Cognitive function, mood and health-related quality of life in hepatitis C virus (HCV)-monoinfected and HIV/HCV-coinfected individuals commencing HCV treatment

Authors

  • HH Thein,

    1. National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia,
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    • Hla-Hla Thein is presently affiliated with the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.

  • P Maruff,

    1. Centre for Neuroscience, University of Melbourne, Parkville, Vic, Australia,
    2. CogState Ltd, Melbourne, Vic, Australia,
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  • M Krahn,

    1. Departments of Medicine and Health Policy, Management and Evaluation and Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada,
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  • JM Kaldor,

    1. National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia,
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  • DJ Koorey,

    1. Gastroenterology and Hepatology Unit, Royal Prince Alfred Hospital, Sydney, NSW, Australia,
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  • BJ Brew,

    1. National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia,
    2. Department of Neurology, St Vincent's Hospital, Sydney, NSW, Australia, and
    3. HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, NSW, Australia
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  • GJ Dore

    1. National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia,
    2. HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, NSW, Australia
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  • *This work was presented in part at the 5th Australasian Hepatitis C Conference, February 2006, Sydney, Australia; the 17th Annual Conference of the Australasian Society for HIV Medicine, August 2004, Hobart, Australia (poster); the 4th Australasian Hepatitis C Conference, August 2004, Canberra, Australia; and the XV International AIDS Conference, July 2004, Bangkok, Thailand (poster).

Associate Professor Gregory J. Dore, National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Level 2, 376 Victoria Street, Darlinghurst NSW 2010, Australia. Tel: +61-2-9385 0900; fax: +61-2-9385 0876; e-mail: gdore@nchecr.unsw.edu.au

Abstract

Objectives

The aim of the study was to examine cognitive function, mood and health-related quality of life (HRQOL), and their interrelationships, among hepatitis C virus (HCV)-monoinfected and HIV/HCV-coinfected individuals.

Methods

Baseline neuropsychological and HRQOL measures of HCV-monoinfected and HIV/HCV-coinfected individuals commencing HCV treatment were examined from a prospective cohort study conducted between April 2003 and August 2005 in Sydney, Australia. Participants' neuropsychological performance and HRQOL were measured using computer-based battery, Trail Making Tests (TMT), Depression Anxiety Stress Scales (DASS), the Hepatitis Quality of Life Questionnaire (HQLQ), and the Visual Analogue Scale (VAS). Neuropsychological measures of HCV-infected patient groups were compared with those of two control groups consisting of HIV-monoinfected and uninfected individuals.

Results

Similar cognitive function, mood and HRQOL were found in HCV-monoinfected (n=19) and HIV/HCV-coinfected (n=15) individuals. When compared with the HIV-monoinfected (n=30) and uninfected control (n=30) groups, subtle cognitive impairment in attention was found in the HIV/HCV-coinfected group (P<0.05). Twenty-one percent of the HCV-monoinfected group were classified as having cognitive impairment compared with 10% or less in the other groups. Sociodemographic characteristics, mood, HRQOL and HCV indices did not correlate with cognitive function.

Conclusions

Our findings indicate no statistically significant difference in neuropsychological and HRQOL impairments between HIV/HCV-coinfected individuals with nonadvanced HIV disease and HCV-monoinfected individuals. This lack of significant difference may relate to the relatively small study population.

Introduction

There is growing evidence that chronic hepatitis C virus (HCV) infection is associated with impairment in cognitive function [1–8]. Forton et al. (2002) [3] compared cognitive function in individuals with HCV viraemia and those with only anti-HCV antibodies. Viraemic individuals showed specific impairment in power of concentration and speed of working memory. One study compared HCV-monoinfected individuals without comorbidities with uninfected individuals and found subtle cognitive impairment in learning efficiency in the HCV-monoinfected group [7]. Other investigations have also shown abnormalities. Magnetic resonance spectroscopy studies showed elevated choline [2,3,7] and reduced N-acetyl-aspartate [7–9] in the white matter in individuals with chronic HCV infection. A proposed mechanism for HCV-related cognitive impairment is some direct effect of HCV on the central nervous system (CNS) mediated through peripherally derived cytokines [10] or primary CNS infection [11,12]. However, given that HCV infection is associated with fatigue, depression and impaired health-related quality of life (HRQOL) [6,13–23], the subtle cognitive deficits observed in HCV infection may at least in part be an indirect consequence of depression or poor health.

Another possible cause of CNS change in HCV-infected individuals is the common coinfection with HIV [24]. While it is clear that HIV infection is associated with cognitive deficits [25], there have been suggestions that these deficits may be exacerbated in the presence of HCV coinfection [26–28]. A study using conventional neuropsychological tests among individuals with advanced HIV disease found greater impairment in executive function in HIV/HCV-coinfected than in HCV-monoinfected individuals [28]. However, another study using highly sensitive electrophysiologic motor tests in HIV-infected individuals with less advanced disease found subtle but similar psychomotor dysfunction in HIV/HCV-coinfected, HIV-monoinfected and HCV-monoinfected individuals [29]. Thus, uncertainty remains in relation to the cognitive consequences of HIV/HCV coinfection, in particular in early HIV disease.

It is known that HRQOL impairment is common in both chronic HCV infection [14,16,23,30] and HIV infection [31–33]. Although HRQOL impairment has been shown to be associated with cognitive impairment in HIV infection [34], it is unclear whether an association exists in HCV infection [1,3]. Further research is therefore required on cognitive function, mood and HRQOL, and their interrelationship, in the setting of early HIV/HCV coinfection. The objectives of the study were to examine cognitive function, mood and HRQOL in HCV-monoinfected and HIV/HCV-coinfected individuals, and to explore the interrelationships among these outcomes.

Methods

Study design and participants

Baseline data were examined from a prospective cohort study of HCV treatment-related health outcomes conducted between April 2003 and August 2005. HCV-monoinfected and HIV/HCV-coinfected individuals who were about to commence HCV treatment were enrolled from tertiary-level hepatitis clinics at St Vincent's and Royal Prince Alfred Hospitals in Sydney, Australia. Study inclusion criteria were age over 18 years, presence of HCV antibody detected by a third-generation enzyme-linked immunosorbent assay and HCV RNA determined by Roche Amplicor Assay (Roche Diagnostics, Sydney, Australia), liver biopsy within the previous 12 months consistent with chronic HCV infection, elevated serum alanine aminotransferase (ALT) level (>30 IU/L) at entry and at least once during the past 12 months, and no previous HCV treatment. Inclusion criteria for HIV/HCV-coinfected individuals were HIV-1 antibody or HIV-1 RNA positivity and either no previous antiretroviral therapy or stability on antiretroviral therapy for 8 weeks prior to enrolment. Exclusion criteria were regular injecting drug use, an alcohol intake of more than 100 g/week, decompensated cirrhosis and hepatocellular carcinoma, chronic liver disease attributable to causes other than HCV, a history of neurological disorders, active opportunistic infection or a CD4 cell count of <200 cells/μL, and pregnancy.

For comparison of cognitive function and mood, asymptomatic HIV-infected individuals and uninfected controls were selected by frequency matching (by age, sex and education) with the HCV-infected patient groups (Table 1). Although the control groups had a similar education level to both the HCV-monoinfected and the HIV/HCV-coinfected groups and were of similar age to the HIV/HCV-coinfected group, they were significantly younger than the HCV-monoinfected group. Asymptomatic HIV-infected individuals also had similar CD4 cell counts to HIV/HCV-coinfected participants. The HIV-infected asymptomatic group was recruited from out-patient departments at major metropolitan hospitals in Melbourne, Australia. All patients were HIV-1 antibody or HIV-1 RNA positive. Exclusion criteria for this group included a history of current CNS infections (determined by magnetic resonance imaging and lumbar puncture), cryptococcal meningitis, toxoplasmosis, neurosyphilis, cerebral lymphoma, cytomegalovirus retinitis, Pneumocystis carinii pneumonia, chronic drug or alcohol use or a history of seizures or major head injury.

Table 1.   Characteristics of groups
CharacteristicHCV-monoinfected
(n=19)
HIV/HCV-coinfected
(n=15)
HIV-monoinfected
(n=30)
Uninfected
(n=30)
P-value
  1. a F0, no liver fibrosis; F1, minimal liver fibrosis; F2, moderate liver fibrosis; F3, severe liver fibrosis; F4, compensated cirrhosis [62].
    b CD4 cell count prior to HCV treatment.
    c Analysis of variance.
    ALT, alanine aminotransferase; HCV, hepatitis C virus; IQ, intelligence quotient; IQR, interquartile range; SD, standard deviation.

Sex (% male)63.2100100100<0.001
Age (years) [mean (SD)]42.6 (6.5)35.5 (7.0)34.7 (7.4)34.8 (8.2)0.002c
Education level (%)
 Secondary level73.766.776.773.3 
 Tertiary level26.333.323.326.70.916
Estimated premorbid IQ [mean (SD)]110.8 (11.1)107.2 (11.5)  0.362
Employment (%)
 Unemployed26.346.7   
 Part-time21.113.3   
 Full-time52.640.0  0.586
Sexual identity (%)
 Heterosexual68.420.0   
 Homosexual/bisexual31.680.0  0.007
Country of birth (%)
 Australia68.466.7   
 Other31.633.3  0.914
≥5 alcoholic drinks in a row in past month (%)
 No79.093.3   
 Yes21.06.7  0.355
History of injecting drug use (%)
 Never10.513.3   
 Past 12 months5.353.3   
 More than 12 months ago84.233.3  0.003
Duration of injecting drug use (years) [median (IQR)]7 (4–13)9 (3–10)  1.000
Perceived risk for HCV acquisition (%)
 Injecting drug use84.253.3   
 Other40.0   
 Don't know15.86.7  0.006
Self-report estimated duration of exposure to HCV (years) [median (IQR)]14.5 (4–24)5 (2–7)  0.019
Number of comorbidities (%)
 079.046.7   
 1–221.053.3  0.075
Serum ALT level (IU/L) [median (IQR)]88 (47–160)112 (73–279)  0.290
Genotype (%)
 126.333.3   
 2/373.766.7  0.656
Stage of liver disease (%)a
 F0–F284.266.7   
 F3–F410.520.0   
 Unknown5.313.3  0.594
CD4 count (cells/μL)b [median (IQR)] 368 (320–648)530 (340–780) 0.263
Antiretroviral treatment (%) 40.0   
Antidepressant medication (%)5.326.7  0.146

Uninfected controls were recruited through advertisements placed at Australian universities. All participants were in good health and reported no difficulties with sleep. Exclusion criteria consisted of smoking, regular to heavy coffee drinking, recreational drug or alcohol use, and neurological illnesses.

Ethics approval for the study was obtained from hospital Human Research Ethics Committees and all patients and controls gave written informed consent before any assessment was conducted.

Data collection measures

Prior to commencement of HCV treatment, participants completed HRQOL measures, a self-administered background questionnaire, and neuropsychological measures. The background questionnaire collected information on sociodemographic characteristics, history of illicit drug use, alcohol consumption, risk factors for HCV transmission, date of HCV diagnosis and probable time of HCV exposure, and perceived HCV-related symptoms. Clinical and laboratory data were collected from case record forms and medical chart reviews. Data collection included comorbid illnesses, prescription medications, HCV genotype, liver biopsy staging of disease, serum ALT, quantitative HCV RNA and HIV RNA, and CD4 cell count.

Neuropsychological measures

Cognitive function was assessed using a test of premorbid intelligence quotient (IQ) [the National Adult Reading Test (NART)] [35], Trail Making Tests (TMT) A and B [36], and a computer-based performance test, CogState [37–39]. CogState consists of eight separate tasks using card stimuli and measures performance in terms of simple detection [simple reaction time (SRT)], simple identification [choice reaction time (ChRT)], simple matching [complex reaction time (CoRT)], continuous attention [monitoring (Mon)], working memory [one-back learning: reaction time (OBK RT) and accuracy], complex matching [matching: reaction time (MAT RT) and accuracy], and memory and learning [associate learning: reaction time (AssL RT) and accuracy] [37–39]. Participants completed a practice followed by two tests to minimize within-testing-session practice effect [40]. Three participants completed only one test at pretreatment. Overall, there were fewer than 5% missing values for each task in the second test. The method of replacement with the first test score was used to impute a missing value [41,42].

Participants' mood status was assessed using the 42-item Depression Anxiety Stress Scales (DASS) [43]. A depression score of 0–9 is considered ‘normal’, 10–13 ‘mild’ depression, 14–20 ‘moderate’ depression, and 21+‘severe’ depression [43].

Health-related quality of life measures

Participants' HRQOL was assessed using the 4-week recall self-administered Hepatitis Quality of Life Questionnaire (HQLQ) [44]. HRQOL scores were computed for each subscale by summing the scores of the component items and converting the sum to a scale ranging from 0 to 100, with higher scores indicating better health. Two summary measures of the Short Form-36 (SF-36) health survey, physical component summary (PCS) and mental component summary (MCS) scores were computed using standard algorithms [45]. SF-36 scores were also translated into utilities using the SF-6D algorithm [46]. In addition, a series of preference-based visual analogue scales (VASs) [47] was used to measure participants' current levels of HRQOL, fatigue, anxiety and depression.

Statistical analysis

Sociodemographic and clinical data for the HCV-monoinfected and HIV/HCV-coinfected groups were compared using the χ2 test or Fisher's exact test for categorical variables and Student's t-test or Mann–Whitney U-test for continuous variables. Effect sizes (ESs) [48,49] were computed by taking the difference between the two sample means, and dividing by the pooled standard deviation (SD), weighted by sample size. Cohen's classification of ES (small=0.20; medium=0.50; large=0.80) was used to determine the magnitude of differences [48].

Cognitive performance raw scores were transformed into z-scores (standard scores) using the control mean and SD. Four composite scores were computed to reflect psychomotor function (SRT and TMT A), visual attention (ChRT, CoRT and Mon), executive function (OBK RT and accuracy, MAT RT and accuracy and TMT B), and memory and learning (AssL RT and accuracy) functions [38,39]. These composite scores were derived from the 12 neuropsychological measures (CogState and TMT) by averaging the standard scores within each domain. Domain scores were then standardized using the control mean and SD. For each individual, an abnormal performance in any of the four domains was classified as having occurred when their domain score was –1.65 SD or less (i.e. P<0.05 one-tailed) [50]. An individual was classified as showing cognitive impairment if they had abnormal scores in two or more domains.

A symptom score was estimated by summing the number of reported HCV-related symptoms. HRQOL scales were evaluated to estimate the reliability of scale scores and to test item internal consistency using Cronbach's alpha [51,52].

Univariate analyses were performed to examine potential confounding factors of cognitive function (n=94) and HRQOL (n=34). Age was the only variable significantly associated with cognitive function (P<0.01). Between-group comparisons for neuropsychological and HRQOL measures were performed using analysis of covariance (ANCOVA) controlling for age. Repeated measures ANCOVA models were used to assess group differences in computer-based performance scores, adjusting for age. Post-hoc pair-wise comparisons were performed using the Bonferroni adjustment for multiple comparisons [53]. Student's t-test was used to compare HRQOL between HIV/HCV-coinfected and HCV-monoinfected groups and age-standardized Australian population norms [54]. Correlations among cognitive function, mood, HRQOL and HCV indices within HCV-monoinfected and HIV/HCV-coinfected groups were conducted using Pearson's product-moment correlation and Spearman correlation coefficients. Because of the exploratory nature of neuropsychological research, a two-sided P-value of 0.05 was retained for statistical significance.

Results

Nineteen HCV-monoinfected, 15 HIV/HCV-coinfected, 30 asymptomatic HIV-monoinfected, and 30 uninfected control individuals met eligibility criteria for the study. Sociodemographic characteristics and clinical data for HCV-infected patient groups are shown in Table 1. Only one participant in each group reported injecting drug use in the previous month.

Cognitive performance and mood status

Significant group differences were observed in the speed of performance relating to TMT A (F3,93=3.86; P=0.012), simple identification (ChRT: F3,93=2.97; P=0.036), and simple matching (CoRT: F3,93=3.30; P=0.024) (Table 2). Post-hoc pair-wise comparisons of the groups using a Bonferroni correction showed no significant differences among groups. HCV-monoinfected and HIV/HCV-coinfected groups performed slightly slower than uninfected controls in performances relating to simple identification (2.73 vs 2.64 ms; P=0.079; ES=−0.94) and simple matching (2.83 vs 2.76 ms; P=0.054; ES=−0.74), respectively. Cognitive performance scores were similar for the HCV-monoinfected and HIV/HCV-coinfected groups. There was also no evidence of poorer cognitive performance in the HIV/HCV-coinfected group, when compared with the asymptomatic HIV-monoinfected group. Twenty-one percent of the HCV-monoinfected group were classified as having cognitive impairment compared with 10% or less in the other groups (Table 3).

Table 2.   Neuropsychological raw scores of groups
Neuropsychological testsHCV-monoinfected
(n=19) Mean
(95% CI)
HIV/HCV-coinfected
(n=15) Mean
(95% CI)
HIV-monoinfected
(n=30) Mean
(95% CI)
Uninfected controls
(n=30) Mean
(95% CI)
P-value
  • Higher scores indicate worse performance. P-values are for analysis of covariance (ANCOVA) and repeated measures analysis of variance (ANOVA) (for computer-based performance scores) between groups adjusting for age. The average of two pretreatment computer-based performance scores is presented.

  • Values are log10 (milliseconds) for reaction time (RT), percent correct for accuracy, and seconds for Trail Making Tests.

  • a

    Post-hoc pair-wise comparisons with Bonferroni adjustments between: HCV-monoinfected individuals and uninfected controls (P <0.001); HIV/HCV-coinfected individuals and uninfected controls (P=0.003); HIV-monoinfected individuals and uninfected controls (P=0.001).

  • CI, confidence interval; DASS, Depression Anxiety Stress Scales; HCV, hepatitis C virus.

Psychomotor function
Simple reaction time – RT2.50 (2.45–2.54)2.49 (2.45–2.53)2.49 (2.46–2.52)2.47 (2.45–2.50)0.664
Trail Making Test A33.39 (29.20–37.57)27.49 (23.27–31.71)33.33 (30.37–36.30)28.47 (25.90–31.03)0.012
Visual attention
Choice reaction time – RT2.73 (2.69–2.77)2.69 (2.65–2.74)2.68 (2.65–2.71)2.64 (2.60–2.68)0.036
Complex reaction time – RT2.85 (2.82–2.89)2.83 (2.79–2.87)2.79 (2.75–2.83)2.76 (2.72–2.80)0.024
Monitoring – RT2.56 (2.50–2.61)2.51 (2.45–2.57)2.53 (2.49–2.57)2.50 (2.46–2.53)0.520
Executive function
One-back learning – RT2.87 (2.83–2.91)2.84 (2.79–2.89)2.80 (2.75–2.85)2.78 (2.72–2.83)0.201
One-back learning – Accuracy93.35 (89.69–97.01)94.98 (91.10–98.85)90.30 (86.73–93.86)94.35 (91.89–96.80)0.117
Matching – RT3.23 (3.18–3.28)3.19 (3.13–3.25)3.14 (3.10–3.18)3.17 (3.14–3.19)0.051
Matching – Accuracy85.87 (76.24–95.50)92.72 (87.98–97.45)84.84 (79.87–89.80)87.12 (84.41–89.83)0.280
Trail Making Test B78.68 (64.25–93.11)62.55 (51.88–73.21)61.20 (56.75–65.65)64.13 (57.85–70.41)0.066
Memory and learning
Associate learning – RT3.12 (3.08–3.16)3.07 (3.02–3.12)3.07 (3.05–3.09)3.06 (3.04–3.08)0.058
Associate learning – Accuracy73.92 (69.26–78.58)75.12 (69.24–81.01)77.00 (72.78–81.21)78.76 (74.22–83.29)0.643
DASS
Depression7.79 (4.94–10.64)7.87 (3.38–12.36)8.77 (7.00–10.53)5.33 (4.84–5.83)0.065
Anxiety5.16 (3.42–6.90)6.67 (3.24–10.10)5.90 (4.51–7.29)5.43 (4.61–6.25)0.564
Stress12.47 (9.10–15.85)12.00 (6.53–17.47)11.47 (10.01–12.93)5.57 (4.90–6.24)<0.001a
Table 3.   Prevalence of impaired cognitive function
 HCV-monoinfected
(n=19)
HIV/HCV-coinfected
(n=15)
HIV-monoinfected
(n=30)
Uninfected
(n=30)
P-valuec
  • Global cognitive function includes psychomotor function, visual attention, executive function and memory and learning. Psychomotor function includes Trail Making Test A and simple reaction time. Visual attention includes choice reaction time, complex reaction time and monitoring. Executive function includes Trail Making Test B, one-back learning – reaction time, one-back learning – accuracy, matching – reaction time, and matching – accuracy. Memory and learning includes associate learning – reaction time and associate learning – accuracy.

  • a

    Global cognitive impairment defined as a deficit of 1.65 standard deviations (SD) below control mean in two or more domains.

  • b

    b Impairment in psychomotor function, visual attention, executive function and memory and learning defined as a deficit of 1.65 SD below control mean.

  • c

    P-value for Fisher's exact test between groups.

  • HCV, hepatitis C virus.

Global cognitive functiona4 (21.1)1 (6.7)3 (10.0)1 (3.3)0.232
Psychomotor functionb3 (15.8)0 (0.0)4 (13.3)2 (6.7)0.406
Visual attentionb4 (21.1)1 (6.7)3 (10.0)1 (3.3)0.232
Executive functionb5 (26.3)2 (13.3)3 (10.0)1 (3.3)0.093
Memory and learningb5 (26.3)3 (20.0)4 (13.3)4 (13.3)0.603

Mean DASS scores were similar among the infected groups (Table 2). However, mean DASS stress scores were significantly different among groups (F3,93=8.66; P<0.001). DASS stress scores were significantly higher in the infected groups than in the uninfected controls (HCV-monoinfected group: 12.47 vs 5.57; P=0.001; ES=−1.52; HIV/HCV-coinfected group: 12.00 vs 5.57; P=0.003; ES=−1.10; and HIV-monoinfected group: 11.47 vs 5.57; P=0.001; ES=−1.94).

Health-related quality of life and self-reported health status

HRQOL, VAS measures, and self-reported health status are presented in Tables 4 and 5. Estimates for score reliability for the SF-36 scales were >0.70 for all SF-36 scales, additional generic scales and hepatitis-specific scales except the SF scale (Cronbach's alpha 0.62). There were no significant differences in the mean SF-36 scores between the HCV-monoinfected and HIV/HCV-coinfected groups (Table 4). Sleep somnolence (75.1 vs 56.8; P=0.035; ES=−0.76) and health distress due to chronic HCV infection (76.7 vs 53.7; P=0.007; ES=–1.00) scores were significantly lower in the HCV-monoinfected group than in the HIV/HCV-coinfected group, even after adjustment for age. Compared with age-standardized Australian population norms [54], both the HCV-monoinfected (41.5 vs 50.1; P<0.001; ES=−0.68) and HIV/HCV-coinfected (40.5 vs 50.1; P=0.001; ES=−0.76) groups had lower MCS scores. However, there were no significant differences in PCS scores between the groups and the Australian population norms (HCV: 47.1 vs 49.7, P=0.133; and HIV/HCV: 48.2 vs 49.7, P=0.558). There were no significant differences in the mean VAS-HRQOL, fatigue, anxiety and depression scores or in the mean SF-6D utility scores between the HCV-monoinfected and HIV/HCV-coinfected groups (Table 4).

Table 4.   Health-related quality of life scores of HCV-monoinfected and HIV/HCV-coinfected groups
 UnadjustedAdjusteda
HCV-monoinfected
(n=19) Mean
(95% CI)
HIV/HCV-coinfected
(n=15) Mean
(95% CI)
P-valueESHCV-monoinfected
(n=19) Mean
(95% CI)
HIV/HCV-coinfected
(n=15) Mean
(95% CI)
P-value
  1. CI, confidence interval; ES, effect size; HCV, hepatitis C virus; HRQOL, health-related quality of life; SF-36, Short Form Health Survey-36; VAS, Visual Analogue Scale.
    SF-6D utility scores were estimated from SF-36 scores using the SF-6D algorithm [63, 64].
    Effect size was computed as the difference between two sample means, divided by the pooled standard deviation weighted by sample size.
    a Mean HRQOL and VAS scores adjusted for age.
    bF1,31=5.07;cF1,31=8.06.

SF-36 scales
Physical functioning75.3 (66.3–84.2)76.3 (63.0–89.7)0.884−0.0579.3 (70.1–88.5)71.2 (60.7–81.7)0.270
Role physical59.0 (43.1–74.8)49.3 (27.6–71.0)0.4430.2761.1 (43.6–78.7)46.6 (26.6–66.6)0.294
Bodily pain70.9 (61.7–80.1)78.3 (65.6–91.1)0.309−0.3673.3 (63.4–83.2)75.3 (64.1–86.6)0.792
General health54.2 (45.3–63.1)52.6 (41.0–64.2)0.8200.0856.8 (47.6–65.9)49.3 (38.9–59.7)0.303
Vitality42.9 (32.8–53.0)55.3 (43.8–66.9)0.094−0.6045.4 (35.5–55.2)52.2 (41.0–63.5)0.378
Social functioning53.6 (46.7–60.5)50.0 (41.3–58.8)0.4910.2455.7 (48.7–62.7)47.4 (39.5–55.4)0.139
Role emotional64.5 (49.3–79.7)53.3 (33.9–72.8)0.3380.3466.5 (50.2–82.8)50.8 (32.3–69.3)0.224
Mental health66.7 (61.2–72.2)65.3 (55.6–75.1)0.7800.1067.7 (60.6–74.8)64.1 (56.1–72.1)0.517
Physical component summary47.1 (43.6–50.6)48.2 (42.7–53.6)0.711−0.1348.4 (44.5–52.3)46.5 (42.1–50.9)0.521
Mental component summary41.5 (37.8–45.3)40.5 (35.4–45.6)0.7300.1242.0 (37.8–46.2)39.9 (35.2–44.7)0.524
Additional generic scales
Positive wellbeing56.6 (48.5–64.6)52.7 (41.0–64.4)0.5500.2157.4 (48.1–66.6)51.6 (41.1–62.2)0.429
Sleep somnolence56.8 (43.2–70.5)75.1 (65.8–84.4)0.035−0.7655.8 (43.9–67.6)76.5 (63.0–89.9)0.032b
Health distress54.0 (42.7–65.2)65.7 (55.4–76.0)0.122−0.5554.4 (43.9–65.0)65.0 (53.0–77.1)0.207
Hepatitis-specific scales
Limitations due to chronic HCV infection69.5 (58.3–80.6)69.8 (55.3–84.3)0.973−0.0172.9 (61.5–84.3)65.5 (52.5–78.5)0.413
Health distress due to chronic HCV infection53.7 (41.9–65.5)76.7 (65.1–88.3)0.007−1.0052.8 (41.4–64.1)77.8 (64.9–90.8)0.008c
VAS scores
HRQOL0.62 (0.54–0.71)0.66 (0.58–0.74)0.5380.210.64 (0.56–0.72)0.64 (0.55–0.73)0.933
Fatigue0.47 (0.35–0.59)0.62 (0.50–0.74)0.0920.600.50 (0.39–0.61)0.58 (0.46–0.71)0.329
Anxiety0.56 (0.46–0.67)0.67 (0.55–0.80)0.1560.500.56 (0.45–0.67)0.68 (0.56–0.80)0.169
Depression0.77 (0.67–0.87)0.82 (0.70–0.93)0.5320.220.78 (0.68–0.88)0.80 (0.69–0.92)0.776
SF-6D utility scores0.75 (0.72–0.77)0.74 (0.70–0.79)0.8520.070.75 (0.72–0.79)0.73 (0.69–0.77)0.383
Table 5.   Self-reported health status of HCV-monoinfected and HIV/HCV-coinfected groups
CharacteristicsHCV-mono
infected
(n=19)
HIV/HCV-
coinfected
(n=15)
P-value
  1. Symptom score was estimated from the total count of the number of perceived HCV-related symptoms.

  2. HCV, hepatitis C virus; SD, standard deviation; SF-36, Short Form-36 Health Survey.

Hepatitis B virus infection (%)
No7 (36.8)7 (46.7) 
Yes4 (21.1)6 (40.0) 
Not sure8 (42.1)2 (13.3)0.215
Perceived HCV-related symptoms (%)
Abdominal pain14 (73.7)5 (33.3)0.019
Poor appetite11 (57.9)9 (60.0)0.901
Poor concentration or memory16 (84.2)7 (46.7)0.030
Depression13 (68.4)8 (53.3)0.369
Fatigue18 (94.7)12 (80.0)0.299
Irritability16 (84.2)7 (46.7)0.030
Jaundice4 (21.1)2 (13.3)0.672
Joint pains7 (36.8)6 (40.0)0.851
Sensitivity to lights9 (47.4)5 (33.3)0.409
Sleep problems10 (52.6)11 (73.3)0.296
Weakness14 (73.7)7 (46.7)0.107
Symptom score [mean (SD)]7.1 (3.1)5.8 (4.3)0.331
SF-36 global health (%)
Very good to excellent2 (10.5)6 (40.0) 
Good12 (63.2)7 (46.7) 
Poor to fair5 (26.3)2 (13.3)0.152

Among perceived HCV-related symptoms, symptoms of abdominal pain (74% vs 33%; P=0.019), poor concentration or memory (84% vs 47%; P=0.030), and irritability (84% vs 47%; P=0.030) were significantly higher in the HCV-monoinfected group than in the HIV/HCV-coinfected group (Table 5).

Relationships among cognitive function, mood, health-related quality of life and HCV indices in HCV-monoinfected and HIV/HCV-coinfected individuals

There were no significant correlations between cognitive function and mood, HRQOL or HCV indices (Table 6). There were also no significant associations between cognitive function and sociodemographic characteristics, injecting drug use or alcohol consumption. Significant correlations were found between severity of depression, anxiety and HRQOL; among DASS-depression and MCS (r=−0.78, P<0.001) and VAS-HRQOL (r=−0.48, P<0.01) scores; and between DASS-anxiety and PCS (r=−0.52, P<0.01) and MCS (r=−0.34, P<0.05) scores.

Table 6.   Correlations between cognitive function and mood, HRQOL, and HCV indices in HCV monoinfected and HIV/HCV coinfected groups
 CognitiveDASS scoresSF-36 scoresVAS scoresALT level
Global z scoreDepressionAnxietyStressPCSMCSHRQOLFatigueAnxietyDepression
  1. The cognitive global z score was derived from 12 neuropsychological measures (CogState and Trail Making Tests).
    aP<0.001;bP<0.01;cP<0.05.
    HCV, hepatitis C virus; HRQOL, health-related quality of life; DASS, Depression Anxiety Stress Scales; PCS, physical component summary; MCS, mental component summary; VAS, Visual Analogue Scale; ALT, alanine aminotransferase.

DASS-depression0.06          
DASS-anxiety−0.120.32         
DASS-stress0.090.41c0.68a        
PCS0.29−0.03−0.52b−0.33       
MCS−0.18−0.78a−0.34c−0.320.06      
VAS-HRQOL0.04−0.48b−0.23−0.100.44b0.41c     
VAS-fatigue0.21−0.14−0.110.080.230.340.44b    
VAS-anxiety0.002−0.27−0.33−0.33−0.130.300.120.20   
VAS-depression0.22−0.472−0.04−0.14−0.250.49b0.240.41c0.46b  
Serum ALT level−0.07−0.05−0.34c−0.35c0.40c0.090.05−0.120.05−0.33 
HCV RNA0.03−0.17−0.21−0.210.080.35c−0.050.220.250.21−0.09

Discussion

Our study conducted in HCV-monoinfected and HIV/HCV-coinfected individuals prior to HCV treatment found similar cognitive function across these two groups. Furthermore, cognitive function was similar between HIV/HCV-coinfected and age-, sex- and level of education- and immunodeficiency-matched HIV-monoinfected individuals. Even when compared with uninfected controls, both HCV-monoinfected and HIV/HCV-coinfected individuals had similar cognitive function, with only attention reaction times being subtly slower in the HIV/HCV-coinfected group. Thus, in individuals with early HIV infection, HCV coinfection was associated with only very subtle cognitive impairment.

HRQOL was also similar between HCV-monoinfected and HIV/HCV-coinfected individuals, with the only significant differences being greater sleep somnolence and health distress due to chronic HCV infection in the HCV-monoinfected group. Consistent with greater health distress, abdominal pain, poor concentration and memory, and irritability were more often reported by HCV-monoinfected individuals. These findings are consistent with the study by Hilsabeck et al. (2003) [4], which also demonstrated frequent subjective symptoms of cognitive impairment, but a low frequency of objective evidence of cognitive impairment.

Our study has several limitations. First, the small sample may have limited power to detect significant differences in outcome variables. Nevertheless, two baseline computer-based neuropsychological tests and repeated measures analysis of variance (ANOVA) provide greater power to detect cognitive effects. Secondly, participants were recruited from tertiary-level treatment settings and included only patients who were offered and subsequently underwent HCV treatment. Thus, pretreatment cognitive function, mood status and HRQOL may differ in both nonreferred and referred but untreated HCV-infected patient groups. Finally, potentially more objective measures of neuropathology such as magnetic resonance spectroscopy or functional magnetic resonance imaging were not employed.

In contrast to other studies [27,28], our study showed that cognitive impairment in HIV/HCV coinfection was not greater than that in HCV monoinfection or asymptomatic HIV monoinfection. An explanation for the contrasting findings in relation to cognitive impairment in HIV/HCV coinfection is the stage of HIV disease of study subjects. Our study was conducted in a relatively nonadvanced HIV disease population, while other studies have included more advanced HIV disease populations [28]. Cognitive impairment related to HIV infection increases with level of immunodeficiency [25,55]. In addition, HCV-related cognitive impairment may be associated with HCV viral load, which increases in advanced HIV disease [56,57]. Letendre et al. [26] found higher HCV viral load in individuals with cognitive impairment. Thus, an additional cognitive impact of HCV in HIV/HCV-coinfected individuals may only be present at more advanced immunodeficiency. However, we did not find any association between cognitive performance and HCV indices including HCV viral load.

Our study found cognitive impairment in 21% of HCV-monoinfected individuals prior to HCV treatment. This finding is consistent with a recent study by Fontana et al. [60] in approximately 200 HCV-infected individuals with advanced fibrosis, which demonstrated that as many as 30% may have evidence of mild cognitive impairment. In their study, both baseline depression and IQ scores were significant predictors of baseline cognitive impairment. In our study, we found no association between cognitive impairment and education level or IQ scores. Although IQ scores were not available for the control groups, education levels were similar in all groups. In addition, the mean IQ scores of the HCV-monoinfected and HIV/HCV-coinfected groups were approximately 110. This suggests that this was a highly educated group of individuals, which may have impeded the ability to detect cognitive impairment. Active injecting drug use has been associated with cognitive impairment [58]. However, similar to previous studies [3,6], we did not find an association between past history of injecting drug use or injecting drug use in the past 12 months and cognitive impairment [3,6].

In agreement with a previous study [59], we found no evidence of greater HRQOL impairment in HIV/HCV-coinfected than in HCV-monoinfected individuals. Fleming et al. [59] also found similar HRQOL impairment in HIV/HCV-coinfected and HIV-monoinfected individuals. Additionally, the mean utility score for HIV/HCV-coinfected individuals (0.74) was also similar to that for HCV-monoinfected individuals (0.75) in our study and to the community-weighted utilities for HIV/HCV coinfection derived from a systematic review [61].

Cognitive impairment has been found to be associated with HRQOL in HIV infection [34]. However, similar to previous studies [1,3,4,6], we did not find an association between cognitive function and HRQOL in either the HCV-monoinfected or the HIV/HCV-coinfected group. This may be attributable to the use of HRQOL measures (i.e. SF-36 and VAS) that do not include cognitive components. Tozzi et al. [34] in their study used a health measure that included cognitive function domain. However, Hilsabeck et al. [4] used a cognitive HRQOL scale, but found no association between subjective cognitive complaints and objective evidence of cognitive impairment. In our study, the severity of depressive symptoms and anxiety were associated with HRQOL but not with cognitive function.

In summary, our study demonstrated that there was no significant difference in cognitive function, mood or HRQOL between a relatively nonadvanced HIV/HCV-coinfected group and an HCV-monoinfected group prior to HCV treatment. Although the sample sizes were relatively small, these findings provide important information that can assist in developing strategies for clinical management of HIV/HCV-coinfected patients. The clinical relevance of the functional impact of frequent neuropsychiatric symptoms observed in HCV-monoinfected individuals, however, requires further investigation.

Acknowledgements

The authors would like to acknowledge the participants for their contribution to the study, St Vincent's Hospital Hepatitis Clinic staff, John McAllister and Zoe Potgieter and Royal Prince Alfred Hospital Gastroenterology Clinic staff, Sue Mason, Sinead Sheils and Suzanne Roche for their clinical assistance, and Dr Jaimie Cox and Dr Lucette Cysique for their support of the study.

The study was partly funded by Roche Products Pty. Ltd. The National Centre in HIV Epidemiology and Clinical Research is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, The University of New South Wales.

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