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The neuropsychological and neurological impact of HCV infection in HIV+
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".....When the liver is dysfunctional, metabolic factors probably impact on neurological performance....
..... The study found an association indicating that there may be a higher prevalence of depressive symptomatology in the HCV/HIV-co-infected group relative to HIV-only subjects...coinfected patients had lower neuropsychological performance...
AIDS: Volume 19 Suppl 3 October 2005 p S64-S71
Clifford, David Ba; Evans, Scott Rb; Yang, Yijunb; Gulick, Roy Mc
aWashington University School of Medicine, St Louis, MO, USA
bHarvard School of Public Health, Boston, MA, USA
cWeill Medical College of Cornell University, New York, NY, USA.
Abstract
Objective: To evaluate the effect of hepatitis C virus (HCV)/HIV co-infection on neuropsychological performance and neurological status in HIV/HCV treatment-naive HIV-1-infected individuals we conducted a cross-sectional study using baseline data from an HIV therapy trial.
Methods: HCV status was determined by the presence of anti-HCV antibodies. Neuropsychological function was evaluated by Trailmaking tests, and the Digit Symbol Task. Depression was assessed using the Center for Epidemiologic Studies - Depression Scale. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index and anxiety by the State-Trait Anxiety Inventory for Adults. A questionnaire was designed grading the severity of a variety of symptoms.
Results:
Of 264 patients with HCV status data, 30 were HCV positive and 234 were HCV negative. Both groups were comparable except that HCV-positive individuals had a higher prevalence of intravenous drug use and lower educational level. The HCV-positive group had a significantly lower neuropsychological performance overall. Multivariate modeling supported an association between HCV infection status with test performance in the Digit Symbol Task and mood parameters even when controlling for potentially confounding variables. Marginal differences were noted with respect to symptom questionnaire scores and global sleep. No differences were noted with respect to anxiety.
Sleep
Marginal differences between the groups were noted with respect to the global sleep score (P = 0.053), with the HCV-positive group displaying poorer overall sleep. An evaluation of sleep components revealed differences in subjective sleep quality (P = 0.008) and marginal differences in sleep disturbance (P = 0.079). No differences were noted between habitual sleep efficiency, sleep duration, or bad dreams. Exploratory multivariate modeling supports the association between HCV infection status and subjective sleep quality even when controlling for potentially confounding variables. No differences were noted with respect to the proportion of subjects with poor overall sleep quality.
Depressed mood
Differences between the groups were also noted with respect to the total depression score, with the HCV-positive group displaying higher depression scores (P = 0.006). Analyses examining the aspects of depression revealed differences between the groups with respect to somatic depression (P = 0.001) and depressed affect (P = 0.006), but not with respect to positive affect and interpersonal relations. Differences were also noted with respect to the proportion of subjects with depressive symptoms suggested by a score of 16 or greater on the CES-D (P = 0.013, Table 3), with 57% of co-infected subjects and 32% of HIV-only subjects displaying depressive symptomatology (odds ratio 2.83 and respective 95% confidence interval 1.32, 6.05). Exploratory multivariate modeling supports the association between HCV infection status and depression scores, somatic depression scores, depressed affect, and depressive symptomatology, even when controlling for potentially confounding variables.
Conclusion: The findings suggest that HCV/HIV co-infection has an adverse impact on neuropsychological function. HCV may also be associated with depressed mood, particularly somatic depressive symptoms. Although confounding contributors to neuropsychological performance are difficult to exclude, exploratory modeling supports the association between HCV infection status and some impairment of neuropsychological performance and depressed mood.
Discussion
The neurocognitive impact of HCV has been difficult to delineate. When the liver is dysfunctional, metabolic factors probably impact on neurological performance. Hepatitis C is most commonly seen in individuals with drug abuse, in which drugs and the other consequences of substance abuse (e.g. trauma, other infections, seizures) are frequent comorbid events. The frequent negative impact of these associations is further seen in the more limited educational attainment and in secondary psychiatric complications, which may also require medication. Medications for hepatitis, particularly the interferons, have significant neurological and psychological impact, with the hazard of the further impairment of performance. In the HIV-infected population, the staging and therapeutic status of the HIV infection are potential confounders when comparing the performance between HCV-positive and HCV-negative groups. Nevertheless, the possibility of a negative central nervous system interaction between these two common infections is a critical concern deserving careful evaluation.
In this study we tested a population before the onset of therapy for HIV or HCV, thus eliminating systematic differences caused by therapy. We investigated the effect of HCV/HIV co-infection on the neuropsychological performance, depressed mood, sleep, anxiety, and neurological symptoms in a clinical trial sample of therapy-naive HIV-positive individuals in this cross-sectional study. Overall, the sample appears to be representative of HIV treatment-naive individuals in the United States initiating therapy, being demographically consistent with the large A5095 sample of subjects [20]. The study revealed that the HCV/HIV-co-infected group had significantly poorer performance on the Digit Symbol Test and more depressive symptoms than the HIV-mono-infected group. Marginal differences were also noted with respect to poorer sleep and more neurological symptoms for the HCV-positive group. However, no differences between the groups were noted with respect to anxiety.
We employed very limited numbers of performance measures, and thus anticipated that the power to determine the characteristics of performance differences would be limited. Our findings were most notable on the Digit Symbol Task, which probes motor persistence, sustained attention, response speed, and visuomotor coordination [27]. The Digit Symbol Task also makes significant demands on motor speed, and thus deficits could reflect a deterioration in motor performance rather than cognitive status. Although this test is also often affected in HIV-associated cognitive disease, we believe that the difference observed was probably HCV related, because both groups had similar untreated HIV disease in relation to the parameters of progression of HIV disease. Similar changes may be caused by uncompensated liver disease, but liver dysfunction itself in the HCV group appeared to be mild in our patients. Finally, after controlling for potentially confounding variables, HCV/HIV co-infection remains associated with poorer performance on neuropsychological tests, particularly the Digit Symbol Test.
Other studies have reported an association between HCV or HCV/HIV co-infection and depression [8,28,29]. We explored this association in this study using the CES-D questionnaire. The study found an association indicating that there may be a higher prevalence of depressive symptomatology in the HCV/HIV-co-infected group relative to HIV-only subjects (P = 0.013, Table 3). Similarly the distribution of the depression score was different between the groups (P = 0.006, Table 2). This is consistent with other reports examining the relationship between HCV status and depression, although these may also have been clouded by therapy for this infection.
Other data collected in the study had been selected to inform us regarding the potential impact of efavirenz on the lives of our patients. It is interesting that consistent with the somatic symptoms that appear to be prominent in the HCV-positive group, our systemic symptom questionnaire developed to probe both systemic and potentially efavirenz-related neuropsychological symptoms also appeared to be consistent with more severe systemic symptoms in the HCV group. Sleep assessments also showed a trend towards more complaints in the HCV-positive group, reflecting the somatic malaise that seems to accompany this condition when carefully assessed. In contrast, anxiety, which was generally at a high level throughout the group of naive subjects about to start their first antiretroviral therapy, did not differ between the groups.
Whether there is an association between HCV/HIV co-infection and poor neuropsychological performance requires further investigation, as there are many factors confounding neuropsychological performance, including drug abuse, alcohol use, head trauma, stage of HIV disease, history of antiretroviral therapy, psychological distress, education, ethnicity, age, gender, and interferon therapy. The groups in this study were well matched for their social demographic status, except intravenous drug use and educational level. After adjusting for potentially confounding variables, HCV/HIV co-infection still remains significantly associated with impaired neurological performance. More detailed and longitudinal studies will be required to elucidate this problem and to evaluate the mechanisms relevant to this disorder. This effort is of paramount importance because of the high prevalence of HCV infection throughout the world.
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