AIDS CLINICAL ROUNDSThe UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicia...
Impact of HCV on the Brain      A Brief Review     Scott Letendre, M.D.
Selected Questions Regarding Impact         of HCV on the Brain    Essential Questions        Related Questions•   Does HC...
Selected Questions Regarding Impact         of HCV on the Brain    Essential Questions        Related Questions•   Does HC...
Author         Journal        Year   Size    Method People with HCV had…HCV Serostatus               Clin Microbiol       ...
Selected Neurocognitive Findings                                                          McAndrews, Hepatology 2005   Hin...
CHARTER HCV RNA Data
CHARTER HCV RNA Data                 X2 = 10.5                 p = 0.005
CHARTER HCV RNA Data
Neuroimaging InvestigationsAuthor      Journal         Year Size Method People with HCV had…Nagarajan   Int J Hepatol   20...
Selected Neuroimaging Findings McAndrews, Hepatology 2005   Nagarajan, Int J Hepatol, 2012
Does HCV Affect the Brain?
Selected Questions Regarding Impact         of HCV on the Brain    Essential Questions        Related Questions•   Does HC...
HCV can Infect Cells that are     Relevant to CNS Pathogenesis• Macrophages/Microglia or Astrocytes  – Letendre et al, J I...
Feray C, Gastroenterology. 2012;142(3):428-31
Autopsy Data Supports that HCV                can Infect Glial CellsHCV antigens in brains by heparin columns by WB   HCV ...
Virologic Evidence that HCV Can         Adapt to the CNS EnvironmentAuthor      Journal        Year Size Finding          ...
Other Mechanisms that May Contribute    to HCV-Associated CNS Injury• Immune Response• Glial Activation  – IDO-TRP-KYN-QUI...
Additional Relevant Findings Paulino et al, J Neurovirol   Letendre et al, 18th CROI     2011 17:327–340              2011...
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) s...
IL28B and HCV• IL28B encodes interferon-13, a type III (or λ) IFN, which  bind to a different receptor complex than IFN-α ...
IL28B and Neurons• Human neuronal cells expressed endogenous  IFN-λ1 but not IFN-λ2/3. Upon activation of  TLR-3 in the ne...
Association of IL28B SNPs with      HCV Seropositivity
Association of IL28B SNPs withHCV Seropositivity & HCV RNA
Selected Questions Regarding Impact            of HCV on the Brain    Essential Questions        Related Questions•   Does...
Treatment with Interferon-Ribavirin                    Fontana RJ. Dig Dis, 2000; 18: 107-116
Treatment-Focused InvestigationsAuthor     Journal        Year Size Finding                                    Reductions ...
UCSD IFN/RBV Project• 40 HCV+ subjects starting IFN/RBV therapy• Comprehensive medical, psychiatric, and cognitive  assess...
Demographic and Other Characteristics    Characteristic                             Mean (SD)      Age (years)            ...
Baseline Medical Characteristics   Characteristic                       Mean (SD)     Hemoglobin                         1...
Summary of Findings
Predictors of Neurocognitive Decline             at 10 Weeks• Multivariable regression identified that worse neurocognitiv...
Predictors of Neurocognitive Decline             at 72 Weeks• Multivariable regression identified that worse neurocognitiv...
Selected Questions Regarding Impact         of HCV on the Brain    Essential Questions        Related Questions•   Does HC...
Additional Research Questions• How well do newer, direct-acting drugs  distribute into tissues other than the liver that  ...
Acknowledgements                      Study VolunteersUCSD HNRC                                     National Institutes•  ...
Impact of HCV on the Brain
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Impact of HCV on the Brain

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Scott Letendre, MD (UC San Diego AntiViral Research Center) presents "Impact of HCV on the Brain"

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Impact of HCV on the Brain

  1. 1. AIDS CLINICAL ROUNDSThe UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicians, physicians andresearchers. The goal of these presentations is to provide the mostcurrent research, clinical practices and trends in HIV, HBV, HCV, TBand other infectious diseases of global significance.The slides from the AIDS Clinical Rounds presentation that you areabout to view are intended for the educational purposes of ouraudience. They may not be used for other purposes without thepresenter’s express permission.
  2. 2. Impact of HCV on the Brain A Brief Review Scott Letendre, M.D.
  3. 3. Selected Questions Regarding Impact of HCV on the Brain Essential Questions Related Questions• Does HCV affect the • What are the best brain? methods to assess• If so, how does HCV HCV’s impact on the affect the brain? brain?• Does HCV-related brain • Can HCV’s effects on injury respond to the brain be reliably therapy? distinguished from• Does HCV infection of those of comorbidities, the brain limit particularly HIV, liver treatment success? disease, and drug and alcohol use?
  4. 4. Selected Questions Regarding Impact of HCV on the Brain Essential Questions Related Questions• Does HCV affect the • What are the best brain? methods to assess• If so, how does HCV HCV’s impact on the affect the brain? brain?• Does HCV-related brain • Can HCV’s effects on injury respond to the brain be reliably therapy? distinguished from• Does HCV infection of those of comorbidities, the brain limit particularly HIV, liver treatment success? disease, and drug and alcohol use?
  5. 5. Author Journal Year Size Method People with HCV had…HCV Serostatus Clin Microbiol IHDS, Worse IHDS & trend toward worse executiveThiyagarajan 2010 72 Inf CogState functioningHinkin J Addict Dis 2008 118 8 domains Worse learning and memoryCherner Neurology 2005 430 14 tests Worse functioning in multiple domainsMcAndrews Hepatology 2005 83 9 tests Worse learningMorgello AIDS 2005 137 14 tests Worse executive functioningRichardson AIDS 2005 220 8 tests More frequent global impairmentRyan Neurology 2004 116 12 tests Worse executive functioningWeissenborn J Hepatology 2004 45 10 tests Worse executive functioning and attention Worse functioning associated with worse liverHilsabeck JINS 2003 21 4 tests fibrosis Computer- Worse concentration and speed of informationForton Hepatology 2002 43 based processingKramer J Hepatology 2002 100 P300 ERPs Prolonged P300 latenciesHCV Viremia In fully adjusted GLM, HCV viremia was notCrystal JAIDS 2012 1338 4 tests associated with scores on any of the cognitive testsClifford Neurology 2009 172 3 tests No difference based on HCV RNA
  6. 6. Selected Neurocognitive Findings McAndrews, Hepatology 2005 Hinkin, J Addict Dis 2008 Cherner, Neurology, 2005
  7. 7. CHARTER HCV RNA Data
  8. 8. CHARTER HCV RNA Data X2 = 10.5 p = 0.005
  9. 9. CHARTER HCV RNA Data
  10. 10. Neuroimaging InvestigationsAuthor Journal Year Size Method People with HCV had…Nagarajan Int J Hepatol 2012 28 L-COSY Higher myoinositol and glutathioneGongvatana J Neurovirol 2011 85 DTI Decreased anisotropy & increased diffusivity J Cerebral Blood MRI Reduced striatal DA and midbrain SERT availability,Heeren 2011 15 Flow & Metab PET glucose metabolismJernigan J Neurovirol 2011 251 sMRI Larger volume of abnormal WMForton J Hepatology 2008 25 MRS Higher myoinositolMcAndrews Hepatology 2005 37 MRS Higher choline, lower NAATaylor JINS 2004 26 MRS Lower NAAWeissenborn J Hepatology 2004 45 MRS Lower NAAForton Hepatology 2002 17 MRS Higher choline in BG, WMForton Lancet 2001 30 MRS Higher choline/creatine ratios
  11. 11. Selected Neuroimaging Findings McAndrews, Hepatology 2005 Nagarajan, Int J Hepatol, 2012
  12. 12. Does HCV Affect the Brain?
  13. 13. Selected Questions Regarding Impact of HCV on the Brain Essential Questions Related Questions• Does HCV affect the • What are the best brain? methods to assess• If so, how does HCV HCV’s impact on the affect the brain? brain?• Does HCV-related brain • Can HCV’s effects on injury respond to the brain be reliably therapy? distinguished from• Does HCV infection of those of comorbidities, the brain limit particularly HIV, liver treatment success? disease, and drug and alcohol use?
  14. 14. 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
  15. 15. Feray C, Gastroenterology. 2012;142(3):428-31
  16. 16. Autopsy Data Supports that HCV can Infect Glial CellsHCV 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
  17. 17. Virologic Evidence that HCV Can Adapt to the CNS EnvironmentAuthor Journal Year Size Finding Brain HCV RNA found in 7. Brain HCV RNA sequencesFishman J Infect Dis 2008 13 differed from liver and blood in 4 (57%) HCV RNA was detected in 5 of 21; sequences in 2 of 5Bagaglio AIDS 2005 21 differed from plasma and PBMCs Sequences of brain-derived HCV RNA differed from other tissues and clustered with lymph nodeForton J Virology 2004 2 sequences; Identified 2 unique brain-derived mutations HCV negative RNA strands were detected in brainRadkowski J Virology 2002 6 tissue from 3 (50%) HCV sequences were found in 8 CSF specimens and 4Laskus J Virology 2002 13 of these exhibited differences from other tissues HCV negative RNA strand sequences differed fromVargas Liver Transpl 2002 2 consensus serum sequences in both HCV RNA was detected in 5 of 19 and sequences didMorsica J Med Virology 1997 19 not differ between CSF and serum
  18. 18. 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 PermeabilityOthers• Past or Ongoing Neurotoxic Drug Use• Liver Disease and Hepatic Encephalopathy• Cryoglobulin-Associated Vasculitis *IFN-α can also increase KYN production
  19. 19. Additional Relevant Findings Paulino et al, J Neurovirol Letendre et al, 18th CROI 2011 17:327–340 2011, Abstract 408
  20. 20. HCV RNA and HCV Core in CSF
  21. 21. Correlates of HCV Core in CSF
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. Association of IL28B SNPs with HCV Seropositivity
  26. 26. Association of IL28B SNPs withHCV Seropositivity & HCV RNA
  27. 27. Selected Questions Regarding Impact of HCV on the Brain Essential Questions Related Questions• Does HCV affect the • What are the best brain? methods to assess• If so, how does HCV HCV’s impact on the affect the brain? brain?• Does HCV-related brain • Can HCV’s effects on injury respond to the brain be reliably therapy? distinguished from• Does HCV infection of those of comorbidities, the brain limit particularly HIV, liver treatment success? disease, and drug and alcohol use?
  28. 28. Treatment with Interferon-Ribavirin Fontana RJ. Dig Dis, 2000; 18: 107-116
  29. 29. Treatment-Focused InvestigationsAuthor Journal Year Size Finding Reductions in basal ganglia Cho/Cr and basal ganglia MI/Cr wereByrnes J Hepatology 2012 15 observed with SVR, but not in non-responders/relapsers Pharmacologic KYN markedly rose during treatment, paralleled by a significantComai 2011 45 Research increase of the Kyn/Trp ratio, an index of IDO activity MRS demonstrated lower NAA in the globus pallidus beforePattullo Liver Intl 2011 40 treatment, which was unchanged with viral clearance SVR was associated with significant improvements in someThein HIV Medicine 2007 34 measures of cognitive function, independent of HRQOL After viral clearance, macrophage IDO activity, plasma TRP andZignego Dig Liver Dis 2007 89 KYN levels returned toward normal values and psychopathology improved IFN-α treatment was associated with significant activation in theCapuron Biol Psychiatr 2005 10 dorsal part of the anterior cingulate cortex on functional MRI
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. Summary of Findings
  34. 34. 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
  35. 35. 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
  36. 36. Selected Questions Regarding Impact of HCV on the Brain Essential Questions Related Questions• Does HCV affect the • What are the best brain? methods to assess• If so, how does HCV HCV’s impact on the affect the brain? brain?• Does HCV-related brain • Can HCV’s effects on injury respond to the brain be reliably therapy? distinguished from• Does HCV infection of those of comorbidities, the brain limit particularly HIV, liver treatment success? disease, and drug and alcohol use?
  37. 37. 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?
  38. 38. Acknowledgements Study VolunteersUCSD HNRC National Institutes• Ronald J. Ellis  Davey Smith of Health• Igor Grant  Tom Marcotte  …Mental Health• Allen McCutchan  Cris Achim  …Drug Abuse• Bob Heaton  Steven Woods  …Neurological• Edmund Capparelli  Eliezer Masliah Disorders and Stroke• Brookie Best IndustryCHARTER and CIT2  Abbott Laboratories• David Clifford  Christina Marra  GlaxoSmithKline• Justin McArthur  Susan Morgello  Merck, Inc.• Ned Sacktor  David Simpson  Janssen• Ann Collier  Ben Gelman  Gilead Sciences  Biogen IDEC

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