Neurological Complications of HCV co-infection

Neurologic AIDS Research Consortium

Neurological Complications of Hepatitis C Co-Infection

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


Co-infection

CNS

PNS

CNS

PNS


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

Neurologic AIDS Research Consortium Source: Sentinel Counties, CDC

Sources of Infection forPersons with Hepatitis C

Sexual 15%

Other* 5%

Unknown 10%

Injecting drug use 60%

Transfusion 10%(before screening)

*Nosocomial; Health-care work; Perinatal


Acute Hepatitis

Chronic Hepatitis

Cirrhosis

Death

Decompensation HCC*

85%

6%

20%

3.6%

4%

HLA type

Male genderAge of onsetAlcoholInterferon

Transplantation

Factors affecting natural history

Hepatitis B*AlcoholInterferon*

Natural Historyof Hepatitis C


HCV and Neuropathy

• HCV is generally the cause for mixed cryoglobulinemia

• Mixed cryoglobulinemia is clearly associated with peripheral neuropathy

Authier, et al


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


Other Neurological Syndromes Reported with HCV

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

strokes

•Polymyositis, cranial neuropathy

Tembl, NEUROLOGY, 1999

Marie, et al 2000


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


What about the brain?

One time too many—David lets his mind wander.


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


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


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;358:38-9


P300 Demonstrates HCV Effect

Kramer, J. Hepatol 2002; 37: 349


HIV/HCV Co-Infection

HCV: 3 million HIV:

1 Million15-30%

IVDU

STD


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


Therapy Complicates Analysis

• HCV therapy – interferonα 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


Viral Impact on Cognitive Disability

Time

Dis

abili

ty

HIV

?? HIV+HCV


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)


Co-Infection May Not Augment Cognitive Dysfunction Much

•Global cognitive functioning similar

•Speed of processing is slower

•Populations differ significantly

Hilsbeck, et al


• 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


Demographics

<0.000129.355.5ALT (+other LFT)

<0.00011737% EtOH dependence

0.087786Gender, % male

<0.000112.711.3Education, y

<0.000136.340.9Age, mean

p ValueHCV-HCV+

NS: Ethnicity, Beck depression, recent METH use, CD4 (mean ~425), on ARV (>90%), tot. bilirubin.


Neuropsych Impairment

Risks

2. METH

3. HIV

4. HCV

***p<0.001**p<0.01*p<0.05


HNRC Results

• HCV+ performed worse on NP testing• HCV+ were >2x 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 <100 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


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


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


Drug Abuse and Co-Infection

• Martin has studied a sample with all individuals drug abusing

• Comparison of HCV monoinfection or co-infection performed


Stroop Performance in Co-infected Subjects Drug Users

Gonzalez, Jacobus, MartinC Inf Dis 2005:41:S45


• 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


Co-Infection

Von Giesen et al. J Acquir Immune Def Syndr 35: 131, 2004


Co-Infection: Electrophysiology

Von Giesen et al. J Acquir Immune Def Syndr 35: 131, 2004

TPF = tremor peak frequencyMRAM = rapidly alternating mvt of fingerRT = simple reaction timeCT = contraction time


• Manhatten brain bank project with advanced HIV subjects

• Subjects selected for advanced HIV• Careful neuropsychometric study• Tissues available for research


Neuropsych Function in

Advanced HIV

Manhattan Brain Bank Cohort


Impairment in Co-infected Advanced HIV Subjects


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


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


A 5097s Study Design

BL

Day 7 Week 4 Week 8 Week 12 Week 24

Neuropsychological Function (NPZ3)

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

Sleep Behavior Assessment

• Pittsburgh Sleep Quality Index

Recreational Drug Use Assessment

• Maryland Addictions Q’aire S

Depression/Anxiety Assessments

• CES Depression Scale• State-Trait Anxiety Inventory

V

V

V

V

‘Subject Experience Questionnaire’

• Developed for this study from prior EFV studies S

Pharmacokinetic Data

• EFV levels 12-28 hours post-dose VS Study specific test Previously validated test


Baseline Demographics

HCV Negative HCV Positive

n=210 n= 25

ACTG 5097sWith Known HepC

Status

Male 168 (80%) 20 (80%)

Median Age 38.1 (+ 8.6) 40.6 (+7.9)

199 (95%) 13 (52%)

11 (5%) 12 (48%)

72 (35%) 11 (44%)

Demography

IV Drug Use History *

250 305Mean CD4

878 996Mean CD8

4.9 4.7Mean HIV-1 RNA

HIV Factors

Never

Current/Former

13.8 (+2.4)

Hepatitis B Status

11.8 (+ 3.1)

* P < 0.05

Education, Yrs *


Mean of Standardized NPTests by Group

Hepatitis C Negative

Hepatitis C Positive

A5097s - mean

NPZ-3 mean score (S.D.)

Digit Symbol

Trailmaking A

Trailmaking B

-0.13 (+1.06) -0.60 (+1.06) -0.26

-0.21 -0.92 -0.35

-0.05 -0.55 -0.27

-0.12 -0.61 -0.16

Z-scoreDS = (subject digit symbol) – (mean control digit symbol)/ SD digit symbol

NPZ3 = (Zdigit symbol + ZtrailA + ZtrailB) / 3

P

0.09

0.11

0.001

0.012


Mean Depression by Group

0.05552%33%Clinical Depression*

0.02317.3 (+11.3)12.5 (+9.8)CES-D (SD)

P

HCV Pos

N = 25

HCV Neg

N = 208

* CES-D > 16


CES-D Subscale Scores by HCV Status

0.3310.80(±1.38)0.58(±1.01)Interpersonal problem

0.0017.24(±4.67)4.58(±3.77)Somatic problem

0.5978.40(±3.08)8.74(±3.06)Positive affect*

0.0785.68(±4.48)4.08(±4.24)Depressed affect

PHCV-Pos N=25

HCV-Neg

N=210

*Because item is reverse scored, lower scores are indicative of higher levels of positive mood.** Table entries are mean ± SD


Hepatic Function

<0.0001 11 (45%)22 (10%)SGOT (>1.5 ULN)

<0.000112 (50%)29 (14%)SGPT (>1.5 ULN)

<0.00156 (14-154)28 (13-157)SGOT (U/L)*

<0.00161 (14-134)28 (7-209)SGPT (U/L)*

P**

HCV Pos

N = 24

HCV Neg

N = 207

*Median (range)** Wilcoxon Two-Sample Test


Predictors of Poor PerformanceDigit Symbol and NPZ3

<0.001-0.020.0030.14CES-D Score

<0.0010.44----CD4 > 200

<0.0010.40<0.0010.03Education

(per 4 yr)

0.14-0.320.032-0.43HCV Status

PEstimatePEstimateVariable

NPZ3Digit Symbol

Note: Use of stepwise selection procedure with entry and stay value=0.05 as cutoff points. Use of recreational Drugs, HIV-RNA level, sex, and alcohol use were not predictors for poor performance in Digit Symbol test.


Change in NPZ from Baseline

0.60110.45250.74940.55 (0.72)0.44<0.0001135

0.68 (1.15)0.520.021515

Mean (SD)MedianSigned-rank (p)N

Week 184

0.0346 0.01190.43150.60 (0.59)0.56<0.0001221

0.50 (0.75)0.410.000429


Week 24

0.0013 0.00680.24690.35 (0.48)0.31<0.0001231

0.23 (0.68)0.250.066629


Day 7

ANCOVAP-value**

ANCOVAp-value*

WilcoxonP-value

HCV- HCV+

* 1st ANCOVA models adjust for baseline NPZ3 score. ** 2nd ANCOVA models adjust for years of education,

IV drug use, and baseline NPZ3 scores


Neuropsychological Failures:Decline of NPZ by 0.4 SD

0.52500.26248 (6%)127 (94%)

2 (13%)13 (87%)

YesNo

Week 184 Failure

0.00620.00754 (2%)217 (98%)

4 (14%)25 (86%)

YesNo

Week 24 Failure

0.00090.00188 (3%)223 (97%)

6 (21%)23 (79%)

YesNo

Day 7 Failure

Logistic regression P-value*

Fisher’s exact P-value

HCV-HCV+

*logistic regression adjusted for baseline NPZ3 score and treatment regimen.


Evidence to Date Does Not Suggest HCV Impact Progresses

Time

Dis

abili

ty

HIV

?? HIV+HCV

•Neuropathology of HCV brain disease and advanced forms not well described to date

•Cross sectional analyses don’t suggest increasing impact of co-infection


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


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


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


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)


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


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


Therapeutic Issues


A5095: Proportion of subjects with HIV-1 RNA <200 and <50 cps/ml

89% (85, 93%)83% (78, 88%)

pt estimate (95% CI) at wk 48

74% (65, 83%)

61% (50, 72%)


Treatment of HIV/HCV Co-InfectionPegylated Interferon + Ribavirin

Overall SVR

Genotype 1 Genotype 2,3

RIBAVIC n=206

AACTG n=67

APRICOT n=289

27%

16%

43%

27%

14%

73%

40%

29%

62%

0%

20%

40%

60%

80%

100%

Per

cen

t R

esp

on

se


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


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; 35:131.


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

Neurological Complications of HCV co-infection

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