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Improved cognitive function as a consequence of hepatitis C virus treatment
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HIV Medicine
Volume 8 Issue 8 Page 520-528, November 2007
* HH Thein11National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia, ,
* P Maruff2,32School of Psychology, La Trobe University, Melbourne, Vic., Australia, 3CogState Ltd, Melbourne, Vic., Australia, ,
* MD Krahn44Departments of Medicine and Health Policy, Management and Evaluation and Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada,
* JM Kaldor11National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia, ,
* DJ Koorey55Gastroenterology and Hepatology Unit, Royal Prince Alfred Hospital, Sydney, NSW, Australia, ,
* BJ Brew1,6,71National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia, 6Department of Neurology, and 7HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, NSW, Australia and
* GJ Dore1,71National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, NSW, Australia, 7HIV/Immunology/Infectious Diseases Clinical Services Unit, St Vincent's Hospital, Sydney, NSW, Australia
*This work has previously been 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 15th International AIDS Conference, July 2004, Bangkok, Thailand (Poster).
In our prospective study, we found that therapeutic HCV clearance was associated with improvement in some measures of cognitive function. Treatment-induced sustained viral clearance was also associated with improvements in both physical and mental HRQOL, but nonclearance was also associated with improvement in mental HRQOL. The magnitude of the impact of treatment on HRQOL was considerable, with limitations in physical and social activities attributable to health in both groups, but no greater HRQOL impact was observed in the HIV/HCV-coinfected than in the HCV-monoinfected group. Cognitive performance, mood and HRQOL in the HCV-monoinfected and HIV/HCV-coinfected groups prior, during and following PEG-IFN and ribavirin therapy were similar.
Abstract
Objective
The aim of the study was to investigate the impact of treatment-related clearance of hepatitis C virus (HCV) on cognitive function.
Methods
A prospective study was conducted in 19 HCV-monoinfected and 15 HIV/HCV-coinfected individuals undergoing pegylated interferon α-2a and ribavirin therapy between April 2003 and August 2005. Neuropsychological, mood, and health-related quality of life (HRQOL) effects were assessed using computer-based battery, Trail Making Tests, Depression Anxiety Stress Scales and the Short Form-36 health survey.
Results
Pretreatment cognitive function, mood status, and HRQOL were similar between the HCV patient groups. Sustained virological response (SVR) rates were similar between HCV-monoinfected (68%) and HIV/HCV-coinfected (73%) groups. SVR was associated with significant improvements in some measures of cognitive function, independent of HRQOL improvement.
Conclusions
Our findings provide evidence to support cognitive effects of HCV independent of mood status and HRQOL profiles.
Introduction
Individuals with chronic hepatitis C virus (HCV) infection, especially those co-infected with HIV, present frequently with neuropsychological symptoms [1,2]. These are thought to reflect direct and indirect effects of the HCV on the central nervous system (CNS) [3-7], although there is controversy over the importance of the direct CNS effects of HCV. The data thus far published are open to the criticism that other factors such as mood and use of illicit drugs may have exaggerated the contribution of HCV to cognitive impairment. This will always be an issue in studies of these patient populations. One approach is to determine whether there is any benefit of effective HCV treatment in terms of cognitive performance. This is a potentially complex area as one of the main therapeutics for HCV infection, interferon (IFN) α, is itself known to depress cognitive function in individuals who do not have HCV infection [8]. However, it seems likely, although not definite, that the magnitude of HCV/IFN-related cognitive impairment will diminish over time as the IFN treatment clears HCV.
Thus, the objective of this study was to test the hypothesis that effective HCV therapy with pegylated IFN (PEG-IFN) α and ribavirin significantly improves cognitive performance independent of effects on mood and health-related quality of life (HRQOL).
Results
Table 1 shows the characteristics of the HCV-monoinfected and the HIV/HCV-coinfected groups who completed pre- and post-treatment assessments and HCV virological assessments. Four HIV/HCV-coinfected individuals were receiving antiretroviral therapy including neuroactive drugs [22] such as efavirenz (n=1), indinavir (n=1), lamivudine (n=3) and zidovudine (n=1).
Cognitive function and mood
Prior to HCV treatment, mean global cognitive performance and DASS scores were similar between the HCV groups (Table 2). At t2, there were no between-group (HCV: -0.19 vs HIV/HCV: 0.10, P=0.568) or within-group (t1 vs. t2, HCV: -0.15 vs -0.19, P=0.630; HIV/HCV: 0.27 vs 0.10, P=0.162) significant differences in the global cognitive performance z-scores. At t3, the mean global cognitive performance z-score improved significantly from t1 in the HIV/HCV-coinfected group (0.27 vs 0.40; repeated measures anova, P=0.024, ES=0.24), with improvement in the performance relating to TMT A (27.98-22.57 s; P=0.024, ES=0.70). Mean depression (7.50-4.83; P=0.006, ES=0.40), anxiety (5.33-3.17; P<0.001, ES=0.51) and stress (12.50-9.50; P<0.001, ES=0.36) scores decreased significantly from t1 to t3 in the HCV-monoinfected group. Mean cognitive performance and DASS score changes from t1 to t3 were similar between the groups.
HRQOL
There were no significant differences in the mean HRQOL scores between the groups at t1 (Table 2). At t3, both mean PCS (47.40-51.67; repeated measures anova, P<0.001) and MCS (41.86-50.28; P<0.001) scores improved significantly from t1 levels in the HCV-monoinfected group. In the HIV/HCV-coinfected group, significant improvement from t1 to t3 was observed only in the PCS score (49.35-53.52; P<0.01, ES=0.37). There were no significant differences in the mean HRQOL change scores between the HCV groups. A mean utility score gain of 0.05 units from t1 to t3 was observed in both groups.
The effect of antidepressant medications and antiretroviral therapy on cognitive function
Both pretreatment (-0.11 vs -0.33; P=0.5) and post-treatment (0.02 vs -0.13; P=0.7) mean global cognitive performance scores were similar between individuals who were receiving antidepressant medications and those who were not. Similarly, there were no significant differences in the pretreatment (-0.12 vs -0.29; P=0.6) and post-treatment (0.01 vs -0.08; P=0.8) mean global cognitive performance scores between individuals who were receiving antiretroviral therapy and those who were not.
The effect of successful therapeutic HCV clearance on cognitive function, mood and HRQOL
Overall, 71% of the patients achieved an SVR on an intention-to-treat analysis, with 13 of 19 (68%) HCV-monoinfected and 11 of 15 (73%) HIV/HCV-coinfected individuals achieving an SVR. An HCV-monoinfected patient who had an ALT level of 10 IU/L at t3 but who did not undergo a virological assessment was assumed to have achieved an SVR at the end of treatment.
Pretreatment mean cognitive performance and DASS scores were similar between individuals who achieved an SVR (n=21) and those who did not (n=9). There were no significant differences in the t3 mean global cognitive performance z-scores or change scores between these two groups. However, patients who achieved an SVR performed slightly better than those who did not in t3 reaction times relating to continuous attention (monitoring, 2.49 vs 2.57 ms; ES=0.78, P=0.055, adjusted for t1 depression and PCS scores) (Fig. 2). A significant improvement in reaction time (from t1 to t3) relating to simple matching (complex reaction time) was observed in individuals who achieved an SVR compared with those who did not (ES=0.76, P=0.032).
HRQOL scores improved significantly in most scales (P<0.01) except for bodily pain in individuals achieving an SVR (Table 3). There was no physical health improvement in those who did not achieve an SVR. Mental HRQOL improvement was similar regardless of SVR status. Post-treatment HRQOL scores were higher in individuals who achieved an SVR than in those who did not, with a significant change score (from t1 to t3) difference observed only in the PCS measure after adjustment for t1 PCS score, global cognitive performance z-score and DASS anxiety score (P=0.009). SVR was associated with a gain of 0.05 units of utilities from t1 estimates compared with 0.02 units gain in those who did not achieve an SVR.
Discussion
In our prospective study, we found that therapeutic HCV clearance was associated with improvement in some measures of cognitive function. Treatment-induced sustained viral clearance was also associated with improvements in both physical and mental HRQOL, but nonclearance was also associated with improvement in mental HRQOL. The magnitude of the impact of treatment on HRQOL was considerable, with limitations in physical and social activities attributable to health in both groups, but no greater HRQOL impact was observed in the HIV/HCV-coinfected than in the HCV-monoinfected group. Cognitive performance, mood and HRQOL in the HCV-monoinfected and HIV/HCV-coinfected groups prior, during and following PEG-IFN and ribavirin therapy were similar.
Our study has several limitations. First, the small sample may have resulted in limited power to detect significant differences in outcome variables. In addition, the high proportions of early liver fibrosis stages [stages < severe fibrosis (F3)] and genotype 2/3, and the high rate of SVR in both HCV groups make data interpretation difficult as there were few genotype 1 patients and nonresponders in each group. 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 nonreferred and referred but untreated HCV patient groups. Thirdly, potentially more objective measures such as magnetic resonance spectroscopy or functional magnetic resonance imaging were not employed. Finally, participants' knowledge of on-treatment virological response may have influenced HRQOL, particularly HRQOL improvement post-treatment. However, this only occurred in seven patients with an SVR who were aware of their post-treatment HCV status prior to post-treatment assessment.
Other studies showed baseline cognitive performance differences between HCV-monoinfected and HIV/HCV-coinfected populations [25,26]. In contrast, our study showed no greater cognitive impairment in the HIV/HCV-coinfected than in the HCV-monoinfected group prior to HCV treatment, possibly related to differences in study populations and the small number of patients in each group. Our study was conducted in a population with relatively nonadvanced HIV disease, while other studies have included higher risk populations such as those with more advanced HIV disease [27] and methamphetamine dependence [25,26]. HIV-related cognitive impairment increases with level of immunodeficiency [28,29]. An additional cognitive impact of HCV in HIV/HCV-coinfected individuals may only be present at more advanced immunodeficiency.
Our findings are also in contrast to those of a recent study [30] investigating the effects of IFN and ribavirin therapy on cognitive performance in an HCV-monoinfected population. In contrast to that study, we did not find significant effects of PEG-IFN and ribavirin therapy on cognitive function in the HCV-monoinfected group. However, in agreement with that study, we found that the deterioration in reaction times during PEG-IFN and ribavirin therapy was reversible after cessation of therapy except for a single task relating to the speed of simple identification. The improvement in some measures of cognitive function following viral clearance in our study supports the hypothesis of an effect of HCV on cognitive performance independent of mood status. Kraus et al. (2005) did not find a post-treatment improvement in cognitive function; however, neuropsychological assessments were 4-6 weeks post-treatment in their study as opposed to our 24-week post-treatment data. We also found that both the cognitive and mood effects of PEG-IFN and ribavirin therapy were comparable in the two HCV groups. The 24-week post-treatment assessment in our study could be considered relatively short, as IFN-induced depressive and mood disorders have been reported to extend for longer periods in some patients [31,32]. Some authors, however, reported resolution of these symptoms within 2-3 weeks after discontinuation of IFN [33].
In agreement with other studies [1,2,34], we found that coinfection with HCV and HIV did not appear to have additive effects on HRQOL prior to HCV treatment. Although the findings of moderate to large HRQOL decrements during HCV treatment and improvements in physical health with sustained viral clearance in the HCV-monoinfected group are similar to those of other studies [7,35,36], it is difficult to interpret the findings in the HIV/HCV-coinfected population as we are unaware of published studies of HIV/HCV-coinfected patients undergoing HCV treatment. Importantly, our study found comparable results for HIV/HCV coinfection to those for HCV monoinfection with HCV treatment. The finding that individuals without sustained viral clearance had no physical HRQOL benefit but some mental HRQOL benefit is intriguing. It is possible that a reduction in HCV viral load as well as HCV treatment in the context of a supportive clinic environment has benefits in relation to mental health, irrespective of virological response. Many of the individuals in the study attended a treatment support group held fortnightly.
In conclusion, our findings demonstrate in the main that HCV therapy is associated with significant improvements in cognitive function, mood and HRQOL. Additionally, there was no greater cognitive, mood or HRQOL impact in a relatively nonadvanced HIV/HCV-coinfected cohort compared with an HCV-monoinfected group at all phases of HCV treatment. The finding that more than two-thirds of patients can achieve an SVR, associated with significant improvements in HRQOL, can assist in the clinical decision-making process for HCV-infected patient groups. Although the sample size was limited, this study suggests that these two populations may have a similar experience during treatment.
Methods
Study design and participants
This was a prospective cohort study conducted between April 2003 and August 2005. A total of 34 individuals (19 HCV-monoinfected and 15 HIV/HCV-coinfected) 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 (Fig. 1). A detailed description of the study methods can be found in Thein et al. [9].
Study inclusion criteria were age over 18 years, presence of HCV antibody detected by a third-generation enzyme-linked immunosorbent assay and HCV RNA (lower limit of detection 100 HCV RNA copies/mL) determined by a Roche Amplicor Assay (Roche Diagnostics, Sydney, Australia), liver biopsy within the past 12 months consistent with chronic HCV infection, elevated serum alanine aminotransferase ( ALT; >30 IU/L) level 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, a CD4 count <200 cells/μL and pregnancy.
The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethics approval for the study was obtained from hospital Human Research Ethics Committees and all patients gave written informed consent before any assessment was conducted.
Study procedures
Participants completed neuropsychological and HRQOL assessments and a background questionnaire (Table 1) prior to starting HCV treatment, at weeks 18 and 42 (for the 48-week treatment group) after starting treatment, and at 24 weeks following completion of treatment.
Neuropsychological measures
Cognitive function was assessed using a test of premorbid intelligence quotient (the National Adult Reading Test) [11], Trail Making Tests (TMT) A and B [12], and a computer-based performance test, CogState [13-15]. Participants completed a practice followed by a test at each assessment to minimize within-testing-session practice effect [16]. Participants' mood status was assessed using the 42-item Depression Anxiety Stress Scales (DASS) [17]. A depression score of 0-9 is considered 'normal', 10-13 'mild' depression, 14-20 'moderate' depression and 21+ 'severe' depression [17].
HRQOL measures
Participants' HRQOL was assessed using the 4-week recall self-administered Short Form-36 (SF-36) health survey [18]. Two summary measures of the SF-36, physical component summary (PCS) and mental component summary (MCS) scores, were computed using standard algorithms [18]. SF-36 scores were also translated into utilities using the SF-6D algorithm [19,23,24].
HCV treatment
All participants received a standard dose of PEG-IFN α-2a (180 μg once weekly subcutaneously) and ribavirin 800-1200 mg (based on HCV genotype and body weight, daily orally in divided doses) following pretreatment assessments. Treatment duration was based upon HCV genotype. Genotype 2 or 3 patients were treated for 24 weeks (except for two HIV/HCV-coinfected patients who received 48 weeks of treatment), and genotype 1 patients were treated for 48 weeks. Sustained virological response (SVR) was defined as HCV RNA in the serum undetectable by qualitative methods at 6 months after the completion of treatment.
Statistical analysis
Pretreatment data analysis included participants who completed pre- and post-treatment assessments and HCV virological assessments (n=30). Participants who completed HCV treatment and study measures at pretreatment (t1), week 18 on-treatment (t2), and week 24 post-treatment (i.e. 24 weeks after treatment completion; t3) were included in further analyses (12 HCV-monoinfected and 10 HIV/HCV-coinfected individuals) to assess between- and within-group differences in neuropsychological and HRQOL score changes over time.
Cognitive performance, DASS, and HRQOL score differences within and between the HCV groups and between the SVR and non-SVR groups were expressed in terms of effect size (ES) [20,21]. Cohen's classification of ES as small (0.20), medium (0.50) and large (0.80) was used to determine the magnitude of differences in scores [20]. Change scores from t1 to t2 and from t1 to t3 were calculated by taking the difference between means at two time-points. Cognitive performance raw scores were transformed into z-scores (standard scores) using the baseline sample mean and standard deviation. The global cognitive performance z-score was computed by averaging the 12 neuropsychological test scores (CogState and TMT).
Differences in sociodemographic characteristics and clinical data between the HCV-monoinfected and HIV/HCV-coinfected groups were examined using the χ2 test, Fisher's exact test, Student's t-test, or the Mann-Whitney test as appropriate. Age was the only factor consistently found to be significantly associated with neuropsychological and HRQOL measures. Between- and within-group neuropsychological and HRQOL score differences were assessed using analysis of covariance (ancova) adjusting for age and repeated measures analysis of variance (anova), respectively. Cognitive performance differences between individuals receiving antidepressant and antiretroviral therapies and those who were not were assessed using Student's t-test. Cognitive performance and HRQOL differences between those with an SVR and those who did not achieve an SVR were assessed using ancova adjusting for potential confounders such as pretreatment PCS, global cognitive performance z-score, and DASS score. A two-tailed significance level of <0.05 was considered statistically significant in all analyses. Although this level of significance was selected to balance the possibility of Type I error against the exploratory nature of the neuropsychological research, ESs were also presented to ensure that small (i.e. ES<0.20) but statistically significant differences were not interpreted as meaningful and clinically relevant differences. Statistical analysis was performed using the stata computer package, version 8.0 (Stata Corporation, College Station, TX).
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