Impact of HCV on the Brain

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AIDS CLINICAL ROUNDS

Impact of HCV on the Brain A Brief Review

Scott Letendre, M.D.

Selected Questions Regarding Impact of HCV on the Brain

• Does HCV affect the brain?

• If so, how does HCV affect the brain?

• Does HCV-related brain injury respond to therapy?

• Does HCV infection of the brain limit treatment success?

• What are the best methods to assess HCV’s impact on the brain?

• Can HCV’s effects on the brain be reliably distinguished from those of comorbidities, particularly HIV, liver disease, and drug and alcohol use?

Essential Questions Related Questions









Author Journal Year Size Method People with HCV had…

HCV Serostatus

Thiyagarajan Clin Microbiol Inf 2010 72 IHDS,

CogState Worse IHDS & trend toward worse executive functioning

Hinkin J Addict Dis 2008 118 8 domains Worse learning and memory

Cherner Neurology 2005 430 14 tests Worse functioning in multiple domains

McAndrews Hepatology 2005 83 9 tests Worse learning

Morgello AIDS 2005 137 14 tests Worse executive functioning

Richardson AIDS 2005 220 8 tests More frequent global impairment

Ryan Neurology 2004 116 12 tests Worse executive functioning

Weissenborn J Hepatology 2004 45 10 tests Worse executive functioning and attention

Hilsabeck JINS 2003 21 4 tests Worse functioning associated with worse liver fibrosis

Forton Hepatology 2002 43 Computer-based

Worse concentration and speed of information processing

Kramer J Hepatology 2002 100 P300 ERPs Prolonged P300 latencies

HCV Viremia

Crystal JAIDS 2012 1338 4 tests In fully adjusted GLM, HCV viremia was not associated with scores on any of the cognitive tests

Clifford Neurology 2009 172 3 tests No difference based on HCV RNA

Selected Neurocognitive Findings

Hinkin, J Addict Dis 2008

Cherner, Neurology, 2005

McAndrews, Hepatology 2005

CHARTER HCV RNA Data


X2 = 10.5 p = 0.005


Neuroimaging Investigations Author Journal Year Size Method People with HCV had…

Nagarajan Int J Hepatol 2012 28 L-COSY Higher myoinositol and glutathione

Gongvatana J Neurovirol 2011 85 DTI Decreased anisotropy & increased diffusivity

Heeren J Cerebral Blood Flow & Metab 2011 15 MRI

PET Reduced striatal DA and midbrain SERT availability, glucose metabolism

Jernigan J Neurovirol 2011 251 sMRI Larger volume of abnormal WM

Forton J Hepatology 2008 25 MRS Higher myoinositol

McAndrews Hepatology 2005 37 MRS Higher choline, lower NAA

Taylor JINS 2004 26 MRS Lower NAA

Weissenborn J Hepatology 2004 45 MRS Lower NAA

Forton Hepatology 2002 17 MRS Higher choline in BG, WM

Forton Lancet 2001 30 MRS Higher choline/creatine ratios

Selected Neuroimaging Findings

McAndrews, Hepatology 2005 Nagarajan, Int J Hepatol, 2012

Does HCV Affect the Brain?









HCV can Infect Cells that are Relevant to CNS Pathogenesis

• Macrophages/Microglia or Astrocytes – Letendre et al, J Infect Dis, 2007, 361: 70 – Wilkinson et al, J Virol 2009, 83(3): 1312-9

• Brain Microvascular Endothelial Cells – Fletcher et al, Gastroenterology 2012, 142: 634-3

• Neuroblastoma and Neuroepithelioma Cells – Fletcher et al, Gastroenterology 2010, 139: 1365-74 – Bürgel et al, J Viral Hepatitis 2011, 18: 562-70

• Peripheral Blood Mononuclear Cells • No publications was identified in my non-

exhaustive literature search that demonstrated infection of neurons

Feray C, Gastroenterology. 2012;142(3):428-31

Autopsy Data Supports that HCV can Infect Glial Cells

HCV antigens in brains by heparin columns by WB HCV antigens in astrocytes of HIV+ HCV+ cases GFAP HCV

HCV-

HCV+ HCV+

Letendre, et al, J Infect Dis, 2007, 361: 70 Slide Courtesy Eliezer Masliah

Virologic Evidence that HCV Can Adapt to the CNS Environment

Author Journal Year Size Finding

Fishman J Infect Dis 2008 13 Brain HCV RNA found in 7. Brain HCV RNA sequences differed from liver and blood in 4 (57%)

Bagaglio AIDS 2005 21 HCV RNA was detected in 5 of 21; sequences in 2 of 5 differed from plasma and PBMCs

Forton J Virology 2004 2

Sequences of brain-derived HCV RNA differed from other tissues and clustered with lymph node sequences; Identified 2 unique brain-derived mutations

Radkowski J Virology 2002 6 HCV negative RNA strands were detected in brain tissue from 3 (50%)

Laskus J Virology 2002 13 HCV sequences were found in 8 CSF specimens and 4 of these exhibited differences from other tissues

Vargas Liver Transpl 2002 2 HCV negative RNA strand sequences differed from consensus serum sequences in both

Morsica J Med Virology 1997 19 HCV RNA was detected in 5 of 19 and sequences did not differ between CSF and serum

Other Mechanisms that May Contribute to HCV-Associated CNS Injury

• Immune Response • Glial Activation

– IDO-TRP-KYN-QUIN mediated neurotoxicity* • Neurotoxic HCV-encoded Proteins • Altered Blood-Brain Barrier Permeability Others • Past or Ongoing Neurotoxic Drug Use • Liver Disease and Hepatic Encephalopathy • Cryoglobulin-Associated Vasculitis

*IFN-α can also increase KYN production

Additional Relevant Findings

Paulino et al, J Neurovirol 2011 17:327–340

Letendre et al, 18th CROI 2011, Abstract 408

HCV RNA and HCV Core in CSF

Correlates of HCV Core in CSF

IL28B and HCV • Ge et al performed a GWAS predicting SVR in subjects from the

Initiating Dialysis Early and Late (IDEAL) study • rs12979860 was the most strongly associated SNP in patients of

European ancestry – 2.5-fold higher relative rate of response among non-Hispanic Caucasian

subjects carrying the C/C genotype. Also associated with better treatment responses in Hispanics and in African Americans

• Suggested that IL28B variation may influence natural clearance of HCV since the chronically infected cohort based had a lower frequency of the C allele than ethnically matched population controls

• Other SNPs Identified: – rs28416813, rs8103142 were strongly linked to rs12979860 – Another study found associations with rs8099917 and 5 others

Urban et al, Hepatology 2012, 56: 361-6 Ge et al, Nature 2009;461:399-401

IL28B and HCV • IL28B encodes interferon-13, a type III (or λ) IFN, which

bind to a different receptor complex than IFN-α (type I IFNs)

• IFN-λs have structural and functional similarity to both interleukins (esp. IL-10) and IFN-αs

• Like other IFNs, IFN-λ activates ISGs via intracellular signaling pathways but some are non-redundant with other IFNs

• IFN-λ may result in relatively slower onset and more prolonged ISG activation than IFN-α

• Expression of IFN-λ receptors appears to be more restricted, with particularly high expression in the liver Urban et al, Hepatology 2012, 56: 361-6

IL28B and Neurons

• Human neuronal cells expressed endogenous IFN-λ1 but not IFN-λ2/3. Upon activation of TLR-3 in the neuronal cells, both IFN-λ1 and IFN-λ2/3 expression was significantly induced

• Human neurons also expressed functional IFN-λ receptor complex, IL-28Rα and IL-10Rβ

Urban et al, Hepatology 2012, 56: 361-6 Zhou et al, Neuroscience 2009, 159: 629-37

Association of IL28B SNPs with HCV Seropositivity

Association of IL28B SNPs with HCV Seropositivity & HCV RNA









Treatment with Interferon-Ribavirin

Fontana RJ. Dig Dis, 2000; 18: 107-116

Treatment-Focused Investigations Author Journal Year Size Finding

Byrnes J Hepatology 2012 15 Reductions in basal ganglia Cho/Cr and basal ganglia MI/Cr were observed with SVR, but not in non-responders/relapsers

Comai Pharmacologic Research 2011 45 KYN markedly rose during treatment, paralleled by a significant

increase of the Kyn/Trp ratio, an index of IDO activity

Pattullo Liver Intl 2011 40 MRS demonstrated lower NAA in the globus pallidus before treatment, which was unchanged with viral clearance

Thein HIV Medicine 2007 34 SVR was associated with significant improvements in some measures of cognitive function, independent of HRQOL

Zignego Dig Liver Dis 2007 89 After viral clearance, macrophage IDO activity, plasma TRP and KYN levels returned toward normal values and psychopathology improved

Capuron Biol Psychiatr 2005 10 IFN-α treatment was associated with significant activation in the dorsal part of the anterior cingulate cortex on functional MRI

UCSD IFN/RBV Project • 40 HCV+ subjects starting IFN/RBV therapy • Comprehensive medical, psychiatric, and cognitive

assessment before and 10, 24, 48, and 72 weeks after treatment initiation

• After 10 weeks, neurocognitive impairment rose from 27.5% to 47.5% (p < .05) – Infection with genotype 1 was significantly (p < .05) associated

with decline

• After 72 weeks, 42.5% remained neurocognitively impaired – Only initial 10-week neurocognitive decline predicted persistent

impairment – Not viral clearance, severity of liver disease, or depressive

symptoms Cattie et al, Submitted 2013

Demographic and Other Characteristics Characteristic Mean (SD)

Age (years) 47.8 (8.5) Education 12.9 (2.0) Sex (#, % male) 20 (50.0) N (%) Caucasian 28 (70.0) Reading literacy (WRAT3) mean (SD) 96.0 (12.5)

Lifetime psychiatric/Substance Disorders

Major depressive disorder # (%) 13 (32.5)

Alcohol 15 (37.5) Cannabis 15 (37.5) Methamphetamine 17 (42.5) Cocaine 16 (40.0) Opioid 10 (25.0) Any substance 25 (62.5)

Slide Courtesy Jordan Cattie

Baseline Medical Characteristics Characteristic Mean (SD)

Hemoglobin 14.2 (1.6) Platelet count 213.0 (77.2) Albumin 4.0 (0.4) ALT 85.2 (59.9) AST 73.2 (48.7) Bilirubin total 1.0 [0.2] AST platelet ratio index (APRI) 0.78 (0.52) log10 HCV RNA 5.8 (0.7) HCV Genotype (n, %)

1 28 (70.0) 2 6 (15.0) 3 5 (12.5) 4 1 (2.5)

Slide Courtesy Jordan Cattie

Summary of Findings

Predictors of Neurocognitive Decline at 10 Weeks

• Multivariable regression identified that worse neurocognitive decline was associated with: – Genotype 1 – Depressive symptoms at baseline or lifetime history of

major depression • Predictors that failed to reach statistical significance:

– Baseline neurocognitive functioning – Baseline APRI or fibrosis stage

Predictors of Neurocognitive Decline at 72 Weeks

• Multivariable regression identified that worse neurocognitive decline was associated with: – Neurocognitive change from baseline to 10 weeks

• Predictors that failed to reach statistical significance: – Early or Sustained Viral Response – APRI or fibrosis stage – Genotype – Baseline cognitive status – Current depression status









Additional Research Questions

• How well do newer, direct-acting drugs distribute into tissues other than the liver that have HCV-infected cells?

• What are the CNS side effects of DAAs and how can they be best managed?

• Does limited distribution of DAAs into the CNS contribute to treatment failure?

• Does the blood-brain barrier and the CNS normalize following successful treatment?

Acknowledgements

UCSD HNRC • Ronald J. Ellis • Igor Grant • Allen McCutchan • Bob Heaton • Edmund Capparelli • Brookie Best

CHARTER and CIT2 • David Clifford • Justin McArthur • Ned Sacktor • Ann Collier

National Institutes

of Health …Mental Health …Drug Abuse …Neurological Disorders and Stroke Industry Abbott Laboratories GlaxoSmithKline Merck, Inc. Janssen Gilead Sciences Biogen IDEC

Davey Smith Tom Marcotte Cris Achim Steven Woods Eliezer Masliah

Christina Marra Susan Morgello David Simpson Ben Gelman

Study Volunteers

Health & Medicine

Impact of HCV on the Brain