Infection with the hepatitis C virus (HCV) is a worldwide healthcare problem, with approximately 170 million individuals affected [1,2]. HCV infection is five times as widespread as infection with HIV-1 . It is expected that the proportion of HCV-infected patients who develop cirrhosis will double over the next decade .
Almost one-third of HIV-infected patients have been found to be co-infected with HCV, particularly individuals infected with HIV through parenteral drug use in which HCV co-infection is reported in 70–90%. These statistics are alarming as HIV has been shown to accelerate the course of HCV disease and the development of cirrhosis, with evidence that HCV may worsen the prognosis of HIV disease [5,6].
There is also growing evidence that both viruses have systemic effects that can cause central nervous system (CNS) dysfunction. Similar to HIV, HCV patients have been shown to have abnormalities of brain structure on magnetic resonance spectroscopy , even when they are clinically asymptomatic. These abnormalities are not only explained by advanced liver disease and hepatic encephalopathy, but are independent of intravenous drug abuse. Coupled with evidence of low but detectable levels of HCV replication in the CNS, these findings suggest that chronic HCV infection can induce CNS damage even in early stages of the disease .
A number of studies have reported neuropsychological deficits in patients with chronic HCV [7–9]. Our group showed that patients with HCV infection have deficits on tasks of attention, concentration and psychomotor speed, with 82% of the patients exhibiting moderate impairment on a measure of sustained visual attention . In addition, we also showed that a greater degree of liver fibrosis (i.e. advanced stages of HCV disease) was associated with a poorer test performance [8,9]. However, no significant correlations were found between neuropsychological test performance and the biochemical indices of liver disease. The studies collectively suggest that the areas of complex attention, concentration and working memory are affected in HCV-infected patients, even in patients with mild histological liver disease [7–9].
Asymptomatic HIV-infected patients have been shown to exhibit preferentially impaired attention/speed of processing and working memory [10,11], similar to the deficits observed among pre-cirrhotic HCV patients. Also, HIV patients with minor cognitive motor disorder demonstrate slowed information processing speed, poor complex attention skills (e.g. sustained attention, divided attention) and depressed learning abilities [12,13]. These deficits are similar to the pattern of deficits found in patients with liver cirrhosis presenting with minimal (subclinical) type C hepatic encephalopathy [14–16]. Although cognitive impairment has been reported in both relatively healthy HCV and HIV patients, the burden of HCV/HIV co-infection on the neuropsychological performance of co-infected patients remains unclear.
In this study we examined a heterogeneous cohort of patients with HCV alone and compared them with clinically stable HCV patients who were co-infected with HIV. The primary aim of the study was to examine the burden of HCV/HIV co-infection on neuropsychological performance among clinically stable patients who do not have hepatic encephalopathy. We hypothesized that both HCV-alone and HCV/HIV-co-infected patients would show neuropsychological deficits on measures of attention, concentration and psychomotor speed. We further hypothesized that the HCV/HIV-co-infected group would demonstrate greater deficits compared with the HCV-alone group because of the burden of both diseases on the CNS [9,17–19]. Finally, we hypothesized that there would be a relationship between the degree of impaired neuropsychological test performance and hepatic fibrosis stage.
Participants in this study consisted of 76 consecutive patients diagnosed with chronic liver disease. The study was approved by our institutional review board, and all patients consented to participate. Forty-seven patients had HCV alone and 29 patients were co-infected with both HCV and HIV. Exclusionary criteria for the following analyses included an inability to read or understand English, current or past neurological illness, a history of loss of consciousness for at least 20 min, or currently receiving interferon or ribavirin antiviral therapy. Information collected from eight co-infected patients reported in Hilsabeck and colleagues  were included in these analyses.
The sample consisted of 51 men (67.1%) and 25 (32.9%) women with a mean age of 45.99 ± 8.6 years. The average education of the sample was 13.34 ± 2.47 years. Sixty-eight per cent were Caucasian, 14.5% were Hispanic, 9.2% were African American, 2.6% were Asian American, and 5.7% were classified as other. Seventy-two per cent of the participants were genotype 1. Although neither urine toxicology nor psychiatric evaluations were performed at the time of testing, to our knowledge our group did not include any active substance users, nor was severe mental illness identified in any of our subjects.
The mean alanine aminotransferase (ALT) level was 76.10 ± 49.59 (normal range < 45). The mean and median CD4 cell count for HCV/HIV-co-infected patients was 479 and 465, respectively, and 58.6% had CD4 cell counts greater than 400. The mean HIV viral load was 16 322 copies/ml, and 65.5% of patients were below the detectable level (< 400 copies/ml). Fifty-one per cent of the patients were known to be clinically stable on highly active antiretroviral therapy.
Liver biopsies were scored according to the METAVIR system in order to determine the fibrosis stage . In this system, a score ranging from 0 to 4 was given to identify the extent of liver fibrosis. A score of 0 was given for no fibrosis, 1 for mild fibrosis (fibrous expansion of portal tract with no septa), 2 for moderate fibrosis (portal fibrosis with rare septa), 3 for severe fibrosis (portal–portal or portal–central bridging with numerous septa), and a score of 4 was given for cirrhosis (loss of architecture and regenerative nodule formation). Seventeen per cent of the patients were found to have no fibrosis (stage 0), 24% had mild fibrosis (stage 1), 8% had moderate fibrosis (stage 2), 13% had severe fibrosis (stage 3), and 30% had cirrhosis (stage 4); 8% were not done or were inadequate for staging (see Table 1).
Cognitive functions were assessed for complex attention and concentration involving visual scanning and tracking, psychomotor speed, and working memory. To assess these domains all patients were administered the Trail Making Test (TMT) parts A and B  and the Symbol Digit Modalities Test (SDMT) , with a subset of patients additionally completing the symbol search subtest of the Wechsler Adult Intelligence Scale – Third Revision (WAIS-III) .
Raw scores, age and education demographically corrected T-scores (mean 50, SD 10) , or age-corrected scaled scores (mean 10, SD 3)  were used for the analyses. In keeping with previous studies of cognitive functioning in patients with HCV [7,8], the criterion for impairment on each measure was performance more than 1 SD below the demographically corrected mean (i.e. T-scores < 40 or an age-corrected scaled score < 7) .
The neuropsychological data were found to be non-normally distributed, as assessed by the Kolmogorov–Smirnov and Shapiro–Wilk tests of normality. Therefore, medians and the range of scores are presented (see Table 2), and differences on cognitive measures between HCV-alone and HCV/HIV-co-infected patients were examined using the Mann–Whitney U test and χ2 analyses for discrete variables. The alpha level was conservatively set at 0.025 in all analyses in order to detect significant differences between groups while accounting for multiple analyses.
There were no differences in age or years of education between the HCV-alone, and HCV/HIV-co-infected groups (t = 1.69, P = 0.096), (t = 1.34, P = 0.19). There were also no differences on the TMT part A (F[4,75] = 1.05, P = 0.39), TMT part B (F[4,75] = 1.86, P = 0.12), WAIS-III symbol search (F[4,26] = 1.51, P = 0.23), and the SDMT (F[4,74] = 0.88, P = 0.48) based upon race. The median scores and range of performance are presented in Table 2. There were no differences on neuropsychological test performance between the HCV-alone and HCV/HIV-co-infected group for any of the neuropsychological measures (TMT A: z = −1.31, P = 0.19; TMT B: z = −0.66, P = 0.51; SDMT: z = −0.07, P = 0.95; WAIS-III symbol search: z = −0.05, P = 0.96). Table 2 lists the percentage of patients that scored at least one standard deviation below the normative mean for the respective neuropsychological measures. The percentage of impaired performance on the neuropsychological measures was compared against the percentage expected in the normal population as reported by Heaton et al. . Using χ2 analyses the HCV-alone group had more impairment than expected on the TMT part B (χ2 = 0.646, P < 0.025), the SDMT (χ2 = 12.62, P < 0.001), and symbol search (χ2 = 4.33, P < 0.05). The degree of impairment did not reach statistical significance for the TMT part A (χ2 = 3.78, P < 0.10). The HCV/HIV-co-infected group reached statistical significance for the percentage of impairment on the SDMT (χ2 = 23.45, P < 0.001). The percentage of impairment on the remaining three tests was not significantly different from the percentage found in the normative sample (TMT part A: χ2 = 1.32; TMT part B: χ2 = 0.62; symbol search: χ2 = 0.96). To characterize the degree of neuropsychological impairment further for both groups we calculated that 27% of the HCV-alone group and 13.8% of the HCV/HIV-co-infected group was impaired on two or more of the neuropsychological tests. The percentage of impairment between the HCV-alone and the HCV/HIV-co-infected groups was not statistically significant for any of the neuropsychological measures (TMT part A: χ2 = 0.63; TMT part B: χ2 = 0.30; the SDMT: χ2 = 0.40; symbol search: χ2 = 0.68). However, the HCV-alone group had a significantly greater percentage of impairment on two or more neuropsychological tests than did the HCV/HIV-co-infected group (χ2 = 3.90, P < 0.05).
There was no relationship between neuropsychological performance and the ALT and CD4 cell counts. The relationship between fibrosis stage and performance on the neuropsychological measures was also evaluated. As there were few cases of cirrhosis in the HCV/HIV-co-infected group, both groups were combined for the analysis. All of the neuropsychology measures were correlated moderately with fibrosis stage such that advanced liver disease (greater fibrosis) was associated with a poorer neuropsychological test performance (Table 3).
The findings from this study show that a significant number of patients with chronic HCV, either alone or when co-infected with HIV, have deficits in the domains of attention, concentration and psychomotor speed when tested using standard neuropsychological tests. The extent of the deficit is different depending upon the measure used. Both the HCV-alone and the HCV/HIV-co-infected group demonstrated impairment on the SDMT. We have previously reported that the SDMT yielded the largest percentage of impairment among our measures of attention, concentration and psychomotor speed , suggesting that this measure may be sensitive in detecting neuropsychological functioning among patients with HCV infection.
The HCV-alone group performed in the impaired range on three of the four administered tests, whereas the HCV/HIV-co-infected group performed in the impaired range on one of the four measures. More than a quarter of the HCV-alone group was also impaired on two or more of the tests administered compared with 13.8% of the HCV/HIV-co-infected group. Similar to our findings, Heaton and colleagues  reported that 30% of asymptomatic HIV-seropositive patients had impaired neuropsychological test performance on two or more measures, whereas Starace and colleagues  found 22% impaired neuropsychological performance among HIV-seropositive individuals. These impairment rates are higher than the 2.5% reported for healthy controls . The finding that the HCV-alone group had a higher percentage of impaired performance, albeit not significantly different, than did the HCV/HIV-co-infected group on our tests may be related to the greater number of cirrhotic patients in the HCV-alone group. Consistent with this supposition is our finding that the severity of liver disease was positively related to a poorer test performance. These findings are also consistent with previous results that HCV is associated with deficits in attention, concentration and psychomotor speed [8,9].
Similar to other studies, neuropsychological performance did not correlate with ALT and CD4 cell counts . As a result of the small numbers of patients with detectable HIV viral load, a correlation between neuropsychological test performance and viral load was not performed. However, there was a correlation between neuropsychological impairment and an increase in the severity of liver fibrosis. Moss and colleagues  reported that neuropsychological deficits in patients with chronic liver disease correlated with the degree of hepatic dysfunction, although the biochemical measures of hepatic injury (ALT levels) did not demonstrate a significant relationship with any neuropsychological measure. The absence of a correlation with biochemical measures of hepatic injury (ALT) is explained by the fact that these measures do not reflect the stage or extent of the liver damage in a disease characterized by slow progressive changes; however, they reflect an ongoing level of hepatic injury.
The current findings of a relationship between neuropsychological performance and fibrosis severity add further support to earlier studies that found that HCV patients have deficits on a number of neuropsychological tests that reflect frontostriatal functioning (i.e. tests of attention, psychomotor and working memory) but demonstrated intact verbal skills and visuoconstructional abilities . In addition, it has been shown that neuropsychological impairment is correlated with a decrease in the bilateral frontotemporal and right basal ganglia regions in end-stage cirrhotic patients compared with control subjects .
The present findings did not support our primary hypothesis that there would be significant differences on measures of attention, concentration and psychomotor speed between patients with HCV alone and HCV/HIV-co-infected patients. This might be related to the fact that 65% of the HCV/HIV-co-infected group had undetectable HIV levels as well as controlled disease. The relative similarity in the neuropsychological deficits among HCV-alone and HCV/HIV-co-infected patients suggests that there may be an overlap in the underlying abnormal frontostriatal circuitry, which is known to be associated with abnormal attention and psychomotor speed. It has also been shown that patients co-infected with both HCV and HIV develop hepatic changes more rapidly than patients with HCV alone . This interaction might result in an increased burden on the CNS and additive effects on neuropsychological performance, particularly perpetuating deficits in attention and working memory. However, von Giesen and colleagues  recently reported that HCV co-infection did not exacerbate psychomotor slowing in their sample of HIV-positive patients. Collectively, these findings underscore the importance of disease stage rather than the presence or absence of the virus itself.
The absence of our expected findings could also be explained by the limitations in our study. We tested a relatively small group of patients, and therefore we may be underpowered with respect to finding subtle neuropsychological differences between the two relatively healthy clinical samples. It is also possible that our measures of attention and concentration may not be sensitive enough to uncover group differences. In addition, we restricted our neuropsychological measures to tests of attention, concentration and psychomotor speed. The present findings, therefore, cannot be generalized to other cognitive domains, such as learning and memory or visuoconstructional abilities, which may be different between the two groups. Finally, inspection of the HCV/HIV-co-infected sample revealed that our co-infected group consisted of a relatively healthy sample (mean CD4 cell count of 479 and only seven patients with severe fibrosis or cirrhosis). Given that previous work has suggested that neuropsychological deficits are related to the stage of liver fibrosis, it is possible that the lack of a difference in neuropsychological performance can be attributed to the relative lack of advanced liver fibrosis among the HCV/HIV-co-infected patients. In this regard we can speculate that the successful treatment of HIV and the absence of cirrhosis may spare patients co-infected with HCV/HIV from significant neuropsychological impairment. This finding is consistent with the work of Arendt and colleagues , who have repeatedly shown that HIV-associated psychomotor slowing improves with treatment. Clearly, larger studies in heterogeneous groups of HCV and HCV/HIV-co-infected patients using a more extensive neuropsychological test battery are needed to determine conclusively whether there are differences in neuropsychological functioning between HCV and HCV/HIV-co-infected patients.
Sponsorship: This work was partly supported by National Institutes of Health grant no. 5 P30 AI36214-05 to University of California, San Diego Center for AIDS Research.
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