Neurological Complications of Hepatitis C CoInfection

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Neurological Complications of Hepatitis C
Co-Infection

• David B. Clifford, M.D.
• Washington University in St. Louis

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Co-infection
CNS PNS
CNS PNS
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World-Wide Prevalence of Hepatitis C

• WHO region Population (M) pos
  Infected (M)
• Africa 858 5.3 31.9
• Americas 785 1.7 13.1
• E. Meditteranean 466 4.6 21.3
• Europe 858 1.0 8.9
• S-E Asia 1500 2.2 32.3
• W. Pacific 1600 3.9 62.2
• Total 5811 3.1 169.7

Source WHO
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Sources of Infection forPersons with Hepatitis C
Injecting drug use 60
Sexual 15
Transfusion 10 (before screening)
Other 5
Unknown 10
Nosocomial Health-care work Perinatal
6
Acute Hepatitis
Natural History of Hepatitis C
Chronic Hepatitis
85
Cirrhosis
20
6
4
Death
3.6
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HCV and Neuropathy

• HCV is generally the cause for mixed
  cryoglobulinemia
• Mixed cryoglobulinemia is clearly associated with
  peripheral neuropathy

Authier, et al
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Distal Sensory Neuropathy and HCV

• Reports of three series suggest that HCV does not
  result in increased incidence of DSP
• McArthur comparison of Australian and Baltimore
  cohorts
• Morgello et al survey of Manhatten Brain Bank
• Letendre analysis of HNRC

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Other Neurological Syndromes Reported with HCV

• Anterior optic neuropathy
• Restless leg syndrome
• CNS vasculitis with ischemic or hemorrhagic
  strokes

Tembl, NEUROLOGY, 1999

• Polymyositis, cranial neuropathy

Marie, et al 2000
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Other Neurological Syndromes Reported with HCV

• Demyelinating myelitis
• Cord biopsy
• Macrophages
• Perivascular lymphocytes
• Loss of myelin
• Reactive gliosis
• No HCV antigen
• ?Immune mediated myelitis

Grewal, J N Sci, 2004
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What about the brain?
One time too manyDavid lets his mind wander.
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Evidence for HCV Replication in Brain

• Negative strand RNA found in brains suggesting
  active replication
• RT-PCR, cloning and sequencing has defined
  quasispecies for HCV internal ribosomal entry
  site (IRES) and hypervariable region 1 (HVR1) in
  autopsy derived brain samples (Forton, 2004)
• Between 24-55 of brain derived IRES sequences
  absent from periphery

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HCV and Neuro Function

• Fatigue associated with neurophysiologic measures
• HCV subjects, excluding confounders for CNS
  function including IFN rx.
• Compare samples of 15 subjects with HCV and low
  or high fatigue rating with controls(healthy,
  matched for age and education)
• NP testing, EEG, MRS performed

Weissenborn et al, 2004
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MRS and HCV

• Histologially mild HCV patients
• Controls healthy volunteers and HBV pts
• Unrelated to hepatic encephalopathy
• Unrelated to IVDU

Forton et al, Lancet 2001 35838-9
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P300 Demonstrates HCV Effect
Kramer, J. Hepatol 2002 37 349
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HIV/HCV Co-Infection
IVDU

HIV 1 Million
HCV 3 million

15-30
STD
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HIV/HCV Co-Infection

• HIV has known cognitive disorder
• If HCV also causes brain disorder, how will these
  two chronic viral infections interact?
• Problems
• Both are typically subtle at onset
• Disease specific markers not available
• Patients tend to be confounded
• Co-morbid drug use complicates analysis

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Therapy Complicates Analysis

• HCV therapy
• interferon? is notorious for causing depression
• May be curative
• HIV therapy
• Demonstrable improvement in cognitive performance
• Role of drugs on long term brain unknown
• Series matching stage of rx or treatment status
  rare
• Often three active conditions potentially
  affecting function including HIV, HCV, and
  recreational drugs

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Viral Impact on Cognitive Disability
?? HIVHCV
Disability
HIV
Time
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Co-infection Data Sources

• Data is available, but all is limited
• UCLA Hepatitis program (Hilsebeck, Hinken)
• San Diego HNRC Cohort (Letendre)
• Chicago, Martin IVDrug User Study
• Dusseldorf HIV Cohort (Arendt)
• Manhatten Brain Bank (Morgello)
• ACTG A5097s Study (Clifford)

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Co-Infection May Not Augment Cognitive
Dysfunction Much

• Global cognitive functioning similar
• Speed of processing is slower
• Populations differ significantly

Hilsbeck, et al
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• Neuropsychological impact of co-morbid HIV and/or
  methamphethamine dependence with HCV
• 430 subject cohort collect for METH study
• HCV 83
• HCV- 347

Neurology 2005
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Demographics
NS Ethnicity, Beck depression, recent METH use,
CD4 (mean 425), on ARV (gt90), tot. bilirubin.
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Neuropsych Impairment

• Risks
• METH
• HIV
• HCV

plt0.001 plt0.01 plt0.05
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HNRC Results

• HCV performed worse on NP testing
• HCV were gt2x as likely to be globally impaired
• HCV levels were higher in plasma with those
  having memory impairment but not global
  impairment
• CSF HIV levels were higher in those that were
  HCV, but not in plasma
• HCV was lt100 copies/ml in CSF in all cases
• HCV associated with higher levels of MCP-1, TNFa
  and sTNFR-II in plasma

Letendre, in press, 2005
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HNRC Study -Conclusions

• HCV independently contributes to deficits seen in
  HIV and METH using subjects
• Many of confounds related to HIV disease status,
  treatment and drug use could statistically
  addressed in this large sample
• HCV seen as common, important, treatable factor
  contributing to cognitive impairment

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Neuro Confounds of IVDU

• High prevalences of co-morbid conditions
• Learning disability
• Attention-deficit hyperactivity disorder
• Posttraumatic stress disorder
• Mood disorders
• Antisocial personality disorder
• Head injury
• Malnutrition
• Systemic infections
• Direct effects of drugs

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Drug Abuse and Co-Infection

• Martin has studied a sample with all individuals
  drug abusing
• Comparison of HCV monoinfection or co-infection
  performed

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Stroop Performance in Co-infected Subjects Drug
Users
Gonzalez, Jacobus, Martin C Inf Dis 200541S45
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• Both HIV and HCV patients show affective
  disorders and psychomotor slowing
• Longitudinal analysis will be important
• Physiologic motor testing may be helpful to
  monitor the HCV related disability

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Co-Infection
Von Giesen et al. J Acquir Immune Def Syndr 35
131, 2004
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Co-Infection Electrophysiology
TPF tremor peak frequency MRAM rapidly
alternating mvt of finger RT simple reaction
time CT contraction time
Von Giesen et al. J Acquir Immune Def Syndr 35
131, 2004
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• Manhatten brain bank project with advanced HIV
  subjects
• Subjects selected for advanced HIV
• Careful neuropsychometric study
• Tissues available for research

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Neuropsych Function in Advanced HIV
Manhattan Brain Bank Cohort
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Impairment in Co-infected Advanced HIV Subjects
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Manhattan Cohort Co-Infection

• Substantial dementia in population
• Advanced HIV disease may obscure HCV neuropsych
  disease
• Difficulty matching populations
• Excess drug use in HCV/HIV
• More stimulant associate major depression
• Trend to worse performance with co-infection
• Differences in performance assoc HCV status, not
  liver function tests
• Co-infected more likely to be diagnosed with AIDS
  dementia

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A5097 Provides Pilot HCV Investigation in
Earlier HIV Infection

• ART naïve, HCV treatment naïve population
  studied at baseline with brief neurological
  performance measures
• A5097 provided a uniformly selected research
  population prior to therapeutic interventions
• Drug and alcohol abuse relatively uncommon in
  this population
• Hepatitis C antibody status reported on 235
  subjects

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A 5097s Study Design
Day 7
Week 4
Week 8
Week 12
Week 24
BL
Neuropsychological Function (NPZ3)
Sleep Behavior Assessment

• Trailmaking test A
• Trailmaking test B
• WAIS R Digit Symbol test

• Pittsburgh Sleep Quality Index

V
Recreational Drug Use Assessment
V

• Maryland Addictions Qaire S

Subject Experience Questionnaire
V

• Developed for this study from prior EFV studies

Depression/Anxiety Assessments
S

• CES Depression Scale
• State-Trait Anxiety Inventory

Pharmacokinetic Data
V

• EFV levels 12-28 hours post-dose

V
S
Study specific test
Previously validated test
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Baseline Demographics
HCV Negative
HCV Positive
ACTG 5097s With Known HepC Status
n210
n 25
Male
168 (80)
20 (80)
Demography
Median Age
38.1 ( 8.6)
40.6 (7.9)
13.8 (2.4)
11.8 ( 3.1)
Education, Yrs
199 (95)
13 (52)
IV Drug Use History
Never
11 (5)
12 (48)
Current/Former
250
305
Mean CD4
HIV Factors
878
996
Mean CD8
4.7
Mean HIV-1 RNA
4.9
72 (35)
11 (44)
Hepatitis B Status
P lt 0.05
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Mean of Standardized NPTests by Group

Hepatitis C Negative
Hepatitis C Positive
A5097s - mean
P
NPZ-3 mean score (S.D.)
-0.13 (1.06)
-0.60 (1.06)
-0.26
0.012
Digit Symbol
-0.21
-0.92
-0.35
0.001
Trailmaking A
-0.05
-0.55
-0.27
0.11
Trailmaking B
-0.12
-0.61
-0.16
0.09
Z-scoreDS (subject digit symbol) (mean
control digit symbol)/ SD digit symbol
NPZ3 (Zdigit symbol ZtrailA ZtrailB) / 3
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Mean Depression by Group
CES-D gt 16
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CES-D Subscale Scores by HCV Status
Because item is reverse scored, lower scores are
indicative of higher levels of positive mood.
Table entries are mean SD
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Hepatic Function
Median (range) Wilcoxon Two-Sample Test
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Predictors of Poor PerformanceDigit Symbol and
NPZ3
Note Use of stepwise selection procedure with
entry and stay value0.05 as cutoff
points. Use of recreational Drugs, HIV-RNA level,
sex, and alcohol use were not predictors
for poor performance in Digit Symbol test.
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Change in NPZ from Baseline
1st ANCOVA models adjust for baseline NPZ3
score. 2nd ANCOVA models adjust for years of
education, IV drug use, and baseline
NPZ3 scores
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Neuropsychological FailuresDecline of NPZ by
0.4 SD
logistic regression adjusted for baseline NPZ3
score and treatment regimen.
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Evidence to Date Does Not Suggest HCV Impact
Progresses

• Neuropathology of HCV brain disease and advanced
  forms not well described to date
• Cross sectional analyses dont suggest increasing
  impact of co-infection

X
?? HIVHCV
Disability
HIV
Time
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Conclusions - Baseline

• Co-infected subjects performed worse on our
  neuropsychometric tests than monoinfected HIV
  subjects
• Depression is more common in the HCV population
  and may be symptom of this infection, or
  co-morbidity
• Somatic symptoms dominate the depression scale
  and typify complaints associated with HCV that
  have been compared to chronic fatigue syndrome

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Conclusions

• Differences in education and depression between
  the groups contribute to differences in
  performance, but even accounting for these
  differences, performance on the digit symbol test
  was significantly worse in HCV infected subjects
• Our findings are consistent with the hypothesis
  that hepatitis C has negative impact on
  neurocognitive functioning
• Multiple confounds identified with HCV status
  still may contribute

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Conclusions - Longitudinal

• HCV appears to contribute to mild performance
  limitations in earlier untreated and treated HIV
  disease
• Performance improves with HIV therapy in both HIV
  and co-infected populations
• After 184 weeks, performance remains stably
  improved, with HCV population similar to
  co-infected subjects
• Larger and longer studies will be required to
  fully investigate the implication of co-infection
  for the nervous system

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Pathophysiology of Co-Infection

• Synergism of two virus
• Replication in same cells (macrophages, T
  lymphocytes)
• HIV therapy facilitates HCV replication
• Immune activation synergy
• Accelerated hepatic failure
• Augmented response to hepatic failure
  (accelerated fibrosis)

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Co-Infection

• Common problem of potential international
  importance
• Substantial evidence exists that there is
  additive neurological dysfunction due to HCV
  co-infection
• No clear evidence of altered behavior of either
  condition
• All data collected to date have significant
  limitations

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Acknowledgements

• Yijun Yang, Scott Evans
• Scott Letendre
• ACTG patients and investigators
• NINDS, NIAID, NIMH

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Therapeutic Issues
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A5095 Proportion of subjects with HIV-1 RNA
lt200 and lt50 cps/ml
pt estimate (95 CI) at wk 48
89 (85, 93)
83 (78, 88)
74 (65, 83)
61 (50, 72)
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Treatment of HIV/HCV Co-InfectionPegylated
Interferon Ribavirin
RIBAVIC n206
100
AACTG n67
80
73
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APRICOT n289
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Percent Response
43
40
40
29
27
27
16
20
14
0
Overall SVR
Genotype 1
Genotype 2,3
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Therapeutic Issues

• Impact of HIV therapy
• May depend on how advanced HIV is
• HCV viral loads increase with HIV therapy
• Raises question of whether HCV therapy should
  precede HIV therapy
• Impact of HCV therapy
• Toxicity significant
• Success limited
• Particular interest in acute HCV rx where
  prognosis may be better

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Conclusions

• Our results are consistent with recently reported
  studies of von Giesen
• Depression was more common in Hep C patients
• Motor slowing was associated with both HIV and
  hepatitis C
• Interaction was suggested by simple reaction time
  prolongation only in the coinfected subjects

J Acquir Immune Defic Syndro 2004 35131.
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Possible Mechanisms of Neurological Injury

• Replication in CNS compartment, most likely in
  macrophage lineage cells
• Infected inflammatory cells may release
  inflammatory factors and attract further damaging
  cells to CNS
• Up-regulation of HIV replication in co-infected
  individual (Letendre in press)
• Via liver injury, possible excitotoxic mechanisms
  (?hyperammonemia)

Letendre, 2005