Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00188201
Status:
UNKNOWN
Last Update Posted:
2005-11-29
First Post:
2005-09-09
Brief Title:
Neurocognitive Functioning in Patients With Hepatitis C Pre- and Post-Treatment With Antiviral Medication
Sponsor:
University Health Network Toronto
Organization:
University Health Network Toronto
Study Overview
Official Title:
An Investigation of Cognitive Functioning and Brain Metabolites in Patients With Non-Cirrhotic Hepatitis-C Both Pre- and Post-Treatment With Antiviral Medication
Status:
UNKNOWN
Status Verified Date:
2005-09
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The estimated global prevalence of hepatitis C HCV infection is approximately 3 170 million individuals In Canada there are an estimated 240000 people infected with HCV The current study addresses the hypothesis that neurocognitive and neurochemical abnormalities may occur in individuals with HCV-infection who do not have liver cirrhosis or vasculitic neuropathy and this may result from a direct effect of HCV on the Central Nervous System CNS The purpose of this study is to assess whether infection with the Hepatitis-C virus is associated with changes in thinking skills and brain chemistry in patients who do not have liver cirrhosis In addition we are examining whether such changes in thinking skills and brain chemistry are reversed by antiviral treatment We are also studying whether factors such as fatigue and depression have an effect on thinking skills in people with Hepatitis-C In order to take into account the impact of having viral hepatitis we will be comparing the results of the Hepatitis-C group to the results of a group of patients with Hepatitis-B and to a group of individuals who do not have Hepatitis
Detailed Description:
The current proposal addresses the hypothesis that neurocognitive and neurochemical abnormalities may occur in individuals with HCV-infection who do not have liver cirrhosis or vasculitic neuropathy and that this phenomenon may result from a direct effect of HCV on the Central Nervous System CNS Our hypothesis originated from the frequently reported complaints of forgetfulness and decreased ability to concentrate brain fog in our patients with chronic HCV-infection as well as from clinical observation of cognitive impairment in a moderate proportion of non-cirrhotic HCV-infected patients Patients with HCV-infection also report significant impairment in most realms of everyday function and greater reductions in quality of life QOL than individuals infected with the Hepatitis B virus HBV These results cannot be attributed to degree of liver inflammation or the mode of acquisition of infection Based on the well-established association between neurocognitive function and quality of life it is reasonable to hypothesize that these QOL differences between HCV and HBV are the result of cerebral compromise in individuals infected with HCV and consequent neuropsychiatric and neurocognitive dysfunction
Non-cirrhotic HCV-infected patients were found to be impaired on speeded measures of sustained attention and working memory relative to control subjects MRS results from the same study suggested that there may also be neurochemical changes associated with HCV that can be observed even in infected individuals with normal liver status as determined by biopsy In particular an increase in choline ratios was detected in the basal ganglia and white matter This pattern appears to be specific to HCV-infection as abnormalities were not found in patients with Hepatitis-B infection Furthermore the degree of neurochemical abnormality was correlated with neuropsychological performance Similar increases in choline levels have been reported in subcortical brain regions in individuals infected with HIV-1 even prior to the onset of symptomatic infection and signs of cognitive dysfunction
Rationale Mechanism through which HCV may have direct CNS effects A plausible mechanism for direct CNS effects of HCV involves passage of the virus into brain tissue through infection of circulating lymphocytes In fact a number of studies have revealed the presence of HCV RNA-negative strand an intermediate of viral replication within peripheral blood mononuclear cells PMBC However the issue of extra-hepatic replication in PBMC remains controversial due to contrary findings and methodological criticisms However more recently Laskus and colleagues demonstrated the presence of HCV RNA-negative strand in PBMC in 40-60 of HCV-infected individuals with HIV-1 co-infection and in a separate investigation determined the presence of HCV RNA-negative strand in monocytesmacrophages CD4 and CD8 lymphocytes and CD19 cells in HCVHIV-1 co-infected individuals Thus it is plausible that HCV enters the brain through circulating lymphocytes and that consequent neuropsychiatric neurocognitive and neurochemical abnormalities are related to the presence of HCV in the CNS in a way that is not yet understood Corroborating this hypothesis is the recent observation by Thomas and colleagues personal communication that HCV can be detected in the brain tissue of infected individuals upon neuropathological examination of autopsy tissue This proposed mechanism for direct CNS effects of HCV-infection is similar to that which is thought to be the cause of HIV-1 associated neurocognitive impaiiment Early in the course of the HIV-1 epidemic came the realization of frequent neurological complications including neuropsychiatric neurocognitive and motor dysfunction These symptoms could not be attributed to opportunistic infection of the CNS eg toxoplasmosis neoplasms and often progressed to a stage of dementia which came to be known as HIV-associated dementia HAD The incidence of HAD has declined drastically subsequent to the advent of antiretroviral treatment HIV-1 is thought to enter the brain very early in the course of initial infection possibly through the infection of peripheral monocytes and macrophages that cross the blood-brain barrier In HAD there is a complex and indirect mechanism of CNS damage that may occur years after initial HIV-1 infection usually under conditions of immunocompromise HIV-1 does not directly infect neurons but rather replicates within brain macrophages and microglia These cells subsequently become immunoactive and release secretory neurotoxic substances that ultimately lead to a breakdown of homeostatic mechanisms and a consequent cascade of inflammatory events The resulting metabolic encephalopathy damages and eventually destroys CNS neurons The most prominent neuropathological features of HAD occur in white matter and deep grey matter regions of the brain and include myelin pallor multinucleated giant cells and occasionally encephalitis characterized by disseminated multifocal microgranulomas composed of elongated microglia macrophages and lymphocytes Thus given preliminary findings of extra-hepatic replication within PBMC as a plausible mechanism for infiltration of CNS by HCV-infected lymphocytes neuropathological detection of HCV within the CNS clinical observation and patient complaints of cognitive deficits and reduction in HRQOL beyond that observed in chronic HBV-infection it is possible that HCV may have direct CNS effects that elicit a consequent inflammatory reaction that interferes with neuronal function in a manner similar to the neuropathological processes associated with HIV-1 infection Furthermore there are parallels between MRS findings for HIV-1 and those reported in HCV-infection in non-cirrhotic patients In particular HIV-1 is marked by an increase in choline-containing compounds Cho similar to the preliminary findings of Forton and colleagues 1999 2000 This increase in subcortical Cho can be found in HIV-1 positive patients even in the absence of cognitive dysfunction suggesting it may be a very early marker of CNS involvement Other changes notably a decrease in N-acetylaspartate are apparent in HIV-1 infected individuals with significant neuropsychological impairment indicating an evolution of CNS disease Of importance antiretroviral therapy appears to reverse the Cho abnormalities and also results in significant improvements in neurocognitive function
Objectives Phase I In the first phase we will determine whether non-cirrhotic individuals with chronic HCV-infection who do not have cryoglobulinemia manifest abnormalities in brain biochemistry and neurocognitive performance This will be accomplished by comparing HCV-infected individuals to subjects with HBV-infection to control for the effects of viral hepatitis and to an age-matched control group on measures of neurocognitive performance and MRS after careful screening to rule out the presence of other conditions that may affect cognitive performance We will also determine whether there is a relationship between MRS-quantified brain biochemistry and neurocognitive performance Finally we will reveal the determinants of neurocognitive impairment and neurochemical abnormalities using multivariate analyses to evaluate the relative contribution of other clinical parameters associated with HCV-infection such as fatigue mood psychiatric symptoms serum aminotransferase levels degree of fibrosis viral load
Phase II In the second phase of our investigation we will determine whether HCV-infected patients who achieve a sustained virological response to antiviral therapy no HCV RNA detectable in serum will show amelioration of cerebral metabolite abnormalities and cognitive impairment at follow-up 6 months following the cessation of treatment compared to patients who do not respond to antiviral treatment and compared to an age-matched control group the same control subjects tested in Phase I of the investigation In the group that does not respond to treatment MRS abnormalities will remain unchanged or may worsen A control group is particularly important for the NP assessment aspect of the investigation in order to account for practice effects that may result from repeated administration of NP tests Patients with HBV-infection will not be re-tested at this point because we do not expect to see any abnormalities in this group at the initial assessment point In addition if HBV-infected patients were started on antiviral treatment following their liver biopsy it is likely that they will still be receiving treatment 1-5 years later The rationale for timing the final assessment of HCV patients 6 months after the cessation of antiviral therapy involves the known neuropsychiatric sequelae of treatment with Interferon which may otherwise affect the cognitive assessment Efficacy of antiviral treatment of HCV with Interferon and ribavirin At the time of this submission treatment with IFNa2b plus ribavirin is the standard of care for patients with chronic HCV-infection However recently published data indicates that when interferon is pegylated covalently bound to polyethylene glycol efficacy is markedly enhanced in comparison to standard IFNa2b plus ribavirin Enhanced efficacy is likely due to the sustained elevation of IFN in serum due to delay of its renal excretion Thus weekly rather than three times weekly injections are required Pilot study data indicates that the efficacy of pegylated IFN alfa-2a plus ribavirin is even more effective This portion of the investigation is an add-on to a safety study involving treatment with 6 or 12 months of Pegylated Interferon alfa-2a plus ribabvirin UHN 01-0082 We expect that the rate of sustained virological responders in non-cirrhotic patients will be approximately 54
METHODS Subjects - In total 150 subjects will participate in the investigation 100 of which will be assessed on two different occasions approximately 15 years apart Fifty patients with chronic Hepatitis C infection HCV fifty with chronic Hepatitis B infection HBV and fifty healthy control subjects will be recruited to participate in the investigation All participants will undergo screening procedures to rule out conditions that can affect cognitive function Those that are deemed eligible on the basis of the inclusion and exclusion criteria will participate in the first phase of the investigation in which they will be assessed with Physical Neurological Psychiatric and Neuropsychological examinations as well as with Magnetic Resonance Spectroscopy In the second phase of the investigation HCV patients and control subjects will be reassessed after an interval of 10 to 15 years to determine whether antiviral treatment is effective at ameliorating neurocognitive and brain biochemical abnormalities identified in the first phase of the investigation
Materials Assessments and Procedures Screening Assessments Liver Biopsy All HCV and BBV patients who have received a liver biopsy as part of their clinical management will be eligible to participate in the current investigation although no patient will receive a biopsy for the purposes of this investigation Instead participants will be recruited from the pool of subjects who are receiving clinical care at the UHNTWH Liver Clinic who have had a recent liver biopsy performed and will be progressing to treatment both HBV and HCV patients
Laboratory Assessment HCV and HBV patients will undergo a screening laboratory assessment that will consist of hematological assessment blood chemistry and urinalysis as per the protocol for the clinical trial that this investigation is being added on to UHN 01-0082 In addition supplementary laboratory assessments will be conducted to screen for other parameters that may be related to cognitive function In particular the following tests will be performed RBCFolate Hb Urea Electrolytes Bl2 TSH Cryoglobulins INR Albumin
Physical Evaluation All HCV and HBV patients will be assessed by the Principle Investigator for clinical signs of liver disease and will also have a general physical examination as specified in the clinical trial protocol UHN 01-0082 HBV patients will be assessed by the Principle Investigator in a similar manner The results of this assessment will be used to screen for signs of clinically significant liver disease eg stigmata asterixis liver size spleen size jaundice ascites or edema as well as for other conditions related to liver disease that could possibly affect cognition and thus exclude the participant from participation in the investigation eg cryogloubulinemia
Neurological Examination Patients will be examined by the study neurologist for the presence of conditions that would result in exclusion from the investigation The neurologist will also examine the patients for signs of peripheral neuropathy that could indicate the presence of cryoglobulinemia eg dysesthesia or hypesthesia motor weakness exaggerated deep tendon reflexes and positive pyramidal signs In addition the neurological examination will be conducted during the final visit in order to determine whether any of the neurological side effects known to be associated with Interferon therapy have persisted beyond the 6 month wash-out period
Psychiatric Examination The patient will be examined by the study psychiatrist to determine current and lifetime presence of psychiatric diagnoses that could result in their exclusion from the investigation Of specific concern are psychiatric diagnoses that could have an impact on cognitive function eg Major Depression Bipolar Disorder Substance Abuse disorder Antisocial Personality Disorder
Non-cirrhotic HCV-infected patients were found to be impaired on speeded measures of sustained attention and working memory relative to control subjects MRS results from the same study suggested that there may also be neurochemical changes associated with HCV that can be observed even in infected individuals with normal liver status as determined by biopsy In particular an increase in choline ratios was detected in the basal ganglia and white matter This pattern appears to be specific to HCV-infection as abnormalities were not found in patients with Hepatitis-B infection Furthermore the degree of neurochemical abnormality was correlated with neuropsychological performance Similar increases in choline levels have been reported in subcortical brain regions in individuals infected with HIV-1 even prior to the onset of symptomatic infection and signs of cognitive dysfunction
Rationale Mechanism through which HCV may have direct CNS effects A plausible mechanism for direct CNS effects of HCV involves passage of the virus into brain tissue through infection of circulating lymphocytes In fact a number of studies have revealed the presence of HCV RNA-negative strand an intermediate of viral replication within peripheral blood mononuclear cells PMBC However the issue of extra-hepatic replication in PBMC remains controversial due to contrary findings and methodological criticisms However more recently Laskus and colleagues demonstrated the presence of HCV RNA-negative strand in PBMC in 40-60 of HCV-infected individuals with HIV-1 co-infection and in a separate investigation determined the presence of HCV RNA-negative strand in monocytesmacrophages CD4 and CD8 lymphocytes and CD19 cells in HCVHIV-1 co-infected individuals Thus it is plausible that HCV enters the brain through circulating lymphocytes and that consequent neuropsychiatric neurocognitive and neurochemical abnormalities are related to the presence of HCV in the CNS in a way that is not yet understood Corroborating this hypothesis is the recent observation by Thomas and colleagues personal communication that HCV can be detected in the brain tissue of infected individuals upon neuropathological examination of autopsy tissue This proposed mechanism for direct CNS effects of HCV-infection is similar to that which is thought to be the cause of HIV-1 associated neurocognitive impaiiment Early in the course of the HIV-1 epidemic came the realization of frequent neurological complications including neuropsychiatric neurocognitive and motor dysfunction These symptoms could not be attributed to opportunistic infection of the CNS eg toxoplasmosis neoplasms and often progressed to a stage of dementia which came to be known as HIV-associated dementia HAD The incidence of HAD has declined drastically subsequent to the advent of antiretroviral treatment HIV-1 is thought to enter the brain very early in the course of initial infection possibly through the infection of peripheral monocytes and macrophages that cross the blood-brain barrier In HAD there is a complex and indirect mechanism of CNS damage that may occur years after initial HIV-1 infection usually under conditions of immunocompromise HIV-1 does not directly infect neurons but rather replicates within brain macrophages and microglia These cells subsequently become immunoactive and release secretory neurotoxic substances that ultimately lead to a breakdown of homeostatic mechanisms and a consequent cascade of inflammatory events The resulting metabolic encephalopathy damages and eventually destroys CNS neurons The most prominent neuropathological features of HAD occur in white matter and deep grey matter regions of the brain and include myelin pallor multinucleated giant cells and occasionally encephalitis characterized by disseminated multifocal microgranulomas composed of elongated microglia macrophages and lymphocytes Thus given preliminary findings of extra-hepatic replication within PBMC as a plausible mechanism for infiltration of CNS by HCV-infected lymphocytes neuropathological detection of HCV within the CNS clinical observation and patient complaints of cognitive deficits and reduction in HRQOL beyond that observed in chronic HBV-infection it is possible that HCV may have direct CNS effects that elicit a consequent inflammatory reaction that interferes with neuronal function in a manner similar to the neuropathological processes associated with HIV-1 infection Furthermore there are parallels between MRS findings for HIV-1 and those reported in HCV-infection in non-cirrhotic patients In particular HIV-1 is marked by an increase in choline-containing compounds Cho similar to the preliminary findings of Forton and colleagues 1999 2000 This increase in subcortical Cho can be found in HIV-1 positive patients even in the absence of cognitive dysfunction suggesting it may be a very early marker of CNS involvement Other changes notably a decrease in N-acetylaspartate are apparent in HIV-1 infected individuals with significant neuropsychological impairment indicating an evolution of CNS disease Of importance antiretroviral therapy appears to reverse the Cho abnormalities and also results in significant improvements in neurocognitive function
Objectives Phase I In the first phase we will determine whether non-cirrhotic individuals with chronic HCV-infection who do not have cryoglobulinemia manifest abnormalities in brain biochemistry and neurocognitive performance This will be accomplished by comparing HCV-infected individuals to subjects with HBV-infection to control for the effects of viral hepatitis and to an age-matched control group on measures of neurocognitive performance and MRS after careful screening to rule out the presence of other conditions that may affect cognitive performance We will also determine whether there is a relationship between MRS-quantified brain biochemistry and neurocognitive performance Finally we will reveal the determinants of neurocognitive impairment and neurochemical abnormalities using multivariate analyses to evaluate the relative contribution of other clinical parameters associated with HCV-infection such as fatigue mood psychiatric symptoms serum aminotransferase levels degree of fibrosis viral load
Phase II In the second phase of our investigation we will determine whether HCV-infected patients who achieve a sustained virological response to antiviral therapy no HCV RNA detectable in serum will show amelioration of cerebral metabolite abnormalities and cognitive impairment at follow-up 6 months following the cessation of treatment compared to patients who do not respond to antiviral treatment and compared to an age-matched control group the same control subjects tested in Phase I of the investigation In the group that does not respond to treatment MRS abnormalities will remain unchanged or may worsen A control group is particularly important for the NP assessment aspect of the investigation in order to account for practice effects that may result from repeated administration of NP tests Patients with HBV-infection will not be re-tested at this point because we do not expect to see any abnormalities in this group at the initial assessment point In addition if HBV-infected patients were started on antiviral treatment following their liver biopsy it is likely that they will still be receiving treatment 1-5 years later The rationale for timing the final assessment of HCV patients 6 months after the cessation of antiviral therapy involves the known neuropsychiatric sequelae of treatment with Interferon which may otherwise affect the cognitive assessment Efficacy of antiviral treatment of HCV with Interferon and ribavirin At the time of this submission treatment with IFNa2b plus ribavirin is the standard of care for patients with chronic HCV-infection However recently published data indicates that when interferon is pegylated covalently bound to polyethylene glycol efficacy is markedly enhanced in comparison to standard IFNa2b plus ribavirin Enhanced efficacy is likely due to the sustained elevation of IFN in serum due to delay of its renal excretion Thus weekly rather than three times weekly injections are required Pilot study data indicates that the efficacy of pegylated IFN alfa-2a plus ribavirin is even more effective This portion of the investigation is an add-on to a safety study involving treatment with 6 or 12 months of Pegylated Interferon alfa-2a plus ribabvirin UHN 01-0082 We expect that the rate of sustained virological responders in non-cirrhotic patients will be approximately 54
METHODS Subjects - In total 150 subjects will participate in the investigation 100 of which will be assessed on two different occasions approximately 15 years apart Fifty patients with chronic Hepatitis C infection HCV fifty with chronic Hepatitis B infection HBV and fifty healthy control subjects will be recruited to participate in the investigation All participants will undergo screening procedures to rule out conditions that can affect cognitive function Those that are deemed eligible on the basis of the inclusion and exclusion criteria will participate in the first phase of the investigation in which they will be assessed with Physical Neurological Psychiatric and Neuropsychological examinations as well as with Magnetic Resonance Spectroscopy In the second phase of the investigation HCV patients and control subjects will be reassessed after an interval of 10 to 15 years to determine whether antiviral treatment is effective at ameliorating neurocognitive and brain biochemical abnormalities identified in the first phase of the investigation
Materials Assessments and Procedures Screening Assessments Liver Biopsy All HCV and BBV patients who have received a liver biopsy as part of their clinical management will be eligible to participate in the current investigation although no patient will receive a biopsy for the purposes of this investigation Instead participants will be recruited from the pool of subjects who are receiving clinical care at the UHNTWH Liver Clinic who have had a recent liver biopsy performed and will be progressing to treatment both HBV and HCV patients
Laboratory Assessment HCV and HBV patients will undergo a screening laboratory assessment that will consist of hematological assessment blood chemistry and urinalysis as per the protocol for the clinical trial that this investigation is being added on to UHN 01-0082 In addition supplementary laboratory assessments will be conducted to screen for other parameters that may be related to cognitive function In particular the following tests will be performed RBCFolate Hb Urea Electrolytes Bl2 TSH Cryoglobulins INR Albumin
Physical Evaluation All HCV and HBV patients will be assessed by the Principle Investigator for clinical signs of liver disease and will also have a general physical examination as specified in the clinical trial protocol UHN 01-0082 HBV patients will be assessed by the Principle Investigator in a similar manner The results of this assessment will be used to screen for signs of clinically significant liver disease eg stigmata asterixis liver size spleen size jaundice ascites or edema as well as for other conditions related to liver disease that could possibly affect cognition and thus exclude the participant from participation in the investigation eg cryogloubulinemia
Neurological Examination Patients will be examined by the study neurologist for the presence of conditions that would result in exclusion from the investigation The neurologist will also examine the patients for signs of peripheral neuropathy that could indicate the presence of cryoglobulinemia eg dysesthesia or hypesthesia motor weakness exaggerated deep tendon reflexes and positive pyramidal signs In addition the neurological examination will be conducted during the final visit in order to determine whether any of the neurological side effects known to be associated with Interferon therapy have persisted beyond the 6 month wash-out period
Psychiatric Examination The patient will be examined by the study psychiatrist to determine current and lifetime presence of psychiatric diagnoses that could result in their exclusion from the investigation Of specific concern are psychiatric diagnoses that could have an impact on cognitive function eg Major Depression Bipolar Disorder Substance Abuse disorder Antisocial Personality Disorder
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| EOP-48307 | None | None | None |