Keywords:
Hepatitis C - Cognitive Disorders - Combined Modality Therapy
Palavras-chave:
Hepatite C - Transtornos Cognitivos - Terapia Combinada
INTRODUCTION
Currently, hepatitis C is one of the most common causes of chronic liver disease all
over the world. It is estimated that approximately 170 to 200 million persons all
over the world are infected by HCV. In Brazil, the prevalence is approximately 1.4%
of the population, representing about two million persons affected[1],[2],[3]. In respect to cognition and neuropsychiatric aspects, parameters below the population’s
average are observed, with greater highlights in the literature for attention deficit,
concentration, memory, information processing, and visual-motor processing speed[4],[5],[6],[7],[8]. Raison et al.[9] state that among the adverse neuropsychiatric effects, there are depression, anxiety,
fatigue, delirium, extreme irritability states, agitation, and in some cases development
of psychosis. The depressive symptoms are found in about 40% of the patients with
harmful effects both in the quality of life as well as in the conformity with the
treatment.
Several evidence lines suggest that the cognitive dysfunction and the depressive symptoms
are related with the release of post-inflammatory cytokines caused by HCV infection
of the central nervous system, which replicates in the mononuclear peripheral blood
cells and in the bone marrow, precursor of the microglial cell in the brain. The putative
inflammatory cytokines are interleukin-1, 4, and 6, the tumor necrosis factor-α and
interferon-α, which could cross the blood-brain barrier and affect the functioning
of the brain[10].Thus, the HCV is introduced in the central nervous system through a “Trojan horse”
mechanism[4],[11],[12],[13]. However, no clear correlation between the HCV viral load and cognitive impairment
could be demonstrated[14]. The presence of HCV in the liver tissue stimulates the endogenous production of
interferon and this substance interferes with the metabolism of tryptophan and reduces
serotonin production in the brain. Therefore, this would represent a pretense induction
mechanism or predisposition to depression[15].
The use of interferon in HCV-infected patients present side effects in several studies,
with those most mentioned being: fever, headache, chills, myalgia, asthenia, arthralgia,
and anorexia[16], with asthenia being the most frequent symptom in patients diagnosed with hepatitis
C. Others neuropsychiatric symptoms frequently reported by patients are irritability,
weariness, emotional instability and depression[17].
As of the second half of 2015, the STD/Aids department of the Ministry of Health announced
that the patients with Hepatitis C under treatment at SUS (National Unified Health
System) would have more drugs available for treatment: sofosbuvir, simeprevir, and
daclatasvir. The new treatments have a cure rate close to 90%, significantly higher
than all the treatments used to this moment, and duration between 12 to 24 weeks,
against 48 weeks duration for the previous therapy. Another advantage lies in the
fact that the treatment is oral, proportioning greater quality of life and comfort
for the patient[18].
The indications for administration of each medication were: Simeprevir was administered
to adult patients with HCV infection genotype 1, treatment virgins, or that failed
previous treatment for interferon, with HIV-1 coinfection and adults with genotype
4 HCV infection (virgin or previously treated)[19]. Sofosbuvir should be administered to patients with infection by HCV genotypes 1,
2, or 3, including those with HCV / HIV-1 coinfection[20]. Daclastavir is indicated for combined with other agents for treatment of chronic
hepatitis C virus HCV-1 infection in adults with compensated liver disease (including
cirrhosis)[21].
The purpose of this study was to check the cognitive performance of patients with
chronic hepatitis C before and after treatment with simeprevir. Sofosbuvir and daclatasvir.
METHODS
A prospective observational study was carried out in three stages: before, soon after
treatment (up to three weeks after final treatment), and six months afterwards. The
participants were selected at Instituto de Infectologia Emílio Ribas, tertiary referral
hospital in the State of São Paulo, Brazil, in the period from 2015 to 2017. The criteria
for inclusion contemplated outpatients with minimum 18 years of age, minimum four
years education, and eligible for antiviral treatment for chronic infection by HCV.
The exclusion criteria were: not having completed the three proposed evaluations,
use of psychotropic substances, hepatic encephalopathy, HIV, HTLV coinfected patients
or chronic hepatitis B, hepatocarcinoma, cirrhosis in transplant waiting list, transplanted
patients with HCV relapse infection, previously documented dementia, and major depression.
The neuropsychological battery consisted of the following tests: Estimated Intellectual
Function: Vocabulary[22] and Matrix Reasoning[22] from WAIS III scale; Memory: Operational- Digit span subtest[22] - WAIS-III, Auditory Episodic Memory - Hopkins Verbal Learning Test (HVLT)[23], Visual Memory: Rey Complex Figures[24]; Visuoconstruction: Rey Complex Figures (copy)[24]; Attention: Sustained - Trail Making A[25], Alternating - Trail Making B[25], Selective - Stroop[25]; Processing Speed: Digit Symbol Coding subtest[22] - WAIS-III; Executive Function: Phonemic Verbal Fluency (F.A.S.)[26] and Category (animals)[27] and Motor Speed: Grooved pegboard test[28]. To analyze the impact in the daily life activities, the Lawton[29] Scale was used, while, the evaluation of depressive symptoms was made with Beck’s
Depression Inventory[30]. Alcohol intake was evaluated for all patients by means of the ASSIST Test[31]. No patient had use of low, moderate, and high-risk substances for the use of alcohol
and drugs, if they had, they would have been excluded from the study. Cigarette smoking
patients were not excluded.
After neuropsychological assessment, the following categories, adapted from the Diagnostic
and Statistical Manual of Mental Disorders (DSM-V)[32], were created:
-
No neurocognitive disorder: no evidence of cognitive decline and independence in daily
activities. Minor neurocognitive disorder: evidence of modest cognitive decline from
a previous performance level, in one or more of the evaluated domains, based on the
concerns of the individual, and a decline in neurocognitive performance, typically
involving test performance within the range of one and two standard deviations below
appropriate norms on formal. The cognitive deficits are insufficient to interfere
with independence.
-
Major neurocognitive disorder: There is evidence of substantial cognitive decline
from a previous performance level in one or more of the domains outlined above based
on the concerns of the individual, and a decline in neurocognitive performance, typically
involving test performance in the range of two or more standard deviations below appropriate
norms on formal. The cognitive deficits are sufficient to interfere with independence.
A sociodemographic questionnaire was applied with questions referring to age, gender,
education, diagnosis time, virus transmission, drugs in use, and presence of cirrhosis.
The genotype was collected in the hospital’s laboratory exam system.
For statistical analysis, described analysis (mean, frequency, and standard deviation),
chi-square (for analysis of category variables [frequencies]), and ANOVA (to test
differences of cognitive performance and of depression in the three moments of the
evaluation) were used. The value of statistical significance adopted was 5%.
RESULTS
One hundred and forty-six patients were consecutively recruited by telephone contact
after the medical information that they were eligible and would start with the new
drugs for hepatitis treatment. Eighty-eight patients were excluded ([Figure 1]). The 58 remaining made the three evaluations foreseen in the study.
Figure 1 Flow diagram.
Most of the patients were of male gender, with average of 58.23 years of age, with
genotype 1 HCV, and absence of advanced hepatic fibrosis. The main form of virus transmission
was by blood transfusion (20 cases - 34.5%). In [Table 1], the main characteristics of the patients in the baseline are presented.
Table 1
Main characteristics in the baseline.
|
Characteristics
|
Mean±SD
|
|
Age
|
58.23 (8.79) years
|
|
Education
|
9.75 (4.43) years
|
|
Gender
|
|
Male
|
30 (51.7%)
|
|
Female
|
28 (48.3%)
|
|
Evolution time
|
10.73 (8.00) years
|
|
Transmission mechanism
|
|
Sexual
|
5 (8.6%)
|
|
Transfusion
|
20 (34.5%)
|
|
Sharp objects
|
14 (24.1%)
|
|
Not known
|
19 (32.8%)
|
|
Cirrhosis
|
28 (48.3%)
|
SD: standard deviation.
During antiviral treatment, the patients kept adequate hemoglobin levels. None of
the participants showed a problematic consumption of alcohol, mental confusion, or
hepatic encephalopathy in the inclusion, during and after the treatment. Thirty-three
(56.8%) patients presented other associated diseases or conditions, like high blood
pressure - 14 (24.1%), diabetes mellitus - 11 (18.9%), hypothyroidism - 4 (6.8%),
cholesterol - 2 (3.4%), rheumatism (this information was provided by the patient),
rheumatoid arthritis, pangastritis, and osteoporosis - 1 (1.7%). All patients showed
independence for daily living activities according to the Lawton Scale criteria.
From the 58 patients, 14 (24.1%) underwent treatment with sofosbuvir+simeprevir, 17
(29.3%) with sofosbuvir+daclatasvir, 26 (44.8%) sofosbubir+daclastavir+ribavirin,
and 1 (1.7%) with sofosbuvir+ribavirin. All patients presented a negative virological
test result for hepatitis C.
Comparing the results of the neuropsychological evaluations (before, soon after conclusion,
and six months after conclusion of the use of HCV drug), a significant improvement
was observed in relation to the acquisition of new knowledge (HVLT - immediate recall
auditory episodic memory, p=0.03), delayed visual memory (Rey Figure - delayed recall,
p=0.01), and a tendency for alternating attention (Trail Making B, p=0.07). No significant
improvement was observed in other neurocognitive domains after treatment, as shown
in [Table 2].
Table 2
Neuropsychological domains in patients before and after antiviral treatment.
|
Test
|
1st Evaluation
|
2nd Evaluation
|
3rd Evaluation
|
p-value
|
|
Vocabulary
|
32.82 (1.15)
|
36.13 (1.05)
|
34.93 (1.24)
|
0.12
|
|
Matrix reasoning
|
9.79 (0.61)
|
10.00 (0.69)
|
10.29 (0.71)
|
0.87
|
|
Estimated IQ
|
93.58 (2.01)
|
97.17 (1.40)
|
97.62 (1.48)
|
0.17
|
|
Digit Span
|
12.62 (0.95)
|
11.20 (0.34)
|
11.51 (0.35)
|
0.24
|
|
Immediate HVLT
|
22.10 (0.65)
|
24.08 (0.66)
|
24.20 (0.59)
|
0.03
|
|
Delayed HVLT
|
7.93 (0.41)
|
8.18 (0.30)
|
8.18 (0.24)
|
0.81
|
|
Recognition HVLT
|
10.08 (0.26)
|
10.31 (0.24)
|
10.44 (0.17)
|
0.54
|
|
Rey - copy
|
27.99 (0.94)
|
28.26 (0.95)
|
34.16 (5,95)
|
0.36
|
|
Rey immediate
|
11.28 (0.89)
|
12.91 (1.07)
|
13.63 (1.01)
|
0.19
|
|
Rey delayed
|
10.48 (0.79)
|
13.10 (0.99)
|
14.03 (0.95)
|
0.01
|
|
Trail A
|
53.15 (3.24)
|
47.34 (3.04)
|
47.86 (2.83)
|
0.35
|
|
Trail B
|
141.78 (14.68)
|
110.98 (6.90)
|
114.74 (8.24)
|
0.07
|
|
Stroop
|
39.63 (2.51)
|
46.81 (4.94)
|
40.15 (3.62)
|
0.33
|
|
Digit Symbol Coding
|
37.22 (1.83)
|
40.29 (2.04)
|
41.06 (1.97)
|
0.34
|
|
F.A.S.
|
30.51 (1.40)
|
29.77 (1.26)
|
31.03 (1.13)
|
0.78
|
|
Animals
|
16.01 (1.13)
|
14.74 (0.47)
|
14.91 (0.46)
|
0.43
|
|
Grooved DH
|
86.81 (3.42)
|
86.10 (3.41)
|
87.70 (3.76)
|
0.95
|
|
Grooved NDH
|
95.39 (3.81)
|
89.71 (3.65)
|
93.36 (4.56)
|
0.60
|
IQ: intellectual coefficient; HVLT: Hopkins Verbal Learning test; F.A.S: Fluency Task
Test, DH: dominant hand; NDH: non-dominant hand.
After antiviral treatment, it was possible to verify an increase in the frequency
of patients with preserved cognitive function, above all on those who presented memory
variation. In contrast, it was not observed a change in the cognitive profile of patients
who presented non-amnestic cognitive impairment, as shown in [Table 3].
Table 3
Distribution of the frequency of cognitive impairment before and after antiviral treatment.
|
1st Evaluation
|
2nd Evaluation
|
3rd Evaluation
|
p-value
|
|
Preserved cognitive function
|
16 (27.5%)
|
23 (39.6%)
|
29 (50%)
|
0.01
|
|
Amnestic MCI - single-domain
|
5 (8.6%)
|
4 (6.8%)
|
4 (6.8%)
|
0.19
|
|
Amnestic MCI multiple-domain
|
16 (27.5%)
|
11 (18.9%)
|
4 (6.8%)
|
0.01
|
|
Non-amnestic MCI - single-domain
|
8 (13.7%)
|
8 (13.7%)
|
9 (15.5%)
|
0.19
|
|
Non-amnestic MCI multiple-domain
|
13 (22.4%)
|
12 (20.6%)
|
12 (20.6%)
|
0.20
|
MCI: mild cognitive impairment.
An improvement in the depressive symptoms, with increase in the frequency from 67.23
to 84.47% in the minimum and mild degrees, was observed (p=0.079). The patients that
presented severe degree before the start of the treatment maintained the same intensity
at conclusion ([Table 4]).
Table 4
Distribution of the frequency of depression.
|
Beck
|
1st Evaluation
|
2nd Evaluation
|
3rd Evaluation
|
|
Degree - Minimum (n/%)
|
30 (51.72)
|
35 (60.34)
|
35 (60.34)
|
|
Degree - Mild (n/%)
|
9 (15.51)
|
7 (12.06)
|
14 (24.13)
|
|
Degree - Moderate (n/%)
|
13 (22.41)
|
12 (20.68)
|
3 (5.17)
|
|
Degree - Severe (n/%)
|
6 (10.34)
|
4 (6.89)
|
6 (10.34)
|
No significant correlations were observed between form of transmission (p=0.70), age
(p=0.47), gender (p=0.48), education (p=0.74), time since diagnosis (p=0.64), and
presence or absence of cirrhosis (p=0.34), as well as improvement of cognitive performance.
DISCUSSION
In this study, the neuropsychological performance and frequency of depression in HCV
infected patients were compared before the start of treatment, soon after the expected
treatment and six months after treatment conclusion. It was observed that the patients
presented significant cognitive improvement in the neurocognitive domains of immediate
verbal episodic memory, late recall visual memory, and tendency to alternating attention.
The chronic hepatitis C virus infection could lead to impairment of the central nervous
system (CNS) by means of diverse mechanisms. CNS impairment could be due to the presence
of the virus in the brain tissue, affecting its function, whether directly by pathogenic
effect of the virus in the tissue, or indirectly, by means of the immune-mediated
injury mechanism, independent of hepatic dysfunction[6].
The normal function of the brain could also be affected in the presence of hepatic
insufficiency, due to toxic levels of ammonia, leading to the development of hepatic
encephalopathy syndrome, condition that promotes the appearance of cognitive and behavioral
changes, which could also arise from and be secondary to the side effects of drugs
used in the treatment of chronic hepatitis C virus infection, especially interferon
alfa[7],[33],[34].
The HCV infected patients could present cognitive changes, characterized by memory
loss, conscience fluctuation and disorientation, attention and difficulty in accomplishing
plain daily activities, condition known as hepatic encephalopathy, related to the
elevation of ammonia serum levels and to astrocytic swelling[7]. Recent evidences point out that about 30% of patients infected hepatitis C virus
present cognitive changes, and in part of these individuals, these changes are independent
of hepatic dysfunction, viral load, or viral genotype. In patients without cirrhosis,
the symptoms characterized by slow thinking and difficulty in concentration are predominant[4],[5],[6],[7],[8].
Several studies[4],[6],[33],[34],[35],[36],[37] using neuropsychological tests batteries have demonstrated cognitive impairment
of sustained attention, concentration, working memory, processing speed, with greater
impairment of sustained attention, and visual-motor processing speed. Studies show
not only significant symptoms of attention deficit and executive function, but greater
prevalence in the depression, anxiety and fatigue symptoms and impact in the quality
of life. Other impaired neuropsychological functions are also observed, such as verbal
learning ability, with an increase in the verbal and working memory deficit after
the use of interferon and ribavirin[33]. It was observed an increase in the probability of dysfunctions when there is association
of hepatic encephalopathy and cirrhosis in the comorbidities presented by HCV bearers[6],[34]. However, there is little data available describing the potential reversibility
of cognitive disturbances after well-succeeded antiviral treatments.
Byrnes et al.[34] carried out a magnetic resonance spectroscopy and a battery of neuropsychological
tests before, during and after antiviral treatment with interferon and ribavirin in
15 HCV infected patients. They concluded that the eradication of HCV had a beneficial
effect on the brain metabolism and better verbal learning and visual and spatial memories.
Kraus et al.[35] carried out a multicentric study including 168 patients with HCV that received antiviral
therapy with interferon and ribavirin. Twelve months after conclusion of the antiviral
treatment, the patients with sustained virological response (SVR) presented significant
improvement in four of five domains (vigilance, shared attention, optical task, and
working memory). Barbosa et al.[36] conducted a study in which they evaluated the cognitive profile of patients submitted
to HCV treatment before and after the treatment (24 and 48 weeks), the result showed
that the patients that reached HCV eradication presented significant improvement in
the immediate and delayed episodic memory.
Kleefeld et al.[37] conducted a longitudinal analysis of the cognitive performance of 22 patients (8
HCV+, 14 HCV+/HIV+) who completed neuropsychological testing at baseline and at week
12 after DAA therapy. At baseline, 54.5% of the patients met the criteria for cognitive
impairment. Follow-up analysis revealed significant improvements in the domains of
visual memory/learning, executive functions, verbal fluency, processing speed, and
motor skills but not in verbal learning and attention/working memory. The findings
showed that successful DAA treatment leads to cognitive improvements in several domains
measured by standard neuropsychological testing.
Marciniewicz et al.[38], conducted a study to assess brain volume changes and the impact on neuropsychological
status in HCV-infected individuals before and after therapy without interferon with
direct-acting antiviral agents (DAA). Eleven HCV genotype 1 patients treated with
ombitasvir / paritaprevir (ritonavir-boosted) and dasabuvir, with or without ribavirin,
underwent brain magnetic resonance imaging (MRI) before and 24 weeks after the end
of therapy. After DAA therapy, a statistically significant improvement was observed
in the performance of the three tasks of the Rey Complex Figure Test, which allows
the evaluation of different functions (attention, planning, work, memory) and also
a significant improvement in the percent responses of the Rey, conceptual level in
the Wisconsin Card Classification Test (a neurocognitive test for assessing executive
function).
In these studies, the patients were submitted to treatment with interferon, but the
results on the improvement of the cognitive performance were similar to those found
in patients submitted to the new treatment proposed by the Ministry of Health of Brazil,
an improvement in relation to the acquisition of new information and visual memory
was also observed. The big difference was in relation to the side effects. The patients
reported only little fatigue and headache, although bearable, whose symptoms occurred
only in the first week.
According to the study conducted by Hahn et al.[39] with 24 patients with chronic HCV infection, before (T1), during (T2: at 4 weeks)
and 12 weeks post-treatment with DAA (T3), concluded that DAA exert positive and persistent
effects on both fatigue and mood in patients with chronic HCV infection. These extrahepatic
benefits are at least partly related to the modulation of TRP metabolism.
In relation to depression, despite the decrease in the frequency of more severe intensities
after the treatment was concluded, no statistically significant difference was observed
between the mean score before and after treatment, result similar to that observed
by Barbosa et al.[36]. It is possible that the greater depression frequency and related symptoms observed
before the antiviral treatment reflected, at least in part, the clinical, social,
and emotional contexts of the patients.
A limitation of the present study was constituted in the lack of an HCV control group
of non-treated patients to exclude some confusion factors, like effect of practice
in the tested neurocognitive domains. Another limitation of the study is the possibility
of the learning effect of the tests applied.
In conclusion, we demonstrated that the patients that reached HCV eradication presented
significant improvement in immediate recall auditory episodic memory and delayed visual
memory. However, the frequency of depressive symptoms did not present a statistically
significant decrease. The hypothesis for these results may be the treatment of encephalopathy,
as well as the elimination of the virus in the central nervous system, since the presence
of one of these two factors may cause multifocal lesions in the white substance predisposing
the individual to neuropsychological alterations and depression[40]. The additional benefit of the improvement in the neurocognitive impairment after
cleansing of HCV with therapy based on the new drugs have clinical implications and
the potential of making the cognitive function a valid result of the treatment.
