Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT00188201 |
| Other study ID # |
01-0827-E |
| Secondary ID |
EOP-48307 |
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
September 9, 2005 |
| Last updated |
November 28, 2005 |
| Start date |
January 2002 |
Study information
| Verified date |
September 2005 |
| Source |
University Health Network, Toronto |
| Contact |
Mirela Mrkonjic |
| Phone |
416-603-5800 |
| Is FDA regulated |
No |
| Health authority |
Canada: Health Canada |
| Study type |
Observational
|
Clinical Trial Summary
The estimated global prevalence of hepatitis C (HCV) infection is approximately 3% (170
million individuals). In Canada there are an estimated 240,000 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.
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 monocytes/macrophages, CD4+ and CD8+
lymphocytes, and CD19+ cells in HCV/HIV-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
(e.g. 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 1.5 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 1.0
to 1.5 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: RBC/Folate, 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 (e.g. 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 (e.g. 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 (e.g. 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 (e.g. Major Depression, Bipolar Disorder, Substance Abuse
disorder, Antisocial Personality Disorder).
