS HIVInfection

ImmuneActivation

Gut HIVInfection


OI’s


PML-Specific Treatments

• History of failed prospects• Orphan disease: unlikely to attract major

corporate effort� Exception: PML mitigation program (Biogen

Idec)� Mefloquine Study


PML Treatment Experience

Drug Rationale for use Highest level of clinical evidence

Efficacy

Cytarabine (ARA-C)

Early reports of clinical benefit Antiviral activity: inhibits JCV replication in vitro

Clinical trial (i.v. ARA-C vs. i.t. ARA-C vs. no treatment) No benefit

Cidofovir (CDV)Antiviral activity: inhibits

replication of mouse polyomavirus and SV40 in vitro

Meta-analysis of retrospecitve clinical series (CDV + cART vs. cART alone) and pilot study (CDV + cART).

No benefit

Topotecan The analog camptothecin inhibits JCV replication in vitro

Prospective clinical series No benefit

a-Interferon Antiviral and immunomodulant activity

Retrospective clinical series Conflicting findings

b-InterferonAntiviral and immunomodulant

activity Anecdotes No benefit

Mirtazapine, risperidone

5HT2a antagonists: blocks JCV cell entry in vitro * Anecdotes Possible benefit

Interleukin-2 Reduces immune suppression Anecdotes Possible benefit


Mefloquine PML Study

• Biogen-sponsored trial• Standard treatment +/- mefloquine

� Inhibits JCV replication in culture system� Penetrates CNS� Favorable pharmacokinetics� Widespread use� Known toxicity profile

• Randomized trial


HIV and the CNS, 2009: Outline

Topics• Continued Opportunistic Disease: PML• Advances in Antiretroviral Therapy (ART)

� New Drugs and Strategies• HIV-Related Brain Disease: Then, Now and

in the FutureBackground Theme• Evolving Diseases and Pathogenetic

Concepts


Advances in Therapy: Treatment Approaches

• HIV is an acquired genetic disease� HIV genome self-replicating and integrated into hos t genome

• ART targets the products of this acquired genome to inhibit their functions or interfere with their int eractions with host molecules� Reduces viral burden� Inhibits effects of HIV� Does not eradicate infection

• ART� New targets

� Integrase� Chemokine receptor (CCR5)

� Old targets, new drugs� Differing resistance profiles� Different formulations and pharmacokinetics

• Adjunctive� IL-2


Current ART

• NRTIs� Zidovudine (ZDV)� Dideoxyinosine (ddI)� Dideoxycytidine (ddC)� Stavudine (d4T)� Lamivudine (3TC)� Abacavir (ABC)� Emtricitabine (FTC)� Tenofovir (TDF)

• PIs� Saquinavir (SQV)� Ritonavir (RTV)� Indinavir (IDV)� Nelfinavir (NFV)� Amprenavir (APV)� Lopinavir/Ritonavir

(LPV/r)� Atazanavir (ATV)� Fos-amprenavir (f-APV)� Tipranavir (TPV)� Darunavir (DRV)• NNRTIs

� Delavirdine (DLV)� Nevirapine (NVP)� Efavirenz (EFV)� Etravirine (ETV)

• Integrase Inhibitor� Raltegravir (RAL)

• Entry and Fusion Inhibitors� Maraviroc (MRV)� Enfuvirtide (ENF)


HIV Replication: Treatment Targets

From: RM Gulick, Topics in HIV Medicine, 10(4) 16, 2002

XX

X

X

X

ProteaseInhibitors X


ART Simplification:Fixed Dose Combinations

• Combivir� ZDV + 3TC (bid )

• Epzicom� ABC + 3TC (qd)

• Trizivir� ZDV + 3TC + ABC (bid )

• Truvada� TDF + FTC (qd)

• Atripla� TDF + FTC + EFV (qd)


HIV and the CNS, 2009

Topics• Continued Opportunistic Disease: PML• Advances in Antiretroviral Therapy (ART)• HIV-Related Brain Disease: Then, Now and in

the Future� Treatment of ADC/HIVE

� Case example of missed diagnosis

� Brain disease in treated patients� Aging with HIV

Background Theme• Evolving Diseases and Pathogenetic Concepts


Case History: A Clinical Anachronism

58 yo woman presented in mid-2006 with progressive cognitive decline, difficulty walking and weight lo ss over 6-12 mo

PMH: depression, B-cell lymphoma abdomen in 1998 treated with CHOP. Episodes of PCP, zoster

Severe confusion (disoriented, low speech output, s low, 1 step commands only), unable to walk

WBC 4.6, hemoglobin 11.6LP: protein 71, WBC 0, oligoclonal bandsFound HIV+: CD4 46, VL >500,000 copies/mLPCP during hospitalizationDiagnosis: AIDS dementia complex (ADC)


Case History: Imaging


Case History: Treatment

• Initial Rx� ZDV, 3TC,

LPV/r

• Interrupted 2ary to pancytopenia• Resumed Rx

� NVP, 3TC, ABC, TFV

4059

0 50 100 150 200 2501

2

3

4

5

6 ART

pla HIV

CSF HIV

HIV

RN

A (l

og10

c/m

L)


Digit Symbol Response

Day 49: 23

Day 78: 30

Day 141: 43

Day 184: 48

Day 112: 35Day 225: 54

4059

0 50 100 150 200 2501

2

3

4

5

6 ART

pla HIV

CSF HIV

HIV

RN

A (l

og10

c/m

L)

0 50 100 150 200 250-10

-8

-6

-4

-2

0

2

QN

ZP

-4

0 50 100 150 200 2500

20

40

60

DSY

Days

Dig

it S

ymbo

l (D

SY

)


ART and CNS HIV-1:

• Compartmentalized infection� Genotypic

� After acute phase� Most notable in ADC/HIVE

� Phenotypic� Drug susceptibility� CCR utilization� Cell tropism� Neuropathogenicity?

• Restricted drug penetration across blood-brain barrier (BBB) and blood-CSF barrier (BCB)

Harrington et al, UNCRW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology

CNS Treatment Strategies

High Medium Low

NRTI ABC 3TC ddIZDV d4T TFV

FTC ddC

NNRTI NVP EFVDLV

PI AMP/r AMP NFVIDV/r ATV RTVLPV/r ATZ/r SQV

IDV SQV/rTPV/r

INT

EI MK0518? T20Letendre et al.

CSF Drug Penetration Classification



HIVReplication

CD4+ cellloss

CNS HIVInfection

ImmuneActivation

Gut HIVInfection


OI’sADC/HIVE


Future: Brain Disease in Treated Patients

• ‘Neurocognitive impairment’ in treated patients• Continued CNS immunoactivation

� CSF� MRS

• Intersection with effects of aging


SMART Study: Some Implications

• Target 6,000 subjects, CD4+ >350• Randomized trial 2 groups

� Drug sparing (DS)� Viral control (VC)

• Stopped early� Superiority of VC

• Differences� Mortality� AIDS-related endpoints� NonAIDS-related endpoints� Cardiovascular, renal, hepatic disease� Cancers

• Associations� Biomarkers of immune activation



HIVReplication

CD4+ cellloss

CNS HIVInfection

ImmuneActivation

Gut HIVInfection


OI’sADC/HIVECV Disease


HIV & Alzheimer’s Disease (AD)

• Increased prevalence of cognitive impairment in HIV with age (?)• Fear of early ADBut• AD pathology not evident in HIV

brains• CSF biomarker profile of HIV

differs from AD


CSF AD Biomarkers in HIV

NAADC

CNS OI

Rx Succ

Rx Fail

Contr

y

ADCont

r o

0

200

400

600

800

1000

1200A. sAPP α

sAP

Pα

(ng/

L)

NAADC

CNS OI

Rx Suc

cRx F

ailCon

tr y AD

Contr

o

0

200

400

600

800B. sAPP β

sAP

Pβ

(ng/

L)

NAADC

CNS OI

Rx Succ

Rx Fail

Contr

y ADCont

r o

0

200

400

600

800

1000

1200C. Aβ1-42

Aβ 1

-42

(ng/

L)

NAADC

CNS OI

Rx Suc

cRx F

ailCon

tr y AD

Contr

o

0

400

800

1200

1600D. t-tau

t-ta

u (n

g/L)

NAADC

CNS OI

Rx Succ

Rx Fail

Contr

y

ADCon

tr o

0

50

100

150

200E. p-tau

p-ta

u (n

g/L)

NAADC

CNS OI

Rx Succ

Rx Fail

Contr

y ADCon

tr o

0.0

0.1

0.2

0.3

0.4F. p-tau/t-tau

p-ta

u / t

-tau


CSF AD Biomarkers in HIV:Principal Component Analysis

• AD segregates independently• ADC & OIs segregate

together• Neuro-

asymptomatics and treated patients segregate separately

sAPPβ

-1 0 1-1

0

1

Aβ1-42

p-tau

t-tauADCNA

OIsCont oCont y

AD

sAPPα

Scaled Score and Loading Vector 1

Sca

led

Sco

re a

nd L

oadi

ng V

ecto

r 2



HIVReplication

CD4+ cellloss

CNS HIVInfection

ImmuneActivation

Gut HIVInfection


OI’sADC/HIVECV DiseaseBrain Aging


Credits and Conflicts

• PML� Paola Cinque� Igor Koralnik� Simonetta Gerevini� Jose Miro

• CSF Studies� Serena Spudich� Magnus Gisslen� Lars Hagberg� Bruce Brew

• Subjects� Generous Volunteers

• Potential Conflicts� Biogen Idec� Merck


References

• Late HIV Nervous System Diseases� Spudich S, Price RW: Chapter 62: Neurological Disea se. In: Dolin R, Masur

H, Saag M, eds. AIDS Therapy, 3rd Edition. Philadelphia: Churchill-Livingston, 2007, pp 1075-1101.

• PML & OIs� http://aidsinfo.nih.gov/contentfiles/Adult_OI.pdf

• Antiretroviral Treatment� http://aidsinfo.nih.gov/contentfiles/AdultandAdoles centGL.pdf� http://aidsinfo.nih.gov/contentfiles/AA_Tables.pdf� Price RW and Spudich S, Antiretroviral therapy and central nervous system

HIV type 1 infection. J Infect Dis 197 Suppl 3: S294-306, 2008. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=R etrieve&db=PubMed&dopt=Citation&list_uids=18447615

• Cognitive Impairment in HIV� Antinori A, et al: Updated research nosology for HI V-associated

neurocognitive disorders (HAND), Neurology, : 69 1789-1799, 2007. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=R etrieve&db=PubMed&dopt=Citation&list_uids=17914061

• My email: [email protected]

Date post:	27-Sep-2018
Category:	Documents
Upload:	phunganh
View:	219 times
Download:	0 times

HIV and the CNS in the Current HIV and the CNS, 2009 ... · February , 12, 2009: Recent Advances in...

Documents