The prevalence of hepatitis C virus (HCV) infection is increasing in the United States and around the world. It is estimated that HCV has infected 170 million people worldwide, whereas HIV has infected an estimated 40 million individuals. In the United States, an estimated 150 000–300 000 people are infected with both HCV and HIV, representing 15–30% of all individuals living with HIV [1–3]. As a result of their shared routes of transmission, chronic HCV infection is increasingly becoming a major cause of morbidity and mortality among HIV-infected individuals.
HCV is a member of the Flavivirides family of viruses that include several other viruses with a predilection for neurological involvement, including West Nile virus, St Louis encephalitis, and dengue. Concern that HCV may also affect the nervous system has received support in numerous reports, with both central and peripheral nervous system involvement implicated [4–13]. HIV has clearly also been implicated as a primary cause of both central and peripheral neurological disease [14–16]. The neurological manifestations of HIV have been extensively described, whereas the neurological manifestations of HCV have been less well characterized and reported. Recent studies suggest an association between an impairment of neurocognitive function and chronic HCV [8,10,11].
In a study by Hilsabeck et al. , impairment of neuropsychological tasks requiring sustained attention was seen in HCV-infected patients even without cirrhosis. The authors found no excess of neuropsychological impairment in HCV-infected patients compared with patients with liver disease of other causes. Such findings have also been reported in the medically asymptomatic stages of HIV infection. Individually, HIV and HCV have each been shown to cause neurological complications; however, the exact way these viruses may interact to promote or amplify neurological disease is not well understood.
HCV has also been associated with psychiatric abnormalities, such as depression and mood disorders . However, it has been difficult in some cases to differentiate the contribution of HCV from the neuropsychiatric complications of IFN-α, the most common treatment for HCV infection [17,18]. Thomas et al.  evaluated chronic fatigue associated with HCV infection, noting that the HCV-infected group had neuropsychological abnormalities. Magnetic resonance spectroscopy evaluations in the HCV group revealed an increase in the ratio of choline to creatine, similar to that reported in HIV-associated dementia .
We evaluated the effect of HCV/HIV infection on neuropsychological performance, sleep quality, anxiety, depressed mood, and neurological symptoms in HIV-infected individuals at baseline using patients from an Adult AIDS Clinical Trials Group (ACTG) study (A5097s). The study enrolled patients who were antiretroviral and IFN-α naive. Studying these subjects at baseline eliminated the potential confounding effects of antiretroviral treatment for HIV and interferon treatment for HCV.
A5097s is a substudy of A5095, a phase III, randomized, double-blind comparison of three protease inhibitor-sparing regimens for the initial treatment of HIV infection of the ACTG . The substudy was designed to evaluate the effects of efavirenz on neuropsychological performance, mood, anxiety, sleep behavior, and neurological symptoms during the initial 24 weeks of antiretroviral therapy in treatment-naive HIV-infected subjects.
All patients who participated in A5097s were eligible for this study. Informed consent for testing was obtained using local institutional review board-approved consent documents from each participating center. Thirty-seven sites participated in A5097s. Hepatitis C antibody status was available in 264 out of 303 patients from 36 sites in A5097s. Demographic data and disease status were available for nearly all subjects and were collected at entry.
HCV co-infection was determined by the presence of HCV antibodies at study entry. HIV serology, CD4/CD8 cell counts, HIV-RNA levels, hepatitis B serology, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and alkaline phosphatase levels were all available.
A brief battery of neuropsychological tests was administered including Trailmaking A and B  and the Wechsler Adult Intelligence Scale III revised  Digit Symbol. These measures have been in use for neurological performance measures in ACTG neurological trials with administrator training at each center provided by the Neurologic AIDS Research Consortium. They are well tolerated by subjects and are sensitive to performance changes in this population. They provide measures of motor persistence, sustained attention, response speed, visuomotor coordination, and conceptual shifting/tracking.
The Trailmaking A and B Test is an assessment of psychomotor speed, visual scanning and tracking, attention and concentration, and sequencing, and has two parts. On part A subjects are asked to connect numbered dots serially that have been scattered on a page. On part B, subjects are instructed to connect consecutively numbered and lettered circles by alternating between two sequences. On both parts the subject is urged to connect the circles as quickly as possible. The time taken (in seconds) to complete each part is recorded.
The Wechsler Adult Intelligence Scale revised Digit Symbol Test is a pencil and paper symbol substitution task consisting of four rows containing 100 small blank squares, each paired with randomly assigned numbers from one to nine. The task is to fill in the blank spaces as quickly as possible with the symbol that is paired with the number in the key. The score is the number of blanks correctly filled at the end of 90 s. The number of correct responses in 90 s is the final score.
A neuropsychological summary score (NPZ3) was defined as the sum of three standardized test scores (Trailmaking A and B and the Digit Symbol Tests), each calculated by subtracting a normative mean from the subject score and dividing by the standard deviation. Normative data were based on an adjustment for age (less than or equal to 39, 40–49, 50–59, and greater than or equal to 60 years). Positive scores indicate above-norm function whereas negative scores indicate below-norm function.
Impairment points were used to define neurological impairment by comparing scores from the three tests to the cut-offs in the established norms (adjusted for education, age, and gender) in Heaton et al. . If the raw score of the test was the same as or worse than the norm under the −2 standard deviations (SD) heading, 2 impairment points were assigned for that test. If the subject's score was exactly equal to a score of −1 SD or was between the −1 SD and −2 SD cut-offs, then 1 impairment point was assigned. Otherwise, no impairment points for that test were assigned. Neurological impairment is defined as having two of the above three tests at 1 SD below the mean or one test 2 SD below the mean.
For an assessment of depression, the Center for Epidemiologic Studies–Depression Scale (CES-D) was administered . The CES-D is a 20-item self-report measure of depressive symptomatology with graded responses from 0 to 3 for each question. Participants rate the frequency with which they have experienced any symptoms during the past week. The CES-D correlates highly (R = 0.70–0.80) with other self-report depression instruments, e.g. the Beck Depression Inventory. The scores ranged from 0 to 60, with higher scores indicating more depression. According to Radloff  and others, a score of 16 or greater indicates the presence of ‘depressive symptomatology’ indicative of possible diagnosable depression. This traditional cut-off score has been reported to result in a false-positive rate of 6.1% and a false-negative rate of 36.4%. The CES-D allows an analysis of contributions to depressive symptoms including somatic symptoms, depressed affect, positive affect and interpersonal relations.
The Pittsburgh Sleep Quality Index was also utilized in this study . This questionnaire has 19 self-report items and subdivides into seven component scores (subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbance, use of sleep medicine, and daytime dysfunction). A global sleep score is calculated from the sum of the seven component scores and ranges from 0 to 21, with a score greater than 5 considered to be indicative of poor overall sleep quality. Differences in individual components were also examined.
The State Anxiety Inventory  was used to evaluate anxiety. It includes 10 calm-polarized items and 10 tense-polarized items. A global anxiety score is the sum of the 20 items. Individual items are scored 1–4, with higher scores indicating more anxiety. Global scores of 40 or more were considered clinically significant levels of anxiety.
An experience questionnaire was specifically developed for A5097s asking the subject to assess the severity of symptoms on a scale of 0 (‘not at all’) to 4 (‘extremely’). The intent was to use this instrument as a sensitive measure to characterize complaints. The questionnaire was structured so that the odd-numbered queries focused on symptoms often reported previously with efavirenz toxicity, exploring the areas of dizziness, sleep, and attention. Even-numbered questions probed systemic symptoms, particularly those that had previously been associated with abacavir. We examined the total score as a measure of clinical symptomatology.
This study was cross-sectional, with data collected at a single timepoint (study entry). The primary comparison was between HCV/HIV-co-infected and HIV-only groups. Descriptive statistics were used to describe the study sample. Summaries were provided by HCV status to compare groups. Frequency distributions and cross-tabulations were used to summarize categorical variables by HCV status. Exact tests were used to test for associations between HCV status and categorical variables. Kruskal–Wallis tests were used to test for differences between HCV-positive and HCV-negative groups with respect to continuous variables. Very few data were missing and no data were imputed. These analyses were considered exploratory, and thus all significance testing was performed at the 0.05 level without adjustment for multiple testing. All reported P values were two-sided. Exploratory linear and logistic regression were employed to adjust for the effects of the following potentially confounding variables: intravenous drug use, race, sex, age, education, CD4 cell count, and HIV-RNA viral load.
A total of 303 individuals were enrolled into A5097s from March 2001 to January 2002, with 264 of these subjects having HCV status data available at entry. The subjects who did not have HCV status identified at entry (N = 39) did not differ with respect to sex, race, age, intravenous drug history, CD4 cell count, HIV-1-RNA level, hepatitis B virus status, or years of education, when compared with subjects who had their HCV status identified at entry. Patient characteristics of the studied sample of 264 subjects in whom the HCV status was recorded are presented by group in Table 1. Thirty of these subjects (11%) were co-infected with HCV and HIV. Current toxic drug screens were not available.
Subjects had a median age of 38 years and the median length of education was 14 years. The majority of subjects were male (80%), and white (53%). The median CD4 and CD8 cell counts were 216 and 795, respectively. The median log10 HIV-1-RNA level was 4.75. Ninety patients (34%) had serological evidence of hepatitis B infection. No differences between the HCV/HIV-co-infected group and the HIV-only group were noted with respect to gender, age, CD4 and CD8 cell counts, hepatitis B virus status, and HIV-1-RNA level. Disparities between the groups were noted with respect to intravenous drug use (P < 0.001), with the HCV-positive group having more intravenous drug use, and years of school education (P < 0.001), with the HCV-positive group having fewer years of education.
Differences between the groups were noted with respect to neurocognitive measures, with the HCV-positive group performing worse than the HCV-negative group. In particular, differences with respect to NPZ3 (P = 0.001) were noted (Table 2). Analyses of the components of NPZ3 revealed differences between the groups with respect to the Digit Symbol Test (P = 0.001) and the Trailmaking B Test (P = 0.006) but not for Trailmaking A (P = 0.113).
Exploratory multivariate modeling that controls for potentially confounding variables supports the association between HCV infection status and Digit Symbol Test results, but not with Trailmaking B test results. No differences in the proportion of subjects with neurological impairment were noted however (Table 3). Post-hoc analysis comparing controls matched 1: 1 for education attainment with co-infected subjects demonstrated a significant decrement in Digit Symbol performance in co-infected subjects (P = 0.005).
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, Table 2). 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 (Table 2). 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.
Differences between the groups were not observed with respect to the global anxiety score (P = 0.368, Table 2) nor with respect to the proportion of subjects with clinically significant anxiety (P = 0.406, Table 3).
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 (Table 3).
Systemic symptom questionnaire
The comparison of a variety of systemic symptom complaints as well as questions targeted at antiretroviral neurological toxicity were collected in the study. Differences between the groups with respect to symptoms at baseline were of marginal significance, with the HCV-positive group displaying more severe symptoms (P = 0.064, Table 2). These results were not confirmed with multivariate modeling.
The study protocol excluded patients with significant hepatic destruction (AST or ALT greater than five times the upper limit of normal). However, involvement of the liver by HCV co-infection was evident when examining liver enzyme tests. The median ALT and AST values were 48 and 45 in the HCV-positive group whereas they were 27.5 and 27, respectively, in the HCV-negative group. These differences were significant (P < 0.001). However, the ranges of values demonstrate that severe abnormalities were not present in this study sample. The paucity of liver dysfunction is further substantiated by normal serum albumin levels in all subjects and a similar prevalence of abnormal total bilirubin levels [one out of 30 (3.3%) HCV-positive and five out of 230 (2.2%) HCV-negative subjects].
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 . 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 . 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.
The authors are grateful to the subjects who volunteered to participate in the study. In addition to the authors, other members of the ACTG A5097s protocol team include the following: Meredith Glicksman, MS, Washington University, St Louis, MO, protocol co-chair; Christina Lalama, MS, Harvard University, Boston, substudy statistician; Nicole Grosskopf, BS, Frontier Science and Technology Research Foundation, data manager; Edward P. Acosta, Pharm.D., University of Alabama, Birmingham, AL, study pharmacologist; David Dorfman, PhD, and David Simpson, MD, Mount Sinai School of Medicine, New York, NY; Karl Goodkin, MD, PhD, University of Miami School of Medicine, Miami, FL; and Karen T. Tashima, MD, Miriam Hospital, Providence, RI, study investigators; and Valery Hughes, NP, Cornell Clinical Trials Unit, New York, NY, field representative.
The A5097s team includes: Diane Gochnour, RN and William E. Maher, MD, Ohio State University (A2301); David Currin, RN and JoAnn Kuruc, University of North Carolina (A3201); Julie Hoffman, RN and Paula Potter, RN, University of California, San Diego (A0701); James Richardson, MD and Janet Hernandez, RN, Indiana University Hospital (A2601); Oluwatoyin Adeyemi, MD and Donna McGregor, NP, Northwestern University (A2701); Deborah A. McMahon, MD and Sharon A. Riddler, MD, University of Pittsburgh (A1001); Janet Nicotera, RN, BSN and Jie Wang, RN, Vanderbilt University (A3651); Tianna Petersen and Phillip Keiser, MD, University of Texas, Southwestern Medical Center (A3751); Christine Hurley, RN and Roberto Corales, DO, University of Rochester Medical Center (A1101); Dr Susan Swindells and Francis Van Meter, University of Minnesota (A1501); Jose L. Santana, MD, Santiago Marrero, MD, University of Puerto Rico (A5401); Robert Schooley, MD, Jim Scott, BSN, University of Colorado Health Sciences Center, Denver (A6101); Mark Rodriguez, RN and Lisa Kessels, RN. Washington University, St Louis (A2101); Martha Silberman, RN and Nathan Thielman, MD, Duke University Medical Center (A1601); Joan Gormley, RN and Katherine Wright, the Miriam Hospital (A2951); Lynn Dumas, RN and Paul Sax, MD, Harvard (Brigham and Women's Hospital) (A0101); Janet Forcht, RN and Marina Queen NYU/Bellevue (A0401); Ron Johnson, RN and Benigno Rodriguez, MD, Case Western Reserve University (A2501); Gwendolyn D. Costantini, FNP and Donna Mildvan, MD, Beth Israel Medical Center (A2851); Todd Stroberg, RN and Marshall Glesby, MD, Columbia University and Weill Medical College of Cornell University (A7802); Clifford Gunthel, MD and Dale Maddox, LCSW, Emory University (A5802); Laura Olin, ARNP and Beck A. Royer, PA-C, University of Washington, Seattle (A1401); Wayne Wagner RN, MSW and Harvey Friedman MD, University of Pennsylvania, PA (A6201).
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