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RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
HIV and the CNS in the Current Treatment Era, 2009
Selected Issues
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
Introduction: Pathogenesis of HIV Diseases
HIVReplication
CD4+ cellloss
CNS HIVInfection
ImmuneActivation
Gut HIVInfection
microbialtranslocation
Spectrum of Diseases
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
“bizarre” astrocte
“Demyelinating” PML
Infected oligodendrocyte (ISH)
“Early” PML
PML: Lytic Oligo Infection
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
PML: Demyelinating Infection
• Demyelination
• JCV-infected oligodendrocytes
• Bizarre astrocytes
• Lipid-laden macrophages
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
JCV & PML:Steps in
Pathogenesis
Acute JCVInfection
JCVExposurePrimary JCV
Infection
Anti-JCVimmunityAnti-JCVimmunity
Chronic JCVInfectionChronic JCV
Carrier State
Acute JCVInfection
JCVExposurePrimary JCV
Infection
BBBBreach: CNS
SeedingDevelopment/Progression
ofPML
HIVInfection
Anti-JCVimmunity
Chronic JCVInfectionChronic JCV
Carrier State
CNS JCVReplicaton
Acute JCVInfection
JCVExposurePrimary JCV
Infection
BBBBreach: CNS
SeedingDevelopment/Progression
ofPML
HIVInfection
Anti-JCVimmunity
Chronic JCVInfectionChronic JCV
Carrier State
cART
CNS JCVSuppression
TreatedPML
CNS JCVReplicaton
Acute JCVInfection
JCVExposurePrimary JCV
Infection
CNS PMLInflammatory
BBBBreach: CNS
SeedingDevelopment/Progression
ofPML
HIVInfection
Anti-JCVimmunity
Chronic JCVInfectionChronic JCV
Carrier State
cART
CNS JCVSuppression
TreatedPML
CNS JCVReplicaton
Acute JCVInfection
JCVExposurePrimary JCV
Infection
JCVActivators
CNS PMLInflammatory
BBBBreach: CNS
SeedingDevelopment/Progression
ofPML
HIVInfection
Anti-JCVimmunity
Chronic JCVInfectionChronic JCV
Carrier State
cART
CNS JCVSuppression
TreatedPML
CNS JCVReplicaton
Acute JCVInfection
JCVExposurePrimary JCV
Infection
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
Diagnosis of PML
• Clinical diagnosis� Progressive focal neurological deficit(s)� Characteristic MRI� Background context
• Laboratory (confirmed) diagnosis� JCV DNA in CSF� Histological/virological
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
‘Classical’ PML: MRI
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
PML: Treatment
• ART• Management of PML-IRIS• ‘Specific’ Treatments• Future Prospects
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
ART and Immune Effects in PML
• Established PML: ART treatment� Initiate� Change� Augment?• Therapeutic Effect:
� Immune restoration� Stabilization/remission in 50%
• Therapeutic Complications� IRIS
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
c.
Courtesy of Pilar Miralles
Paradoxical Worsening of PML after ART
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
Pathogenesis of HIV Diseases
HIVReplication
CD4+ cellloss
CNS HIVInfection
ImmuneActivation
Gut HIVInfection
microbialtranslocation
OI’s
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
PML-Specific Treatments
• History of failed prospects• Orphan disease: unlikely to attract major
corporate effort� Exception: PML mitigation program (Biogen
Idec)� Mefloquine Study
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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)
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
HIV Replication: Treatment Targets
From: RM Gulick, Topics in HIV Medicine, 10(4) 16, 2002
XX
X
X
X
ProteaseInhibitors X
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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)
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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)
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
Case History: Imaging
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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)
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
)
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
Pathogenesis of HIV Diseases
HIVReplication
CD4+ cellloss
CNS HIVInfection
ImmuneActivation
Gut HIVInfection
microbialtranslocation
OI’sADC/HIVE
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
Future: Brain Disease in Treated Patients
• ‘Neurocognitive impairment’ in treated patients• Continued CNS immunoactivation
� CSF� MRS
• Intersection with effects of aging
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
Pathogenesis of HIV Diseases
HIVReplication
CD4+ cellloss
CNS HIVInfection
ImmuneActivation
Gut HIVInfection
microbialtranslocation
OI’sADC/HIVECV Disease
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
Pathogenesis of HIV Diseases
HIVReplication
CD4+ cellloss
CNS HIVInfection
ImmuneActivation
Gut HIVInfection
microbialtranslocation
OI’sADC/HIVECV DiseaseBrain Aging
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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
RW Price-SFGH/UCSFFebruary , 12, 2009: Recent Advances in Neurology
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: rwprice@sfgh.ucsf.edu
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