In 2002, about 42 million people worldwide lived with HIV infection (www.unaids.org). Chronic hepatitis C virus (HCV) infection is estimated to affect more than 170 million people worldwide. 1 Both HIV and HCV may lead to chronic viral infection with persistent plasma viremia. In contrast to HIV, HCV can be eradicated. At present, an important and still ongoing epidemic of HIV/HCV coinfection can be observed. Recently, the weighted overall estimate of HCV prevalence in an HIV-seropositive AIDS Clinical Trial Group (ACTG) cohort was reported to reach 16.1%. 2 HIV/HCV coinfection thus constitutes a major health issue. 3 It is well established that HIV enters the central nervous system (CNS) early during the individual course of infection. 4 The effects of HIV on the CNS can be diverse and affect different cognitive, motor, and emotional domains 5 in otherwise asymptomatic subjects. Accordingly, a variety of neuropsychologic tests have been applied and proven to detect relevant abnormalities. 6–12 Minor motor deficits are of utmost importance for the individual patient, because large American 13 and European 14 studies have independently shown that these disorders, quantified, for instance, by psychomotor slowing, predict the later manifestation of AIDS, HIV-associated dementia, and even the death of the patient. Not only can HCV be detected in the cerebrospinal fluid of HCV-infected patients, 15 but it can replicate in the CNS 16 and lead to cognitive impairment in patients with chronic HCV infection. 17–20 Cognitive domains that have been described to be affected in HCV infection comprise attention and psychomotor speed. The precise pattern of deficits, however, is yet unclear. We examined the potential influence of HIV and/or HCV (co)infection on a variety of neuropsychologic domains, including attention, memory, construction, depressed mood, self-reported somatic and psychiatric complaints, and psychomotor speed.
Since 1987, we prospectively followed an increasingly large cohort of HIV-positive patients. The number of patients seen in the Department of Neurology until December 31, 2001, was 1949. Of these patients, we retrospectively defined all HIV-positive patients (n = 43) with a positive HCV polymerase chain reaction. Further, 43 HIV-positive patients with no HCV infection as well as 44 HIV-negative patients with HCV infection served as controls. Demographic data of all patients at the date of their first visit in our department are given in Table 1. HIV-positive patients were attributed to non-AIDS and AIDS stages according to the revised Centers for Disease Control and Prevention (CDC) classification. 21 The type of antiretroviral treatment (ART) at the first visit is also noted: untreated, a combination of 2 nucleoside analogues, or highly active antiretroviral therapy (HAART).
Patients with a past or ongoing history of intravenous (IV) drug use and patients without such a history were analyzed separately to determine a potential influence of drug use in each group. Patients with HIV-associated dementia according to defined clinical criteria, 5 with primary CNS lymphoma proven by stereotactic brain biopsy, or with clinical or neuroradiologic evidence of CNS opportunistic infections as well as patients with liver cirrhosis and hepatic encephalopathy were excluded to avoid any interference between these CNS diseases and test performance. Hepatitis C was diagnosed by positive HCV antibody and HCV RNA.
All patients were negative for hepatitis B surface antigen. Hepatitis B thus did not represent a confound. According the Child Pugh score 22 for clinical staging of liver cirrhosis, liver function was assessed in all patients by serum albumin, bilirubin, prothrombin time, and standard tests for hepatic encephalopathy. Ammonia levels were not routinely measured. Ultrasound examinations showed no signs of liver cirrhosis or portal hypertension in all patients. Therefore, clinically significant liver cirrhosis (according to the Child-Pugh criteria) could be excluded. Any interference with potential hepatic encephalopathy could thus be avoided in the present analysis. Liver biopsies were not routinely performed. Liver biopsies were performed in 5 HIV-negative HCV-infected patients before they entered a controlled therapeutic trial and showed no liver cirrhosis.
The Mehrfachwortauswahltest (MWT-b) 23 was used to assess premorbid verbal intelligence, and the Raven Progressive Matrices test 24 was applied to assess current nonverbal intelligence. Thus, both intelligence quotients (IQs) were determined. The Syndrom-Kurztest (SKT) 25,26 is a brief neuropsychologic test battery consisting of 9 performance subtests that define 2 independent factors: memory and attention. It requires about 15 minutes to administer and has 5 parallel forms. Individual results of the SKT were adjusted for age and IQ and were classified in 4 scoring categories: 0 (normal), 1 (light), 2 (moderate), or 3 (severe disturbances of memory and attention). The Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie (AMDP) system 27 describes and evaluates self-reported complaints in 7 psychiatric and 6 somatic domains. Each item is listed separately in Table 2. According to the patient's report, a score was set for each item (eg, sleep disorder) on the scale of normal (0) or disturbed (slight , moderate , or severe ). To assess depressive symptoms, the Hamilton Depression Rating Scale (HAM-D) 28 was used, which consists of a semistructured interview evaluating 21 different items. Finally, the HIV dementia scale (HDS) 29 was applied to all patients. It comprises 4 tasks evaluating the domains of memory (recall of 4 items at 5 minutes), attention (antisaccadic errors), psychomotor speed (timed written alphabet), and construction (cube copy time).
Electrophysiologic Motor Tests
The electrophysiologic test battery used in this study has repeatedly been shown to describe different aspects of fine motor performance in defined basal ganglia diseases like Parkinson disease, 30 Wilson disease, 31 Huntington chorea, 32 or HIV infection of the CNS. 33,34 The 4 parameters tested are affected differentially in these diseases. The entire test battery was now applied in HCV-infected individuals to find out about potential minor motor deficits. To avoid any learning effects, only the results of a first series of tests were analyzed. Briefly, a lightweight accelerometer taped to the nail of the subject's index finger was used for recording the tremor peak frequency (TPF) and the frequency of most rapid alternating index finger movements (MRAMs). For TPF, subjects were asked to hold their arms in a horizontal position with the forearms fully pronated and the fingers completely outstretched. A spectrum analysis was performed off-line, with the frequency of the dominant peak of the average spectrum being defined as the TPF. For MRAMs, subjects were told to flex and extend the index finger at the metacarpophalangeal joint as rapidly as possible. For recordings of most rapid contractions, the index finger was firmly attached to a force transducer. Subjects were asked to extend the finger as soon as possible after hearing a “go” signal. Parameters measured in this context were simple reaction time (RT), which is the time span between the acoustic go-signal and the onset of a most rapid isometric index finger extension, and contraction time (CT), which is the time span between the onset of extensor indicis contraction and the point at which the contraction reaches its maximum. Ninety-eight HIV/HCV-seronegative healthy volunteers served as a control group to establish normal values. 35 In HIV-positive patients, these tests are not influenced by IV drug use, 35 peripheral nerve slowing, 36 or depressive mood. 37 These aspects are discussed in more detail later.
Statistics were performed with the commercially available software package Statview for Windows, version 5.0.1 (SAS Institute, Cary, NC). Absolute numbers were determined for defined conditions. Descriptive statistics were performed on the demographic data at baseline visits. For parametric data, ANOVA was used to test for significant differences between groups. The Scheffé F test was used to test for post hoc significance. Contingency tables were used to test nominal parameters.
Demographic data of all patients included are given in Table 1. Male patients prevailed in the HIV-positive groups, whereas women formed the majority of the HIV-negative but HCV-positive group. Patients in this latter group were also significantly older than patients coinfected with both viruses (P = 0.0376, Scheffé F test). The duration of HIV seropositivity, mode of HIV infection, distribution of non-AIDS/AIDS stages, CD4 cell counts, plasma viral load, and type of ART were comparable in both HIV-infected groups. HIV-uninfected but HCV-infected patients were all untreated, and the mode of infection remained undetermined in 21 patients. Twenty-seven patients in both HIV-infected groups and 8 patients in the HIV-negative but HCV-positive group had acquired HIV infection through IV drug use, thus accounting for the majority of the patients. IV drug users and nonusers were also analyzed separately. Mean serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were elevated in all groups but did not differ among groups.
Premorbid verbal intelligence and actual nonverbal intelligence did not differ among groups (for further results, see Table 2). HIV-positive but HCV-negative patients showed only minor disturbances (mean = 0.25) in the SKT, but there were no significant differences among groups for mean SKT scores. There were no significant differences in all AMDP psychiatric and somatic items, with the exception of affective disorders. HIV-negative but HCV-positive patients scored significantly lower than both HIV-infected groups (Scheffé F test, P = 0.0445 vs. HIV/HCV-coinfected patients, P = 0.0181 vs. HIV-infected but HCV-uninfected patients). For no item did the mean score reach 2 (ie, moderate). Significant differences could be shown with regard to the sum score (items 1–21) of the HAM-D. HIV-uninfected but HCV-infected patients scored significantly lower than both HIV-infected groups (P < 0.0001 each in post hoc testing). HIV/HCV-coinfected patients performed slightly worse in the HDS psychomotor speed task, but the overall HDS score and all subscores did not differ significantly among all groups. IV drug users and nonusers were analyzed separately in all 3 groups. For no parameter were significant differences found in more than 1 patient group. Thus, there is no systematic influence of IV drug use on psychometric testing in our patients.
Electrophysiologic Motor Tests
Electrophysiologic motor tests results are given in Table 3. MRAMs (right hand) and CTs (both hands) significantly discriminated between patients and HIV/HCV-uninfected controls. There are no significant differences among patient groups for these 3 parameters. Again, IV drug users and nonusers were compared separately. No systematic influence of IV drug use on psychomotor speed was detected in any of the 3 groups. No systematic correlation between motor test results and liver enzymes existed.
Both HIV infection and HCV infection may cause encephalopathy. Because up to 16% of HIV-infected patients 2 are estimated to be coinfected with HCV, the question arises as to whether this coinfection accelerates the development of HIV-associated CNS disease. Recent studies suggest that HCV coinfection in HIV-infected patients prevents the realization of substantial therapeutic benefits. 38 With this background, the present study compares the performance of HIV-infected and/or HCV-infected patients in cognitive, motor, and emotional tests. The suspected kind of interaction could be possible, because HCV genomic sequences can be detected in the CSF of HIV/HCV-coinfected patients. 15 Evidence that HCV may also replicate within the CNS 16 is increasing, probably within cells of the macrophage/monocyte lineage. Also, HCV may cause cognitive dysfunction 18 in the absence of liver cirrhosis. None of our patients suffered from hepatic encephalopathy, and liver cirrhosis was excluded in all patients. HCV-associated CNS dysfunction may affect the domains of attention, learning, psychomotor speed, and mental flexibility in a pattern similar to that reported in HIV-associated CNS disease. Studies with event-related potentials revealed pathologic findings both in HCV-infected 19 and HIV-infected patients. 39–42
Neuropsychologic findings in HCV-infected patients were also reproduced by another group, 17 which demonstrated that concentration and speed of working memory were especially altered. The present study provides data in patients with HIV/HCV coinfection and in those infected with either virus alone. One major weakness of this study is its cross-sectional character. A longitudinal follow-up of patients is necessary to underline the first results presented in this report. IV drug use represented the mode of infection in a significant number of patients in all groups. In accordance with our own findings in HIV-positive patients 35 and with the literature on HCV-positive patients, 17,20 we did not find any systematic differences with regard to past or ongoing IV drug use. Other manifestations of HCV in the nervous system described so far include a vasculitic neuropathy associated with cryoglobulinemia 43,44; however, only 2 patients in the HIV-infected but HCV-uninfected group and 7 patients in the HIV/HCV-coinfected group showed signs or symptoms of peripheral nerve disease. Results in these patients were not significantly different from those in patients without peripheral nervous system (PNS) damage and were thus in agreement with a previous study, where we showed that PNS dysfunction does not alter 36 CNS motor function as assessed by our test battery. Psychometric testing did not reveal any significant differences with regard to premorbid (MWT-b) or actual (Raven) intelligence. Attention and memory (SKT) were also not systemically different among groups.
The AMDP rating did not show a significant difference with the exception of affective disorders. Accordingly, the HAM-D proved HIV-negative but HCV-positive patients to be less depressed. We recently showed that basal ganglia–mediated psychomotor speed in HIV infection is not influenced by any concomitant depressive symptoms, however. 37 Similar findings have been reported for HCV-infected patients, in whom depression did not account for cognitive impairment. 17 Electrophysiologic motor testing accounted for interesting and significant findings. HIV/HCV-coinfected patients can be clearly distinguished from the HIV/HCV-uninfected control group both by significantly slowed MRAMs and prolonged CTs, parameters that have repeatedly been proven to be the most sensitive ones 33,35 in detecting virus-induced CNS damage. The present report demonstrates for the first time that this effect can also be found in HCV-infected but HIV-uninfected patients, meaning that HCV can also cause subclinical psychomotor slowing. These pathologic results of HIV-infected and HCV-infected patients do not deteriorate further in HIV/HCV coinfection, however. Small but insignificant differences among groups in favor of the HIV-infected groups may be a result of the fact that the majority of HIV-infected patients were under treatment, whereas all HIV-negative but HCV-infected patients were untreated at the time of investigation. In contrast to these findings, RT (right hand) was significantly prolonged only in the HIV/HCV-coinfected group compared with the other 3 groups. Seen as a whole, these findings imply that HCV coinfection (at least in early stages, as examined in this study) does not exacerbate HIV-induced basal ganglia–mediated psychomotor slowing as measured by MRAMs and CT, whereas other parameters such as RT may depend on other factors, a finding in accordance with other recent reports on synergistic effects of both viruses on CNS injury. 45 It might also be assumed that these findings are a result of the effects of ART in both HIV-positive groups, because it has repeatedly been shown that HIV-associated psychomotor slowing improves under therapy. 34,46–48 One may suspect that psychomotor slowing would be more pronounced in a group of HIV/HCV-coinfected but untreated patients. When analyzing the 12 coinfected and untreated patients of our cohort separately, however, no significant differences from the other patients were observed. Instead, evidence is growing that HIV-associated cognitive and motor dysfunction results from secondary immunologic mechanisms rather than from directly infectious mechanisms. It is therefore tempting to speculate that both HIV and HCV cerebral infection induces similar local immune responses resulting in a comparable clinical pattern. The prolongation of RT, on the other hand, may be attributed to additionally affected pathways or different predilection sites of HCV in CNS pathology. One method to further clarify the underlying pathomechanisms both in HIV and HCV infection of the CNS is magnetic resonance (MR) spectroscopy. 17,49–52 Interestingly, the results of all these studies are compatible with prominent signs of cellular proliferation in the absence of signs of neuronal loss in the basal ganglia region. Underlying common pathomechanisms may therefore indeed result in a similar pattern of cognitive/motor disturbances and basal ganglia metabolism in HIV-positive and HCV-positive patients. Electrophysiologic motor tests represent an adequate method to quantify an aspect of this pathology in both infections, which must be further clarified by spectroscopic and molecular methods.
1. WHO. Global surveillance and control of hepatitis C. Report of a WHO consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat. 1999; 6:35–47.
2. Sherman KE, Rouster SD, Chung RT, et al. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US Adult AIDS Clinical Trials Group. Clin Infect Dis. 2002; 34:831–837.
3. Dodig M, Tavill AS. Hepatitis C and human immunodeficiency virus co-infections. J Clin Gastroenterol. 2001; 33:367–374.
4. Gray F, Scaravilli F, Everall I, et al. Neuropathology of early HIV-1 infection. Brain Pathol. 1996; 6:1–15.
5. Janssen RS, Cornblath DR, Epstein LG, et al. Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Neurology. 1991; 41:778–785.
6. Atkinson JH, Grant I, Kennedy CJ, et al. Prevalence of psychiatric disorders among men infected with human immunodeficiency virus. Arch Gen Psychiatry. 1988; 45:859–864.
7. Deutsch R, Ellis RJ, McCutchan JA, et al. AIDS-associated mild neurocognitive impairment is delayed in the era of highly active antiretroviral therapy. AIDS. 2001; 15:1898–1899.
8. Ellis RJ, Deutsch R, Heaton RK, et al. Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group. Arch Neurol. 1997; 54:416–424.
9. Gonzalez R, Heaton RK, Moore DJ, et al. Computerized reaction time battery versus a traditional neuropsychological battery: detecting HIV-related impairments. J Int Neuropsychol Soc. 2003; 9:64–71.
10. Grant I, Caun K, Kingsley DPE, et al. Neuropsychological and NMR abnormalities in HIV infection. Neuropsychiatry Neuropsychol Behav Neurol. 1992; 5:185–193.
11. McArthur JC, Cohen BA, Selnes OA, et al. Low prevalence of neurological and neuropsychological abnormalities in otherwise healthy HIV-1-infected individuals: results from the Multicenter AIDS Cohort Study. Ann Neurol. 1989; 26:601–611.
12. Sacktor N, McDermott MP, Marder K, et al. HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol. 2002; 8:136–142.
13. Sacktor NC, Bacellar H, Hoover DR, et al. Psychomotor slowing in HIV infection: a predictor of dementia, AIDS and death. J Neurovirol. 1996; 2:404–410.
14. Arendt G, Hefter H, Hilperath F, et al. Motor analysis predicts progression in HIV-associated brain disease. J Neurol Sci. 1994; 123:180–185.
15. Morsica G, Bernardi MT, Novati R, et al. Detection of hepatitis C virus genomic sequences in the cerebrospinal fluid of HIV-infected patients. J Med Virol. 1997; 53:252–254.
16. Radkowski M, Wilkinson J, Nowicki M, et al. Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J Virol. 2002; 76:600–608.
17. Forton DM, Thomas HC, Murphy CA, et al. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology. 2002; 35:433–439.
18. Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology. 2002; 35:440–446.
19. Kramer L, Bauer E, Funk G, et al. Subclinical impairment of brain function in chronic hepatitis C infection. J Hepatol. 2002; 37:349–354.
20. Forton DM, Taylor-Robinson SD, Thomas HC. Cerebral dysfunction in chronic hepatitis C infection. J Viral Hepat. 2003; 10:81–86.
21. CDC. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR. 1992; 41:1–19.
22. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973; 60:646–649.
23. Lehrl S, Triebig G, Fischer B. Multiple choice vocabulary test MWT as a valid and short test to estimate premorbid intelligence. Acta Neurol Scand. 1995; 91:335–345.
24. Raven J. The Raven's progressive matrices: change and stability over culture and time. Cognit Psychol. 2000; 41:1–48.
25. Kim YS, Nibbelink DW, Overall JE. Factor structure and scoring of the SKT test battery. J Clin Psychol. 1993; 49:61–71.
26. Overall JE, Schaltenbrand R. The SKT neuropsychological test battery. J Geriatr Psychiatry Neurol. 1992; 5:220–227.
27. AMDP. Das AMDP-System. Manual zur Dokumentation psychiatrischer Befunde. 6. Aufl. ed. Göttingen: Hogrefe-Verlag Göttingen; 1997.
28. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23:56–63.
29. Power C, Selnes OA, Grim JA, et al. HIV Dementia Scale: a rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol. 1995; 8:273– 278.
30. Hefter H, Hömberg V, Freund H-J. Quantitative analysis of voluntary and involuntary motor phenomena in Parkinson's disease. In: Przuntek H, Riederer P, eds. Early Diagnosis and Preventive Therapy in Parkinson's Disease. New York: Springer Verlag; 1989:65–73.
31. Hefter H, Arendt G, Stremmel W, et al. Motor impairment in Wilson's disease. I: slowness of voluntary limb movements. Acta Neurol Scand. 1993; 87:133–147.
32. Hefter H, Hömberg V, Lange HW, et al. Impairment of rapid movement in Huntington's disease. Brain. 1987; 110:585–612.
33. Arendt G, Hefter H, Elsing C, et al. Motor dysfunction in HIV-infected patients without clinically detectable central-nervous deficit. J Neurol. 1990; 237:362–368.
34. Arendt G, Hefter H, Buescher L, et al. Improvement of motor performance of HIV-positive patients under AZT therapy. Neurology. 1992; 42:891–896.
35. von Giesen HJ, Hefter H, Roick H, et al. HIV-specific changes in the motor performance of HIV-positive intravenous drug abusers. J Neurol. 1994; 242:20–25.
36. von Giesen HJ, Köller H, Hefter H, et al. Central and peripheral nervous system functions are independently disturbed in HIV-1 infected patients. J Neurol. 2002; 249:754–758.
37. von Giesen HJ, Bäcker R, Hefter H, et al. Depression does not influence basal ganglia mediated psychomotor speed in HIV-1 infection. J Neuropsychiatry Clin Neurosci. 2001; 31:88–94.
38. Klein MB, Lalonde RG, Suissa S. The impact of hepatitis C virus co-infection on HIV progression before and after highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2003; 33:365–372.
39. Farnarier G, Somma-Mauvais H. Multimodal evoked potentials in HIV infected patients. Electroencephal Clin Neurophysiol Suppl. 1990; 41: 355–369.
40. Goodin DS, Aminoff MJ, Chernoff DN, et al. Long latency event-related potentials in patients infected with human immunodeficiency virus. Ann Neurol. 1990; 27:414–419.
41. Arendt G, Hefter H, Hoemberg V, et al. Early abnormalities of cognitive event-related potentials in HIV-infected patients without clinically evident CNS deficits. Electroencephal Clin Neurophysiol Suppl. 1990; 41:370–380.
42. Baldeweg T, Gruzelier JH, Catalan J, et al. Auditory and visual event-related potentials in a controlled investigation of HIV infection. Electroencephal Clin Neurophysiol. 1993; 88:356–368.
43. Heckmann JG, Kayser C, Heuss D, et al. Neurological manifestations of chronic hepatitis C. J Neurol. 1999; 246:486–491.
44. Tembl JI, Ferrer JM, Sevilla MT, et al. Neurologic complications associated with hepatitis C virus infection. Neurology. 1999; 53:861–864.
45. Letendre S, Cherner M, Ellis RJ, et al. Individuals co-infected with hepatitis C (HCV) and HIV are more cognitively impaired than those infected with either virus alone. J Neurovirol. 2002; 8(Suppl 1):14.
46. Arendt G, von Giesen HJ, Hefter H, et al. Therapeutic effects of nucleoside analogues on psychomotor slowing in HIV infection. AIDS. 2001; 15:493–500.
47. von Giesen HJ, Koller H, Theisen A, et al. Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HIV-1–infected patients. J Acquir Immune Defic Syndr. 2002; 29:363–367.
48. Sacktor NC, Lyles RH, Skolasky RL, et al. Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Multicenter AIDS Cohort Study (MACS). Neurology. 1999; 52:1640–1647.
49. Chang L, Ernst T, Leonido-Yee M, et al. Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex. Neurology. 1999; 52:100–108.
50. Meyerhoff DJ, Weiner MW, Fein G. Deep gray matter structures in HIV infection: a proton MR spectroscopic study. AJR Am J Neuroradiol. 1996; 17:973–978.
51. Meyerhoff DJ, Bloomer C, Cardenas V, et al. Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. Neurology. 1999; 52:995–1003.
52. von Giesen HJ, Wittsack HJ, Wenserski F, et al. Basal ganglia metabolite abnormalities in HIV-1 associated minor motor deficits. Arch Neurol. 2001; 58:1281–1286.